Musculoskeletal

Ultrasound-Guided
Regenerative
Medicine
Yasser El Miedany
Editor

123
Musculoskeletal Ultrasound-Guided
Regenerative Medicine
Yasser El Miedany
Editor

Musculoskeletal
Ultrasound-Guided
Regenerative Medicine
Editor
Yasser El Miedany
Institute of Medical Sciences
Canterbury Christ Church University
Canterbury, Kent, UK

ISBN 978-3-030-98255-3    ISBN 978-3-030-98256-0 (eBook)

https://doi.org/10.1007/978-3-030-98256-0

© Springer Nature Switzerland AG 2022

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To my friends
True friends are never apart, may be in distance,
never in heart
Foreword

It is my pleasure to write this foreword for the textbook Musculoskeletal

Ultrasound and Interventional Regenerative Medicine. Ultrasonography of
the musculoskeletal system began over 50 years ago primarily focusing on
the diagnosis of tendon pathology. Since then, we have seen significant
advances in technology and now we are able to visualize structures as small
as peripheral nerve branches. We have also subsequently advanced our ability
to image musculoskeletal pathology. Subtle areas of tendinosis, partial tear-
ing of small ligaments of the fingers, and peripheral nerve disorders are now
readily identified. Color Doppler applications also allow us to identify neo-
vascularity within tendinosis and inflammation in synovitis.
Paralleling these advancements in imaging of anatomy and pathology is
our further understanding of pathology on a histologic and biochemical level.
This information has allowed us to investigate novel treatments for musculo-
skeletal pathology. Musculoskeletal sonography now plays an important role
where subtle pathology can be identified and then treatments can be directed
to the area of concern using ultrasound guidance. Such treatments have pro-
gressed from routine anesthetics and corticosteroids to new regenerative
medicine applications.
This textbook reviewing the current state of ultrasound guided regenera-
tive medicine is a timely body of work. The authors have nicely reviewed
essential topics to provide an overview of regenerative medicine. Subsequently,
diagnostic and interventional musculoskeletal ultrasound techniques are
reviewed specific to each joint and other applications. In addition to regenera-
tive medicine treatments, other novel topics include spine applications and
high frequency peripheral nerve ultrasonography. I commend the editor and
authors of this textbook for providing an essential overview of an important
topic that has the potential to alter how we think about the diagnosis and treat-
ment of musculoskeletal disorders.

Professor of Radiology, University of Cincinnati Jon A. Jacobson

Cincinnati, OH, USA

vii
Preface

Regenerative medicine is the branch of medicine that develops methods to

repair, regrow, or replace damaged or diseased cells, organs or tissues.
Broadly, it includes the generation and use of therapeutic stem cells, tissue
engineering and the production of artificial organs. The year 2021 represents
the dawn of a new era of regenerative medicine, as the field of regenerative
medicine reached a remarkable milestone. By mid-2021, four women
regained full sexual function after the successful implantation of lab-grown
vaginas created from their own cells. In August 2021, the Alliance for
Regenerative Medicine (ARM), in collaboration with GlobalData, published
a new report highlighting that 2021 has already been a “year of firsts and
records” for the regenerative medicine sector with significant clinical mile-
stones, commercial progress and investment.
For the first time ever, CRISPR gene-editing technology was deployed
in vivo in human patients — to treat ATTR amyloidosis — with extremely
positive interim Phase 1 results. An ex vivo approach has shown compelling
early-stage results in sickle cell and beta thalassemia patients. Regenerative
medicine is on track to have the highest annual number of regulatory approv-
als of new gene therapy and gene-modified cell therapy products, with three
already approved and an additional four to receive regulatory decisions across
the USA and Europe in the remainder of 2021.
The rationale for this book is a gap that needs filling on the application of
regenerative medicine in musculoskeletal diseases both in terms of concepts
and management. So, this book has been written aiming at discussing the
recent developments in regenerative medicine and its therapeutic potential,
guided by musculoskeletal ultrasonography scanning. The book starts with
an introductory section including three chapters on the principles of regenera-
tive medicine and regenerative options for musculoskeletal disorders. Next is
the section of diagnostic and interventional musculoskeletal ultrasound which
includes eight chapters representing a clinician’s guide to region-specific
musculoskeletal ultrasonography and image optimization. The following sec-
tion deals with regenerative medicine procedures carried out under ultra-
sound guidance This include six chapters discussing hydrodissection,
high-frequency peripheral nerve ultrasound, prolotherapy, interventional
physiatry and US-guided spinal procedures. The fourth section includes the
role of regenerative therapies in sports medicine. The section comes in three
chapters discussing US-guided exercises, musculoskeletal US in sports, and

ix
x Preface

the use of US and regenerative therapies in sports injuries. The last section
deals with the challenges, perspectives and future directions for regenerative
medicine.
The main theme of this book is to deliver a very practical and reader-­
friendly guide. It delivers the science-based evidence and advanced knowl-
edge of regenerative medicine. Further, it provides the most recent
developments in this field together with examples of recent practical
approaches which would be of value for the readers/researchers in their stan-
dard practice/clinical trials. With its 21 key chapters, this book is expected to
fill an important void in the current literature. It represents what can be con-
sidered the best current thinking on regenerative medicine. Therefore,
Musculoskeletal Ultrasound Guided Regenerative Medicine can serve as both
an excellent introductory material and a very good reference as well as
resource for implementation in standard clinical practice and future reading.
Special thanks to my colleagues and friends for their support throughout the
whole project which helped to make this book complete.
This book has been the outcome of cooperative effort of a large interna-
tional cohort of leaders in regenerative medicine and musculoskeletal ultraso-
nography. They have done a superb job in producing authoritative chapters
including vast amounts of scientific and clinical data to create state-of-the-art
descriptions of regenerative medicine and its application in the variable mus-
culoskeletal disorders. Special thanks to Jeimylo do Castro, Medical Director
at SMARTMD, Philippines, for his support and collaboration throughout the
whole project which helped to make this book complete. Personally, I feel
privileged to have compiled this work and am enthusiastic about all that it
offers our readers. I hope you too will find this edition a uniquely valuable
educational resource.

Canterbury, UK Yasser El Miedany

London, UK
26 December 2021
Contents

Part I Regenerative Medicine

1 
Fundamentals and Applications of Regenerative Medicine ��������   3
Yasser El Miedany
2 
Regenerative Options for Musculoskeletal Disorders������������������ 25
Daniel Habbal, Kaitlin Jayendran, Nagib Atallah Yurdi,
William D. Murrell, Nicola Maffulli, and Gerard A. Malanga
3 
The Nuts and Bolts of Regenerative Medicine as It Pertains
to the Joint���������������������������������������������������������������������������������������� 35
Joseph Purita

Part II Diagnostic and Interventional MSK Ultrasound

4 Image Optimization ������������������������������������������������������������������������ 59

Franklin San Pedro Domingo
5 Shoulder�������������������������������������������������������������������������������������������� 69
Daniel R. Lueders, Alexander R. Lloyd,
and Allison N. Schroeder
6 Ultrasound-Guided Elbow Injection Techniques�������������������������� 109
Tolga Ergönenç
7 Wrist and Hand�������������������������������������������������������������������������������� 119
Vincenzo Ricci and Levent Özçakar
8 
Ultrasound of the Hip/Thigh: Regenerative Medicine Focus������ 141
Robert Monaco, Hector L. Osoria, and Piyaporn Pramuksun
9 
Ultrasound Imaging of the Knee Joint������������������������������������������ 177
Daniel Chiung-Jui Su and Ke-Vin Chang
10 
Ultrasound-Guided Orthobiologics of the Foot and Ankle���������� 195
Lauren Vernese, Adam Pourcho, and Troy P. Henning

Part III Back and Spine

11 
Ultrasound-Guided Regenerative Injections for the Spine���������� 223
Donald Tsung-Yung Tang and Chih-Peng Lin

xi
xii Contents

12 Spinal Regenerative Medicine�������������������������������������������������������� 249

Jeffrey D. Gross

Part IV Dentistry

13 Regenerative
 Medicine in Dentistry ���������������������������������������������� 263
Samia Elazab

Part V Musculoskeletal Ultrasound in Regenerative Medicine

14 Regenerative
 Medicine Procedures Under
Ultrasound Guidance���������������������������������������������������������������������� 287
Jeimylo C. de Castro
15 Ultrasound-Guided Nerve Hydrodissection
for Pain Management: From Anatomy to Techniques������������������ 343
King Hei Stanley Lam, Yung-Tsan Wu,
and Kenneth Dean Reeves
16 High-Frequency
 Peripheral Nerve Ultrasound ���������������������������� 355
Jeffrey A. Strakowski
17 Dextrose-Based Perineural Injection Treatment,
and Ultrasound Hydrodissection���������������������������������������������������� 375
Liza Maniquis-Smigel, Paschenelle Celis, and Dean Reeves
18 Ultrasound-Guided Spinal Procedures������������������������������������������ 397
Jonathan Kirschner and Aditya Raghunandan
19 Musculoskeletal Ultrasound-­Guided Regenerative Medicine������ 417
Angela N. Cortez and Rhoel James Timothy O. Dejano

Part VI Sports Medicine

20 Ultrasound-Guided Exercises �������������������������������������������������������� 425

Michael Francis Obispo
21 Evolution
 of Sports Ultrasound������������������������������������������������������ 437
Jeffrey Smith, Allison N. Schroeder, Alexander R. Lloyd,
and Kentaro Onishi
22 Use
 of Musculoskeletal Ultrasound and Regenerative
Therapies in Sports�������������������������������������������������������������������������� 469
Jeimylo C. de Castro

Part VII Future of Regenerative Medicine

23 Regenerative
 Medicine: Challenges and Opportunities �������������� 539
Susan Plummer and Yasser El Miedany

Index���������������������������������������������������������������������������������������������������������� 549
Contributors

Paschenelle Celis Physical Medicine & Rehabilitation Department, Clinica

OS Habitares, Quezon City, Philippines
Ke-Vin Chang Department of Physical Medicine and Rehabilitation,
National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
Angela N. Cortez Department of Physical Medicine & Rehabilitation,
University of California at Davis, Sacramento, CA, USA
Jeimylo C. de Castro Chair, Physical Medicine and Rehabilitation
Department, The Medical City-South Luzon, Sta. Rosa, Laguna, Philippines
Medical Director/CEO, SMARTMD Center for Non-Surgical Pain
Interventions, Makati City, Philippines
Rhoel James Timothy O. Dejano Department of Internal Medicine,
University of Cebu Medical Center, Cebu City, Philippines
Franklin San Pedro Domingo Department of Physical Medicine &
Rehabilitation, Center for Regenerative Medicine, Pain Management Service,
Makati Medical Center, Makati City, Philippines
Samia Elazab Galala University, Suez, Egypt
Faculty of Dentistry, Cairo University, Giza, Egypt
Yasser El Miedany Institute of Medical Sciences, Canterbury Christ Church
University, Canterbury, Kent, UK
Tolga Ergönenç Akyazı Hospital Pain and Palliative Care, Sakarya, Turkey
Jeffrey D. Gross Stem Cell Whisperer, SPINE & ReCELLebrate, Henderson,
NV, USA
Daniel Habbal Sydney Kimmel Medical College, Thomas Jefferson
University, Philadelphia, PA, USA
Troy P. Henning Rehabilitation and Performance Medicine, Swedish
Medical Group, Seattle, WA, USA
Kaitlin Jayendran McMaster University, Hamilton, ON, Canada

xiii
xiv Contributors

Jonathan Kirschner Department of Physiatry, Hospital for Special Surgery,

New York, NY, USA
Department of Rehabilitation Medicine, UT Health San Antonio, TX,
San Antonio, USA
King Hei Stanley Lam The Hong Kong Institute of Musculoskeletal
Medicine, Kowloon, Hong Kong
Department of Family Medicine, The Faculty of Medicine, The Chinese
University of Hong Kong, New Territory, Hong Kong
Department of Family Medicine, The Faculty of Medicine, The University of
Hong Kong, Hong Kong, Hong Kong
Chih-Peng Lin Department of Anesthesiology, National Taiwan University
Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Alexander R. Lloyd University of Pittsburgh Medical Center, Department
of PM&R, Pittsburgh, PA, USA
Daniel R. Lueders University of Pittsburgh Medical Center, Pittsburgh, PA,
USA
Nicola Maffulli Department of Musculoskeletal Disorders, University of
Salerno School of Medicine and Dentistry, Salerno, Italy
Queen Mary University of London, Barts and the London School of Medicine
and Dentistry Centre for Sports and Exercise Medicine, Mile End Hospital,
London, UK
Gerard A. Malanga New Jersey Regenerative Institute LLC, Cedar Knolls,
NJ, USA
Department of Physical Medicine and Rehabilitation, Rutgers University,
New Jersey Medical School, Newark, NJ, USA
Liza Maniquis-Smigel Hilo, HI, USA
Robert Monaco Department of Sports Medicine, Atlantic Health System,
Morristown, NJ, USA
William D. Murrell Plancher Orthopaedics and Sports Medicine, Fellowship
Program, New York City, NY, USA
411th Hospital Center, Jacksonville Naval Airstation, Jacksonville, FL, USA
Michael Francis Obispo, MD, PTRP, RMSK Department of Physical and
Rehabilitation Medicine, De La Salle Medical and Health Sciences Institute,
Dasmariñas, Cavite, Philippines
Kentaro Onishi University of Pittsburgh Medical Center, Department of
PM&R and Orthopedic Surgery, Pittsburgh, Pennsylvania, USA
Contributors xv

Hector L. Osoria Department of Sports Medicine, Atlantic Health System,

Morristown, NJ, USA
Levent Özçakar Hacettepe University Medical School, Department of
Physical and Rehabilitation Medicine, Ankara, Turkey
Susan Plummer Faculty of Medicine, Health and Social Care, Canterbury
Christ Church University, Canterbury, Kent, UK
Adam Pourcho Rehabilitation and Performance Medicine, Swedish Medical
Group, Seattle, WA, USA
Piyaporn Pramuksun Department of Physical Medicine and Rehabilitation,
Bhumibol Adulyadej hospital, Bangkok, Thailand
Joseph Purita The Institute of Regenerative Medicine, Boca Raton, FL,
USA
Aditya Raghunandan Department of Physiatry, Hospital for Special
Surgery, New York, NY, USA
Department of Rehabilitation Medicine, UT Health San Antonio, TX,
San Antonio, USA
Dean Reeves Private Practice of Physical Medicine and Rehabilitation,
Roeland Park, KS, USA
Kenneth Dean Reeves Private Practice of Physical Medicine and
Rehabilitation, Roeland Park, KS, USA
Vincenzo Ricci Physical and Rehabilitation Medicine Unit, Luigi Sacco
University Hospital, ASST Fatebenefratelli-Sacco, Milano, Italy
Allison N. Schroeder University of Pittsburgh Medical Center, Pittsburgh,
PA, USA
Jeffrey Smith University of Pittsburgh Medical Center, Department of
PM&R, Pittsburgh, Pennsylvania, USA
Jeffrey A. Strakowski Department of PM&R, The Ohio State University,
OhioHealth Riverside Methodist Hospital, Columbus, OH, USA
Daniel Chiung-Jui Su Department of Physical Medicine and Rehabilitation,
Chi-Mei Hospital, Tainan, Taiwan
Donald Tsung-Yung Tang Department of Pain Managemet, Taichung Tzu
Chi Hospital, Taichung, Taiwan
Lauren Vernese Rehabilitation and Performance Medicine, Swedish
Medical Group, Seattle, WA, USA
Nagib Atallah Yurdi Reem Hospital, Abu Dhabi, United Arab Emirates
xvi Contributors

Yung-Tsan Wu Department of Physical Medicine and Rehabilitation, Tri-­

Service General Hospital, School of Medicine, National Defense Medical
Center, Taipei, Taiwan
Integrated Pain Management Center, Tri-Service General Hospital, School of
Medicine, National Defense Medical Center, Taipei, Taiwan
 Part I
Regenerative Medicine
 Fundamentals and Applications
of Regenerative Medicine
1
Yasser El Miedany

Introduction Applying the term “regenerative medicine,” to

musculoskeletal injuries, describes a rapidly
Regenerative medicine (RM) is a new medical growing new approach of musculoskeletal medi-
specialty that implements advances in the study cine, which employs evidence-based treatments
of cells and tissue engineering to understand how that focus on augmenting the body’s endogenous
the body repair/heals itself. The capability to suc- repair capabilities. This is not only limited to the
cessfully generate replacement cells, heal tissues, specific injury site but also the region of injury.
and repair ligaments has been one of the most This has been made possible by the precise appli-
fascinating and anticipated medical develop- cation of autologous, allogeneic, or proliferative
ments of the twenty-first century. Gradually, the agents. Musculoskeletal (MSK) diseases encom-
concept of RM has expanded and become multi- pass more than 100 disorders characterized by
faceted, including cell therapy, tissue engineer- injuries to joints and soft tissue [3]. Worldwide,
ing, and gene therapy. Global attention to the the market for regenerative medicine is quite big.
field is growing at a rapid pace. A Nobel Prize In December 2016, the US Congress passed the
winner in medicine (2012), Dr. Shinya Yamanaka, twenty-first Century Cures Act with the intent of
is a prime example of this recognition, for his dis- further incentivizing pharmaceutical and medical
covery in converting a human skin cell to a stem device companies to pursue advancements in
cell [1]. This rapidly expanding science is technology that aid patients who are in dire need
expected to become a breakthrough solution of care. The Act was intended to create a compre-
through its potential impact across many thera- hensive policy framework for RM, which allowed
peutic areas. This has been reflected by the level the US Food and Drug Administration (FDA) to
of investment in this science, as the global market more efficiently expedite its development and
is estimated to reach $50.5 billion by 2025 [2]. In approval processes by building on already estab-
real-life application, RM is anticipated to play a lished approaches, including fast-track, break-
major transformative role in mainly in two thera- through therapy designation, accelerated
peutic areas, cardiovascular and musculoskeletal approval, and priority review [4]. In response, in
diseases. November 2017, the FDA established a new
framework called RM Advanced Therapy
(RMAT) designation [5].
The chapter will expand to discuss phases of
Y. El Miedany (*)
Institute of Medical Sciences, Canterbury Christ the regenerative medicine, existing and new cell
Church University, Canterbury, Kent, UK sources, as well as its clinical applications,

© Springer Nature Switzerland AG 2022 3

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_1
4 Y. El Miedany

including both the potential regenerative medi- domized controlled trial (RCT), published in
cine interventions for the treatment of major 2017, compared intra-articular steroid injections
musculoskeletal diseases, their limitations, and to normal saline injections for the treatment of
the convergence of regenerative medicine and knee osteoarthritis over a 2-year follow-up period.
rehabilitation. The chapter will conclude with the Results did not show any association with
potential for transforming healthcare through improvement in pain. In addition, in the cohort
regenerative medicine, ethics in musculoskeletal treated with steroid injections into the knee joints,
regenerative medicine, the need for regenerative there was evidence of accelerated osteoarthritis as
medicine curriculum particularly for next-­ shown in MRI scans [12]. There is substantial evi-
generation physicians, and lastly a look forward dence that the standard local steroid injections,
toward achieving maturity of the regenerative which usually is combined with local anesthetic,
medicine field. have toxic effects on chondrocytes both in vivo
and vitro. This negative impact on the cartilage
has been attributed to the steroids therapy [13,
Standard Forms of Therapy vs. 14]. Regarding the use of steroids in treating ten-
Regenerative Medicine dinopathy, a meta-analysis of 41 RCTs outcomes,
published in 2010 by Coombes and colleagues,
To understand the innovative role of regenerative revealed that “at four weeks post-­injection, the
medicine, it would be very helpful to compare it non-injection groups had better pain and function
to the standard management approaches. This in comparison to the injected group” [15]. In addi-
was reviewed in a recent review article by tion, a randomized controlled trial, which com-
Mulvaney et al. [6]. Standard treatment modali- pared local steroid injections to placebo (saline)
ties, basically, act by stopping/minimizing the injections, demonstrated worse outcomes in the
pain levels or reduction of the inflammatory pro- corticosteroid injection group after 1 year [16].
cess with the aim of facilitating the endogenous The pathophysiologic basis for using anti-­
repair mechanisms. Management modalities vary inflammatory therapy for the treatment of tendi-
to include pharmaceutical agents such as anti-­ nopathies was a matter of debate, if not rebutted.
inflammatory drugs [7, 8], destructive modalities In an early published study (1999) authored by
(e.g., radio frequency ablation of nerves, botuli- Kraushaar and Nirschl, sections of human lateral
num toxin injections) [9], and surgical methods epicondyle tendons from patients suffering from
that permanently alter the functioning of a joint, tendinitis of the extensor tendons were assessed
including joint fusion, spine fixation, and partial using electron microscopy. Results revealed that
or total arthroplasty. there was a noticeable absence of cells associated
with inflammation; hence, “tendinitis” can be a
misnomer. They successfully demonstrated that,
Standard Pharmacotherapy instead, the underlying pathology represented a
chronic degenerative status referred to as “tendi-
Anti-inflammatory therapy includes both nonste- nosis” [17].
roidal anti-inflammatory drugs (NSAIDs) and Considering local spinal injections, epidural
corticosteroid medications. These are widely rec- steroid injections is considered one of the most
ommended for acute and chronic painful muscu- common procedures in the setting of subacute
loskeletal conditions. However, published and chronic lumbar pain. An updated Cochrane
Cochrane Database Systemic Reviews revealed review, which evaluated the outcomes of 18
that in the medical literature, there is poor justifi- RCTs, concluded that “there is currently insuffi-
cation to show that these anti-inflammatory medi- cient evidence to support the use of steroid injec-
cations are able to promote better long-term tissue tion therapy in subacute and chronic low-back
healing [10, 11]). In fact, NSAIDs may interfere pain” [18]. Many standard orthopedic surgeries,
with tissue healing [2, 3]. A well-­executed ran- including arthroscopic surgery for the repair of
1 Fundamentals and Applications of Regenerative Medicine 5

knee meniscal tears in patients over the age of 40, Table 1.1 Reasons for inadequate or failed self-repair
process in musculoskeletal pain
have been shown in a recent meta-analysis of
nine RCTs to be no better than sham surgery or 1. The body fails to recognize an injury and
consequently fails to initiate an effective healing
conservative treatment; in fact, they accelerate response
the degeneration process in the affected knee 2. The repair mechanism is overwhelmed by ongoing
joints [19, 20]. tissue insults such as chronic repetitive movements
Lastly, opioid therapy has also long been a without adequate recovery, ligamentous laxity
resulting in pathologic joint movement, and
cornerstone in the management of chronic non-
functional movement disorders resulting in
neoplastic musculoskeletal pain. However, pathologic movement
chronic narcotic therapy has inadvertently con- 3. The repair mechanisms are inhibited by a suboptimal
tributed to a national epidemic of opioid-related healing milieu
deaths [21]. This is in addition to the well-known
opioid-associated adverse effects. These include
opioid-induced hyperalgesia, constipation, as At some point, this slow senescence becomes
well as tolerance or lack of long-term efficacy or clinically manifested in the form of chronic
improved quality of life [22]. injuries.
Lastly, when compared to other allopathic The net result of such metabolic changes is
options, including knee and hip arthroplasty with impairment of the body’s ability to self-repair,
a 90-day mortality rate of 0.7% in the Western which sometimes may reach a state of failure in
hemisphere [23], regenerative medicine treat- the setting of chronic injury. Several reasons have
ment modalities have a lower incidence of been identified for such inadequate or failed self-­
adverse events with a growing body of statisti- repair process; these are shown in Table 1.1.
cally significant medical literature illustrating
both their safety and efficacy [24].
 he Potential of Regenerative
T
Medicine in Achieving Metabolic
Basics of Regenerative Medicine Balance

Local Tissue Metabolic Changes These data paved the way for healthcare profes-
sionals to consider alternative approaches for
Studying the metabolic process in painful muscu- patients’ management. The regenerative medi-
loskeletal conditions and the associated local tis- cine treatment model represents an innovative
sue metabolic changes reveals a shift toward a treatment modality, where there is a shift in the
catabolic state. Such catabolic, sub-optimal heal- balance from catabolism and tissue degeneration
ing environment has been attributed to several toward anabolism and tissue repair on a local
factors including the following: exposure to tox- and/or regional level. In fact, each of the reasons
ins (including many pharmaceuticals), obesity, for failure to self-repair can be considered a
poor diet, lack of regular exercise, chronic sys- potential target for regenerative medicine. One
temic inflammation, chronic infection, poor sleep target of regenerative medicine treatment is to
quality, hormonal disturbances, and chronic augment the anabolic environment through the
stress [25, 26]. stimulation of native and natural processes.
In addition, with aging, the body moves Therefore, regenerative medicine offers solutions
toward senescence (a condition or process of to repair, restore, or replace skeletal elements and
deterioration with age or loss of a cell’s power of associated tissues that are affected by acute
division and growth) with a gradual shift from a injury, chronic degeneration, genetic dysfunc-
balanced catabolic/anabolic status to one that tion, or cancer-related defects [6]. The goal is to
slightly favors catabolic environment, conse- improve quality of life and outcomes for people
quently resulting in gradual tissue degeneration. with musculoskeletal injury or degradation.
6 Y. El Miedany

The Induction of Self-Regeneration Alternatives, such as allogeneic and/or xenoge-

neic transplants, need further analysis regarding
Conceptually, although the term “regenerative the risk of rejection, disease transmission, and/or
medicine” includes the creation of artificial teratogenicity.
organs and their subsequent implantation; its The therapeutic potential of each strategy
most realistic definition refers to the set of pro- depends on the nature of damage to repair. Its
cesses used to repair or replace tissue or organ widespread application is still subject to the reso-
function by stimulating and inducing their own lution of technical and biological aspects; how-
self-regeneration. Schematically, this discipline ever, advances in this field are growing rapidly, in
encompasses two therapeutic strategies: those particular those related to cellular therapies
based on the use of living cells or cell-based ther- applied to musculoskeletal diseases, one of the
apies and those based on tissue engineering using most promising fields for medium-term treat-
different scaffolds and matrices with biocompat- ments [31–33].
ible materials, alone or in combination, to pro-
vide support and facilitate the repair of tissue
damage [27, 28]. Among cell therapies, one may Phases of the Regenerative
differentiate two types of products based on Medicine
mature cells, grafts or implants, and those using
stem or progenitor cells. Most of the techniques adopted in regenerative
The application of different regenerative tech- medicine interventions depend on precise injec-
niques has enabled the development of different tions of autologous, allogeneic, or proliferative
basic, preclinical and clinical studies with agents, which initiate (or reinitiate) a productive
encouraging results for the treatment of various healing cascade by stimulating a repair response.
diseases, including those of musculoskeletal ori- Often this is accomplished in three phases
gin [29, 30]. The first set of strategies to repair (Fig. 1.1): First comes phase 1: an acute inflam-
damage to the bone or cartilage tissue consisted matory reaction is initiated in the target tissue.
of transplantation or implantation of autografts to This focuses the body’s ability to heal itself by
provide a supply of cells able to provide an influx providing “initial injury debridement” through
of osteo- or chondro-inducting factors. However, the action of macrophages and subsequently
these methods have limitations in their bioavail- paves the way for the proliferative phase of tissue
ability and the size of the lesion to be repaired. repair, among many other key functions [34].

Fig. 1.1 Phases of

regenerative medicine Initial tissue debridment
enhanced tissue healing
Acute inflammatory reaction Duration: 10-days

Proliferative healing phase

Angiogenesis to facilitate tissue

Duration: 30-days
repair

Remodelling phase

Type III collagen fibres replaced by

Duration: 300-days
the stronger type I collagen fibres
1 Fundamentals and Applications of Regenerative Medicine 7

This inflammatory phase lasts for 10 days. This is cellular therapies are considered drugs and as
followed by phase 2: the “proliferative healing such must meet all stages of drug development,
phase” lasts for 30 days and involves chemical including their adequate manufacturing practices
messengers released from the injury site, which and conditions (GMP). By definition, the princi-
recruit fibroblasts to the injury location and pal component or “active ingredient” of cell ther-
induce local angiogenesis at the site to facilitate apy is the cell itself, while the “carrier” would be
tissue repair. Lastly, comes Phase 3: “the remod- represented by growth factors and/or biomateri-
eling phase” is the final phase of tissue healing, als that facilitate structural integration or differ-
during which the rapidly laid down type 3 colla- entiation of cells. The cell component may be
gen fibers are gradually replaced by stronger, composed of mature or undifferentiated cells.
more organized type 1 collagen fibers [35]. This Thus, chondrocytes or cartilage explants devel-
remodeling takes up to 300 days to complete. oped for the treatment of chondral defects are an
example of the first type. However, the use of dif-
ferentiated cells has not satisfactorily met expec-
The Importance of Image Guidance tations. Currently, attention has focused on the
progenitor cells with improved biological proper-
Successful regenerative medicine treatment relies ties and superior plasticity to those already dif-
not only on an accurate diagnosis but also on pre- ferentiated [40, 41].
cise guidance of injections. Most of the injectates A stem or progenitor cell is defined in terms of
administered in regenerative medicine are costly its ability to divide asymmetrically, i.e., self-­
to prepare or purchase; therefore, an ultrasound-­ renewing itself while maintaining its undifferen-
guided application, along with detailed knowl- tiated state, or divide and differentiate into other
edge of sonographic anatomy, plays an important cell types. Broadly speaking, and depending on
role in the success of the procedures [36]. It their origin, stem cells are grouped into two cat-
would be also nearly impossible to assess the egories: embryonic stem cells (ESC) and adult
effectiveness of therapies without knowing pre- stem cells (ASC). This classification carries other
cisely where they were placed in or near the intrinsic differentiation potential. Thus, embry-
injured tissue. Hall [37] carried out a review of onic stem cells (ESC), deriving from the embry-
palpation-guided versus ultrasound-guided onic blastocyst can differentiate into cells
peripheral injections; he reported a remarkably belonging to any of the three embryonic layers:
low level of accuracy when injections are per- ectoderm, endoderm, and mesoderm (from which
formed based on palpation-guided landmarks. skeletal tissues originate) (Fig. 1.2).This totipo-
Thus, it is highly recommended that soft tissue tency (ability of developing into a complete
structures, such as ligaments, tendons, joint cap- organism or differentiating into any of its cells or
sules, and muscles, should be injected using real-­ tissues), however, can cause problems when
time ultrasound guidance. Many spine targets undergoing therapeutic application, arising from
have reasonable medical literature supporting the their high proliferation capacity and the possibil-
use of ultrasound guidance [38, 39]. Fluoroscopic ity of ectopic teratoma formation. Thus, the most
guidance is suitable for intervertebral disc and reasonable approach, from the point of view of
transforaminal epidural injections, as well as for their therapeutic application, is to use cells with
subchondral and intraosseous injections. limited differentiation potential, specific to an
embryonic single-layer lineage.
Experimentally, it is possible to induce repro-
Fundamentals of Cell Therapies gramming of adult cells to a pluripotent (capable
of giving rise to several different cell types)
To understand the fundamentals and the potential immature state, called induced pluripotent stem
of cell therapies in musculoskeletal diseases, cells (iPSC), but its application is still under
analogies can be drawn with the composition of a investigation. While scientific advances to avoid
classic drug. Not surprisingly, and to bridge gaps, the risk arising from the application of the previ-
8 Y. El Miedany

Adult stem Human-induced

Human embryonic
cells pluripotent stem cell
stem cells (hESC)
e.g. BM-MSCs (hiPSC)
Pros: Pros: Pros:
Multipotent
Pluripotent / allogenic Pluripotent / autologous
Autologous
Extensive proliferation Extensive proliferation
Comprehensive
without senescence
characterization without sensscence
High yield
Clinically, well established High yield
Cons:
Cons:
• Limited proliferation • Possile Cons:
and differentiation Immunogenicity
• Low
capacity. • Ethical
reprogramming
• Senescence considerations.
• Heterogeneity • Risk of teratomas • Epigenic memory
• Low yields • Risk of teratoma

Ectoderm Endoderm Mesoderm

Epidermis of skin. Nervous Epithelium of digestive, Musculoskeletal systems. Muscular layer of

system. Sensory organs. respiratory, excretory and stomach and intestine, excretory system,
Pituitary and adrenal medulla. reproductive systems. Thymus, circulatory & lymphatic system, lining of
Jaw and teeth. Germline cells thyroid and parathyroid glands body cavity, adrenal cortex, skin dermis

Fig. 1.2 Pros and cons of using adult stem cells and plu- obtained through reprogramming somatic cells using the
ripotent stem cells for clinical applications. Comparison forced expression of OCT4, SOX2, KLF4, and
of the BM-MSCs, hESCs, and hiPSCs for application in NANOG. These cells can subsequently be differentiated
regenerative medicine. Pluripotent stem cells derivation into any derivative of the three germ layers (ectoderm,
and subsequent tissue generation ability. hESCs can be endoderm, and mesoderm). BM-MSC bone marrow-­
derived from the inner cell mass of a blastocyst at the final derived mesenchymal stem cell, hESC human embryonic
stage of preimplantation development. hiPSCs can be stem cell, hiPSC human-induced pluripotent stem cell

ous cell types have been made, the best current although adipose tissue, along with bone marrow,
option is the use of natural skeletal progenitor is the most common source of MSC. However,
cells, mesenchymal stem cells (MSC) [27]. the frequency of MSCs in tissues decreases with
age [45], and more importantly, the tissue of
origin seems to confer particular characteristics
 he Mesodermal Embryonic Stem
T that can alter their immunomodulatory proper-
Cells ties [46, 47]. This variability may be related to
the fact that MSCs are actually a heterogeneous
Mesenchymal stem cells (MSCs) are meso- population of cells. In fact, due to the absence of
dermal embryonic stem cells from which adult a single common tag, the definition of an MSC
connective tissues develop. Therefore, they con- is performed according to the performance of
stitute progenitor cells of other specialized cells, three minimum criteria: their ability to adhere
such as chondrocytes, osteoblasts, adipocytes, to culture medium, the presence of various cell
tenocytes, myoblasts, as well as others. They surface markers and the absence hematopoietic
retain their self-renewal capacity, which facili- lineage markers, and, finally, their in vitro abil-
tates their in vitro expansion [42, 43]. In addi- ity to commit to osteogenic, chondrogenic, and
tion to differentiating into different lineages, if adipogenic lineages, generally determined by
subjected to an appropriate postimplantation histochemical staining. Given the relative lax-
stimulus in vitro or in vivo, they have immu- ity of the selection criteria, one of the challenges
nomodulatory properties [44]. Originally, they lies in the unambiguous characterization of MSC
were described in the bone marrow stroma. They as a single entity, a task that has not yet been
are currently known to be virtually ubiquitous, achieved.
1 Fundamentals and Applications of Regenerative Medicine 9

The immunomodulatory functions of MSC, peripheral nerve injury model, except from gen-
one of the aspects of their therapeutic potential, erating neurons, transplanted embryonic spinal
are gaining more importance and have already cord cells were found to have a regulatory effect
been applied in different pathologies. The study on local Schwann cells in the distal nerve and
of the immunomodulatory potential of MSCs induced them to produce proximal axons to facil-
was described originally by studying their effect itate nerve regeneration.
on regulatory T cells, such as Ras initiation and Amyotrophic lateral sclerosis (ALS) is a pro-
mediators of transplant rejection. Numerous evi- gressive disease that affects nerve cells in the
dences have shown that under inflammatory con- brain and spinal cord, causing loss of muscle
ditions, MSC may inhibit T cell effector responses control. Due to the low bioavailability and short
or increase Treg-mediated regulatory function. half-life in vivo, in clinics, the expected outcomes
Furthermore, they can also exert various effects of the intrathecal administration of neurotrophic
on other immune cells. Thus, MSC inhibit the factors alone were hard to achieve. Pawlukowska
maturation of dendritic cells, preventing their et al. [51] performed a clinical study using the
migration to the lymph nodes and their antigen-­ autologous lineage negative (Lin−) stem cells to
presenting function; they modulate macrophages treat ALS. The authors thought Lin− stem cell-­
and NK cells, and suppress the proliferation and based therapy would be a reasonable and promis-
terminal differentiation of B15 cells. The mecha- ing alternative for classic ALS treatments,
nisms through which they carry out these func- because the Lin− stem cells could produce the
tions are both dependent on cell contact and trophic support for the host’s neurons, stimulate
through secretion of soluble factors [48, 49]. the secretion of neurotrophins (NTs), and differ-
entiate into oligodendrocyte progenitor cells or
neurons. The authors completed a clinical trial to
Stem Cell-Microenvironment assess the impact of intrathecal administration of
Communication bone marrow Lin− stem cells in 32 patients suf-
fering from ALS on articulation; it was demon-
Manipulation of the tissue microenvironment has strated that 6 patients achieved the improvement
become a promising method to enhance the of articulation after 28 days, 23 patients remained
regenerative abilities of stem cells/progenitors stable, and 3 deteriorated. Although some valu-
for musculoskeletal repair. The composition of able findings were observed, several limitations
the microenvironment is determined by the resi- should be acknowledged, such as the small num-
dent cells, extracellular matrix, cytokines, and ber of patients, the lack of control group, and a
chemokines as well as the biomechanical prop- short observation period.
erty and nutrient status. The microenvironment is During muscle regeneration, as reviewed by
altered by the homeostasis and degenerative stage Dort et al. [52], the spatial recruitment of pro-­
of the native tissue. All the alterations of the sur- inflammatory and anti-inflammatory macro-
rounding host microenvironment will definitely phages was reported to be different and is related
change the biology of the implanted stem cells/ to their temporal recruitment, meaning that pro-­
progenitors. Thus, a thorough understanding of inflammatory macrophages were found located
the stem cell-microenvironment communication close to proliferating satellite cells, while anti-­
would therefore accelerate the success of muscu- inflammatory macrophages were found close to
loskeletal repair [43]. the regenerating area containing differentiated
The interaction between stem cells and local myoblasts. Depletion of pro-inflammatory mac-
microenvironment goes in both directions. Not rophages resulted in impaired muscle regenera-
only the microenvironment can impose on the tion in animal models. The suppression of the
fate of stem cells but also stem cells can posi- switch of macrophage from pro-inflammatory
tively affect the local microenvironment of phenotype to anti-inflammatory phenotype
injured tissues. In Fang’s study [50] using a rat reduced muscle fiber growth but did not affect the
10 Y. El Miedany

clearance of necrotic tissues. At the cellular level,blood to separate into its various components.
pro-inflammatory macrophages promote myo- The plasma, which contains growth factors and
blast proliferation and inhibit differentiation, platelets, is drawn from the solution and
while anti-inflammatory macrophages inhibit injected into the tendons, ligaments, muscles,
myoblast proliferation and stimulate their differ- and joints due to its healing property. There
entiation and myofiber growth. Direct coculture have been several studies publishing the bene-
of macrophages also promoted proliferation and fits of PRP treatment, and its presence helps
inhibited apoptosis of myogenic cells. Altogether, increase treatment options for specific muscu-
these findings suggest that different subsets of loskeletal ailments [56].
macrophages have complementary roles in the Stem cells obtained from adipose tissue repre-
regulation of satellite cell/myoblast function, sent a viable source. Adipose tissue stem cells are
myogenesis progression, and optimal muscle obtained via needle biopsy or liposuction. The
regeneration. sample must be minced profusely washed and
chemically treated and then incubated for 30 min-
utes and neutralized. This process is similar for
Existing and New Cell Sources both bone marrow and placenta stem cells, which
also have to be aspirate and harvested appropri-
Most regenerative medicine strategies rely on an ately prior to usage [57].
ample cell source, but identifying and obtaining Each option for stem cells has its own risks
sufficient numbers of therapeutic cells is often a and benefits. For example, cells obtained from
challenge. Stem, progenitor, and differentiated adipose tissue and bone marrow include more
cells derived from both adult and embryonic tis- available stem cells compared to PRP, whereas
sues are widely being explored in regenerative the PRP has the advantage of being easier to
medicine, although adult tissue-derived cells are obtain and utilize. The advantage of the stem
the dominant cell type used clinically to date due cells, obtained from the amniotic tissue, is that is
to both their ready availability and perceived has been used for wound healing, while adipose
safety [53, 54]. All FDA-approved regenerative stem cells have been utilized in surgeries to speed
medicine therapies and the vast majority of strat- up tissue repair.
egies explored in the clinic use adult tissue-­ Studies aiming to understand the processes
derived cells. There is great interest in obtaining that control stem cell renewal are being leveraged
greater numbers of stem cells from adult tissues for both purposes, with the prototypical example
and in identifying stem cell populations suitable being studies with hematopoietic stem cells
for therapeutic use in tissues historically thought (HSCs) [58]. For example, exposure of HSCs
not to harbor stem cells [55]. in vitro to cytokines that are present in the HSC
Therefore, sources can be stratified into two niche leads to significant HSC expansion, but this
main types of stem cells, embryonic and non-­ increase in number is accompanied by a loss of
embryonic. Embryonic stem cells (ESC) are repopulation potential [59, 60]. Coculture of
obtained from embryos, whereas non-embryonic HSCs with cells implicated in the HSC niche and
stem cells (NESC) are derived from essentially in microenvironments engineered to mimic
any adult tissue, such as placenta, blood, the native bone marrow may improve maintenance of
umbilical cord, and adipose tissue. As noted HSC stemness during expansion, enhancing stem
above, most of the treatments available or under cell numbers for transplantation. For example,
evaluation are related to the non-embryonic stem direct contact of HSCs with MSCs grown in a 3D
cell treatment. environment induces greater CD34+ expansion
Platelet-rich plasma treatment or PRP is very than with MSCs grown on 2D substrate [61].
popular, given its association with professional Another example is that culture of skeletal mus-
athletes. PRP is a patient’s own blood that is spun cle stem cells on substrates with mechanical
down in a machine, which will allow for the properties similar to normal muscle leads to
1 Fundamentals and Applications of Regenerative Medicine 11

greater stem cell expansion [62] and can even [73], aim to encourage infiltration of stem cells
rescue impaired proliferative ability in stem cells from the marrow spaces of the underlying sub-
from aged animals [63]. chondral bone, to stimulate repair of the damaged
tissue. Restorative techniques such as mosaic-
plasty [74] involve removing cartilage plugs from
Standard Interventions non-load-bearing regions of the joint and implant-
for the Treatment of Major ing them into the osteochondral defect zone.
Musculoskeletal Diseases and Their Another restorative surgical technique is autolo-
Limitations gous chondrocyte implantation (ACI) [75]; here,
patient-derived autologous chondrocytes are har-
Osteoarthritis vested from the non-load-bearing region of the
Osteoarthritis (OA) is considered the most com- articular cartilage, expanded in monolayer cul-
mon joint disease mainly among older adults ture, and implanted at the site of the defect under-
[64], with a high global prevalence [66]. As life neath a periosteal flap. This technique often
expectancy is surging for both men and women utilizes a collagen scaffold to support the
worldwide, the years of life lived with disability implanted cells and is referred to as matrix-­
is also expected to increase. This demonstrates assisted ACI (MACI). Following recently pub-
the impact of increased life span without a cor- lished NICE guidelines (2017) [76], ACI is now a
responding improvement in health span. The recommended treatment; however, patient selec-
underlying pathology of OA includes degrada- tion criteria are restrictive. While ACI has been
tion of the hyaline articular cartilage and the relatively successful compared to other tech-
abnormal remodeling of the joint tissues, which niques such as mosaicplasty [75], there are a
results in loss of joint function. Cartilage is avas- number of drawbacks associated with the treat-
cular, has low cellularity, and, therefore, has a ment (Table 1.2).
limited capacity for repair. Daily wear and tear or
injury leads to the structural deterioration of Osteoporosis
articular cartilage at the joint surface. The early Osteoporosis is a disease characterized by low
stages of OA are characterized by the formation bone mass and structural deterioration of bone
of partial thickness chondral defects. If left tissue, leading to bone fragility. Worldwide, it has
untreated, the defects will extend into the marrow high prevalence with an estimated 22 million
spaces of subchondral bone, giving access to women, and 5.5 million men being affected
bone marrow stem cells (BMSCs). The repair tis- within the EU [77], and over 8.9 million fractures
sue formed by infiltrating BMSCs is typically annually of osteoporotic fractures [78].
fibrous rather than hyaline [65]. Osteoporosis is caused by an imbalance in
Effective treatments for OA are currently bone turnover homeostasis, leading to accelerated
lacking [66]. Early-stage management includes trabecular bone loss that results in a more porous
glucosamine/chondroitin supplement therapy structure. When associated with falls, the inci-
and hyaluronic acid injections. However, their dence of osteoporotic fractures gets higher [79].
efficacy has been highly debated [67, 68]. On the Osteoporosis predominantly affects the older
other hand, surgical management is mainly in the adults, and in association with increased fracture
form of total joint replacement, which is widely risk, there is a corresponding increase in the like-
used; however, surgeries are considered a late-­ lihood of morbidity. Unlike OA, there are a num-
stage treatment option and, as expected, carry ber of effective pharmacological treatments
significant risks, which gets higher with patient available for osteoporosis. Treatment types can be
age [69, 70]. Other early-stage interventions are divided into two categories: antiresorptive and
available and focus on initiating cell-based repair. anabolic agents. Antiresorptive treatments reduce
Reparative techniques, such as abrasion arthro- bone turnover and preserve bone mineral density
plasty [71], debridement [72], and microfracture (BMD). Anabolic agents stimulate bone forma-
 12
Table 1.2 Standard treatment options vs cell therapy for chronic musculoskeletal diseases
Musculoskeletal Standard
disease Risk/incidence management Challenges Cell/tissue therapy Challenges
Fracture healing Worldwide incidence Plate and screw Nonunion Mesenchymal stem cells (MSC) Uncontrolled MSC cell
of osteoporotic combined with/without calcium differentiation
fractures: sulfate Immunologic rejection
 8.9 million Allogenic bone graft containing
fractures each year stem cells
G-CSF-mobilized Hemopoietic
stem cells with collagen scaffold for
nonunion fracture healing
Osteoarthritis Worldwide incidence Moderate OA: Conflicting outcomes (some Restorative techniques: Expensive
of:  Glucosamine in favor, others not)  Mosaicplasty  Invasive process to procure
 Knee OA: 3.8% sulfate Late-stage option  Autologous chondrocyte chondrocytes,
 Hip OA: 0.85% Hyaluronic acid Risk of infection implantation (ACI)  Limited number of cells
Lifetime risk of injections Need for redoing  Matrix-assisted ACI (MACI)  Dedifferentiation during
developing Severe: Limited repair option monolayer expansion
symptomatic knee  Total joint Results, typically, in  Recommended for patients with
OA: replacement fibrocartilaginous tissue knee OA who did not receive any
 Men: ∼40% Reparative previous treatments
 Women: ∼47% techniques:  Formation of fibrocartilaginous
Higher risk in obese  Abrasion tissue
people arthroplasty
 Debridement
 Microfracture
Osteoporosis Incidence in EU: Pharmacotherapy Poor adherence Stem cell therapy: Uncertainty of stem cell fate and
 Women: 22 million Antiresorptive: Concerns regarding  Introduction of exogenous biodistribution following cell
 Men: 5.5 million  Bisphosphonates long-term therapy-associated mesenchymal stem cells transplantation
Denosumab side effects  Small molecules that recruit
Anabolic: Atypical femur fracture endogenous stem cells to
 Parathyroid Osteonecrosis of the jaw osteoporotic sites
hormone Limited duration of therapy  Stem cell stimulation and
Combined: Expensive transplantation have the ability to
 Romosozumab reverse bone demineralization
Others:
 Calcium and
vitamin D
Y. El Miedany
 1
Myopathy Sarcopenia (mean age Resistive exercise Difficulty to do without Myogenic stem cells to improve Massive rapid death of transplanted
67 years): assistance due to frailty of regeneration of old muscles donor cells
Men: 4.6% the sufferers Minimal cell dispersal that is
Women: 7.9% Limited success required to supply all muscles
throughout the body
Duchenne muscular Genetic intervention Need to target skeletal and Autologous bone marrow Only a small percentage of stem
dystrophy: steroids heart muscles mononuclear cells replaced the damaged muscles
 Males:1 in Side effects Autologous myoblasts Often must administer stem cells
3500–6000 Masks/delays symptoms Myoblasts from donors
 Women: only
1:50,000,000
Fundamentals and Applications of Regenerative Medicine
13
14 Y. El Miedany

tion, thereby increasing BMD. It has been shown result in an increase in both muscle mass and
that some forms of combination or sequential strength, making treatment for myopathies
therapy may offer a synergistic effect on BMD extremely limited [90].
[80, 81]. While these treatments have been sug-
gested to slow the progression of osteoporosis,
they fail to offer long-term effective solutions [77]  he Convergence of Regenerative
T
and are associated with variable side effects [82, Medicine and Rehabilitation
83], particularly with longer duration of therapy.
Regenerative rehabilitation lies at the intersec-
Myopathies tion of regenerative medicine and rehabilita-
Myopathies (muscular diseases) are a key group tion research. While regenerative medicine
of diseases that affect a fair percentage of the approaches provide unique opportunities to
population [84, 85]. A common form of myopa- regenerate, repair, and/or replace various tis-
thy is sarcopenia [86], which is age-related loss sues and organs, these approaches often fall
of muscle mass and strength. Sarcopenia is asso- short in the long-term treatment of chronic,
ciated with frailty and is more prevalent in older disabling conditions. Regenerative medicine or
adults. There are also numerous genetic diseases, rehabilitation approaches provide a foundation
such as muscular dystrophies [87], for example, for the restoration of tissue architecture, promo-
Duchene muscular dystrophy (DMD), and limb tion of organ function, reduction of disability,
girdle muscle dystrophy. So far, there are limited or improvement of quality of life. However, it
effective treatments to combat the progression of is the combination of both approaches work-
muscular degeneration. Muscle itself has a resi- ing synergistically that can optimize or maxi-
dent population of stem cells, known as satellite mize the functional outcome of the individual
cells [88]. These cells are responsible for the (Fig. 1.3) [91].
regeneration of muscle fibers following exercise Current approaches in regenerative medicine
or injury. However, the satellite cell-mediated involve the use of cells and/or biologics with or
repair mechanism can become compromised. For without scaffolding materials with the goal of
example, Duchene muscle dystrophy is charac- replacing injured or lost tissue resulting from
terized by continuous rounds of degeneration and trauma or disease. However, the medical care
regeneration of muscle fibers that results in a process does not stop after transplantation of the
depletion of the muscle stem cell pool [89], lead- cell or tissue construct in the clinic. Using the
ing to a loss of skeletal muscle mass. Currently, principles of rehabilitation sciences to maximize
there are no approved drugs that consistently the outcome in the treatment of disabling condi-

Fig. 1.3 Merging

rehabilitation and
Regenerative medicine Rehabilitation
regenerative medicine:
the goals of the *Cells and tissues *External stimulation
*Matrices / scaffolds *Assistive
regenerative *Biologics Technology
rehabilitation approach *Enabling technology *Therapeutic
are to synergize Physical activity
regenerative medicine
approaches with
rehabilitation techniques
to enhance the clinical
outcomes for the patient

Regenerative rehabilitation
*Enhance tissue / organ function
*Reduce disabilities
*Increase quality of life
1 Fundamentals and Applications of Regenerative Medicine 15

tions by regenerative medicine, impose the need venation, regeneration, and replacement (the
to reconsider the standard management 3R’s), is shifting the paradigm in healthcare from
approaches, taking into account the role of post- symptomatic treatment in the twentieth century
transplantation rehabilitation. For example, the to curative treatment in the twenty-first century
consequences of central nervous systems injuries [96–98]. This is evidenced by the rapid increase
illustrate the need for collaboration in clinical in regenerative medicine clinical trials in each
care and research in regenerative medicine and specialty [99, 100], which can be broadly classi-
rehabilitation. Trauma to the central nervous sys- fied as using either cell- or tissue-based products.
tem not only involves nerve cells but also the The Food and Drug Administration in the US and
peripheral targets these cells innervate, including the European Medicines Agency have more com-
internal organs and the musculoskeletal system. plex classification systems of regenerative medi-
Rehabilitation prior to regenerative therapies can cine products, including cellular therapy, gene
set the stage for improved recovery by precondi- therapy, stimulators of endogenous repair,
tioning the individual, while posttransplant phys- biologic-­device combination products, and
ical activity may help cells to integrate and form human tissue and xenotransplantation [101].
appropriate connections with the host tissue. Broadly, the regulatory requirements can be
Activity-dependent performance of tasks not based on the pillars of sterility, stability, and
only shapes behaviors but also strengthens syn- potency, and these need to be addressed prior to
apses and promotes neuronal plasticity [92, 93]. successful clinical translation in the future [102].
In general, the timing, dosing, and duration of Cell-based therapies work either via stimula-
rehabilitation strategies for neurologic or muscu- tion of endogenous repair through extracellular
loskeletal injuries varies, and their optimal inte- factors or differentiation and functional replace-
gration with regenerative therapies is an area in ment of endogenous cell types [100]; they
need of further study. include stem cell implantation or infusion to
On the other hand, the inappropriate pairing of treat hematopoietic diseases, cardiac conditions,
regenerative and rehabilitative approaches can and Parkinson’s disease. Most of the pioneering
have deleterious side effects (e.g., pain and spas- work has been performed using hematopoietic
ticity following inappropriate peripheral inputs) stem cells due to the early bone marrow trans-
and requires monitoring [94]. Thus, the founda- plant work, making them the most well-studied
tion for regenerative rehabilitation can be laid by stem cell type [103]. In particular, adult mesen-
harnessing physical substrates to refine, direct, chymal stem cells have gained interest as they
and mold components to the desired regenerative avoid the ethical concerns of using embryonic
endpoint while monitoring for adverse effect to stem cells, which can be rapidly expanded
restore and improve the functionality of the in vitro and avoid immunogenicity. Studies have
­individual [95]. As new regenerative medicine shown contradictory results on the efficacy of
strategies enter human clinical trials, increased the transplanted cells, with patient variability
collaborations with rehabilitation clinicians will with regard to response; further work is needed
be important to optimize outcomes. It will also be to elucidate cell identity and health to ensure
important for rehabilitation clinicians to plan for patient safety (Fig. 1.4).
potential changes in rehabilitation practice to The tissue engineering strand of regenerative
accommodate regenerative medicine treatments. medicine incorporates cells with biodegradable
scaffolds to engineer replacement tissues like
dermis or cartilage [104] and whole organs such
Transforming Healthcare Through as trachea and bladder [105]. Limitations of syn-
Regenerative Medicine thetic polymer scaffolds, such as infection, extru-
sion, and degradation product toxicity, have
The expansion of regenerative medicine as a sci- encouraged interest in decellularized matrices as
entific discipline, with its core principles of reju- well biologics for use as scaffolds as one of the
16 Y. El Miedany

Stage At risk of Early stage Surgery Late stage

disease disease indicated disease

Birth Death

• Substitute * Preventing
• Return to surgery progression
health state
Objective
Postpone Supplement
• Prevention
surgery surgery

Improve surgical outcomes

Fig. 1.4 Therapeutic objectives for the different stages of each musculoskeletal diseases

more effective ways of replicating native tissue can contribute not only to increased public aware-
anisotropy [106]. Decellularized matrices pro- ness but also inflated expectations of regenerative
vide durability, enhanced integration, and bio- medicine products, and there continues to be a
compatibility while avoiding allosensitization significant gap between the perceived and realis-
[105]. This may explain why many of the signifi- tic benefits [114]. A concerted effort from the sci-
cant breakthroughs and first-in-man studies have entific community as well as robust outcome data
utilized this technique, combined with autolo- from clinical trials will be needed to temper unre-
gous cell seeding with some success [105–107], alistic claims [99, 100].
and even showed promise in vitro for more com-
plex structures, such as pulmonary and aortic
valves as well as whole organs such as heart and Ethics in Musculoskeletal
liver [108, 109]. Regenerative Medicine

Recent challenges emerged between clinical sci-

Controversies in Regenerative entists and research ethical committees (RECs)
Medicine when choosing or evaluating the regenerative
medicine clinical trials for a musculoskeletal dis-
The regenerative medicine field has been order and choosing the appropriate regenerative
shrouded in controversy. Significant potential medicine (RM) comparator. RM is an umbrella
gains have led to several high-profile allegations term for a variety of techniques, including cell-­
of research misconduct [110, 111]. There is also based interventions, biomaterial implantation,
a growing stem cell tourism industry based on gene transfer, and tissue engineering1e4. Due to
unproven treatments that aims to capitalize on the characteristics of RM interventions, such as
stem cell hype [112, 113]. Desperate patients the invasive nature, the application of such tech-
would rather approach private clinics offering nologies in early-stage disease, and the novelty
experimental stem cell treatments, with unproven and even hype of the field, a new light is shed on
safety and efficacy profiles, than wait for out- ethical challenges [115, 116]. Therefore, in
comes of clinical trials [113]. Media coverage regenerative medicine, ethical considerations go
and direct advertising of stem cell therapies as hand in hand with scientific questions.
well as the political, ethical, and religious contro- Basically, the objectives of RM interventions
versies surrounding human embryonic stem cells are closely linked to the stage of the disease. The
1 Fundamentals and Applications of Regenerative Medicine 17

natural course of a disease over time can follow a less appropriate for musculoskeletal RM inter-
staged pattern, progressing from mild to worse. ventions that aim at preventing disease or substi-
In musculoskeletal disorders, four main stages tuting a surgical treatment. The latter may be
can be identified: (1) at risk of the disease, (2) compared to “standard of care.” A placebo as a
early-stage disease with minor symptoms, (3) comparator can also be applied within an add-on
intervention indicated, and (4) late-stage disease design, which means that it is provided on top of
with severe symptoms (conservative measures standard treatment [121–123].
only) (Fig. 1.4) [117]. Currently, musculoskeletal
RM interventions are being developed for the full Informed Consent Another condition for
range of these different stages, and in all these determining the acceptability of sham is whether
stages, one or more objectives can be discerned. valid informed consent can be obtained by tak-
Accordingly, seven types of RM interventions ing the elements of disclosure, competence, and
can be defined based on disease stages. In the “at voluntariness into account [124]. It has been
risk” stage of disease, the objective of the inter- suggested that the use of an invasive interven-
vention is prevention, while in an early stage of tion, such as sham, could foster therapeutic mis-
disease, the objective is return to a healthy state conception [125].
or slow the progression of disease. RM can be
aimed at substituting the surgical treatment, or at Here, the participant confuses care with
supplementing treatment. Other interventions are research, which could compromise a valid con-
aimed at postponing surgery. RM in a late-stage sent. Therapeutic misconception may especially
disease, where an alternative is lacking, is aimed occur in the field of RM, where expectations of
at slowing disease progression or restoration of researchers and participants are high [126].
function [116, 117]. Therefore, in sham-controlled RM trials, one
should take safeguards to decrease the chance of
The comparator in RM clinical trials Although therapeutic misconception, for example, by pro-
conducting clinical trials for invasive interven- longed reflection time, reevaluation of under-
tions involve practical and ethical hurdles, the standing prior to inclusion and during a trial, and
RCT is the default when the objective is to assess avoiding confusing linguistics [127, 128]. In gen-
efficacy of an intervention [118–120]. The main eral, efforts should be made to enhance under-
types of comparators in RCTs are placebo, stan- standing, both through the content and the
dard of care, or no intervention. Examples of manner of providing the information in consent
standard of care include the following: a conven- forms [129, 130]. Furthermore, one should be
tional surgical procedure, another RM interven- aware whether the potential participant is in an
tion, pain management, and physiotherapy. As acute or chronic stage of disease: a participant
RM interventions are invasive interventions, a with a recent onset disease might not fully under-
placebo that optimally blinds participants and stand the consequences of participating due to
investigators requires an invasive placebo, or a anxiety and stress, and also voluntariness might
sham intervention. For symptomatic patients, be impaired [131]. In participants with chronic
delayed treatment or historical control groups disease, the competence and voluntariness is less
can be considered and approved by the Food and expected to be compromised.
Drug Administration (FDA). However, optimal
comparability with historical and delayed treat-
ment control groups should be ensured to limit  egenerative Medicine Curriculum
R
bias. This can be achieved by proper demo- for Next-Generation Physicians
graphic analysis and ensuring comparability in
follow-up. However, though a sham procedure is To ensure that regulated regenerative therapies
demonstrated to be an ethically acceptable com- are provided for patient care, educating a special-
parator in RM trials with certain objectives, it is ized workforce that can distinguish safe and valid
18 Y. El Miedany

regenerative options is warranted [132, 133]. lation and iterative optimization; (iv) all-­inclusive
Regenerative approaches, however, remain group discussion involving patients and faculty
underemphasized in medical school education, along with students; and (v) online education
including in the United States [134, 135]. As a modules and medical student presentations to
result, there is a paucity of physicians adequately ensure learning proficiency. Encompassing a
trained in regenerative principles and practices, patient-centric paradigm, the “Regenerative
necessitating earlier and systematic introduction Medicine and Surgery Course” is a prototype
to this transdisciplinary field that imposes a novel dedicated to medical students and integrated
lexicon and new know-how [136, 137]. within the medical school curriculum. Assessment
Curriculum development and its outcomes: of outcomes which includes completion of learn-
Ongoing efforts aim to bridge curricular gaps and ing objectives is monitored by online tests, group
prepare the next generation physician. The regen- teaching, and simulated clinical examinations,
erative medicine curriculum for medical students along with continuity across medical school
offers a comprehensive educational experience training. Success is documented by increased
that encompasses discovery, development, and awareness and proficiency in domain-relevant
delivery of next-generation patient management content, as well as specialty identification through
modalities targeted to address root cause of dis- practice exposure, research engagement, clinical
ease [138]. Guiding principles for the introduc- acumen, and education-driven practice advance-
tory “Regenerative Medicine and Surgery ment [139] (Fig. 1.5).
Course” included the following: (i) early intro- Regenerative medicine shapes education:
duction of regenerative medicine concepts in Regenerative therapies will permeate the future
medical education training; (ii) dynamic teaching clinical landscape, in particular for diseases
methods, such as interactive, simulation, and lab- that have been proven intractable to current
oratory experiences to maximize student engage- management strategies [140]. Yet, education in
ment; (iii) multidisciplinary, patient-centric regenerative medicine is lagging behind scien-
approach to comprehend bench-to-bedside trans- tific and clinical advances. This threatens to

Fig. 1.5 Regenerative

medicine and surgery
curriculum.
Fundamental principles
of the “regenerative
medicine and surgery
course” curriculum are
introduced early in
medical school training
and longitudinally
expanded in residency B
and clinical fellowship,
allowing for core
proficiency to develop
into advanced expertise p b
of the next-generation
specialized workforce

s
1 Fundamentals and Applications of Regenerative Medicine 19

leave the physicians-in-training ill-equipped to In conclusion, regenerative technologies,

address the changing needs in patient care aimed at restoring form and function, inform the
[141]. A systematic review of medical school prospect of transforming standard-of-care prac-
curricula included no reports of regenerative tices.1,2 The evolution from the traditional per-
medicine courses dedicated for medical stu- spective of “fighting disease” to the increasingly
dents [142]. In line with the projection that actionable paradigm of “restoring health” begets
regenerative care will represent 10% of all a new skill set imperative for the developing
healthcare in the next decade [143], a compre- healthcare practitioner.3 This lack of ethical stan-
hensive, patient-centered course is needed to dards creates difficulties for scientists and
prepare healthcare providers. research ethical committees when designing or
evaluating RM clinical trials. The quest for regen-
erative solutions has, however, exposed a major
Maturity of the Regenerative gap in current healthcare education. A call for
Medicine Field evidence-based adoption has underscored the
necessity to establish rigorous regenerative medi-
The ultimate goal of regenerative medicine is to cine educational programs early in training.
completely restore missing or damaged tissues to
a level functionally and aesthetically indistin-
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 Regenerative Options
for Musculoskeletal Disorders
2
Daniel Habbal, Kaitlin Jayendran,
Nagib Atallah Yurdi, William D. Murrell,
Nicola Maffulli, and Gerard A. Malanga

Introduction inflammatory gels, and intra-articular corticoste-

roid injections. These approaches aim to provide
Given the aging US population, and increasing symptom relief and improve quality of life but
prevalence of obesity, the prevalence of osteoar- are shown to only be effective in the short term
thritis (OA) can be expected to increase in the [3]. Conservative approaches have not been
coming decades. It has been projected that by the proven to significantly modify disease progres-
year 2040, one in four adults aged 18 years and sion or successfully prevent final joint replace-
older will have doctor-diagnosed arthritis [1]. OA ment in the advanced disease stage [4]. In cases
significantly diminishes quality of life through of more advanced OA, operative approaches
pain and loss of joint function and can present a include high tibial osteotomy, unilateral joint
significant economic burden. In 2013, the arthroplasty, and partial and total joint arthro-
national arthritis-attributable medical costs plasty. Unfortunately, these procedures can fail
totaled to $140 billion, which is equivalent to due to implant loosening, infection, persistent
$2,117 of additional medical costs per adult with pain, and instability indicating a more complex
arthritis [2]. Current treatments for early OA revision procedure [5]. Implant durability pres-
include conservative approaches such as weight ents a particular challenge for younger patients.
loss, physical therapy, utilization of nonsteroidal The lifetime risk of revision in younger patients,
anti-inflammatory drugs (NSAIDs), topical anti-­ under the age of 70 years, has shown to reach up

N. Maffulli
D. Habbal
Department of Musculoskeletal Disorders, University
Sydney Kimmel Medical College, Thomas Jefferson
of Salerno School of Medicine and Dentistry,
University, Philadelphia, PA, USA
Salerno, Italy
e-mail: [email protected]
Queen Mary University of London, Barts and the
K. Jayendran
London School of Medicine and Dentistry Centre for
McMaster University, Hamilton, ON, Canada
Sports and Exercise Medicine, Mile End Hospital,
e-mail: [email protected]
London, UK
N. A. Yurdi e-mail: [email protected]
Reem Hospital, Abu Dhabi, United Arab Emirates
G. A. Malanga
W. D. Murrell (*) New Jersey Regenerative Institute LLC,
Plancher Orthopaedics and Sports Medicine Cedar Knolls, NJ, USA
Fellowship Program, New York City, NY, USA
Department of Physical Medicine and Rehabilitation,
411th Hospital Center, Jacksonville Naval Airstation, Rutgers University, New Jersey Medical School,
Jacksonville, FL, USA Newark, NJ, USA

© Springer Nature Switzerland AG 2022 25

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_2
26 D. Habbal et al.

to 35% [6]. In order to reduce medical costs and mesenchymal stem cell markers in situ” and were
risks to patients, improved strategies for early both found to be “clonally multipotent in culture”
disease management and treatment of OA are [13]. It is hypothesized that blood vessel walls
needed. Orthobiologics may be an option to harbor reserves of these progenitor cells, which
prevent patient OA progression prior to an
­ activate and detach at the site of breakage and
advanced disease state. inflammation [7]. These MSCs are considered to
have immunomodulatory, anti-inflammatory, and
trophic properties; they provide bioactive mole-
Basic Science of Orthobiologics cules to the site of inflammation or injury that
locally inhibit immune response and apoptosis,
Regenerative treatment methods are the new as well as accelerate the process of regenerative
frontier of surgical intervention – the use of repair [7].
orthobiologic therapies holds the potential to Orthobiologic medicine harnesses the immu-
transform medical and surgical practices signifi- nomodulatory capacity of MSCs to provide ther-
cantly and is already heralded as the most mod- apeutic effects against a variety of clinical
ern method of healing and therapeutics in current pathologies and injuries [7]. As we further our
medicine [7]. The term orthobiologics refers to understanding of MSCs, we in turn further our
biologically augmented substances, derived from understanding of the regenerative capacity of
naturally occurring biomaterials, used to heal individuals. Current research clearly demon-
musculoskeletal injuries. Orthobiologics are used strates that every bodily tissue has ubiquitous,
to improve the healing of ligaments, bones, and intrinsic regenerative abilities due the presence of
muscles, as well as accelerate the biological pro- tissue-specific progenitor cells [11]. Careful
cesses of regeneration and repair in response to manipulation of this regenerative ability could
injury [8]. produce enhanced clinical outcomes, ranging
Primary studies conducted by orthopedic sur- from accelerating healing to scar-less regenera-
geon John Connolly and others inspired the mod- tion [10]; therein lies the basis of orthobiologics
ern use of bone marrow in surgical treatments in modern medicine. The most common orthobi-
[7], as it was concluded that bone marrow, upon ologic therapy is platelet-rich plasma (PRP) –
transplantation, could act as versatile osteogenic which is composed of platelets, which are
reconstructors at the site of injury [9]. It was dis- nonnucleated cells with vesicles containing bio-
covered that bone marrow contained mixed con- active factors that regulate wound healing [7] and
nective tissue progenitors – more commonly plasma containing both bioactive molecules and
known as “mesenchymal stem cells (MSC)” as chemokines that assist in the detachment of
coined by Arnold Caplan, the researcher credited MSCs from their perivascular origins, as well as
for providing their most common name [7]. As mitogens, which stimulate MSC replication [14].
described by Caplan, MSCs are “infinitely divis- The introduction of PRP results in signaling an
ible progenitor cells whose progeny may possi- increased presence of MSCs at the site of injury
bly give rise to skeletal tissues, such as bone, and is expected to enhance regeneration and heal-
cartilage, marrow stroma, adipocyte, muscle, ten- ing. The working concentration of PRP is typi-
don, ligaments, [and] connective tissue.” cally 1,000,000 platelets/μl in 5 ml of plasma,
However today, we know that this is not the case and this composition has been associated with
and that most likely the cells are more immuno- improved clinical outcomes [15].
modulating in nature [10, 11]. Current scientific The ability to biologically engineer MSC-­
evidence suggests that MSCs are derived from mediated immunomodulatory activity is the fun-
perivascular cells called pericytes [12], as both damental principle behind a large spectrum of
fetal and adult MSCs “expressed both pericyte clinical trials using orthobiologic therapies. The
2 Regenerative Options for Musculoskeletal Disorders 27

modern challenges we face involve delivery of Lateral Epicondylitis

such therapies, in the right amounts, in the right
places, and at the right time. It is important to PRP – A systematic review and meta-analysis of
acknowledge that MSCs harvested from differ- nine RCTs by Huang et al. compared PRP to cor-
ing anatomical locations, and from a variety of ticosteroid (CS) in the management of lateral epi-
donors, are expected to have differing intrinsic condylitis [19]. Short-term data analysis showed
biochemistries. However, recent clinical trials a statistically significant improvement with CS
have reported that such differences do not over PRP for pain relief with medium effect size,
significantly impact the efficacy of isolated
­ while the improvement in pain scores reversed
autologous or culturally expanded allogeneic long term with PRP providing significantly better
MSCs [7]. pain relief with a very large effect size [19].
BMAC – Singh et al. studied the treatment of
tennis elbow patients with a single injection of
 elected Orthobiologics to Treat
S BMA and showed a significant improvement in
Primary MSK Conditions short- to medium-term follow-up [20].
ASC – Khoury et al. studied the effect of
Rotator Cuff Tendinopathy adipose-­derived stromal cell (ASC) injection as
a therapeutic procedure on the common exten-
PRP – It was found to be incredibly effective in sor tendinopathy. Eighteen tennis players with
treating rotator cuff tendinopathies, as seen in a chronic, recalcitrant lateral epicondylitis (LE)
random-effects meta-analysis by Hamid et al. underwent clinical evaluation and MRI before
that reviewed eight RCTs. Four studies compared intervention. Tennis players with recalcitrant
PRP injection with normal saline, and four RCTs LE showed significant clinical improvement
used rehabilitation programs and dry needling as and structural repair at the origin of the com-
control interventions. The meta-analysis showed mon tendon origin after injection of autologous
that PRP injection was a safe and effective treat- ASCs [21].
ment for long-term pain control and shoulder
function in patients with rotator cuff tendinopa-
thies [16]. KOA
BMAC ± PRP – One systematic review by Di
Matteo et al. looked at the available clinical evi- PRP – Orthobiologics have been increasingly
dence on the application of cell-based therapies used to treat musculoskeletal conditions such as
for the management of rotator cuff tears. All the OA and tendinopathies. Belk et al. performed a
papers included suggested an improvement of meta-analysis on 18 studies that compared the
rotator cuff tendinopathies with cell-based efficacy and safety of PRP with hyaluronic acid
approaches with a satisfactory safety profile. The (HA) in the treatment of knee OA (KOA). The
study also highlights a lack of high-level evidence meta-analysis showed a benefit of using PRP
and the presence of controversial issues with the over hyaluronic acid in treating OA with six out
standardization of these biologic approaches, spe- of 11 studies showing significantly better VAS
cifically in regards to inter-­product variability and scores at latest follow-up, and three out of six
application strategies [17]. studies showing significant improvement in sub-
MFAT – In addition, Robinson et al. studied jective IKDC outcome scores. ​​Additionally, the
the safety and clinical outcomes of patients meta-analysis showed that leukocyte-poor PRP
treated with micro-fragmented adipose tissue for may be a superior line of treatment for KOA over
shoulder pain secondary to rotator cuff pathol- leukocyte-rich PRP [22].
ogy. Significant improvements in VAS scores and BMAC – Bone marrow aspirate and concen-
pain disability index scores with no major adverse trate are a heterogeneous mixture of mixed con-
events were observed at 6 months [18]. nective tissue progenitors that have been found to
28 D. Habbal et al.

accelerate bone regenerative repair and have the gous blood with gold particles (GOLDIC®) and
ability to be immunomodulatory [23]. One sys- injection in patients. This prospective observa-
tematic review by Keeling et al. used eight stud- tional study that was retrospectively assessed was
ies to evaluate the efficacy of isolated BMAC performed on 64 patients, with 89 knees (mean
injection in the treatment of OA of the knee joint. age: 64.8 years; 89 knees) treated with gold-­
Patients demonstrated significant improvement induced cytokines (GOLDIC) with moderate to
from baseline to latest follow-up across 34 of 36 severe KOA with radiographically proven
patient-reported outcomes, and the authors con- KOA. All participants received four ultrasound-­
cluded that BMAC injection is effective in guided intra-articular knee injections of
improving pain and patient-reported outcomes in GOLDIC® at 3–6 day intervals. Western Ontario
patients with KOA at short- to midterm follow- and McMaster Universities Osteoarthritis Index
­up. However, BMAC did not demonstrate superi- (WOMAC) and Knee Injury and Osteoarthritis
ority in relation to other biologic therapies Outcome Score (KOOS) were evaluated at base-
commonly used in the treatment of OA, including line; 1, 3, and 6 months; and 1, 2, and 4 years
PRP and MFAT [24]. (T1–T6). The incidence of treatment-related
MFAT – Gobbi et al. performed a multicen- severe adverse events (SAEs) was recorded.
tric, international, open-label study to assess the Intra-articular gelsolin level in patients with effu-
use of micronized adipose tissue (MFAT) in sion was determined. KOOS and WOMAC
elderly patients with 2-year follow-up. Patients scores improved for the full duration of the study
were followed up to 24 months with Knee Injury (P < 0.05), and minimal clinically important dif-
and Osteoarthritis Outcome Score (KOOS). ference (MCID) was observed at all time points
Statistical models were used to assess KOOS in all KOOS subscores, with no reported SAEs.
subscores and the probability of exceeding the No statistically significant evidence of an associ-
minimally clinically important difference ation between patient demographics and outcome
(MCID) or patient acceptable symptom state were identified. Nine patients failed treatment,
(PASS) and to assess the effect of the treatment with 32 months mean time to failure, and under-
variables on KOOS – pain. Seventy-five patients went total knee arthroplasty. This study demon-
with 120 primary treatments, mean age of strated that GOLDIC is good for conservative
69.6 years (95%CI 68.3–70.9), BMI of 28.4 management of moderate to severe KOA. The
(95%CI 27.3–29.6), and KL grade of 2–4 KOA CAS produces rapid and sustained improvements
were treated with a single MFAT injection. in all indices after treatment, with no SAEs [26].
Patients with KL grade 2 disease had the best SVF – There is also a growing body of
results in KOOS – pain (P = 0.001), at 6, 12, and research supporting the use of adipose-derived
24 months. Fourteen treatments (11.7%, 9 mesenchymal stem cells to treat orthopedic con-
patients) failed prior to the study endpoint and ditions. Autologous stromal vascular fraction
underwent knee arthroplasty. This study demon- (SVF) has recently been used as an efficient
strated that a single-dose MFAT injection can medium for the administration of adipose-derived
lead to clinical, functional, and quality of life mesenchymal stem cells. A systematic review of
improvement at 2 years in elderly patients, in 11 studies by Shanmugasundaram et al. evaluated
KL grades 2–4 of KOA. These findings provide the safety and efficacy of SVF injection for the
evidence that this treatment modality could be a treatment of KOA. The majority of patients
safe and cost-effective option to other com- reported improvement in pain, range of motion
monly available treatments in carefully selected (ROM), and functional outcome scores. The
patients [25]. authors concluded SVF injection is a safe and
CAS – The use of conditioned autologous effective technique for the management of KOA
serum has been assessed for treating KOA by and could serve as an interim option for patients
Schneider and co-workers in their recent publica- who failed other conservative and arthroscopic
tion a novel technique of preconditioning autolo- options [27].
2 Regenerative Options for Musculoskeletal Disorders 29

In the future, stem cell-based injection therapy showed a substantial improvement in the level of
can possibly be used as an alternative conserva- tendon integrity at the 10-year follow-up visit for
tive treatment. Before mainstream adoption, patients treated with BMAC [31]. Further investi-
additional evidence, especially for cost-­gation is needed into these new and evolving
effectiveness, long-term safety, and additional treatments; however, they show promise for
adverse event reporting, needs to be demon- improving rotator cuff repair healing and func-
strated for treatment in several MSK conditions. tional outcome.
This is particularly true for those who have failed
nonoperative treatment before surgical repair is
taken. ACL Tears

Regenerative therapies have the potential to

 rthobiologics to Augment Current
O improve current surgical interventions in the area
Orthopedic Surgical Procedures of ligament repair via improved graft incorpora-
tion and strengthening, trophic induction, and
Rotator Cuff Tears microenvironment facilitation [7]. Andriolo et al.
performed a systematic review of all the preclini-
Rotator cuff tear, both partial and full thickness, cal and clinical papers dealing with the applica-
can be a debilitating source of pain and can cause tion of PRP as a biological enhancer during ACL
significant shoulder dysfunction. As surgical reconstructive surgery [32]. The majority of
repair has become the gold standard, one would papers did not show beneficial effects in terms of
assume that all repairs heal. However, some lit- graft integration; however, there was some evi-
erature shows that the failure rate of rotator cuff dence that PRP administration could positively
repair exceeds 50%. Higher repair rates could be contribute to graft maturation over time [32].
achieved by adding orthobiologics to help reat-
tachment to the bone [7].
PRP – It has been shown to stimulate tendon Meniscal Tears
stem cells to differentiate into tenocytes and
facilitate collagen extracellular matrix produc- Biomechanical and clinical data by Baratz et al.
tion [28]. One systematic review and meta-­ have demonstrated the importance of the menis-
analysis by Ryan et al. investigated the clinical cus and of meniscal preservation for protection of
and imaging outcomes of 4 types of PRP thera- the articular cartilage, distribution of forces, and
pies in rotator cuff repairs and found significant as a secondary stabilizer [33]. Given the limited
reductions in retear rates [29]. blood supply, there has been an increasing inter-
BMAC – Another study by Cole et al. com- est in biologic augmentation of these repairs to
pared the clinical outcome of arthroscopic rotator enhance healing [7]. Kaminski et al. performed
cuff repair with and without augmentation using an RCT to study the effect of PRP augmentation
BMAC to identify persistent structural defects for meniscus repair and found improvements in
following surgery [30]. MSCs injected into the both meniscus healing and functional outcome
shoulder at the time of surgical repair showed [34]. Another study by Massey et al. reviewed the
improved tendon quality on postoperative MRI at results of meniscus repairs with and without bone
1-year postop [30]. The longest-term study with a marrow aspiration concentrate [35]. Both the
10-year follow-up was carried out by Hernigou control group and BMAC meniscus repair group
et al., which compared 45 patients who received had improved outcomes at 1-year postoperatively
BMAC during a rotator cuff repair to a matched with respect to VAS, Lysholm, and IKDC. Authors
control group of 45 patients who did not receive found that meniscus repair outcomes were
MSCs. Nearly 100% of repairs with MSC aug- improved at 6 weeks and 3 months postopera-
mentation had healed by 6 months versus 67% of tively when BMAC was used in the repair [35].
repairs without MSC treatment. The study also On the other hand, the use of ASCs for meniscal
30 D. Habbal et al.

repair is largely unexplored [36]. One recent of orthobiologic treatments. This includes quality
study by Sasaki et al. studied the effects of ASC-­ measures, characterization of injectate, cost,
seeded hydrogels on the repair of a meniscal adverse events, and long-term follow-up [40].
transplant model and found that ASC-seeded Therefore, there has been a great effort to increase
hydrogels preloaded enhanced healing of radial available evidence, based on clinical outcomes,
meniscal tears [36]. More studies are needed to to provide a potential road map on delivering
properly assess the use of this biologic in the quality for facilities providing orthobiologic ther-
treatment of meniscal pathologies. apies [41]. To provide feedback on the safety and
efficacy of these treatments, observational prac-
tice registries have emerged in clinical environ-
Cartilage Repairs ments throughout the world [42]. A clinical
outcomes registry is an organized system for col-
Cartilage repair has long been an area of diffi- lecting patient outcomes as data points relevant
culty within orthopedics. There have been many to the effect of treatment on pathology or injury.
recent studies that have been published studying A key benefit of this type of registry is its agility;
the effects of biologics on the treatment of carti- the registry can quickly identify underperforming
lage pathology. treatments by linking the treatment to patient-­
PRP – Campbell et al. reported on the quality reported outcome measures (PROs) and adverse
of three meta-analyses that evaluated PRP injec- events (AEs). For the field of orthobiologics, this
tion therapy for cartilage degenerative condi- is critical, as data and information about the effi-
tions. Authors found that IKDC scores improved cacy of treatments is growing, but not fully
at 6-month follow-up, and WOMAC and VAS known [43, 44].
improved at 3- and 6-month follow-ups com- One recent outcome registry, by Drs. Rogers,
pared to hyaluronic acid (HA) [37]. Malanga, and Bowen, provides comprehensive
BMAC – Another study by Cotter et al. demon- coverage of a broad array of regenerative medi-
strated that BMAC may also help stimulate hya- cine treatments. This includes PRP, hyaluronic
line cartilage repair. Results showed robust tissue acid, bone marrow, adipose-derived mesenchy-
response with cartilage restoration procedures at mal cells, and a variety of other regenerative
various defined time points after surgery [38]. medicine treatments. The most common orthobi-
PBPC – Peripheral blood progenitor cells use ologic treatment employed in the registry was
in cartilage repair was studied in an RCT by Saw PRP (64%), followed by adipose (17%), and then
et al., with 50 patients randomized to control (HA) by BMAC (12%). Although still in its early
and intervention (PBSC + HA) groups [39]. stages, registries will allow physicians to begin
Histologic and MRI evaluation showed that​​ injec- patient-reported outcome data collection and
tions of autologous PBSC in combination with HA contribute to reporting outcomes of the successes
resulted in an improvement of the quality of articu- and failures of biologic therapy. The future holds
lar cartilage repair over isolated HA injections many potential avenues of progression for this
[39]. Although results are promising, the use of tracking system, with one potential next-gen
orthobiologics in cartilage repair continues to application being a data biologics software that
require additional evidence to support clinical use. will streamline the collection and reporting of
these important outcome data.

Quantifying Outcomes
of Orthobiologics Future of Orthobiologics

The use of orthobiologics is growing rapidly in The overall field of orthobiologics is at a critical
both research, translation, and clinical applica- junction in time. Scientists, translation clini-
tions. However, there has been a scarcity of real-­ cians, and practitioners jointly have to collabo-
world patient outcome data for the vast majority rate to ensure that the necessary evidence
2 Regenerative Options for Musculoskeletal Disorders 31

needed for further legitimizing the use of ortho- last? A systematic review and meta-analysis of case
series and national registry reports with more than 15
biologics is established and accepted by regulat- years of follow-up. Lancet. 2019;393(10172):655–63.
ing bodies and professional organizations. https://doi.org/10.1016/S0140-­6 736(18)32531-­5 .
Recently, there has been increased regulatory Epub 2019 Feb 14. Erratum in: Lancet. 2019 Feb 20;:
action of the use of orthobiologics clinically, PMID: 30782341; PMCID: PMC6381229.
6. Bayliss LE, Culliford D, Monk AP, Glyn-Jones S,
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 The Nuts and Bolts
of Regenerative Medicine
3
as It Pertains to the Joint

Joseph Purita

Regenerative medicine has dramatically changed Articular Cartilage

the approaches of treating degenerative condi-
tions in a joint. Typically, when we are discussing Joints are unique in that they are subjected to
joints, there are a few major aspects that we need decades of wear and tear. Articular cartilage is
to address. Rather than deal with the esoteric, the hyaline cartilage and is 2–4 mm thick [1]. Unlike
focus of this chapter is on the more common most tissues, articular cartilage does not have
afflictions of joints and how regenerative medi- blood vessels, nerves, or lymphatics. It is com-
cine may effectively treat them. These conditions posed of a dense extracellular matrix (ECM) with
can be divided into three major aspects. Those a sparse distribution of highly specialized cells
affecting the articular cartilage, those affecting called chondrocytes. The ECM is principally
the soft tissue aspects of the joint, and finally composed of water, collagen, and proteoglycans,
those conditions affecting joint circulation. The with other non-collagenous proteins. The glyco-
soft tissue aspects deal with the ligaments, ten- proteins present in lesser amounts. Together,
dons, and muscles that contribute to the integrity these components help to retain water within the
of the knee. We must keep in mind that typically ECM, which is critical to maintain its’ unique
these conditions are many times interrelated to mechanical properties. The articular cartilage is
each other. One condition may predispose the divided into four main sections.
joint to other problems and combine with other The superficial zone has Type II collagen with
problems. The main emphasis of this chapter is an orientation that is parallel to joint. The super-
on conditions of the articular cartilage. A word of ficial zone protects the deeper layers from shear
caution should be given. Some of the recommen- stresses and makes up approximately 10–20% of
dations in this chapter may not be allowed in your articular cartilage thickness. It has flattened
country. We urge that you check with the appro- chondrocytes, condensed collagen fibres, and
priate authorities in your country if you have sparse proteoglycans sparse proteoglycans. It is
questions on certain procedures. the only zone where articular cartilage progenitor
cells have been found. The integrity of this layer
is imperative in the protection and maintenance
of deeper layers. Of significance in this layer is
a compound called lubricin. Lubricin was origi-
nally identified as a lubricating glycoprotein
J. Purita (*) present in the synovial fluid (SF). It is specifi-
The Institute of Regenerative Medicine, cally synthesized and expressed by articular
Boca Raton, FL, USA

© Springer Nature Switzerland AG 2022 35

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_3
36 J. Purita

c­ hondrocytes of the superficial zone. It is recog-  igaments and Tendons and Their
L
nized to have a major protective role in prevent- Effects on Joint Problems
ing cartilage wear, helps in synovial cell adhesion
and proliferation, and reduces the coefficient of Ligaments and tendons are intimately related to
friction of the articular cartilage surface. the joint. A malfunction in one or both of these
The intermediate layer has Type II collagen, entities can result in a disaster for the joint. The
having an oblique or random organization. It is treatment of ligamentous and tendon injuries is
the thickest layer with round chondrocytes and similar yet different from that of the joint. These
abundant proteoglycan content. The intermedi- structures are similar in composition, but there
ate layer represents 40% to 60% of the total car- are some significant differences. In the tendon,
tilage volume. Functionally, the intermediate the collagen fibrils are aligned parallel to each
layer is the first line of resistance to compressive other and to the long axis of the tendon, whereas
forces. in the ligament, the fibrils are not as uniformly
The deep zone is responsible for providing the orientated to allow for multiaxial loading pat-
greatest resistance to compressive forces, given terns. The treatment of these injuries is similar to
that collagen fibrils are arranged perpendicular to articular cartilage injuries.
the articular surface. The deep zone contains the
largest diameter collagen fibrils in a radial dispo-
sition, the highest proteoglycan content, and the Platelet-Rich Plasma (PRP)
lowest water concentration. The rounded chon-
drocytes are typically arranged in columnar ori- In regenerative medicine procedures, a good con-
entation, parallel to the collagen fibres, and cept to consider is that one is planting a garden.
perpendicular to the joint line. The deep zone Any garden has three main components. It con-
represents approximately 30% of articular carti- sists of soil or in this case a scaffold, seeds which
lage volume. in our case are regenerative cells including stem
The last zone is called the tidemark. The tide- cells, and fertilizer which in our case are growth
mark divides the superficial, uncalcified cartilage factors derived from among other things plate-
from the deeper calcified cartilage division. The lets. Platelet-rich plasma is derived from the
tidemark is found only in joints. patient’s own blood; therefore, it is an autologous
When we are dealing with regenerative pro- product. Platelets are composed of three main
cedures in the joint, we are most interested in components. The three main components are
the chondrocytes [2]. Chondrocytes are meta- lysosomes, the dense granules, and the alpha
bolically active cells that synthesize and turn- granules. The alpha granules contain the most
over a large volume of extracellular matrix important factors controlling regeneration. The
(ECM) components, such as collagen, glycopro- following diagram illustrates these facts
teins, proteoglycans, and hyaluronan. They do, (Fig. 3.1). It gives an excellent breakdown of
however, respond to a variety of stimuli, includ- each entity and its various subparts. As we can
ing growth factors, mechanical loads, piezoelec- see, a platelet is a complicated structure.
tric forces, and hydrostatic pressures. The The growth factors are one of the most impor-
metabolic activities of chondrocytes are altered tant aspects of the platelets for our purposes.
by many factors that are present within their However, we cannot minimize the importance of
chemical and mechanical environment. Most other aspects such as dense granules and lyso-
important among these factors are the pro- and somes. The question as to what the most impor-
anti-inflammatory cytokines and growth factors tant growth factors from the platelets are is like
that have anabolic and catabolic effects. In asking what the most important instruments in a
essence, regenerative medicine is attempting to symphony orchestra are. They all have impor-
manipulate these cytokines to lead to repair and tance. For discussion purposes, we will centre on
decreased inflammation. a hand full of these factors. Numerous protein
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 37

Fig. 3.1 PRP growth

factors PRP growth factors
Platelet alpha granules and dense granules

-Arabinoside Elastase
-Galactosidase Collagenase
Lysosomes
-Glucuronidase Cathepsin
n-Acetylglucosaminidase

ADP, ATP
Dense granules Serotonin
Ca++
Epinephrine
-Granules Histamine
Platelet
Chemokines
Coagulation factors IL-8
Factor V NAP-2
2-Macroglobulin
Factor XI RANTES
2-Antiplasmin
Factor XIII Plasmin, Plasminogen MCP-1,-3 Regulators of
Prothrombin MIP-1 growth and
Protein S
Antithrombin -Thromboglobulin
PAI-1, TFPI angiogenesis

Adhesion molecules Immunologic molecules bFGF EGF

HGF CTGF
P-Selectin Complement factors IGF-1 TGF-
Von Willebrand factor Platelet factor H VEGF-A, -C Angiopoietin-1
Vitronectin 1H Globulin PDGF-AA,-AB,-BB SDF-1
Fibrinogen Factor D BDNF MMP-1,-2,-9
Integrin llb 3 C1 Inhibitor Angiostatin Endostain
Integrin V 3 lgG PF4 TIMP-1,-4
Fibronectin Thymosin- 4 Thrombospondin BMP-2,-4,-6

growth factors are contained in the alpha gran- assays demonstrate that sustained release is
ules of platelets: platelet-derived growth factor achieved over periods as long as 10–15 days. HA
(PDGF), transforming growth factor (TGF), itself can have many different properties, includ-
platelet factor interleukins (IL), platelet-derived ing acting as a signalling molecule [5].
angiogenesis factor (PDAF), vascular endothelial Realize that growth factors from platelets rep-
growth factor (VEGF), epidermal growth factor resent only one source of growth factors. The
(EGF), insulin-like growth factor IGF, fibronec- other major source comes from various types of
tin, and a host of others. When we are dealing stem cells, cells of the immune system, and other
with the different growth factors, we need to real- regenerative cells. Many studies have shown that
ize they typically consist of a family [3]. For the growth factor release from platelets lasts
instance, there are a few types of IGF. Most about 7 days. A few years back, it was very popu-
growth factors have more than one type, some lar to activate the platelets ahead of their injec-
such as FGF can have 22 different types (realize tion. This was typically done by adding thrombin
that some of these forms can have significantly to the platelet mixture. However, there were some
different effects). Both age and gender account potential problems with the thrombin, such as an
for variations in specific GFs present in PRP. This allergic reaction by the patient. That being said,
may partially explain some of the inconsistent we must realize that when platelets come into
results of PRP clinical trials. It is well known that contact with collagen, they become activated.
the biological half-lives of most growth factor Essentially, most all tissue contains collagen.
peptides are very short, and this may limit the Also, when there are some RBCs in the platelet
effectiveness of the current intra-articular injec- product, they will contribute some thrombin and
tion therapies [4]. Combining a growth factor further activate the platelets. There are some con-
with hyaluronic acid (HA), for example, allows ditions which may require the use of only the
for a more prolonged delivery of the growth fac- platelet growth factors without the platelets.
tor, potentially enhancing this widely used clini- When we are only using the platelet growth fac-
cal treatment for cartilage degeneration and joint tors, this is called platelet lysate. There are no
pain. HA gels have been prepared as injectable platelets in a lysate. A lysate may be used in some
carrier vehicles for growth factors and bioactivity intravenous applications. A good method of pro-
38 J. Purita

ducing a lysate is by using an ultrasonic cleaner WBCs with platelet activation and either 5× more
and using it to lysis the platelets. platelet concentration from baseline (Type 4A) or
When we are looking at a PRP product, we less than 5× platelet concentration from baseline
must realize that a PRP is more than platelets. The (Type 4B). This is a very good attempt in trying to
following diagram (Fig. 3.2) shows the various compare “apples to apples” when we are looking
components of a PRP product [6]. An effective at clinical studies. It gives us some indication as to
PRP preparation has many different components. what the PRP was composed of.
Where we get into problems when dealing with a Another paper by Lana and Purita et al. further
PRP preparation is what type of preparation are classifies PRP [6]. In their paper, they expanded
we dealing with. In other words, how was it the classification to include other perimeters.
made? What does it consist of? These perimeters included method made, pres-
The problem we have discovered is that there is ence of red blood cells, the number of spins used
no consistent classification of PRP products. This to produce the PRP product, and finally light acti-
may be one the reasons why there is a discrepancy vation. We are now realizing the that light activa-
in results that are reported. A good attempt to clas- tion is becoming more and more important in the
sify PRP products was made by Mirsha et al. They field of regenerative medicine. There is more to
classified PRP according to platelet content, WBC follow later in the chapter concerning photo mod-
content, and platelet activation. There were four ulation. A synopsis of classification of Lana et al.
main classifications. Type 1 had increased amounts can be found below (Table. 3.1). It is called the
of WBCs and no platelet activation with either 5× MARSPILL PRP classification.
or more of platelet concentration from baseline The ultimate question becomes the following:
(Type 1A) or less than 5× concentration from Which form of PRP works best? Should different
baseline (Type 1B). Type 2 is similar with the dif- forms of PRP be used for different clinical condi-
ference being activated platelets and 5× more tions? Is a leucocyte poor (LP) PRP product
(Type 2A) or 5× less (Type 2B) concentration of (sometimes called a pure PRP) more effective in
platelets from the baseline. Type 3 had minimal or the joint than a leucocyte-rich (LR) PRP product?
no WBCs with no platelet activation and either 5× Unfortunately, there are no easy answers here.
more (Type 3A) or 5× less (Type 3B) platelet con- However, when we sift thru science, some impor-
centration than baseline. Type 4 had little or no tant trends emerge.

Fig. 3.2 PRP contents

PRP–contents
1. Platelets
2. Neutrophil (PMN) – 40–75% of circulating leukocytes
3. Monocyte macrophage – 2 –10% of circulating
leukocytes. Highly motile and migrate to soft tissues
4. Fibroblast – produce collagen, reticular fibers,
glycosaminoglycans, glycoprotein
5. Endothelial cell – permeability barrier, regulate blood
flow and vascular reactivity, vasodilators, vasoconstrictors,
regulate inflammation and immunity
6. Keratinocyte – stratified, squamous epithelial cells Primary
function is to act as a barrier
7. HSCs (represent 0.06% of circulating TNCs)
translates into 3–7KHSCs per ml of blood
processed
8. Pluripotent small embryonic like stem cells
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 39

Table 3.1 MARSPILL PRP classification

Marspill PRP classification

Table 2. Marspill classification
Letter Relates to Type
M Method Handmade (H)
Machine (M)
A Activation Activated (A+)
Not activated (A–)
R Red blood cells Rich (RBC-R)
Poor (RBC-P)
S Spin One spin (Sp1)
Two spins (Sp2)
P Platelet number PL 2–3 PL 6–8
(folds basal) PL 4–6 PL 8–10
I Image guided Guided (G+)
Not guided (G–)
L Leukocyte concentration Rich (Lc-R)
Poor (Lc-P)
L Light activation Actived (A+)
Not activated (A–)
Lc: Leukocyte concentration; PL: Platelet concentration; RBC: Red blood cell.

There are some misconceptions in the field of Granted we do want diminished numbers of
PRP that I call “Urban Legends of PRP”. It seems RBCs. But there is a prevailing attitude that
that many times companies are using their mar- RBCs cause inflammation. There is no litera-
keting ploys and trying to represent them as clini- ture supporting this. On the contrary, there are
cal science. There are very few papers showing good clinical examples that RBCs do not cause
clinical evidence that (LP) PRP is more effective inflammation. When a patient tears an ACL liga-
than (LR) PRP in the joint. However, there is ment, he or she typically develops a bloody effu-
ample systemic review and meta-analysis show- sion. The patient may have discomfort from the
ing that (LR) is more effective. Dr. William effusion, but they typically do not develop an
Parrish [7] has presented a number of peer-­ inflammatory response from the blood. Another
reviewed articles on these concepts. There are good example concerns the use of a blood patch
some huge takeaways that we obtain from the for a spinal leak. If something (in this case whole
various Parrish articles. Realize these concepts blood) were inflammatory, would we want to put
are not just those of Dr. Parrish but are prevailing it on the dura? What other purpose might RBCs
scientific attitudes. As Dr. Parrish mentions serve. They are a source of thrombin, which is
“growth factors represent only a single aspect of of the upmost importance for helping platelet
the bioactivity of platelets. Furthermore, platelets activation. Furthermore, the RBCs help in the
represent only one aspect of the potential bioac- growth factor release from the platelets. In addi-
tivity of PRP”. tion, RBCs also release nitric oxide and glutathi-
Let us take a better look at some of these one, both of which can have beneficial effects on
ideas. We can start with red blood cells (RBCs). the cellular matrix and environment.
40 J. Purita

Another misconception is the presence of neu- tissue repair. They also give a stop signal to turn
trophils. In many circles, neutrophils are vilified off an inflammatory cycle.
as one of the major causes of inflammation. We know that we can manipulate the neutro-
Again, as Dr. Parrish explains, only under certain phils a bit with photo modulation. Photo modula-
conditions are neutrophils actually bad as far as tion, as evidenced by Morgan et al. [9], has an
regeneration is concerned [8]. The following dia- effect on neutrophils. Studies indicates that pho-
gram is from one of Parrish’s papers. As is totherapy can have a significant impact on neu-
pointed out, neutrophils cause inflammation trophils, the effect of which varies according to
when they are activated. We see that they will the specific type of phototherapy. We have uti-
secrete those cytokines, which cause inflamma- lized photo modulation for years in our clinic.
tion. This is the classical injury-induced inflam- While photo modulation may help the neutro-
mation. This is what will hopefully get a bacterial phils produce some anti-inflammatory growth
infection under control. Remember, neutrophils factors, there are other aspects of neutrophils to
are powerful antibacterial agents. In their destruc- consider.
tion of bacteria, they will cause some collateral
damage to the surrounding tissue. When the neu-
trophils are primed but not activated, some inter- Macrophages: A Secret Weapon
esting things happen. The neutrophils actually in a PRP
secrete anti-inflammatory growth factors, which
can lead to repair. The following diagram is an Another important cell group found in a proper
excellent summation of this concept put forth by PRP product involves monocytes, which become
Parrish (Fig. 3.3). As we can see in the diagram, macrophages. The concept that macrophages
the neutrophils actually produce IL-10 and IL-1 should be part of PRP product is steadily becom-
antagonist which are potent master anti-­ ing more accepted. The macrophage is at the cen-
inflammatory cytokines. They also produce TGF-­ tre of the “immune solar system”. They have
b. These three cytokines can be instrumental in profound effects on various immune cells. Our

Parrish et al Journal of Exercise, Sports, and Orthopedics

Injury induced classical inflamation Aseptic injection Anti-inflammatory
Clasical injury Sterile injury or aseptic injection

Resting neutrophil
Resting neutrophil
Primed neutrophil
Vessel Primed neutrophil

STOP signals
Activated platelets Endothelium
• TGF-
• IL-10
Endothelium Red blood cells • IL-1ra
• sTNFR,
Primed but • Lipaxins
not activated
neutrophil
Activated neutrophil
Resting neutrophils are recruited from the circulation and become Physiologically balanced platelet rich injectate includes leukocytes and RBCs
Platelets and leukocytes are in resting state when introduced to tissue
primed by migrating through the endothelium
Once in the tissue primed neutrophils are activated by platelets Platelet activation from contact with tissue drives injectate coagulation and
to produce inflammation amplifiers leukocyte priming
With aseptic injection no separate activation signals present and leukocytes
TNF-
remain primed but not activated
IFN-
IL-1 Primed but not activated neutrophils cooperate with platelets to generate
IL-B anti-inflammatory and pro-resolving STOP signals
TNF-
Neutrophil inflammatory mediators induce recruitment of more neutrophils IL-10
and mononuclear cells from the circulation and further enhance inflammatory
response to ensure infection control and adequate tissue debridernent Tissue IL-1ra
Soluble TNF receptor (sTNFR)
Enhanced inflammation can cause collateral damage to healthy tissue and Pro-resolving lipoxin lipid mediators
delays the transition to the proliferation phase of healing
STOP signals prevent recruitment and activation of leukocytes from the circulation
and surrounding healthy tissue
Promotes resolution of inflammation and transition to proliferation phase of
wound healing

Fig. 3.3 Parrish et al. Journal of Exercise, Sports, and Orthopedics. (Used with the permission of DR. W. Parrish)
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 41

immune system and stem cell therapy are inti- lage formation, ligamentous and tendon healing,
mately related. There are two types of macro- and the list goes on and on.
phages in the immune system. Macrophages have In summation, we can see that a proper PRP
prominent plasticity and are classified into acti- product is required for the best chance of success
vated M-1 or activated M-2 macrophages [10]. in regenerative medicine. As Dr. Parrish’s has
The macrophage type depends on the specific pointed out, we want to use the full complements
micro-environment they are found in. These two of the whole blood. We certainly need to concen-
types have significantly different actions not only trate the platelets but at the same time need other
in the immune system but also in general repair. components of the whole blood to complement
M-1 macrophages are pro-inflammatory and pos- platelet action. A PRP works like a symphony
sess remarkable antimicrobial abilities via the orchestra. All components contribute to the
secretion of various inflammatory cytokines and whole. Platelets, RBCs, and leucocytes work
chemokines. M-2 macrophages are immunomod- synergistically to accomplish repair. They help to
ulatory by releasing IL-10 (interleukin 10) and control the magnitude and duration of the repair
trophic factors to promote tissue repair and process. There is no doubt that a “pure” PRP
resolve inflammation. Put in simple terms, (LP-PRP) product will typically cause less of an
M1-type macrophages release cytokines that inflammatory response. The reason for this is
inhibit the proliferation of surrounding cells and typically the LP- PRP product may be an inferior
damage contiguous tissue, and M2-type macro- one. I base this on my clinical experience over the
phages release cytokines that promote the prolif- last dozen years or so and thousands of cases.
eration of contiguous cells and encourage tissue We utilize PRP treatments in the less severe
repair. The clinical impact of M-1/kill and M-2/ conditions. This includes disorders of the shoul-
repair responses is immense, playing pivotal der, including bursitis and rotator cuff tears. Also
roles in curing (or causing) many diseases, included in this grouping, we find tendonitis of a
including infections, cancer, autoimmunity, and variety of tendons, including tennis elbow,
atherosclerosis. Realize that mesenchymal stem Achilles tendonitis, and plantar fasciitis. PRP
cells and their secretory patterns have a profound typically works well with muscle tears, sprains,
effect on the polarization of macrophages. trigger points, and meniscus tears of the knee. We
In the field of regenerative medicine, we are have had good success with mild to moderate
more concerned with the M-2 macrophage. The degenerative arthritis of various joints and disor-
M-2 macrophage conversion is influenced by its ders of the spine especially facet joints. Most of
environment. This is where mesenchymal stem the time, in our primary treatments PRP will be
cells can be of great importance. By secreting combined with a free fat graft. Experience has
certain growth factors, such as IL-3 and IL-4, taught us that many articular cartilage problems
they are able to influence the polarization of the require bone marrow aspirate combined with
macrophages to move towards the M-2 category. PRP and a fat graft. There are platelets found in a
IL-4-induced macrophages stimulate arginase bone marrow aspirate; however, their numbers
activity by converting arginine to polyamines and are not like those found in the peripheral blood.
collagen precursors that are crucial for tissue We typically perform an additional PRP (pro-
modelling and wound healing. Macrophages cessed from the blood) when using bone marrow
were shown to be responsible for regeneration by aspirate. There are many different commercial
actively metabolizing arginine with arginase into preparations for a bedside PRP. It is probably
ornithine and urea. This is of upmost importance, wise when one is starting out to use one of these
since ornithine is required for many repair pro- kits. As more experience is obtained, then one
cesses. It is a precursor of the polyamines can manufacture their own PRP. Some final
required for cell proliferation and collagen syn- thoughts concerning PRP preparations. It has
thesis for extracellular matrix construction. been described in the literature (2018) that sub-
Collagen synthesis is critical for articular carti- jecting a PRP preparation to four degrees centi-
42 J. Purita

grade for approximately 20 minutes and at the tion in blood (up to 6 mg/ml). It inhibits MMPs
same time reducing the amount of plasma in the and ADAMTS degradation proteases while bind-
total volume to no more than 25% will enhance ing and helping regulate cytokines and grow fac-
the release of the growth factors from the alpha tors. There are a number of commercially
granules [11]. available kits that can concentrate the A2M. This
One final thought on PRP products. A new may help in the overall repair process. It does not
concept concerning PRP products is called seem to be a game changer.
platelet microparticles. Platelet-derived mic-
roparticles (PMP) are the small plasma mem-
brane vesicles (0.05–1 μm) shed from platelets Stem Cells: The Drivers
upon their activation, constituting the major of Regeneration
pool of microparticles circulating in the blood,
and are considered a communication mediator Some Generalities
between cells, triggering responses such as
inflammation and angiogenesis. P-EVs might Getting back to the gardening concept, the stem
be not only a next-­generation alternative to PRP cells represent the seeds in the regenerative
but also a potential vehicle for the administra- medicine garden. We must realize that we are
tion of drugs and other molecules, including lucky if a few percent of the stem cells survive.
mRNA, miRNA, and lncRNA. They are likely We need to be cognizant of the fact that we
to provide a better option than exosomes, which would live about 2 days without stem cells. The
are derived from expensive stem cells or pro- major sources of stem cells in the regenerative
genitor cells, to modulate cell activity in treat- medicine field are those derived from typically
ing many disorders. the bone marrow as an aspirate or those found in
adipose tissue. There are a limited number of
stem cells found in the circulating blood. The
Matrix Metalloproteases (MMP) A2M two main types of stem cells we are dealing with
include mesenchymal stem cells and hemopoi-
Before moving on to stem cells, matrix metallo- etic stem cells. We shall discuss both. Before
proteases (MMP) need to be addressed. At neu- discussing the various aspect of different stem
tral pH, only specialized MMPs can degrade cell types, we should present some of their basic
across the triple helix of the extracellular matrix. science.
Degradation of cell attachment substrates When we are discussing a cell, we will typi-
induces a special form of apoptosis in ECM- cally give it a specific name rather than calling it
dependent mesenchymal cells (anoikis). MMPs a mesenchymal cell etc. The specific name will
can also release suppressive effects and stimu- typically begin with the initials CD. CD stands
late cellular proliferation and differentiation. for cluster of differentiation. The CD designation
MMPs can also exert various anti-inflammatory represents the cell surface molecules, which are
and pro-healing effects. MMPs can destroy old used to identify the stem cells and the stage of a
or excessive matrix to provide room for cells. stem cell. Stem cell identification can be made by
Protease cleavage plays a role in inactivation of having a particular CD marker (CD+) or not hav-
inflammatory cytokines and is imperative for ing it (CD-). Some examples include the follow-
activation of anabolic growth factors. One of the ing: mesenchymal stem cells (MSC) (CD 70+,
best-known clinical compounds in the MP world CD90+, CD105+, CD34-) and hematopoietic
is called A2M. A2M is also known as alpha stem cells (HSC) (CD34+, CD59+, CD90+,
2-­macroglobulin. It is produced in the liver and CD133). Adult stem cells are found in many
in macrophages. It is a broad-spectrum multipur- ­tissues. The primary role of stem cells is to main-
pose protease inhibitor having a high concentra- tain and repair the tissue in which they are found.
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 43

Most adult stem cells are multipotent, not plu- What Are the Major Stem Cells
ripotent. The vast majority of procedures will
involve multipotent cells. However, there is one Embryonic Stem Cells
type of cell called a very small embryonic-like
stem cell that is pluripotent. More will be dis- There are many different types of stem cells, but
cussed about this cell later in the chapter. we basically deal with a handful. The first cell to
There are distinct differences between stem discuss is the embryonic cell. This is a cell that is
cells and progenitor cells. Stem cells are typically draped in controversy. Putting ethical issues
self-renewing, they are long lived, and they have aside, why do we not want to use these cells?
a low regenerative capacity. On the other hand, There are two concerning facts about these cells.
progenitor cells (often referred to as transit-­ First, they are unpredictable. They could poten-
amplifying cells) are non-renewing, they are tially form a tumour in the host patient. This is
short lived, and they have a high proliferative sometimes referred to as a teratoma. Secondly,
capacity. they act as a foreign tissue. When they are recog-
nized by the body, there could be an allergic reac-
tion triggering what is called a graft vs. host
Stem Cell Niche disease. This can be a life-threating problem of
which there is not typically an easy solution.
When discussing stem cells, we need to discuss With our present technology, these cells seem
their environment. This is called the stem cell destined to be used for disease modelling. They
niche [1]. The niche is composed of many mov- have great potential but not with our present tech-
ing parts. The first part of the niche consists of nology. One fact to mention about these cells is
various cellular components: such as tissue spe- that they have what are called Yamanaka factors.
cific cells such as mesenchymal cells and other These are four proteins called SOX2, OCT4,
cells and tissues such as blood vessels. The sec- KLF4, and c-myc. These factors are the four
ond component deals with secreted factors. master genes that allow cells to be rejuvenated
These include chemokines and their receptors, and reprogrammed. These genes wind back the
growth factors, and their receptors, hormones, developmental clock. They are typically found in
etc. The third component deals with inflamma- pluripotent cells. If one sees these factors in a
tion and scarring. This component works closely cell, then that cell typically will have some plu-
with macrophages, T-cells, and the immune sys- ripotent qualities. This seems to be a common
tem. The fourth component deals with the extra- thread in cells, which seem to have great regen-
cellular matrix. This component has fibronectin erative potential.
and collagen in addition to the basement mem-
brane. The fifth component involves physical
forces, such as elasticity, stiffness, and shear I nduced Pluripotent Stem Cells
forces. The sixth and last component deals with (IPS CELLS)
hypoxia and metabolism and its various ramifi-
cations. Realize that all these components are Induced pluripotent stem cells (IPS) are another
interacting with cell surface of the stem cell. The type of stem cell. They are produced when adult
cell surface should be considered the eyes and cells have been genetically reprogrammed to an
ears of the cell. Unfortunately, bad omega-6 fatty embryonic stem cell-like state. This practice
acid tends to accumulate in this area. To combat involes expressing genes and factors important for
the omega-6s, we try to give the patient omega- maintaining the defining properties of embryonic
3s and omega-9 to displace the omega-6s. Diet stem cells. This reprogramming is typically done
and supplements contribute to the niche health. by means of a viral vector or by enzymatic means.
This is one of the reasons why diet and supple- Clinically, these cells are still not ready for wide-
ments are so important. spread use. But iPS cells have made their mark in
44 J. Purita

a different way. They have become an important world. They were first described in 2006 by
tool for modelling and investigating human dis- Ratajczak et al. [12] They were discovered in
eases, as well as for screening drugs. Time will bone marrow aspirate. They have some unique
tell where these cells will lead us to. One potential properties. They have pluripotent markers SSEA-­
problem with these cells is that although they may 1, Oct-4, Nanog, and Rex-1. V cells have an open
act as a pluripotent cell, their DNA is old and may chromatin with a high nucleus/cytoplasm ratio.
reflect upon the functioning of the cell. Telomere They also have large amounts of telomerase tell-
degradation is a problem not just with these cells ing us that their DNA should be fairly well pre-
but most stem cells in general. If we can reverse served. V cells are about one third the size of
some telomere damage, we might make a more regular cells. Typically, the V cells circulate in
efficient stem cell. Nevertheless, IPS cells seem to the blood in an inactive form. They are “awak-
hold great regenerative potential. ened” by a physiological stress. In a clinical set-
ting, these cells are kept at four degrees centigrade
in a hypoxic setting for approximately 12 hours.
Multilineage-Differentiating This temperature and hypoxic stress will activate
Stress-­Enduring Cells (Muse Cells) the cells. There are a number of methods which
are utilized to increase the release of these cells
A Muse cell is found in adipose or bone marrow into the circulation from the bone marrow.
tissue. They are typically isolated in fat using Vitamin A or intravenous CoQ-10 are known
severe cellular stress conditions, including long-­ stimulators of these cells. They are used in both
term exposure to the proteolytic enzyme collage- an intravenous and intra-articular fashion. They
nase, serum deprivation, low temperatures, and also have a specific marker on their cell mem-
hypoxia. Under these conditions, a highly purified brane for parathyroid hormone (PTH). We use
population of Muse-AT cells is isolated without parathyroid hormone not only on V cell proce-
the utilization of cell sorting methods. These cells dures but also on all of our stem cell procedures.
are probably pluripotent, not multipotent like It is pointed out in the literature that PTH is
other adult stem cells. These cells have a very chondro-­regenerative [13]. PTH seems to
high survival rate upon transplantation into other increase stem cell output from the marrow. The
parts of the body. Unlike embryonic cells, they do PTH is delivered via a patch (should be available
not seem to form tumours! They are highly resis- in early 2019) with penetrating molecules and
tance to the following: hypoxia, acidosis, change also in an oral homeopathic form. One very
of temperatures, toxic environment, etc. These important aspect of these cells is that in clinical
cells may take on more importance as time goes studies, they seem to cause lengthening of the
on. They seem well suited to the joint due to their telomeres of the immune system when they are
ability to survive harsh conditions, such as those given intravenously. Typically, we are as healthy
found in the joint. At present, it seems that we will as our immune system. These cells will certainly
have more success in harvesting these cells from become more widely accepted as time goes on.
adipose tissue. Their harvesting is relatively sim- What role they will play in joint regeneration
ple, and typically the harvest will produce ade- remains to be seen, but I suspect they will eventu-
quate numbers. ally play a significant role. Typically, approxi-
mately 200 CCs of blood will produce about 30
CCs of the final product. Most of the time, the V
Very Small Embryonic-Like Stem Cells cell solution is given intravenously. Many times,
(V Cells) five or so CCs will be given as an intra-articular
injection. We are still in the process of evaluating
Very small embryonic-like stem cells (V Cells) the V cells as a viable option of articular
are slowly gaining acceptance in the scientific problems.
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 45

Mesenchymal Stem Cells their antibacterial properties. They produce a

compound called LL-37 or human cathelicidin
Mesenchymal stem cells have a long and storied antimicrobial peptide [15]. This will help prevent
history. For quite some time, they were thought infections in joints when MSCs are utilized. The
to be the omnipotent cells of the stem cell field. LL-37 is responsible for preventing women from
This concept has changed somewhat due to the developing sepsis during their menstrual periods
input of Dr. Arnold Caplan of Case Western due to the high number of MSCs in the menstrual
Reserve. Dr. Caplan coined the term mesenchy- blood. Like macrophages, MSCs can polarize
mal stem cell in 1987; in 2011, he coined the term into two different types. The inflammatory milieu
medicinal signalling cell and declared it was out- determines the path the MSCs take [13].
side of the stem cell category [14]. Dr. Caplan has Following an injury, the inflammatory milieu is
now given us the concept that the mesenchymal typically high. The high level of inflammatory
stem cell is more of an immune modulator rather products results in a type II MSC. The type II
than an actual driver of tissue regeneration. This MSC results in immune modulation, increases
concept is still not universally accepted but is Treg cell production while suppressing T-cell
steadily gaining acceptance. Some general char- responsiveness. They also produce a number of
acteristics of the MSCs are as follows. They have valuable growth factors, such as TGF, FGF, IGF,
plastic adherence. They are positive for the fol- IL-10, and CXCL-12. These are all important in
lowing CD markers 73, 90, and 105. They are regeneration. The type I MSC results in the acti-
negative for hematopoietic CD markers 45, 34, vation of M-1 macrophages and T-cells, which
14 or 11b, 10 or 79α, and HLA-DR. They are among other things contributes to autoimmune
multipotent in nature. They seem to possess both diseases. In regenerative medicine, we are more
immunomodulatory and tropic properties. interested in the type II MSC. As can be seen,
We need to have the realization that this class regenerative medicine is intimately tied in to the
of cells can be isolated from almost every tissue immune system. They can profoundly affect each
in the human body. The central connecting aspect other. It is imperative to understand their
to explain this fact is that all of these tissues are symbiosis.
vascularized and that every blood vessel in the
body has mesenchymal cells in abluminal loca-
tions. These perivascular cells can be summarily MSCs Sources
called pericytes. Eventually, when an injury
occurs, these pericytes become activated MSCs. MSCs are found in many different tissue types.
MSCs are being used therapeutically because From a clinical point of view, there are two main
they undergo homing to the sites of inflammation sources of these cells. They are found in the bone
or tissue injury and they secrete massive levels of marrow aspirate, but typically as the age of the
bioactive agents [12]. The injury response will patient increases, the number of MSCs dimin-
make the MSC become immunomodulatory. This ishes in the bone marrow. When we start out as a
immune modulation has some profound effects newborn, one out of every 10,000 cells in our
on the immune system, such as T-cells, Treg marrow is an MSC; by the time we reach age 80,
cells, and dendritic cells. At the same time, MSCs one out of every two million cells is an
have some trophic effects, including angiogenic, MSC. Herein lies the problem; as we age, do we
mitotic, antiapoptotic, chemoattractive, and have enough MSCs from the bone marrow alone?
regenerative. Perhaps a good way to look at No one knows the answer to this question. I feel
MSCs is to consider them as the body’s Navy that the MSCs from the marrow need to be sup-
Seals. They get injected into a hostile area. plemented. One very good solution to this prob-
Chances are they will not survive. But they will lem is the use of adipose tissue. Adipose tissue is
secure the area so that the rest of the other cells a rich source of MSCs [15]. The supply stays
can do their job. One other aspect of MSCs is relatively constant and does not vary much with
46 J. Purita

age. Adipose tissue is rich in many different cell appear to be short lived and not as effective as
types, MSCs being one of them. A potential prob- those in the bone marrow. Are there any draw-
lem with the MSCs in adipose is to release them. backs to SVF? As was stated earlier in the chap-
Free fat grafts work well as a supply of MSCs ter, one needs to check the regulatory issues in
and Muse cells. However, when we want to the country they are practicing as it pertains to the
increase the number of stem cells per volume, legality of SVF. From a scientific point of view,
then it will be necessary to break down the adi- there are some concerns when using SVF. The
pose tissue to release the MSCs. The method of question is when creating SVF if we are throwing
harvesting the cells is a simple liposuction tech- away some important cells such as Muse cells.
nique similar to that employed by a plastic sur- Furthermore, the structural niche of the adipose
geon. When doing the liposuction, it is performed tissue might be damaged, which dramatically
with tumescent fluid consisting of a mixture of 30 reduces the viability of the cells [16].
CCs of 2% lidocaine and one ampule of epineph- Nevertheless, SVF is a good choice in the treat-
rine in 500 CCs of normal saline. Typically, the ment of joint afflictions in the field of regenera-
harvesting is performed from the abdominal tive medicine. Typically, when SVF is employed,
region around the waist line, where the cell con- it is given as both an intra-articular injection and
centration is greatest. One caveat to keep in mind, intravenously. Some studies indicate that the
not all fat is the same. There are more cells for cells get trapped in the lungs when given intrave-
CC in a lean person when compared to an obese nously. This may very well be the case, but they
person. Also, the cell profile in a lean person is will nevertheless release their growth factors hav-
different from that of an obese person. The lean ing a systemic effect on the body. There now
person will have a cell profile which is more con- seems to be an explanation for the long-term
ducive to regeneration. The lean person will have effects of stem cells yet their short survivability.
more regenerative cells. The profile can be It is felt that monocytes phagocytize MSCs and
changed somewhat when pretreating the patient ultimately produce Treg cells, which have rather
with certain cytokine growth factors. long-lasting effects [17]. Is adipose tissue alone
There are many methods of breaking down the the best treatment for a joint? There is no clear-­
adipose tissue into its component parts. These cut answer, and this I suspect will continue to be
methods involve both enzymatic breakdown of an ongoing controversy. My opinion is to use
the fat. There are machines which utilize mechan- both adipose tissue and marrow aspirate. We like
ical methods of breaking down the adipose tissue a free fat graft in most of our initial procedures.
to its component parts. The automated machines The amount of graft used depends on the joint
are fairly expensive as are the processing kits that size. It can be from 4 to 8 CCs of free fat graft.
come with them. For most people in the field, a Also, the use of a free fat graft seems to potenti-
more cost-effective choice involves a simple kit, ate the effect of the SVF.
which includes either collagenase or lecithin.
This is a step-by-step process that is easily repro-
ducible and produces a fairly reliable SVF prod- Hematopoietic Stem Cells
uct. The automated kits offer a timesaving but a
great cost of money. MSCs are very important in the field of regenera-
The product produced when fat is broken tive medicine. They are the ultimate immune
down is called stromal vascular fraction (SVF) modulators and at the same time cause some
[16]. One of the main components of the SVF is trophic regeneration of tissue. They are the
­
the mesenchymal stem cells. There are a number body’s Navy Seals. However, the cells which
of other cell types in the SVF. Some of these cells truly drive regeneration are the hematopoietic
include adipocytes and attached progenitor cells, stem cells (HSCs). By far, the largest concentra-
Treg cells and macrophages, endothelial cells, tion of HSCs in the body is found in the bone
and fibroblasts. The hemopoietic stem cells marrow. The primary engine of new bone and
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 47

cartilage formation in vivo is through the recruit- aspirate was taken for one geographic area,
ment and differentiation of cells classically resulting in whole blood “contamination”. Many
defined as hematopoietic in origin. physicians would aspirate 60 CCs for one loca-
Numerous scientific articles have pointed out tion. This was an easy technique, but it typically
that the HSCs are the true drivers of regeneration results in low numbers of regenerative cells. It
[18]. The classical marker of human HSC is did result in a large amount of whole blood being
CD34. HSCs are thought to possess a good deal aspirated. In order to get rid of the whole blood,
of plasticity. Plasticity refers to the capacity of it was necessary to perform centrifugation. This
cells (stem or differentiated) to adopt the biologi- is a very simplistic approach. There may now be
cal properties (gene expression profile, pheno- some better alternatives.
type, etc.) of other differentiated types of cells Centrifugation does concentrate the various
(that may belong to the same or different lin- stem cells found in the marrow, giving us higher
eages). If MSCs are considered Navy Seals, then numbers on a CC per CC basis. For years, this
HSCs can be considered the regular army. was considered the gold standard of bone marrow
Although HSCs are found in many different tis- aspiration. Now some changes are in the wind.
sues, they are found in the biggest concentration There are now a number of physicians who are
in the bone marrow. When we are discussing recommending a non-centrifuged bone marrow
bone marrow, the best source is in the region of aspirate. There are some important concepts that
the posterior superior spine near the S.I. joint. It non-centrifuged marrow brings forth. One ques-
is not recommended to obtain marrow aspirate tion to ask is what cells are discarded when mar-
from a long bone due to the diminished numbers row aspirate is centrifuged. An excellent paper by
of stem cells. Bhartiya et al. [21] discussed the fact that among
other cells, the V cells seem to be discarded with
centrifugation. Further evaluation of centrifuga-
 echniques for Obtaining HSCs
T tion shows both good and bad aspects. Some
From Bone Marrow aspects attributed to centrifugation include the
fact that it can change the shape of the cells and
Bone marrow should be harvested from the pos- interfere with their secretory pattern. The stress
terior ilium. Bone marrow aspiration is very tech- of centrifugation can increase growth factor
nique driven. Drs. Muschler and Hernigou have release. Centrifugation can decrease the “respira-
given us some excellent techniques when draw- tory burst” from neutrophils diminishing oxygen
ing bone marrow aspirate [19]. Dr. Hernigou availability to cells diminishing cell viability.
et al. concluded that the optimal syringe size was Decreased “respiratory burst” may point macro-
10 mL combined with a rapid pull of the plunger phages more towards an M-1 inflammatory mac-
optimizing the negative pressure [20]. This may rophage. Thus, we see both the good and bad of
cause more pain, but cell numbers will be much centrifugation. A hybrid product may provide the
higher! Dr. Muschler has shown that the best best of both worlds. You make sure that you have
aspirations result when there is not a large aspi- the pluripotent cells and non-disturbed cells from
rate from one area. It is the recommendation of the initial non-centrifuged marrow aspirate.
the author that bone marrow aspirations be per- Centrifuge another portion of marrow aspirate to
formed with multiple 10 CC syringes. In each increase the cell numbers of multipotent cells and
syringe, harvest approximately 3–4 CCs of mar- growth factor release. This is the perfect marriage
row aspirate (each syringe should have approxi- of multipotent and pluripotent cells. It straddles
mately 1 CC of heparin). At the same time, each both schools of thought. We call this the Hybrid
aspiration must be performed from a different Purebred™ technique.
geographic area. Initially, a few years ago, all We must remember that bone marrow aspirate
bone marrow aspirates underwent centrifugation. is much more than just HSCs. There are a whole
The reason for this was that the bone marrow plethora of different cell types, including MSCs,
48 J. Purita

RBCs, WBCs, platelets, V cells, and many other SVF produced, some would be injected into the
different cell types. One fact to keep in mind is joint, while the rest would be given intravenously.
that typically bone marrow aspirate is much We must remember that bone marrow supplies
richer in cytokine growth factors than a PRP. For large numbers of HSCs while fat, especially SVF,
example, there is approximately 23 times more supplies large numbers of MSCs. This is the
interleukin 1 antagonist in bone marrow aspirate combination we strive for. Once the initial injec-
versus PRP [22]. This is one of the reasons bone tions are performed, we will usually have the
marrow always tromps PRP as a better alterna- patient get three additional PRP injections spaced
tive. However, sometimes bone marrow aspirate about 1 month apart. We also utilize growth fac-
may be an overkill for a minor problem. tor patches on every patient. Many of the patients
I typically use a Jamshidi needle for bone are also utilizing oral cytokine formulas.
marrow harvesting. We will harvest from several
different depths and different locals. Only local
anaesthesia (10 CCs lidocaine) is used on the Avascular Necrosis
periosteum. Also, avoid a drill which will burn and Ligamentous Problems
the bone. A hammer works much better and gives
the operator more control. Another pearl to pass We will mention these problems in passing. In
along. Depending upon the joint, we will utilize avascular necrosis (AVN), there is a problem
approximately 12 CCs of uncentrifuged marrow with the circulation in a portion of the bone of the
and 30 CCs of marrow aspirate to produce 5CCs joint. The causes are varied in nature. We have
of concentrated marrow aspirate. If you have a had good success in treating these problems simi-
patient who is a difficult blood draw, then you larly to an osteoarthritis of the joint. There is
can obtain the blood from the bone marrow stick some new research that suggests injecting the
after harvesting the marrow aspirate. Just aspirate affected bone directly with the cell combination.
from one area. Time will tell if this is a better treatment method
of this problem. Most extra-articular ligamentous
problems can usually be handled with a PRP
 hat Cell Combinations Seem
W injection, possibly enhanced with a free fat graft.
to Work Best for the Joint? When one is dealing with an injury to a ligament
that is intra-articular such as an ACL injury, then
When we are dealing with a degenerative arthritis there appears to be better results utilizing the
of a joint, a protocol that has worked well for us same method as an osteoarthritis. In another
involves bone marrow, PRP, and a free fat graft. words, a combination of bone marrow, PRP, and
At the initial procedure, we are utilizing all of fat would be utilized while at the same time uti-
these components. The amount of material lizing some type of imaging.
injected depends upon the joint. For a knee, there
is typically no problem with the amount of mate-
rial injected. This may include 8 CCs of a PRP  hy Does There Seem
W
product, 6–8 CCs of a free fat graft, and 10–17 to Be Differences in Success
CCs of a combination bone marrow product (both Between Different Joints?
centrifuged and non-centrifuged). For a hip or
ankle, the amounts will be less typically about Many experienced regenerative medicine physi-
one half the amount put into the knee. For shoul- cians will mention the fact that there is a differ-
ders, the amounts injected would be similar to the ence in success between different joints in the
knee. If one wants the best possible combination body. For instance, knees and ankles seem to be
of cells, then I would add SVF. I have done these more successful than hips when discussing treat-
combinations many times at my clinics outside ment outcomes. What is the reason for this?
the United States. Depending upon the amount of There was recently an article published [23],
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 49

which gives a good explanation on the reason for and differentiation. Finally, ESWT therapy
the discrepancy. Apparently, we can generate includes release of NO (nitric oxide) and various
new proteins in joint cartilage, and this ability is other growth factors. Extracorporeal shock waves
more pronounced in joints farther from the centre significantly promoted the proliferation and self-­
of the body, such as the ankles, than in those renewal of MSCs in vitro and accelerated the car-
nearer, such as the hips. The researchers found tilage repair process in vivo, indicating favourable
that the prevalence of younger proteins was tied clinical outcomes. The scientific studies indi-
to the abundance of a microRNA that blocks the cated that there was an increase in mitochondria
action of a messenger RNA that inhibits the pro- size and activity in the stem cells. There are vari-
duction of new collagen proteins. This may be an ous EWST machines on the market. We consider
explanation as to why typically there is more suc- them a valuable adjunct in our treatment
cess in ankle and knee treatments than in hips. protocols.

 hat Else Is Used to the Stem Cell

W Hyperbaric Oxygen Therapy
Procedures for Better Efficiency?
A number of studies suggest that hyperbaric oxy-
There is quite a bit of interest in products that are gen will mobilize stem cells in the body, making
derived from cord blood, amniotic, and placenta them available for repair. A study by S. Thom
tissue. These products have many desirable com- et al. (Univ of Penn) showed that hyperbaric oxy-
ponents, including, in some cases, actual stem gen will cause rapid mobilization of stem/pro-
cells. However, for instance, in the United States, genitor cells in humans [25]. The mobilization is
these products contain growth factors but typi- thought to be caused by a nitric oxide (NO)-
cally not stem cells that are metabolically active. dependent mechanism [25]. Stem cell activation
Having metabolically active stem cells is not occurs via release of stem cell active cytokine
allowed under current FDA guidelines. C-kit ligand (SCF). Over a course of 20 treat-
Nevertheless, these products have their place as ments, the marrow stem cell output increased
an adjunct when using autogenous stem cells eightfold. It is this increase in stem cells that
especially in an older patient. One needs to keep seems to be responsible for the clinical results
aware of the shifting rules of various regulatory obtained from hyperbaric oxygen. The practical
bodies concerning these products. drawbacks with hyperbaric oxygen are that it is
expensive and time-consuming. What we have
used as a substitute is a nitric oxide generator.
Extracorporeal Shock Wave Therapy As we age, we find that the amounts of NO in
(ESWT) our bodies diminishes. Most of the time, instead
of hyperbaric oxygen, we will utilize a NO gen-
ESWT is a high-power sound wave that causes erator to hopefully increase the levels. We have
mechanical stimulation of cells, resulting in found that an excellent source of NO is a product
increased expression of cytokines and growth called Neo-40. Neo-40 is a product that was
factors [24]. ESWT applied to an area of chronic developed by the Univ. of Texas. It is taken orally
inflammation may enable acute inflammatory and produced from a beet derivative. We will
mediators to be released, facilitating an appropri- typically have the patients take two to three tab-
ate progression of healing. It will allow stem cells lets a day. There is one very important fact to
to hom to the area. There are other physiological remember. NO actions depend upon the neigh-
changes, including changes to the cell membrane bourhood it is found in. In some circumstances, it
and its permeability, release of neurotransmitters, can act as an inflammatory agent and not contrib-
and antibacterial effects. ESWT also includes ute towards regeneration. These actions are
induction of vessel growth, stem cell migration, dependent on which enzyme produces NO. This
50 J. Purita

enzyme is called nitric oxide synthase. There are irritation, are considered. When adipose and bone
three forms of synthase called inducible, neuro- marrow-derived stem cells are extracted from an
nal, and endothelial. Inducible is actually inflam- individual, the cells are in a semi-dormant state,
matory, and the NO it produces works to destroy due to lack of physiological activation. In the
bacteria and others; unfortunately, it will also body, stem cells and progenitor cells are activated
destroy cells as a collateral damage. The endo- by a detailed and complex physiological cascade
thelial is the one which affects the bone marrow repair system. This involves the release of growth
and will have a direct effect on the release of stem factors and chemokines from platelets. Moreover,
cells from the bone marrow. Also, it helps to when the adipose-derived or bone marrow stem
increase circulation. As one reads the literature, cells are photoactivated for 20 minutes with the
one will discover that NO is a very important sig- AdiLight device, they show increased release of
nalling molecule. It can have very profound signalling factors, such as integrins, vascular
effects on the body. endothelial growth factor, thymosin beta 4, and
interleukin 1 receptor antagonist.
When we are discussing photo modulation,
 hotoactivation of PRP and Stem
P we would be amiss if we did not discuss low-­
Cells level light therapy (LLLT), more commonly
known as laser therapy. Molecular and cellular
Photoactivation is thought to act at least in part mechanisms of LLLT are becoming better under-
by modulating the pro- and anti-inflammatory stood. Mitochondria are principal photorecep-
properties of leucocytes. However, it appears to tors, while ATP, cAMP, NO, and ROS are primary
have effects on all cells [23]. Photo biomodula- mediators. Certain transcription factors, such as
tion (PBM), also known as low level light ther- NF-kB, AP-1, etc., are activated. Transcription
apy, is the use of red, near-infrared, and other factors are proteins involved in the process of
colours of light to stimulate healing, relieve pain, converting or transcribing DNA into RNA; they
and reduce inflammation [26]. The primary chro- help turn genes on and off at the right time. Laser
mophores have been identified as cytochrome c therapy is pro-survival, antiapoptotic, anti-­
oxidase in mitochondria and calcium ion chan- inflammatory, pro-angiogenic, and pro-­
nels (possibly mediated by light absorption by proliferation. Whatever cells are designed to do
opsins). Secondary effects of photon absorption will be improved by LLLT. Cells with lots of
include increases in ATP, a brief burst of reactive mitochondria respond well to LLLT [27]. Also,
oxygen species, an increase in nitric oxide, and pain relief is significant and inflammation is
modulation of calcium levels. Tertiary effects reduced.
include activation of a wide range of transcrip-
tion factors leading to improved cell survival,
increased proliferation and migration, and new Prolotherapy
protein synthesis [24]. In my experience, I have
utilized the AdiLight for many years with excel- The author of this chapter does not have first-­
lent success. The AdiLight works on a few differ- hand knowledge of the use of prolotherapy in
ent levels. When white blood cells (WBC) from treating joint problems. Prolotherapy is a proce-
the peripheral blood are photoactivated under dure where a natural irritant is injected into the
AdiLight for 10 minutes, pro-inflammatory cyto- soft tissue of an injured joint. The irritant kick-­
kines (IL1, IL2, IL6, and TNF alpha) are inhib- starts the body’s healing response. The irritant
ited and anti-inflammatory cytokines (IL1Ra and used can include high-concentration dextrose.
IL10) are induced as well as the observation of Some of the newer thinking now is that a PRP is
beta endorphin release. This is a highly desired a prolotherapy treatment. Prolotherapy works by
response when pathophysiological conditions, causing a temporary, low-grade inflammation at
resulting from chronic inflammation states and the injection site, activating fibroblasts to the
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 51

area, which, in turn, synthesize precursors to pro- there is much interest in various products from
duce mature collagen and thus reinforce connec- placenta, cord blood, and amniotic tissue.
tive tissue. This is essentially the mechanism of Typically, these products are registered with the
action of PRP, etc. Many prolotherapists recom- US FDA as a 361-tissue product. A 361-tissue
mend injection’s both intra-articular and product contains tissue but does not contain live
extra-articular. cells that have a metabolic purpose. The tissue is
rich in a variety of growth factors, etc. However,
if these products contain live cells with a meta-
Ozone Therapy bolic profile, then they become a 351 with the
FDA, which requires an Investigational New
Ozone therapy pulls from a few different fields. It Drug (IND) application, clinical testing, and sev-
is postulated that ozone has analgesic, anti-­ eral years of analysis. The bottom line is that
inflammatory, immunomodulatory, and trophic these products essentially only contain growth
properties Typically, ozone (O3) is injected into factors and not live active cells. They can be used
the joint. The cost of a medical grade ozone gen- as an adjunct to PRP and other procedures. If
erator is 500 dollars and up. A series of injections indeed there are live cells in these products, then
are given usually about once a week for about 6 this is probably a violation of FDA regulations.
or 7 weeks. The injection will consist of 10–20 However, this is beyond the scope of this chapter.
CCs of ozone injected into the joint. Some physi- One other word of caution, many of these prod-
cians recommend the additional injections of ucts are said to be immune privileged. This is
some homeopathic compounds called Traumeel probably not an accurate statement. A better term
and Zeel. The concentration of ozone is variable to describe these cells is to say that they are
according to various studies. We have used a con- “immune evasive”. This means that the immune
centration of 10–40 μg/ml. Some recommenda- system of the body will ultimately attack these
tions are to start with a lower dose and then give cells. There is always a possibility that these cells
higher doses. Ozone has a number of effects on can cause an immune response, especially if
the joint, including PGE2 inhibition, NO synthe- given intravenously.
sis, inhibition of pro-inflammatory cytokines (IL-­
1, TNF, IFN), stimulation of anti-inflammatory
cytokines (IL-4, IL-10, IL-13), and growth fac- Cytokine Therapy
tors, such as TGF beta and IGF-1. There seems to
be some promise to ozone therapy, and further Cytokines are proteins that are secreted by a wide
clinical trials are underway. It seems to be a good variety of cells. They have a specific effect on the
adjunct in regenerative therapies. One other interactions of the cells. Cytokines are various
important aspect of ozone therapy is the ability it growth factors that act as signalling molecules
has on affecting the NAD/NADH ratio, which is telling cells what to do. Cytokines can be com-
so important in the production of cellular energy pared to the body’s cell phone system. This is how
in the form of ATP. cells communicate with each other. These forms
of communication are called the “crines” of com-
munication. One type of communication is auto-
Allogenic Cell Products crine, in which the cell acts upon itself. Another
type is juxtacrine, in which the cell requires close
Most of the cell products, we are utilizing come contact with a neighbouring cell. The third type of
from the patient himself. However, there are a communication is paracrine, in which one cell tar-
number of products that are allogenic in that they gets a neighbouring cell. Lastly, the final form of
come from another person. One must be aware of cellular communication is endocrine. This is
the regulations of the country in which they are where one cell will communicate with a distant
practicing. For instance, in the United States, cell. There are many different subclasses of cyto-
52 J. Purita

kines. Most all problems in medicine are a result SIGMOLECS. SIGMOLECS molecules induce
of an imbalance of cytokines. Many conditions signals to key amino acid sensors that govern
have either too much or too little of certain cyto- gene expression of amino acid metabolism that
kines. We must realize that the different cells we then trigger specific physiological and meta-
inject into a patient typically do not survive very bolic activity. These SIGMOLECS molecules
long in a hostile area such as the joint. Their are structured according to these key amino acid
important mission is to release various growth sensors to trigger specific regenerative tasks.
factors, which cause a variety of reactions such as
stem cell homing to the area and telling various
cells what to do. The stem cells found in the body  tem Cell Ageing Pathways May
S
are what ultimately achieve repair. Be the Key to Regenerative Success
When we are discussing cytokines, it boils
down to about six major cytokines. There are There is an old adage, namely, how stem cells age
three master inflammatory cytokines and three is how we age. There are a number of different
master anti-inflammatory cytokines. The master pathways; however, we will address the major
inflammatory cytokines are IL-1, TNF, and IL-6. pathways. Perhaps one of the most important
These cytokines typically cause most of the pathways concerns what are called the sirtuins.
symptoms associated with the symptoms of There are seven major sirtuin proteins. Sirtuins
degenerative arthritis of the joint. The master are a family of proteins that regulate cellular
anti-inflammatory cytokines are IL-1 antagonist, health. Sirtuins play a key role in regulating cel-
IL-10, and IGF-1. The anti-inflammatory cyto- lular homeostasis. Homeostasis involves keeping
kines are found in PRP and bone marrow aspirate the cell in balance. The sirtuins have critical
in varying concentrations. We have found that as importance in the health of the mitochondria and
we age, the concentrations of different anti-­ subsequent production of ATP. Stem cells pro-
inflammatory cytokines diminish. We have used duce energy by glycolysis, which has low energy
supplemental cytokines for a number of years demands; however, when stem cells begin differ-
with good clinical success. We have used these entiating, then more ATP is needed and energy
cytokines in various methods. Currently, we uti- production switches to oxidative phosphoryla-
lize a formula consisting of a blend of various tion. NAD and its substrates are of critical impor-
cytokines that are mixed with penetrating mole- tance of proper functioning of the sirtuins.
cules. They are placed on a Tegaderm patch, and Another very important pathway is called the
the growth factors penetrate down into the joint. AMPK pathway. AMPK stands for adenosine
They should be commercially ready for sale monophosphate-activated protein kinase. One of
towards the last quarter of 2018. We have also the central regulators of cellular and organismal
found that an oral cytokine mixture that is metabolism in eukaryotes is AMP-activated pro-
absorbed sublingually also seems to benefit the tein kinase (AMPK), which is activated when
patients. There are two sources of these oral cyto- intracellular ATP production decreases. AMPK
kines. They are Guna from Italy and Viatrexx has critical roles in regulating growth and repro-
from Canada. There are a number of combina- gramming metabolism. AMPK acts as a master
tions which seem to work well. A word of caution switch to regulate cell functions, such as uptake
is to probably avoid the oral growth factors on of glucose, burning of fats, and formation of new
patients who have a history of a cancer other than mitochondria. If the AMPK pathway is under
the common skin cancers. control, then there is a better chance of regenera-
Perhaps, the newest and most exciting aspect tive medicine success. Some compounds that will
of cytokine therapy is from a company in stimulate this pathway include metformin and a
Switzerland called Contrad. They have designed supplement called berberine.
a GMP FDA registered growth factors transder- The FOXO family of forkhead transcription
mal patches. The technology is called factors plays an important role in longevity and
3 The Nuts and Bolts of Regenerative Medicine as It Pertains to the Joint 53

tumour suppression, by upregulating target genes late growth factors, proteases, and inflammatory
involved in stress resistance, metabolism, cell factors that disrupt normal tissue function.
cycle arrest, and apoptosis. Senescent cells have long been implicated in age-
FOXO proteins activate genes that maintain ing and decreased success in stem cell proce-
healthy joints and bone structure. People with dures. There now exist agents to eliminate these
osteoarthritis have significantly lower FOXO cells. These agents are called senolytic agents.
proteins. FOXO transcription factors modulate There is now much research into senolytic agents,
autophagy, which promotes cellular turnover, and which will destroy senescent cells in the hope of
maintenance FOXO factors are important for reversing osteoarthritis. Typically, people accu-
stem cell production and DNA repair. FOXO1 mulate significant senescent cell burdens around
and FOXO3 promote mitophagy, which is mito- age 60. It seems that the use of senolytic agents
chondrial autophagy. FOXO proteins suppress may become the standard treatment as time goes
tumorigenesis in cancer. FOXO factors increase on. There are a number of supplements such as
the antioxidant capacity of cells, and reactive quercetin, fisetin, and black tea. We have had
oxygen species and oxidative stress activate fairly good use with the senolytic agents in our
FOXO pathway to adapt to the stress. Inactivity office.
of FOXO factors accelerates atherosclerosis and
compromises stem cell proliferation. FOXO pro-
teins inhibit adipogenesis or the differentiation of Supplements to Increase Success
adipocytes. Thus, they promote fat burning and
prevent fat gain. FOXO3 activity protects against Supplements have a place in the field of regenera-
Parkinson’s disease and promotes neuronal sur- tive medicine. We have utilized a number of sup-
vival. FOXO transcription factors play an impor- plements. To go to the specifics of each
tant role in determining ageing and longevity. supplement is beyond the scope of this chapter. I
The Nrf2 pathway has been referred to as the will touch upon a few of the important ones. I am
“master regulator of antioxidant, detoxification very high on a product called Neo-40. This is a
and cell defense gene expression”. The Nrf2 supplement that is taken orally. It seems to
pathway modulates numerous genes responsible increase the amount of nitric oxide (NO) in the
for inflammatory response, rebuilding tissue, body. Hopefully, this in turn will have a similar
immune system response, inhibiting cancer pro- effect as hyperbaric oxygen. We know that hyper-
duction, and preventing its spread, cognitive pro- baric oxygen works on a principle of increasing
cesses. It regulates production of crucial NO, which will increase stem cell output. Another
antioxidants, such as glutathione and superoxide product high on the list is UltraCur. This is a
dismutase, or SOD. product which utilizes a very potent form of
One must remember that there are other ­curcumin. It is potent in that it has much higher
important pathways that can have a direct effect bioavailability than the typical curcumin product.
on stem cells and their environment. This will hopefully reduce inflammation in the
extracellular matrix. It seems to help block inter-
leukin 1 actions. The third product is called
Senescent Cells StemXCell. This product seems to increase stem
cell output from the bone marrow. Tests in the lab
One topic that is often overlooked is that of show it to be similar to GCSF. The last product
senescent cells. Although senescent cells can no we use is called CH-Alpha. This appears to be a
longer replicate, they remain metabolically active product that has a number of clinical studies,
and commonly adopt an immunogenic pheno- which show that it appears to be a good source of
type, consisting of a pro-inflammatory secretome collagen to help accomplish repair. Of course, a
(cytokines). These cells are capable of doing good multivitamin and hormonal balance also is
damage on a molecular level. They will accumu- needed for higher success.
54 J. Purita

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use on the basis of cellular, chemical, structural and
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2. Akkiraju H, Nohe A. Role of chondrocytes in carti-
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5. Litwiniuk M, Krejner A. Hyaluronic acid in
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2017;3:e1518.
 Part II
Diagnostic and Interventional
MSK Ultrasound
 Image Optimization
4
Franklin San Pedro Domingo

Desiderius Erasmus once said that, “in the king- The Piezoelectric Effect
dom of the blind, the one-eyed man is king”.
And, in the world of ultrasound, the transducer is Most ultrasound probes are fitted with piezoelec-
the one eye that has to be optimized. tric crystals. And when electrical energy is
applied to these crystals, it induces the crystals to
vibrate, producing sound waves that are transmit-
 ow an Ultrasound Image Is
H ted to the tissues under the ultrasound probe.
Generated Some of these sound waves are reflected back
into the probe. The piezoelectric crystals can be
Physics defines sound as a form of mechanical said to be listening to these returning sound
energy transmitted by pressure waves in a mate- waves. These echoes that are going back to the
rial medium. Humans are capable of hearing probe then cause the crystals to vibrate. These
sound in the frequency of 20–20,000 Hz. vibrations are then converted back into electrical
Ultrasound is anything above the range of the energy [4]. These electrical signals are then pro-
capability of human beings to hear sound. This is cessed by the ultrasound machine and are dis-
above the range of 20,000 Hz [1]. Diagnostic played as dots or pixels on the screen. The
ultrasound is usually in the range of 3–17 MHz, stronger the returning echo received, the brighter
which is well above the upper limit of hearing the dot on the screen. Many ultrasound machines
[2]. Novel systems using ultrahigh-frequency make use of 256 shades of grey to allow for good
ultrasound use frequencies up to 70 MHz. This resolution on the generated image [5]. The pro-
may allow better assessment of ultrastructural cess of sending, receiving and processing sound
changes of very superficial peripheral nerves and waves happens numerous times in just 1 second.
other thin structures, such as pulleys, retinacula, There are newer systems that replace the piezo-
and tendons [3]. electric crystal with a silicon chip. In develop-
ment are submicrometre silicon-on-insulator
resonator for ultrasound detection with the poten-
tial for imaging at a resolution comparable to that
achieved with optical microscopy [6].
F. S. P. Domingo (*)
Department of Physical Medicine & Rehabilitation,
Center for Regenerative Medicine, Pain Management
Service, Makati Medical Center,
Makati City, Philippines

© Springer Nature Switzerland AG 2022 59

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_4
60 F. S. P. Domingo

Transducers on the screen. This gives it the advantage of hav-

ing a wider field of view.
There are different kinds of transducers. And,
they are described in the way that the transducer
crystals are arranged in the head of the probe.  he Effect of Frequency, Gain
T
The two most common types of transducers are and Focus on the Character
the linear and the curvilinear (Fig. 4.1). The lin- of the Ultrasound Image
ear array is arranged in a straight line of crystals,
giving it the ability to focus on the area directly Frequency
below it. The image generated by this probe is
rectangular or trapezoidal [7]. The thickness or The ultrasound machine has the capability to
slice of the ultrasound beam generated is very alter its transmitted frequency. The higher the fre-
thin. This means that the needle has to be within quency, the better the resolution. This comes at
this thin area when doing an ultrasound-guided the expense of having less penetration. This is
procedure with the orientation of the needle because higher frequencies are more attenuated
being parallel to the probe. A curvilinear array is or absorbed as they go thru tissue. These fre-
arranged in an arc. This generates a fanlike image quency settings can be used for targeted struc-
tures that are shallow. Lower frequency settings
give the advantage of better penetration. This
allows for the appreciation of deeper structures.
However, this comes at the price of a poorer reso-
lution [8]. Lower frequencies are best used for
targeted structures that are deeper such as the hip.

Depth

Adjusting depth allows for the optimization of

the size of the target tissue relative to the image
seen on the monitor of the ultrasound machine
[2] (Fig. 4.2). A good guide would be to keep the

Fig. 4.1 A linear array on the left, generating a rectangu- Fig. 4.2 Depth setting on arrow. And, gain setting on
lar scan field. And, a curvilinear array on the right, gener- arrowhead. (Photo credits to Maria Olivia Domingo)
ating an arc shaped scan field. (Illustration credits to Anna
Melissa Domingo)
4 Image Optimization 61

area of interest in the middle third of the screen

by adjusting the depth accordingly. A too shallow
depth setting may prevent the visualization of
deeper relevant structures. And a too deep setting
may take up the majority of the size of the screen.
This leads to a smaller area on the screen to visu-
alize the target structure.
When blood vessels or lung tissue are very
close to the target area, proper depth adjustment
is necessary. Satisfactory visualization of the said
structures during the preliminary scan is needed
to improve patient safety. There is usually a
numerical guide on one side of the screen that Near field
can be used to approximate the depth of the tar-
get. This is also needed in planning the angle of
approach and the length of the needle to be used
during a procedure.
Focal zone

Gain

The gain setting enables the ultrasound machine Far field

to listen harder for the returning echo sent by the
piezoelectric crystal. And the higher the gain, the
Fig. 4.3 Focus of an ultrasound beam. (Illustration cred-
more it can listen to the returning echoes. This its to Anna Melissa Domingo)
would then lead to a brighter image on the
screen. Gain setting can be calibrated for the far
field, near field or the whole field. There can be
problems with too much or too little gain. Too
much gain can give a very bright washed-out
appearance. And too little gain may give a very
dark image. Too much or too little gain would
prevent the appreciation of important surround-
ing structures. The proper adjustment for gain
will not be evident until the probe is applied on
the skin [2]. Fig. 4.4 An ultrasound scan of the distal biceps tendon.
The open arrow is showing the focus indicator on the
monitor. Note that the area of interest is at the middle third
Focal Zone of the screen

Proper adjustment of the beam focus is necessary

for image clarity. The right focal zone setting which the ultrasound beam is at its narrowest and
allows for the improvement of the lateral resolu- most dense. Some machines do this automati-
tion at the area of interest (Fig. 4.3). Lateral reso- cally by assuming that the area of interest is at the
lution refers to the ability of the transducer to middle third of the screen. Other ultrasound
discriminate between two objects positioned side machines allow for the adjustment of the focal
by side. This is achieved by adjusting the depth at zone independent of the depth [2] (Fig. 4.4).
62 F. S. P. Domingo

 oppler and Its Utility

D  echniques to Improve Needle
T
in Identifying Vascular Structures Visualization

The use of the Doppler function is important in Probe Manipulation

identifying vascular flow. Proper identification of
these structures will help to avoid inadvertently The ultrasound probe allows for the visualization
puncturing them during a procedure. Doppler can of the target structure in two dimensions. And,
also be useful in helping to distinguish between proper manipulation of the transducer can facili-
nerves and vessels. Arteries can be distinguished tate the formation of a mental picture of the
by their more pulsatile flow and non-­compressible scanned area in three dimensions.
nature [9]. Correct transducer handling allows for the
proper acquisition of the target structure on the
screen. The American Institute of Ultrasound in
Orientation Marker Medicine has defined these five transducer planes
of manipulation [10]:
Every transducer has a marker or notch on one
side (Fig. 4.5). This enables the user to orient the • Sliding glides the probe along the short or long
probe properly in relation to what is being axis of the structure (Figs. 4.6 and 4.7). This is
scanned under the probe. This is important in done without rocking or tilting the probe.
doing ultrasound-guided procedures in order to • Rocking the probe refers to doing a heel-toe
be able to determine on what side of the monitor manoeuvre (Fig. 4.8). This can be used to
the incoming needle will be displayed. On most
machines, the orientation marker usually corre-
sponds to the left side of the screen.
Some ultrasound probes have markers on their
broader side that correspond to the middle or cen-
treline of the screen. These machines may also
have an option that allows the display to have a
guideline running down the centre of the screen.
This guides the interventionist when doing an
out-of-plane injection.

Fig. 4.5 Probe orientation marker on the arrowhead.

Centreline indicator on the broader side of the transducer Fig. 4.6 Long-axis linear slide. (Photo credits to Maria
on the arrow. (Photo credits to Jose Franco Domingo, Olivia Domingo, Jose Franco Domingo and Sofia Victoria
Sofia Victoria Domingo) Domingo)
4 Image Optimization 63

Fig. 4.8 Heel-toe manoeuvre. (Photo credits to Maria

Olivia Domingo, Jose Franco Domingo and Sofia Victoria
Domingo)
Fig. 4.7 Short-axis linear slide. (Photo credits to Maria
Olivia Domingo, Jose Franco Domingo and Sofia Victoria
Domingo)

decrease anisotropy when scanning in the long

axis. This can also be used to improve the field
of view. This manoeuvre can be done to facili-
tate better visualization of the needle during
the injection of deeper structures. This can be
done by doing a heel-toe manoeuvre to angle
the transducer to be more parallel in relation
to the needle in long axis. If one side of the
probe loses contact with the skin during this
manoeuvre, more gel can be added to the area.
This is sometimes called a gel standoff
technique.
• Tilting, wagging or toggling the probe can be
done by doing a side-to-side motion (Fig. 4.9).
This is done without moving the base or slid-
ing. This changes the angle of incidence of the
sound waves on the tissue.
• Rotating the transducer turns the probe in a
clockwise or counterclockwise manner
(Fig. 4.10). During an intervention, this
Fig. 4.9 Tilting the transducer. (Photo credits to Maria
manoeuvre helps in the visualization of the Olivia Domingo, Jose Franco Domingo and Sofia Victoria
needle tip on its way to the target area. Domingo)
64 F. S. P. Domingo

may cause veins to collapse and cause subcu-

taneous tissue to appear thinner. This manoeu-
vre may be used for the visualization of deeper
structures.

Ergonomics

Proper positioning of the patient and interven-

tionist can be critical to the success of the proce-
dure. Not only does this improves patient comfort
and safety, but it also reduces the incidence of
developing a repetitive stress injury [1].

Clinical Pearls
• Do an initial scan to survey the area and
to confirm the diagnosis while looking
out for structures to avoid.
• Visualize the target structure in three
dimensions based on the two-­
dimensional ultrasound images.
• Plan for a shallow angle of approach to
maximize needle visibility if feasible.
• Consider using the curvilinear probe for
Fig. 4.10 Rotating the transducer. (Photo credits to deeper structures.
Maria Olivia Domingo, Jose Franco Domingo and Sofia • Practice good ergonomics to improve
Victoria Domingo)
hand-eye coordination and needle to
beam alignment.
• Apply a relaxed and even grip on the
transducer while holding it at the base
using the first three digits of the hand
(Fig. 4.12).
• Stabilize the transducer by anchoring
the fourth and fifth digit along with the
heel of the palm on the patient.
• Do not add more than necessary com-
pression on the patient’s body with the
transducer.

Fig. 4.11 Compression manoeuvre. (Photo credits to

Maria Olivia Domingo, Jose Franco Domingo and Sofia For beginners, it is best to start with an easy
Victoria Domingo) procedure they are comfortable with. The patient
should be lying between the interventionist and
• Compression involves pressing down on the the monitor. Position the patient in order for the
transducer (Fig. 4.11). Too much compression physician to be able to align his eye with the nee-
4 Image Optimization 65

Fig. 4.13 Proper positioning of the patient allowing for a

single line of sight from the interventionist, to the needle,
the probe and the monitor. Note that the physician is com-
fortably seated with the right forearm resting on the bed
for support. The linear probe can be seen to have the ori-
Fig. 4.12 How to hold the probe properly. (Photo credits entation marker that is used as a visual reference to
to Maria Olivia Domingo, Jose Franco Domingo and improve the alignment of the slice of the ultrasound beam
Sofia Victoria Domingo) relative to the needle. (Photo credits to Michael Francis
Obispo)
dle, the transducer and the monitor all in one line
of sight (Fig. 4.13). It is preferable for the patient
to be in a supine or prone position to prevent a the imaging of the targeted structure. The fusion
vasovagal reaction. of image optimization, proper needle visualiza-
In summary, preparation is crucial to perform- tion, correct ergonomics and adequate preproce-
ing ultrasound-guided interventional procedures. dural planning is needed to be able to guide the
It starts with a good knowledge of anatomy com- needle to the right place at the right time
bined with a firm grasp on how to best optimize (Figs. 4.14 and 4.15)
66 F. S. P. Domingo

Fig. 4.15 Out-of-plane approach for an acromioclavicu-

lar joint injection. Note the centreline dots at the middle of
Fig. 4.14 In-plane approach for a hip procedure. The the screen. This corresponds to the trajectory of the needle
open arrows are pointing to the needle. The use of a curvi- using the walk down technique. To do this technique, the
linear transducer allows for better needle visualization. A needle is initially inserted superficially. Then, when the
needle with a larger bore size is also easier to visualize. needle tip becomes visible, the needle is withdrawn and
(Photo credits to Maria Olivia Domingo) inserted at a deeper trajectory. This is done repeatedly at a
steeper angle until the target is acquired. Note that in the
picture, the non-dominant left hand is used to hold the
needle. Practicing with the non-dominant hand can be
helpful for more advanced procedures that require more
Clinical Pearls dexterity. In addition, the depth of the target structure can
be measured using the guide on the left side of the monitor
• When injecting, hand movements
to plan the pathway of the needle to the target. (Photo
should be very minimal, smooth and credits to Maria Olivia Domingo)
gradual.
• Use mainly the short axis linear slide
manoeuvre to guide the needle. And,
only use the tilt manoeuvre when
necessary. • Keep the bevel of the needle facing up to
• Move only the probe or the needle. Do allow for better visibility.
not move both at the same time. • To improve needle tip visibility, use a
• Ensure that what is being visualized pri- very minimal in and out or jiggling
marily is the needle tip and not what manoeuvre. A minimal side-to-side lat-
looks like a partially visible short-­ eral movement can also be used.
appearing shaft. • A small amount of saline solution can
• Do not move the needle if it is not also be injected to confirm needle tip
visible. position.
4 Image Optimization 67

Acknowledgements Photo credits to Maria Olivia 4. Schwantes J, Byerly DW. Biceps Tendon Sheath
Domingo, Jose Franco Domingo, Sofia Victoria Domingo Injection. 2021 Aug 15. In: StatPearls [internet].
and Michael Francis Obispo. Treasure Island: StatPearls Publishing; 2021.
Illustration credits to Anna Melissa Domingo. 5. Bruno MA. 256 Shades of gray: uncertainty and diag-
nostic error in radiology. Diagnosi. 2017;4(3):149–57.
6. Shnaiderman R, Wissmeyer G, Ülgen O, Mustafa
Q, Chmyrov A, Ntziachristos V. A submicrometre
References silicon-­
on-insulator resonator for ultrasound detec-
tion. Nature. 2020;585(7825):372–8.
1. Strakowski JA. Introduction to musculoskeletal ultra- 7. Bianchi S, Martinoli C. Ultrasound of the musculo-
sound: getting started. New York: Demos Medical skeletal system. Berlin: Springer; 2007. p. 12.
Publishing; 2016. 8. Bowness J, Taylor A. Ultrasound-guided regional
2. Smith J, Finnoff JT. Diagnostic and interventional Anaesthesia: Visualising the nerve and needle. Exp
musculoskeletal ultrasound: part 1. Fundamentals. Med Biol. 2020;1235:21.
PM R. 2009;1(1):64–75. 9. Smith J, Finnoff JT. Diagnostic and interventional
3. Albano D, Aringhieri G, Messina C, De Flaviis musculoskeletal ultrasound: part 2. Clinical applica-
L, Sconfienza LM. High-frequency and ultra-­ tions. PM R. 2009;1(2):162–77.
high frequency ultrasound: musculoskeletal imag- 10. AIUM technical bulletin. Transducer manipulation.
ing up to 70 MHz. Semin Musculoskelet Radiol. American Institute of Ultrasound in Medicine. J
2020;24(2):125–34. Ultrasound Med. 1999;18(2):169–75.
 Shoulder
5
Daniel R. Lueders, Alexander R. Lloyd,
and Allison N. Schroeder

Long Head of the Biceps Brachii For ultrasound evaluation of the LHBB, the
patient should rest their arm adducted to the side
Anatomy and Ultrasound Evaluation and in neutral to slight external rotation. This
brings the tendon anteriorly and allows the
The biceps brachii has two heads – short and long – sonographer to trace the biceps tendon from its
which act together to flex the shoulder and elbow distal point at the pectoralis major to its proximal
and assist with forearm supination. The long head portion within the rotator interval. Failing to do
of the biceps brachii (LHBB) originates on the this and leaving the patient internally rotated can
supraglenoid tubercle, rim of the glenoid, superior hinder initial localization of the tendon and can
glenoid, and the joint capsule. The short head of the prevent comfortable positioning of the probe to
biceps brachii (SHBB) originates at the coracoid allow for optimal visualization of the tendon. The
process of the scapula. These heads merge at the LHBB is generally superficial even in obese
level of the pectoralis major and insert on the radial patients, making a high-frequency linear probe
tubercle and as the lacertus fibrosus onto the deep the best choice for exam. Decreasing both depth
fascia of the forearm. The LHBB follows a curvi- and focal zone to evaluate the proximal position
linear course from its origin and passes through the of the tendon can improve visualization. The
rotator interval formed by the superior border sub- probe should be carefully adjusted to achieve a
scapularis inferiorly, anterior border of the supra- perpendicular view of the tendon and to eliminate
spinatus superiorly, and the base of the coracoid artifact from anisotropy. This may be challeng-
process medially. The coracohumeral ligament and ing, given the curvilinear path of the tendon, and
the glenohumeral ligament also overlie the LHBB requires constant reorientation of the probe.
within this interval and restrain medial movement. Maintaining a discrete visualization of the cortex
The LHBB is encased in a synovial sheath that of the humerus as a well-defined, hyperechoic
communicates with the glenohumeral joint. structure underlying the biceps tendon indicates
the probe is perpendicular to the contour of the
bone and can assist with proper probe
D. R. Lueders (*) · A. N. Schroeder
University of Pittsburgh Medical Center, alignment.
Pittsburgh, PA, USA The scan begins with the transducer in the
e-mail: [email protected]; transverse plane on the anterior aspect of the
[email protected] proximal shoulder. The LHBB tendon is identi-
A. R. Lloyd fied in short axis within the bicipital groove of the
University of Pittsburgh Medical Center, humerus. (Fig. 5.1) The tendon should be scanned
Department of PM&R, Pittsburgh, PA, USA

© Springer Nature Switzerland AG 2022 69

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_5
70 D. R. Lueders et al.

Fig. 5.1 Transverse view of the biceps brachii long head Fig. 5.3 Longitudinal view of the biceps brachii long
tendon in the intertubercular groove, or biceps tunnel. The head tendon in the intertubercular groove, or biceps tun-
biceps tendon (*) is seen as a dense, homogenous hyper- nel. The biceps (*) courses adjacent to the humerus at the
echoic ovoid structure sitting between the humeral lesser biceps tunnel, and the transverse humeral ligament (^) can
tuberosity (LT) and greater tuberosity (GT). The hyper- be seen superficial to the tendon securing it in place
echoic fibrillar-appearing transverse humeral ligament (^)
sits superficial to the biceps long head tendon and secures
it within the biceps tunnel superior to the epiphyseal line

Fig. 5.4 Longitudinal view of the biceps brachii long

head tendon (*) adjacent to the humeral head and deep to
deltoid
Fig. 5.2 Transverse view of the biceps brachii long head
tendon at the rotator interval. The biceps tendon (star) is
seen as a dense, homogenous hyperechoic ovoid structure The tendon should then be followed inferiorly
sitting on the humeral head and deep to deltoid. The ante- to the level of its myotendinous junction just cau-
rior, or leading edge, of supraspinatus forms the posterior dad from the traversing pectoralis major tendon,
margin of the rotator interval, while the cephalad-most
fibers of subscapularis form the anterior margin of the
which is visualized emerging in long axis medial
rotator interval. The superficial rotator interval is com- to the biceps long head tendon and subsequently
prised of the coracohumeral ligament (+), and the deep traversing superficial to biceps tendon to insert
rotator interval is bordered by the superior glenohumeral on the lateral aspect of the humerus. Doppler
ligament (^)
evaluation should also be performed to identify
an ascending branch of the anterior circumflex
proximally through the rotator interval as this is a artery, which courses lateral to the LHBB tendon
common site of pathology. (Fig. 5.2) The LHBB in the bicipital groove. Also of note, the trans-
tendon has an oval shape proximal to the bicipital verse humeral ligament overlies the bicipital
groove and migrates medially toward the glenoid groove and appears as a thin, hyperechoic band
at this point. This should not be confused for ten- superficial to LHBB tendon. The tendon should
don subluxation. The tendon generally cannot be then be evaluated in a long axis view (Fig. 5.3).
followed all the way to its origin on the supragle- Maintaining this view over the entire course of
noid tubercle because of the overlying bony anat- the tendon can be challenging, particularly as the
omy. Some fibers may be seen blending with the tendon curves into the rotator interval (Fig. 5.4).
surrounding tissues at this level as they move to Increased pressure on the distal end of the trans-
their origin on the capsule and labrum. ducer may assist with bringing the tendon paral-
5 Shoulder 71

fill the vacancy of the ruptured tendon and mimic

an abnormal tendon [6].
The tendon sheath of the LHBB usually con-
tains minimal to no fluid. However, because of the
tendon sheath that communicates with the gleno-
humeral joint space, a glenohumeral joint effu-
sion greater than 5 mL can result in peritendinous
extravasation of the effusion down the tendon
sheath to the level of the bicipital groove [7]. As a
Fig. 5.5 Longitudinal view of the biceps brachii long
result, effusion within the LHBB sheath may indi-
head tendon (*) at its myotendinous junction distally. The cate both LHBB tendon and glenohumeral joint
broad, flat tendon of pectoralis major (^) is visualized pathology. Fluid resulting from glenohumeral
superficial to the biceps tendon just proximal from the effusion is usually evenly distributed circumfer-
biceps myotendinous junction
entially around and along the LHBB tendon and is
not focally tender. This is in comparison to focal
lel to the plane of the transducer. The tendon tenosynovitis, which is often painful with sono-
should again be scanned from proximal to distal palpation and demonstrates focal fluid deposition.
to evaluate for pathology at the myotendinous Areas of tenosynovitis may also demonstrate
junction (Fig. 5.5). hyperemia that can be seen with Doppler imag-
ing. The presence of the anterior circumflex artery
lateral to the tendon should not be confused with
Pathology hyperemia. Fluid in the tendon sheath may finally
be associated with rotator cuff tear. This is partic-
LHBB tendon pathology is seen most commonly ularly the case when an effusion of the subacro-
within the first 3.5 cm from the tendon origin and mial/subdeltoid bursa is also present [7, 8].
within, or close to, the rotator interval [1]. Subluxation or dislocation of the LHBB ten-
Chronic degenerative injury to the LHBB may don occurs in the medial direction and generally
result in tendinosis. This phenomenon represents results from disruption of the coracohumeral lig-
the noninflammatory mucoid degeneration and ament. Suspicion for subluxation or complete
chondroid metaplasia of chronically injured ten- dislocation of the tendon should arise when the
dons [2]. Tendinosis manifests as hypoechoic tendon is not seen in the bicipital groove. During
defects with changes to the fibrillar architecture subluxation, the tendon can be observed sublux-
of the tendon that give it an ill-defined heteroge- ating medially out of the bicipital groove with
nous appearance [3]. Concomitant thickening of external rotation and relocating back into the
the tendon and Doppler flow may also be seen in bicipital groove with internal rotation. When dis-
the abnormal areas [3]. location has occurred, the tendon has perma-
Anechoic clefts or irregularities in the superfi- nently migrated medially and may be difficult to
cial contour of the biceps tendon may indicate visualize. LHBB subluxation or dislocation
partial-thickness tearing [4]. Full-thickness should not be confused with a complete tear of
­tearing results in the complete absence tendon in the tendon, which may similarly show an empty
the bicipital groove due to its retraction distally bicipital groove. To differentiate between the
into the arm. The full extent of the bicipital two, examiners must scan distally to visualize the
groove should be evaluated distally to locate the most proximal portion of the tendon that can be
retracted stump of the tendon. Of note, the col- visualized. This should then be followed more
lapsed bicipital tendon sheath may appear as a proximally. An abnormal tendon course that
hyperechoic fascial structure within the bicipital courses medial to the humerus indicates sublux-
groove and should not be mistaken for the biceps ation or dislocation, while discontinuity indicates
tendon [5]. Reactive effusion and debris can also rupture of the tendon.
72 D. R. Lueders et al.

While LHBB tendon pathology may be focal • Needle selection – 25–27-gauge 1.5–2.5-inch
and isolated, it can be an indicator of glenohumeral needle, depending on body habitus
joint or rotator cuff pathology [7–9]. Even damage • Injectate selection – Anesthetize with local
to the LHBB tendon itself may reflect abnormal anesthetic. Inject with 5mL or less of volume
biomechanics within the shoulder triggered by including steroid, prolotherapy, or orthobio-
pathology elsewhere in the rotator cuff [9]. logic therapy. Volumes of 5mL or more com-
monly enter the glenohumeral joint and may
be used for adhesive capsulitis [7].
Interventional Procedures • Needle trajectory and target – In-plane, lateral
to medial, target is just superficial to the ten-
Limited evidence exists for dedicated regenera- don within the sheath to ensure the safety of
tive procedures performed at the LHBB tendon. the ascending artery from the anterior humoral
Prolotherapy protocols involving injection of the circumflex artery.
proximal biceps tendon almost always do so as • Accuracy – Ultrasound-guided injections of
part of a larger protocol for rotator cuff disease the biceps tendon sheath are significantly
with multiple other tendons injected [10, 11]. It’s more accurate than palpation-guided injec-
difficult to make definitive conclusions as a tions. Many practitioners struggle to accu-
result, because improvements in pain or function rately identify the correct location of the
may have been related to effects at other loca- biceps tendon with palpation, leading to fre-
tions. No studies have been performed with pro- quent needle placement error [14]. Recent
lotherapy on isolated biceps tendon pathology. comparative studies have found ultrasound-­
With reference to PRP, a single pilot study eval- guided injections to be between 85% and
uated the effect of PRP injections to the LHBB ten- 100% accurate with superior effectiveness
don in eight spinal cord injured patients with good [15–17]. Palpation-guided injections range in
overall outcomes [12]. Beyond this, no data was accuracy from 26% to 68% (Hashiuchi et al.
found about PRP injections for isolated proximal [16]; Yiannakopoulos et al. [17]).
biceps tendon pathology. As previously mentioned, • Pearls/Pitfalls
the biceps tendon may be affected by significant –– The lesser tuberosity can be used as a back-
pathology of the supraspinatus and subscapularis stop for the needle trajectory to facilitate
tendons through disruption of the rotator interval proper placement
and rotator pulley that may lead to tendon dysfunc- –– Injectate should flow easily and disseminate
tion [13]. Additionally, there is likely some bursal within the tendon sheath. Focal collection
communication between the subacromial-subdel- of the fluid indicates the needle is either
toid bursa and the biceps tendon sheath when sig- outside of the sheath or within the tendon.
nificant rotator cuff tearing is present [7]. However, –– The anterior circumflex humeral artery,
use based on this evidence is largely speculative. which typically lies lateral to the tendon,
No systematic studies have been performed should always be visualized with Doppler
examining the effects of mesenchymal stem cells prior to the injection and avoided during
or hyaluronic acid on the biceps tendon. the procedure.

Injection Approach #1 Injection approach #2

• Patient positioning – Supine. • Patient positioning – Supine

• Transducer selection – High-frequency linear • Transducer selection – High-frequency linear
array transducer (>10MHz) array transducer (>10MHz)
• Transducer position – Short axis to the long • Transducer position – Long axis to the long
head of the biceps tendon at the intertubercu- head of the biceps tendon at the intertubercu-
lar groove lar groove
5 Shoulder 73

• Needle selection – 25–2-gauge 1.5–2.5-inch spinatus forms the posterosuperior border of the
needle depending on body habitus rotator interval, which surrounds the proximal
• Injectate selection – Same as above portion of the LHBB.
• Needle trajectory and target – In-plane, infe- Ultrasound evaluation of the medial, proximal
rior to superior, target is just superficial to the supraspinatus tendon is obscured by the bony
tendon within the sheath acromion at rest in a neutral position. Placing the
• Accuracy – As above patient in a Crass position (hand behind the back
• Pearls/Pitfalls with shoulder extension and internal rotation) or
–– This approach provides another option in modified-Crass position (hand on the hip with
the event that approach #1 is not possible. shoulder in extension) angles the greater tuberos-
–– While this approach allows for a longer ity anteriorly, pulling a larger portion of the
tendon target, it lacks simultaneous visu- supraspinatus out from underneath the acromion.
alization of the anterior circumflex The Crass position may obscure the rotator inter-
humeral artery and lacks a bony backstop val because of the internal rotation and be painful
if the injector misjudges the needle for patients with pathology [5]. The modified
depth. Crass is more commonly used as a result, but it
should be noted that this position may overesti-
mate the size of tendon tears [20]. It should be
Supraspinatus Tendon noted that part of the tendon will always be
obscured by the coracoacromial arch and the
Anatomy and Ultrasound Evaluation supraspinatus should be evaluated to the maximal
extent possible posterior and anterior to the acro-
The supraspinatus tendon originates from the mial arch, recognizing the inherent limitations
supraspinous fossa of the scapula. It courses presented by the overlying bony architecture.
superolaterally to pass under the acromion and The supraspinatus tendon is superficial and
over the superior aspect of the glenohumeral joint can generally be imaged with a high-frequency
before inserting on the middle and superior facet linear probe within a few centimeters of the skin
of the greater tuberosity. The supraspinatus mus- surface. The probe is placed over the superior and
cle has a complex architecture that permits it to anterior aspect of the shoulder in a coronal
provide significant stability to the humeral head oblique plane with the medial end of the trans-
during rotation and abduction at a variety of ducer pointed towards the patient’s ear. This will
angles. This includes a ventral or anterior portion show the supraspinatus tendon in a long axis
that inserts more anteriorly on the greater tuber- view (Fig. 5.6). The insertion of the supraspina-
osity and acts as an internal rotator, as well as a tus tendon classically has a convex “bird’s beak”
posterior portion that inserts posteriorly on the
greater tuberosity and serves to abduct the shoul-
der [18, 19]. Each of these portions is subdivided
into superficial, middle, and deep portions, each
with its own insertion [18]. This complex archi-
tecture with resulting complex movement is
thought to contribute to its susceptibility to injury
[18]. The supraspinatus musculature and tendon
are separated from surrounding musculature and
bony prominences by the subacromial-subdeltoid
(SASD) bursa, which functions to facilitate
movement of the tendon. The SASD bursa is Fig. 5.6 Longitudinal view of the insertional supraspina-
described separately. As the supraspinatus tus (*) onto humerus. Deltoid (^) is superficial to
courses laterally toward its insertion, the supra- supraspinatus
74 D. R. Lueders et al.

appearance as it inserts on the greater tuberosity. [22–24]. As the tendon is scanned distally, it will
In this view, the greater tuberosity, bursal, and thin as the articular portion of the humerus gives
articular surfaces of the tendon can be evaluated way to the more angulated facets of the greater
for pathology. The tendon will appear fibrillar tuberosity. The supraspinatus will insert on the
and hyperechoic with fibrocartilage often seen superior and superior half of the middle facet.
deep to the tendon over the facets. Hypoechoic The infraspinatus will also be seen inserting onto
articular cartilage may also be seen over the the middle facet at this level and the fibers of both
humeral head. Heel-toe of the transducer should tendons often mingle at this level, making a
be used over the insertion of the supraspinatus to definitive differentiation difficult. As with the
eliminate anisotropy caused by the downward long-axis portion of the scan, the transducer
curve of the tendon at the insertion on the should be translated anteriorly until the biceps
humerus. tendon is visualized within the rotator interval
The footprint of the supraspinatus covers and posteriorly until the infraspinatus is viewed
approximately 25 mm of the greater tuberosity, to ensure the entire footprint has been evaluated.
and the entire footprint should be scanned [21]. Dynamic evaluation is then performed to eval-
The boundaries of the supraspinatus can be iden- uate for any visible signs of subacromial impinge-
tified by scanning anteriorly until the biceps ten- ment. With the supraspinatus footprint and the
don is seen within the rotator interval and acromion in view, the patient should slowly
posteriorly until the infraspinatus comes into abduct and adduct the shoulder. The supraspina-
oblique view. The tendon should then be scanned tus will be observed passing underneath the acro-
superiorly in long axis until the acromion is mion. The sonographer should observe for
encountered. The SASD bursa may be seen as a bunching of bursal tissue against the acromion,
thin, hypoechoic line overlying the supraspinatus collecting fluid at the edge of the acromion repre-
tendon, although it is collapsed in those without senting an effusion in the bursa, or correspon-
pathology and may be difficult to visualize. dence of pain with this movement.
Once long-axis evaluation has been com- The musculature of the supraspinatus can be
pleted, the transducer should be rotated 90° to visualized posteriorly for echotexture changes
evaluate the tendon in short axis (Fig. 5.7). that may suggest muscle pathology such as
Scanning should be started at the level of the denervation or disuse. Short-axis panoramic
humeral head with the proximal tendon in view views of the muscle can allow comparison to the
over underlying articular cartilage. The tendon infraspinatus and teres minor for reference. The
thickness generally measures 5–6 mm in thick- musculature should have a “starry sky” appear-
ness 1–2 cm from the insertion and may vary by ance with a largely hypoechoic echotexture inter-
approximately 0.5 mm between men and women spersed with hyperechoic connective tissue.
Increased hyperechogenicity should raise con-
cern for underlying fatty or fibrous infiltration.
The musculature can be traced into the tendon up
until its passage under the acromion.
The deltoid musculature is also commonly
viewed during diagnostic scans in this area,
although dedicated diagnostic scanning is far less
common than imaging of the rotator cuff. This is
largely based on the low levels of pathology seen
in the deltoid relative to the muscles of the rotator
cuff. The muscle originates on the lateral third of
Fig. 5.7 Transverse view of the supraspinatus insertion
the clavicle, the acromion, and on the spine of
onto humerus. The long head biceps brachii tendon (*) is
visualized at the rotator interval and leading anterior edge scapula. It inserts onto the anterolateral surface
of supraspinatus of the humerus. Because of its broad origins, the
5 Shoulder 75

deltoid muscle assists with a variety of actions be used to deduce underlying pathology. These
around the shoulder, including flexion, extension, signs include cortical irregularity at the footprint,
internal rotation, external rotation, and abduc- effusion seen in the SASD bursa, a glenohumeral
tion, although abduction is its main action. It is joint effusion, or a cartilage interface sign (hyper-
supplied by the axillary nerve and may show echoic line over the surface of the articular carti-
signs of denervation – atrophy, fibrosis, or fatty lage under the contour of the supraspinatus
infiltration – in cases of axillary nerve injury The tendon) [3].
muscle may also be injured by direct blow result- The location of a partial-thickness tear should
ing in contusion or muscle injury, which can also also be defined as intrasubstance, bursal-sided,
be visualized under ultrasound. or articular-sided. An intrasubstance tear occurs
within the tendon and does not extend to a sur-
face of the tendon. Bursal-sided tears lead to
Pathology loss of superficial fibers on the surface of the
tendon, causing thinning of the tendon. The sur-
The supraspinatus tendon is the most commonly rounding deltoid muscle and SASD bursa may
torn tendon in the rotator cuff [25]. Ultrasound then dip into this defect, causing loss of the typi-
has been shown in several meta-analyses to be at cal convex appearance of the tendon. This is less
least 90% specific and as good as MRI and poten- common in articular-sided tears, because the
tially MR arthrogram in evaluating tearing of the cortical and articular surfaces underlying the
tendon [26, 27]. Degenerative tears are frequently tendon preserve the convex appearance of the
seen posterior to the biceps tendon near the junc- tendon.
tion of the supraspinatus and infraspinatus ten- Chronic degeneration of the supraspinatus can
dons [28]. The anterior supraspinatus tendon at result in tendinosis, which appears as a
the articular-sided footprint is also commonly hypoechoic lesion within the tendon as described
affected, and concomitant cortical irregularity in more detail previously. Tendinosis should
representing chronic injury may be seen [25]. always be carefully differentiated from anisot-
Acute tears tend to occur more proximally and ropy. In particular, the convexity of the inser-
often lack the cortical irregularity seen in degen- tional footprint of the supraspinatus tendon may
erative tears [5]. mislead sonographers into believing that tendino-
Tears are hypoechoic or anechoic areas within sis or tearing is present in the areas of hypoecho-
the substance of the tendon. Tears are described genicity, when this actually represents anisotropic
as partial- or full-thickness involving part of or tendon fibers. Tears in the supraspinatus may also
the entire thickness of the tendon. Full-thickness involve other tendons of the rotator cuff. This is
tears appear as well-defined, hypoechoic, or particularly the case for the infraspinatus, which
anechoic disruptions in the fibrillar architecture intermingles fibers of its insertion toward the lat-
of the tendon and may only affect part of the eral edge of the supraspinatus tendon insertion on
width of the tendon. Smaller tears may not the middle facet. Tearing of the supraspinatus
change the overall shape of the tendon, while that extends posterior to the middle facet ­indicates
larger tears can lead to tendon volume loss, which likely involvement of the infraspinatus tendon.
flattens the typical convex appearance of the ten- Tearing can also extend anteriorly into the rotator
don [5]. Mixed hypoechoic and hyperechoic interval, coinciding with pathology of the sub-
components can occur when a portion of the torn scapularis and biceps tendon.
residual tendon is surrounded by fluid within the The supraspinatus tendon is the most common
tear [29]. A complete tear is described as a full-­ rotator cuff tendon affected by calcific disease
width, full-thickness tear. Some partial-thickness [30, 31]. The precise pathogenesis of tendon cal-
tears may be difficult to evaluate based on their cifications is unclear, and multiple different eti-
location or orientation, and secondary signs can ologies have been proposed [30–32]. Calcific
76 D. R. Lueders et al.

lesions follow a predictable progression, result- Interventional Procedures

ing in the deposition of hydroxyapatite crystals
within the tendon [32]. This involves a precalcific While corticosteroids are commonly used for
stage, where fibrocartilaginous metaplasia occurs shoulder pain, their utility for treatment of tendon
within the tendon, followed by the painful forma- injury has been increasingly questioned, given
tion of hydroxyapatite crystals on these meta- the non-inflammatory etiology of most chronic
plastic tissues that then calcify [32]. This is tendon abnormalities and the potentially harmful
followed by resorption of the calcific lesion, impact steroid has on tendon healing [2, 38]
which may also be painful secondary to increased Attention has turned to alternative modes of
edema and intratendinous pressure [30]. The pain treatment as a result, including platelet-rich
in both of these stages may be related to ingrowth plasma (PRP), prolotherapy, and mesenchymal
of neovessels and neonerves [33]. The area of stem cells.
previous calcification is eventually replaced by Precise data on treatment of the supraspinatus
granulation tissue that is gradually remodeled tendon is muddied by the frequent use of the
into normal tendon [30]. imprecise term “rotator cuff” in the literature,
On ultrasound, the appearance of these lesions rather than specifying the tendons being treated.
can vary, and several classification systems have This makes it difficult to evaluate exactly what
been devised to describe them as noted below was targeted in many of these studies and to
[34]. While many lesions are hyperechoic with determine whether one or multiple tendons were
posterior acoustic shadowing, they may also be addressed with the intervention. Additionally,
amorphous in appearance without significant pos- much of the research has been done within the
terior shadowing [34]. They may also take on sev- orthopedic community using platelet-rich plasma
eral different appearances, including arc-­shaped, as an adjunct to surgical intervention as a way to
fragmented with multiple components, nodular augment healing outcomes. Several high-quality
without shadowing, or cystic with an anechoic studies in these cases found borderline effects or
center [34]. The consistency of calcifications can failed to show an effect of PRP in these cases
also vary from hard, soft, or nearly liquid [35]. [39–43]. Some studies have reported faster heal-
Soft or liquid calcifications may be isodense on ing, decreased retear rates, and lower rates of sur-
ultrasound and absent on radiographs, making gical failure or incomplete healing, but this may
identification challenging. In these cases, the cal- be more reliably the case for small to medium
cification can be identified as an amorphous tears rather than large or massive tears [41, 44,
echotexture within the tendon that will not become 45]. The degree to which this reflects an improve-
anisotropic with movement of the ultrasound ment in functional outcomes is also questionable
probe [5]. As mentioned earlier, these lesions may [44, 46]. A Cochrane review found similar find-
also show color and power Doppler signal as a ings to this effect [47].
result of closely associated neovessels. Variable results have been reported for PRP
injections as a nonoperative option for treatment
Calcific Disease Classification Systems of supraspinatus pathology. An RCT comparing
Gärtner and Heyer Classification [36] PRP to saline injections into interstitial supraspi-
Type I Dense, well-circumscribed calcification natus tears found no difference between PRP and
Type II Soft contour/dense or sharp/transparent saline [48]. At least one study comparing the
Type III Translucent/cloudy, not clearly effectiveness of dry needling with PRP to the
circumscribed
Molé et al. Classification [37]
supraspinatus tendon found a beneficial effect on
Type A Sharp contour, dense, homogenous pain and disability when PRP was injected into
Type B Sharp contour, dense, segmented the lesion under ultrasound guidance [49].
Type C Soft contour, heterogeneous Another study by Kesikburun et al. found no dif-
Type D Dystrophic calcification at the tendon ference between PRP and saline, but the injec-
insertion tions were placed in the subacromial space rather
5 Shoulder 77

than in the tendon [50]. A recent meta-analysis analysis done by Osti et al. showed effectiveness
by Lin et al. comparing PRP to steroid and prolo- of hyaluronic acid in treatment of shoulder pain
therapy found some indication that PRP improved in shoulders with rotator cuff tears; however, the
long-term function more than other therapies and studies included also reported a mix of intra-­
that prolotherapy improved long-term pain more articular and subacromial locations for injection
than other therapies [51]. They also noted signifi- [57]. A 2019 study by Cai et al. found increased
cant heterogeneity in their data [51]. In particu- effectiveness of PRP injections when combined
lar, the included studies contained a mix of with hyaluronic acid injections, when injections
diagnoses including supraspinatus tendinitis, were performed in the subacromial space [58].
clinically diagnosed subacromial impingement, Of note, research done by Wu et al. examining
and chronic tendinosis with 19 studies perform- the effect of intratendinous injections of hyal-
ing a subacromial injection and only two per- uronic acid into the Achilles tendon showed a
forming a supraspinatus tendon injection [51]. persistent inflammatory response lasting approx-
The effect of PRP composition on effectiveness imately 42 days with a significant increase in
is an additional consideration that likely influ- neovascularization [59]. These findings led them
ences outcome [52]. This was demonstrated in a to recommend against intratendinous injection of
2019 study by Kim et al. that found improved hyaluronic acid [59].
response to PRP injection for degenerative rota- While significant enthusiasm has surrounded
tor cuff tendinopathy when the injectate had the use of mesenchymal stem cells (MSC), either
higher levels of IL-1β or TGF-β1 [53]. This level derived from adipose tissue or bone marrow, few
of detail is often not obtained or reported in most studies have been performed on the effectiveness
PRP studies. of these interventions on tendon pathology of the
As mentioned above, prolotherapy has been rotator cuff. Kim et al. evaluated the use of BMAC
considered for treatment of rotator cuff pathol- for rotator cuff pathology compared to an exercise
ogy, both alone and as an adjuvant to other regen- program [60]. They found marginal improvement
erative therapies. However, prolotherapy has in pain and function scores at 3 months compared
received significantly less research attention than to exercise alone [60]. Jo et al. recently reported
PRP. A 2019 meta-analysis of prolotherapy trials an unblinded, uncontrolled case series of adipose-
for rotator cuff disease found only five derived MSC injection into rotator cuff tears,
randomized-­controlled trials and three additional although which tendons of the rotator cuff were
non-randomized trials [10]. While their synthesis targeted was not clarified in the study [61]. Those
of the data showed potential for effectiveness in in the high-dose treatment group (1x108 cells
pain reduction, range of motion improvement, injected) improved in shoulder pain and disability
and functional improvement, they also noted sig- index (SPADI) and visual analogue scale (VAS)
nificant risk of bias and highly variable findings with other tested parameters largely nonsignifi-
[10]. This was related to the heterogeneous and cant (Jo et al. [61]). These studies have yet to be
often small populations studied, variable sites replicated, and caution should be exercised in
and methods of injection, differing controls, and extrapolating their findings.
differing protocols used. While several studies
found positive short-term results with intratendi-
nous injection, long-term follow-up did not show Injection Technique
significant differences compared to controls [54–
56]. Definitive conclusions about the effective- • Patient positioning – Lateral decubitus with
ness of prolotherapy cannot be made at this time. affected side facing up
Hyaluronic acid has also been proposed as a • Transducer selection – High-frequency linear
treatment for rotator cuff tendinopathy, but results array transducer (>10MHz)
of trials to this effect are difficult to interpret, • Transducer position – Long axis to the supra-
given the variable location of injection. A meta-­ spinatus tendon
78 D. R. Lueders et al.

• Needle selection – 25–27-gauge 1.5–2.5-inch One-Needle Technique

needle, depending on body habitus and depth
of target. • Patient positioning: Supine with several pil-
• Injectate selection – Anesthetize with local lows under the affected shoulder to elevate it
anesthetic. Inject with ~3 mL of volume • Transducer selection – High-frequency linear
including steroid, prolotherapy, or orthobio- array transducer (>10MHz)
logic therapy. • Transducer position – Long axis to the supra-
• Needle trajectory and target – In-plane, lateral spinatus tendon with the calcification in view
to medial. Target area of tendon pathology. • Needle selection – 16–25-gauge needles have
• Accuracy – Specific studies have not been per- been used, but 18-gauge 2.5-inch needle is
formed on injections into the supraspinatus, recommended
although targeting specific lesions within the • Injectate selection – Anesthetize down to the
tendon without guidance would be extremely lesion. 10mL syringe with 3 mL of 2% lido-
challenging. Many studies noted above use caine and 3 mL normal saline attached to the
injection into the subacromial space with first 10 mL syringe to aid with anesthetizing
accuracy for these injections reported in the the lesion. Subsequent syringes can be filled
section on the SASD bursa. with 6 mL of normal saline.
• Pearls/Pitfalls • Needle trajectory and target – In-plane, lateral
–– It is common to see apparent extension of to medial. Target calcification.
the lesion under ultrasound guidance as the • Description – Puncture the calcification at a
injectate expands collapsed areas of tearing single location if possible. Once the needle is
with the injectate filling these potential within the calcification, the plunger of the
spaces. syringe should be gently pumped using back
–– The overall space within an area of pathol- pressure to extract the calcific debris. Calcific
ogy may be very limited. Significant pres- debris should be seen returning into the
sure should not be exerted during the syringe when pressure is released. Once the
procedure. Once significant resistance is syringe becomes cloudy, it should be switched
met, the needle can be withdrawn and redi- for another syringe. This procedure should be
rected to another area of pathology. repeated until no further calcific debris returns.
–– Some practitioners perform needle tenot- • Pearls/pitfalls
omy during injection of PRP to further –– The needle and syringe should be held in a
stimulate inflammation and healing in the dependent positioning, so that gravity car-
area. [62]. ries debris away from the needle inlet to
avoid reinjection of calcific debris.
Percutaneous needle barbotage/lavage of –– A single-entry point should be used for
intratendinous calcific lesions has been found best effect. If multiple puncture sites are
to be a safe and effective means of treating made, it may not be possible to generate
these lesions [63]. However, while short-term the intralesional back pressure that facili-
results after this procedure appear promising, tates the removal of calcific debris.
one long-­ term follow-up study done by de –– Ensure multiple syringes with normal saline
Witte et al. found no difference in pain, func- are readily available prior to beginning the
tion, or radiographic findings between those procedure, since multiple are commonly
who had undergone barbotage and those who required before all calcific debris is removed.
had an isolated subacromial corticosteroid –– If the needle becomes clogged during the
injection [64, 65]. They theorize that this may procedure, the needle can be withdrawn
be related to the natural course of calcific into the surrounding tissue and then
lesions, which often resolve on their own [30, threaded with a 25-gauge needle to clear
32, 64]. the blockage.
5 Shoulder 79

Two-Needle Technique distal end of the subscapularis tendon is seen in

long axis medial to the biceps tendon during
• Patient positioning: Same position as above short-axis evaluation of the proximal biceps ten-
• Transducer selection – High-frequency linear don (Fig. 5.2). Positioning the patient in adduc-
array transducer (>10MHz) tion and external rotation brings more the distal
• Transducer position – Long axis to the supra- tendon into view and allows for Fig. optimization
spinatus tendon with the calcification in view to better evaluate for pathology (Fig. 5.8). Heel-­
• Needle selection – 16–25-gauge needles have toe movements of the transducer eliminate
been used, but 18-gauge 2.5-inch needle is anisotropy at the footprint of the tendon as it
recommended wraps around the humeral head. Full evaluation
• Injectate selection – Anesthetize down to the of the more proximal tendon is limited because of
lesion. 6 mL NS attached to 10 mL syringe for its depth and surrounding bony anatomy. The
calcific tendinosis transducer should be translated superiorly and
• Needle trajectory and target – In-plane, lateral inferiorly at the lesser tuberosity to ensure that
to medial. Target calcification. the entirety of the subscapularis tendon is evalu-
• Description – In this technique, two needles ated in long axis.
are placed within the calcification: one anteri- The transducer is then rotated 90° to evaluate
orly that will serve as the injecting needle and the tendon in short axis. The subscapularis con-
one posteriorly in a dependent position that tains several hypoechoic divisions within the ten-
will serve as the draining needle. When both don in this plane, which represent different
needles have been placed, the syringe is tendon bundles and should not be interpreted as
attached to the anterior needle, and the calcifi- partial- or full-thickness tearing of the tendon
cation is irrigated with normal saline, which is (Fig. 5.9).
allowed to drain from the posterior needle.
This is done until no further calcific debris
drains from the needle.
• Pearls/pitfalls
–– This technique is ideal when back pressure
is lost as a result of multiple punctures.
–– If desired, the anterior needle may be repo-
sitioned after the procedure to perform a
SASD bursa injection.

Subscapularis Tendon Fig. 5.8 Longitudinal view of the insertional subscapu-

laris onto humerus
Anatomy and Ultrasound Evaluation

The subscapularis muscle originates in the sub-

scapular fossa on the ventral side of the scapula. It
then courses posteromedially to the humerus
under the coracoid process to insert anteromedi-
ally on the lesser tuberosity of the humerus. The
subscapularis lies medial to the biceps tendon
over the anterior shoulder and inferior to it in the
rotator interval. It serves to internally rotate the
shoulder.
Fig. 5.9 Transverse view of the insertional subscapularis
The subscapularis is often evaluated after the onto humerus. The subscapularis tendon has a unique
biceps tendon because of its close proximity. The multipennate appearance
80 D. R. Lueders et al.

nal rotation [5]. Avulsion tears will often demon-

strate posterior acoustic shadowing behind the
hyperechoic fragment.
It is important to recognize that subscapularis
tears are often associated with biceps long head
tendon instability, particularly in tearing of the
cephalad subscapularis, because of the subscapu-
laris contribution to the rotator interval and stabi-
lizing ligaments that overlie the biceps tendon
Fig. 5.10 Longitudinal view of subscapularis (*) medi-
and constrain medial movement [13].
ally deep to coracoid Subcoracoid impingement occurs as the sub-
scapularis passes deep to the coracoid process.
Dynamic evaluation is performed to evaluate This impingement occurs with internal rotation
for subcoracoid impingement medially and bur- and shoulder flexion, when the lesser tuberosity
sal fluid that may become more prominent with of the humerus comes into closest proximity with
shoulder internal and external rotation (Fig. 5.10). the coracoid, and can contribute to tendon degen-
The subscapularis tendon is visualized in its long eration, further exacerbating the impingement
axis with the coracoid process visible medially and increasing tendon thickness [67]. Subcoracoid
and the humeral head visible laterally. The shoul- impingement is much less common than subacro-
der is then both passively and actively internally mial impingement but may be seen in the settings
and externally rotated while visualizing the ten- of postoperative and post-traumatic lesser tuber-
don passing under the coracoid process. Any dys- osity abnormalities [67].
kinetic bunching of tissue at the coracoid process, The subcoracoid bursa is located deep to the
collection of fluid, or pain with this maneuver conjoined tendon of the short head of the biceps
suggests an underlying pathology. and coracobrachialis. It is an extension of the
subacromial subdeltoid bursa and does not com-
municate with the glenohumeral joint. It is com-
Pathology monly enlarged in the setting of anterior rotator
cuff pathology [6]. External rotation can draw the
Subscapularis tendon tears commonly occur as a bursa out from underneath the coracoid and
result of acute trauma with the arm abducted and improve visualization [5]. It should be differenti-
externally rotated and have a similar sonographic ated from the nearby subscapularis recess. This
appearance as described in the section on the recess (sometimes known as the subscapularis
supraspinatus. Isolated subscapularis tears are bursa) is a recess of the glenohumeral joint and
uncommon and should prompt more thorough overlies the portion of the subscapularis tendon
evaluation of the rotator cuff [66]. Partial-­ closest to the scapular neck. The recess is typi-
thickness subscapularis tears can be bursal-sided, cally not visible during routine scanning but may
interstitial, or articular-sided. The cephalad por- be visible in the setting of an intra-articular effu-
tion of the tendon is more commonly torn than sion. If present, it lies in close proximity to the
the caudad portion and is commonly associated subscapularis tendon just caudal to the coracoid
with a supraspinatus tear [6, 66]. process [6].
Full-thickness subscapularis tears can be seen Several studies have attempted to establish
as a discontinuity in the tendon structure or out- defined normal and abnormal coracohumeral
right retraction if the tear is large or complete. distances, but multiple studies have shown
Tears of this nature are most common at the lesser mixed results regarding the predictive value of
tuberosity and can be seen more clearly in exter- coracohumeral distance [68]. While distance is
5 Shoulder 81

unlikely to be indicative in and of itself, abnor- Infraspinatus

mal sonographic appearance of the subscapu-
laris tendon combined with abnormal contact Anatomy and Ultrasound Evaluation
under the coracoid in the setting of correspond-
ing anterior shoulder pain is strongly suggestive The infraspinatus originates within the scapular
of impingement. infraspinous and courses laterally over the poste-
rior glenohumeral joint to insert on the middle
facet of the humoral greater tuberosity. The
Interventional Procedures patient can be examined either seated or side-­
lying with the shoulder neutrally positioned. The
Data regarding the effectiveness of PRP for treat- lateral inserting tendon is superficial and should
ment of subscapularis pathology suffers from the require minimal depth with a superficial focal
same lack of specificity in language, target site, zone for evaluation. A high-frequency linear
intervention protocols, and choice of outcome probe is usually the best choice for this evalua-
measures as the supraspinatus literature. In spite tion. Examination of the medial infraspinatus
of the differences between pathology affecting muscle belly requires greater depth to visualize
the subscapularis and supraspinatus, both are the entirety of the muscle belly. This should be
often grouped together as rotator cuff pathology possible with a linear probe in most individuals
with most injections taking place within the sub- but may require a lower frequency curvilinear
acromial space. As a result, specific data on sub- probe in more muscular or obese individuals.
scapularis pathology and the effectiveness of To identify the infraspinatus, the transducer
PRP, prolotherapy, MSC, or hyaluronic acid is is aligned in an axial oblique plane inferior to
lacking at this time. the spine of the scapula. The hyperechoic cen-
tral ­tendon can be followed from medial to the
• Patient positioning – Supine with arm exter- lateral insertion of the tendon on the middle
nally rotated facet of the humeral greater tuberosity
• Transducer selection – High-frequency linear (Fig. 5.11). The full width of the tendon should
array transducer (>10 MHz) be scanned in cephalad to caudad manner, with
• Transducer position – Long axis to the sub- the most superior aspect of the tendon demar-
scapularis tendon cated by the supraspinatus tendon inserting on
• Needle selection – 25–27-gauge 1.5–2.5-inch the superior and middle facets. It’s important
needle, depending on body habitus and depth not to confuse anisotropy from oblique supra-
of target. A longer needle is often needed for spinatus fibers for infraspinatus pathology.
the subscapularis due to depth of the targeted
structures.
• Injectate selection – Anesthetize with local
anesthetic. Inject with ~3 mL of volume
including steroid, prolotherapy, or orthobio-
logic therapy.
• Needle trajectory and target – In-plane, lateral
to medial. Target area of tendon pathology.
• Accuracy – Studies to have not been per-
formed evaluating the accuracy of these kinds
of injections beyond general accuracy of
injections into the subacromial space men-
Fig. 5.11 Longitudinal view of infraspinatus (*) overly-
tioned elsewhere. ing the posterior glenohumeral joint. Deep to infraspina-
• Pearls/pitfalls – None tus, the glenoid (^) and humeral head are visualized
82 D. R. Lueders et al.

Infraspinatus tearing appears similar to supraspi-

natus tearing as described previously. Full-­
thickness tears usually indicate concomitant
supraspinatus tearing and rarely occur in isola-
tion [5]. Chronic tendon injury can lead to tendi-
nopathy and calcific disease in the infraspinatus
through a similar process to that seen in the
supraspinatus, although this pathology is less
commonly seen [69].
Articular surface tearing of the infraspinatus
Fig. 5.12 Transverse view of infraspinatus overlying the
scapula tendon may also be seen in shoulder internal
impingement. This occurs in a position abduction
and external rotation of the shoulder [70, 71].
Such tearing is particularly common close to the
infraspinatus-supraspinatus junction and may
also been seen in conjunction with SLAP tears
[70]. These injuries are commonly seen in throw-
ing athletes, and the same torsion forces, s­ hearing,
and peel-back forces that result in a SLAP tear
are also responsible for articular-sided infraspi-
natus tears [70]. Chronic microtrauma to the pos-
terior capsule leads to thickening, fibrosis, and
Fig. 5.13 Transverse view of infraspinatus (*) overlying subsequent malpositioning of the humerus during
the humeral head near its insertion abduction and external rotation [70]. Identification
of an articular-sided infraspinatus tear should
Toggling or rotating the probe should eliminate prompt supraspinatus evaluation and a shoulder
these areas of hypoechogenicity. MRI to assess the labrum.
The infraspinatus should also be evaluated in
short axis. The transducer is placed in a sagittal ori-
entation just caudal from the spine of the scapula Interventional Procedures
overlying the infraspinatus in short axis (Fig. 5.12).
The musculature and punctate hyperechoic central The evidence for regenerative treatment of the
tendon can be traced from medial to the lateral infraspinatus is limited. The vast majority of
humeral insertion (Fig. 5.13). The appearance of existing evidence has been done for generic rota-
the muscle belly of the infraspinatus should be tor cuff pathology with injection into the sub-
compared to the appearance of the supraspinatus acromial space as described in the section on the
teres minor, since changes in muscle echotexture supraspinatus. At time of writing, no systematic
may reflect underlying fatty infiltration from studies exist examining treatment specifically of
chronic disuse, tearing, or denervation. The use of the infraspinatus tendon with regenerative thera-
the panoramic scanning feature can facilitate visu- pies. However, given the previously mentioned
alization of the supraspinatus, infraspinatus, and data on effective treatment regimens for the
teres minor in one image across the scapula to com- supraspinatus and rotator cuff, outcomes of simi-
pare muscle bulk and echotextures. lar treatment in the infraspinatus may be similar.

• Patient positioning – Lateral decubitus with

Pathology affected side facing up
• Transducer selection – High-frequency linear
Isolated infraspinatus injury is rare, and tearing array transducer (>10 MHz) or low-frequency
often coincides with supraspinatus pathology. curvilinear transducer (<10 MHz) may be
5 Shoulder 83

used for deep targets or to facilitate needle teres minor is very short relative to the infraspi-
placement natus and is obliquely oriented relative to the
• Transducer position – Long axis to the infra- humerus because of its superolateral direction
spinatus tendon of insertion (Fig. 5.14). The muscle and tendon
• Needle selection – 27-gauge 1.5-inch or should be evaluated in short axis from the ori-
27-gauge 2.5-inch needle, depending on body gin on the scapula to the insertion on the greater
habitus and depth of target. tuberosity (Fig. 5.15). While the infraspinatus
• Injectate selection – Anesthetize with local and teres minor can be differentiated over the
anesthetic. Inject with ~3 mL of volume scapula, some examiners may find it easier to
including steroid, prolotherapy, or orthobio- visualize the tendons over the humerus and
logic therapy. trace the tendons back into the musculature to
• Needle trajectory and target – In-plane, lateral ensure the correct structure is evaluated. In
to medial. Target area of tendon pathology. these cases, the teres minor will be the smaller
• Accuracy – Studies to have not been per- and more inferior tendon seen inserting on the
formed evaluating the accuracy of these kinds inferior facet.
of injections beyond general accuracy of As previously mentioned, the thickness and
injections into the subacromial space. echotexture of the teres minor should be evalu-
• Pearls/pitfalls: None ated relative to the musculature of the other rota-
tor cuff muscles in the dorsal plane of the scapula.
This comparison can be easily achieved for the
Teres Minor infraspinatus given the proximity of the muscle

Anatomy and Ultrasound Evaluation

The teres minor muscle primarily originates from

the axillary border of the scapula caudal to the
infraspinatus but also has two aponeurotic lami-
nae that arise from the infraspinatus and teres
major muscles. The muscle courses superolater-
ally to insert onto the humeral greater tuberosity
inferior facet and directly on the shaft of the
humerus. The teres minor externally rotates and
adducts the humerus. It is important to note that
the fusion of the infraspinatus and teres minor Fig. 5.14 Longitudinal view of teres minor (*) at its
humeral insertion
muscles is a normal variant that may be seen. In
this case, the paired muscle bellies share a com-
mon aponeurosis that inserts broadly on the
greater tuberosity [6].
For ultrasound examination, the patient can
be maintained in the same neutral position as
the infraspinatus evaluation. The teres minor
muscle is identified just caudal from the infra-
spinatus muscle and has a more rounded
appearance in short axis compared to the elon-
gated appearance of the infraspinatus. A subtle
ridge in the infraspinatus fossa may also be Fig. 5.15 Transverse view of the teres minor (*) at its
seen in short axis separating the muscle bellies humeral insertion. Infraspinatus (^) is visualized cepha-
of each muscle. In long axis, the tendon of the lad/proximal on the humerus from the teres minor
84 D. R. Lueders et al.

bellies. Comparison between all three muscles Subacromial/Subdeltoid Bursa

requires panoramic evaluation. Since the teres (SASD Bursa)
minor is the smallest of the rotator cuff muscles
and is rarely injured, it often serves as a helpful Anatomy and Ultrasound Evaluation
reference point for pathology of the supraspina-
tus and infraspinatus. The SASD bursa is located deep to the acromion,
deltoid, and subdeltoid fascia [74] and superficial
to the supraspinatus tendon [75, 76]. It averages
Pathology 55.6 mm medial to lateral length and 55.7 mm in
anterior to posterior width. It is a potential space
Teres minor pathology is rare relative to the and is very thin when not inflamed, scarred, or
other muscles of the rotator cuff. Teres minor distended with fluid [75]. It may extend as far
tendon injury is usually related to acute trauma anterior as the acromioclavicular (AC) joint [75].
directly affecting the area. Extension of tears The SASD bursa does not communicate with the
from the infraspinatus tendon into the teres glenohumeral (GH) joint [76], unless a full-­
minor tendon is also rare [5]. Signs of denerva- thickness rotator cuff tear exists. As it passes
tion may be observed in the teres minor and are around the proximal humerus, the axillary nerve
commonly caused by impingement of the axil- courses about 1.0 cm caudal to the posterolateral
lary nerve in the quadrilateral space as discussed boarder of the SASD bursa (range 0.0–1.4 cm)
elsewhere in this chapter. While the deltoid may [74, 77].
be involved, isolated teres minor atrophy can On ultrasound evaluation of the SASD bursa,
also occur, depending on the exact location the patient’s arm in held in adduction and neutral
where the innervating nerve is entrapped [72]. rotation. The probe is oriented in long axis to the
The innervation of the teres minor has been supraspinatus tendon in the coronal or coronal-­
found to be variable, likely explaining how the oblique plane with the acromion in view (image
teres minor might be selectively affected over of probe placement). A high-frequency linear
other muscles innervated by the axillary nerve array transducer is optimal and will be utilized in
[72]. The bundles within the teres minor may even the most muscular or obese patients, given
even be selectively affected, as noted in a 2019 the relatively superficial location of the bursa.
study by Kang et al. [73]. The SASD is a thin potential space in normal
states, appearing as a thin hypoechoic plane over-
lying the rotator cuff tendons (Fig. 5.16). When
Interventional Procedures acutely or chronically inflamed, the bursa appears
as a 2 mm or thicker complex comprised of an
No systematic studies of regenerative treat-
ment for the teres minor tendon pathology have
been performed, likely because the rarity of
teres minor pathology, so recommendations
beyond those made for the general rotator cuff
as discussed in the section on the supraspinatus
cannot be made. If quadrilateral space pathol-
ogy is suspected as a possible cause of dener-
vation of the teres minor, evaluation and
injection for this space is discussed in the sec-
tion on the quadrilateral space. Injections into
Fig. 5.16 The subacromial-subdeltoid bursa (*) in nor-
the teres minor and muscle are rare but follow mal states is visualized as a thin, hypoechoic stripe super-
the same procedural guidelines as those for the ficial to the longitudinal supraspinatus and the hyperechoic
infraspinatus. peribursal fat deep to the overlying deltoid
5 Shoulder 85

inner layer of hypoechoic fluid between two lay- ies have reported on the injection of orthobiologics
ers of hyperechoic peribursal fat [78]. In cases of into the SASD bursa [84, 85]. Nejati et al. com-
subtle bursal effusion, fluid accumulates in the pared two ultrasound-guided injections of
most distal and dependent aspect of the bursa and leukocyte-­rich platelet-rich plasma (PRP) into
may be visualized several centimeters distal to the SASD bursa and about the rotator cuff ten-
the insertion of the rotator cuff by sliding the dons (RTC) to a course of physical therapy that
probe laterally [8, 78]. Care should be taken to progressed from passive range of motion exer-
apply minimal pressure with the probe over the cises (ROM) to strengthening of the scapular sta-
bursa so as to not artifactually displace a bursal bilizers. Both interventions effectively reduced
effusion. pain and disability with the physical therapy
cohort showing greater improvement [84]. One
study has compared a palpation-guided
Pathology leukocyte-­poor PRP injection to corticosteroid
injection and showed that the corticosteroid
Inflammation of the SASD bursa and pathology injection significantly improved pain and func-
involving underlying rotator cuff tendons can lead tion compared to the PRP injection [85]. These
to bursitis, and subacromial impingement occurs studies show that PRP can improve pain, func-
as the enlarged or distended bursa is mechanically tion, and ROM but remain inferior to the more
traumatized between the rotator cuff tendons and established corticosteroid injections and physical
the acromion. Pain related to SASD bursitis or therapy [86].
impingement occurs with shoulder abduction, The accuracy of US-guided SASD bursa
flexion, and internal rotation. SASD bursitis and injections is 65–100% [87, 88], as compared to
subacromial impingement are associated with 29–100% accuracy of palpation-guided injec-
supraspinatus tendon thickening (0.6 mm thicker, tions [87, 89–92]. A systematic review and meta-­
p = 0.048) that occupation of a greater percentage analysis comparing US-guided versus
of the subacromial interval between the acromion palpation-guided SASD bursa corticosteroid
and humerus (7.5%, p = 0.014) when measured injections showed statistically significant differ-
on ultrasound [79]. Dynamic ultrasound can iden- ences in pain (p = 0.003), function (p < 0.001),
tify dynamic subacromial impingement by pas- and range of motion (p < 0.001) [83] favoring US
sively or actively abducting the arm and evaluating guidance.
for dyskinetic obstruction of the normal gliding of Procedural protocol:
the SASD bursa under the acromion and pooling
of fluid in the distal and lateral SASD bursa [78, • Patient position – Lateral decubitus on the
80]. Treatment of SASD bursitis and subacromial contralateral, unaffected side. The arm of the
impingement consist of physical therapy to affected side should be adducted, slightly
improve rotator cuff the glenohumeral stability, extended, and in slight internal rotation.
relative rest from provoking or exacerbating activ- • Transducer selection – High-frequency, linear
ities, oral or transdermal non-steroidal anti-­ array transducer (>10 MHz).
inflammatory drugs (NSAIDs), physical • Transducer position – Long axis to supraspi-
modalities (therapeutic ultrasound, manual ther- natus tendon toward its humeral insertion with
apy), interventional procedures (injections), and the acromion in view. The SASD bursa is
surgery [81, 82]. identified superficial to the supraspinatus ten-
don and deep to the deltoid.
• Needle selection – 30-gauge, 1-inch;
Interventional Procedures 27-gauge, 1.5-inch; or 25-gauge, 2-inch
(depending on body habitus).
SASD bursa corticosteroid injections can suc- • Injectate selection – Anesthetize with lido-
cessfully palliate symptoms [83]. Only two stud- caine or Marcaine. Inject steroid or orthobio-
86 D. R. Lueders et al.

logic (most commonly PRP). Typically inject Static stabilizers of the AC joint include the
3–5 mL of fluid. superior, inferior, anterior, and posterior acro-
• Needle trajectory and target structure – In-­ mioclavicular ligaments, the coracoclavicular
plane, lateral to medial approach to the SASD ligaments, and the coracoacromial ligaments.
bursa. The coracoclavicular ligaments reinforce the
• Pearls/pitfalls inferior aspect of the AC joint and prevent supe-
–– Given the convexity of the shoulder, an rior displacement. Dynamic reinforcement of the
entry point distal and lateral to the trans- joint is provided by the fascia of the overlying
ducer should be chosen to ensure that the deltoid and trapezius muscles.
needle trajectory is perpendicular to the Ultrasound evolution of the AC joint can be
ultrasound beam. performed with the patient seated or supine. The
–– The SASD bursa exists between the deltoid arm is adducted to the side and shoulder held in
and rotator cuff tendons, which demonstrate neutral rotation. The AC joint is superficial and
differential motion in shoulder internal and best evaluated with a high-frequency linear array
external rotation movements and shoulder transducer. Localization of the joint can be facili-
abduction. Slight movement in those planes tated and confirmed by multiple approaches. One
can produce differential motion on ultra- reproducible means is to initially place the trans-
sound and aid in confirmation of the exact ducer in an anatomic sagittal plane transversely
tissue plane of the SASD bursa. over the mid-clavicle. The clavicle then appears
–– A non-distended bursa can be a relatively as a hyperechoic convexity of bone. The trans-
non-distinct tissue plane, which can make ducer is then carefully translated laterally toward
confident identification and accurate injec- the acromion, maintaining the clavicle in this
tion challenging. Care must be taken to transverse view, until the convex diaphysis of the
ensure intrabursal flow and not intratendi- clavicle flattens and broadens at its epiphysis
nous or intramuscular deltoid deposition. before falling off into the hypoechoic joint space.
Accurate intrabursal deposition may The transducer is then maintained at this same
accomplish transient retro- or anterograde position and rotated 90 degrees to longitudinal
bursal distension and resolution as the view of the distal clavicle at its articulation with
injectate disperses throughout the bursa. the acromion (Fig. 5.17).
Accumulation of fluid in one location with- Normal AC joint space width has been
out dispersion suggests extrabursal place- reported in radiographic studies as 1–3 mm at the
ment [83] and should prompt repositioning superior margin of the joint [94]. However, there
of the needle tip. can be significant variability in joint space mea-
surement because of individual anatomic varia-
tions and US probe location. If concern for joint
Acromioclavicular Joint

Anatomy and Ultrasound Evaluation:

The acromioclavicular (AC) joint is a diarthro-

dial articulation of the acromion and clavicle in
the anterolateral shoulder that acts as a strut to
anchor the complex movements of the scapula
and arm to the thorax [93]. The articular surfaces
of the acromion and clavicle are covered with
hyaline cartilage. A meniscus-like fibrocartilagi-
nous disc separates those surfaces but has a neg- Fig. 5.17 Longitudinal view of the acromioclavicular
ligible contribution to joint function [93]. joint
5 Shoulder 87

separation or widening exists, the contralateral capsular musculature (which is often ineffective),
AC joint width should be measured and assessed activity modification, NSAIDs, and intra-­
for symmetry. Dynamic evaluation for sono- articular joint injection [95].
graphic widening or narrowing and correspond- Acromioclavicular joint separation can occur
ing pain can be performed by having the patient secondary to a traumatic ligamentous sprain or
cross-body adduct their ipsilateral hand to the chronic, attritional ligamentous disruption of one
contralateral shoulder. The acromioclavicular or several of the static stabilizers of the joint. The
ligament is seen overlying the joint capsule. Rockwood classification system is the most com-
Other ligamentous stabilizers of the AC joint are monly used system to classify injuries but is based
obscured from sonographic visualization by sur- on radiographic findings from bilateral anterior-
rounding bony anatomy. to-posterior, axillary, and Zanca views. US corre-
The joint can also be evaluated in a long-axis lates to the Rockwood classification are described
and anatomic sagittal view by scanning along the in Table 5.1. Joint widening, superior clavicular
clavicle in a sagittal oblique plane until the hyper- displacement, and increased joint mobility can be
echoic contour of the clavicle rises up superfi- identified by ultrasound evaluation; however,
cially before dropping off into the hypoechoic many ligaments that stabilize the AC joint cannot
joint space, which contains the hypoechoic fibro- be directly visualized with ultrasound, and US
cartilaginous disc. This view is rarely used for measurements of displacement can be inconsis-
diagnostic purposes but can be used for in-plane tent, both of which can limit its diagnostic sensi-
visualization of a needle during an AC joint injec- tivity in the context of suspected separation. AC
tion, as described below. The supraspinatus ten- joint effusion is identified as a hypoechoic, com-
don is deep to the AC joint, and a small extent of pressible fluid collection that superiorly distends
the tendon can often be visualized through to the in the joint space greater than 3 mm, and may
joint space. result from acute injury, chronic degenerative
changes, or communicating from the glenohu-
meral joint in the context of a full-­ thickness
Pathology supraspinatus tear [98]. Treatment of AC joint
separation depends on the type; anesthetic injec-
The most common AC joint pathologies are tions can be performed for pain control.
osteoarthritis and ligamentous injury resulting in An os acromiale results from incomplete
AC joint separation. AC joint osteoarthritis is fusion of the anterior epiphysis of the acromion
characterized by joint space narrowing and corti- and is present in about 8% of the population and
cal irregularities of the clavicle and/or acromion. is present bilaterally in about one third of that
AC joint degeneration can occur due to age-­ population [100]. The os acromiale can relate to
related degeneration, post-traumatic arthropathy, the lateral acromion by means of a separate artic-
and, less commonly, distal clavicle osteolysis, ulation, a fibrocartilaginous union, or nearly
inflammatory arthropathy, septic arthritis, and complete fusion [100]. Pain can result from
joint instability [95], each of which can contrib- anterosuperior impingement of the underlying
ute to fraying or tearing of the intra-articular disk subscapularis tendon by a mobile os body or by
and maceration of the chondral surface of the secondary osteophytes. This synchondrosis
diarthrodial joint [96]. Patients with AC joint should not be mistaken for a fracture or for the
arthritis will have tenderness with palpation true AC joint. The acromion’s articulation with
directly over the AC joint and pain with cross-­ the os acromiale can be differentiated from the
body shoulder adduction [97]. AC joint arthritis true acromioclavicular joint by its orientation,
is treated conservatively with physical therapy which is approximately perpendicular to the
focused on ROM and strengthening of the peri-­ plane of the acromioclavicular joint [6, 101].
88 D. R. Lueders et al.

Table 5.1 AC joint separation Rockwood classification with ultrasound correlation

Definition
AC CC
Type ligament ligament Radiographs US description
1 Sprain Normal Normal Asymmetric joint space widening. Irregular-­
appearing capsular fibers. Hypoechogenic edema
within the joint space. No step off between the
clavicle and acromion
2 Torn Sprain Superiorly displaced lateral Visible step off between the (medial) clavicle and
clavicle. Increased (lateral) acromion. Joint space widening and
coracoclavicular distance <25% increased clavicle mobility when stressed
3 Torn Torn Superiorly displaced lateral More prominent step off between the clavicle and
clavicle. Increased acromion. Joint space widening and increased
coracoclavicular distance clavicle mobility when stressed
25–100%
4 Torn Torn Posteriorly displaced lateral Horizontal instability with dynamic maneuvers with
clavicle posterior clavicular displacement [99]
5 Torn Torn Superiorly displaced lateral Acromioclavicular step off greater than 100%. Joint
clavicle. Increased space widening when stressed
coracoclavicular distance
>100%
6 Torn Torn Inferiorly displaced lateral There is a larger step off between the acromion and
clavicle clavicle with the clavicle displaced inferiorly

An AC joint cyst results from glenohumeral ultrasound-guided injection of 15% dextrose pro-
joint fluid tracking into the acromioclavicular lotherapy into the AC joint (one or two injections
joint because of a massive rotator cuff tear, lead- 1 month apart) or near the distal acromion and
ing to significant distension of the superior joint showed substantial pain reduction with average
capsule. On coronal evaluation of the AC joint, visual analog scale (VAS) reduction of 4.3 points
this can appear as hypoechoic fluid emerging (p < 0.01) [108].
from the underlying narrow joint space and Despite the superficial location of the AC
termed a “geyser sign.” This finding should joint, accuracy of palpation-guided AC joint
prompt a full evaluation of the rotator cuff. injections is very low (36.5–72%) [91, 109–112].
Ultrasound-guided injections of various
approaches have accuracies of 90–100% but have
Interventional Procedures not been directly compared [109, 110].
Procedural protocol: AC joint injection, ante-
AC joint anesthetic injection can be performed rior to posterior
for diagnostic purposes in the context of AC joint
arthritis or cysts to assist the clinic • Patient position – Supine or seated. The ipsi-
­decision-­making [102–104] and for analgesia in lateral shoulder and arm are held at the side in
the setting of AC joint separation [105]. AC joint comfortable, neutral anatomic positions.
corticosteroid injections have been reported to • Transducer selection – High-frequency, small-­
have poor efficacy in symptom palliation and to footprint linear array transducer (>10MHz).
achieve only short-term benefit [103, 106]. The small footprint aids in maneuverability of
Definitive management can include surgical the probe and needle.
resection of the distal clavicle, but this can result • Needle selection – 30-gauge, 1-inch; or
in postoperative joint instability [95, 103, 106, 27-gauge, 1.5-inch.
107]. Orthobiologics can be used to treat AC joint • Injectate selection – Local anesthesia is often
pathology, but only one study on prolotherapy not used since the joint is so superficial. Inject
has been reported. That study describes the use of anesthetic (for diagnostic purposes), steroid,
5 Shoulder 89

orthobiologic (PRP or prolotherapy). Typically jectory of the needle to inform whether

inject <1 mL of fluid. withdrawal and redirection is necessary to
• Technique #1. ensure its c­ontinued accurate trajectory
–– Transducer position – Short axis to clavicle and its final location within the joint
over joint with no bony structures in view. space.
Anatomic sagittal plane. The hypoechoic Pearls/pitfalls
AC joint space is identified between the • Utilizing the walk-down technique is
hypoechoic margins of the clavicle and helpful in executing the injection.
acromion. • The AC joint is very small; therefore,
–– Needle trajectory and target – In-plane, a small amount of fluid should be
anterior to posterior into AC joint. injected.
–– Pearls/pitfalls • The transducer can be rotated 90
The AC joint is very small; therefore, degrees to determine the anterior-­
only the smallest volume as needed posterior location of the needle tip
should be injected, usually about 1 mL. within the joint.
The location of the needle insertion site • Technique #3: Lateral to medial AC joint
at the skin should take into account the injection
convexity of the anterior shoulder and –– Patient position – Supine or seated. The
the depth of the joint space from the ipsilateral shoulder and arm are held at the
skin and the joint capsule to facilitate a side in comfortable, neutral anatomic
near-parallel trajectory to the joint for positions.
optimal needle visualization. –– Transducer selection – High-frequency,
The transducer can be rotated 90 degrees small-footprint linear array transducer
to confirm that the needle tip is in the (>10 MHz).
joint in an out-of-plane visualization –– Transducer position – Long axis to clavicle
between the clavicle and acromion. and acromion with those bony contribu-
• Technique #2 tions to the joint completely visualized.
–– Transducer position – Long axis to clavicle Anatomic axial plane. The hypoechoic AC
and acromion with those bony contribu- joint space is identified between the hyper-
tions to the joint completely visualized. echoic convex margins of the clavicle and
Anatomic axial plane. The hypoechoic AC acromion.
joint space is identified between the hyper- –– Needle selection – 30-gauge, 1-inch; or
echoic convex margins of the clavicle and 27-gauge, 1.5-inch.
acromion. –– Injectate selection – Injection of local anes-
–– Needle trajectory and target – Out-of-­ thesia with lidocaine or Marcaine, as the
plane, anterior to posterior into the AC subcutaneous needle course is slightly lon-
joint. ger than anterior-to-posterior approaches.
–– In an out-of-plane approach, the needle is Inject anesthetic (for diagnostic purposes),
visualized as a hyperechoic, punctate dot. steroid, or orthobiologic (PRP or prolother-
The ultrasound transducer should be apy) to the joint. Typically inject about
translated anteriorly (toward the sternum) 1 mL of fluid.
to meet the needle tip shortly after it is –– Needle trajectory and target – In-plane, lat-
inserted into the skin to identify its loca- eral to medial into AC joint.
tion and to estimate it’s trajectory. Small-­ A generous gel standoff at the lateral
caliber translations anteriorly and aspect of the transducer overlying the
posteriorly will aid in the triangulation of acromion will facilitate an improved nee-
the superficial/deep and medial/lateral tra- dle visualization, as there is often only a
90 D. R. Lueders et al.

small amount of tissue overlying the acro- Pathology

mion and AC joint. A gel standoff permits
needle visualization and redirection Injuries of the SC joint are uncommon, but acute
before skin entry to optimize the approach injuries can be severe to life-threatening.
to the joint and improve ultimate accu- Ultrasound can identify subluxation or disloca-
racy of needle placement. A skin entry tion of the SC joint as an excessive, asymmetric
that is too far lateral may dictate an step off between the sternum and clavicle.
approach trajectory that is too far media Comparison to the contralateral side is helpful.
or lateral and can make entry into the joint US can also identify atraumatic pathology, most
unnecessarily challenging or impossible. commonly arthritis. SC joint arthritis occurs most
commonly in patients with rheumatoid arthritis;
is characterized by narrowing of the joint space,
Sternoclavicular (SC) Joint osteophytes, and para-articular cysts; and is ame-
nable to corticosteroid injections. Septic arthritis
Anatomy and Ultrasound Evaluation is associated with increased joint fluid of mixed
echogenicity and often requires aspiration and
The SC joint is a saddle-shaped joint between the analysis of joint fluid or surgical washout [116].
manubrium of the sternum and first rib medially
and the medial end of the clavicle laterally [113].
It is the only articulation between the thorax and Interventional Procedures
the upper limb. The SC joint is stabilized by the
anterior and posterior sternoclavicular ligaments, Description of the use of orthobiologics to treat
the interclavicular ligaments, and the costocla- the SC joint is scarce in the literature. One case
vicular ligaments [113, 114]. A fibrocartilaginous reports the use of orthobiologics in the treatment
disk separates the joint into clavicular and sternal of SC joint instability and describes the use of six
compartments. Age-related degeneration can injections of prolotherapy (a mixture of 22% dex-
result in communication between these compart- trose and procaine was used for some injections
ments [114, 115]. and “more traditional” prolotherapy for others)
The sternoclavicular joint is visualized sono- and one leukocyte-poor PRP injection, followed
gramphically with the probe in a coronal or axial by seven additional prolotherapy injections (22%
plane spanning the joint, with the clavicle visual- dextrose and 1 mL of sodium morrhuate and pro-
ized in long axis, and the sternum visualized caine) into the bilateral SC joint capsular and
medially (Fig. 5.18). A small-footprint linear ligamentous tissue that resulted in resolution of
array transducer is most commonly used and pain and popping symptoms [117].
should be scanned in a cephalad to caudad The SC joint is not commonly injected, and
maneuver to evaluate the entire joint. different methods of guidance have been reported.
Palpation-guided injections of the SC joint have a
reported accuracy of 78%. Computed tomogra-
phy (67% accuracy) [118, 119] and fluoroscopy
[120] have been successfully used for needle
guidance into the SC joint. Sonographic guid-
ance is reported to have a 100% accuracy for
injection of the SC joint [121].
Procedural protocol:

• Patient position – Supine or seated. The arm

of the affected side is in neutral anatomic
Fig. 5.18 Longitudinal view of the sternoclavicular joint position.
5 Shoulder 91

• Transducer selection – High-frequency, small-­ noid to extend the depth of the glenoid socket by
footprint linear array transducer (>10 MHz). 50%. The lax and redundant glenohumeral joint
• Transducer position – Spanning the SC joint capsule allows for a wide range of motion and
with the clavicle in long axis. extends from the margins of the glenoid rim and
• Needle selection – 30-gauge 1-inch; or labrum to the anatomic neck of the humerus. The
27-gauge 1.5-inch. capsule has several recesses in which fluid can
• Injectate selection – Can anesthetize with accumulate in the setting of effusion (dependent
lidocaine or Marcaine. Inject anesthetic (for axillary pouch, posterior and anterior recesses,
diagnostic purposes), steroid, or orthobiologic subscapularis recess, sheath of the long head of
(PRP or prolotherapy). Typically inject <1 mL the biceps tendon).
of fluid. The joint is stabilized by both static and
• Needle trajectory and target – Out-of-plane, dynamic stabilizers. The glenohumeral ligaments
anterior to posterior into the SC joint. provide static stability to the joint (Table 5.2).
• Pearls/pitfalls. The glenoid labrum is composed of a fibrocarti-
–– A hyperechoic intra-articular disk may be laginous tissue and additionally contributes to
visualized within the joint.
–– Take caution to avoid advancement of the Table 5.2 Static stabilizers of the glenohumeral joint
needle beyond the SCJ where it can injure
Ligament Biomechanics
neurovasculature. Superior Restraint to anteroinferior
–– The transducer can be rotated 90 degrees to glenohumeral translation of long head of
confirm that the needle tip is in the joint. Ligament biceps (biceps pulley) and
inferior translation at 0 degrees
of abduction
This injection can also be performed with the
Middle Resists anterior and posterior
same setup using an in-plane, lateral to medial glenohumeral translation in the midrange of
technique with gel standoff. This involves a lat- Ligament abduction (~45 degrees of
eral gel standoff and toe-ing in the medial side of external rotation)
the transducer. The smaller footprint and greater Inferior Most important restraint to
glenohumeral posterior subluxation at 90
maneuverability of a small-footprint linear array Ligament (Posterior degrees of flexion and internal
transducer makes this easier. Such an approach, Band) rotation
standoff, and small-footprint transducer improve Tightness is linked to SLAP
the ease of injection, given the minimal subcuta- lesions
Inferior Primary restraint to anterior/
neous tissue in this area through which to guide glenohumeral inferior translation 90 degrees
or redirect a needle to ensure placement within Ligament (Anterior abduction and maximal external
the joint space. Band) rotation
Weak link predisposing to
Bankart lesions
Inferior Most important stabilizer of the
 lenohumeral (GH) Joint
G glenohumeral joint
and Rotator Interval Ligament (superior
band)
Anatomy and Ultrasound Evaluation Coracohumeral From coracoid to rotator cable
ligament Limits posterior translation with
should in flexion, adduction, and
The GH joint is a shallow ball and socket joint internal rotation
comprised of the articulation between the pear-­ Limits inferior translation in
shaped glenoid fossa of the scapula and the external rotation and adducted
position
­spheroidal humeral head. The shallow nature of Thickened in adhesive capsulitis
this articulation affords the most range of motion SGHL superior glenohumeral ligament, MGHL middle
of any joint in the body. The glenoid labrum is a glenohumeral ligament, IGHL inferior glenohumeral liga-
fibrocartilaginous tissue that encircles the gle- ment, SLAP superior labrum from anterior to posterior
92 D. R. Lueders et al.

static stability by helping to create 50% of the

glenoid socket depth. The anterior labrum
anchors the inferior glenohumeral ligament, and
the superior labrum anchors the biceps tendon.
Several normal variants of the glenoid labrum
occur and must not be mistaken for pathology,
including a cord-like middle glenohumeral liga-
ment (MGHL), sublabral foramen, sublabral
foramen plus cord-like MGHL, and a Buford
complex, which consists of an absent anterosupe-
rior labrum and cord-like MGHL. Dynamic sta- Fig. 5.19 Posterior glenohumeral joint. The posterior
articulation the humeral head laterally with the glenoid,
bilizers consist of the periscapular muscles, medially. The infraspinatus is visualized superficial to the
biceps tendon, rotator interval, and rotator cuff joint space, and the glenoid labrum (*) is visualized as a
muscles (supraspinatus, infraspinatus, teres hyperechoic triangular-appearing structure contiguous
minor, subscapularis). The rotator cuff muscles with the glenoid
provide dynamic stability by compressing the
humeral head against the glenoid. proximal long head of the biceps tendon. The
At the rotator interval, the capsule is rein- SGHL is located at the subscapularis side of the
forced externally by the coracohumeral ligament biceps brachii tendon with fibers merging with
(CHL) and internally by the superior glenohu- the CHL that lies superficial to the biceps tendon.
meral ligament (SGHL) and traversed by the The supraspinatus tendon lies posterolateral to
intra-articular portion of the long head of the the biceps tendon at the rotator interval, and the
biceps tendon [13]. The interval lies between the hypoechoic ligament, which separates them,
anterior margin of the supraspinatus and superior should not be misinterpreted as a tendon tear
margin of the subscapularis tendon [13]. The [122]. (Fig. 5.2).
intra-articular portion of the biceps tendon and
the biceps pulley system lie within the rotator
interval [13]. Pathology
On ultrasound evaluation, the posterior GH
joint is evaluated using a liner array transducer A glenoid labral tear can occur secondary to
with the patient seated and the shoulder in neutral trauma or repetitive microtrauma of overhead
rotation. A lower frequency curvilinear array activities (SLAP). A labral tear is described by
transducer may be necessary in patients with a its location and can occur concomitantly with
large or more muscular body habitus. The trans- internal impingement, glenohumeral internal
ducer is placed in an oblique axial plane with the rotation deficit (GIRD), rotator cuff tears, and
lateral end of the probe angled superiorly toward scapular dyskinesis. Ultrasound can be a highly
the humeral head just inferior to the scapular specific tool to identify a posterior labral tear
spine. The GH joint is visualized deep to the cen- (98%), although it is not highly sensitive (63%)
tral tendon of the infraspinatus (Fig. 5.19). The [123]. There is a substantial agreement between
articulation between the humeral head and gle- sonoarthrography and MR arthrography for the
noid should be evaluated from proximally under diagnosis of posterior labral tears [124].
the acromion to distally to the humeral surgical Glenohumeral joint injection can be both diag-
neck. The posterior glenoid labrum can also be nostic (using anesthetic) and therapeutic for
visualized and can be made more conspicuous labral injuries [125].
with shoulder internal and external rotation. Ultrasound can be applied to accurately
The anterior GH joint and rotator interval are evaluate the shoulder after an acute dislocation
evaluated with the patient in a modified Crass or subluxation and has been shown to have
position and the transducer in short axis to the 100% accuracy in several studies in identifying
5 Shoulder 93

the characteristic hypoechoic or anechoic Nonsurgical management of GH adhesive

interval between the humeral head and the gle- capsulitis can include PT, extracorporeal shock
noid [126, 127]. Ultrasound can also identify a wave therapy, corticosteroid injections, and cap-
Hill-Sachs lesion and dynamically visualize sular hydrodistension. Most patients will see
engagement of the humeral lesion within the complete resolution of pain and full return of gle-
glenoid rim, an indication for surgical evalua- nohumeral motion after conservative treatment
tion [128]. and time [137–142]. Manipulation under anes-
GH joint arthritis affects up to 32.8% of those thesia or arthroscopic capsular release can be
over 60 years old and can develop after shoulder considered in refractory cases [137].
trauma, in the setting of rotator cuff degenera-
tion, or secondary to rheumatoid arthritis [129].
Findings on ultrasound can include marginal Interventional Procedures
osteophyte formation and joint space narrowing.
Nonsurgical management of GH osteoarthritis In patients with GH joint arthritis, injection of
includes activity moderation and modification, HA has had shown mixed outcomes. Several
NSAIDs, injection therapies, and physical ther- small retrospective case series [143–147] and one
apy (PT) focused on periscapular strengthening retrospective case-control study [148] reported a
and stretching [130, 131] (1, 12. Surgical inter- significant reduction in pain and improvement in
ventions can consist of debridement and capsular function in patients with GH arthritis treated with
release, or a type of shoulder replacement) HA, but two large randomized controlled trial did
[131–133]. not show superiority of HA to placebo [149,
Adhesive capsulitis is characterized by limited 150]. The majority of the studies utilized palpa-
range of motion (ROM) followed by shoulder tion guidance for the injections, which may con-
pain. Shoulder external rotation is most com- found the results [144, 146–150]. Only one study
monly affected. It can be idiopathic or can be reports the injection of PRP into the GH joint,
associated with diabetes mellitus, trauma, and and this was in the context of GH adhesive capsu-
immobilization. It is characterized by three clini- litis. Cell-based therapies have limited evidence
cal stages (Table 5.3). The most sensitive and in treating patients with GH joint arthritis. One
specific ultrasound finding reported is a dimin- case series of 115 patients with GH joint arthritis
ished sliding movement of the supraspinatus ten- with or without RTC tear showed improved pain
don beneath the acromion with shoulder and physical function for up to 2 years following
abduction, which has a 91% sensitivity, 100% bone marrow aspirate concentrate (BMAC) injec-
specificity, and 92% accuracy for detecting adhe- tion, but the study was limited by heterogeneity
sive capsulitis [134]. Abnormal hypoechogenicity in the patient population and lack of a control
and hyperemia at the rotator interval have been group [151]. A case series of the use of micro-
demonstrated in up to 86% of patients with adhe- fragmented adipose tissue (MFAT) to treat 20
sive capsulitis [135]. Thickening of the coracohu- patients with GH arthritis and concomitant rota-
meral ligament (3 mm vs 1.39 mm in controls) is tor cuff tear resulted in improvements in pain and
also seen [136]. function at 12 months [152].
Although orthobiologic injections into the GH
joint are sometimes implemented to treat glenoid
Table 5.3 Clinical stages of adhesive capsulitis
labral pathology, there are no PubMed indexed
Clinical studies describing or supporting PRP injections
stage Description
Freezing/ Gradual onset of diffuse pain
to treat labral pathologies [153].
Painful (6 weeks–9 months) Ultrasound-guided interventional procedures
Frozen/Stiff Decreased ROM affecting activities of are commonly performed to treat GH adhesive
daily living (4–9 months or more) capsulitis. Corticosteroid injections are generally
Thawing Gradual return of motion (5–26 months) accepted as a mainstay of treatment with short-­
94 D. R. Lueders et al.

term efficacy, although a high degree of variance is be placed just lateral to the inferior scapular
seen in the dose of corticosteroid administered, spine.
location of injection, and performance of concom- • Needle selection – 25-gauge, 2.5-inch (or lon-
itant procedures at the time of steroid injection ger if larger body habitus)
[154–159]. Several studies have compared the • Injectate selection – Anesthetize with lido-
clinical efficacy of anterior (rotator interval) to caine or Marcaine. Inject steroid or orthobio-
posterior GH joint injections in patients with fro- logic (most commonly PRP). Typically inject
zen shoulder with two studies showing no clinical 3–5 mL of fluid or > 10 mL if treating adhe-
difference [160, 161] and one showing faster and sive capsulitis.
more significant improvement with steroid injec- • Needle trajectory and target structure – In-­
tion into the rotator interval [162]. Hydrodistension plane, lateral to medial approach into to the
of the joint capsule with a high volume of injectate GH joint. Needle will traverse through the
is commonly used to treat adhesive capsulitis, but infraspinatus musculotendinous unit. Greater
one meta-analysis of 12 studies reported that it had glenohumeral internal rotation and cross-body
only a small, clinically insignificant effect [140]. adduction will pull the infraspinatus tendon
The use of orthobiologics to treat adhesive capsu- anteriorly, ensuring that the needle traverses
litis is emerging, with one study demonstrating more through musculature than tendon. Ensure
that injection of a single dose of intra-articular that the needle tip is deep to the infraspinatus
PRP was more effective than intra-articular corti- and glenoid labrum, adjacent to the hypoechoic
costeroid injection on improving pain, function, articular cartilage of the humeral head
and ROM [163] and was more effective than pro- • Pearls/pitfalls
caine on pain and function [164]. Some advocate –– Take care to identify to not to injure the
for the use of orthobiologics rather than corticoste- glenoid labrum.
roids to treat adhesive capsulitis in diabetics to –– The injectate should flow readily into the
minimize blood sugar elevation, but this has not large, accommodating GH joint. Visible
been specifically reported in the literature. accumulation of injectate in one area sug-
The use of ultrasound guidance greatly gests extraarticular placement and should
improves the accuracy of GH joint injections prompt redirection of the needle tip.
relative to palpation-guided injections. Palpation-­ –– Placement of the needle superficial and
guided anterior GH joint injections are 26–95.7% medial to the GH joint poses risk of injury
accurate [165, 166] and posterior GH joint injec- to neurovascular structures in spinoglenoid
tions 42–96% accurate [92, 167–169]. Ultrasound notch.
guidance of injections to the GH joint improves
accuracy to 92% with an anterior approach (rota- Procedural protocol: Anterior approach to GH
tor interval) [170] and to 92.5–100% with a pos- joint at rotator interval
terior approach [168, 170–173].
Procedural protocol: Posterior approach to • Patient position – Supine. The arm adducted
GH joint and in slight GH external rotation.
• Transducer selection – High-frequency linear
• Patient position – Lateral decubitus with the array transducer (>10MHz)
affected side up. The arm should be in neutral • Transducer position – Anatomic axial plane
or slight internal rotation. over the rotator interval with the long head of
• Transducer selection – Low-frequency, curvi- the biceps tendon in short axis.
linear (>10 MHz), or midrange linear array • Needle selection – 27-gauge 1.5-inch; or
transducer 25-gauge 2.5-inch
• Transducer position – Short axis to the joint in • Injectate selection – Anesthetic with lidocaine
the oblique axial plane. The transducer should or Marcaine. Inject steroid or orthobiologic.
5 Shoulder 95

Volume of about 5 mL, or > 10 mL if treating engorgement of the vein when the arm is in exter-
adhesive capsulitis. nal rotation should not be mistaken for a spinogle-
• Needle trajectory and target – In-plane, lateral noid notch cyst.
to medial approach into the space deep to the
coracohumeral ligament and superficial to the
LHBT. Pathology
• Pearls/pitfalls.
–– Slight external rotation of the arm improves Compression of the suprascapular nerve in the
visualization of the long head of the biceps spinoglenoid notch results in infraspinatus
tendon and structures of the rotator interval. denervation. Neural injury can be secondary to
a spinoglenoid notch ganglion cyst [176, 177],
GH paralabral cyst secondary to posteroinferior
Spinoglenoid Notch glenoid labral tear (most common) [178, 179],
or traction injury, as seen in volleyball players
Anatomy and Ultrasound Evaluation [180]. Cysts can be difficult to visualize on
ultrasound due to their deep location. Placing
The spinoglenoid notch is formed between the the ipsilateral hand on the contralateral shoul-
lateral side of the scapular spine and the posterior der may make spinoglenoid notch more superfi-
part of the glenoid, and the spinoglenoid liga- cial and improve diagnostic assessment.
ment spans these two bony structures of the scap- Paralabral cysts are most commonly visualized
ula [174]. The suprascapular nerve traverses the in the superficial region of the spinoglenoid
spinoglenoid notch before innervating infraspi- notch. If denervation has occurred, the infraspi-
natus. The suprascapular artery and vein course natus muscle will appear atrophied and hyper-
lateral to the suprascapular nerve in the spinogle- echoic relative to the ipsilateral supraspinatus
noid notch and occupy 68.5% of the suprascapu- and to the contralateral infraspinatus. The vol-
lar notch [175]. ume of a paralabral cyst has been shown to
During sonographic evaluation, the spinogle- directly correlate with the degree of infraspina-
noid notch is localized medial to the posterior GH tus atrophy [179]. Infraspinatus denervation
joint by translating the transducer medial and can be confirmed with electrodiagnostic stud-
from the joint and rotating the medial end of the ies. Varicosities and enlarged spinoglenoid
transducer slightly cephalad (Fig. 5.20). Color notch veins are also seen at the spinoglenoid
doppler should be applied to identify the vascular notch. Veins are not stationary and will dynami-
structures within the spinoglenoid notch. Dynamic cally vary in size with different shoulder move-
ments. Color Doppler should be used to rule out
the presence of blood flow in any cystic-appear-
ing structure.

Interventional Procedures

A sonographically lateral-to-medial spinoglenoid

notch paralabral cyst aspiration can have up to an
86% success rate for pain reduction [181]. The
use of orthobiologics to treat pathology of the
Fig. 5.20 The spinoglenoid notch (*) is visualized
spinoglenoid notch region has not been reported.
between the scapular spine medially and the glenoid later-
ally. The suprascapular nerve lies within the spinoglenoid Procedural protocol: Spinoglenoid notch
notch and infraspinatus superficial to that nerve injection or cyst aspiration
96 D. R. Lueders et al.

• Patient position – Lateral decubitus with the Table 5.4 Suprascapular notch anatomy
affected side up. The arm should be in neutral Rate of
or slight internal rotation. Type occurrence Description
1 6–22% Notch is absent. The superior
• Transducer selection – Low-frequency, curvi-
border forms a wide depression
linear (>10 MHz) from the medial angle to the
• Transducer position – Just inferior and paral- coracoid process
lel to the lateral edge of the spine of the scap- 2 8–31% Notch is a blunted V-shaped
ula. The medial end of the transducer should occupying the middle third of the
superior boarder
be rotated slightly cephalad to optimize visu-
3 29–60% Notch is U-shaped with nearly
alization of the spinoglenoid notch. parallel margins
• Needle selection – 27-gauge, 1.5-inch; 4 3–13% Notch is V-shaped and very small
25-gauge, 2.5-inch (or longer if larger body 5 6–18% Notch is minimal and U-shaped
habitus) needle can be used for local anes- with a partially ossified ligament
6 2–6% Notch is a foramen since the
thetic. An 18-gauge 2.5- or 3.5-inch needle
ligament is completely ossified
should be used for aspiration of a cyst.
• Injectate selection – Anesthetize with lido-
caine or Marcaine. Inject steroid or orthobio-
logic (most commonly PRP). Typically inject
3–5 mL.
• Needle trajectory and target structure – In-­
plane, medial to lateral approach to the spino-
glenoid notch cyst.
• Pearls/pitfalls
–– Color Doppler should be used to rule out
the presence of blood flow in any cystic-­
appearing structure to ensure that the tar-
geted structure is not vasculature. Fig. 5.21 Longitudinal view of the suprascapular notch (*)
–– If one wishes to both aspirate/inject in the
spinoglenoid notch and to inject into the scapular ligament traverses superficial to the
posterior GH joint, the same needle entry notch and forms a roof to a foramen through
point can be used by slightly withdrawing which through suprascapular nerve travels. The
the needle from the spinoglenoid notch and suprascapular artery travels superficial to the lig-
redirecting the needle more steeply to the ament [183].
more lateral GH joint. Ultrasound evaluation of the suprascapular
notch is performed using a curvilinear array
transducer with the patient in the seated posi-
Suprascapular Notch tion. The transducer is placed in long axis to the
supraspinatus tendon within the supraspinous
Anatomy and Ultrasound Evaluation fossa just cephalad to the scapular spine. The
transducer is angled in a caudad direction and
The suprascapular notch is a U- or V-shaped oriented almost directly in a coronal plane,
notch in the lateral body scapula within the supra- which facilitates visualization of the notch
spinous fossa, which is located just medial to the (Fig. 5.21). Depth and focus should be adjusted
base of the coracoid and about 3 cm medial from to optimize the image of the deep suprascapular
the supraglenoid tubercle [182]. Table 5.4 details notch as the muscular bulk of lateral trapezius
the six different anatomical classifications of the and supraspinatus can vary greatly between
notch character [183]. The superior transverse individuals [184].
5 Shoulder 97

Pathology Procedural protocol: Suprascapular nerve

block at the suprascapular notch
Compression of the suprascapular nerve at the
suprascapular notch can occur secondary to a • Patient position – Seated with ipsilateral hand
glenohumeral paralabral cyst, a space-occupying placed on contralateral shoulder.
lesion, or a massive supraspinatus tear or from • Transducer selection – Low-frequency, curvi-
repetitive traction related to overhead sports linear (<10 MHz)
[185]. The notch type (V-shaped is more com- • Transducer position – Parallel to the spine of
monly associated with pathology) and distance the scapula over the supraspinatus fossa with
from the glenoid may be correlated with injury US beam angled caudally to visualize the
risk [186, 187]. Pathologic compression can suprascapular notch.
result in infraspinatus atrophy and possibly • Needle selection – 25-gauge, 3.5-inch needle
supraspinatus atrophy, and patients may com- • Injectate selection – Anesthetize with lido-
plain of shoulder pain, demonstrate arm abduc- caine or Marcaine. Inject anesthetic or steroid.
tion and external rotation weakness, and maintain Typically inject 3–5 mL.
intact sensation. Ultrasound evaluation should • Needle trajectory and target – In-plane,
assess for supraspinatus and infraspinatus atro- medial to lateral (preferred) adjacent to the
phy, manifested as muscular hyperechogenicity suprascapular nerve within the suprascapu-
relative to adjacent or superficial musculature lar notch and deep to the superior transverse
and loss of muscular bulk. A paralabral cyst or scapular ligament. Injection can also be per-
other space-occupying lesion may be visualized formed lateral to medial; however, this
within or adjacent to the suprascapular notch as a requires a much steeper angle of injection,
rounded or oval hypoechoic lesion with well-­ which decrease clarity of needle visualiza-
defined margins that remains relatively fixed with tion and makes needle tracking more
dynamic shoulder movements [184]. challenging.
• Pearls/pitfalls
–– Toe-ing in of the lateral end of the trans-
Interventional Procedures ducer or application of a beam-steering
mode will improve needle visualization.
The suprascapular nerve provides sensation to –– Color Doppler should be applied to iden-
the posterior GH joint and can be blocked prior to tify the suprascapular artery above the
surgical procedures or in the setting of severe GH superior transverse scapular ligament and
joint pathology not amenable to surgery. The to plan an injection course that ensures its
accuracy of ultrasound-guided suprascapular safety.
notch injections for suprascapular neural block-
ade has been reported to be 100% in one cadav-
eric study [188]. However, another study utilizing Quadrilateral Space
EMG current intensity reported that only 18.5%
of suprascapular nerve injections were believed Anatomy and Ultrasound Evaluation
to be close enough to the nerve; however, it could
be reasonably postulated that the spread of anes- The axillary nerve and posterior circumflex
thetic injectate or other medication could still humeral artery course from the axilla anteriorly
result in a sufficient neural blockade [189]. Other to the posterior shoulder through the quadrilat-
studies have shown no difference between eral space, which is bordered superiorly by the
ultrasound-­ guided and landmark-guided supra- teres minor, inferiorly by the teres major, medi-
scapular nerve blocks [190, 191]. There are no ally by the long head of triceps, and laterally by
reports of the injection of orthobiologics agents the humeral surgical neck. Beyond the quadrilat-
near the suprascapular notch. eral space, the axillary nerve innervates the del-
98 D. R. Lueders et al.

toid and teres minor and provides sensation from Pathology

the lateral arm.
A linear transducer is used to evaluate the Quadrilateral space syndrome (QSS) results from
quadrilateral space with the patient in a prone or compression or traction of the axillary nerve (neu-
sitting position and the arm internally rotated. A rogenic), the posterior circumflex humeral artery
posterior longitudinal view of the humeral head (PCHA) (vascular), or both structures as they tra-
and surgical neck is obtained with the teres minor verse the quadrilateral space. QSS is most com-
visualized transversely. The posterior circumflex mon in volleyball [192–195], baseball [137,
humeral artery and axillary nerve can be visual- 196–198] (17, 18, 20, 21, 22), and swimming ath-
ized in short axis at the inferior boarder of the letes, who perform repetitive overhead move-
teres minor at the humerus. Tracing those neuro- ments of abduction and external rotation [199].
vascular structures more proximally along their Additional etiologies include mechanical com-
course and medially, the humerus falls off and pression secondary to improper crutch use or cast
then the true quadrilateral space is visualized application, fibrous bands [200], and paralabral
(Fig. 5.22). Translating more laterally, the poste- cysts [179], or iatrogenic injury during shoulder
rior humeral circumflex artery and axillary nerve arthroscopy [201]. QSS with involvement of the
are distinctly visualized adjacent to humerus axillary nerve will result in selective atrophy of
(Fig. 5.23). The transducer can then be rotated 90 the teres minor and sparing of deltoid, as axillary
degrees to evaluate the neurovascular structures innervation to deltoid occurs proximal from the
in long axis. quadrilateral space. Isolated teres minor weakness
and shoulder external rotation can be difficult to
diagnose clinically. Ultrasound can identify iso-
lated teres minor atrophy with an intact distal ten-
don, manifested as relative loss of bulk and
muscular hyperechogenicity compared to the
adjacent infraspinatus [184]. Ultrasound can also
be used to dynamically evaluate the quadrilateral
space compressive lesions or masses.

Interventional Procedures
Fig. 5.22 The posterior humeral circumflex artery (*)
and axillary nerve (^) are visualized coursing between the Diagnostic axillary neural blockade within the
teres minor and teres major within the quadrilateral space
quadrilateral space is the most common inter-
vention at this location [202]. There are no stud-
ies to date describing the injection of an
orthobiologic agent in the management of quad-
rilateral space syndrome. The accuracy of injec-
tion into the quadrilateral space has not been
described.
Procedural protocol: Quadrilateral space/axil-
lary perineural injection

• Patient position – Lateral decubitus on contra-

lateral side. The affected side should be up and
Fig. 5.23 The posterior humeral circumflex artery (*)
the affected arm fully abducted with the
and axillary nerve (^) are visualized adjacent to the poste-
rior humerus, caudal from the teres minor patient’s hand resting on the back of their head.
5 Shoulder 99

• Transducer selection – High-frequency, linear The tendon of the pectoralis major has a unique
(>10 MHz) U shape with the anterior fibers coming from the
• Transducer position – In the axial plane, and clavicular head and superior sternal segments and
mid-humerus. Find the long head of the tri- the posterior fibers coming from the inferior ster-
ceps at the spiral groove and follow the triceps nal and abdominal segments [204].
proximally into the axilla to the humeral head. Ultrasound examination of the pectoralis
Visualize the axillary nerve anterior to the major tendon at its insertion is most commonly
inferior joint capsule. carried out using a linear transducer with the arm
• Needle selection – 25-gauge 2-inch needle (or abducted and externally rotated while the patient
larger depending on body habitus) is supine. The transducer is placed in the ana-
• Injectate selection – Anesthetize with lido- tomic axial plane over the bicipital groove with
caine or Marcaine. Inject anesthetic or steroid. the bicep tendon in short axis. The transducer is
Typically inject 3–5 mL. then moved distally, and the pectoralis major
• Needle trajectory and target – In-plane, pos- will come into view as it courses from medial to
terolateral to anteromedial through the triceps lateral. It can be visualized in long axis coursing
long head and targeting the axillary nerve and superficial to the coracobrachialis and biceps on
a perineural injection. its way to insert on the lateral edge of the bicipi-
• Pearls/pitfalls: tal groove (Fig. 5.24). The integrity of the tendon
–– The patient can be positioned prone, and a and the entire craniocaudal and mediolateral
needle trajectory through the teres major course should be evaluated. The tendon should
can be taken, rather than a lateral decubitus have a fibrillar pattern and the superficial cla-
position and approach through the long vicular/sternal head and the deeper sternal/
head of the triceps. abdominal heads can be evaluated [205]
(Fig. 5.25). The transducer can be moved medi-
ally to evaluate the muscle bulk as well. The
Pectoralis Major muscle can be followed all the way to its origin
on the clavicle, sternum, and ribs, but this is less
Anatomy and Ultrasound Evaluation commonly performed.

The pectoralis major is a broad muscle in the

anterior chest and shoulder that functions as a Pathology
strong adductor and internal rotator of the shoul-
der. It has three heads of origin and a lateral Traumatic rupture of the pectoralis major is an
insertion to the lateral lip of the humeral bicipital uncommon sports injury that typically occurs
groove. The clavicular head originates from the while performing a bench press during maximal
anteromedial two thirds of the clavicle and supe-
rior sternum. The sternal head originates from the
inferior sternum and costal cartilage of the medial
first through fifth ribs. The abdominal head origi-
nates from the fifth and sixth ribs. Each head
forms a lamina, and those laminae fuse to form a
trilaminar distal tendon that twists 90 degrees just
before it’s insertion on the lateral lip of the bicipi-
tal groove, such that the clavicular head inserts
more distally and the sternal and abdominal
heads more proximally on the humerus [203].
The tendon measures about 5 cm in medial to lat- Fig. 5.24 Longitudinal view of the distal pectoralis
eral length and 4 cm in craniocaudal width [204]. major tendon (*) inserting onto humerus
100 D. R. Lueders et al.

Technique #1

• Patient position – Supine, shoulder held at

side and externally rotated
• Transducer selection – High-frequency, linear
(>10 MHz)
• Transducer position – In the axial plane just
distal to the deltopectoral interval. Find the
biceps brachii long head in its transverse
plane, and track it to its myotendinous junc-
Fig. 5.25 Transverse view of the distal pectoralis major
tendon (*). The long head biceps brachii tendon (^) is tion. Just cephalad to biceps long head myo-
visualized deep to the pectoralis major tendon tendinous junction, the pectoralis major
tendon is visualized as a laminar-appearing
Table 5.5 Anatomic classification of pectoralis major tendon in its longitudinal axis to its humeral
tears [209] insertion.
Type Injury Pattern • Needle selection – 25-gauge 2-inch needle (or
I Contusion or sprain larger depending on body habitus and
II Partial tear muscularity)
III Complete tear • Injectate selection – Anesthetize with lido-
 III-A  at muscle origin caine or Marcaine. Inject anesthetic or steroid.
 III-B  at muscle belly Typically inject 3–5 mL.
 III-C  at myotendinous junction
• Needle trajectory and target – In-plane, lateral
 III-D  at tendinous insertion
to medial in plane with the tendon at its
humeral insertion to perform a peritendinous
eccentric contraction with the arm in forced injection.
external rotation with extension and abduction of
the humerus [206, 207]. Tear occur most com- Technique #
monly in active men between the ages of 20–40
[208]. Tears have historically been classified by • Patient position – Supine, shoulder held at
the system described by Tietjen in 1980 side and externally rotated
(Table 5.5) [209]. Rupture most commonly • Transducer selection – High-frequency, linear
occurs at the distal insertion of the inferior fibers (>10 MHz)
of the sternocostal head, followed by the superior • Transducer position – In the anatomic sagittal
fibers of the sternocostal head or the myotendi- plane just distal to the deltopectoral interval.
nous junction [206]. In cases of rupture, the ten- Find the biceps brachii long head in its longi-
don will either have a wavy appearance (if tear tudinal plane, and track it to its myotendinous
occurs in the muscle or near the myotendinous junction. It is here the it sits deep to the tendon
junction) or will not be visualized (distal tear), of pectoralis major. This plane can be trans-
and edema or fluid can be seen anterior to the lated medially to identify and to target a pec-
coracobrachialis muscle. The tendon of the pec- toralis major myotendinous injury.
toralis major is a stabilizer to the long head of the • Needle selection – 25-gauge 2-inch needle (or
biceps, so when it is ruptured, the biceps tendon larger depending on body habitus and
will be elevated off of the humerus [184]. With muscularity)
time, adhesions may form a pseudotendon • Injectate selection – Anesthetize with lido-
between the retracted muscle and stump of the caine or Marcaine. Inject anesthetic or steroid.
actual tendon [210]. Anatomic surgical repair Typically inject 3–5 mL.
results in better outcomes than conservative treat- • Needle trajectory and target – Cephalad to
ment alone [211]. caudad, in an anatomic sagittal plane trans-
Procedural protocol: Pectoralis major verse to the pectoralis major.
5 Shoulder 101

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 Ultrasound-Guided Elbow
Injection Techniques
6
Tolga Ergönenç

 ltrasound-Guided Elbow Injection

U (a) Brief anatomy
Techniques (b) Common cause
(c) Injection indications
This chapter describes the injection techniques (d) Equipment needed
that are most commonly used around the elbow (e) Injection technique
joint. The objective is to precisely define the (i) Patient position
position and alignment of the transducer and nee- (ii) Transducer position
dle to ensure accurate tissue placement. This sec- (iii) Needle direction and approach
tion also includes short clinical descriptions of (iv) Target
each condition with anatomical details. The
drugs, doses, and volumes mentioned are those
used in clinical practice by the author. This sec- Elbow Joint Injection
tion includes the following injection techniques
commonly used in the elbow: (a) Brief Anatomy

1. Elbow joint injection The distal humerus, proximal radius, and

2. Common extensor tendon injection (tennis proximal ulna comprise the elbow joint, which
elbow) is a complicated and compound joint produced
3. Common flexor tendon injection (golfer’s by the articulations of three bones. The
elbow) humeral/ulnar joint functions similarly to a
4. Olecranon bursa injection hinge joint, allowing elbow flexion and exten-
5. Ulnar collateral ligament (UCL) sion. Forearm rotation is possible, thanks to
6. Ulnar nerve at the elbow the proximal radioulnar joint and the radio-
7. Deep branch of radial nerve at the elbow (pos- humeral joint. The joint capsule encases the
terior interosseous nerve syndrome) entire elbow joint.
The posterolateral approach is the safest and
Each procedure includes the following most straightforward method which accessing
subheadings: the elbow joint.

T. Ergönenç (*)
Akyazı Hospital Pain and Palliative Care,
Sakarya, Turkey
e-mail: [email protected]

© Springer Nature Switzerland AG 2022 109

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_6
110 T. Ergönenç

(b) Common Cause

Elbow intra-articular injections can be used to

treat a variety of pathologic conditions.
Symptoms of a painful elbow joint may be
caused by either an intrinsic process, such as infec-
tion or osteoarthritis, or an extrinsic process, such
as a fracture or dislocation. Repetitive stress and
overuse can also cause injury and pain in the joint.

(c) Injection Indications

The etiology of a painful and swollen joint can

be determined by ultrasound-guided diagnostic
aspiration of joint fluid to evaluate if the accumu-
lation is due to inflammatory or noninflammatory
Fig. 6.1 The patient’s position of the posterior elbow
arthritis, infection, or crystal-induced arthropathy. joint injection. The elbow joint flexes to 90 degrees, and
Steroids, hyaluronic acid, local anesthetic, the arm droops over the table’s edge
Platelet Rich Plasma (PRP), and ozone can be
injected into the joint in various situations.

(d) Equipment Needed

• 25-gauge needle.
• One syringe (5 ml).
• High-frequency linear array transducer/
small hockey stick.
• Injectate: 1.0 mL of local anesthetic and
1 mL of injectable corticosteroids
(2–3 mL ozone 15–25 mcg/ml).
(e) Injection Technique
(i) Patient Position
• Prone, propped up on a cushion with
elbows overhead (lateral elbow
joint) or elbow over the edge of the
examination table with arm droop-
ing over the edge of the table (poste- Fig. 6.2 The patient and transducer position of the poste-
rior elbow joint injection with an in-plane approach
rior elbow joint injection) (Figs. 6.1
and 6.2).
• Sitting, the arm resting on a table (iii) Needle Direction and Approach
with the elbow in slight flexion, the • Out-of-plane approach, posterior to
forearm pronated. anterior direction (Fig. 6.4a, b).
(ii) Transducer Position • In-plane approach, distal to proxi-
• The radial head and capitellum are mal direction (Fig. 6.5).
easily identified when the transducer (iv) Target
is placed in the long axis of the • Radiocapitellar joint (Figs. 6.6, 6.7,
radius above the posterior portion of and 6.8).
the radiohumeral joint (Fig. 6.3).
6 Ultrasound-Guided Elbow Injection Techniques 111

 ommon Extensor Tendon Injection

C sor digiti minimi tendon, and the extensor carpi
(Tennis Elbow) ulnaris tendon are the four major components of
the common extensor tendon (CET) anatomically
(a) Brief Anatomy which are origin on the anterior facet of the lat-
eral epicondyle of the humerus. Wrist extension
The extensor carpi radialis brevis tendon, the and radial/ulnar deviation are the functions of the
extensor digitorum communis tendon, the exten- CET.

Fig. 6.3 The transducer position of the elbow joint injec-

tion. The elbow in slight flexion, the forearm pronated.
Move the transducer over the posterior aspect of the radio-
humeral joint to identify the gap between the radial head Fig. 6.5 In-plane approach, the needle is inserted at 45
and capitellum of the humerus degrees to the transducer in a distal to proximal direction

a b

Fig. 6.4 (a) For best visualization of the radiohumeral joint, tilt the transducer. (b) Out-of-plane approach, the needle
is inserted at 45 degrees to the transducer in a lateral to medial direction
112 T. Ergönenç

physically demanding activities such as sport are

implicated in the etiology.

(c) Injection Indications

Capitulum
CET injection can be performed on patients
Radius
with persistent pain despite that conservative
treatment. Steroids, local anesthetic, PRP, and
ozone can be injected for extensor tendinopathy.

(d) Equipment Needed

Fig. 6.6 Long-axis sonogram of the radiocapitellar joint • 25-gauge needle.
(*). Out-of-plane walk-down approach. White circle nee- • One syringe (5 ml).
dle tip
• High-frequency linear array transducer.
• Injectate: 1.0 mL of local anesthetic and
1 mL of injectable corticosteroids
(1–2 mL ozone 15–25 mcg/ml).
(e) Injection Technique
(i) Patient Position
• Supine or sitting, the arm resting on
Capitulum
a table with the elbow at approxi-
Radius mately 90 degrees of flexion.
(ii) Transducer Position
• The common extensor tendon is eas-
ily identified when the transducer is
placed in the long axis to the CET at
Fig. 6.7 Long-axis sonogram of the radiocapitellar joint. its origin on the lateral epicondyle
In-plane approach
(Fig. 6.9).
(iii) Needle Direction and Approach
• The needle is inserted distal to prox-
imal into the transducer at a
45-degree angle, passing through the
extensor tendon to reach the epicon-
dyle’s anterolateral facet.
• In-plane (Fig. 6.9).
(iv) Target
• CET/lateral epicondyle anterolateral
facet (Fig. 6.10).
Olecranon

Fig. 6.8 Sonogram of the posterior elbow joint injection

 ommon Flexor Tendon Injection
C
with an in-plane approach (Golfer’s Elbow)

(a) Brief Anatomy

(b) Common Cause
The anterior aspect of the medial epicondyle
Extensor tendinopathy (tennis elbow) is a con- is the origin of the common flexor tendon (CFT)
dition caused by repetitive stress/overuse injuries at the elbow. The CFT comprises four superficial
and microtrauma. Occupational disorders and group muscles of the forearm’s flexor (pronator
6 Ultrasound-Guided Elbow Injection Techniques 113

there are many occupations where repetition and

excessive grasping are necessary that can cause
inflammation and degeneration of the medial
epicondyle.

(c) Injection Indications

CFT injection can be performed on patients

with persistent pain despite that conservative
treatment. Steroids, local anesthetic, PRP, and
ozone can be injected for flexor tendinopathy.

(d) Equipment Needed

• 25-gauge needle.
• One syringe (5 ml).
• High-frequency linear array transducer.
Fig. 6.9 The patient and transducer position of the com- • Injectate: 1.0 mL of local anesthetic and
mon extensor tendon injection with an in-plane approach.
The transducer is placed long axis over the lateral elbow 1 mL of injectable corticosteroids
joint. The needle is inserted distal to proximal into the (1–2 mL ozone 15–25 mcg/ml).
transducer at a 45-degree angle, passing through the (e) Injection Technique
extensor tendon to reach the epicondyle’s anterolateral (i) Patient Position
facet
• Supine or sitting, the arm resting on
a table with the wrist in supine and
medial compartment facing the
interventionist (Fig. 6.11).

CET

Lateral Epicondyle

Fig. 6.10 Long-axis sonogram of the common extensor

tendon and radiocapitellar joint. Injection for the tennis
elbow with an in-plane approach

teres, palmaris longus, flexor carpi radialis, flexor

carpi ulnaris). Forearm pronation, wrist flexion,
and wrist flexion-adduction are all functions of
the CFT muscles.

(b) Common Cause Fig. 6.11 The patient and transducer position of the com-
mon flexor tendon injection with an in-plane approach.
The transducer is placed long axis over the medial elbow.
Flexor tendinopathy (golfer’s elbow) is a con- The needle is inserted distal to proximal into the trans-
dition caused by repetitive stress/overuse injuries ducer at a 45-degree angle, passing through the flexor ten-
and microtrauma. Another consideration is that don to reach the medial epicondyle’s interface
114 T. Ergönenç

(ii) Transducer Position (b) Common Cause

• The common flexor tendon is easily
identified when the transducer is Olecranon bursitis can be caused by various
placed in the long axis to the CFT at factors, including direct trauma such as a fall or
its origin on the medial epicondyle blow to the olecranon, infection such as septic
(Fig. 6.11). bursitis, and inflammatory conditions such as
(iii) Needle Direction and Approach rheumatoid arthritis and gout.
• The needle is inserted distal to prox-
imal into the transducer at a (c) Injection Indications
45-degree angle, passing through the
flexor tendon to reach the medial Chronic or recurring bursitis that has not
epicondyle’s interface. responded to conservative treatment can be
• In-plane. treated with aspiration of the olecranon bursa. In
(iv) Target the case of septic bursitis, corticosteroids should
• CFT/anterior facet of the medial epi- not be injected.
condyle. Injection should not be per-
formed to the medial collateral (d) Equipment Needed
ligament (Fig. 6.12). • 18-gauge needle.
• One syringe for aspiration (10–20 ml).
• One syringe for injectate (5 ml).
• High-frequency linear array transducer.
Olecranon Bursa Injection
• Injectate: 1.0 mL of local anesthetic and
1 mL of injectable corticosteroids.
(a) Brief Anatomy
(e) Injection Technique
The olecranon bursa is located between the (i) Patient Position
skin of the extensor surface of the elbow and the Supine, prone, or sitting.
olecranon process of the ulna, and it aids in the • Supine: the shoulder is internally
reduction of friction between two adjacent sur- rotated and with about 30 degrees
faces. It contains very little fluid in its normal flexion.
state and is not visible with ultrasound. It has no • Sitting: with the arm resting on a
communication with the joint. table in front and the elbow flexed at
the edge of the examination table,
with the shoulder partially abducted,
and the elbow flexed, the distal arm
hangs off the side, to approximately
90 degrees.
• Prone: the shoulder partially abducted
CFT
and the elbow flexed at the edge of
Medial Epicondyle the examination table, allowing for
the distal arm to hang off of the side.
(ii) Transducer Position
• Supine, prone, or sitting: the trans-
ducer is positioned long axis or short
axis over the bursa of the olecranon.
(iii) Needle Direction and Approach
Fig. 6.12 Long-axis sonogram of the common flexor
tendon and medial epicondyle. Injection for the golfer’s • The needle punctures the skin at a
elbow with an in-plane approach 45-degree angle with an in-plane
6 Ultrasound-Guided Elbow Injection Techniques 115

approach, that directly visualizes the (iv) Target

bursa is allowed (Figs. 6.13 and • Center of the olecranon bursa.
6.14).

Ulnar Collateral Ligament (UCL)

(a) Brief Anatomy

The medial stabilizer of the elbow is the ulnar

collateral ligament (UCL) that consists of three
portions as an anterior, posterior, and transverse
segment.

(b) Common Cause

The anterior segment of the UCL is responsi-

ble for the primary stabilization of the medial
elbow, and this segment is critical during joint
valgus stress.
During the overhead throwing, a tremendous
amount of valgus stress is applied to the elbow in
Fig. 6.13 The patient and transducer position of the olec-
ranon bursa injection with an in-plane approach. The trans-
many cases. Repetitive microtrauma or single-­
ducer is placed long axis over the olecranon bursa. The throw injury can occur in sports activities.
needle is inserted parallel into the transducer, lateral to
medial. The olecranon bursa is not visible in its usual state (c) Injection Indications

Injection of regenerative solutions or only

needle tenotomy can be performed on patients
with persistent pain despite that conservative
treatment.

(d) Equipment Needed

• 25-gauge needle.
• One syringe (5 ml).
• High-frequency linear array transducer.
• Injectate: 1.0 mL of local anesthetic and
1 mL of injectable corticosteroids.
(e) Injection Technique
(i) Patient Position
• Supine or sitting, elbow flexion with
30 degrees and the shoulder exter-
nally rotated, and the arm abducted
Fig. 6.14 The patient and transducer position of the olec- at least 45 degrees.
ranon bursa injection with an in-plane approach. The (ii) Transducer Position
transducer is placed long axis over the olecranon bursa.
• On the medial elbow, a slight oblique
The needle is inserted parallel into the transducer, proxi-
mal to distal. The olecranon bursa is not visible in its usual plane exists. To the CFT, the UCL
state appears to be quite deep (Fig. 6.15).
116 T. Ergönenç

Ulnar Nerve at the Elbow

(a) Brief Anatomy

The ulnar nerve arises from the C8 and T1

nerve roots. It travels through the cubital tunnel
before entering the flexor compartment of the
forearm, where it is found between the two heads
of the flexor carpi ulnaris muscle. About 5 cm
proximal to the wrist, the ulnar nerve splits into
dorsal and palmar branches.

(b) Common Cause

Numerous mechanisms can result in the

entrapment or injury of the ulnar nerve at the
elbow (cubital tunnel) or wrist (Guyon’s canal).
Dynamically evaluating the ulnar nerve at the
elbow is beneficial in detecting ulnar subluxation,
Fig. 6.15 The patient and transducer position of the ulnar one of the most common causes of neuropathy.
collateral ligament injection with an in-plane approach.
Elbow flexion with 30 degrees and the shoulder externally
rotated, and the arm abducted at least 45 degrees
(c) Injection Indications

Patients who have prolonged pain owing to

ulnar nerve entrapment despite conservative
treatment may benefit from the ulnar perineural
injection. It could also be utilized for diagnostic
purposes.
CFT
Medial
Epicondyle
(d) Equipment Needed
• 25-gauge needle.
• One syringe (5 ml).
• High-frequency linear array transducer.
• Injectate: 1.0 mL of local anesthetic and
Fig. 6.16 Long-axis sonogram of the common flexor 1–2 mL of injectable corticosteroids.
tendon and medial epicondyle and ulnar collateral liga- • For hydrodissection of the nerve up to
ment (white arrows). The needle should be inserted distal
10–15 mL total volume (0.9% NaCl, local
to proximal with an in-plane approach to the transducer
anesthetic, ± dextrose solution).
(e) Injection Technique
(iii) Needle Direction and Approach (i) Patient Position
• The needle should be inserted distal • Supine, the shoulder abducted 90
to proximal with an in-plane degrees and the elbow flexed approx-
approach to the transducer. imately 90 degrees.
(iv) Target • Sitting, the elbow flexed 90 degrees
• Hypoechoic area of the pathologic with the hand on the table.
ligament (Fig. 6.16). (ii) Transducer Position
• Take care to locate the ulnar nerve • At the elbow, place the transducer
and avoid injecting too posteriorly, transverse position to the ulnar
where the ulnar nerve may be located. nerve.
6 Ultrasound-Guided Elbow Injection Techniques 117

(iii) Needle Direction and Approach

• The needle should be inserted medial
to lateral with an in-plane approach
(Fig. 6.17).
• The needle should be inserted distal
to proximal with an out-of-plane
approach (Fig. 6.18).
(iv) Target
• Spread medication around the cir-
cumference of the ulnar nerve.
Create a “target sign” of injectate
around the nerve (Fig. 6.19).

 eep Branch of Radial Nerve at

D
the Elbow (Posterior Interosseous
Nerve Syndrome) Fig. 6.18 The patient and transducer position of the ulnar
perineural injection with an out-of-plane approach. The
(a) Brief Anatomy elbow flexed 90 degrees with the hand on the table

The posterior interosseous nerve (PIN) is the

terminal motor branch of the radial nerve.

Medial
Epicondyle

Fig. 6.19 Axial view of the ulnar nerve (*) at the cubital
tunnel level. Out-of-plane walk-down approach. White
circle needle tip

(b) Common Cause

Numerous mechanisms can result in the

entrapment or injury of the median nerve PIN
near or below the supinator muscle. Hypertrophy
of the supinator muscle, fibrous bands, soft-tissue
Fig. 6.17 The patient and transducer position of the ulnar
perineural injection with an in-plane approach. The elbow masses, radial head, and neck fractures may
flexed 90 degrees with the hand on the table cause and compress the PIN.
118 T. Ergönenç

(c) Injection Indications humerus, find the radial nerve, and

follow it distally until it splits into
Patients who have prolonged clinical signs the superficial sensory branch and
due to PIN syndrome despite conservative treat- PIN.
ment may benefit from this injection. (iii) Needle Direction and Approach
• The needle should be inserted lateral
(d) Equipment Needed to medial with an in-plane approach
• 25-gauge needle. (Fig. 6.20).
• One syringe (5 ml). (iv) Target
• High-frequency linear array transducer. • Spread medication around the cir-
• Injectate: 1.0 mL of local anesthetic and cumference of the PIN. Create a
1–2 mL of injectable corticosteroids. “target sign” of injectate around the
• For hydrodissection of the nerve up to nerve (Fig. 6.21).
15–20 mL total volume (0.9% NaCl, local
anesthetic, ± dextrose solution).
(e) Injection Technique
(i) Patient Position
• Sitting, the elbow flexed 90 degrees
with the hand on the table and the
forearm neutral or pronated
(Fig. 6.20). Brachioradiali
(ii) Transducer Position
• Place the transducer in a transverse SHS
position at the level of the distal
DHS
Radiu

Fig. 6.21 Sonogram of the deep branch of the radial

nerve (white arrow), PIN injection with a short-axis in-­
plane approach. Deep head of supinator (DHS). Superficial
head of supinator (SHS)

Fig. 6.20 The patient and transducer position of the PIN

injection with a short-axis in-plane approach
 Wrist and Hand
7
Vincenzo Ricci and Levent Özçakar

Introduction Wrist – Sonoanatomy

and Interventional Techniques
In clinical practice, disorders of the wrist and
hand are commonplace and may result in signifi- Due to the high anatomical complexity of the
cant functional limitations in daily activities. wrist and the small sizes of the structures, US
Owing to the superficial localization of most of examination of this region can be “planned” with
the anatomical structures in this region, ultra- standardized positions of the patient, the sonog-
sound (US) imaging is widely considered a suit- rapher, and the probe. Herewith, during the
able modality for diagnostic and therapeutic examination, they need to be dynamically modi-
procedures [1, 2]. Tendons, joints, ligaments, fied depending on the anatomical structure and/or
nerves, and other peculiar soft tissues of the wrist the clinical question [2–4].
and hand are all potential pain generators, and if Starting with the patient in sitting position
clearly visualized, they are all “reachable” under (face-to-face with the physician) and the forearm
US guidance for prompt interventions [1–4]. pronated over the examination bed, a dorsal lon-
The aim of this chapter is to provide a practi- gitudinal scan can be used as the initial window
cal guide as to how US imaging and guidance can to explore joint fluid [2]. Axial scan can be per-
be used to correctly plan for regenerative inter- formed for prompt “sonographic navigation” as
ventions of this anatomical region. The authors regards the six extensor compartments [2]. Using
will try to illustrate how relevant anatomical Lister’s tubercle as a bony landmark, the probe
structures (commonly involved in hand/wrist can be shifted from ulnar to radial and vice versa
pathologies) can be thoroughly scanned and (with a fan-like movement). Immediately on the
safely accessed [5]. radial side of the tubercle, it is possible to visual-
ize the extensor carpi radialis brevis and longus
tendons (2nd compartment) and the extensor pol-
licis brevis and abductor pollicis longus tendons
(1st compartment) more radially. Immediately on
V. Ricci (*)
Physical and Rehabilitation Medicine Unit, Luigi the ulnar side of the tubercle, it is possible to
Sacco University Hospital, ASST Fatebenefratelli- visualize the extensor pollicis longus tendon (3rd
Sacco, Milano, Italy compartment). Moving further ulnar, the exten-
L. Özçakar sor indicis proprius and extensor digitorum com-
Hacettepe University Medical School, Department of munis tendons (4th compartment), the extensor
Physical and Rehabilitation Medicine,
digiti minimi tendon (5th compartment), and the
Ankara, Turkey

© Springer Nature Switzerland AG 2022 119

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_7
120 V. Ricci and L. Özçakar

a b

Fig. 7.1 Positioning the probe (black rectangle) in a articular injection of the distal radioulnar joint (DRUJ)
transverse plane over the dorsal aspect of the wrist (a), (b). Void arrows fan-like movement of the probe, V vein,
Lister’s tubercle (LT) and the extensor tendons can be 2, 2nd extensor compartment, 3, 3rd extensor compart-
visualized in the short-axis view (b). Using the in-plane ment, 4, 4th extensor compartment, 5, 5th extensor com-
technique, the needle (black arrow) (a) can be advanced partment, dotted arrow needle’s pathway
from ulnar to radial direction in order to perform an intra-­

extensor carpi ulnaris tendon (6th compartment) window, US-guided (regenerative) injection for
can be imaged as well [2]. As the probe is shifted this small ligament can readily be performed
distally/proximally, tendons of the 1st and 3rd using an out-of-plane technique and dorsal to
compartments will be seen as crossing over the volar approach (Fig. 7.2).
2nd compartment as the proximal and distal To better evaluate the 1st extensor compart-
intersections, respectively [6]. In this position, ment, we can ask the patient to move the forearm
an US-guided injection of the distal radioulnar in a neutral position over the examination bed,
joint (DRUJ) can also be performed using an in- with a supportive object in the palm to stabilize
plane technique and ulnar to radial approach the hand (Fig. 7.3) [4]. In this particular position,
(Fig. 7.1). The needle tip must be advanced deep US-guided injections for the synovial sheaths of
to the extensor digiti minimi tendon, overcoming the tendons (and/or hydrodissection of the inter-
the joint capsule, in order to release the drug face between the tendons and the extensor reti-
inside the articular space between the two bony naculum) can be performed with an in-plane
surfaces [7]. technique and dorsal to volar approach – also
Once identified in the short-axis view, each avoiding the radial artery (Fig. 7.3) [10]. Rotating
and every extensor tendon can be scanned in the the probe 90 degrees, US-guided needling of the
long-axis view throughout their courses, i.e., dorsal retinaculum (e.g., in case of chronic thick-
from the proximal myotendinous junction until ening/fibrosis) can be performed using an in-­
the distal attachment. Of note, the extensor digiti plane technique and distal to proximal approach
minimi tendon is usually located just superficial (Fig. 7.3). For sure, both short- and long-axis
to the distal radioulnar joint [8], and through a views of the 1st extensor compartment (Fig. 7.3)
slightest tilt/shift of the probe, the dorsal radioul- can be used for intra-tendinous injections (e.g.,
nar ligament can be clearly visualized immedi- with orthobiologic agents) if clinically indicated.
ately below this tendon (Fig. 7.2). This ligament In the same position, dynamic sonotracking of
normally presents a “sloped” course due to the the 1st extensor compartment (i.e., elevator tech-
different alignment of the distal ends of radius nique) in a distal direction allows to visualize the
and ulna [9]. Using this sonographic acoustic crossing between the tendons and the radial
7 Wrist and Hand 121

a b

Fig. 7.2 Positioning the probe (black rectangle) in a the needle (black arrow) (a) can be advanced from cranial
transverse plane over the dorsal aspect of the wrist (a), the to caudal direction in order to target the ligament (b). V
dorsal radioulnar ligament (void arrowheads) can be visu- vein, DRUJ distal radioulnar joint, 4, 4th extensor tendon
alized in the long-axis view just below the extensor digiti compartment, white dot, needle in the short-axis view
minimi tendon (5) (b). Using the out-of-plane technique,

a b

c d

Fig. 7.3 Positioning the probe (black rectangle) in a sheath injection and/or hydrodissection of the interface
transverse plane over the radial aspect of the wrist (a), the between the retinaculum and the tendons (b). Rotating the
1st extensor compartment (1) can be visualized in the probe (black rectangle) 90 degrees (c), the needle (black
short-axis view between the cortical bone of the radius arrow) can be advanced for a distal to proximal direction
and the retinaculum (calipers) (b). Using the in-plane to perform the needling of a thickened retinaculum (cali-
technique, the needle (black arrow) (a) can be advanced pers) (d). RA radial artery, dotted arrow, needle’s
from dorsal to volar direction in order to perform intra-­ pathway

artery at the level of the carpal bones and in a partments (Fig. 7.4). Of note, the intersection
proximal direction allows to identify the anatom- sites are considered as potential pain generators
ical intersection between the 1st and 2nd com- in the wrist due to excessive friction with inflam-
122 V. Ricci and L. Özçakar

a b

Fig. 7.4 Positioning the probe (black rectangle) in a 2nd (2) extensor compartments is clearly visible (b). Of
transverse plane over the radial aspect of the wrist and note, the tendinous and muscular components of the
using the “elevator technique” in a distal to proximal extensor units are both present at this level. V vein, red
direction (a), the intersection between the 1st (1) and the arrow, tendon-tendon interface

a b c

d e f

Fig. 7.5 Positioning the probe (black rectangle) in a Using the in-plane technique, the needle (black arrow) (b)
transverse plane over the radial aspect of the wrist and can be advanced from dorsal to volar direction in order to
using the “elevator technique” in a proximal to distal perform hydrodissection of the nerve from the nearby soft
direction (a–c), the superficial branch of the radial nerve tissues (e). CV cephalic vein, Br brachioradialis muscle,
(yellow arrowhead) (d) can be seen piercing the superfi- RA radial artery, V vein, 1, 1st extensor compartment, 2,
cial fascia of the forearm (e) and diverging in different 2nd extensor compartment, dotted arrow, needle’s
ending branches (void yellow arrowheads) distally (f). pathway

matory phenomena and overuse tendinopathies. sonotracking for the superficial branch of the
Indisputably, US-guided interventions can easily radial nerve (SBRN) is possible (Fig. 7.5) [12]
be planned at any specific level for any specific whereby it pierces the antebrachial fascia and
target alike [11]. Without changing the position splits into its terminal branches [13]. Using this
of the patient (as in Fig. 7.3), a proximal to distal acoustic window, US-guided hydrodissection of
7 Wrist and Hand 123

this sensory nerve from the surrounding soft tis- Using the same position, an US-guided injection
sues can be performed using an in-plane of the TFCC/ulnocarpal space can be readily per-
­technique and dorsal to volar approach (Fig. 7.5). formed with an out-of-plane technique and dorsal
This procedure might be clinically indicated in to volar approach in regenerative medicine
patients with proximal intersection syndrome or (Fig. 7.7) [17]. It is noteworthy that the TFCC is
chronic De Quervain syndrome coupled with crucial for the stabilization of the distal radial-­
neural irritation (i.e., neuritis) or after surgical ulnar and ulnocarpal joints. It is composed of an
release of the 1st extensor compartment with articular disk, meniscus homolog, ulnocarpal
local adhesions that impair physiological gliding ligament, dorsal and volar radioulnar ligaments,
of the SBRN [14, 15]. and ECU tendon sheath. Of note, the prestyloid
As previously underlined, continuous reposi- recess is a synovial space between the articular
tioning of the forearm may be necessary to “fol- disk and the meniscus homolog that may be filled
low” a specific structure and/or correctly visualize with minimal fluid in a normal condition [18].
a small/curved target. Indeed, asking the patient Following the ECU tendon in the long-axis view,
to grip an object with the fingers, it is possible to its distal attachment to the base of the 5th meta-
“raise” the wrist from the examination bed in carpal bone can also be visualized (Fig. 7.8).
order to easily scan the extensor carpi ulnaris While the dorsal transverse approach is useful
(ECU) tendon at the level of the ulnar groove and to promptly evaluate the extensor tendon com-
over the ulnocarpal joint (Fig. 7.6) [3, 4]. partments of the wrist, the dorsal longitudinal
Likewise, an US-guided injection of the synovial scan is paramount to correctly differentiate the
sheath of the ECU tendon or hydrodissection of carpal bones and the articular surfaces [2, 3].
the interface between the tendon and the retinac- Positioning the probe “bridged” between the dis-
ulum can be performed using an in-plane tech- tal end of the radius and the 2nd metacarpal bone,
nique and dorsal to volar approach (Fig. 7.6). scaphoid and trapezoid can be seen. Herein, a
Rotating the probe 90 degrees (longitudinal portion of the dorsal radiocarpal recess is located
plane), the triangular fibrocartilage complex superficial to the scaphoid cortex (Fig. 7.9).
(TFCC) would be scanned in the ulnocarpal Progressively shifting the probe towards the ulnar
space deep to the ECU tendon (Fig. 7.7). An side, the scaphoid and capitate bones can be seen
active radial deviation of the wrist is paramount at the level of Lister’s tubercle (Fig. 7.10). More
to increase the size of the ulnocarpal space in laterally, scaphoid is replaced by lunate and the
order to better visualize the deep tissues [16]. dorsal radiolunotriquetral (RLT) ligament is

a b c

Fig. 7.6 Positioning the probe (black rectangle) in a advanced from dorsal to volar direction in order to per-
transverse plane over the ulnar aspect of the wrist and form an intra-sheath injection of the extensor carpi ulnaris
using the “elevator technique” (a), the 6th extensor com- tendon (b) or hydrodissection of the interface between the
partment (6) can be visualized in the short-axis view in the tendon and the retinaculum (c). White arrowhead, reti-
ulnar groove (b) and over the carpal bones (c). Using the naculum, dotted arrow, needle’s pathway
in-plane technique, the needle (black arrow) (a) can be
124 V. Ricci and L. Özçakar

a b

Fig. 7.7 Positioning the probe (black rectangle) in a lon- end of the ulna and the carpal bones (b). Using the out-of-­
gitudinal plane over the ulnar aspect of the wrist under plane technique, the needle (black arrow) (a) can be
active radial deviation (a), the articular disk (D), the advanced from dorsal to volar direction in order to reach
homologous meniscus (yellow arrowhead), and the pre- the ulnocarpal space and target the TFCC. White dot,
styloid recess (white dotted line) can all be visualized needle in the short-axis view located inside the prestyloid
under the extensor carpi ulnaris (ECU) tendon and ulnar recess
collateral ligament (white arrowheads), between the distal

a b

Fig. 7.8 Positioning the probe (black rectangle) in a lon- tendon to the base of the 5th metacarpal bone (5MC) can
gitudinal plane over the ulnar aspect of the wrist/hand (a), be easily visualized and targeted (b). White dotted circle,
the distal attachment of the extensor carpi ulnaris (ECU) enthesis of the extensor carpi ulnaris tendon

clearly visible in the short-axis view (Fig. 7.11). for effusion and/or synovitis [2, 3]. Shifting the
Using this position, an US-guided injection of the probe more laterally (ulnar), the ulnocarpal space
dorsal recess of the radiocarpal joint (e.g., for is seen with the TFCC interposed between the
synovitis) can be performed with an out-of-plane distal end of ulna and the carpal bones (Fig. 7.13).
technique and dorsal to volar approach [10, 19]. Using this acoustic window, an US-guided injec-
Rotating the probe in a transverse oblique tion of the ulnocarpal space/TFCC can be per-
plane, the dorsal RLT ligament can be depicted in formed with an out-of-plane technique and dorsal
the long-axis view [8, 9] whereby an US-guided to volar approach [17].
injection (in-plane, radial to ulnar approach) can Starting from the basic scan at the level of
be performed (Fig. 7.12). Lister’s tubercle in a transverse plane (Fig. 7.1), it
The longitudinal dorsal approach of the wrist is possible to slowly shift the probe more distally
allows a panoramic evaluation of the dorsal until the dorsal scapholunate ligament is clearly
radiocarpal and midcarpal recesses to be checked visualized in its long-axis view (Fig. 7.14) [8, 9].
7 Wrist and Hand 125

a b

Fig. 7.9 Positioning the probe (black rectangle) in a lon- asterisk, radiocarpal joint, yellow asterisk, midcarpal
gitudinal plane over the dorsal aspect of the wrist between joint, white asterisk, carpometacarpal joint, white arrow-
the distal end of the radius and the 2nd metacarpal bone heads, dorsal radiocarpal recess
(2MC) (a), scaphoid and trapezoid are visible (b). Red

a b

Fig. 7.10 Positioning the probe (black rectangle) in a asterisk, radiocarpal joint, yellow asterisk, midcarpal
longitudinal plane over the dorsal aspect of the wrist joint, white asterisk, carpometacarpal joint, white arrow-
between Lister’s tubercle (LT) and the 3rd metacarpal heads, dorsal radiocarpal recess, yellow asterisk, dorsal
bone (3MC) (a), scaphoid and capitate are visible (b). Red midcarpal recess

Especially after wrist trauma, sonographic evalu- to precisely evaluate this anatomical structure in
ation of this ligament is paramount because an routine daily clinical practice [21].
eventual partial/complete tear may be associated In patients with synovitis of the radiocarpal
with acute/chronic instability of the carpal bones joint, this sonographic window can be used to
[20]. In addition to the direct signs of ligament perform an US-guided injection of the dorsal
injury (i.e., focal/complete defect of the echo-­ recess (overlying the dorsal scapholunate liga-
structure), the indirect ultrasonographic sign ment) with an in-plane technique and ulnar to
(enlargement of the scapholunate space as com- radial approach (Fig. 7.14). With the same tech-
pared to the contralateral side) and dynamic nique, the needle tip can be advanced until/inside
imaging (separation of the bones during active the injured ligament (in the space between the
radial/ulnar deviation) would, for sure, be useful bones) for an injection [19].
126 V. Ricci and L. Özçakar

a b

Fig. 7.11 Positioning the probe (black rectangle) in a in order to visualize it in the short-axis view (white dot)
longitudinal plane over the dorsal aspect of the wrist inside the dorsal radiocarpal recess (white arrowheads)
between the distal end of the radius and the 3rd metacar- (b). Red asterisk, radiocarpal joint, yellow asterisk, mid-
pal bone (3MC) (a), lunate and capitate are visible (b). carpal joint, white asterisk, carpometacarpal joint, yellow
Using the out-of-plane technique, the needle (black arrowhead, dorsal radiolunotriquetral ligament (short-axis
arrow) (a) can be advanced from dorsal to volar direction view)

a b

Fig. 7.12 Positioning the probe (black rectangle) in a plane technique, the needle (black arrow) (a) can be
transverse oblique plane over the dorsal aspect of the wrist advanced from radial to ulnar direction to target the liga-
(a), the dorsal radiolunotriquetral ligament (void arrow- ment (b). Void arrow, needle’s pathway, RCJ radiocarpal
heads) is visible in the long-axis view (b). Using the in-­ joint

Another basic scan of the wrist is the trans- moving the probe towards the fingers, the proxi-
verse (palmar) approach at the level of the distal mal and distal segments of the carpal tunnel can
third of the forearm. Radius, ulna, and the overly- be depicted using specific bony landmarks, i.e.,
ing pronator quadratus muscle can be easily rec- scaphoid and pisiform for the proximal carpal
ognized to “orientate” the sonographic evaluation tunnel (Fig. 7.16) and trapezium and hamate for
(Fig. 7.15). Of note, unlike the dorsal view, radius the distal carpal tunnel (Fig. 7.17) [2, 22, 23].
and ulna present a regular alignment on the same Herein, complete sonotracking of the median
horizontal plane in the volar view. Progressively nerve, from proximal to distal, is necessarily per-
7 Wrist and Hand 127

a b

Fig. 7.13 Positioning the probe (black rectangle) in a before the injection (b). Of note, using the dorsal approach
longitudinal plane over the dorsal aspect of the wrist (a), is more difficult to clearly distinguish the different com-
the ulnocarpal space is clearly visible between the distal ponents of the TFCC as compared with the ulnar approach
end of the ulna and the carpal bones (b). Using the out-of-­ shown in Fig. 7.7. As such, this acoustic window would be
plane technique, the needle (black arrow) (a) can be useful if the ulnocarpal space (but not a specific smaller
advanced from dorsal to volar direction until it is visual- structure) is the target of the injection
ized in the short-axis view (white dot) in the “target space”

a b

Fig. 7.14 Positioning the probe (black rectangle) in a arrow) (a) can be advanced from ulnar to radial direction
transverse plane over Lister’s tubercle (LT) and gradually to inject the dorsal radiocarpal recess, overlying the liga-
moving the probe distally (a), the dorsal scapholunate ment (white asterisks) (b). Of note, with the same tech-
ligament (void arrowhead) is visible in its long-axis view nique, the dorsal scapholunate ligament can be targeted.
(b). Using the in-plane technique, the needle (black Void arrow, needle’s pathway

formed in the transverse view (elevator tech- radial to ulnar (or ulnar to radial) approach for
nique) exploring the sonoanatomy of different several purposes (perineural corticosteroid injec-
sections of the tunnel. Again, US-guided perineu- tion, nerve hydrodissection using dextrose, etc.)
ral injections can easily be performed in the (Fig. 7.16) [24, 25]. Additionally, the ulnar nerve
short-axis view using the in-plane technique and can also be sonotracked proximally (starting
128 V. Ricci and L. Özçakar

a b

Fig. 7.15 Positioning the probe (black rectangle) in a be used as an anatomical landmark (b). RA radial artery,
transverse plane over the volar aspect of the distal third of UA ulnar artery, FT flexor tendons, white arrowhead,
the forearm (a), the pronator quadratus (PQ) muscle can interosseous membrane

a b

Fig. 7.16 Positioning the probe (black rectangle) in a flexor tendons (FT), and the transverse carpal ligament
transverse plane over the pronator quadratus muscle and (white arrowhead) (b). Of note, with the same technique,
gradually moving the probe distally (a), the proximal sec- a perineural injection can also be performed. FCR flexor
tion of the carpal tunnel is clearly visible (b). Using the carpi radialis tendon, FCU flexor carpi ulnaris tendon, UA
in-plane technique, the needle (black arrow) (a) can be ulnar artery, UN ulnar nerve, dotted arrows, needle’s
advanced from radial to ulnar direction to hydrodissect the pathways
interfaces between the median nerve (yellow arrowhead),

from Guyon’s canal) in order to visualize the ori- Rotating the probe 90 degrees, the median
gin of the dorsal cutaneous branch in the anatom- nerve can be visualized in its long-axis view
ical space located between the flexor carpi ulnaris (Fig. 7.19), particularly useful to confirm its
and pronator quadratus muscles (Fig. 7.18) [12]. compression while passing under the transverse
At this level, both nerves can be targeted under carpal ligament (i.e., hourglass sign) [26].
US guidance with an in-plane technique and Keeping the probe in a longitudinal plane, it is
ulnar to radial approach. possible to shift it in an ulnar direction to visual-
7 Wrist and Hand 129

a b

Fig. 7.17 Positioning the probe (black rectangle) in a heads) appears thicker compared to its proximal segment.
transverse plane over the palmar aspect of the hand (a), Also note the anisotropy pertaining to the flexor carpi
the distal section of the carpal tunnel can be evaluated (b). radialis (FCR) tendon. Yellow arrowhead, median nerve,
At this level, the transverse carpal ligament (white arrow- UA ulnar artery

a b

Fig. 7.18 Positioning the probe (black rectangle) in an muscles (b). Using the in-plane technique, the needle
oblique transverse plane over the volar aspect of the distal (black arrow) (a) can be advanced from ulnar to radial
third of the forearm (a), the dorsal cutaneous branch (void direction to target the neural structures (b). UN ulnar
yellow arrowhead) of the ulnar nerve (yellow arrowhead) nerve, UA ulnar artery, V vein, dotted arrows, needle’s
can be visualized in the anatomical space between the pathways
flexor carpi ulnaris (FCU) and pronator quadratus (PQ)

ize the attachment of the flexor carpi ulnaris ten- Hand – Sonoanatomy
don to pisiform (anatomical location of a small and Interventional Techniques
insertional bursa) (Fig. 7.20). Similarly, shifting
the probe in a radial direction, the flexor carpi With the patient in sitting position (face-to-face
radialis tendon is visualized passing over scaph- with the physician) and the forearm supinated
oid and attaching to the base of the 2nd metacar- (resting on the examination bed or a pillow), a
pal bone (Fig. 7.20) [27, 28]. volar approach can be considered as the simplest
130 V. Ricci and L. Özçakar

a b

Fig. 7.19 Positioning the probe (black rectangle) in a During active flexion/extension of the fingers, the nerve
longitudinal plane over the volar aspect of the wrist (a), can be visualized to glide but less than the tendons. PQ
the median nerve (yellow arrowheads) in the long-axis pronator quadratus muscle
view can be seen superficial to the flexor tendons (FT) (b).

a b

c d e

Fig. 7.20 Positioning the probe (black rectangle) in a the volar surface of the scaphoid bone can be used as an
longitudinal plane over the volar and ulnar aspect of the anatomical landmark to promptly recognize the overlying
wrist (a), the attachment site of the flexor carpi ulnaris flexor carpi radialis tendon (white arrowheads) (d). At
tendon (void arrowheads) over the pisiform bone is well this level, gently tilting the probe, the anatomical course
visualized (b). Of note, in some patients, a synovial bursa of the tendon over the distal pole of the scaphoid (void
can be located in the tendon-bone interface (yellow aster- arrow) is better depicted (e). This is a critical point where
isk). On the other hand, shifting the probe (black rectan- excessive friction can lead to tenosynovitis and/or
gle) at the radial side of the wrist (c), the peculiar shape of tendinopathies
7 Wrist and Hand 131

way to start with [2]. Positioning the probe in a torum profundus tendon on the base of the distal
longitudinal plane over the metacarpophalangeal phalanx can be visualized distally (Fig. 7.21).
(MCP) joint, flexor tendons overlying the volar Using either the long- or short-axis views, an
plate are easily recognized (Fig. 7.21). In addi- US-guided injection of the synovial sheath of the
tion to static imaging, tendons’ gliding can be tendons (and/or of the interface pulley-tendon)
thoroughly assessed during active and passive can easily be performed using an in-plane tech-
flexion/extension [29]. Of note, the dynamic part nique (Fig. 7.22) [19, 30]. Herewith, to reduce
of the examination is paramount if mechanical the procedure-­ related pain, an interdigital
impingement between the tendons and the sur- approach avoiding the puncture of the highly
rounding tissues (e.g., hypertrophic pulley, ste- innervated palmar skin of the hand has also been
nosing tenosynovitis, postsurgical adhesions, described [19, 31].
local osteophytes, cortical irregularities after a The long-axis view of flexor tendons can be
trauma, subluxation of the small joints of the fin- considered as a useful sonographic approach also
gers) is clinically suspected [3, 4, 29]. In the for diagnosis and interventions of pathologies
same plane, the attachment site of the flexor digi- related with the palmar aponeurosis (i.e., tiny

a b

c d

Fig. 7.21 Positioning the probe (black rectangle) in a direction (c), the attachment site of the deep flexor tendon
longitudinal plane over the volar aspect of the finger at the (FTD) to the base of the distal phalanx (DP) can be
level of the metacarpophalangeal joint (a), the superficial depicted (d). MH metacarpal head, PP proximal phalanx,
(FTS) and deep (FTD) flexor tendons are easily recogniz- white dots, cartilage, MP, middle phalanx, void arrow-
able just over the volar plate (yellow asterisk) (b). head, articular recess
Gradually shifting the probe (black rectangle) in a distal
132 V. Ricci and L. Özçakar

a b

Fig. 7.22 Positioning the probe (black rectangle) in a arrow) can be advanced from a distal to proximal direc-
longitudinal plane over the volar aspect of the finger (a), tion (a) to inject the synovial sheath of the tendons and/or
an intervention can be planned in patients with patholo- to hydrodissect the interface between the tendons and the
gies of the flexor tendons (FT) (e.g., tenosynovitis, trigger pulley (white arrowheads) (b). MH metacarpal head, PP
finger). Using the in-plane technique, the needle (black proximal phalanx, dotted arrow, needle’s pathway

anatomical structure located superficial to the ing, both joints can also be targeted using an
flexor tendons) (Fig. 7.23) [32]. For instance, out-of-plane technique and radial to ulnar
fibrous nodules originating from the palmar fas- approach [33]. At this level, another important
cia of the hand (i.e., Dupuytren’s disease) are anatomical structure, potentially involved in
common in clinical practice whereby dynamic thumb pain, is the flexor pollicis longus tendon. It
assessment of the tendons allows the physician to courses between the superficial and deep heads
promptly evaluate the presence of local adhe- of the flexor pollicis brevis muscle (Fig. 7.26)
sions [29, 32]. This dynamic/precise evaluation is [34]. Following this tendon in the short-/long-­
paramount to correctly plan for the details of the axis view from proximal to distal, its relationship
US-guided procedure, e.g., injection inside the with the (radial and ulnar) sesamoid bones of the
nodule and/or hydrodissection of the tendons and thumb at the level of the 1st metacarpophalangeal
the palmar aponeurosis [4, 19]. joint is well depicted [35].
Rotating the probe 90 degrees, the short-axis Using a large amount of gel and gentle com-
view of the flexor tendons (Fig. 7.24) will allow pression of the probe, the dorsal aspect of the MCP
full evaluation using the “elevator technique” and joint can be clearly visualized, i.e., recognizing the
dynamic scanning to observe the tendon motions cartilage of the metacarpal head, the dorsal plate,
from a different perspective. As mentioned above, and the capsule interface (Fig. 7.27) [2]. This
this acoustic window can also serve as a conve- sonographic window can be used to perform an
nient/safe way for guided injections of the inter- US-guided injection of the MCP joint with an out-
face between pulley and flexor tendons (and/or of-plane technique and radial to ulnar (or vice
their sheath) with an in-plane ulnar to radial (or versa) approach [1, 19]. Of note, with the same
radial to ulnar) approach [19, 30]. technique, the proximal and distal interphalangeal
Keeping the forearm supinated, it is possible joints can be injected under US guidance as well.
to put the probe in a longitudinal oblique plane Likewise, it is again possible to visualize/target the
over the volar aspect of the thenar eminence to extensor tendons of the fingers using different
visualize the trapezio-scaphoid and trapezio-­ techniques, i.e., static and dynamic, short- and
metacarpal joints (Fig. 7.25). Using this position- long-axis views (Figs. 7.28 and 7.29) [4, 36].
7 Wrist and Hand 133

a b

c d

Fig. 7.23 Positioning the probe (black rectangle) in a (black rectangle) in a transverse plane (c), the same proce-
longitudinal plane over the volar aspect of the hand (a), dure can be performed with the in-plane technique and
the needle (black arrow) can be advanced from a distal to radial to ulnar (or ulnar to radial) approach (d). Void
proximal direction (a) to inject a focal thickening (white arrow, needle’s pathway, FT flexor tendons, MH metacar-
arrowheads) of the palmar aponeurosis in Dupuytren’s pal head, PP proximal phalanx, yellow asterisk, volar
contracture (b). On the other hand, positioning the probe plate, void arrowhead, articular recess

Asking the patient to grip an object within the sary, US-guided injections of the sagittal bands
fingers, it would be possible to “tension” the sag- can be performed using this acoustic window
ittal bands and identify them as curved (Fig. 7.30).
hypoechoic structures originating from the dor- Last but not least, another important ligament
sal interossei muscles – incapsulating the exten- of the thumb, frequently involved in traumatic
sor tendons (Fig. 7.30) [36]. These sagittal bands injuries and thus a possible target for regenerative
(i.e., the main component of the extensor hood) interventions, is the ulnar collateral ligament
are thin structures made of connective tissue, [38]. Asking the patient to lie the thumb over an
and they act as passive stabilizers (the “cuff”) of object while the forearm is partially pronated,
the extensor tendons in the dorsal aspect of the this ligament can be visualized statically or
MCP joints during finger flexion/extension [37]. dynamically – during movements of the interpha-
Like elsewhere, seeing under US also means langeal joint of the thumb (helping to distinguish
access to any structure; therefore, when neces- the ligament from the overlying adductor pollicis
134 V. Ricci and L. Özçakar

a b

c d

Fig. 7.24 Positioning the probe (black rectangle) in a avoiding the neurovascular bundle (white arrow) (b).
transverse plane over the volar aspect of the finger and During active flexion/extension of the finger (double
using the “elevator technique” (a), the superficial (white black arrow) (c), axial twisting (yellow dotted arrows) of
asterisk) and deep (yellow asterisk) flexor tendons can be the superficial and deep flexor tendons can be promptly
completely evaluated (b). Using the in-plane technique, evaluated, also paying attention to the anisotropy (d). L
the needle (black arrow) can be advanced from ulnar to lumbricals, white dotted arrow, needle’s pathway, red
radial (or radial to ulnar) direction (a) to inject the syno- asterisk, volar plate, white dots, cartilage, MH metacarpal
vial sheath of the tendons and/or to hydrodissect the inter- head
face between the pulley (void arrowhead) and the tendons,

a b

Fig. 7.25 Positioning the probe (black rectangle) in a other hand, keeping the probe in the same position and
longitudinal oblique plane over the volar aspect of the the- using the in-plane technique, the needle (black arrow) can
nar eminence (a), trapezio-scaphoid (yellow dot) and be advanced from a distal to proximal direction (c) to
trapezio-­metacarpal (white dot) joints can be depicted (b). inject the trapezio-metacarpal joint with hypertrophic
Using the out-of-plane technique, the needle (black synovitis (yellow asterisk) and bulging of the capsule
arrow) can be advanced from radial to ulnar direction (a) (white arrowhead) (d). I MC, 1st metacarpal bone, void
to target one or both of the articular surfaces (b). On the arrow, needle’s pathway
7 Wrist and Hand 135

c d

Fig. 7.25 (continued)

a b

c d

Fig. 7.26 Positioning the probe (black rectangle) in a if an intervention must be performed at this level (b).
transverse oblique plane over the volar aspect of the the- Rotating the probe (black rectangle) 90 degrees (c), the
nar eminence (a), the flexor pollicis longus tendon (white same tendon (white arrowheads) can be evaluated, in the
arrowhead) is visualized in the short-axis view (b). The long-axis view, encircled by the superficial (sFPB) and
close spatial relationship between the tendon and the digi- deep (dFPB) components of the flexor pollicis brevis
tal nerve of the thumb (yellow arrowhead) is noteworthy muscle (d). I MC, 1st metacarpal bone
136 V. Ricci and L. Özçakar

a b

Fig. 7.27 Positioning the probe (black rectangle) in a line), and the extensor tendon (white arrowheads) are all
longitudinal plane over the dorsal aspect of the metacar- imaged using enough gel and gentle compression of the
pophalangeal (MCP) joint (a), the articular surface inter- probe (b). Using the out-of-plane technique, the needle
posed between the metacarpal head (MH) and the (black arrow) can be advanced from radial to ulnar (or
proximal phalanx (PP) can be clearly visualized (b). The ulnar to radial) direction (a) to target/inject the joint space
cartilage surface of the metacarpal bone (white dots), dor- (white dot) between the two bones (c). V vein
sal plate (yellow asterisk), joint capsule (white dotted

a b

Fig. 7.28 Positioning the probe (black rectangle) in lon- plane technique, the needle (black arrow) can be advanced
gitudinal plane over the dorsal aspect of the proximal from distal to proximal direction (a) to target the tendon
interphalangeal (PIP) joint (a), a focal and hypoechoic (b). MP; middle phalanx, PP; proximal phalanx, dotted
thickening of the extensor tendon (void arrowheads) is arrow; needle’s pathway, white asterisk; joint effusion
depicted in a patient with hand trauma (b). Using the in-­
7 Wrist and Hand 137

a b

Fig. 7.29 Positioning the probe (black rectangle) in a extensor tendon (white arrowheads) over the base of the
longitudinal plane over the dorsal aspect of the distal distal phalanx (DP) can be visualized (b). Void arrow,
interphalangeal (DIP) joint (a), the attachment site of the nail, MP middle phalanx

a b

Fig. 7.30 Positioning the probe (black rectangle) in a cal tension” over the metacarpal heads (MH) (b). Using
transverse plane over the dorsal aspect of the metacarpo- the in-plane technique, the needle (black arrow) can be
phalangeal (MCP) joints (while the patient is gripping the advanced from ulnar to radial (or radial to ulnar) direction
gel tube) (a), the anatomical complex composed of the (a) to target the (injured) sagittal bands (b). V vein, void
extensor tendon (yellow asterisk) and the sagittal bands arrow, needle’s pathway
(void arrowheads) can be depicted in a state of “mechani-
138 V. Ricci and L. Özçakar

a b

Fig. 7.31 Positioning the probe (black rectangle) in a bone and the proximal phalanx (PP) of the thumb (b).
longitudinal oblique plane over the ulnar aspect of the Using the out-of-plane technique, the needle (black
base of the thumb (a), the ulnar collateral ligament (white arrow) can be advanced from cranial to caudal direction
arrowheads) is seen between the 1st metacarpal (I MC) (a) to target the ligament (yellow dot) (b)

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­ Radiographics. 2002;22(2):237–56.
Nerve. 2019;59(2):174–80. 38. Draghi F, Gitto S, Bianchi S. Injuries to the collateral
26. Wu CH, Chang KV, Özçakar L, et al. Sonographic ligaments of the metacarpophalangeal and interpha-
tracking of the upper limb peripheral nerves: a picto- langeal joints: sonographic appearance. J Ultrasound
rial essay and video demonstration. Am J Phys Med Med. 2018;37(9):2117–33.
Rehabil. 2015;94(9):740–7.
27. Luong DH, Smith J, Bianchi S. Flexor carpi radialis
tendon ultrasound pictorial essay. Skeletal Radiol.
2014;43(6):745–60.
 Ultrasound of the Hip/Thigh:
Regenerative Medicine Focus
8
Robert Monaco, Hector L. Osoria,
and Piyaporn Pramuksun

Introduction Posterior: Piriformis/external rotators, sciatic

nerve, hamstring origin
Injuries to the hip and thigh are some of the most Thigh: Anterior quadriceps complex, poste-
common in all of musculoskeletal medicine. Hip rior hamstring complex
injuries represent at least 6% of all sports injuries There is broad overlap of structures and pain
affecting adults and are even more prevalent referral patterns in these regions requiring clini-
among older individuals. The thigh is the most cians to have extensive anatomic knowledge and
commonly injured muscle group in the body. The a broad differential diagnosis. Radiographs are
hip joint is often affected by arthritis, and many the initial assessment for all types of pathology
tendons around the hip region can be involved in in the region and may help the clinician narrow
pathology. Secondary to the wide length and down differential diagnosis. Ultrasound is lim-
depth of the region and its structures, it is best to ited in its ability to assess deep intra-articular
break down the hip into selective regions. These injuries affecting the osteoarticular surface in the
include the following with the key structures hip and groin. Examples include articular carti-
listed in each area. lage injuries, subtle fractures or bone stress inju-
ries, and small labral tears. These are better
evaluated using MRI or MRI arthrography. The
Regions of the Hip role of ultrasound is growing rapidly for diagno-
sis and interventional procedures. Ultrasound
Anterior: Hip joint, acetabular labrum, iliopsoas can help assess both intra- and extra-articular
complex, rectus femoris, lateral femoral cutane- collections of fluid including joint, bursal, or
ous nerve synovial pathology. It is extremely useful for the
Medial: Adductor tendons, pubic symphysis, assessment of muscles and tendon pathologies.
inguinal region, femoral neurovasculature It is the test of choice for the evaluation of snap-
Lateral: Greater trochanter, gluteal tendons, ping in the region due to its ability to perform
iliotibial tract dynamic maneuvers. Ultrasound is readily avail-
able, relatively low in cost, has short exam times,
R. Monaco (*) · H. L. Osoria and can be done at the point of care. These attri-
Department of Sports Medicine, Atlantic Health butes make it an excellent choice to start the pro-
System, Morristown, NJ, USA cess of hip pain evaluation and for guided
P. Pramuksun injections.
Department of Physical Medicine and Rehabilitation,
Bhumibol Adulyadej Hospital, Bangkok, Thailand

© Springer Nature Switzerland AG 2022 141

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_8
142 R. Monaco et al.

Common clinical indications for sonography 3. Articular cartilage

of the region are: 4. Hip labrum

1. Evaluation for effusion/synovitis and to guide Extra-articular:

aspiration or injection
2. Evaluation for bursal or fluid collection in the 1. Rectus femoris tendons (direct and indirect)
region for aspiration/injection (bursitis, 2. Sartorius
seroma, labral cyst, etc.) 3. Iliopsoas complex
3. Evaluation for athletic hip pain, especially of 4. Femoral neurovascular structures
the groin 5. Lateral femoral cutaneous nerve (if clinical
4. Evaluation for muscle, tendon, bursal, or her- history warrants)
nia pathology
5. Evaluation for snapping in the region The hip joint is a synovial ball-and-socket
joint between the femoral head and the pelvic
Other indications include the postoperative hip acetabulum. The joint capsule surrounds the joint
replacement patient with continued pain, which is and is reinforced by three ligaments – the ilio-
beyond the scope of this regenerative text chapter. femoral (Y ligament of Bigelow), ischiofemoral,
A variety of ultrasound frequencies are used, and pubofemoral ligaments. The femoral head
in general to scan the wide regions of the hip and should be, in general, egg shaped but may have
thigh. This will depend on the anatomy of the abnormalities such as cam or other developmen-
patient and the depth of the structure being evalu- tal deformities. The capsule inserts anteriorly at
ated. A curvilinear probe at 2–6 MHZ is ideal for the intertrochanteric line; however, it reflects
many of the deeper structures, particularly in the redundantly back to the femoral head-neck junc-
posterior hip region. High-frequency linear tion; these layers are 2–3 mm each and therefore
probes are used for the evaluation of the superfi- about 4–6 mm when viewed under ultrasound at
cial tendons. A focused exam protocol of each the level of the femoral head-neck junction. The
region should be followed. The hip joint should femoral head is covered by hyaline cartilage,
be evaluated in all regions as it may refer pain to whereas the acetabulum is lined by hyaline carti-
all these areas. lage in an inverted U shape with a fibrocartilage
We will review the common sonoanatomy of labrum attached to the acetabular rim [60, 75].
the regions and discuss common clinical patholo- The acetabulum of the pelvis is a deep socket,
gies with specific focus on those where regenera- providing more inherent stability in conjunction
tive ultrasound-guided procedures can assist in with the acetabular labrum and ligamentous
diagnosis and treatment options. structures, compared to the shoulder. However,
despite the greater stability of the joint, there is
still a great degree of mobility in all planes – sag-
Anterior Hip Region ittal, transverse, and frontal [46]. In addition to
functionally increasing the surface area of the
Sonoanatomy acetabulum, the labrum also provides a suction-­
A common framework for assessing the anterior seal mechanism to help maintain the femoral
hip is to divide it into intra-articular and extra-­ head positioned in the acetabulum. Under ultra-
articular structures. The following structures sound, the fibrocartilage of the labrum should be
should be evaluated when performing an ultra- hyperechoic and appear triangular in shape [44,
sound of the anterior hip: 46]. Ultrasonography of the anterior hip joint is
Checklist: best accomplished with a curvilinear probe due
Intra-articular: to the depth of the hip joint. One can use the bony
landmarks to orient the probe quickly over the
1. Hip joint and capsule joint. Placing it at the mid distance between the
2. Femoral head bone anatomy anterior superior iliac spine and the pubic tuber-
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 143

Fig. 8.2 Anterior longitudinal sonographic view of the

hip joint. (A) Acetabulum, (L) acetabular labrum

to insert into the lesser trochanter. The Iliopsoas

bursa, the largest in the body, lies between the
iliopsoas muscle complex and the surfaces of the
pelvis and proximal femur [3, 17]. Visualization
of the iliopsoas tendon can be achieved with the
transducer first in the transverse plane over the
femoral head (Fig. 8.3c); then the lateral edge of
Fig. 8.1 Schematic of probe placement (blue box) for the the transducer is angled superiorly to align the
assessment of the anterior hip joint in-plane with the fem- probe in parallel with the inguinal ligament until
oral head-neck junction, bisecting the plane between the
the AIIS is visualized in this view. The hyper-
ASIS and the pubic tubercle
echoic iliopsoas tendon will be seen here in the
short axis just superficial to the bony contour of
cle at a 30-degree angle will line up with the joint the ilium, distal to the AIIS, with hypoechoic ilia-
(Fig. 8.1). One can also find the joint by placing cus muscle still partially surrounding the tendon
the probe transversely on the thigh to visualize more proximally. This is also where the iliopsoas
the hyperechoic outline of the femur and pivot 30 bursa would be visualized for abnormal fluid vol-
degrees to line up parallel with the femoral head ume. The iliopsoas tendon should be evaluated
and neck. Normal sonoanatomy of the hip joint is along its length in both long and short axes.
noted in Fig. 8.2. With further medial translation, The rectus femoris is primarily a knee exten-
one may also identify the femoral neurovascular sor; however, it is also a weaker hip flexor rela-
bundle. These are best visualized in the trans- tive to the iliopsoas complex. The rectus has two
verse plane. main heads and is really a muscle within a mus-
The bony anatomy of the hip and pelvis pro- cle. The direct head of the rectus femoris origi-
vides attachment points for various muscular nates at the anterior inferior iliac spine, whereas
structures that cross the hip joint and provide the indirect head attaches at the superior-­posterior
movement about the hip (Fig. 8.3). aspect of the acetabulum [17]. The origin of the
The iliopsoas tendon is formed by the continu- direct head of the rectus can be easily identified
ation of the iliacus muscle combined with the just proximal and medial to the joint space at its
psoas muscle to form this common tendon which attachment into the anterior inferior iliac spine. It
crosses the anterior-medial aspect of the hip joint is easy in longitudinal views to see its attachment
(Fig. 8.3b). It courses deep and slightly laterally and muscle tendon junction (Fig. 8.4a). With the
144 R. Monaco et al.

a b c

Fig. 8.3 (a) Cadaveric iliopsoas complex, tendon over view of the iliopsoas tendon (yellow arrow) the iliopectin-
the eminence. (b) Note the iliopsoas tendon in the long eal eminence (E)
axis over the acetabulum and femoral head, (c) transverse

a b

Fig. 8.4 (a) Longitudinal view of the rectus femoris (RF) (green arrow). (b) Longitudinal view of the indirect head
with its tendon (yellow arrows) seen attaching to the ante- of the rectus femoris (arrow)
rior inferior iliac spine (AIIS); myotendinous junction

direct head in a transverse plane axis, one can the level of the inguinal ligament to assess for
translate the probe laterally to partially reveal the nerve entrapment [44, 86]. Sonopalpation can be
indirect head traveling proximally and deep, used to help identify nerve pathology and a con-
though it will be anisotropic at this angle tralateral comparison to help determine irregulari-
(Fig. 8.4b). Pivot 30 degrees cranially to line up ties. There are natural variants in the location of
on the tendon attachment to the posterior acetab- the nerve which include posterior to and across
ulum [44]. the ASIS; anterior to the ASIS but within the sub-
More cephalad originating at the anterior stance of the inguinal ligament; through the tendi-
superior iliac spine are the sartorius and the ten- nous origin of the sartorius muscle; between the
sor fasciae latae muscles. A tensor fasciae latae sartorius tendon and thick fascia of the iliopsoas
does not cross the hip anteriorly but courses later- muscle; and deep to the inguinal ligament, overly-
ally and inserts into the iliotibial band. ing the thin fascia of the iliopsoas muscle [5].
The lateral femoral cutaneous nerve exits to
the pelvis under the inguinal ligament and pro- Pathologies Common pathologies in the region
vides sensation to the lateral thigh [17] (Fig. 8.5). with potential regenerative procedural options
The nerve can be traced in the tissue plane very are noted below. It is important to distinguish
superficial to the sartorius muscle and medial to between intra-articular and extra-articular pro-
the ASIS, and it should be followed proximally to cesses, but these may overlap.
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 145

a b

Fig. 8.5 (a) Schematic of typical path of the lateral femoral cutaneous nerve. (b) Transverse view of the LFCN (green
outline)

Intra-articular Hip effusion/joint (mechanical

vs. inflammatory), labral pathology.

The clinician should first try to determine if

the source of pain is from an intra-articular and/
or an extra-articular source. Evidence of a hip
effusion is strongly suggestive of an intra-­
articular process. Fluid in the joint can be sec-
ondary to multiple etiologies, and ultrasound
cannot distinguish this directly. These include,
but are not limited to, mechanical joint irritation, Fig. 8.6 Hip effusion: hypoechoic effusion (*) which
synovitis, systemic inflammatory conditions, does not follow the femoral head contour
tumors (pigmented villonodular synovitis), and
infections. The clinician needs to clinically cor-
relate to determine the appropriate evaluation sound, an effusion is diagnosed when there is
and treatment steps. When indicated, aspiration 7 mm or great capsular distension as measured
or diagnostic injection may provide further from the femoral neck surface to the outer edge
information. of the joint capsule or when there is a greater than
The most common source of an intra-articular 1 mm side-to-side difference compared to the
hip effusion and pain in adults is hip osteoarthri- non-affected side [44] (Fig. 8.6).
tis. It is the second most common form of arthri- The hip labrum can be visualized under ultra-
tis. It usually presents unilaterally with pain – usually sound but only a small portion. For the diagnosis
felt in the groin or thigh, stiffness, and restricted of labral tears, it has a sensitivity of 81% and a
range of motion of which internal rotation is specificity of 49% [85]. However, the visualized
often the earliest to be limited. Pain from hip part is the most commonly injured section.
arthritis is typically exacerbated by both active Dynamic testing can help evaluate labral detach-
and passive movement and alleviated by rest [2]. ment. Criteria for labral tears are displacement or
Inflammatory conditions which can manifest in absence of labrum, hypoechoic cleft through the
the hip and present similarly to hip osteoarthritis base of the labrum causing detachment with or
include, but are not limited to, rheumatoid arthri- without displacement, intrasubstance hypoechoic
tis, psoriatic arthritis, and reactive arthritis. These linear clefts (Fig. 8.7a), and cystic (Fig. 8.7b) or
would typically also present with systemic or irregular formations. Mixed echogenicity with-
other extra-articular exam findings associated out definite tearing and irregular margins are
with these conditions. Many pathologies in the interpreted as degenerative changes [88]. Linear
joint can cause an effusion, specifically injuries probes with high frequency are recommended.
to the labrum and hyaline cartilage. Under ultra- However, MR arthrogram is a gold standard for
146 R. Monaco et al.

a b

Fig. 8.7 (a) Transverse view of the hip joint showing labral cyst (*): well-defined cyst near the labrum of the
intrasubstance hypoechoic cleft suggesting labral tear hip joint. Acetabulum (A), labrum (L), iliopsoas (IP),
with cyst formation. (b) Longitudinal view showing para- femoral head (FH)

the diagnosis of labral tears. Femoral acetabular nal rapid torsion of a flipped psoas tendon within
impingement (FAI) is a condition in which the the iliacus muscle when the hip goes from the
shape of the femoral head and acetabular sockets FABER position to extension and neutral [3, 29,
are not compatible due to inappropriate bony 40]. Sonographic assessment for this form of medial
overgrowth of the femoral head, acetabulum, or “internal” snapping hip is performed by assess-
and/or both and can be a cause of labral pathol- ing the iliopsoas tendon in transverse axis and hav-
ogy. The location of the overgrowth determines ing the patient ask to reproduce the snapping
the type of FAI: pincer type involves overgrowth sensation, usually by bringing the hip into flexion,
of the acetabulum, cam impingement occurs with abduction, and external rotation, then straightening
overgrowth of the femoral head, and combined the leg. If the patient has a snapping hip caused by
type involves both. The clinical presentation of the psoas major tendon, there will be an abrupt
FAI typically involves pain with hip flexion, snapping of the psoas major tendon from internally
internal rotation, and/or adduction. Often, the over the accessory tendon or occasionally over the
bony deformity leads to damage to the cartilage superior pubic ramus [40]. The abnormal move-
of the acetabular labrum or the femoral head. ment of the psoas tendon during the snap has been
Physical examination of these patients typically associated with irritation of the tendon leading to
reveals limited internal rotation of the hip and iliopsoas bursitis and tendonitis. The patient may
reproduction of pain with the hip flexed at 90°, also have lateral or “external” snapping hip, which
internal rotation, and adduction. Although is usually caused by snapping of the gluteus maxi-
ultrasonography can assist with identification mus tendon or iliotibial band over the greater tro-
of the femoral head morphology, MRI may still chanter [21].
be needed to better evaluate for a chondral Often, the irregular snapping of the iliopsoas
injury or labral pathology. tendon can cause tendon irritation and inflamma-
tion leading to an iliopsoas tendinopathy or ten-
Extra-articular Hip dinitis. Another potential cause of this
“Snapping hip” is a common name for the symp- tendinopathy is an overly tight iliopsoas unit
toms of audible or palpable and often painful snap- which rubs against the underlying acetabular
ping of the iliopsoas tendon during movement. The labrum and may also cause labrum pathology.
original pathophysiology was described as the ilio- Direct overuse in athletes will also cause tendon-
psoas tendon translating taughtly translating over itis. This iliopsoas pathology may cause hip bur-
the iliopectineal eminence of the pelvis [66]. While sitis in the adjacent iliopsoas bursa [3]. Iliopsoas
this is one mechanism, more recent dynamic ultra- bursitis, the largest bursa in the body, can mimic
sound imaging studies have actually demonstrated hip effusion (Fig. 8.8). However, bursitis is
that the more frequent cause of the snap is an inter- ­outside the joint capsule; thus, it will not distend
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 147

power Doppler signal. The tendon is more often

strained or tendinopathic than completely avulsed
off the AIIS [17]. One should also assess for a
rectus tendon tear or bony avulsion of the AIIS in
adolescents or growing athletes.
The indirect head injury is more common in
kicking sports and dancers and may be missed
clinically. The common presentation is chronic
hip pain which may mimic labral or other hip
joint pathology and are more commonly seen as
overuse injuries as opposed to acute traumatic
injuries. Rectus femoris indirect head pathology
Fig. 8.8 Well-defined thin-walled hypoechoic fluid col-
may be more common than direct head [13].
lection (*) along the line of the iliopsoas tendon in a short-­ Pathology can also progress to direct head.
axis view with the femoral artery (a) seen medially Lateral femoral cutaneous nerve (LFCN):
Entrapment or neuroma of this nerve can cause
meralgia paresthetica. This condition usually
results from chronic compression of the
LFCN. The patient may present with numbness,
paresthesia, hyperesthesia, or neuropathic pain in
the anterior lateral thigh which is innervated by
the LFCN [39].

Procedures
Fig. 8.9 Longitudinal views of the rectus femoris direct
Ultrasound injections around the hip joint may be
head show a myotendinous junction hypoechoic tear (yel-
low arrowhead) and insertional AIIS attachment extremely valuable for both diagnostic and thera-
hypoechoic defect (white arrowhead) of the rectus peutic purposes. Injections can help diagnose or
femoris narrow down the pain generator, help manage
painful conditions, and/or serve as a bridge to
the joint. Fifteen percent of iliopsoas bursitis can delay surgery. Percutaneous procedures around
communicate with the joint. Iliopsoas bursitis the hip joint are an excellent alternative to more
can extend all the way up into the pelvis. Like invasive procedures. Ultrasound is the ideal
any fluid collection, it can have multiple etiolo- modality for this secondary to its real-time guid-
gies including mechanical irritation and infec- ance, low cost, portability, lack of ionizing radia-
tion. The use of Doppler may help assist in tion, and additional diagnostic information
categorizing the type of fluid, but aspiration and obtained. Due to the complexity of the region
analysis and/or injection may be indicated to including its neurovascular structures, with rare
definitively diagnose and treat the condition. exception, all hip procedures should be ultra-
The rectus femoris tendon may also experi- sound guided.
ence various pathologies that can be assessed via The most common procedures in the anterior
ultrasound. These include tendinosis, calcifica- hip region are the following:
tions, and partial or full thickness tears (Fig. 8.9).
Common changes seen in tendinopathies include 1. Hip joint/labral complex injection/aspiration
sonographic appearance of hypoechoic tendon 2. Iliopsoas injection/bursal aspiration
with loss of fibrillar pattern, tendon thickening 3. Lateral femoral cutaneous nerve
with or without partial tearing, and positivity to hydro­dissection
148 R. Monaco et al.

 ip Joint/Labrum Injection/
H fluid which gives better visualization of the joint
Aspiration space. Align the probe along the long axis of the
femoral neck. Before injection, use Doppler to
Ultrasound-guided hip joint procedures can be evaluate the femoral neurovascular structures.
performed in the office setting with no risk of They reside a good 2.5 cm from the joint. One also
radiation exposure with an excellent accuracy of wants to avoid the femoral circumflex vessels
around 97–100% [26]. There are multiple tech- anterior using Doppler. The needle path should be
niques to inject the hip joint (Table 8.1). planned aiming at the femoral head-neck junction
The anterior approach is the most common using a lateral to media, distal to proximal
where the needle is directed in-plane down to the approach (Fig. 8.10). A long needle, usually a 22
femoral head-neck junction. The patient should lie gauge 3 inch or longer, is needed depending on
in a supine position with the leg extended. Rolling body habitus. In obese patients, coated needle or
the leg into internal rotation can help increase joint beam steer mode will assist and improve needle

Table 8.1 Hip joint injection approaches

Anterior approach (in plane) Transverse approach (in plane) Lateral approach (out of
Technique (Fig. 8.10) (Fig. 8.11) plane) (Fig. 8.12)
Patient Supine position with the leg in neutral or internal position Side-lying position
position
Probe Halfway between ASIS and pubic Probe oriented axially over the Transversely on the
positioning symphysis (not tubercle), the hip joint femoral head and acetabular trochanter with the
will be at 2.5 cm medial rim in view acetabulum in view
Target Femoral head-neck junction Pierce the thick joint capsule into the joint
Needle size 25 g 1.5 inch for local anesthesia; 18–22 g 3–4 inch for injection
Probe Low frequency curvilinear or high Curvilinear frequency
frequency linear for transverse
Injected Corticosteroids (40–80 mg)
agents Hyaluronic acid (vary by product/prefer single dose)
Platelet Rich Plasma/bone marrow aspirate/microfat 3–6 ml
25% dextrose with 0.5% lidocaine 4–8 ml

Fig. 8.10 Anterior approach targeted at the femoral head-neck junction (arrow). Note and avoid femoral circumflex
vessels
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 149

visualization if available on the machine. A curvi- or labrum (Fig. 8.11). A third approach is the lon-
linear low-frequency probe is often used. The nee- gitudinal anterior approach. With this approach,
dle position should be confirmed in both one can also target the gluteal tendons as well as
longitudinal and transverse planes before injec- the joint with one injection approach (Fig. 8.12).
tion. Injection should be under sterile technique, The most common injection in the hip region
while watching the flow into the joint or use power is diagnostic lidocaine with or without steroid.
Doppler to see flow in the joint to confirm posi- Diagnostic anesthetic intra-articular hip injec-
tion. One can also aspirate if an effusion is present tions help differentiate between intra- and extra-­
or to confirm intra-articular position. articular pathology and help predict a response of
Another technique is a transverse approach. total hip arthroplasty [28]. Studies to date have
This approach has shorter skin to target distance shown short-term benefit of steroid injections
which may be suitable for larger patients. The into the hip joint for osteoarthritic-type inflam-
patient is supine and the probe is placed trans- matory conditions. Steer et al. showed a signifi-
versely on the femoral head with the acetabulum cant response up to 8 weeks after injection;
in view. The needle is introduced lateral to however, there was no significant change in any
medial, targeted toward femoral cartilage, psoas, imaging finding of effusion-synovitis [84].

Fig. 8.11 Transverse approach: anterior supine position, lateral to medial approach to inject the joint at the labral
complex. Note femoral vessels medial

Fig. 8.12 Side-lying position, posterior to anterior approach, longitudinal view, out-of-plane technique. Acetabulum
(A), femoral head (FH), needle target (asterisk)
150 R. Monaco et al.

Effusion does not seem to be helpful in properties and anti-inflammatory and regenera-
­determining who will respond. Recent studies tive effects [88]. Currently, there is no level 1
also showed some potential adverse joint find- RCT on treating hip OA. However, early limited
ings, accelerated OA progression, subchondral studies show very good potential for good clini-
insufficiency fracture, complication of osteone- cal outcomes. Mardones et al. [59] studied ten
crosis, and rapid joint destruction, including bone patients with three doses weekly of intra-articular
loss after intra-­articular corticosteroid injection hip autologous BM-MSC injection. They showed
in some patients [52]. Patient involvement in an improvement in pain, function, and range of
decision making on using steroid injections in motion with no safety issues after the follow-up
this joint is advised. period of 16–40 months. Another preliminary
Hyaluronic acid may be another choice for results from six patients using autologous
inflammatory hip conditions. There are limited adipose-­derived MSC also showed a positive out-
studies compared to the knee with older studies come with no reported adverse effect after intra-
suggesting a reduced effectiveness. More recent articular hip injections [23].
work indicates that intra-articular injections for
mild-moderate hip OA may help in reducing pain
and improving function [56]. With the ease of Labrum Injection
office-based ultrasound injections, this is now a
reasonable option in the treatment paradigm; One may occasionally inject in or around the
however, cost is an issue as it is usually not cov- labrum in specific cases. These include distinct
ered by many insurance plans. labral tears or large labral cysts or calcifications
Orthobiologics have an increasing role in hip in the region causing pain. Positioning is similar
pathology, including arthritis. Platelet-rich in the supine position with the needle being
plasma (PRP) has shown promising outcomes in directed to the labral pathology (Fig. 8.13). Intra-­
osteoarthritis condition, particularly of the knee. articular injections can also be used in cases as it
Multiple randomized controlled studies have will bathe the labrum with the injectate. Hip
shown both improvements of pain and increased labrum mainly consists of fibrocartilage and
function as compared to placebo or hyaluronic dense connective tissue which is thought to be
acid. Studies to date have been mixed on PRP in avascular; therefore, like other fibrocartilage, it
the hip, as studies have suffered from multiple may be difficult to heal [57]. PRP has been used
issues, such as lack of classification of the PRP
products and other methodological weaknesses.
One randomized controlled study showed that
PRP had statistically significant reduction in VAS
at 6 months in hip OA patients when compared
with hyaluronic injection [24], while three other
RCTs showed no statistically significant changes
[10, 30, 31]. PRP may have more efficacy in early
osteoarthritis of the hip. Unfortunately, most hip
osteoarthritis is picked up later in the process.
PRP appears to be safe with limited to no side
effects. Further research needs to be done in the
area.
Recently, mesenchymal stem cells/medicinal
signaling cells (MSCs) have been used more fre-
quently in treating patients with osteoarthritis.
Bone marrow and adipose tissue contain mesen- Fig. 8.13 Longitudinal view of the labrum with needle
chymal stem cells, which have chondrogenic above the anterior hip labrum
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 151

to help augment cartilage tissue healing through to lift off the iliopsoas tendon from the acetabular
the natural healing process [89]. According to a brim of the ilium and halo the tendon. This helps
recent pilot study by De Luigi et al., the use of confirm the appropriate needle tip placement.
leukocyte-rich PRP injection has shown promis- This should be the area consistent with pathology
ing outcome in improving function and reducing on the dynamic ultrasound exam. Diagnostic
pain in eight labral tear patients [27]. maneuvers postinjection are needed to help
assess if this is the source of pain.
In cases of tendon pathology, the long-axis
Iliopsoas Bursal Injection approach on tendon can be easier for tenotomy or
peritendinous injection as a greater length of ten-
The iliopsoas tendon/bursal complex can be don is accessible with one approach. See Fig. 8.3b
injected and/or aspirated for a variety of condi- for longitudinal views.
tions (Table 8.2), most commonly bursal collec- Anesthetics, cortisone, and orthobiologics are
tions, snapping tendon, and iliopsoas tendinosis/ the primary substances injected. Results of a
tendinitis. study performed by Blankenbaker et al. [12]
Iliopsoas bursitis injections are commonly per-
formed in the supine position with the leg extended
in neutral. The ultrasound probe should start in the
transverse plane over the femur then translated
superiorly towards the femoral neck; when the
elongation of the femoral neck is noted, the medial
portion of the probe should be rotated superiorly to
angle in parallel with the inguinal ligament and
femoral neck. Long-axis views should be used for
confirmation. The femoral neurovascular struc-
tures should be identified medially. The needle is
inserted in a lateral to medial approach targeting
the hypoechoic fluid collection.
For snapping hips, the same approach is used.
If bursal/tendon fluid is not well visualized, the
Fig. 8.14 Iliopsoas tendon complex. Transverse view of
needle tip should be placed between the iliopsoas needle path using a lateral to medial approach. Note the two
and the ilium (Fig. 8.14). Watch the flow of fluid heads iliopsoas tendon at the level of the acetabular rim

Table 8.2 Iliopsoas tendon/bursa injection approaches

Pathology Iliopsoas bursitis Snapping hip Iliopsoas tendinopathy
Patient Supine position with the leg in neutral or internal position
position
Probe Transversely over the femoral head, then shifted superiorly and Consider switch to the long
positioning angled parallel to the inguinal ligament axis for better needle
positioning
Target The hypoechoic fluid collection (Fig. 8.20) Iliopsoas tendon at the Pathologic tendon
or between the iliopsoas and the ilium area of pain and
(unclear bursa) snapping
Needle size 25 g 1.5 inch for local anesthesia; 18–22 g 1.5–3 inch for injection
Probe Medium to high frequency linear
Injected Corticosteroids (40–80 mg)
agents Platelet- Rich Plasma/bone marrow aspirate/microfat 3–6 ml
25% dextrose with 0.5% lidocaine 4–8 ml
Tenotomy
152 R. Monaco et al.

showed that US-guided corticosteroid injection damage. Inject the fluid and watch fluid flow
in the iliopsoas bursa has diagnostic and thera- around the nerve. Inject until the entire nerve is
peutic benefits for patients with groin pain and haloed; oftentimes, 20 cc or more of fluid may be
clinically suspected snapping iliopsoas tendon, needed.
even if the snapping cannot be demonstrated Hydrodissection with normal saline, 25% dex-
sonographically. A positive response to cortico- trose or leukocyte-poor PRP or PPP has been
steroid injection is a predictor of a good surgical used in treating nerve entrapment. Although,
outcome if surgical release of the iliopsoas ten- there have been limited studies showing efficacy
don is needed. High-volume injection may be on treating meralgia paresthetica, case reports
tried, but no clinical outcome studies are avail- and the authors clinical experience have shown
able. Orthobiologic injection as well as tenotomy immediate, long-term relief of numbness
may play a role in case of tendinosis, tendinitis, associated with severe, chronic MP after
­
or partial tear. Although limited study has been hydrodissection [64].
done, orthobiologic studies with PRP have shown
good efficacy in treating tendon pathology in
similar tendons, particularly for tendinosis. Medial Hip Region
Further research is needed.
Introduction
 ydrodissection on Lateral Femoral
H
Cutaneous Nerve The medial hip region is an anatomically com-
The lateral femoral cutaneous nerve, when well plex region for which pathology often presents as
visualized, is amenable to high-volume injection groin pain. Groin pain is very common, espe-
(Table 8.3). Ultrasound with clinical palpation is cially in certain sports that involve repetitive cut-
required to identify and reproduce symptoms in ting, planting, and pivoting. The close proximity
the patient. In a supine position, the ultrasound of the inguinal structures in males makes the
probe is placed to locate the nerve as previously evaluation of this region very challenging.
described. It is best found transversely near the Discussion of inguinal-related pain including
ASIS and between the sartorius and the tensor hernias is not reviewed in this chapter but should
fasciae latae. The needle is introduced in a lateral strongly be considered in the differential. The
to medial approach, targeting just below the primary musculoskeletal structures involved in
LFCN in the fascial plane. The needle bevel medial hip pathology are the adductor tendons,
should be turned facing the nerve to avoid nerve the rectus abdominis insertion, and the pubic
symphysis. Fortunately, unlike the posterior hip,
Table 8.3 Lateral femoral cutaneous nerve injection many of the structures are superficial. Many
approach terms are used interchangeably in the literature to
Patient Supine position with the leg in neutral or describe groin pain. Athletic pubalgia, sports her-
position internal position nia, sportsman’s hernia, Gilmore groin, adductor
Probe Over the nerve where abnormality is noted dysfunction or tendinopathy, and osteitis pubis
positioning or pain/Tinel’s sign on sonopalpation
are various terms used to describe entities that are
Target LFCN in the fascial plane between the
sartorius and the tensor fasciae latae either in the same spectrum of disease or share
Needle size 25 g 1.5 inch for anesthesia and injection similar mechanisms of injury and clinical mani-
Probe Highest frequency linear festation [18]. Clinicians should clearly define
Injected Normal saline pathologic structures. While ultrasound is very
agents Corticosteroids (40 mg) useful in evaluating this region, MRI is often
25% dextrose with 0.5% lidocaine
Leukocyte-poor PRP additionally needed to fully assess the entire
5–20 cc around the nerve – enough to region including the osseous structures.
dissect tissue and halo the nerve
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 153

Sonoanatomy To identify the AL, AB, and AM layered from

The following structures should be visualized as superficial to deep, follow them proximally to
part of the medial hip checklist: their insertion at the pubis – attachments at the
pubis from superficial to deep should proceed
1. Symphysis pubis as follows: AL tendon, AL muscle, AB muscle,
2. Rectus abdominis AM muscle [70, 76] (Fig. 8.15).
3. Adductor tendons
4. Pectineus muscle Rectus Abdominus
5. Inguinal structures and hernia evaluation are Superficially overlying the pubis, there is a con-
beyond the scope of this chapter tinuous aponeurosis connecting the AL tendon
and the rectus abdominis. This aponeurosis also
The medial hip and thigh are highlighted by blends with the fibrocartilage disc and capsule of
the adductor muscle group – the adductor lon- the pubic symphysis. Notably, fibers of the apo-
gus (AL), adductor magnus (AM), and adduc- neurosis both remain ipsilateral and cross to the
tor brevis (AB), the gracilis and pectineus contralateral side of the rectus abdominis.
muscles [17, 46]. The primary proximal attach- Sonographic evaluation of the distal rectus inser-
ment of the adductor muscles is the AL on the tion is accomplished by continuing to scan in the
inferior aspect of the pubis. The tendon has cranial direction from the adductor insertion and
approximately 40% anterior tendon attachment rotating the probe slightly to the true sagittal
and 60% posterior direct muscular attachment. plane in line with the rectus abdominis. The rec-
It makes an aponeurosis with the tendon of the tus tendon should be scanned across its width and
rectus abdominis. The AL is the most superfi- proximally to the myotendinous junction.
cial of the three prime adductors with the AB Additionally, the probe should be rotated 90
and AM respectively deeper and have near degrees and the tendon should be scanned in
complete muscular attachments at the pubis just short access [44, 70].
lateral to that of the AL. The gracilis is the most
medial of the adductor group and attaches infe- Pubic Symphysis
rior to the AB and AL on the anterior-medial The pubic symphysis is a nonsynovial joint con-
border of the pubis. Ultrasonography of the taining a fibrocartilaginous disc covered by a thin
adductor groups is best accomplished when the layer of hyaline cartilage. It unites the superior
patient is positioned supine with the hip in flex- rami of the pubic bones bilaterally connecting the
ion and abduction with a linear transducer in anterior aspect of the pelvic ring [1]. The pubic
the longitudinal axis to the adductor muscles. symphysis can be accessed with ultrasound by

a b

Fig. 8.15 (a) Overview of anatomy. Note rectus, adduc- longus (AL), adductor brevis (AB), and adductor magnus
tor, obliques, and proximity of structures of inguinal canal (AM) attached to the pubic symphysis (P)
in men. (b) Longitudinal view of layers of the adductor
154 R. Monaco et al.

placing the probe with the midline of the synthesis insertion can include tendinopathic thickening
in the transverse plane. From this view, a side-to- greater than the normal 3–4 mm, full or partial
side comparison of the rectus-adductor aponeuro- tendon tears, or calcific tendinopathy (Fig. 8.16).
sis over the pubic bones can also be made. Full thickness AL tendon tears are rare, but if
present, there may be tendon retraction and hema-
toma noted in these cases [44, 70] (Fig. 8.17).
Pathology Alternatively, if the pathology is located at the
rectus aponeurosis attachment to the pubis, one
Adductor/Rectus Aponeurosis may see a hypoechoic fluid layer in between the
Groin pain is a symptom of many possible pathol- rectus-adductor aponeurosis and the pubic bone
ogies, with adductor/rectus injury at the pubis or thickening of the aponeurosis; this is more eas-
being the most common. Adductor attachment ily assessed with a simultaneous side-­ to-­
side
injuries may result from overuse microtears or comparison of both aponeuroses over the pubic
acute injuries. This is a common and difficult symphysis in the transverse plane if there is not
problem to manage particularly in athletes in bilateral pathology. MRI is more useful than ultra-
sports involving frequent twisting and cutting sound in evaluating these subtle defects and can
movements. The adductor longus attachment is also evaluate for bone edema in the region.
most typically the involved site; however, the dis- Ultrasound is useful for dynamic study as well.
tal rectus attachment at the pubis and rectus-­
adductor aponeurosis may also be implicated [58, O  steitis Pubis
61, 62, 77]. Pathologies of the adductor tendon Osteitis pubis is a degenerative condition associ-
ated with various possible factors including
trauma, overuse, inflammatory conditions, and
infections. Studies in athletes have demonstrated
biomechanical factors associated with osteitis
pubis including decreased hip range of motion
and muscle imbalances and environmental fac-
tors such as participation in sports with frequent
kicking, twisting, and cutting [4, 72]. Ultrasound
findings of osteitis pubis are cortical irregularity
along the borders of the pubic bone, capsular
thickening, and increased fluid in the pubic sym-
physis [1] (Fig. 8.18b). Dynamic ultrasound may
Fig. 8.16 Longitudinal view of adductor showing cal- show joint instability; however, MRI is more sen-
cific tendinopathy (green arrow) at the pubic symphy-
sis (P) sitive than ultrasound for the evaluation of the
bone in this region.

Procedures

In patients with groin pain who fail to improve

with conservative treatment, local injection can
be useful for diagnostic purposes as well as thera-
peutic treatment. There are two common
­injections: the adductor/rectus aponeurosis and
osteitis pubis (Table 8.4). For injections of the
Fig. 8.17 Longitudinal full thickness adductor longus adductor origin, the patient is positioned supine
tendon tear with the leg slightly abducted and externally
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 155

a b c

Fig. 8.18 (a) Transverse view demonstrating a normal showed intense marrow edema both sides of the symphy-
pubic symphysis, (b) cortical irregularities and edema sis pubis with subchondral sclerosis
which can be seen in osteitis pubis, (c) MRI coronal plane

Table 8.4 Adductor and pubic symphysis injection

techniques
Procedure Adductor injection Osteitis pubis
Patient Supine with the leg Supine with frog
position slightly abducted leg position
and externally
rotated
Probe At adductor tendonAbove pubic
positioning symphysis
(Fig. 8.18)
Target Pathologic tendon Irregularity of the
joint or into joint
capsule
Needle size 25 g 1.5 inch for anesthesia and injection Fig. 8.19 Longitudinal view of needle placement for
Probe Medium to high frequency linear adductor calcification at the pubis (P)
Injected Corticosteroids Corticosteroids
agents (40 mg) (40 mg) thies, PRP injection also has promising outcomes
PRP 4–6 ml PRP 2 ml
Tenotomy 25% dextrose with after intratendinous injection. According to a ret-
0.5% lidocaine rospective case series of 408 consecutive patients
treated by a single ultrasound-guided PRP injec-
tion for tendinopathy in various sites, adductor
rotated at the hip. Place the probe longitudinally longus tendinopathy demonstrated significantly
at the adductor longus tendon (Fig. 8.15), and use improved functional outcome [25]. If a tear of the
transverse planes to confirm the three tendons. adductor is associated with spread up the aponeu-
Injection is usually performed with a 25 g 1.5 rosis (sports hernia) and particularly to the oppo-
inch needle in the long axis, approaching distal to site side, surgical fixation is most likely
proximal. Because of the superficial nature of the warranted. Percutaneous tenotomy or barbotage
tendon and tight position, a small hockey stick using a needle (Fig. 8.19) or Tenex™ may also be
probe can help facilitate the injection. A gel considered for severe calcifications. New research
standoff pad is often required secondary to the is being done on ultrasound-guided tendon
sharp angle of the tendon anteriorly. Alternate release as well. No data is available on the use of
between long and short axes during the injection microfat or bone marrow cells in this tendon.
to help better identify needle position and span For osteitis pubis injections, patients lay
the pathologic area. supine. The joint can be injected in a variety of
Adductor tendon pathology can be effectively manners. The most common is in-plane with a
treated with corticosteroid injection. The study standoff gel pad used to facilitate needle visual-
showed injection of local anesthetic and steroid ization. Alternatively, the clinician can use an
into the adductor enthesis may help in pain relief out-of-plane technique with a walk-down tech-
for up to 1 year [79]. Like in other tendinopa- nique with probe placed over the anterior aspect
156 R. Monaco et al.

of the pubic symphysis. Neurovascular structure

should be identified. A 25 g 1.5 inch needle
should be introduced anterosuperior to posteroin-
ferior approach aiming at pathology of irregular-
ity of the pubic symphysis or direct into the joint
capsule the pubic symphysis has a very tight joint
space, so only 1–2 ml can be injected.
Local steroid injections are most commonly
used for osteitis pubis treatment. Various studies
report short-term pain relief. There is a high rate of
nonresponder [20]. The underlying condition caus-
ing the joint irritation needs to be addressed for
successful long-term treatment. This is usually the
hip adductor myotendinous junction or adductor
tendon-rectus sheath aponeurosis. Orthobiologic
injections have limited studies in this pathology
with only some case reports or small pilot studies.
One study showed that monthly injection for two
consecutive treatments of prolotherapy showed
Fig. 8.20 sf superior-posterior facet, af anterior facet, lf
efficacy in athletes with groin pain [87]. Another lateral facet, pf posterior facet
case report found that combining PRP with nee-
dle tenotomy effectively improved the symptoms
[80]. Further research is needed. lar attachments, and a large bursa protecting the
area. The trochanter is easily palpable and con-
sists of four facets (Fig. 8.20), of which the lat-
Lateral Hip Region eral facet is palpable [71].
The tendons originate on the ilium, with the
Introduction gluteus minimus being the deepest structure. The
gluteus minimus attaches to the anterior facet and
Lateral hip pain is an extremely common problem runs deep to the gluteus medius on the ilium. The
requiring evaluation. Pain in this region is most gluteus medius is bipennate and has two muscu-
commonly associated with tendon and bursa lar attachments, the main one into the superior-­
abnormalities at the greater trochanter. Pain can lateral facet while its thick posterior band inserts
also be referred to this area from other structures, into the superior aspect of the posterior facet [42]
most commonly the hip joint. Evaluation starts (Fig. 8.2). The maximus muscle does not attach
with a thorough history and physical exam focus- to the trochanter; instead, it runs superficially
ing the evaluation of the entire hip complex. A sending fibers to insert onto the linea aspera of
kinetic chain approach to movement deficits is the femur and posterior hooks into the iliotibial
helpful in addressing the underlying origin of band (ITB). Underneath the maximus lies the tro-
pain. Ultrasound is critical to providing informa- chanteric bursa covering the posterior facet and
tion on the diagnosis of pathology and in guiding parts of the lateral facet above the medius. The
interventions. small bursa also sits between the attachment of
the medius and minimus at the respective facets.
The tensor fasciae latae and iliotibial band
Sonoanatomy (ITB) originate at the superior ilium and anterior
superior iliac spine (ASIS), just posterior to the
The lateral hip is defined by the greater trochan- iliac tubercle. The ITB begins in the posterior lat-
ter, an essential landmark with prominent muscu- eral aspect forming from the fascia of the tensor
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 157

fascia lata (TFL). There is a coalescence of these 3. Gluteus medius bipennate muscle with
fibers from the TFL, ITB, and gluteal aponeuro- attachments
sis over the trochanter before they disperse dis- 4. Trochanteric bursa
tally to multiple sites. The ITB is involved in 5. Iliotibial band
lateral hip and lateral knee stabilization. These 6. Tensor fasciae latae
are best seen in a longitudinal plane. 7. Gluteus maximus muscle
The gluteal muscles are the main external
rotators and abductor muscles of the hip and Start the evaluation by positioning the
assist in hip extension and stabilization. They are patient in the lateral decubitus position, prefer-
active during standing and walking motion. ably with the hip slightly flexed to a fetal posi-
tion. Place the probe transversely over the
trochanter (Fig. 8.21) and identify the facets.
Ultrasound Technique The apex of the greater trochanter demarcates
the division between the anterior and lateral
The following structures should be visualized as facets. Assessment of the gluteus minimus
part of the lateral hip checklist: attachment at the anterior facet is done by rotat-
ing the probe and translating anteriorly to have
1. Trochanter facets (anterior, superficial poste- the anterior facet centered in the transverse
rior lateral, lateral, posterior) plane, then rotating 90° to assess the tendon in
2. Gluteus minimus tendon and muscle the longitudinal axis (Fig. 8.22). The same

Fig. 8.21 Schematic and corresponding transverse view over the greater trochanter demonstrating gluteal muscle
attachments

Fig. 8.22 The picture

showed a bipennate
gluteus medius, one
band attached to the
superior-posterior and
lateral facets
158 R. Monaco et al.

technique should be used over the lateral and Pathology

superoposterior facets for the assessment of the
two gluteus medius attachments. Returning to Pain at the lateral hip is usually referred to as
the apex of the greater trochanter and translat- greater trochanteric syndrome. It is most com-
ing slightly posteriorly to the lateral facet will monly seen in females in the 50s and 60s. It is
allow for best visualization of the trochanteric best to describe the actual pathology using
bursa [45]. ultrasound. It has a reported prevalence of
Evaluate the tendons for pathology in both around 18% [81]. The etiology of greater tro-
longitudinal and transverse planes. As in many chanteric pain is often multifactorial, with
tendons, anisotropy may be encountered, mim- symptoms arising from a variety of structures
icking a tear. Evaluate the posterior zone for fluid including gluteal tendinopathy, bursopathy,
in the bursa and in the small bursal area at each intra-articular hip disorders, posterior external
tendon-bone interface. Characterize any bursal rotator structures, and the sacroiliac or spine/
fluid. If there is pain or it is clinically, evaluate lumbar complex. At the trochanter, the gluteus
the TFL at its origin and ITB. The TFL tendon is medius is the most ­common anatomic patho-
on average about 2 mm thick and should have no logic injured structure followed by the mini-
significant side-to-side difference; look for any mus. Isolated bursopathy is uncommon among
tendinopathy or partial tear. symptomatic patients. Ultrasound compares
If the patient has snapping, perform dynamic favorably to MRI for the evaluation of these
maneuvers for subluxation of the ITB and gluteus tendons with a sensitivity of 90% and a speci-
maximus over the greater trochanter. Ultrasound ficity of 95% [91] and may exceed it for spe-
with its dynamic capabilities is the test of choice. cific tendon disease secondary to its dynamic
Perform with the probe transverse over the tro- component and high spatial resolution. The ten-
chanter. Move the hip into flexion and extension dons have a similar spectrum of pathology to
and evaluate for tissue movement and sonopalpa- other tendons (partial tear, complete, tendino-
tion of reproducible snap. The ITB/gluteal apo- sis, calcifications, etc.). Tendons may fail in the
neurosis may snap over the anterior trochanter anterior aspect initially and then proceed poste-
with flexion and extension of the hip. It may also riorly similar to the rotator cuff [42]. Look for
be seen with adduction and internal rotation of diffuse thickening and hypoechoic signal as the
the hip with flexion/extension of the leg and hallmarks of tendinosis (Fig. 8.23b).
flexed knee. Evaluation with light probe pressure Enthesopathic changes in the tendon are not
or in the standing position may be required to uncommon and may not correlate with pain and
reproduce symptoms. should be clinically correlated. Abnormal

a b

Fig. 8.23 (a) Ultrasound view showed a normal gluteal tendon (yellow arrows). (b) Gluteus medius severe tendinosis
demonstrating significantly thickened tendon (yellow arrows) with small cortical irregularity at the greater trochanter
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 159

Doppler tendon vascularity is less conspicuous in should also include systemic inflammatory disor-
these tendons than others. Muscle disorders of ders and rarely infection. Most trochanteric bur-
the gluteal tendons are less common. One may sal swelling is secondary to tendon pathology,
see some changes associated with tendon pathol- especially of the medius. Again, isolated bursal
ogy such as atrophy and retraction. Complete swelling is uncommon.
tears may appear similar to the rotator cuff with a
“bald” facet. Calcific deposits are often associ-  luteus Medius Bursitis
G
ated with tendinopathy, but like in the shoulder Chronic tendon pathology likely leads to an
may be benign findings. A variety of presenta- impingement-type phenomenon and chronic bur-
tions can occur from small lesions at the enthesis sal issues similar to the shoulder. Abnormal hip
to large deposits causing significant bursal pain. mechanics secondary to intra-articular pathology
Hydroxyapatite deposition and varying stages of likely plays a large role. Pain can also be referred
calcific tendon pathology may be present [53]. to this area from the hip joint and other areas as
Clinical correlation is critical. previously noted.
Trochanteric bursal swelling is infrequent Pain proximal to the trochanter at the ilium
unless direct trauma is present (Fig. 8.24). Direct should be evaluated for tendinosis of the ITB or
trauma may cause significant large swelling. Like TFL (Fig. 8.25). In TFL tendon pathology, it is
all bursitis and fluid collections, the differential commonly seen as a repetitive overuse injury in

a b

Fig. 8.24 (a) Trochanteric bursitis (asterisk) with ante- fluid collection (asterisk) with gluteus medius and gluteus
rior calcification (white arrow) at the gluteus minimus minimus partial tear
tendon. (b) Ultrasonography showed hypoechoic area of

Fig. 8.25 Sonographic

longitudinal view of
TFL partial tear (long
axis)
160 R. Monaco et al.

runners/cross trainers. It is more common in The patient is placed in the side-lying (lateral
females and presents as local pain. Full thickness decubitus) fetal position. The probe is placed
tears are rare. transversely to identify the facets and/or the ten-
Snapping can occur as previously noted and don/bursal pathology. A 25 g or above needle is
is associated with ITB/gluteal aponeurosis used for local soft tissue anesthesia. Then a 22 g
thickening. 3 inch needle is used to advance in plane with the
transducer from posterior to anterior. The target
is primarily the trochanteric bursa (Fig. 8.26), but
Procedures depending on diagnosis may be the tendon for
regenerative procedures. Long-axis views of the
The common procedures to the lateral hip revolve tendon can also be used. It is best to determine
around the gluteal tendons (Table 8.5). A variety this on an individual case basis.
of substances can be injected, each with varying Corticosteroids with anesthetics can play a
pros and cons. These include corticosteroid, dex- role in acute inflammation control. This can allow
trose, saline, and biologics such as PRP, MFAT, pain reduction facilitating physical therapy.
and BMAC. Labrosse et al. noted on average a 55% reduction
The procedures in the region are noted below. in pain [54]. These injections are best done ultra-
Tendon: tenotomy, barbotage, orthobiologics, sound guided through the same technique
high-volume injection described above. These injections should be lim-
Bursa: injection and aspiration ited secondary to long-term potential risk of cor-
ticosteroids on tendons. The clinician should
Table 8.5 Lateral hip injection techniques inject the bursa directly and avoid the tendon
Gluteal using steroids. Cortisone should not be used in
Pathology Trochanteric bursitis tendinopathy high-grade partial or full thickness tears second-
Patient Placed in the side-lying fetal (lateral
ary to rupture possibilities. As previously noted,
position decubitus) position
Probe Placed transversely to identify the facets since most bursal issues are secondary to tendon
positioning and/or the tendon/bursal pathology pathology, treating the tendon is critical. For ten-
Target Trochanteric bursa Pathologic tendon dinopathy, a recent high-quality study by
Needle size 25 g 1.5 inch for anesthesia and 22 g 3 Fitzpatrick showed excellent results of single-­
inch for injection dose leukocyte-rich PRP injection under ultra-
Consider larger needles (18 g) for
tenotomy or use specialized equipment sound guidance in patients with chronic gluteal
with Tenex™ tendinopathy >4 months when compared with
Probe Medium to high frequency linear corticosteroid injection with sustained improve-
Injected Corticosteroids (40–80 mg) ment for 2 years [36]. There was also a promising
agents Platelet Rich Plasma/bone marrow
outcome in treating gluteus medius tendinopathy
aspirate/microfat 3–6 ml
Tenotomy (6–9 needle passes) from combining LR-PRP injection with needle
tenotomy [55]. A systematic review study also
showed a clinical improvement of PRP injection
in recalcitrant greater trochanteric pain syndrome
when compared with surgery [90]. Moreover, a
study comparing LP-PRP injection with cortico-
steroid injection in 24 patients with greater tro-
chanteric pain syndrome revealed that PRP
injection helps decrease pain up to 24 weeks, sig-
nificantly longer than cortisone [11]. Platelet-rich
plasma may also have indications for tendon
pathology at the origin of the ITB and TFL in
Fig. 8.26 Transverse view of the trochanteric bursa dem- cases of pathology not responsive to standardized
onstrating the needle trajectory (arrow) for a lateral to treatments. High-volume dissection was also
medial approach
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 161

shown to be effective in greater trochanteric pain. and kinetic chain movement pattern analysis. A
A case series study showed short to medium pain kinetic chain approach to movement deficits is
relief after high-volume dissection with 10 ml helpful in addressing the underlying origin of
0.5% Marcaine and 50 mg hydrocortisone into pain. Ultrasound with sonopalpation is critical to
the area of greatest pain over the greater trochan- provide information on the diagnosis of pathol-
ter followed by structured rehabilitation [64]. ogy and guide interventions. Guided diagnostic
The use of MSCs in the gluteal tendon still has injections can also be helpful to differentiate the
limited study. One case report reported a significant pain generator for further treatment options.
improvement in pain and function after pure bone
marrow injection in a gluteus medius tendon with
calcific tendinopathy [41]. Tendon calcifications Sonoanatomy
can be treated with barbotage/aspiration or needle
tenotomy. Tenotomy has been studied by Jacobson The posterior hip/subgluteal space encompasses
with good results [45]. A large needle is passed the region. The area encompasses the following
through the tendon to facilitate controlled tendon key structures to be scanned.
injury and stimulate tendon recovery; the number Posterior hip checklist:
of tendon passes is often based on feel with return Deep external rotators:
to normal tissue characteristics. Sonographic guid-
ance is critical. Recovery usually takes 3 months 1. Piriformis
[45]. Instrumented procedures such as Tenex™ can 2. Obturator internus
also be used for large calcifications or tendinosis. A 3. Gemelli
recent case series on percutaneous ultrasonic tenot- 4. Quadratus femoris
omy in gluteal tendinopathy with a 22-month fol- 5. Sciatic nerve
low-up showed an improvement in VAS, functional 6. Ischial tuberosity/bursa – hamstring origin
score with no reported complication, and good
patient satisfaction [7]. Its boundaries are posteriorly, the gluteus
maximus; anteriorly, the posterior acetabulum,
hip joint capsule, and proximal femur; laterally,
Posterior Hip Region the gluteal tuberosity; medially, the sacrotuber-
ous ligament; superiorly, the inferior margin of
Introduction the sciatic notch; and inferiorly, the proximal ori-
gin of the hamstrings at the ischial tuberosity.
The posterior hip is one of the most challenging The superior and inferior gluteal, sciatic, poste-
areas for evaluation. It may best be referred to as rior femoral cutaneous, and pudendal nerves tra-
the sub- or deep gluteal space. The area has mul- verse the deep gluteal space (Fig. 8.27).
tiple structures and deep layers of tissue, making The sciatic nerve is a key structure in the
physical exam, sonographic imaging, and inter- region. It runs out the sciatic notch with the supe-
ventions challenging. Pain can be from the ten- rior gluteal artery and neve. It runs posterior to
dons of the external rotators, as well as the the piriformis though six variations are noted in
extensive neurological structure in the area, par- the literature. Limited research suggests these
ticularly the sciatic nerve. Multiple pathologies variations do not appear to be associated with
in this area have been incorporated into the all-­ increased pain [4]. The nerve then heads laterally
inclusive “piriformis syndrome,” which lacks to the thigh and exits the space over the quadratus
diagnostic precision. femoris muscle between the ischium and the tro-
Deep gluteal syndrome is perhaps a better chanter. It is about 1.2 cm from the ischial tuber-
term to encompass pain in this region [68]. Pain osity with close association to the hamstring
in the region is commonly referred to from the origin. Fibrous bands may be located along the
spine as well. Evaluation starts with a thorough course of the nerve causing tethering and in some
history and physical exam, including the spine cases pain and sciatica-like symptoms [16].
162 R. Monaco et al.

Ilium
(Os ilium)
Piriformis Muscle
(Musculus piriformis)

Superior Gemellus Muscle

(Musculus gemellus superior)

Obturator Internus
Muscle
(Musculus obturatorius
internus)
...
Quadratus Femoris Muscle
(Musculus quadratus femoris)

Ischium
(Os ischii)
Femur
(Femur)

Fig. 8.27 Anatomy of the deep posterior hip musculature in relation to the sciatic nerve

The muscle tendon units in the space include Just distal and medial to the quadratus sits the
from superior to inferior the piriformis, superior ischial tuberosity and the attachment of the ham-
gemellus, obturator internus, inferior gemellus, string tendon. The hamstrings originate from the
and quadratus femoris (Fig. 8.27). The pirifor- ischial tuberosity, except for the short head of the
mis occupies a key position and runs laterally biceps femoris; the semimembranosus tendon is
through the greater sciatic foramen, becomes attached to the superolateral facet of the ischial
tendinous, and inserts in the medial aspect of the tuberosity and the conjoint tendon of the biceps
trochanter. Its attachment is often not distinct femoris, and the semitendinosus is attached to the
from the conjoint tendons of the obturator inter- inferomedial facet. The sciatic nerve lies approxi-
nus and superior and inferior gemelli. The piri- mately 1.2 cm lateral to the ischial tuberosity or the
formis is a key external rotator and is stretched outer border of the semimembranosus tendon.
with hip flexion, adduction, and internal rota- Thus, the proximal part of this muscle complex is
tion. The most important of the conjoint tendons close to the sciatic nerve. The position of the ten-
is the obturator internus, which makes a don attachments of the conjoint tendon and semi-
90-degree turn to the anterior pelvis. These ten- membranosus is noted in Fig. 8.28.
dons also work to stabilize the hip and externally
rotate. The quadratus femoris is a quadrilateral-
type muscle that sits between the trochanter and Ultrasound
the ischium. It can be involved in ischiofemoral
impingement of the muscle and sciatic nerve Sonographic evaluation in this region is done
which sits directly in this space. with the patient prone and a pillow placed under
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 163

a b

Fig. 8.28 (a) Transverse image of hamstring origin. Note teus maximus (GMAX) superficially. (b) Longitudinal
the conjoint tendon (CON) attachment at the ischium image of hamstring origin (BF biceps femoris long head,
(ISCH), the adductor magnus (ADM) medially, semi- ST semitendinosus)
membranosus (SM), sciatic nerve (SN) laterally, and glu-

a b

c d

Fig. 8.29 Scanning sequence of the posterior hip from superior-posterior border of the greater trochanter (GT).
cranial to caudal. (a) The hyperechoic ilium is first noted (d) Caudal to the piriformis the characteristic right-angle
in the lateral posterior region. (b) At the notch the pirifor- appearance of the obturator internus hooking around the
mis is well visualized with the sciatic nerve (S, green out- superior border of the obturator fossa and attaching to the
line). (c) The piriformis is seen attaching to the greater trochanter

the pelvis. A curvilinear probe is required to best (Fig. 8.29a). Move distally until the sciatic notch
see these structures. The effective use of sonopal- is apparent. The use of Doppler may help localize
pation and dynamic maneuvers may assist in the the superior gluteal artery that runs with the sci-
evaluation of the pain generators. atic nerve (Fig. 8.29b). An attempt to find the sci-
Scanning of the posterior hip should be done atic nerve at this level can be done but is
sequentially beginning with the hyperechoic challenging in obese patients. Evaluate the piri-
ilium first noted in the medial posterior region formis – which runs at a 30-degree angle through
164 R. Monaco et al.

the notch – in the long axis by pivoting the probe can include pathology to multiple structures vs. piri-
toward the trochanter (Fig. 8.29c). Dynamic formis syndrome. Four main entities will be
maneuvers of hip external and internal rotation reviewed.
help identify the muscle. Take note of the muscle
complex thickness as it may be associated with Piriformis Pain Syndrome Piriformis syn-
piriformis syndrome and comparison to the oppo- drome is a subgroup of deep gluteal syndrome,
site side may be needed. Transverse views of the but not all deep gluteal syndrome is piriformis.
posterior gluteal region may provide further diag- Potential pain in the piriformis complex can occur
nostic information, however are more challeng- from multiple sources including hypertrophy of
ing and take extensive practice. Recent literature the muscle, spasm, possibly anomalous course of
suggests ultrasound may be of value in diagnos- sciatic, or anomalous fibrous attachments and
ing piriformis syndrome, but more work needs to lastly postsurgical fibrosis [16, 51, 68].
be done [92]. Moving the probe more distally,
one will note the obturator internus running into Gemelli-Obturator Internus Syndrome The
the pelvis and the conjoint tendon (Fig. 8.29d). gemelli-obturator is often painful to palpation.
Again, dynamic maneuvers are very helpful for The sciatic runs under the piriformis and over the
localization. complex and may be affected by a scissor-like
The quadratus muscle is seen easily between effect between the two muscles causing entrap-
the ischium and the posterior trochanter. Note ment. The obturator is often more painful to clini-
the sciatic nerve sitting in the fossa (Fig. 8.30). cal exams than the piriformis [48]. The nerve is
Use extreme internal/external rotation to evalu- attached to the gemelli-obturator internus com-
ate ischiofemoral impingement. Dynamic plex by connective tissue, which can lead to sci-
maneuvers may help illicit pain and help evalu- atic entrapment [8]. Muscular spasm or
ate for potential ischiofemoral impingement. myofascial pain syndrome, acute strain, hema-
toma, abscess/pyomyositis, tendinitis, and bursi-
tis of the obturator internus can cause posterior
Pathology hip pain as well [51]. Ultrasound and MRI exams
are often negative or show subtle changes, but
Pathology in this region is difficult to note on imag- pain is noted over the tendon suggestive of
ing tests and may be multifactorial. It is best to use mechanical wear.
the term subgluteal/deep gluteal syndrome which
Quadriceps Femoris and Ischiofemoral
Impingement Ischiofemoral impingement (IFI)
is a hip pain related to narrowing of the space
between the ischial tuberosity and lesser trochan-
ter of the femur (Fig. 8.30). This leads to muscle
tendon and neurological changes. The space typi-
cally measures about 23 mm and can be consid-
ered narrowed if less than 17 mm. Most
measurements are based on static MR images
[74]. The condition can be related to repetitive
overuse or inflammation in the area entrapping
the muscle and/or sciatic nerve. Patients usually
Fig. 8.30 Transverse view of posterior pelvis over the
present with pain for prolonged sitting and with a
quadratus femoris muscle between greater trochanter and
ischial tuberosity with sciatic nerve superficially. Note long stride. Injection can be helpful both diag-
hamstring origin (arrow) (I ischium, S sciatic nerve, GT nostically and therapeutically. It is mainly seen in
greater troch, QF quadratus femoris)
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 165

middle-aged to elderly women but can also be string – tear, acute, chronic partial, tendinosis,
identified in pediatric patients [69]. calcifications (Fig. 8.31), apophyseal injuries –
can occur. These can cause chronic inflammatory
Fibrous/Fibrovascular Bands Fibrous-type changes and adhesion causing fibrous scar and
bands are not uncommon in the region and can effect the sciatic nerve in the ischial tunnel.
compromise the sciatic nerve and result in Patients often have pain with sitting and pain on
entrapment-­like syndromes. Symptoms present firing of the hamstring muscles. It is often seen in
similar to sciatica but no back pain. These bands runners and may not respond well to therapy.
are often found in cases during arthroscopy Three
types of bands occur, starting at the sciatic notch,
then obturator-gemelli complex, and lastly in the Procedures
area of the ischial tunnel [16].
Clinicians can perform diagnostic and therapeu-
Hamstring Conditions affecting the proximal tic injections (Table 8.6) in the region to assist in
origin of the hamstring may also be a source of evaluation and treatment. Most injections will
pain. A full spectrum of pathology at the ham- use a curvilinear probe at lower frequencies. The

a b

Fig. 8.31 (a) Transverse and (b) short-axis view of a calcific and tendinopathic hamstring origin with needle path
shown in A

Table 8.6 Posterior hip injection techniques

Peri-sciatic
Procedure Piriformis injection hydrodissection Ischiofemoral space Hamstring origin
Patient Placed in prone position (place a rolled pillow under the pelvis)
position
Probe Placed transversely over the piriformis and Transversely transverse on Transverse over the
positioning confirmation is done with ext/int rotation sciatic, long view on origin
quadratus femoris
Target Superior to the Peri-sciatic area Quadrangle shape of the quad Pathologic tendon of
piriformis or piriformis femoris with the sciatic nerve hamstring origin
muscle belly above it
Needle size 25 g 1.5 inch for anesthesia and 22 g 3 inch for injection
Probe Low frequency curvilinear Medium to high
frequency linear
Injected Corticosteroids (40 mg) Corticosteroids
agents 25% dextrose with 0.5% lidocaine (40 mg)
Normal saline PRP
PRP (consider LP-PRP or PPP on peri-sciatic area) Tenotomy
5–20 cc around the nerve – enough to dissect tissue and halo the nerve
166 R. Monaco et al.

target of the injection should be based on history, Ischiofemoral Space/Peri-sciatic

physical exam, and imaging findings, including Hydrodissection
sonopalpation.
The piriformis muscle may be a source of pain Pain may be isolated more closely to the ischiofe-
and can be easily targeted. Injections can be help- moral space requiring a diagnostic and/or thera-
ful diagnostically and potentially therapeutic. peutic injection. Differential in this area includes
The setup for this injection is as follows: The sciatic nerve entrapment, ischiofemoral impinge-
patient is placed in the prone position – it may be ment, hamstring tendinosis, and ischial bursitis.
helpful to place a rolled pillow under the pelvis to The injection will be done in the prone position
allow for an easier sonographic window with less with a pillow placed under the pelvis to reduce
probe tilting. The probe is placed transversely probe angle and facilitate better needle visualiza-
over the piriformis and confirmation is done with tion. The space is found as described prior
external/internal rotation. Identify the location of between the ischium and the trochanter. The
the sciatic nerve, in most cases deep (anterior) quadrangle shape of the quadriceps femoris is
and medial to the piriformis. Use Doppler to con- easily recognized with the sciatic nerve sitting
firm neurovascular structures to avoid. One enters above it. Again, dynamic maneuvers of internal/
in-plane from a lateral to medial approach, external rotation will help facilitate its vision.
though a medial to lateral approach can also be The probe will be placed transversely to see a
used. At first, a 25/27 gauge needle is used for transverse view of the sciatic and long view of
superficial anesthesia, then followed by a 22 the quadratus. The approach will be from a lateral
gauge approximately 3 inch needle. There is to medial aspect. Depending on the pathology,
debate on the location of the injectate in the lit- one can position the needle in multiple positions.
erature. We perform the following when this is For a diagnostic evaluation, one can target the
the possible pain source: first, fluid is placed in area in the quadratus that shows pain or changes
the fascia superior to the piriformis, particularly on MRI which is usually deep and lateral to the
if it appears more hyperechoic and enlarged ver- sciatic nerve. For those having sciatic-type symp-
sus the opposite side; then do a hydrodissection toms, a peri-sciatic hydrodissection can be done
with saline of this fascia; next, the muscle belly of the sciatic nerve [15]. This may help alleviate
of the piriformis may be targeted with an injec- symptoms, especially if fascial bands are present
tion by moving the needle slightly anterior into along the sciatic. The sciatic will need to be tar-
the muscle. geted at different regions but usually is affected
If pain is in the obturator-gemelli complex or from the obturator complex down through the
abnormality is noted, the same technique should quadratus femoris space. In cases of prior ham-
be used to inject it. Carefully track the sciatic string injury, the sciatic may also be encompassed
nerve to avoid iatrogenic injury. A medial to lat- in hyperechoic fibrous scar tissue and cause
eral approach may be easier in some cases to symptoms mimicking hamstring pain or sciatic-­
avoid the sciatic. Hydrodissection of this area type pain. Regardless of the site of sciatic pathol-
may be beneficial if no pathology is visualized as ogy, the technique will remain the same. Locate
accessory bands may play a role in pain of the the sciatic again using a transverse ultrasound
sciatic. The accuracy of US-guided piriformis scan. A lateral to medial approach will be used.
injections has been validated in cadaver studies, After anesthesia, a 22 g 3 inch needle can be used
with an accuracy of 95% in a 2008 study by to place copious saline around the nerve to halo
Finnoff et al. [34] In a study of 57 patients, the nerve and hydrodissect the region. Typical
US-guided anesthetic-only injection into the piri- volumes are around 10–20 cc. Pure (leukocyte-­
formis was shown to have a significant benefit in poor) PRP or PPP may be used or saline with
pain reduction. Corticosteroid may not provide dextrose. Depending on the length of symptoms,
additional benefit over lidocaine alone [63]. one may need to do multiple areas.
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 167

Hamstring Origin volume dissection may also help in recalcitrant

cases to hopefully decrease fascial adhesions.
The hamstring origin is often a source of pain in In ischiofemoral impingement patients, corti-
the posterior gluteal region and may be associ- costeroid injection under ultrasound guidance at
ated with ischiogluteal bursitis. Injection can be the quadratus femoris muscle has shown promis-
of value in this area for diagnostic and therapeu- ing outcome in 2 weeks’ follow-up [6]. An injec-
tic purposes. The patient is again placed in the tion of 8 mL of 0.25% lidocaine at the quadratus
prone positions with pillows to prop up the pel- femoris in lower buttock pain patients also
vis. Placing the leg off the table in slight flexion showed to help decrease pain with good patient
can also assist in the evaluation of the tendon satisfaction [49]. Orthobiologic studies are lim-
insertion. The approach will be with the probe ited in this area. One case report showed a good
transverse over the origin from a lateral to medial outcome after five injections of prolotherapy
approach. The sciatic will sit more anterior and with polydeoxyribonucleotide sodium [50].
lateral to the tendon. The position is similar to the
ischiofemoral space injection but slightly more
distal on the body. Usually a needle between 1.5 Hamstring Origin
and 3 inches will suffice depending on body habi-
tus. Use Doppler and note the sciatic nerve posi- The effects of corticosteroid peritendinous injec-
tion. The target in these injections is usually the tion at proximal hamstring tendinopathy were
tendinopathic origin of the hamstring, usually the good in various studies. Zissen et al. stated that
conjoint tendon of the semitendinosus and biceps corticosteroid injection under effective technique
femoris. Oftentimes, calcifications and entheso- is safe with intermediate- to long-term clinical
pathic changes are the target. Occasionally, there improvement [93]. Because of cortisone effects
is an isolated ischiogluteal bursitis that is isolated on tendons, this should be done in a limited
and can be injected. However, more commonly amount of times and avoided in high-grade
tendon pathology is the source of bursal swelling. injuries.
Corticosteroids are targeted toward the bursa, The use of PRP injection in this area is also
while orthobiologic preparations would be tar- common with studies showing promising out-
geted toward the tendon. comes. A retrospective study concluded that PRP
Piriformis cortisone injections under ultra- injection helped improve clinical outcome in the
sound guided have shown an improvement in majority of the patients in the study [33]. A
half of the subjects, as noted by Jeong et al. double-­blind randomized controlled trial in 19
[47]. Using a physiotherapy protocol combined hips showed outcomes improvement in both PRP
with triamcinolone injections, Fishman et al. and whole blood intratendinous injection [9].
[35] found that 279 (79%) of 353 patients with Tenotomy with PRP injection demonstrated a
piriformis syndrome had at least 50% improve- good clinical outcome as well as improvement of
ment. The use of orthobiologic in this area still tendon echogenicity and intratendinous calcified
has limited study to date; however, the outcome resolution [34]. Adipose tissue combined with
might be promising like treating tendon pathol- high-density platelet-rich plasma (HD-PRP) has
ogy in other areas of the body. More research is been reported in one case report which showed
needed. clinical improvement after injection [67].
Deep gluteal pain or piriformis pain may be
associated with sciatic pathology. If sciatic
entrapment is considered, a high-volume injec- Conclusion
tion of the nerve can be done. Burke et al. reported
50% had extended relief [15]; however diagnosis The posterior hip is a challenging area to diag-
was not subsetted making it difficult to determine nose and treat. The anatomy is complex, and pain
responders and the underlying diagnosis. High-­ may be multifactorial and referred. Ultrasound
168 R. Monaco et al.

can be helpful in making an accurate diagnosis

and developing a treatment plan and is critical to
guided injections in the region.

Thigh

Introduction

The thigh muscles are the most commonly

injured in the body. Muscle trauma mainly results
from sporting activities and accounts for 15–50%
of sports injuries. Muscle injuries are the most
common injuries in sports, with hamstring inju- Fig. 8.32 Schematic and corresponding transverse view
of quadriceps muscles at the proximal third of the thigh.
ries accounting for 29% of all injuries in athletes. Vastus lateralis (VL), rectus femoris (RF), vastus interme-
Muscle contusion is one of the most common dius (VI), vastus medialis (VM)
causes of morbidity from sports-related injuries,
together with sprains and strains. The region is
broken down into the anterior thigh focusing on then semimembranosus; these should be identi-
the quadriceps and the posterior hamstrings. Our fied in the short axis at the mid-thigh. The short
discussion is limited to the proximal aspects head of the biceps femoris lies deep to the long
around the hip. Sonography can provide valuable head and adjacent to the shaft of the femur. It is
information to the clinician at the point of care. not commonly involved in proximal hamstring
This section will focus on high-grade muscle injuries. At the proximal hamstring, the semi-
injuries, hematoma evacuation, Morel-Lavallée membranosus is primarily a tadpole-like periph-
injuries, and review regenerative procedures. eral tendon and the semitendinosus is very
muscular. Within the semitendinosus muscle,
there is a notable hyperechoic raphe [44]. The
Sonoanatomy semitendinosus and biceps long head come
together to form the conjoint tendon to attach at
The anterior thigh is made up of the quadriceps the ischial tuberosity. The sciatic runs under the
muscles. With a transducer in the transverse biceps/semitendinosus muscle and above the
plane over the mid-thigh, the most superficial adductor magnus (Fig. 8.33).
structure is the rectus femoris muscle which is
overlying the vastus intermedius, and the two are
separated by a fascial plane. Deep to the vastus Pathology
intermedius is the femur. Medially adjacent to the
rectus femoris and vastus intermedius lies the Muscle Injuries
vastus medialis and laterally the vastus lateralis.
Evaluation is best in the transverse plane with Injuries to the muscles of the thigh can involve
confirmation in the longitudinal plane for pathol- partial or complete muscle tears. These are the
ogy (Fig. 8.32). most commonly injured muscles in the body.
Evaluation of the posterior thigh involves the There are various grading systems of muscle
assessment of the muscles of the hamstring – the injuries based on both clinical and imaging crite-
semimembranosus, semitendinosus, and biceps ria [18, 38]. It is best to describe the pathology on
femoris long and short heads – and the sciatic ultrasound in its entirety including length and
nerve. The orientation of the muscles from lateral cross-sectional area of injury, involvement of ten-
to medial are biceps femoris, semitendinosus, don pathology, proximity to sciatic nerve, amount
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 169

Fig. 8.33 (a) Cross

section schematic of the a
posterior proximal thigh
(b). Transverse view of
the proximal third of the
hamstring. Biceps
femoris (BF), sciatic
nerve (S),
semitendinosus (ST),
semimembranosus
(SM). Note the b
peripheral
semimembranosus
tendon (arrow) and the
raphe (arrowhead)
through the
semitendinosus

a b

Fig. 8.34 (a) Transverse view of rectus femoris strain with normal central tendon and (b) with central tendon
involvement

of hematoma, retraction of tendon, calcifications, raphy with fluid around the central tendon or an
and Doppler activity, to name a few. In general, ill-defined central tendon [32] (Fig. 8.34).
you find the following: grade 1 injuries subtle, In the hamstring, the biceps is the most com-
focal changes in echogenicity with no architec- mon injured muscle (Fig. 8.35b). Injuries to the
tural distortion; grade 2 injuries may demonstrate conjoint tendon will have a worse and longer
some discontinuous muscle fibers with localized prognosis for recovery.
hypervascularity and altered echogenicity result-
ing from hematoma; and grade 3 injuries demon-
strate complete discontinuity of muscle fibers, Hematoma
hematoma, and muscle fiber retraction [38].
The most commonly injured muscle in the Hematomas can be identified as hypoechoic fluid
anterior thigh is the rectus femoris. Most injuries collections (Fig. 8.36). There are two main types –
to the rectus femoris are at the proximal myoten- those caused by direct trauma and indirect from
dinous junction. Injuries in the proximal third can muscle tears. Hematomas form in the intermuscu-
be to the muscle. More significant injuries may lar and/or intramuscular c­ ompartments. Sometimes,
demonstrate altered echogenicity on ultrasonog- mixed hematomas can occur. Ultrasound is useful
170 R. Monaco et al.

a b

Fig. 8.35 (a) Transverse view through the proximal thigh membranosus (sm), as well as a tear of the biceps femoris
showing a partial tear (yellow arrow) of semimembrano- (bf). At the conjoint tendon consistent with a high-grade
sus muscle. (b) Note hypoechoic fluid around the semi- sprain (g gracilis muscle)

a b

Fig. 8.36 (a) Short-axis view of vastus intermedius (VI) muscle hematoma seen deep to the rectus femoris (RF). (b)
Longitudinal view of vastus intermedius hematoma

for the evaluation of muscle hematoma, to charac-

terize the type of fluid, its extent, and its volume. A
hematoma may be underappreciated on physical
exams, especially in large athletes. Acutely the
fluid is hypoechoic, but will turn to mixed echo-
genicity in time as the heme products settle and are
metabolized. The best time to evaluate for a hema-
toma is usually about 48–72 hours from injury. The
hematoma’s length may play a greater role in
recovery than width. Evacuation of large hemato- Fig. 8.37 Longitudinal view of the thigh showed a
mas using ultrasound may help accelerate recovery hypoechoic fluid collection (asterisk) between subcutane-
from injury [73]. ous tissue and muscle consistent with a Morel-Lavallée
lesion

Morel-Lavallée Lesions/Seroma results in a collection of blood, lymph, fat,

plasma, and/or debris in this potential space.
A post-traumatic condition which can be readily These lesions tend to be well defined and
diagnosed with ultrasound as a fluid collection smoothly marginated, especially as they age. In
between the subcutaneous tissue and the underly- early stages of less than 1 month, they tend to be
ing thigh fascia is known as a Morel-Lavallée more heterogeneous with more irregular margins
lesion (Fig. 8.37). A traumatic injury to the thigh [65]. There are six subtypes of these injuries, and
8 Ultrasound of the Hip/Thigh: Regenerative Medicine Focus 171

they have a high rate of recurrence. Ultrasound minor injuries will require no regenerative treat-
can easily identify this pathology, which often ments. PRP may play a role in hamstring injuries,
can be missed if the clinician does not have a but the data to date has been mixed. Animal stud-
high level of suspicion. ies suggest that platelet-poor plasma (PPP) may
be a much better choice to stimulate myocytes
[19]. At this time, high-dose platelet/leukocyte-
Procedures rich PRP should likely be avoided. Data seems
more optimistic on leukocyte-poor/low-platelet-
Hematoma/Seroma Aspiration dose PRP or platelet-­poor plasma (PPP) in these
The most common procedure in the thigh revolves injuries. Bradley et al. showed an improvement in
around aspiration of hematomas or seromas. return times of one game in NFL players treated
Hematomas or seromas, if large (greater than with ACP/leukocyte-poor/low-platelet PRP prod-
5–10 ml), should be considered to be evacuated, ucts [14]. Rossi showed that a single injection of
particularly in the active athlete requiring an autologous PRP with a rehabilitation program
accelerated return to play. The approach to the significantly shortened time to return to sports
hematoma will be dependent on the location. after an acute grade 2 muscle injury when
Most will require large needles usually in the ­compared with the control group; however, the
range of 14–18 g depending on the echogenicity rate of recurrence was not significant between the
and age of the hematoma/seroma [43]. In chronic two groups [78]. Grassi et al. in a systematic
situations, one may need to irrigate the hema- review and meta-analysis concluded there was no
toma. Hematomas and seromas have high rates of evidence for an improvement in return to sport or
recurrence and should be compressed post aspi- reduction in future injury in PRP-treated cases
ration and followed closely with ultrasound, usu- [37]. The studies were limited by methodological
ally every few days until resolved. matters as there were tremendous heterogeneities
There is really no data to help determine if regarding the injectant preparation, optimum
injection of medications post aspiration is help- platelet concentration, presence of leukocytes,
ful. Some things to consider would be chronicity, and volume of PRP which should be adminis-
where with chronic hematomas it may make tered as well as the number of and timing of treat-
sense to add a corticosteroid to assist in the pro- ments. Sheth concluded PRP may help in grade
cess of emulsifying older fibrous tissue and blood 1–2 muscle strains but not in the hamstring [82].
products. In cases of recurrent hematomas, it Further research is needed on this, in particular
may make some sense to use platelet-rich fibrin potential doses, volume, and timing issues. The
or platelet-poor plasma, but no data is available. use of microfat/adipose may be of value in grade
Anecdotal evidence and basic science suggests 3 tears requiring scaffolding, but no research is
avoiding corticosteroids in the acute traumatic available to guide treatment decisions at this
hematoma. In regard to seromas, for recurrence, time.
one of the options to consider is the use of scle- Percutaneous injection treatments may also
rosing agents such as doxycycline; platelet-rich play a role in chronic injuries that have developed
fibrin can alternatively be considered, but this has fibrosis, particularly around the sciatic nerve
not been adequately studied to date [9, 83]. (Fig. 8.38). As previously discussed, high-­volume
hydrodissection around the sciatic nerve may be
Muscle Injections of value in fibrosis (Fig. 8.38b). Similar tech-
Muscle tears of the thigh may be treated with niques can also be used around chronically
regenerative approaches, particularly after hema- fibrosed muscle tears with poor healing. Further
toma aspiration. Most treatments will be of grade research is needed as cases are limited to case
two injuries and higher, as minor injuries as reports [22].
172 R. Monaco et al.

a b

Fig. 8.38 (a) Cross-sectional view demonstrating fibrosis around the sciatic nerve (S); (b) needle placement during
peri-sciatic nerve hydrodissection

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musculoskeletal area for sonography. Multiple its susceptibility to compression and injury. Plast
layers in this broad region, deep structures, Reconstr Surg. 1997;100(3):600–4.
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R, Keene JS. Correlation of ultrasound-guided cor-
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 Ultrasound Imaging of the Knee
Joint
9
Daniel Chiung-Jui Su and Ke-Vin Chang

Introduction

Knee pain is one of the most common complaints

that patients seek help for. When checking for
knee problems, we have to see the whole lower
limb as a unit and look for if there are other
defects of biotensegrity existing in other joints,
such as hips and ankles. Malalignment of the
lower limb will cause serial problems and cannot
be treated completely if the malalignment has not
been identified and corrected.
Once we address the biotensegrity of the lower
limb, we can specify our target into the knee Fig. 9.1 By asking the patient to forcefully extend the
knee, we can assess the effusion amount in the suprapatel-
joint, where we can divide the knee into the ante-
lar recess
rior region, medial region, posterior region, pos-
terior medial corner, posterior lateral corner, and
ligament-capsule-menisci complex. before the injection to ensure that the concentra-
tion of the injectate is sufficient (Figs. 9.1 and 9.2).
The extension mechanism of the knee is main-
Anterior Region tained through the quadriceps tendon, patellar
bone, patellar tendon, patellar retinacula, Hoffa’s
In the anterior region, the suprapatellar recess is fat pad, and the prepatellar tissue [1].
used as the target for intra-articular injection of Tendinopathy in this region, or increased blood
platelet rich plasma (PRP) or high concentra- flow under the power Doppler imaging, may
tion glucose. Effusion should be aspirated first imply failure of the extension mechanism.
Therefore, we should always check for the integ-
D. C.-J. Su rity of the lower limb globally before we look
Department of Physical Medicine and Rehabilitation, into local injuries.
Chi-Mei Hospital, Tainan, Taiwan The anterior cruciate ligament (ACL) is the
K.-V. Chang (*) major stabilizer during anterior drawing of the
Department of Physical Medicine and Rehabilitation, tibia at all flexion angles and during internal rota-
National Taiwan University Hospital, Bei-Hu Branch, tion of the tibia at flexion angles less than 35
Taipei, Taiwan

© Springer Nature Switzerland AG 2022 177

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_9
178 D. C.-J. Su and K.-V. Chang

degrees. Therefore, if the patient is presented ultrasound or through magnetic resonance imag-
with a positive anterior drawer test or Lachman ing. ACL insertion can be seen under the ultra-
test, we should further check the ACL under sound with the maximal flexion of the knee.
Three bony landmarks, including the anterior
notch over the tibia plateau, intermeniscal liga-
ment, and intercondylar eminence, can be used to
identify the position of the ACL (Fig. 9.3).
Insertion of the ACL is inside the anterior notch
at the tibia plateau, and the fiber of the ACL
should be in between the intermeniscal ligament
and the intercondylar eminence (Fig. 9.4). By
performing an anterior drawer test, we can assess
the ACL more easily (Fig. 9.5). The anteromedial
and posterolateral bundles can be differentiated
by pivoting the probe (Fig. 9.6). The posterolat-
eral bundle is more hyperechoic compared to the
anteromedial bundle due to its course [2]
Fig. 9.2 Effusion may appear in the suprapatellar recess.
If so, the effusion should be aspirated first before the
(Fig. 9.7).
injection to ensure that the concentration of the injectate The coronary ligaments of the knee, also
(PRP or high concentration glucose) is sufficient known as the meniscotibial ligaments, help to

Fig. 9.3 Probe position of the ACL insertion in a transverse view. ACL is inserted at the medial corner of the anterior
notch at the tibia plateau. The anterior notch at the tibia plateau is the first marker to identify the ACL position
9 Ultrasound Imaging of the Knee Joint 179

Fig. 9.4 The intermeniscal ligament (white arrow) and Fig. 9.5 Dynamic testing by performing an anterior
the intercondylar eminence (red arrow) as the second and drawer test can make the morphologic change of the ACL
third landmarks of the ACL (yellow arrow). The blue more easily seen. A swollen ACL is seen (yellow arrow)
arrow is the position of the anterior notch at the tibia pla-
teau, as a fulcrum to pivot from a transverse view to
the longitudinal view of the ACL

Fig. 9.6 Proper probe position to scan the anteromedial (AM) and posterolateral (PL) bundle of the ACL
180 D. C.-J. Su and K.-V. Chang

a b

Fig. 9.7 The posterolateral bundle is more hyperechoic than the anteromedial bundle due to its course that is more
parallel to the probe. (a) Anteromedial bundle. (b) Posterolateral bundle

stabilize the meniscus on the tibia plateau, by verse view of the ALL. Injection through the
connecting the inferior edge of the menisci to the short axis can cover all the structures includ-
periphery of the tibial plateau. These ligaments ing the Gerdy’s tubercle, fibular head, and ALL if
are easily sprained or torn and can cause symp- injured.
tomatic discomfort. Ultrasound-guided regenera-
tive injection in this ligament can help prevent
hitting the genicular artery/vein accidently. Medial Region
The anterolateral ligament (ALL) functions as
a stabilizer for internal rotation of the tibia when The medial side of the knee is a common area
the knee is flexed to more than 35 degrees. where painful symptoms exist. Several structures
Proximally, ALL originates near the origin of the including the medial collateral ligament, medial
lateral collateral ligament (LCL), and distally, it coronary ligament, medial meniscus, medial plica,
attaches on the area between Gerdy’s tubercle posterior oblique ligament, and pes anserinus
and the fibular head (Fig. 9.8). By flexing the bursa can all lead to tenderness. The muscle at the
knee to more than 35 degrees and internally rotat- medial knee including semimembranosus, semi-
ing the tibia, lesions over the ALL (Fig. 9.9) will tendinosus, sartorius, gracilis, and adductor mus-
be more prominent [3–5]. cles should be checked for potential tendinopathy.
By putting the probe between the Gerdy’s With the probe turns to the coronal plane, we
tubercle and the fibular head, we can have a trans- can obtain the longitudinal view of the medial
9 Ultrasound Imaging of the Knee Joint 181

a b

Fig. 9.8 Anterolateral ligament (ALL). (a) Anatomy of tudinal view of the ALL (yellow arrow). Popliteus tendon
the ALL – the ALL has the common origin as the LCL and (PT), lateral femoral condyle (LFC), lateral meniscus
inserts in between the fibular head and Gerdy’s tubercle. (LM)
(b) Probe position of the ALL. (c) Sonogram of the longi-

collateral ligament. The superficial and deep lay- ular nerve underneath it (Fig. 9.11). These nerves
ers of the MCL can be identified. Swelling, par- make it a sensitive area and susceptible to chronic
tial tear, or even complete tear of the MCL can be pain when overuse or chronic friction due to
seen with tenderness when compressed malalignment and/or laxity [7]. Regenerative
(Fig. 9.10). Coexisting injury of the MCL with injection in this region can strengthen the area if
ACL or PCL is common. We can use the Swain there is tendinopathy, whereas biotensegrity of
test to detect MCL complex injury. When the the lower extremity from the foot up to the hip
knee is flexed to 90 degrees, rotate the tibia exter- has to be treated to truly eliminate the problem.
nally to tighten the MCL and to test the tensegrity
of the ligament complex. Pain along the medial
side of the knee indicates injury to the MCL com- Posteromedial Corner
plex [6].
The pes anserinus is a conjoined tendon con- From the posterior border of the superficial
sisting of the sartorius, gracilis, and semitendino- MCL to the medial border of the PCL is the
sus tendon. It is a highly tensioned area with region called the posteromedial corner (PMC).
infrapatellar branch of the saphenous nerve lying In this area, the important structures include
on top of it and inferomedial branch of the genic- the posterior oblique ligament, three arms of
182 D. C.-J. Su and K.-V. Chang

Fig. 9.9 Anterolateral ligament (ALL) helps to prevent flexing the knee to more than 35 degrees and internally
the tibia from excessive internal rotation when the knee rotating the tibia, lesions over the ALL will be more prom-
flex is more than 35 degrees. (a) Normal morphology of inent with an extruded lateral meniscus
the ALL. (b) Injured ALL in knee neutral position. (c) By

a b

Fig. 9.10 Medial collateral ligament (MCL). (a) Probe Swelling and partial tears of both the superficial and deep
position for scanning the MCL (b) Normal appearance of layer of MCL
the MCL, consisting of superficial and deep layers. (c)
9 Ultrasound Imaging of the Knee Joint 183

Fig. 9.10 (continued)

Fig. 9.11 Pes anserinus

is in between the
infrapatellar branch of
saphenous nerve (yellow
arrow) and inferomedial
genicular nerve (green
arrow)

the semimembranosus tendon, oblique popli- and is therefore an important region for regenera-
teal ligament, and posterior horn of the medial tive medicine [9].
meniscus [8]. When we move the probe posteriorly, the pos-
The PMC is the primary stabilizer of the knee terior oblique ligament (POL) can be seen
in extension during weight-bearing. It provides (Fig. 9.12). Unlike the MCL, it only has one sin-
one-third of the restraint to valgus stress when gle layer. Its main function is to help stabilize the
the knee is in extension. Injury to this region will posterior tibial translation in knee extension and
cause anteromedial rotatory instability (AMRI), plays a crucial role in patients with posterior cru-
which is defined as anterior translation and exter- ciate ligament laxity [8, 10, 11].
nal rotation of the tibia relative to the femur. This The semimembranosus muscle inserts on the
area is likely to be injured together with the ACL posterior side of the tibia. It has several attach-
184 D. C.-J. Su and K.-V. Chang

b c

Fig. 9.12 Posterior oblique ligament. (a) Sonogram of a longitudinal view of the POL, which consists of one layer
only. (b) Swelling of the POL. (c) Probe position of the POL, which is more posterior of the MCL

ments distal to the main common tendon, includ- PCL. This makes the midportion of the OPL a
ing the direct arm (Figs. 9.13 and 9.14), the potential entrapment site [12–14].
anterior arm (Fig. 9.15) that circles to the front of
the tibia, and the oblique popliteal arm (Fig. 9.16)
that contributes to the oblique popliteal ligament. Posterior Region
Of the three arms, the oblique popliteal arm is
found to be the primary ligamentous restraint to The popliteus muscle originates from the lateral
knee hyperextension. It expands from the semi- condyle of the femur as a rounded tendon and
membranosus tendon and courses superolater- inserts on the posterior surface of the tibia. It is
ally, then attaches to the fabella or the tendon of an intra-articular and extra-synovial structure at
the lateral head of the gastrocnemius. There is the femoral origin and extra-articular at the mus-
also an aponeurotic fascia extending from the cular or myotendinous portion. The popliteus
OPL to the medial gastrocnemius and plantaris, muscle, the popliteus tendon, and the popliteal
which helps dissipate stress concentration at fibular ligament make up the popliteus musculo-
the enthesis, thereby reducing tear. tendinous complex [15, 16]. It provides dynamic
In addition, the middle genicular neurovascu- and static resistance to external rotation, assum-
lar bundle passes through the midportion of the ing a major role with higher degrees of knee
OPL and supplies the posterior knee capsule and flexion.
9 Ultrasound Imaging of the Knee Joint 185

a b

Fig. 9.13 Direct arm of the semimembranosus tendon. ance of the direct arm of the semimembranosus tendon in
(a) Anatomy of the semimembranosus direct arm. (b) a longitudinal view
Proper probe position. (c) Normal sonographic appear-

It helps create initial flexion from full exten-

a
sion, assists PCL when running downhill, and
pulls on the lateral meniscus while bending the
knee [17, 18].
It is often locked in a flexed shortened position
after patients undergo knee surgery or experience
severe trauma to the knee. Under ultrasound
b scanning, we should look for partial tear or sprain
of the muscle or tendinopathy (Fig. 9.17).
Regenerative injection could be done under ultra-
sound guidance to prevent injury of the popliteal
vessels and tibial nerve.
The plantaris muscle originates from the infe-
Fig. 9.14 Sonograms of the semimembranosus direct rior part of the lateral supracondylar ridge and
head. (a) Semimembranosus tendinopathy. (b)
Calcification of the semimembranosus tendon inserts on the medial side of the calcaneus. Partial
186 D. C.-J. Su and K.-V. Chang

a b

c d

Fig. 9.15 Anterior arm of the semimembranosus tendon. Avulsion of the anterior arm. (d) Calcification of the ante-
(a) Probe position for the anterior arm of the semimem- rior arm
branosus tendon. (b) Tendinopathy of the anterior arm. (c)

tear at the muscle combined with tendinopathy is cle. It also has a close relationship with the pero-
not uncommon in athletes [19, 20] (Figs. 9.18 neal nerve [24]. Dynamic ultrasound scanning
and 9.19). can identify if there is peroneal nerve snapping/
The PCL serves as one of the main stabilizers entrapment related to the fabella and can be
of the knee and helps resist excessive posterior treated by ultrasound-guided hydrodissection.
translation of the tibia relative to the femur.
Therefore, chronic laxity of the PCL causes shear
force to the anterior knee ligaments combining Posterolateral Corner
with an increased pressure over the patellofemo-
ral joint and leads to anterior knee pain. The posterolateral corner (PLC) is the most
Regenerating a torn PCL (Figs. 9.20 and 9.21) important restraint to varus stress, and it also acts
can help stabilize the knee and restore the tenseg- as a secondary restraint to posterior tibial transla-
rity [21–23]. tion. Three major structures have been described
The fabella is a sesamoid bone and is more as the primary stabilizers of the PLC: the lateral
prevalent in Asian population. It serves as the collateral ligament, the popliteal fibular ligament,
common origin of the OPL, the arcuate ligament, and the popliteus tendon. Besides the three major
and the FFL, as well as part of the plantaris mus- structures, the fabellofibular ligament and arcuate
9 Ultrasound Imaging of the Knee Joint 187

a b

Fig. 9.16 Oblique popliteal ligament (OPL). (a) arrow), expanding from the semimembranosus tendon to
Anatomy of the OPL. (b) Probe position of the OPL. (c) the lateral femoral condyle
Sonogram of the longitudinal view of the OPL (yellow

a b

Fig. 9.17 Popliteus muscle and tendon. (a) Anatomy of muscle (yellow arrowhead) in a longitudinal view. (d)
the popliteus muscle, which is underneath the popliteal Near complete tear of the popliteus muscle (green
artery (red arrowhead). (b) Probe position of the longitu- arrowhead)
dinal view of the popliteus muscle. (c) Normal popliteus
188 D. C.-J. Su and K.-V. Chang

c d

Fig. 9.17 (continued)

a b

Fig. 9.18 Plantaris muscle. (a) Anatomy of the plantaris muscle (yellow arrowhead). (b) Probe position of the plantaris
muscle
9 Ultrasound Imaging of the Knee Joint 189

Fig. 9.19 Plantaris muscle. (a) Longitudinal view of the normal plantaris muscle. (b) Longitudinal view of a near
complete tear of the plantaris muscle

Fig. 9.20 Sonogram of the normal posterior cruciate Fig. 9.21 Sonogram of the torn posterior cruciate liga-
ligament in the longitudinal view ment in the longitudinal view
190 D. C.-J. Su and K.-V. Chang

Fig. 9.22 Lateral collateral ligament. (a) Probe position right above the lateral meniscus (LM). Note that the LCL
of the LCL. (b) Sonogram of the longitudinal view of the joins the insertion of the biceps femoris at the fibular head
LCL (yellow arrowhead). The lateral inferior genicu- and should not be misdiagnosed as ligament injury
lar artery and nerve are underneath the LCL and lying

ligament are crucial for the tensegrity of this vious problematic leg, then a combined PLC and
region [25]. PCL injury is indicated because the PCL is
The dial test is used in detecting isolated or responsible for rotational stability when the knee
concomitant PCL injury. The test is used to test flexion is at 90 degrees [17].
the integrity of the posterior and posterolateral The lateral collateral ligament (LCL) is the
corner of the knee, when performing regenerative primary varus stabilizer of the knee. It also limits
injection. external rotation and posterior displacement of
The test is performed in two steps. First, put the tibia. It has a broad insertion (Fig. 9.22) and
the patient in a prone position with both knees covers 38% of the fibular head [26].
flexed to 30 degrees and externally rotate the tibia The popliteal fibular ligament (PFL) is a ten-
simultaneously. If more than 10 degrees of exter- dinous band and acts as a major stabilizer of the
nal rotation is noted comparing to the other one, PLC. It originates from the popliteus tendon
PLC injury is likely. Second, flex the knee to 90 proximal to the myotendinous junction and
degrees and perform external rotation again. If inserts on the fibular styloid process. Using the
there is still increased external rotation in the pre- posterior fibular head as the fulcrum, the probe is
9 Ultrasound Imaging of the Knee Joint 191

a The arcuate ligament is inversely related to

the FFL (Fig. 9.25). It extends from the femur
condyle to the tip of the fibular head, which is
hard to differentiate with the posterior capsule
sometimes [16].
Both the FFL and arcuate ligament, together
b with PFL and LCL, help guard the tensegrity of
the PLC.
When injecting PLC for regeneration,
the peroneal nerve and popliteal vessels should
be marked after ultrasound scanning, to prevent
iatrogenic injury to the nerve.
Fig. 9.23 Popliteal fibular ligament (PFL). (a)
Longitudinal view of the PFL (yellow arrow). (b) Probe
position of the PFL Ligament-Capsule-Menisci Complex

The menisci are crescent-shaped wedges of the

b fibrocartilage situated on the medial and lateral
aspect of the knee. Menisci are stabilized through
a ligament-capsule-menisci complex. The loss of
the complex integrity leads to a significant
increased amount of extrusive displacement of
the menisci.
When there is chronic instability of the knee
due to ligament laxity or tear, menisci will be
a damaged eventually. Therefore, when there is a
meniscus tear, we must not treat the meniscus
only, but also have to treat the ligament-capsule-­
menisci complex and all the stabilizing ligaments
Fig. 9.24 Fabellofibular ligament (FFL). (a) Probe posi- which are compromised.
tion of the FFL. (b) Sonogram of the longitudinal view of Meniscus tear can be divided into four grades
the FFL (yellow arrowhead). The tendon of the gastrocne- (0–3) based on the MRI findings according to
mius muscle (green arrow) can be identified surrounding
the fabella and embedding it Reicher et al. [27]. Studies have shown that intra-
meniscal injections of PRP have the ability to
achieve pain relief and halt progression on MRI
pivoted 45 degrees toward the center of the knee. over 6 months in patients with grade 2 meniscal
A hypoechoic ligament will be seen as a ligament lesions [28].
connecting the popliteus tendon and fibular head The posterior meniscofemoral ligament
(Fig. 9.23). The fibular end of the ligament is (PMFL), or the ligament of Wrisberg, helps sta-
posterior to the insertion of the lateral collateral bilize the lateral meniscus. The PMFL originates
ligament [16, 18]. from the lateral meniscus and crosses superiorly
The fabellofibular ligament (FFL) serves as behind the PCL and inserts on the medial con-
a static stabilizer of the knee, which tenses in dyle of the femur. Using the curve probe, find the
full extension. It runs from the base of the posterior medial border of the lateral meniscus
fabella to the styloid process of the fibular first and pivot it to align the other end of the
head (Fig. 9.24). probe to the lateral border of the medial condyle.
192 D. C.-J. Su and K.-V. Chang

Fig. 9.26 Posterior

a b
meniscofemoral
ligament (PMFL). (a)
Sonogram of the
longitudinal view of the
PMFL (yellow arrow).
The green dots indicate
the posterior edge of the
lateral meniscus. (b)
Probe position of the
PMFL

Fig. 9.25 Arcuate

a
ligament (AL). (a)
Anatomy of the AL. (b)
Probe position of the
AL. (c) Sonogram of the
longitudinal view of the
AL (yellow arrow). The
size of the AL is
inversely related to
FFL. We can see marked
AL with relatively thin
and FFL blended
together with the tendon
of the gastrocnemius
muscle in this patient
without fabella
b c

This will result in a clear view of the PMFL revealed that resection of the AIML leads to sub-
(Fig. 9.26). stantial changes in knee biomechanics [29].
Other than the aforementioned coronary liga- Regenerative injection of the supporting struc-
ments and PMFL, there is another structure worth tures helps stabilize the menisci.
noting: the anterior intermeniscal ligament Under ultrasound, once we localized the
(AIML). It connects the anterior horn of the ACL by a previously described method, the
medial and lateral menisci. Matthieu et al. AIML is seen as a hyperechoic, dot-like struc-
9 Ultrasound Imaging of the Knee Joint 193

ture lying above the ACL. After localizing the 14. Morgan PM, LaPrade RF, Wentorf FA, Cook JW,
Bianco A. The role of the oblique popliteal ligament
dot, we can pivot the probe 90 degrees to have a and other structures in preventing knee hyperexten-
longitudinal view of the AIML and have an in- sion. Am J Sports Med. 2010;38(3):550–7.
plane injection. 15. Barker RP, Lee JC, Healy JC. Normal sonographic
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Am J Roentgenol. 2009;192(1):73–9.
16. Chahla J, Moatshe G, Dean CS, LaPrade
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 Ultrasound-Guided Orthobiologics
of the Foot and Ankle
10
Lauren Vernese, Adam Pourcho,
and Troy P. Henning

Introduction cytes, as well as increase the risk of infection,

lower the immune system response, temporarily
Chronic pain affects over one-fifth of adults, with raise blood sugar, and increase the risk of tendon
an estimated 50% related to chronic musculo- rupture [6, 7]. As more evidence emerges reveal-
skeletal disorders [1, 2]. Over 54 million ing long-term and potentially short-term harmful
Americans alone have arthritis, with one in four effects of corticosteroid on cartilage, physicians
reporting persistent pain [3]. According to the and patients are turning to other injectable options
Centers for Disease Control and Prevention, the such as prolotherapy, autologous blood products,
total medical costs and lost earnings related to or placental-derived tissues with the goal of influ-
arthritis in 2013 were 3.5 billion US dollars or encing tissue regeneration or disease modulation.
1% of the gross domestic product [4]. The hope of regenerative medicine is to restore
Tendinopathy affects a large number of athletes the homeostasis of the affected tissue and if pos-
and nonathletes and constitutes approximately sible replace or regenerate human cells or tissues
30% of consultations for musculoskeletal pain in to restore normal function, through stimulation
the general practice setting [5]. of the body’s natural intrinsic pathways [8].
For patients who have persistent foot and While still an emerging field, regenerative medi-
ankle joint-related pain that is recalcitrant to con- cine has touched nearly every field of medicine
servative treatment, corticosteroid injections are and has been applied to congenital defects,
typically offered to help alleviate pain. However, chronic disease, trauma, and aging [9].
numerous studies of corticosteroids have been Regenerative treatment options in the current
shown it to be toxic to tenocytes and chondro- musculoskeletal research and clinical practice for
management of foot and ankle injuries include
autologous blood products such as platelet-rich
L. Vernese · A. Pourcho
plasma (PRP), mesenchymal cells (“stem cells”)
Rehabilitation and Performance Medicine, Swedish
Medical Group, Seattle, WA, USA (MSC) derived from bone marrow aspirate con-
e-mail: [email protected]; centrate (BMAC) and/or adipose tissue,
[email protected] placental-­derived products, prolotherapy, micro-
T. P. Henning (*) fracture, and autologous chondrocyte implanta-
Rehabilitation and Performance Medicine, Swedish tion [10–15] (Table 10.1).
Medical Group, Seattle, WA, USA
Until recently, most insurers in the United
Swedish Rehabilitation and Performance Medicine, States have not included orthobiologic therapies
Seattle, WA, USA
as a covered benefit. However, the use of ortho-
e-mail: [email protected]

© Springer Nature Switzerland AG 2022 195

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_10
196 L. Vernese et al.

Table 10.1 Types of orthobiologics joint, resulting in primarily dorsiflexion and plan-
Platelet-rich Concentrated autologous platelets: tarflexion motion [17] (see Fig. 10.1a).
plasma (PRP) defined as greater than circulating Three major ligamentous complexes are
volume, generally four to eight times required for dynamic stability of the ankle mor-
that found in serum
Mesenchymal Bone marrow Autologous
tice: the tibiofibular syndesmosis, the lateral col-
cells (MSC) aspirate concentrated lateral ligament, and the medial collateral (or
concentrate MSCs and PRP deltoid) ligaments. The tibiofibular syndesmosis
(BMAC) consists of the anterior inferior tibiofibular liga-
Adipose derived Autologous ment (AITFL), the posterior tibiofibular liga-
MSCs
mechanically ment, and the interosseous membrane. The lateral
separated from collateral ligaments include the anterior talofibu-
fat tissue lar ligament (ATFL), calcaneofibular ligament
Placental Allogenic commercially available (CFL), and posterior talofibular ligament (PTFL).
derived (amnion product; available as sheets of tissue
and amniotic or injectable solution
The medial collateral ligaments include the ante-
fluid) rior and posterior tibiotalar, tibionavicular, and
tibiocalcaneal portions of the deltoid ligament
complex. Distal to the talocrural joint is the sub-
biologics may be more cost effective and less talar joint, a tri-planar, uniaxial joint between the
invasive than alternatives when compared head-­ talus and the calcaneus (Fig. 10.1b).
to-­head. In fact, a recent meta-analysis of level 1 The foot is divided by regions: the hindfoot
randomized controlled trials (RCTs) assessing (talus and calcaneus), midfoot (navicular, cuboid,
PRP in the treatment of knee arthritis estimated it and cuneiforms), and forefoot (metatarsals and
would be on average $1192.08 less annually than phalanges). The hindfoot and midfoot consist of
hyaluronic acid or saline injections [16]. Further seven irregularly shaped tarsal bones that are fur-
comparisons of other regenerative options are ther organized into three rows: proximal, inter-
needed to substantiate these results. mediate, and distal. The proximal row includes
Before reviewing the current literature avail- the talus and calcaneus.
able for clinic-based musculoskeletal regenera- The calcaneus is the largest of the tarsal
tive medicine about the foot and ankle, this bones. It has two joints including the subtalar
chapter will review pertinent anatomy of the foot (talocalcaneal) joint superiorly and the calcaneo-
and ankle structures that may be amenable to cuboid joint anteriorly. Its posterior aspect, the
regenerative techniques. calcaneal tuberosity, is the attachment site of the
Achilles tendon. Its medial aspect has a shelf-
like facet known as the sustentaculum, to which
Ankle Anatomy the talus rests on as well as the calcaneonavicu-
lar “spring ligament” (CNL) complex attaches
Osseous and Ligamentous Anatomy (Fig. 10.2a, b).
The next row (intermediate) contains the
The ankle complex is composed of three joints navicular bone and its articulation with the talus
from the lower leg and the foot: the talocrural, posteriorly, the three cuneiforms anteriorly, and
subtalar, and inferior tibiofibular joint. the cuboid laterally. The navicular bone’s medial
The ankle joint proper, also known as the talo- plantar surface has a tuberosity that serves as an
crural or tibiotalar joint, is a hinged synovial joint attachment site for the posterior tibialis tendon
formed by the articulation between the talus and (PTT). The distal row of the midfoot contains the
the distal tibia and fibula. The malleoli of the three cuneiforms (lateral, intermediate, and
tibia and fibula provide constraint for this hinge medial) and the cuboid. The cuneiforms articu-
late with the first through third metatarsals. The
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 197

a b
Tibia

Fibula
Posterior talofibular
True ankle ligament (PTFL)
Talus joint
Anterior talofibular
ligament (ATFL)
Anterior view
Subtalar
joint

Calcaneus

Lateral view
Calcaneofibular
Achilles
ligament (CFL)
tendon

Fibula
Tibia

Posterior tibiotalar ligament

Tibiocalcaneal ligament
Deltoid
Medial Anterior tibiotalar ligament ligament
malleolus
Tibionavicular ligament

Talus bone

Calcaneus

Sustentaculum Navicular
tali of calcaneus bone

Fig. 10.1 Ankle bony and ligamentous anatomy. (a) calcaneal (subtalar joint). (b) Lateral ligamentous anat-
Anatomy of bones of the ankle from lateral and anterior omy of the ankle. (c) Medial ligamentous anatomy
views, demonstrating the tibiotalar (ankle joint) and talo- demonstrating the deltoid ligamentous complex

cuboid, the most lateral bone, sits proximal to the the distal fibula and interosseous membrane to
fourth and fifth metatarsals. The tarsometatarsal insert on the dorsal base of the fifth metatarsal,
articulations are known as the Lisfranc joint line. although can have varying origin and insertion. It
The forefoot consists of the metatarsals and their has been found to be absent in 10.5–18.5% of the
respective phalanges. Important ligamentous population [18, 19]. Overlying the anterior ten-
complexes of the foot include the CNL and dons is the extensor retinaculum. Important ante-
Lisfranc ligaments (Fig. 10.2a). rior neurovascular structures that travel deep to
the extensor retinaculum include the tibial artery
and superficial and deep fibular (peroneal) nerves
Muscle, Tendon, and Neurovascular (Fig. 10.3a).
Anatomy The lateral ankle tendons include the fibularis
(peroneus) longus and brevis, and these are cov-
Across the anterior ankle are three main tendons: ered by the superior and inferior peroneal reti-
the tibialis anterior (located medially), the exten- nacula. An estimated 5–21% of patients will have
sor hallucis longus, and the extensor digitorum a peroneus quartus, an accessory fibular muscle
longus (most lateral). The peroneus tertius is that typically inserts on the retrotrochlear emi-
along the anterolateral region and extends from nence or blends in with the native fibularis longus
198 L. Vernese et al.

Phalanges
Distal phalanx
Middle phalanx

Forefoot Proximal phalanx

Metatarsals
Medial, intermediate,
and lateral cuneiform

Midfoot Base of fifth

metatarsal
Cuboid
Navicular

Talus

Hindfoot

Calcaneus

Fig. 10.2 Foot bony anatomy. Anatomy of bones of foot divided into regions, hindfoot, midfoot, and forefoot

[20–22]. The lateral ankle also is the origin for tendons. Between the flexor digitorum and FHL
the extensor digitorum brevis muscle, arising tendons is the neurovascular bundle – the tibial
from the lateral calcaneus and extensor retinacu- artery, tibial vein, and tibial nerve. Overlying
lum (Fig. 10.3b). these structures is the flexor retinaculum, form-
Laterally, the sural nerve moves from midline ing the tarsal tunnel.
to the lateral edge of the Achilles tendon in the Just distal to the flexor retinaculum and around
distal lower leg, then continues to move lateral the origin of the abductor hallucis, the tibial
until it passes posterior to the lateral malleolus. nerve divides into the medial and lateral plantar
Just distal and posterior to the lateral malleolus it nerves. The lateral plantar nerve gives off a
branches into lateral calcaneal, lateral dorsal branch before traversing the plantar foot, known
cutaneous, and medial dorsal cutaneous nerves as the inferior calcaneal (Baxter’s) nerve. Rarely,
(Fig. 10.3b). this nerve may come off more proximal from the
Tendons at the medial ankle include the PTT main tibial nerve [23].
(most anterior), flexor digitorum longus (FDL), The posterior ankle’s main structure is the
and flexor hallucis longus (FHL) (most posterior) Achilles tendon, inserting onto the posterior cal-
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 199

a Tibialis b
anterior
Tibialis anterior
Deep
Extensor Extensor hallucis longus
peroneal Peroneus
digitorum longus nerve brevis Tibialis anterior synovial sheath
Anterior Peroneus Extensor digitorum longus
Extensor tibial longus
hallucis longus artery Superior extensor retinaculum
Peroneus
Superior longus and Superior extensor
extensor brevis retinaculum
Inferior extensor retinaculum synovial Extensor digitorum
retinaculum sheath
Tibialis anterior longus synovial
synovial sheath sheath
Extensor
Extensor
digitorum longus
hallicus
synovial sheath
longus synovial
sheath
Superior and Extensor hallicus
inferior peroneal longus synovial
retinacula sheath

c
Flexor digitorum longus
Tibialis posterior tendon
synovial sheath
Flexor digitorum longus Posterior tibial
tendon sheath artery
Flexor retinaculum Tibial nerve
Flexor hallucis
longus synovial
sheath

Medial calcaneal
branch of tibial
nerve

Fig. 10.3 Ankle musculotendinous anatomy. (a) Anterior ankle musculotendinous and neurovascular anatomy. (b)
Lateral ankle musculotendinous anatomy. (c) Medial ankle musculotendinous and neurovascular anatomy

caneal tuberosity. Additionally, the plantaris,  rthobiologic Use About the Foot
O
which can be absent in 7–20% of individuals, can and Ankle Interventional
have a variable insertion along the medial Achilles Procedures: Joints
tendon to the calcaneus [24–27] (Fig. 10.3b).
The most common target in the plantar hind- The majority of orthobiologic research related to
foot for regenerative therapies is the plantar fas- joint disease has focused on the treatment of knee
cia, which originates off the plantar calcaneus as osteoarthritis [13, 29]. Several studies highlight
a thick aponeurosis supporting the arch of the the role of leukocyte concentration in clinical out-
plantar foot. The plantar fascia originates from comes. Riboh et al.’s meta-analysis comparing
the medial calcaneal tuberosity and has three leukocyte-poor (LP) to leukocyte-rich (LR) plate-
components: medial, central, and lateral bands let-rich plasma (PRP) to hyaluronic acid (HA) or
[18]. At the posterior heel, the Achilles tendon placebo found the greatest improvements in
and plantar fascia remain in continuity by a Western Ontario and McMaster Universities
paratenon (“the windlass mechanism”); however, Osteoarthritis Index (WOMAC) scores in the LP
this is typically lost with age, leaving few if any group [30]. Conversely, Filardo et al.’s study com-
fibers [28] (Fig. 10.4). paring LR-PRP to HA found no difference
200 L. Vernese et al.

Görmeli et al. demonstrated improved efficacy of

PRP versus hyaluronic acid or saline injection for
talar OCD lesions following microfracture sur-
gery [34]. Guney et al. also assessed the addition
of PRP to microfracture surgery on the talar
dome and demonstrated that the combination was
superior to microfracture alone for the long-term
treatment of symptomatic OCD lesions in terms
of pain reduction and functional outcomes [36].
With regard to osteoarthritis about the foot
Central and ankle, Repetto et al. evaluated the effects of
four weekly PRP injections on 20 ankles with
symptomatic osteoarthritis of the tibiotalar joint
Medial and found a significant improvement on pain and
Lateral
function and high patient satisfaction rates, with
a mean follow-up of 17.7 months [37]. Fukawa
et al. reported similar reduction in pain and
improved function following three PRP injec-
tions at an interval of 2 weeks on 20 patients with
symptomatic ankle osteoarthritis [33]. Neither
study reported significant adverse side effects. A
2010 study on prolotherapy for chronic ankle
Calcaneus
pain demonstrated a significant improvement in
pain level, stiffness, and quality of life after an
average of 4.4 prolotherapy treatments, with an
Fig. 10.4 Plantar fascia anatomy. Plantar fascia anatomy.
average follow-up of 21 months [2]. Despite
Note the central, medial, and lateral bands of the plantar promising results from these studies, interpreta-
fascia. The central band is the most commonly affected tion of findings is limited due to small sample
with plantar fascia pathology sizes, poorly controlled protocols, lack of control
for leukocytes or reporting of concentrations, and
between the treatment groups [31]. Furthermore, lack of placebo-controlled interventions.
Braun et al. found greater synoviocyte death in General considerations when doing treatments
LR-PRP than LP-PRP suggesting some formula- about the foot and ankle are as follows:
tions or PRP may be counterproductive in the
treatment of degenerative/arthritic joint diseases • Ultrasound guidance (USG) is recommended
[32]. Current evidence for foot and ankle intra- to ensure accuracy of injectate in treatment
articular injection of these products is limited to a target [38].
small number of studies, small study population, • No matter the injectate, the injection approach
frequent lack of placebo control, and variability in is essentially the same.
product preparation and administration [33–35]. • Needle gauge may vary depending on the size/
A 2012 study by Mei-Dan et al. demonstrated viscosity of the injectate.
intra-articular tibiotalar therapeutic injections of –– One study demonstrated that platelets are
PRP to be superior to hyaluronate in the manage- prematurely lysed and activated when
ment of talar osteochondral defects (OCD) [35]. small bore (<21 gauge) needles were
In this study of 30 patients, there was reduction in used [39].
pain and stiffness and improved function for both • Patient and provider positioning are optimized
groups. However, there was statistically signifi- for comfort and proper ergonomics and to
cant higher reduction from the PRP group in the facilitate visualization of the needle approach-
28-week follow-up period. A 2015 study by ing/entering the target.
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 201

• Prior to the injection, the region should be Injection Volume

adequately cleansed to reduce the risk of
infection. • 0.5–5 ml injectate dependent on joint volume
• Local anesthetic is typically performed using size
USG along the intended needle pathway.
• Anesthetic infiltration into the target tissue is
minimized to ensure optimal functioning of Approaches
the orthobiologic.
• Linear array high-frequency (optional hockey  ong Axis to Joint, in-Plane with Td
L
stick) Tds should allow for optimal visualiza- With the patient in lateral recumbent position
tion of all structures. with pillow between knees and treatment limb
• Ability to adjust the focal zones, frequency away from the table, the US Td is placed in the
range, and gain can help optimize image of sagittal or axial to the long axis of the joint. The
certain regions such as the plantar fascia. needle is then advanced in-plane with the Td into
• In-plane techniques are generally and techni- the target joint ensuring the articular cartilage is
cally easier to perform. avoided with the needle. The injectate should
• Using a gel standoff technique can aid in visu- then easily flow into the joint under little to no
alization of the needle and target in regions resistance. Care should be taken to monitor pres-
with less compliant tissue between the skin sure while injecting to ensure the joint is not
and target. overly distended, which can increase pain follow-
• An understanding of at-risk structures and ing procedure (Fig. 10.5a, b) – example of in-­
anatomy with pre-scanning prior to any injec- plane ankle injection through anterior talofibular
tion is recommended. This will allow the pro- ligament.
vider to choose the safest path to complete the
procedure. Out-of-Plane with Td
• Consider performing a tibial nerve block prior The US Td is placed to create an anatomic long-­
to plantar fascia procedures to aid in pain axis view of the desired joint. The needle is then
reduction during and after procedure. advanced using a walk-down technique from
superficial to deep, to a position within the target
joint. This can also be done in-plane by turning
 ltrasound-Guided Joint Injections
U the transducer 90 degrees (Fig. 10.6a–c).
of the Foot and Ankle

Positioning  ltrasound-Guided Subtalar Joint

U
Injection
• Patient: supine or lateral recumbent (subtalar
joint) with knee straight and foot/ankle in  osterior Subtalar (Talocalcaneal)
P
relaxed position Joint Injection

Td Type Given the relative complexity of injecting the

subtalar joint over the other joints about the foot
• High-frequency linear array and ankle, it will be described here in greater
detail. The subtalar joint consists of two facet
Needle joints, which do not often communicate when
injected [40]. Therefore, positioning to optimally
• Anesthetic: 25–30 gauge, 25–38 mm inject the desired facet of the subtalar joint is
• Orthobiologic: 21 gauge or larger, 25–38 mm recommended.
• Aspiration: 18 gauge or larger, 38 mm
202 L. Vernese et al.

a b

Fig. 10.5 Ultrasound-guided tibiotalar joint injection. needle (arrowheads) through the right anterior talofibular
(a) External view of a right (RT) ankle with Td (solid rect- (ATF) ligament, within the tibiotalar (ankle) joint. (c) US
angle) placement and needle approach (solid arrow) for image, with DIST to the right, showing a hyperechoic
an in-plane transligamentous injection of the tibiotalar needle (arrowheads) within the RT ATF ligament for
(ankle) joint. (b) Ultrasound correlate, with distal (DIST) orthobiologic injection. F fibula, T talus, LAX long axis,
to the right, showing an in-plane view of hyperechoic DIST distal

a b

Fig. 10.6 Ultrasound-guided metatarsophalangeal joint out-of-plane medial-to-lateral approach showing a hyper-
injection. (a) External view of the right (RT) foot demon- echoic needle tip (arrowhead) within the MTP joint (star).
strating Td placement and needle direction (solid arrow) (c) USG correlate of an in-plane approach showing a
for out-of-plane (solid rectangle) and in-plane (dotted hyperechoic needle (arrowheads) within the MTP joint
rectangle) medial-to-lateral approach to injecting the first (star). MC metacarpal, PP proximal phalanx, MED
metatarsophalangeal (MTP) joint. (b) USG correlate of an medial, DIST distal
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 203

Approaches ficial to deep, to a position within the subtalar

joint (Fig. 10.7a, b).
Posteromedial
The patient is in the lateral recumbent position, Anterolateral
with involved extremity towards the table and The patient is in the lateral recumbent position,
contralateral side bent out of the way. The US Td with involved side further from the table. The US
is placed in the anatomic coronal plane giving a Td is placed in the anatomic sagittal plane, visu-
short-axis view of the subtalar joint, overlying alizing the calcaneus, talus, and fibula. The loca-
the talus and calcaneus. The at-risk tibial artery, tion of the at-risk peroneal tendons should be
nerve, and vein should be noted prior to injec- noted prior to injection. The needle is then
tion, with needle trajectory adjusted appropri- advanced anterior to posterior in a walk-down
ately. The needle is then advanced anterior to technique from superficial to deep, to a position
posterior in a walk-down technique from super- within the subtalar joint (Fig. 10.8a, b).

a b

Fig. 10.7 Ultrasound-guided posteromedial subtalar subtalar joint via an out-of-plane approach. Note the loca-
joint injection. (a) External photo showing transducer tion of the medial plantar nerve (MPN) just plantar
(Td) and needle (solid arrow) placement for out-of-plane (PLNT) to the posteromedial subtalar joint as well as the
injection of the right (RT) posteromedial subtalar joint adjacent posterior tibialis (PT), flexor digitorum longus
from a distal to proximal direction. (b) USG correlate (FDL), and flexor hallucis longus (FHL) tendons. SAX
showing a hyperechoic needle tip (arrowhead) within the short axis, T talus, C calcaneus

a b

Fig. 10.8 Ultrasound-guided anterolateral subtalar joint the subtalar joint via an out-of-plane approach. Note the
injection. (a) External photo showing transducer (solid location of the sural nerve (dotted arrow) just plantar to
rectangle) and needle (solid arrow) placement for out-of-­ the anterolateral subtalar joint as well as the peroneus bre-
plane injection of the right (RT) anterolateral subtalar vis (PB) and peroneus longs (PL) tendons. SAX short axis,
joint from a distal to proximal direction. (b) USG corre- F fibula, T talus, C calcaneus, DRSL dorsal
late showing a hyperechoic needle tip (arrowhead) within
204 L. Vernese et al.

I nterventional Procedures: Soft dinopathies such as Achilles tendinopathy. Rather

Tissue Structures – Regenerative than an inflammatory issue, microscopic analy-
Introduction ses have supported a chronic degenerative pro-
cess with disruption of collagen matrix, fiber
Tendinopathy has been well established to be disorganization, microscopic tears, and abnormal
less of an inflammatory response and more of blood flow zones [54, 55]. Typical conservative
a chronic degradation of the tendon, with management includes rest, activity modification,
pathophysiology consisting of degenerative stretching, heel cups or orthotics, night splints,
microtearing, collagen fiber disorganization, immobilization, physical therapy, shock wave
hypercellularity, and angiofibroblastic hyperpla- therapy, ice, and oral anti-inflammatories. While
sia of the tendon proper [41]. Chronic tendinopa- about 80–90% of patients improve within
thies affect approximately ten million patients 9 months of symptom onset, over 10% of
per year, requiring frequent physician visits and a patients develop recalcitrant chronic plantar fas-
large economic health burden [42, 43]. Often ciopathy and corticosteroid injections or surgery
despite months of extensive conservative treat- has been the traditional next step [55, 56]. In
ment such as rest, activity modification, physical refractory cases, surgery with either an open or
therapy, oral and topical medications, and orthot- endoscopic approach has been described with
ics and/or bracing, more advanced treatment success rates of 67–82% reported in the litera-
options such as injections and surgery are sought ture [57, 58]. Surgical release has also demon-
for pain relief [42, 43]. Traditionally, corticoste- strated alteration of the “windlass mechanism”
roid injections are offered as the next step in the with increased stress risers on the ligaments and
treatment approach. However, as more evidence bones of the midfoot and forefoot [55].
emerges revealing potential harms of corticoste- Emerging treatment options with hopefully
roids on soft tissues such as risk of t­endon rup- fewer adverse effects include regenerative injec-
ture and fat pad atrophy, physicians are turning tions such as PRP or prolotherapy and USG
to other injectable options such as prolotherapy, tenotomy/fasciotomy [59].
autologous blood products, or placental-derived
products; needle tenotomy with or without
orthobiologic injectate; and neovessel ablation Platelet-Rich Plasma
[44–50]. The current literature has not revealed
the most effective regenerative treatment option Many recent studies have compared PRP injec-
but is more consistently demonstrating that a tion against the more traditional CS injection for
combination approach with an injection plus chronic PF. At least four trials have demonstrated
rehabilitation may be more effective than either that a single injection of PRP or CS for chronic
alone [51, 52]. PF results in significantly reduced pain and
improved function at 3 months [54, 55, 60]. CS
typically has similar to slightly superior short-­
 lantar Fascia: Regenerative
P term results as compared to PRP. However, at
Evidence 12 months, a single injection of PRP results in
significantly improved outcomes than CS, while
Plantar fasciopathy (PF) is an extremely painful patients receiving CS typically return near base-
condition classically causing pain with the first line [54, 55, 61, 62]. Jimenez-Perez et al. com-
few steps out of bed but can persist throughout pared two injections of LR-PRP versus CS and
the day limiting one’s function and quality of life found significantly improved pain scores and
[53]. It affects approximately two million people functional scores at 6 and 12 months, and this
per year with a lifetime prevalence of 10% [53]. effect was sustained in even longer follow-up
Although considered a fascia or aponeurosis, the [56]. Additionally, it was noted that at least 90%
pathophysiology is thought of as the same as ten- of the PRP group at 6 and 12 months had good or
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 205

excellent outcomes, whereas only 15% of the CS ciitis. A 2013 feasibility study performed in 45
group had good outcomes at 6 months and 0% at patients with refractory PF demonstrated that a
12 months [56]. Tabrizi et al. evaluated 3 weekly landmark-guided, single injection of reconsti-
injections of PRP versus a single CS injection in tuted dHACM yielded a significant improvement
obese patients with PF and found that both groups in symptoms at 1 week and at the 8-week study
had a better foot function score but CSI had better end period as compared to a saline injection [67].
pain score at 24 weeks [63]. Of note, this study They also assessed different volumes of dHACM
did not restrict oral anti-inflammatory use which injectate and found no difference between 0.5 cc
is typically considered standard protocol to avoid and 1.25 cc [67]. In 2018, Cazzell et al. per-
interference with the PRP’s action [64, 65]. The formed a multicenter study comparing a
studies used a variety of PRP injectate volumes landmark-­ guided, single injection of 1 mL
ranging from 2 ml to 6 ml with variable volumes micronized dHACM versus 1 ml 0.9% sodium
of anesthetic if used. Most studies implemented a chloride placebo performed in 73 and 72 heels,
needle tenotomy “peppering” technique with a respectively [68]. The intervention group yielded
single skin portal site. Overall, a vast majority of significantly lower pain scores and improved
studies support that one to two injections of PRP function scores at a 3-month follow-up [68].
for chronic PF are as effective as CS at 3 months Additionally, they assessed longer-term (12-­
and have a more durable effect than CS at 1 year month) safety, and only three adverse events
[61, 62]. were considered possibly related to the dHACM
Despite the successes of the abovementioned product – two cases of postinjection pain at injec-
studies, these studies are not without their limi- tion site and one case of postinjection itching
tations. Foremost, most lack a placebo control. [68]. Based on so few studies, it is difficult at this
There is significant variability among study time to draw a conclusion on the use of AM
methods including the PRP composition, injec- derivatives for the treatment of refractory PF.
tate volume, injection frequency, and injection
approach. Most of the abovementioned studies
involve landmark-guided injections rather than Prolotherapy
USG injections, and it has been suggested that
USG injections result in more reliable and suc- In 2018, Ersen et al. compared three USG prolo-
cessful outcomes [38, 66]. Before drawing con- therapy (15% dextrose with lidocaine solution)
clusions about the effectiveness of PRP to other injections with a non-injection, rehabilitation
treatments for reducing pain and improving control [69]. A significant improvement in pain
function in patients with chronic PF, higher- and function was achieved in both groups during
quality RCTs with larger sample sizes are follow-up, with inter-group comparisons demon-
needed. Additionally, it would be beneficial to strating superior results in the prolotherapy group
have RCTs comparing different PRP prepara- at a 42- and 90-day follow-up [69]. At 360 days,
tions and applications to determine the most there was no significant difference between the
effective PRP composition, volume of injectate, two groups [69]. Furthermore, 77% of the
and frequency of injections for chronic PF to treatment group reported good and excellent
­
improve consistency among comparison trials results, whereas only 17% of the treatment group
with other interventions. reported these outcomes [69]. A study by Mansiz-
Kaplan et al. demonstrated clinical improvement
from prolotherapy as compared to placebo injec-
Amniotic Membrane Derivatives tion in 65 patients with chronic PF [70]. The
study included administration of 15% dextrose
Dehydrated human amnion/chorion membrane solution or saline solution two times at 3-week
(dHACM) products have been studied in only a intervals and demonstrated statistically signifi-
few trials for the treatment of chronic plantar fas- cant superior improvement in the prolotherapy
206 L. Vernese et al.

group at a 7- and 15-week follow-up [70]. Kim of the tarsal tunnel with 5–10 ml of local anes-
et al. in 2014 performed a comparison of two thetic ensuring that the medial and lateral
USG prolotherapy (15% dextrose/lidocaine solu- plantar and medial calcaneal nerves are ade-
tion) versus PRP injections for chronic PF and quately encircled with anesthetic solution.
found that each treatment was effective for Most commonly, USG is used to direct a 27-
improving pain, disability, and activity limita- or 25-gauge, 38 mm needle via a posterior-to-­
tions [71]. anterior approach adjacent to the tibial nerve
In a study comparing USG CS, extracorporeal complex.
shockwave therapy (ESWT), PRP, and prolother- • Additional local anesthetic solution is kept in
apy in 158 patients with chronic PF, CS was most reserve for local anesthesia of the skin or sub-
effective in the first 3 months, ESWT is effective cutaneous tissue if the nerve block was not
in the first 6 months for pain, whereas PRP and 100% effective.
prolotherapy effects were seen within 3–12 months
[72]. At a 36-month follow-­ up, no differences Approach
were found among the four treatments [72].
Similar to the overall concerns with the PRP • In our experience, the medial-to-lateral
research, the prolotherapy investigations have approach is easiest to perform as it creates sta-
significant variety in terms of volume of injectate bility of the treatment limb and allows easy
and frequency of repeated injections, making manipulation of the needle during performance
comparison between treatments quite challeng- of the procedure. Furthermore, this prevents
ing. Overall, the studies suggest that prolotherapy the need to puncture the plantar surface of the
is a safe and effective treatment in the short to foot which theoretically increases the risk of
medium term for chronic PF. infection as well as fat pad atrophy.

Regenerative Technique: Regenerative Medicine/

Ultrasound-Guided Plantar Fascia Orthobiologic Injection With or
Procedures Without Fenestration

Positioning Needle: 18–21 gauge, 38–50 mm

Injection Volume: 3–5 mL orthobiologic
• Patient: lateral recumbent with treatment side injectate
on table and pillow between knees, to facili-
tate an in-plane medial-to-lateral approach Approaches
(Fig. 10.9a)
• Provider: seated with US screen directly in Medial to Lateral, in-Plane with Td
front of line of sight We recommend the patient is positioned in the
previously mentioned lateral recumbent position
Td Type with the provider seated at the foot of the bed fac-
ing the plantar aspect of the foot and US machine.
• High-frequency linear array The orthobiologic is typically injected along with
fenestration (repeated passing of the needle
Needle through the diseased tissue), approximately
15–20 passes. Orthogonal long- and short-axis
• Anesthetic: Author’s preferred technique is to views can be used to assure proper position of
perform an USG tibial nerve block at the level needle and injectate (Fig. 10.9b, c).
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 207

a b

Fig. 10.9 Ultrasound-guided plantar fascia injection. (a) lateral approach showing a hyperechoic needle (arrow-
External view of the right (RT) foot demonstrating Td heads) within the central band of the PF. (c) USG correlate
placement and needle direction (solid arrow) for an in-­ of an out-of-plane, medial-to-lateral approach showing a
plane (solid rectangle) and out-of-plane (dotted rectan- hyperechoic needle tip (arrowhead) within the central
gle), medial-to-lateral approach to injecting the plantar band of the PF with large partial thickness tear (star). C
fascia (PF). (b) USG correlate of an in-plane, medial-to-­ calcaneus

Achilles Tendon: Introduction progressive tendon loading via eccentric exer-

cises and more recently heavy-slow exercises,
Chronic midportion Achilles tendinopathy (AT) along with analgesics, anti-inflammatories, ice,
is a common overload injury most commonly manual therapy, and correction of biomechanics
seen in running and jumping athletes, affecting when appropriate [48, 73, 74]. For recalcitrant
7–9% of active runners [73]. Despite its high cases, options may include injection therapy,
incidence, there remains no gold standard in shock wave therapy, and surgery [76, 77].
management. This likely reflects a poor under- Examples of current interventional treatment
standing of the true pain generator(s) which options include high-volume injection (HVI) or
requires a more comprehensive treatment tendon scraping with neovessel ablation, intra-­
approach. Based on imaging and histologic anal- tendinous platelet-rich plasma (PRP) injection,
yses, it is believed that chronic overload results in needle tenotomy, and ultrasonic tenotomy [73,
ingrowth of new vessels with associated nerve 77–80].
endings (neurovascularization), intra-tendinous To date, there is no study comparing the effi-
microtears, and chronic degeneration [74, 75, cacy of different treatment options, and therefore
76]. The most commonly diseased portion of the no definitive superior method. Therefore, deci-
Achilles tendon is the hypovascular midportion, sion on technique remains a personalized deci-
located about 2–7 cm proximal to the insertion on sion based on unique patient factors, imaging
the calcaneus [75, 76]. findings, and provider expertise/comfort level.
Typically, chronic AT has been managed with Despite lack of strong evidence for the modality,
overload reduction and rehabilitation including a study by Boesen et al. in 2017 demonstrated
208 L. Vernese et al.

superiority of the combined effect of injection Td Type

therapy with progressive eccentric tendon load-
ing compared to either performed independently • High-frequency linear array
[73]. This suggests that a comprehensive
approach is prudent for patients with chronic AT. Needle
Anesthetic: A 25-gauge 50 mm needle is used
to deliver local anesthetic via a preferred medial-­
Ultrasound-Guided Achilles Tendon to-­lateral USG approach
Procedures Approaches
Lateral to medial or medial to lateral depen-
 chilles Tendon Injection Technique
A dent on the location of the sural nerve.
Positioning The needle (18–21 gauge, 38–50 mm) is
directed via USG either in-plane or out-of-plane
• Patient: prone position with the feet dangling to the Td while fenestrating the diseased portion
off the edge of the bed/table (Fig. 10.10a) of the tendon and injecting the orthobiologic or
• Provider: seated with US screen directly in prolotherapy solution (Fig. 10.10b).
front of line of sight

a b

Fig. 10.10 Ultrasound-guided Achilles tendon injection. heads) within a partial thickness intra-substance tear
(a) External view of the right (RT) ankle demonstrating (star) of the AT. Note the location of the sural nerve (dot-
Td placement and needle direction (solid arrow) for an ted circle) just lateral to the Achilles tendon. (c) USG cor-
in-plane (solid rectangle) and out-of-plane (dotted rect- relate of an out-of-plane, medial-to-lateral approach
angle), medial-to-lateral approach to injecting the Achilles showing a hyperechoic needle tip (arrowhead) within the
tendon (AT). (b) USG correlate of an in-plane, medial-to-­ AT. Lax long axis, DIST distal, LAT lateral, K Kager’s fat
lateral approach showing a hyperechoic needle (arrow- pad
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 209

 chilles Tendon Neovessel Ablation:

A Ultrasound-Guided Achilles Tendon
High-Volume Injection and Tendon Neovessel Ablation (Scraping)
Scraping with HVI

Background: With the idea of reduction/abla- Positioning

tion of neovessel formation for pain relief from
chronic AT, tendon scraping and high-volume • Patient: prone position with the feet dangling
paratenon stripping has been suggested as pos- off the edge of the bed/table (Fig. 10.11a)
sible treatment avenue for mid-substance • Provider: seated with US screen directly in
AT. Maffulli et al. performed HVI using 10 ml front of line of sight
of 0.5% bupivacaine hydrochloride, 25 mg
aprotinin, and up to 40 ml of injectable normal Td Type
saline in a series of 94 athletes with recalci-
trant midportion Achilles tendinopathy and • High-frequency linear array
showed improved VISA-A scores from base-
line 41.7 ± 23.2 to 74.6 ± 21.4 by 12 months Needle
[78]. A randomized, placebo-controlled trial
by Boesen et al. compared the effectiveness of • Anesthetic: A 25-gauge 50 mm needle is used
HVI plus eccentrics, PRP plus eccentrics, and to deliver local anesthetic via a preferred
eccentrics alone in 58 middle-aged men with medial-to-lateral USG approach.
chronic midportion AT [73]. After 12 weeks of
the intervention, the injection groups proved Approach
more effective in reducing pain symptoms,
improving activity level and function, and • In general, a medial-to-lateral approach is pre-
reducing tendon thickness and intra-tendinous ferred to avoid the superficial and more poste-
vascularity than eccentric rehabilitation alone rior (relative to tibial nerve) located sural
[73]. In the short term (6 and 12 weeks), HVI nerve.
appeared more effective at improving pain, • During procedure – Regardless of approach,
function, and patient satisfaction than PRP, but the use of orthogonal long- and short-axis
both had similar outcomes in the long term views (relative to tendon and device) should
(24 weeks) [73]. Additionally, HVI only be utilized to ensure device location, thus
required one injection, whereas the PRP group avoiding injury to the respective sural and
underwent multiple injections [73]. tibial nerves.
Hakan Alfredson was the first to demon-
strate that neovessel ablation “tendon scrap- Procedure
ing” technique resulted in decreased pain and Once a decision is made on the approach, a
improved function in patients with AT [48]. 25-gauge, 50 mm needle is used to anesthetize
Good results with interval reduction in pain the skin, Kager’s fat pad, and paratenon of the
with both open and USG percutaneous neoves- Achilles tendon in the region of abnormality.
sel ablation techniques for midportion AT were Using a fanning technique under USG 5–10 ml of
reported [48]. The same group demonstrated local anesthetic, with or without epinephrine, is
good long-term (2–13 years) clinical outcomes used to ensure the region is adequately anesthe-
with high satisfaction rates in 241 tendons fol- tized. A small stab incision is made with a #11
lowing the same technique, suggesting that blade and a dual-bladed meniscotome is intro-
neovessel ablation is a safe and effective treat- duced through the incision with USG via the
ment for chronic AT [74]. same medial-to-lateral approach deep to the ten-
210 L. Vernese et al.

a b c

Fig. 10.11 Ultrasound-guided Achilles tendon neovessel the sural nerve (dotted circle) just lateral to the Achilles
ablation (scraping) and high-volume injection. (a) Single-­ tendon. (d) USG correlate of an out-of-plane, medial-to-­
use dual-bladed meniscotome. (b) External view of the lateral approach showing a hyperechoic meniscotome
left (LT) ankle demonstrating Td placement and menisco- (arrowhead) between the AT and K for tendon scraping
tome insertion via a medial-to-lateral approach for procedure. The meniscotome is then toggled distal to
neovessel ablation (tendon scraping) procedure. Note a proximal to scrape the bottom of the tendon, separating it
#11 blade was used to create a stab incision for introduc- from Kager’s fat pad. (e) USG image of a hyperechoic
tion of the meniscotome. In this patient, the area of pathol- needle tip (arrowhead) between the AT and K performing
ogy required two incision points. (c) USG correlate of an a high-volume injection. Notice the separation of the K
in-plane, medial-to-lateral approach showing a hyper- from the AT as the injectate (star) is injected. LAX long
echoic meniscotome (arrowheads) between the Achilles axis, SAX short axis, DIST distal, LAT lateral
tendon (AT) and Kager’s (K) fat pad. Note the location of

don between Kager’s fat pad and the Achilles ten- to continually confirm correct placement and
don. Alternatively, an 18-gauge, 50–89 mm complete hydrodissection. Care must be taken
hypodermic needle or a 16-gauge, 38 mm Nokor throughout the procedure to ensure the tip of the
needle (Becton, Dickinson and Company, needle does not pass too far (lateral or medial) as
Franklin Lakes, New Jersey) may be used for this to avoid injury to the respective sural or tibial
technique if preferred. Following US confirma- nerves.
tion of correct placement, a proximal-to-distal
sweeping motion is used to separate the fat pad
from the tendon. Once a separation plane is cre- Achilles Tendon Intra-tendinous
ated with the needle, the meniscotome is with- Platelet-Rich Plasma (PRP) Injection
drawn and an 18-gauge 50 mm needle is with or Without Needle Tenotomy
introduced with USG through the incision.
Subsequently, 20–40 mL of 0.9% NS sterile 0.9% Background: The application of PRP injections
normal saline is injected to hydrodissect the fat for chronic AT has been used clinically to treat
pad away from the tendon (Fig. 10.11a–e). chronic AT despite inconsistent evidence for its
Orthogonal short- and long-axis views are used efficacy in clinical studies. The heterogeneity
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 211

in preparation of PRP, volume of injectate, be utilized to ensure device location, thus

number of injections, and postinjection proto- avoiding injury to the respective sural and
col makes comparing studies a challenge. A tibial nerves.
2018 m ­ eta-­analysis of four level 1 randomized
controlled trials involving a total of 170 partici-
pants (85 treated with PRP injection and eccen-  endon Sheath Injections:
T
tric training and 85 treated with saline injection Regenerative Evidence
and eccentric training) found no significant dif-
ference in outcomes between the two groups at Non-Achilles ankle tendinopathies may involve
a 1-year follow-­up [81]. A 2019 meta-analysis the PTT, anterior tibialis (AT), peroneus longus
of five RCTs including a total of 189 patients (PL) and/or brevis (PB), and FHL [83]. The
with chronic AT concluded the same [82]. pathology is generally accepted to be that of
Boesen et al. was the first randomized placebo- intra-tendinous microtears and chronic degenera-
controlled trial to demonstrate PRP in combina- tion of the tendon proper, similar to other
tion with eccentric training program had a described tendinopathies [84]. Management of
positive effect when compared with the sham such tendinopathies is similar to the aforemen-
treatment [73]. In this study, 19 tendons were tioned Achilles and plantar fasciopathy with a
treated with four injections of PRP at 2-week trial of conservative management such as activity
intervals, whereas the other studies performed modification, immobilization, stretching, oral
only one injection, possibly indicating more and topical medications, bracing and orthotics,
injections may be superior. Additionally, the and physical therapy [84, 85]. Refractory cases
recovery and rehabilitation differed from prior such as PTT tendon dysfunction with a rigid
studies with early return to eccentric exercises adult-­acquired flatfoot deformity may progress to
after 10 days rather than 4–6 weeks in other surgical fixation [86].
investigations [82]. Further studies with consis- There is a paucity of literature for regenerative
tent protocols are needed to further support or treatment options for non-Achilles ankle tendinop-
refute the use of PRP injection for chronic mid- athies. Currently, only case reports and small case
portion AT. studies exist for these specific tendon disorders.
Angthong et al. assessed the outcomes of PRP
injections for four cases of PTT tendinopathy and
Key Recommendations noted improvement in pain scores but not for SF-36
scores [87]. Finnoff et al. reported USG needle
• Anesthetizing the periphery of the tendon can tenotomy and platelet-rich plasma injection
help to reduce pain with the procedure. resulted in improvements in functional scores and
• Consider performing the neovessel ablation/ tendon appearance on 31 subjects with lower
hydrodissection along with Achilles tendon extremity tendinopathies, including one patient
procedures to address the neovessel with PTT tendinopathy [88]. Mautner et al. reported
formation. on 180 patients with chronic tendinopathy, 1
• Location of the at-risk sural nerve and tibial involving the posterior tibialis, 2 peroneus brevis,
nerves (particularly the medial calcaneal and 3 peroneus longus tendons, with 95% of
branch) should be noted prior to any proce- patients reporting no pain at rest and 68% reporting
dure about the Achilles tendon. no pain with activities [89]. Oloff and Lam docu-
• In general, a medial-to-lateral approach is pre- mented successful treatment of PTT in a soccer
ferred to avoid the neurovascular structures. player with PRP, with improved post-­procedure
• During procedure – Regardless of approach, imaging and full return to soccer at 31 weeks [90].
the use of orthogonal long- and short-axis Given the scarcity of data on orthobiologics
views (relative to tendon and device) should for less common tendinopathies about the foot
212 L. Vernese et al.

and ankle, outcomes regarding these treat- Approaches: Posterior Tibialis Tendon
ments remain unclear.
Posterior to Anterior, in-Plane with Td
With the patient in lateral recumbent position with
 osterior Tibial, Achilles, and Peroneal
P the affected limb on the table and a pillow between
Tendon Injection Technique the knees, the Td is placed short axis to the tendon
in the anatomic axial plane. If needle tenotomy is
Positioning planned, a tibial nerve block may be performed as
documented in the “Plantar Fascia” section above
• Patient (varies depending on the tendon being and can be performed prior to a local anesthetic
treated) along the target tendon. Following decision ade-
–– Anterior tibialis – supine with the ankle in quate anesthesia, the needle is advanced from an
relaxed position anterior to posterior direction, in-plane with the
–– Posterior tibialis – lateral recumbent with Td, until confirmed in the tendon sheath
treatment side on the table (Fig. 10.12a, b). Although a posterior approach
–– Peroneal tendons – lateral recumbent with can be undertaken, the anterior approach is pre-
treatment side up ferred to avoid the tibial neurovascular bundle.
• Provider: seated with US screen directly in Furthermore, the medial malleolus may be used
front of line of sight as a bony backstop for the needle.

Td Type Tibialis Anterior Tendon

• High-frequency linear array Medial to Lateral, in-Plane with Td

The patient is lateral recumbent with the affected
Needle limb on top and pillow between the knees. If nee-
dle tenotomy is planned, a fibular nerve block or
• Anesthetic: 25 to 22 gauge, 38 mm local anesthetic injection can be performed prior.
• Procedure: 21 to 18 gauge, 38 mm After anesthetic, the Td is placed short axis to the
tendon over the region of primary pathology. The
Injection Volume needle is advanced from a posterior to anterior
direction, in-plane with the Td, until confirmed
• Anesthetic: 1–2 mL 1% lidocaine within the tendon sheath. This allows the lateral
• Orthobiologic injectate: 1–3 mL malleolus to be used as a bony backstop.

a b

Fig. 10.12 Ultrasound-guided posterior tibialis tendon tendon. (b) USG correlate of an in-plane, posterior-to-­
injection. (a) External view of the right (RT) ankle dem- anterior approach showing a hyperechoic needle (arrow-
onstrating Td placement (solid rectangle) and needle heads) within the PT tendon sheath. SAX short axis, POST
direction (solid arrow) for an in-plane posterior-to-­ posterior
anterior approach to injecting the posterior tibialis (PT)
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 213

Peroneus Longus and Brevis Tendon studies for the treatment of chronic ankle insta-
bility. A 2014 study by Laver et al. was one of the
Posterior to Anterior, in-Plane with Td first to report on PRP use for ankle sprains, and
The patient is in the lateral decubitus with the lat- they compared two ultrasound-guided PRP injec-
eral ankle of interest superior. The ankle is tions (separated by 7 days) followed by a reha-
slightly inverted and plantarflexed, using a towel bilitation program versus rehabilitation alone for
roll as needed for optimal patient comfort and grade 3 AITFL injuries [98]. This resulted in a
procedure visualization. The physician sits distal, statistically significant earlier return to play (40.8
facing the foot/patient. The Td is placed short versus 59.6 days) and improved pain scores in the
axis to the tendon at the retro-malleolar groove as PRP group. Another study of PRP injections for
the tendons share a common synovial sheath at syndesmotic injuries found that a single
this level. The needle is advanced from a poste- ultrasound-­guided PRP injection into the AITFL
rior to anterior direction, in-plane with the Td, tear resulted in earlier return to play as compared
until confirmed within the tendon sheath, taking to a historical cohort (48.6 vs. 69.3 days) [99]. A
care to avoid the sural nerve which should be just 2015 randomized placebo-controlled trial failed
posterior to the tendons at this level. to show a statistical difference in pain or function
following a single, ultrasound-guided injection of
3–4 cc of PRP for patients with acute ankle
 igament Injections: Regenerative
L sprains (details of sprain not included in study
Evidence details) presenting to the emergency department
at 3, 8, and 30 days’ assessments [100]. A 2019
Acute ankle sprains account for around 15% of randomized controlled trial by Blanco-Rivera
sports-related injuries among collegiate athletes, et al. compared rigid immobilization followed by
with rates as high as 3.85 per 1000 basketball a rehabilitation protocol with or without a single,
players [91, 92]. The majority (up to 60.5–90%) landmark-guided 5 ml PRP injection into the
of ankle sprains involve the lateral ligament com- ATFL for patients presenting to the emergency
plex, 73% of which involve the anterior ­talofibular department within 48 hours of a grade 2 ankle
ligament (ATFL) [93–95]. Syndesmotic “high sprain [101]. Although similar outcomes at
ankle” sprains involving the anterior inferior tib- 24 weeks, the PRP group demonstrated signifi-
iofibular ligament (AITFL) and/or medial ankle cant improvements in pain and American
sprains involving the deltoid ligament complex Orthopedic Foot and Ankle Scores (AOFAS) at
occur less frequently but often requiring a pro- earlier assessment points (3, 5, and 8 weeks)
longed treatment course compared to lateral [101]. These studies have numerous limitations,
ankle sprains [93–96]. Lateral ankle sprains have including a small patient population, variable
a high rate of recurrence and chronic ankle insta- procedure techniques, and relatively short
bility. A study of athletes from 25 NCAA sports follow-up.
over 6 academic years found that 1 in 8 lateral One retrospective observational study reported
ligamentous complex sprains was recurrent [95]. on the use of prolotherapy for chronic ankle pain
A 7-year follow-up study of patients after an and showed favorable outcomes [102]. The
acute inversion ankle sprain found that 212 (32%) authors performed on average 4.4 treatment ses-
of patients reported ongoing ankle disability [97]. sions of 20–30 injections of 0.5–1 cc of a 15%
Studies to evaluate the effectiveness of ortho- dextrose, 0.2% lidocaine solution around the
biologic interventions on pain reduction and ankle at areas of tenderness. At least 50%
functional improvement after acute ankle sprains improvement in pain was reported in 90% of
are limited and with mixed results. To the best of patients, and 78% reported full resolution of pain
the authors’ knowledge, there are no available and stiffness.
214 L. Vernese et al.

Anterior Talofibular Ligament Anterior Talofibular Ligament

and Anterior Inferior Tibiofibular
Ligament PRP Injection Techniques Distal to Proximal, in-Plane with Td
The patient is lateral recumbent with the affected
Positioning limb on top and pillow between the knees.
Anesthetic is often not necessary given superfi-
• Patient: lateral recumbent with treatment side cial position of the ligament and to prevent inhib-
up itory interaction with the orthobiologic. The Td is
• Provider: seated with US screen directly in placed long axis to the ligament, with a gel stand-
front of line of sight off to improve access to the ligament and visual-
ization of the needle. The needle is advanced
Td Type from a distal to proximal direction, in-plane with
the Td, until confirmed within the edematous
• High-frequency linear array ligament or at site of ligament tear.

Needle Anterior Inferior Tibiofibular Ligament

• Procedure: 21 gauge, 38 mm Medial to Lateral, in-Plane with Td

The patient is either supine or in lateral recum-
Injection Volume bent with the affected limb on top and pillow
between the knees (Fig. 10.13a). The ankle
• Orthobiologic injectate: 1–2 mL should be placed in slight plantarflexion to
improve access. Anesthetic is often not necessary
Approaches given superficial position of the ligament and to

a b

Fig. 10.13 Ultrasound-guided anterior inferior tibiofibu- right, showing an out-of-plane, distal-to-proximal or
lar ligament injection. (a) External view of the right (RT) proximal-to-distal approach of a hyperechoic needle tip
ankle demonstrating Td placement (solid rectangle) and (arrowhead) within the ligament (star). (c) USG correlate
needle direction for an out-of-plane (black arrow) and in-­ of an in-plane, medial-to-lateral approach showing a
plane (white arrow) anterior inferior tibiofibular ligament hyperechoic needle (arrowheads) within the ligament
injection. (b) USG correlate, with medial (MED) to the (star). SAX short axis, F fibula, T tibia
10 Ultrasound-Guided Orthobiologics of the Foot and Ankle 215

prevent inhibitory interaction with the orthobio- placed long axis to the ligament. The needle is
logic. The Td is placed long axis to the ligament, advanced from an anterior to posterior direction,
with a gel standoff to improve access to the liga- out-of-plane with the Td, until confirmed within
ment and visualization of the needle. The needle the edematous deltoid ligament or at site of liga-
is advanced from a medial to lateral direction, in-­ ment tear (Fig. 10.14b).
plane with the Td, until confirmed within the
edematous AITFL or at site of ligament tear Anterior to Posterior, in-Plane with Td
(Fig. 10.13b). Alternatively, with the deltoid ligament imaged
in short axis, the needle can be advanced using an
Distal to Proximal, Out-of-Plane with Td in-plane approach from anterior to posterior, to a
Alternatively, with the AITFL imaged in long position within the desired portion of the injured
axis, the needle can be advanced using an out-of-­ ligament (Fig. 10.14c).
plane, walk-down technique from superficial to
deep, to a position within the desired portion of
the injured ligament (Fig. 10.13c). Post-procedure Rehabilitation
Protocol
Deltoid Ligament
There is no consensus on post-procedure reha-
Anterior to Posterior, Out-of-Plane with Td bilitation protocols nor activity limitations fol-
The patient is in lateral recumbent with the lowing any of the aforementioned procedures.
affected limb on the table (Fig. 10.14a). Post-procedure activity limitations and weight-­
Anesthetic is often not necessary given superfi- bearing status are largely driven by expert opin-
cial position of the ligament and to prevent inhib- ion and tolerance of the activity by individual
itory interaction with the orthobiologic. The Td is patient factors. It is the authors’ general practice

a b

Fig. 10.14 Ultrasound-guided deltoid ligament injec- cent posterior tibialis (PT) and the flexor digitorum longs
tion. (a) External view of the right (RT) ankle demonstrat- (FDL) tendons. (c) USG correlate of an in-plane, distal-­
ing Td placement and needle direction (solid arrow) for to-­
proximal approach showing a hyperechoic needle
an out-of-plane (solid rectangle) and in-plane (dotted (arrowheads) within the tibiocalcaneal portion of the del-
rectangle) and distal-to-proximal approach to injecting toid ligament. Note similar approaches can be used to tar-
the deltoid ligament. (b) USG correlate of an out-of-­ get the posterior and anterior tibiotalar and tibionavicular
plane, distal-to-proximal approach showing a hyperechoic portions of the deltoid ligament complex. LAX long axis,
needle tip (arrowhead) within the tibiocalcaneal portion C calcaneus, PLNT plantar, DIST distal
of the deltoid ligament (D). Note the location of the adja-
216 L. Vernese et al.

to follow a four-phase protocol after needling of leukocyte concentration, platelet/MSC, dHACM,

any tendon about the foot or ankle (Achilles ten- or dextrose concentration, frequency of injec-
don, plantar fascia, PTT, etc.). Phase one involves tions, and post-procedure protocols are needed
the use of protected weight-bearing device, CAM to validate the promising early publications on
boot, for 2–4 weeks following tendon needling mentioned procedures.
procedure, regardless of injectate/device used.
This is done out of an abundance of caution to
reduce the risk of tissue/tendon rupture and help References
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 Part III
Back and Spine
 Ultrasound-Guided Regenerative
Injections for the Spine
11
Donald Tsung-Yung Tang and Chih-Peng Lin

Introduction omy and biomechanics is needed in choosing

adequate targets of injection. Ultrasound is one
Chronic spinal pain is one of the most common of the imaging modalities used in interventional
complaints encountered in pain clinic. The preva- treatments, with advantages in the cost, portabil-
lence and burden of disability has increased ity, and no radiation exposure [3]. For precision
markedly in recent decades [1]. In the aging pop- and safety injection therapies in ultrasound-­
ulation, the prevalence, severity, and complexity guided regenerative injection, comprehensive
are even more escalated. Diagnosis of spinal pain understanding of the anatomy and sonoanatomy
is usually challenging because of the nonspecific, is mandatory. In this chapter, the anatomy, sono-
overlapping clinical presentation. Laboratory and anatomy, and injection techniques for axial struc-
imaging studies could help in ruling out red flags; tures of cervical, thoracic, and lumbosacral levels
however, the diagnostic value is less than satis- will be reviewed.
factory. Therefore, for a definite diagnosis, diag-
nostic or prognostic injection is usually needed
before proceeding to invasive pain management.  eck Pain and Regenerative
N
Regenerative injection, which is based on the Medicine
concept of regeneration and enhancement of tis-
sue integrity in the biotensegrity model, is one of Neck pain is one of the most common complaints
the modalities in the interventional category. The and the leading cause of disability worldwide.
targets of regenerative injection also include The estimated mean point, annual, and lifetime
some structures which are not proven pain gen- prevalence is 7.6%, 37.2%, and 48.5%, respec-
erators like ligaments and muscle entheses [2]. tively [4]. The probable pain generators of the
Therefore, for practitioners of regenerative injec- cervical spine are facet joints, intervertebral
tion, clinical reasoning with knowledge of anat- discs, muscles, ligaments, and nerve root com-
pression or spinal stenosis leading to radicular
symptoms [5]. The clinical presentations of dif-
D. T.-Y. Tang
Department of Pain Managemet, Taichung Tzu Chi ferent etiologies share certain similarities; there-
Hospital, Taichung, Taiwan fore, it is usually challenging to make a definite
C.-P. Lin (*) diagnosis without a comprehensive assessment
Department of Anesthesiology, National Taiwan protocol for all possible differential diagnoses.
University Hospital and National Taiwan University Moreover, these pain-generating structures may
College of Medicine, Taipei, Taiwan
have negative impact on biomechanics of the cer-

© Springer Nature Switzerland AG 2022 223

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_11
224 D. T.-Y. Tang and C.-P. Lin

vical spine, deteriorate the overall stability, and mal pattern. Herniated disc or spinal stenosis
induce another pain generator. Since the history, may be revealed by imaging studies like CT or
physical findings, and imaging studies are often MRI; however, these findings are not specific. To
not specific, diagnostic block or provocative test confirm the causative relationship between the
is commonly regarded as the standard of making image findings and clinical symptoms, electrodi-
a diagnosis. agnostic tests could help. Selective nerve root
The clinical presentation of cervical radicular injection by ultrasound guidance could provide
pain secondary to nerve root compression or spi- pain relief to the patients, albeit the spread of
nal stenosis is relatively specific when compared injectate is not consistent with a transforaminal
to other cervical spine pain generators. It t­ ypically epidural injection (Fig. 11.1). Although selective
leads to neck pain and/or arm pain in a dermato- cervical nerve root injection is not commonly

a b

Fig. 11.1 Ultrasound-guided cervical selective nerve transforaminal technique. (a) C7 ultrasound-guided
root block (SNRB), vs. fluoroscopy-guided transforami- SNRB on the posterior tubercle of C7. (b) Fluoroscopic
nal epidural injection. The injectate is actually out of the demonstration with contrast after (a). (c) Typical
neuroforamen when compared to the fluoroscopy-guided fluoroscopy-­guided transforaminal epidural injection
11 Ultrasound-Guided Regenerative Injections for the Spine 225

performed in the practice of regenerative medi- Anatomy and Sonoanatomy

cine, cervical radicular pain is commonly of the Cervical Spine
encountered in clinical pain practice, and the
technique will be briefly summarized in this For ultrasound scanning or guidance of interven-
chapter. tion of the cervical spine, a high-frequency linear
As a crucial component of the cervical spine array transducer is usually recommended. For
biomechanics, cervical facet joint is the most sonographic scanning and injection of the cervi-
important structure in axial neck pain. In cal nerve roots, the patient is usually placed in a
chronic neck pain population, the prevalence of semi-decubitus or lateral decubitus position. The
facetogenic pain could be up to 55% [6]. There transducer is placed in the transverse plane of the
are several neck muscles inserting onto the cer- neck to obtain the short-axis view of the cervical
vical facet joint and capsular ligament, respon- spine. Moving the transducer in cephalad or cau-
sible for the biomechanical integrity of the dal direction, the transverse process (TP) of the
posterior cervical spine. The facetogenic pain C5, C6, and C7 levels could be visualized
could be related to the instability, laxity, or (Fig. 11.2). In typical cases, the anterior tubercle
weakness of capsular ligaments and neck mus- of the C6 TP, which is also called Chassaignac’s
cles. Contussional injury to the facet joints or tubercle, is the most prominent anterior tubercle
strain of the capsular ligaments caused by in the lower cervical spine levels. The size of
whiplash-like injury and may further predis- anterior and posterior tubercle of the C5 TP is
pose to the overall biomechanical failure and similar, while at the C7 level, the anterior tuber-
degeneration [7], which ultimately cause cle is absent or remnant. Ultrasound-guided cer-
chronic neck and upper back pain and limited vical root injection is performed with an in-plane,
range of motion. posterior-to-anterior approach. Before advance-
For the diagnosis of facetogenic neck pain, ment of the needle, always check blood vessels in
clinical diagnosis by physical tests is attempted the vicinity of the nerve roots with Doppler ultra-
[8]; however, currently, the gold standard for sound (Fig. 11.1d).
diagnosis remains diagnostic facet joint injection Injection of the cervical facet joint could be
or medial branch block with local anesthetics [9]. performed with either lateral or posterior
Up to now, in the literature, there is no report approach. In the lateral approach, the patient is
regarding the necessity of diagnostic block in placed in the lateral decubitus position, with the
regenerative injection. Clinically, diagnostic symptomatic side uppermost. The level is identi-
injection is usually not a routine for clinicians fied by visualizing the TP of C1 and the inferior
practicing regenerative injection. Future works articular process (AP) of the C2, with the latter
are needed to clarify the role of diagnostic injec- presenting as an oblique bony drop-off just cranial
tion in regenerative injection. to the C2–3 facet joint (Fig. 11.3). The C2–3 facet
When treating the chronic spinal pain with joint could be used as a starting point to count the
regenerative injection, choosing the crucial tar- following levels. The articular pillar appears as
gets is of paramount importance. The choice of hyperechoic wavy lines, and the facet joint is the
targets usually depends on tenderness to palpa- anechoic gap between the APs. Facet joint injec-
tion, dynamic tests according to the biome- tion on the lateral side could be performed in this
chanics, and dynamic ultrasound scanning [10]. long-axis view of the cervical spine with an out-­
In the following section, the sonographic scan- of-­plane technique or rotate the transducer 90
ning of the cervical spine will be briefly degrees to the short-axis view then perform injec-
reviewed. tion with the in-plane technique (Fig. 11.4). In the
226 D. T.-Y. Tang and C.-P. Lin

a b

c d

Fig. 11.2 Ultrasound-guided cervical selective nerve absent or rudimentary anterior tubercle of the TP. (d)
root injection. (a) Typical C5 appearance: comparable Abundant vascularity including the vertebral artery tra-
sizes of the anterior and posterior tubercle of the trans- verse around the C7 nerve root. To avoid intravascular
verse process (TP). (b) Typical C6 appearance: prominent injection or injury to the vessels, Doppler ultrasound scan
anterior tubercle of the TP, which is also named is highly recommended prior to any cervical spine
“Chassaignac’s tubercle.” (c) Typical C7 appearance: procedures

Fig. 11.3 C2–3 facet joint. Red dashed line the steep Fig. 11.4 The in-plane, posterior-to-anterior cervical
slope of the C2 interior articular process, yellow line C2–3 facet injection. Red overlaying shadow the articular pillar
facet joint cleft and the transverse process of the cervical spine
11 Ultrasound-Guided Regenerative Injections for the Spine 227

perspectives of regenerative medicine and bio- axis view by identifying the most rostral bifid of
tensegrity, the degeneration or symptoms of a spinous processes. Scanning in the sagittal plane
joint could be secondary to the injury or laxity of and moving caudally, the level of treatment could
its supporting structures. Winkelstein et al. [11] be identified. When the level was identified, move
conducted an anatomical investigation of the the transducer laterally to see the interlaminar
human cervical facet capsule and found that space and then the articular pillar of the facet joints
22.4 ± 9.6% of the capsular area was inserted and (Fig. 11.5). The articular pillar of the facet joints
supported by the paraspinal muscles. Therefore, will present as “saw sign” in the sonographic view.
the in-plane approach, which is performed from The needle is introduced immediately caudal to
posterior to anterior in the short-axis view of the the transducer, with an in-plane, caudal-to-cranial
cervical spine, may be more favorable than the approach. This approach has three advantages.
out-of-plane approach. This lateral in-plane First, the caudal-to-cranial needle trajectory is par-
approach allows more comprehensive treatment allel to the angulation of the cervical facet joints,
on the facet capsule and muscle entheses. which makes it easier to obtain an intra-articular
The posterior approach of cervical facet joint needle placement. Second, it is possible to inject
injection is performed with the patient placed in more than one joint in one needle puncture. Last
the prone position. Bilateral injection could be but not least, as we know, there are several muscle
performed at the same time without changing insertions on the joint capsule, and these muscles
position. Place the transducer sagittal first on the are biomechanically important to the cervical facet
midline to identify the C1 spinous process, which joint pain. It is possible to scatter the injectate
has no or rudimentary spinous process. The C2 extensively along the joint capsules and muscular
spinous process could be ascertained in the short-­ attachments with this posterior approach.

a b

c d

Fig. 11.5 Cervical spine sonoanatomy: posterior dura. (b) Cervical facet joints, posterior approach. (c)
approach, sagittal scan of the cervical facet joints. (a) Cervical facet joints, posterior approach, with overlaying
Interlaminar plane. C2, C3, C4, C5, C6 the lamina of the shadow indicating the cervical articular pillar. (d)
corresponding level, arrowhead anterior and posterior Morphology of the cervical articular pillar in MRI
228 D. T.-Y. Tang and C.-P. Lin

Clinical Pearls of Specific Structures process. In clinical assessment, the first step is
always ruling out the red flags including neo-
 ervical Facet Joint
C plastic, infectious, traumatic, or systemic inflam-
The cervical facet joints are diarthrodial joints, matory disorders. Radicular distribution is
which are formed by the articulation of inferior usually not presented in facet joint pain patients.
AP of the above vertebra and the superior AP of Currently, the gold standard for diagnosis is still
the below vertebra. These joints contain synovial image-guided diagnostic block. To reduce the
cells and joint fluid and are surrounded by a joint false-positive rates, dual or controlled diagnostic
capsule, functioning similar to the knee joint blocks with at least 75% pain relief are recom-
[12]. The orientation of the joint is angulated at mended [19]. The treatment modalities for cervi-
about 45 degrees at C2–3 cervical facets [13] and cal facetogenic pain are intra-­articular injections
getting more vertical, close to the coronal plane with steroid, medial branch block, and radiofre-
at lower cervical facet joints (Fig. 11.6), which quency neurotomy [20]. Regenerative injection
lie nearly in the orientation of thoracic facet for the cervical facet joints with dextrose or
joints [14]. The orientation of the cervical facet orthobiologics, albeit the evidence is less than
joints provides the freedom of movement of the well established, it could be a novel and promis-
cervical spine in all three planes. This freedom of ing intervention [12].
movement makes the cervical spine susceptible
to acceleration-deceleration, rotation, or com-
pressive injury.  horacic Back Pain
T
The facet joints are innervated by the articular and Regenerative Medicine
branches from the medial branches of dorsal
rami from the spinal nerves above and below the Upper or middle back pain without neck or low
level. The medial branches lie on the waists of back pain is relatively less common than neck
the articular pillars of corresponding vertebrae pain and low back pain in clinical practice. The
(Fig. 11.7). Clinically, the pain referral patterns incidence of thoracic pain ranges from 3% to
are not dermatomal [15–18] (Fig. 11.8) and usu- 26% and the prevalence is from 5% to 34% [21].
ally give rise to the difficulties in the diagnostic The prevalence of thoracic facetogenic pain in

Fig. 11.6 The

orientation of the
cervical facet joints. The
C2–3 facet faces
anteroinferior, in 45
degrees from the
horizontal plane. In
lower cervical facets, the
joint lines get more
vertical and are close to
the coronal plane at
lower cervical facet
joints, which lie nearly
in the orientation of
thoracic facet joints
11 Ultrasound-Guided Regenerative Injections for the Spine 229

Fig. 11.7 The

Dens
innervation of the
cervical facet joints.
Below the C2–3 facet
joint, each facet joint
was innervated by the
medial branch of the Third occipital
dorsal rami from the nerve (TON)
spinal nerves of the C2-3 and C3-4
above and below level. foramina
C3
(From Manchikanti et al. C2 and C3
[75], with permission spinous processes
from Springer) Medial branch of C3

Medial branch of C4
C4
Medial branch of C5

C4, C5 and C6
articular pillars
C5

C6 C5-6 and C6-7

face joints

C7

Medial branch of C8

C8 T1

thoracic spine pain ranges from 34% to 48% Anatomy and Sonoanatomy
[22]. Pain generators other than the facet joints of the Thoracic Spine
are the thoracic discs, costotransverse joints
(CTJ), and costovertebral joints [23–25]. Due to For ultrasound-guided thoracic spine regenera-
their close proximity, the pain referral patterns tive injections, the two most important and viable
from these structures are overlapping and indis- structures are the thoracic facet joints and the
tinguishable, and usually a definite diagnosis CTJs. Procedures on these two structures are per-
could not be established before a diagnostic or formed in a relatively shallow depth and are rela-
provocative injection. For ultrasound-guided tively simple and easy. However, to avoid
injection, thoracic intervertebral discs and cos- complications which could be fetal or permanent,
tovertebral joints are hardly accessible due to a more comprehensive understanding of the spa-
their deep location and so are beyond the scope tial relationship with several vital structures is
of our discussion. Some red flags, like thora- mandatory and will be described in this section.
coabdominal visceral pathology, great vessel In any spine interventions, counting level is of
pathology, neoplasms, or infectious spinal dis- paramount importance. In the thoracic level, the
orders, should always be ruled out first before clinician could count the level from the cephalad
starting injection therapy. at the T1 level, at which is the first rib located, or
230 D. T.-Y. Tang and C.-P. Lin

a b
C2/3, C3
C2-3
C2/3, C3/4, C4
C3/4, C4/5, C3
C3-4 C4/5, C5/6, C4, C5
C4-5
C6/7, C6/, C7
C5-6 C4/5, C5/6, C4

C6-7

C7/Th1, C7

Fig. 11.8 The pain referral patterns from different inves- (c) The referral patterns of all subjects obtained by mini-
tigators [16–18]. (a) Cervical facet pain distribution in mal threshold stimulation of their right third occipital
healthy volunteers. (b) Pain distributions for the facet nerve and C3 to C8 medial branches. (From Manchikanti
joints from C0/C1 to C7/T1 and the dorsal rami C3 to C7. et al. [75], with permission from Springer)

from the caudad, begin with the most caudal rib performed using this view at the area 7–8 cm lat-
at the T12 level or the lumbosacral junction. The eral to the midline. Moving the transducer medi-
scanning usually begins in the sagittal plane at ally from the intercostal view, when approximating
the ribs and the intercostal spaces (Fig. 11.9). The to the midline, a “jump” from the rib to the TP
ribs are separated, hyperechoic, round bony representing the costotransverse junction could
structures. The intercostal space, which is located be visualized (Fig. 11.10). If the target of injec-
between the ribs, contains the intercostal mus- tion is the CTJ, rotating the transducer 90 degrees
cles, vessels, and nerves. The pleura is a hyper- to the transverse plane at this level, the CTJ could
echoic line beneath the intercostal space. The be visualized as a small cleft between the rib and
intercostal nerve block, which is utilized in both the TP (Fig. 11.11). The needle could be advanced
acute and chronic pain management, is usually with a lateral-to-medial, in-plane approach.
11 Ultrasound-Guided Regenerative Injections for the Spine 231

a b

Fig. 11.9 The intercostal spaces in the sagittal plane (a) with MR correlation (b). ESM the erector spinae muscles, R
rib, dashed line the pleura

a b

Fig. 11.10 The costotransverse joint in the sagittal scan (a) with elucidation by sketch in (b). R rib, TP transverse
process

a b

Fig. 11.11 The costotransverse joint in the transverse scan (a) with MR correlation (b). R rib, TP transverse process,
red line the costotransverse joint line

Moving the transducer more medially in the logical appearance could be used as a clue to dif-
sagittal plane, the transverse process view could ferentiate the two structures. The sonographic
be obtained (Fig. 11.12). It is crucial to distin- appearance of the ribs appears as hyperechoic
guish ribs from the TP in the preprocedural scan. semicircular lines, and the TP is in a rectangular
Besides the anatomical relationship, the morpho- shape in the sonographic view (Fig. 11.13). The
232 D. T.-Y. Tang and C.-P. Lin

a b

Fig. 11.12 The thoracic transverse processes in the sagittal scan (a) with MR correlation (b). TP transverse process

an interfascial spread of injectate between the

erector spinae muscles and the TP (Fig. 11.14).
Besides the interfascial plane as a target of nerve
block, there are several attachments of ligaments
and muscle entheses to the TP. The anterior sur-
face was attached by the costotransverse liga-
ment, while the posterior surface was attached by
deep back muscles which are crucial to the stabil-
ity of the thoracic spine. The superior costotrans-
verse ligament connects the ribs to the inferior
surface of the TP of the above vertebrae. The
intertransverse ligament connecting the adjacent
TP also stabilizes the thoracic spine by limiting
the lateral flexion [27]. Although there is few evi-
dence in the literature regarding regenerative
injection on the thoracic TP, the thoracic TP theo-
retically could be a good candidate to be “regen-
erated” based on the concept of biotensegrity.
More medially to the TP, the sagittal thoracic
facet joint view could be obtained. The thoracic
facet joint space lies almost in the coronal plane,
Fig. 11.13 Morphological comparison of the ribs and the
transverse processes. Notice the cross section of the ribs is with a certain degree of anterior tilting depending
relatively round, while the cross section of the transverse on the level. The sonographic appearance of the
processes is relatively in square thoracic facet joint appears as small cleft between
horizontal lines, which are the APs of the tho-
erector spinae plane block (ESPB), which could racic vertebrae (Fig. 11.15). The thoracic facet
provide a certain degree of pain relief of myofas- joint injection is executed in this view. When the
cial upper back pain [26], is performed in the sag- targeted facet joint is optimally scanned, the nee-
ittal transverse process view with an in-plane dle is introduced immediately caudal to the trans-
approach. The choice of target level depends on ducer and advanced in-plane in a caudal-to-cranial
the indication and level of pain generator. The direction. Sometimes an intra-articular needle
needle tip is placed on the tip of the TP, obtaining placement is hindered by the degenerative
11 Ultrasound-Guided Regenerative Injections for the Spine 233

a b

Fig. 11.14 Erector spinae plane block (a) and the interfascial spreading of the injectate (b). TP transverse process,
arrowheads the needle

a b

Fig. 11.15 The thoracic facet joint in the sagittal scan (a) with MR correlation (b). SAP superior articular process (of
the above level), IAP inferior articular process (of the below level)

changes or morphological factors, fine needle thoracic interlaminar space, avoiding an

adjustment is needed, and fluoroscopy verifica- ­inadvertent epidural injection, intrathecal injec-
tion should be considered. In our experience, a tion, or spinal cord injury. The interspinous liga-
periarticular injection without penetration of the ments and supraspinous ligaments at the
capsule also gains some therapeutic benefit. anatomical midline sometimes are targets for
Medial to the facet joint column, the lamina regenerative injection. Although landmark-
and interlaminar spaces (Fig. 11.16) lie in close guided injection for these two superficial struc-
proximity to the facet joints. Before injecting a tures could be performed easily, ultrasound
thoracic facet joint, the clinician should always guidance could further optimize the safety and
scan more medially to the facets and identify the precision of the therapy. The thoracic spinous
234 D. T.-Y. Tang and C.-P. Lin

Clinically, the patient may present with bilat-

eral or unilateral paravertebral pain without neu-
rologic deficit. The pain worsens with prolonged
standing, hyperextension, or rotation of the tho-
racic spinal column [30]. Paraspinal tenderness
to palpation is common yet not specific. Imaging
modalities such as CT or MRI could help to
exclude red flags such as malignancy or infec-
tious disorder and, however, are not necessary in
clinical assessment. Due to the overlapping clini-
cal presentations of different pain generators in
the thoracic spine pain, a definite diagnosis of
thoracic facet joint pain could not be obtained
without a diagnostic block on the medial branches
Fig. 11.16 Thoracic interlaminar space: this image could or directly to the joint.
be obtained by medially tilting the ultrasound transducer
from the thoracic facet joint view (Fig. 11.15). Scanning  ostotransverse Joint (CTJ)
C
this view is crucial to prevent dural puncture in thoracic
facet joint injection
The CTJ is the joint between the TP and the ipsi-
lateral rib and plays an important role in provid-
process also receives several attachments from ing stability to the thoracic spine [31]. While the
muscles and ligaments including the superior and thoracic facet joints are innervated by the medial
lateral costotransverse ligaments, intertransverse branches from the dorsal rami, the CTJs are
muscles and ligaments, and deep back muscles, innervated by the lateral branches of the dorsal
which are important for the biomechanical stabil- rami [32]. It could be one of the pain generators
ity of the upper torso. Including the spinous pro- in thoracic back pain, along with the thoracic
cess, interspinous ligaments, and supraspinous facet joint and intervertebral disc. In contrast to
ligaments in the regenerative injection protocol the thoracic facet joint, the area of tenderness is
would further optimize the therapeutic benefit. usually more localized to the joint [33] and is
mainly presented with unilateral middle back
pain. In some cases, the pain may refer to the
Clinical Pearls of Specific Structures anterior chest, leading to atypical chest pain [34].
There are few clinical reports regarding regen-
 horacic Facet Joint
T erative injection on the CTJ. Besides the joint
The thoracic facet joints, like the cervical ones, itself, the main supporting structures to the joint
are formed by the articulation of the inferior AP are superior, lateral, posterior, and inferior costo-
of the vertebra above and the superior AP of the transverse ligaments [32, 35]. These ligaments
vertebra below. The superior AP faces posteri- attach to the lamina, the neck of the rib, the TP,
orly, superiorly, and laterally [28], with the joints and across the posterior joint capsule, and these
inclined anteriorly about 25–30 degrees from the structures could theoretically be targets of regen-
frontal plane [29]. Each joint receives dual inner- erative injection. The costovertebral joint and
vation from the medial branches from the dorsal CTJ provide biomechanical stability to each
rami of the spinal nerves above and below the other, and it is reasonable to consider a costover-
joint. The orientation of the facet joint provides tebral joint injection when the tentative diagnosis
the freedom of rotational movement, while the is CTJ pain. However, costovertebral joint injec-
flexion, extension, and lateral flexion movements tion under ultrasound guidance could be techni-
are limited. The thoracic facet joint could be a cally difficult and dangerous due to the acoustic
pain generator when sustaining degenerative shadow of the TP and rib, the depth of the joint,
changes, inflammation, infection, or trauma. and its close proximity to the pleura. For safety,
11 Ultrasound-Guided Regenerative Injections for the Spine 235

regenerative injection for the CTJ should be lim- not only the classic pain generators like facet
ited to the joint itself and the supporting liga- joints or SIJs but also ligaments, entheses, and
ments, instead of going deeper to the fascial systems. In a proof-of-concept review
costovertebral joint. and case description [10], common targets of
regenerative injection are described. These
structures are thoracolumbar fascia (TLF), apo-
 ow Back Pain and Regenerative
L neurosis of the erector spinae muscles, interspi-
Medicine nous ligaments, supraspinous ligaments,
insertions of the multifidi, lateral raphe of
Low back pain is one of the most common prob- abdominal wall muscles and lumbar interfascial
lems in clinical pain practice. The exact preva- triangle (LIFT) [37], the origins or insertions of
lence of low back pain is variable among different the gluteus muscles. The quadratus lumborum
studies; however, it is a recurrent problem (QL) muscles, lumbar facet joints, iliolumbar
throughout most people’s lives and causes sig- ligaments (ILLs), SIJs, and posterior sacroiliac
nificant health care-related burden [36]. ligaments are also possible pain generators or
Traditionally, on an interventional and anatomi- targets for regenerative injection.
cal basis, the common pathologies are nerve Choosing the correct targets of injection usu-
roots, facet joints, intervertebral discs, and sacro- ally depends on tenderness to palpation, dynamic
iliac joints (SIJs). As possible pain generators, tests according to the biomechanics, and dynamic
muscles, ligaments, and tendons are usually over- ultrasound scanning [10]. In this section, the
looked in low back pain. When a definite pain anatomy and sonoanatomy of the lumbosacral
generator could not be identified, the patient is spine will be discussed as a fundamental back-
often categorized into myofascial pain syndrome ground for ultrasound-guided interventional pro-
or idiopathic low back pain. The more common cedures. The paraspinal muscles, ligaments, and
scenarios are when a single patient has more than the TLF will also be included. Scanning and
one pain generator, different pathologies may injection techniques will be described for differ-
share overlapping clinical features. In this kind of ent structures. Biomechanics of respective struc-
patients, an interplay between different structural tures are beyond the scope of this chapter.
deficits may further exaggerate the severity of
pain and dysfunction, making a higher failure
rate of conservative therapies and lower probabil- Anatomy and Sonoanatomy
ity of precise plan of interventional pain manage- of the Lumbosacral Spine
ment. To conquer this tough situation, the low
back pain patient could also be managed in a For ultrasound scanning or guidance of interven-
more comprehensive way by regenerative injec- tion of the lumbosacral spine, a low-frequency
tion with the concept of biotensegrity. curved array transducer is usually recommended
The key concepts of successful regenerative due to the depth of the adult lumbosacral neur-
injection are knowledge of biotensegrity and axial structures. In scanning the lumbosacral
fascial anatomy. In the model of biotensegrity, spine, there are seven commonest sonographic
the bones float in a tension network, which con- views for interventional procedures or neuraxial
sists of muscle, tendon, ligament, and fascial anesthesia [38]. In the seven views, four are
system. The bones are moved passively in the obtained in the sagittal plane and three are in the
network when the dynamics of the tension sys- transverse plane (Table 11.1). While performing
tem change. When there is instability or deficit regenerative injection, which commonly targets
in the tension network, pain or dysfunction may the fascial systems and entheses, we can move
present. Regenerative injection focuses on the ultrasound transducer more laterally to the
“rebuilding” the overall stability of the network, junction of the QL muscle and the lateral raphe of
which means the focuses of injection include the abdominal wall muscles. The lateral exten-
236 D. T.-Y. Tang and C.-P. Lin

sion of scanning could be achieved easily in the line, the hyperechoic line formed by the spinous
transverse plane. process could be visualized (Fig. 11.17). The tip
In the series of sagittal scanning, one can of the spinous process is the shallowest part of
begin at the spinous process on the midline, then the lumbosacral bony structures. Sometimes the
move the transducer laterally to see the lamina ultrasound transducer may “slip off” from the
and interlaminar spaces, facet joints and articular spinous process and falls onto the laminar view,
pillar, and TPs. A lateral-to-medial scanning pro- especially when the patient is in a thin habitus.
tocol, which begins at the TPs and ends on the When the supraspinous ligaments or the interspi-
midline, was used by some clinicians. Our pre- nous ligaments are the target of treatment, one
ferred protocol is the medial-to-lateral one. When can move the transducer back and forth to make
targeted structures are localized, scanning back sure the location of the spinous process, avoiding
and forth to verify the correct position could fur- mistaking the spinous process for the lamina or
ther optimize the precision of injection. vice versa. Moving the transducer laterally with a
In the medial-to-lateral approach, the first step certain degree of medial tilting, the lamina and
is identifying the midline by palpating the spi- interlaminar space could be visualized. In this
nous process. Placing the transducer on the mid- view, the bony cortex of the lamina looks like
horseheads (Fig. 11.18), facing to the caudad of
Table 11.1 Common sonographic views of the lumbar the spine. Ultrasound-guided neuraxial anes-
spine thetic procedures are usually performed in this
Sagittal plane view. When performing an interventional proce-
Spinous process view dure, level counting is of paramount importance
Interlaminar view for precise treatment. Counting level could be
Facet joint view reliably done by using the interlaminar view.
Transverse process view
More laterally in the sagittal plane, the lumbar
Transverse plane
Transverse process view facet joints and articular pillar could be visual-
Interlaminar view ized. The bony cortex of the articular pillar is in a
Transverse oblique foraminal view wavy appearance, or so-called “camel hump”

a b

Fig. 11.17 The spinous process view in the sagittal plane of the lumbar spine (a) with MR correlation (b). SP spinous
process, SsL supraspinous ligament
11 Ultrasound-Guided Regenerative Injections for the Spine 237

a b

Fig. 11.18 The interlaminar view in the sagittal plane of the lumbar spine (a) with MR correlation (b). Note the
“horsehead” appearance of the lamina. L lamina, yellow shadow posterior dura, arrows anterior complex

a b

Fig. 11.19 The facet joint view in the sagittal plane of the lumbar spine (a) with MR correlation (b). Note the “camel
hump” appearance of the articular pillar. AP articular pillar, yellow shadow joint cleft of the lumbar facets

sign (Fig. 11.19). When the lumbar facet joint is could provide some pain relief in some idiopathic
the target of treatment and the level is ascer- back pain, or when a diagnosis is not clear and
tained, one can rotate the transducer 90 degrees the red flags have been ruled out.
to the transverse view; the lumbar facet joint The series of transverse views could be
could be visualized as a small cleft between the scanned when the TP of a certain level is identi-
inferior AP of the level above and the superior AP fied. Rotating the transducer 90 degrees into the
of the level below. The injection could be done in transverse orientation, the transverse process
a lateral-­to-medial, in-plane approach. Lateral to view (Fig. 11.21) could be obtained. In this view,
the articular pillar, we can visualize the TP in the part of the superior AP and the TP could be visu-
sagittal plane. The bony cortex of the TP appears alized. The medial branch of the lumbar dorsal
as separated round structures, or so-called “tri- rami is located at the junction of the superior AP
dent” sign (Fig. 11.20). Again, counting level is and TP. Ultrasound-guided lumbar medial branch
of paramount importance in spinal interventional block is usually performed in this view, with an
procedures; the view of the TP could also be used in-plane, lateral-to-medial approach. Moving the
to identify the correct level of treatment. In this transducer a little bit cranially, the transverse
view, the muscles above the TP are the erector view of the lumbar facet joint could be visualized
spinae muscles, and the below is the psoas mus- (Fig. 11.22). An in-plane, lateral-to-medial facet
cle. ESPB could be performed in this view. It joint injection could be executed in this view.
238 D. T.-Y. Tang and C.-P. Lin

a b

Fig. 11.20 The transverse process view in the sagittal plane of the lumbar spine (a) with MR correlation (b). Note the
“trident” appearance of the transverse processes. TP and arrows transverse process

a b

Fig. 11.21 The transverse process view in the transverse plane of the lumbar spine (a) with MR correlation (b). ESM
erector spinae muscle, QL quadratus lumborum muscle, PsM psoas major muscle, TP transverse process

a b

Fig. 11.22 The facet joint view in the transverse plane of the lumbar spine (a) with MR correlation (b). Arrows lumbar
facet joint cleft
11 Ultrasound-Guided Regenerative Injections for the Spine 239

Moving the transducer in cephalad or caudal transducer in a caudal-to-cephalad direction or

direction from the transverse process view, the vice versa, the hyperechoic bony structures could
transverse interlaminar view could be obtained be visualized like a swimmer in the butterfly
(Fig. 11.23). In this view, the contents in the spi- style, with the period of hands and shoulders up
nal canal including epidural space, dura, spinal corresponding to the TP and facet joint, and the
cord, and even vertebral body could be visual- period diving into the water corresponding to the
ized. In the transverse plane, when moving the transverse interlaminar view. Moving the trans-
ducer laterally in the transverse plane with medial
tilting, one can obtain the transverse oblique
a foraminal view (Fig. 11.24), which is usually uti-
lized in the peri-radicular or transforaminal injec-
tion for lumbar radicular pain. More laterally
from the transverse oblique foraminal view at the
L3–4 level, the transverse quadratus lumborum
view (Fig. 11.25) could be obtained. In this view,
the QL muscle is in spindle shape and relatively
hypoechoic when compared to the erector spinae
muscles and the psoas muscle. Several important
b pivots in the TLF system, such as the lateral raphe
and LIFT, could be visualized in this view and
intervened with ultrasound guidance. Placing the
QL muscle in the center of the ultrasound scan,
rotating the transducer to the long axis of the QL
muscle, we can see the enthesis of the QL onto
the iliac crest (Fig. 11.26), which is also an
important target for regenerative injection. For
correctly counting the level in the interventional
procedure in the lumbar spine, always remember
utilizing both sagittal and transverse views, and
validate the precise location by each other.
Fig. 11.23 The interlaminar view in the transverse plane In addition to the lumbar spine, the SIJ also
of the lumbar spine (a) with MR correlation (b). PD pos-
terior dura, AP articular pillar, TP transverse process, TS plays a crucial role in chronic low back pain. The
thecal sac, AC anterior complex, VB vertebral body SIJ is a synovial joint between the sacrum and the

a b

Fig. 11.24 The transverse oblique foraminal view of the psoas major muscle, L lamina, VB vertebral body, IVC
lumbar spine (a) with MR correlation (b). ESM erector inferior vena cava, yellow shadow assumed location of the
spinae muscle, QL quadratus lumborum muscle, PsM neuroforamen
240 D. T.-Y. Tang and C.-P. Lin

c­ audal-to-­cranial technique from the caudal hia-

a
tus. The final target of an intra-articular injection
is the cleft between the hyperechoic bony struc-
tures, which are the ilium laterally and the sacrum
medially (Fig. 11.27). In some patients, the pos-
terior joint line lies almost in the sagittal plane; as
such, an out-of-plane approach of injection
should be considered. In the practice of regenera-
tive injection, the dorsal interosseous ligament
[39] in the upper pole of the posterior surface of
b
the SIJ is more commonly targeted (Fig. 11.28).
Some pitfalls should always be kept in mind
when injecting the SIJ: one is the inferior pole of
the joint often lies on the same level with the S2
posterior foramen; always move the transducer
cranially or caudally to verify the continuation of
joint line instead of S2 posterior foramen.
Another issue is the volume of the SIJ is quite
small. Extravasation of local anesthetics from the
joint cavity would probably cause sciatic nerve
blockade and motor weakness of the lower limbs;
extravasation of high concentration dextrose
Fig. 11.25 The transverse quadratus lumborum view of
would induce nerve irritation on the sacral plexus.
the lumbar spine (a) with MR correlation (b). ESM erector
spinae muscle, QL quadratus lumborum muscle, PsM
psoas major muscle

Clinical Pearls of Specific Structures

 umbar Facet Joint

L
The lumbar spine and lower extremities support
the weight of the human torso; therefore, the
lumbosacral spine is susceptible to degenerative
changes or traumatic injuries. The weight-­bearing
mechanism consists of the anterior column (ver-
tebral bodies and intervertebral discs) and the
posterior pillars (facet joints). The facet joints are
diarthrodial and synovial joints and are the prin-
cipal supporting structure of the lumbar spine.
The capsular ligament encloses the facet joints
and supports mechanical stability of the joints;
Fig. 11.26 The long-axis view of the quadratus lumbo- therefore, the instability of the capsular ligaments
rum muscle with its insertion on the iliac crest. QL qua- is likely to cause low back pain [40]. Generally,
dratus lumborum muscle the anterior one-third of the joints are oriented
coronally, and the posterior two-thirds of the
ilium and lies in a posteromedial to anterolat- joints are oriented in sagittal direction [40]. The
eral direction bilaterally. When scanning the lower lumbar facet joints tend to orient in the
SIJ, there are two recommended methods, one coronal plane when compared to the upper ones;
is the cranial-to-caudal technique from the pos- consequently, the lower ones are more suscepti-
terior superior iliac spine and another is the ble to degenerative changes.
11 Ultrasound-Guided Regenerative Injections for the Spine 241

a b

Fig. 11.27 The sonographic appearance of inferior pole plane of the posterior sacral foramen, either S2 or S3.
of the sacroiliac (SI) joint (a) with MR correlation (b). Avoid mistaking the posterior sacral foramen for the SI
Note the SI joint cleft could be in the same transverse joint

a b

Fig. 11.28 The sonographic appearance of inferior pole of the sacroiliac joint (a) with MR correlation (b). DIOL dor-
sal interosseous ligament, PSIS posterior superior iliac spine, SIJ assumed location of the upper pole of the SI joint

The lumbar facet joints are innervated by the omy of the nociceptive innervation of the lumbar
medial branches of the dorsal rami from the spi- facet joints is crucial in performing diagnostic
nal nerves at the corresponding level and the block. Incorrect needle tip placement or exces-
above level (Fig. 11.29). After departed from the sive volume of local anesthetics would lead to
spinal nerves, the dorsal rami divide into lateral, high false-­positive rates.
intermediate, and medial branches. For L1 to L4 Clinically, lumbar facet joint pain is one of the
medial branches, they run between the osseous differential diagnoses in axial low back pain,
grooves between the TP and the superior AP and with the prevalence ranging from 15% to 45% in
then under the mamilloaccessory ligament. The the low back pain population [42] and higher
medial branches innervate the multifidi, rates in the aged groups. It is usually unreliable to
­interspinous ligaments, and the bony structures make a clinical diagnosis of lumbar facetogenic
along their routes. The trajectory of the L5 dorsal pain with only history and physical exam.
rami is different from other lumbar dorsal rami Paraspinal tenderness is a common physical sign
[41]. It goes along the osseous groove between but is not specific. Imaging studies are usually
the S1 superior AP and the sacral ala. The anat- not specific but could be helpful in excluding red
242 D. T.-Y. Tang and C.-P. Lin

pain is relatively in minority [47, 48] and contro-

versial [49]; however, positive result was obtained
from a randomized controlled trial [50]. Platelet-­
rich plasma, which is a concentrate of whole
L1 DR
blood, containing high concentration of platelet
and growth factor, demonstrates positive result
L1 VR for facetogenic low back pain, superior to
is ­intra-­articular corticosteroid injection [51]. The
a question is, is it correct to treat only the facet
L2 VR
joint in a patient with lumbar facetogenic low
back pain? Or a more comprehensive and indi-
vidualized approach is needed? Needless to say, a
mb comprehensive approach meets the principal
a
Ib concept “biotensegrity” much more than a tradi-
tional, single-structural approach. When a com-
prehensive approach is utilized, important
ib
structures associated with the TLF system should
be considered in the regenerative injection proto-
ibp col. Not all the related structures should be
ib
injected in each patient; the choice of targets
depends on clinical assessment. As the treatment
a
L4 VR algorithm could be optimized and standardized in
the future, the benefits of regenerative injection
TP
in facetogenic low back pain would probably be
more significant.
ZJ
 horacolumbar Fascia (TLF)
T
L5 DR and Paraspinal Muscles [52]
The TLF is a girdling system that is crucial in
lumbosacral stability and movement of the lower
torso. It is a multilayer, multi-compartment sys-
tem that separates paraspinal muscles from the
Fig. 11.29 Innervation of the lumbar facet joints. The
muscles of posterior abdominal wall, QL, and
lumbar facet joints receive dual innervation by the medial
branch of the dorsal rami from the above and below spinal psoas major and serves as a bridging system
nerves. (From Manchikanti et al. [75], with permission between the trunk and extremities. For this fas-
from Springer) cial system, both two-layer and three-layer mod-
els have been described. Although they are in
flags or other occult pathology. For diagnosis of different nomenclatures, the concepts of both
facetogenic low back pain, either facet joint models share much similarities. The middle layer
injection or medial branch block has diagnostic in the three-layer model corresponds to the ante-
value. Intra-articular injection of corticosteroid rior layer in the two-layer model, while the ante-
with local anesthetics provides limited therapeu- rior layer in the three-layer model is the fascia
tic benefit [43], and currently, the mainstay of transversalis in the two-layer model. The three-­
interventional management of lumbar facet joint layer model is the most commonly used. In this
pain remains radiofrequency denervation [44] or section, we will discuss the anatomy and its clini-
pulsed radiofrequency neuromodulation of lum- cal relevance with the three-layer model.
bar medial branches [45, 46]. The clinical evi- In the three-layer system, the posterior layer is
dence of prolotherapy for lumbar facetogenic further divided into the superficial lamina and
11 Ultrasound-Guided Regenerative Injections for the Spine 243

deep lamina. The superficial lamina is the apo- means the biomechanics of different parts of the
neuroses of the latissimus dorsi and serratus pos- TLF is interconnected and should be considered
terior inferior, while the deep lamina encapsulates as a whole when doing regenerative injection.
the paraspinal muscles and enhances the stability. Based on the above anatomical descriptions
The middle layer lies between the paraspinal and the concept of biotensegrity, the stability of
muscles and the QL and is responsible for the several attachments or connecting structures
tensional connection between the abdominal wall between muscles, ligaments, bones, and fascia
muscles and paraspinal muscles; the anterior should be considered as targets of regenerative
layer runs anterior to the QL and posterior to the injection. That is why in regenerative injection,
psoas major. In the center of the whole fascial structures like the supraspinous ligament, inter-
system, the paraspinal muscles, which are the spinous ligament, lateral raphe, LIFT, ILL, TP
iliocostalis, longissimus, and multifidus, are con- (insertion of the QL), and spinous process (inser-
tained in the paraspinal retinacular sheath and tion of the multifidus muscle) are common tar-
reinforced by attachments to the spinous pro- gets of treatment.
cesses and the TPs and stabilize the lumbosacral
spine. In the lumbosacral junction, the anterior  he Iliolumbar Ligament (ILL)
T
fascial sheath of the paraspinal muscle fuses with The ILL is one of the three most important verte-
the ILLs and the posterior sacral joint capsule, bropelvic ligaments; the others are the sacrotu-
while the posterior one attaches to the posterior berous and sacrospinous ligaments. It originates
superior iliac spine and extends to and fuses with from the TP of the L5 vertebrae and inserts on the
the gluteus maximus and sacrotuberous ligament. superomedial part of the iliac crest (Fig. 11.30).
The lower border of the middle layer fuses with The most common description of the subdivision
the ILL and inserts onto the iliac crest. The lateral of this ligament is a two-band model, in which
extreme of the TLF system is joined by the apo- there are anterior and posterior bands [53]. The
neurosis of the transverse abdominis, forming the anterior band is broad and flat, with 30–40 mm in
anatomical linchpin called the “lateral raphe,” length, 5–10 mm in width, and 2–3 mm in thick-
and the triangular structure called the lumbar ness [54]. It runs in the coronal plane and blends
interfacial triangle. The fascia encapsulating the with the periosteum of the iliac crest. The poste-
paraspinal muscles also joins the aponeurosis of rior band is almost in round shape with 10–12 mm
the transverse abdominis around this area, which in length and 5–7 mm in diameter [54]. It runs

a b

Fig. 11.30 The iliolumbar ligament in sonographic scan (a) with MR correlation (b). TP transverse process, ILL ilio-
lumbar ligament, IC iliac crest, arrowheads in the MRI iliolumbar ligament
244 D. T.-Y. Tang and C.-P. Lin

obliquely and inserts onto the posterior margin of webpage are presented as hyperlinks to the ref-
the crest. The QL muscle is sandwiched between erences while it is not. I would like to make sure
the two bands. The anterior border is the psoas it is just numbers. The dorsal rami of the lumbar
muscle and the posterior border is the erector spi- spinal nerves could be entrapped in the edema-
nae muscle. Pool-Goudzwaard et al. [55] reported tous or scarred ILL and further exaggerate the
more detailed anatomy of the ILL, in which there symptoms [54]. In a typical case, the patient
are at least seven parts that could be found con- complains of unilateral, well-localized pain on
sistently in the human cadavers. the posterior iliac crest. The pain could be pro-
The presence of the ILL may be related to the voked by prolonged standing or sitting and lat-
upright position of the human beings [56, 57]. eral bending to the unaffected side. Referred
Biomechanically, the ILL is responsible for the pain could be noticed in various areas including
stability of the lumbosacral junction, in coordina- the hip, groin, and perineum, with a non-­
tion with lumbar discs, ligaments, and facet joints dermatomal nature. No neurologic deficit should
[58]. The anterior band restrains lateral bending be noticed in a typical iliolumbar pain patient.
[56, 58] and may prevent tilting of the vertebra in The iliolumbar pain syndrome could be
the coronal plane; the posterior band controls for- explained by the enthesopathy of the ILL, espe-
ward flexion of L5 on S1 and may prevent ante- cially of the insertion on the iliac crest [61].
rior slipping of the L5 vertebra [53, 56]. Flexion When treating patients with symptoms from the
and extension are restricted by bilateral ligaments ILL by regenerative injection, treating the
instead of unilateral control [58]; therefore, when entheses, especially the side of the iliac crest,
treating the ILL, bilateral injection should be should not be missed out.
considered. The ILL is also important in main-
taining torsional stability of the lumbosacral  he Sacroiliac Joints (SIJs)
T
junction, protecting the L5-S1 disc especially in The SIJ is a diarthrodial joint with interosseous
the presence of unstable lumbar facet column portion [62], connecting the sacrum and the pel-
[59]. The presence of the strong ILL may explain vis. It is the pivot that transmits the forces from
why the L4–5 spondylolisthesis is more frequent the spine to the lower extremities or vice versa.
than the L5-S1 spondylolisthesis. When the disc The superior third of the SIJ is lined by hyaline
becomes more degenerative, the biomechanical cartilage and strongly attached to the surrounding
stability provided by these ligaments becomes ligaments, and the inferior third of the joint has
more important [57]. Attachment of the ligament some synovial characteristics [63]. In the low
to the anterior layer of the TLF was described back pain population, the prevalence of SIJ pain
[52]. When treating musculoskeletal pain or is around 15–30% [64]. It is more common in
spine pain on a regenerative basis, it is crucial to patients after lumbar spinal fusion [65], preg-
apply the concept of biotensegrity meticulously nancy, or trauma [66]. The clinical presentation,
and never neglect the continuity and connection like other types of low back pain, is not specific
of the fascial system in different parts of the and not diagnostic. Imaging studies are usually
human body. not diagnostic and, however, could assist in
The ILL is one of the primary causes of revealing red flags like malignancy, inflamma-
chronic low back pain because: [60] (1) it is the tory disorders, or occult trauma. The cluster of
weakest part of the multifidus triangle; (2) Laslett [67], in which more than three positive
increased susceptibility due to its angulated tests in the six clustered tests indicating high
insertion; (3) it is the primary inhibitor of exces- probability of SIJ pain.
sive sacral flexion; (4) it has rich nociceptive To obtain a definite diagnosis of SIJ pain,
and proprioceptive innervation; and (5) the comparative blocks using either different local
loading to this ligament is increasingLow back anesthetics or local anesthetics and saline are
painIliolumbar ligament when the lumbosacral mandatory. However, on the basis of regenerative
disc becomes degenerative. The numbers on the medicine, any musculoskeletal pain or spinal
11 Ultrasound-Guided Regenerative Injections for the Spine 245

pain should be considered in a whole picture anesthetics, neuromodulation, or radiofrequency

instead of a single structure origin. Therefore, in denervation, and these interventions usually tar-
the framework of “regeneration,” performing get single specific painful structure. Structures
comparative diagnostic blocks seems not to like muscle entheses, ligaments, or fascial sys-
change the treatment plan a lot and is not a rou- tems are not recognized as valid pain generators;
tine practice in regenerative-based pain practice. however, they play a certain role in the anatomy
Another important issue is the target structure and biomechanics of spine pain and could be tar-
of injection. Traditionally, when treating a ­painful gets of treatment in regenerative injection. In
SIJ, an intra-articular injection is usually the tar- recent decades, thanks to the rapidly evolving
get of treatment, and positive clinical result of ultrasound-guided interventional technique,
intra-articular prolotherapy or PRP has been accurate injection on delicate yet pivotal struc-
obtained in a randomized controlled trial [68, tures like attachment of fascia or muscle enthesis
69]. In regenerative pain practice, however, the is possible. Although the evidence is not yet fully
supporting ligaments [70] including the anterior established in the literature, with the knowledge
sacroiliac ligament, the posterior sacroiliac liga- of anatomy and biomechanics and precision of
ment, the long posterior sacroiliac ligament, the injection technique with ultrasound guidance,
ILL, the sacrospinous ligament, and the sacrotu- regenerative injection could potentially be a pow-
berous ligament should be taken into consider- erful treatment modality for chronic spinal pain
ation. Histologic pathology in the ligaments of in the future.
the SIJs has been correlated to SIJ pain [71]. The
anterior side is hard to inject due to the vicinity of
pelvic viscera; however, the posterior structures References
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 Spinal Regenerative Medicine
12
Jeffrey D. Gross

Introduction this chapter does not take up the topic of spinal

fusion, which is a surgical augmentative process
Following just a close step behind the rapidly enhanced by regenerative products for the better
advancing successes in applying regenerative part of two decades.
medical treatments to the extremity joints and The organization of this chapter is designed to
related structures, a blossoming field with break down the differing anato-physiological
encouraging results in applying similar therapies regenerative medicine targets of the spine, sub-­
to spinal structures serves as the impetus for the organized by a review of the specific biologics
present manuscript. Slow to be adopted by main- which have been applied to these spinal targets.
stream medical policy, regenerative approaches When mixed biologics are described having been
to the spine represent a disruptive and paradigm delivered to a spinal element, they are discussed
shifting biotechnology with the potential to as grouped with their more potently perceived
meaningfully reduce pain and dysfunction of spi- element (PRP and growth factors first, extracel-
nal origin, with less dependence on surgical lular matrix and other amniotic supportive con-
reconstruction. This chapter outlines the current tents, next followed by cellular therapies, and
cutting edge in biological spinal regenerative then exosomal biologics). There is not yet unifor-
medicine (exclusive of prolotherapy), surely but mity whereby each regenerative method has been
excitingly to be at least partially outdated by the comparatively applied to all structures of the
time of publication. The presentation here is a spine, let alone adequate blinded, randomized tri-
general overview of the practical and clinical als. This comment is not meant to be critical, but
considerations involving the spine and is not instead is an observation as to the analytic cau-
intended to review the scientific foundation of tions and limitations to the present availability of
regenerative biology and medicine. This chapter scientifically grounded studies [1].
serves more specifically to review regenerative As always, clinicians are recommended to use
targets of painful pathologies of the spine, short best judgment in acting in a patient’s best interest
of neuro-regeneration, and therefore does not with a clear and thorough description of all
include review of a large body of study on options and the pros and cons of each as part of a
addressing spinal cord pathologies. Additionally, fully informed consent process.

J. D. Gross (*)
Stem Cell Whisperer, SPINE & ReCELLebrate,
Henderson, NV, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2022 249

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_12
250 J. D. Gross

 egenerative Medicine by Spinal

R Perhaps the most frequent and robust founda-
Target tion in support of regenerative approaches to the
spine involves treatment with platelet-rich plasma
The following section serves to review regenera- (PRP). Beginning with facet intra-articular injec-
tive approaches to the spine by location(s). These tions, Wu et al. [12] reported on 15 of 19 patients
targets include paraspinal myofascial structures, having received intra-articular facet PRP injec-
facetogenic structures, epidural spaces, intradis- tions. It was concluded that such a procedure is
cal targets, and intervertebral/subchondral tar- safe and effective in a 3-month time frame. The
gets. Each area is discussed with both a rationale study was limited for lack of a control group, lim-
for the approach and a review of related study ited outcome measures (5-point benefit scale),
results. Most studies are noted to be anecdotal and relatively short follow-up. The same group in
collections and serve as a starting place, as did 2017 compared intra-articular facet joint PRP to
most great advances in any field of medicine or traditional corticosteroid/local anesthetic injec-
other discipline. Given that this chapter is focused tion, finding statistically significant improvement
on clinical aspects applying regenerative thera- in the PRP group as far as 6 months after injec-
pies to the spine, the topic of the biological tion, whereas the non-regenerative group results
advantage of such approaches (including anti-­ waned over time [13]. Although not suitable for
inflammatory, analgesic, rehabilitative, and referencing, there is a large additional body of
anato-physiological restorative augmentation) is anecdotal support for using PRP for facetogenic
deferred. pain. However, a meta-analysis concluded that
facet joint PRP may be effective in managing dis-
cogenic, radicular, and facet joint pain [14]. It is
Regenerative Facet and/or Paraspinal not trivial that delivering PRP to facet joints has
Injections been shown to assist with other pain generators
of the spine. The American Society of
It is well understood that a common source of Interventional Pain Physicians Guidelines indi-
spinal pain and dysfunction, involving all seg- cate PRP treatment for facet joints is based upon
ments of the spine, can be facetogenic: arising of class IV evidence [15]. Each year, the scientific
the facet joint(s) and their surrounding structures evidence improves to support PRP and other
[2, 3]. Traditional treatment beyond physical regenerative approaches to the spine [16].
rehabilitation and anti-inflammatory (or stron- Growth factors (a component of PRP) have
ger) medications include injections into the facet been studied as injected into facet joints, but only
joint, into the facet joint capsule, and/or targeting when combined with other spinal areas (see
by injection and/or denervation the local innerva- below). Aufiero et al. reported on the benefits in a
tion by way of the medial branch nerves [3]. series of three PRP injections to the facet joints
Although said treatments are reasonably effec- and surrounding ligaments via ultrasound guid-
tive, often measured for up to months in the case ance, finding meaningful pain reduction mea-
of repeat rhizotomies [4–10], regenerative sured at 6 months and up to 12 months in some of
approaches seek to enhance and restore anatomi- the cases [17]. Cameron et al. also injected PRP
cal and/or physiological defects causing faceto- into the lateral masses, facet joints, lateral gut-
genic pain and dysfunction without the need for ters, spinal ligaments, and related posterior spinal
degenerative or neuro-ablative treatments, which structures for herniated disc-related pain, finding
themselves may beget cumulative and acceler- significant pain reduction for a mean of 5 years
ated degeneration. Not considered in this chapter [18]. This study however suffers from lack of
are the many studies referencing use of biologics confirmation of a pain generator prior to
more generically for any joint(s); however, it is treatment.
reasonable to extrapolate those findings to facet Few have reported on the use of stem cell
joints [11]. preparations in any form delivered to facet joint
12 Spinal Regenerative Medicine 251

structures. One report contained a treatment arm a “self-sustained vicious cycle which start with
of bone marrow concentrate (BMC) to the facet an injury to either the disc, muscle,” or the
joints, ligaments, and sacroiliac joints [19]. facet joint…can lead to further injury to the
Although the results were not positive, this other two components”) as reported by Hussein
study’s main limitations in the present context and Hussein [23] demonstrated continued pain
include a problematic assumption that all reduction at 24 months in 74/104 patients,
discogram-­negative patients had facetogenic pain although began soon after injection, in theoreti-
and that more than just the facet joints were cal relation to serotonin release. Additionally,
injected. There are no identifiable scientific stud- MSCs (mesenchymal stem cells) have been
ies looking at adipose, or adipose-derived stem used to address spinal (and limb) muscular
cells for use in the posterior spinal elements, atrophy in Duchenne’s muscular dystrophy
inclusive of facet joints, although such proce- successfully [24]. At the time of this writing,
dures are clinically available. there is an open study looking in part at the use
Bennett reported on the use of cryopreserved of paraspinally delivered BMC for spinal cord
amniotic membrane and umbilical cord (AMUC) injury [25, 26]. Regenerative approaches to
particulate for facet joint syndrome [20]. He paraspinal muscles are also being looked at to
found statistically significant pain reduction as address adolescent idiopathic scoliosis [27] and
far as 6 months posttreatment. Other more amyotrophic lateral sclerosis [28].
generic studies dealing with amniotic products Direct injection of growth factors (particularly
for joint pain may be practically extrapolated to PRGF-Endoret) to facet articulations has also
facet joints [20]. been described [29]. Statistically significant pain
Extracellular vesicles/exosomes have also reduction was found, lasting to 6 months.
been used to address facetogenic spinal pain. In Drawbacks of this study include the 6-month
2019, Li et al. demonstrated the utility of bone (short) end point.
marrow-derived stem cell exosomes to address Clinical considerations for applying regenera-
lumbar pain behavior in an animal facetogenic tive strategies to facet joint structures include first
injury model, whereby the subchondral facet confirming the presence of facetogenic pain clin-
joint bone was injected [20]. The facet bone mar- ically and/or by local block. Such can be more
row is known to house stem cells and has relation efficiently accomplished with imaging guidance
to the health of local ligaments [21]. As exosomes for more specific localization of the spinal levels.
act to vitalize the metabolism of cells within Fluoroscopy and ultrasound are the more effi-
reach, facet joint bone marrow health can be most cient methods, with ultrasound making in-office
directly influenced by subchondral injection, procedures more accessible. Biological theory
although also reachable by capsular, intra-­ supports subchondral injections as being the
articular, and paraspinal approaches, perhaps due most direct and effective, but it is not fully known
to shared blood flow. Further discussion and ref- if such is practically superior to intra-articular,
erence to the therapeutic potential of exosomes peri-facetal, or even paraspinal injections. The
deal with joints in general [22]. choice of biologics is left to the good judgment of
Regenerative paraspinal injections have an individual clinician, with considerable non-
also been utilized to address spinal pain. These clinical factors of cost, accessibility, and govern-
are discussed in the facetogenic pain sec- mental regulation(s). Another factor for
tion, being so closely anatomically related to consideration is the number of injections to offer.
the facet joints, and due to a shared vascular- It appears most reasonable to start with one series
ity with same. Additionally, paraspinal injec- and observe the result before offering any accu-
tions often also involve the facet joint capsules mulative booster treatments.
and local peri-­facetal ligamentous structures. As I hope other clinicians have experienced
Regenerative paraspinal injections for spinal anecdotally, I continue to be amazed by the
pain with spinal muscular atrophy (as part of results of the rather simple application of regen-
252 J. D. Gross

erative biologics to facet/paraspinal structures. It with additional and progressive improvement

is my opinion, and I look forward to a more beginning at the 6-month mark [32].
robust, large trial of study, in which concentrated A double-blind, randomized trial in compar-
perinatal sourced exosome-containing prepara- ing fluoroscopically delivered caudal leukocyte-­
tions delivered to the facet capsule and its sur- rich PRP to corticosteroids was reported by
rounding myoligamentous structures provide the Ruiz-Lopez and Tsai [33]. In this study, PRP had
multimodal anti-inflammatory and regenerative a longer pain-relieving effect and longer improve-
cellular activity transformations to support ana- ment in quality of life. Bise et al. [34] reported on
tomical and physiological improvements to facet CT-guided interlaminar PRP vs. steroid injec-
joints and local muscles for which pain and tions for radicular pain, but the end point measure
related dysfunction are mitigated. was oddly limited to 6 weeks, which is not logi-
It is almost too perfectly simplistic that the cal for a regenerative medicine study. Nonetheless,
biological rehabilitation of spinal muscles (para- PRP was found to produce similar results when
spinal, multifidus) has a benefit in addressing compared to steroidal injections in this refer-
­spinal pain of various sources. Although tradi- enced study.
tionally addressed through physical rehabilita- PRP and epidural platelet lysate were deliv-
tion, biological augmentation can be delivered ered to two patients by an interlaminar approach,
with ultrasound or without guidance in a clini- one with an acute large lumbar extruded disc.
cian’s office without much ado. This has been my The procedure was repeated 3 months later.
personal experience as well. These anecdotal results described significant
resorption of disc herniation and resolution of
radicular symptoms [35] (Fig. 12.1) is repro-
Regenerative Epidural Injections duced from this reference to demonstrate signifi-
cant but not complete resorption of the extruded
The following section considers epidural place- L4–5 disc (although the particular imaging slices
ment of regenerative biological preparations, are not identical when comparing the before
including by various delivered routes (interlami- treatment vs. after treatment views). The reactive
nar, transforaminal). Such endeavors embody the immune activity in the epidural space and the
helpful alternative strategies versus corticoste- impact of regenerative strategies appear to imbue
roid injections and/or surgical approaches to more efficacy on sequestered disc herniations
related spinal pain and dysfunction. than on protrusions. An enhanced understanding
Epidural PRP has been utilized in multiple in this particular arena will be clinically useful
studies for different types of pain of spinal origin [36, 37]. Additionally, the pain reduction benefits
(including discal pathologies) and/or neurologi- of interlaminar epidural injections have been
cal/radicular involvement. Brian Lemper, DO confirmed by Correa et al. [38] in supporting
reported on the use of epidural PRP in a pregnant regenerative over “palliative” medicine for the
woman to avoid the use of corticosteroids [30]. treatment of lower back pain. More recently, Xu
He noted lumbar pain was resolved by 3 months. et al. [39] published on a comparison of lumbar
Bhatia et al. described the use of PRP via inter- transforaminal epidural PRP vs. steroid injection
laminar injection for pain associated with pro- for lumbar disc herniation by ultrasound guid-
lapsed intervertebral disc [31]. Improvements in ance, demonstrating equivalent benefit to pain
pain measures were seen at 3 months, although and function at a 1-year follow-up (Fig. 12.2).
this study was also limited by its short follow-up PRP has also been delivered via the caudal epi-
period. Radicular pain was addressed by transfo- dural approach to address complex chronic
raminal or interlaminar lumbar epidural injection degenerative spinal pain [40].
of platelet lysate in another study resulting in sig- Therefore, although further study is needed,
nificantly less radicular pain (and improved func- various epidural deliveries appear useful in
tion) through 24 months, although progressing addressing lower back pain and radicular pain,
12 Spinal Regenerative Medicine 253

a b

c d

Fig. 12.1 (a–d) Top row is prior to PRP. Bottom row was taken 3 months after the second of two interlaminar epidural
PRP injections

both with radicular pain taking longer to respond.

Although longer studies are desired, clinical ben-
efits appear to be less acute, but more sustained
when compared to corticosteroids, but not less
than equivalent to steroidal injections in some
studies. Epidural delivery of PRP is also helpful
to address lower back and radicular pain associ-
ated with discal herniation (and possibly acceler-
ate and encourage resorption of herniated
fragments). PRP has also been used to address
symptoms related to CSF leak-related symptoms
[41, 42] and to prevent postsurgical scar forma-
Fig. 12.2 Spinal ultrasound from Xu et al. [39] tion in the epidural space [43].
254 J. D. Gross

There are no identifiable studies of amniotic beyond, and a small number of patients had
components, extracellular matrix, or noncellular improvement in MRI findings after intradiscal
elements applied to the epidural space. Despite PRP injection [49]. The results of pain reduction
anecdotal unpublished experiences, there are no from intradiscal PRP were reproduced by Levi
present studies of epidural exosomal stem or cell et al. [50]. A randomized controlled study of
applications published for review. However, it is intradiscal PRP also confirmed significant pain
not unreasonable to consider these regenerative reduction at 8 weeks through 1 year [51].
biologics for use in the epidural space, as it Uncontrolled follow-up for 2 years demonstrated
appears that steroid injections are not superior, at sustained clinical benefit [51]. Furthermore, Lutz
least in the case of PRP-type preparations. [52] reported improved MRI findings (consistent
Clinical factors may allow the inclusion of those with better discal hydration) 1 year after intradis-
with discal herniations and/or radiculopathy, cal PRP (Fig. 12.3). The same group published a
independent from pain of spinal origin. In an 5–9-year follow-up, extending the promising
effort to be complete, it is worthy of mention that results for this approach [53].
exosomes have been used in a cellulose mem- Buck injected amniotic membrane and umbil-
brane to successfully prevent epidural fibrosus in ical particulate into discs of patients with positive
a rabbit model [44] and are a quickly blossoming discograms. He found progressive pain reduction
area for clinical research and trial. through the 6 months of the study in most of the
patients [1].
Studies demonstrating the clinical outcomes
Regenerative Intradiscal Injections from intradiscal delivery of stem cells are limited
[54]. After a failed trial by Haufe and Mork [55]
Perhaps the most robust area in reported applica- in 2006, the earliest related beneficial studies are
tion of regenerative treatments to the spine is for European: Meisel et al. [56, 57] and Hohaus et al.
discogenic pain and pathology. Not unlike large [58] reported intradiscal autologous culture-­
lower extremity joints, the spinal disc is exposed expanded disc cell transplantation as an adjunct
to daily, cumulative, and injurious stresses and is to (although 12 weeks after) lumbar discectomy
uniquely susceptible. This section remains agnos- surgery. The treatment group fared better with
tic to intradiscal regenerative procedures being pain reduction, increased discal hydration on
an adjunct of surgery, or separate, de novo percu- MRI, and with adjacent segment disc hydration
taneous treatment, with the clinical goals uni- on MRI at 2 years. These results were confirmed
formly being pain reduction and improved by Mochida et al. through a 3-year follow-up
function [45] and with additional benefits such as [59]. Other stem cell types, including juvenile
improved disc hydration and height (at the treated chondrocytes [60] and nasal chondrocytes, have
and even adjacent discs). also shown promise [61]. Additionally, MSC-­
Platelet-rich plasma has been reported for the encapsulated hydrogels have been shown to be
purpose of addressing intervertebral disc chondrogenic [62]. Noriega et al. [63] trialed
degeneration-­related pain on the heels of a large allogenic intradiscal MSCs, followed for 1 year,
number of in vitro and animal studies. Masuda, finding quick and significant reduction in pain
Akeda, and their colleagues have reported clini- and improvement in function in 40% of the treat-
cal improvement in pain sustained through ment group when compared to controls. Discal
6 months of observation after intradiscal injec- appearance on MRI improved in the treatment
tion (by fluoroscopic guidance) in patients with group while worsening in the control group. This
discographically confirmed discogenic lower clinical result echoed animal models, demon-
back pain. MRIs taken after treatment did not strating the same [64]. Others have confirmed
demonstrate significant change [45–48]. Navani similar results: intradiscal culture-expanded
et al. reported 50% pain reduction and increased MSCs were found to be safe when delivered by
function by 3 months, and for 6 months and fluoroscopy [65] and showed continued benefits
12 Spinal Regenerative Medicine 255

a b

Fig. 12.3 (a, b) From Lutz et al. [52] showing improved hydration after intradiscal injection of PRP. (The left panel is
prior to treatment. The right panel is posttreatment showing increased T2 signal, consistent with improved hydration)

as far out as 72 months [66, 67]. Disc “bulge” Perhaps the most notable clinical series of
size reduction was observed in the majority of intradiscal MSCs is reported by Pettine et al.,
patients who underwent post-procedural who have published their results at the 1-, 2-, 3-,
MRI. Wolff et al. published on the use of fluoro- and 5-year marks. The 5-year outcomes were
scopically guided intradiscal autologous BMC, superior to a 2-year post-fusion comparative with
finding improvement of at least 50% in pain in up the stem cell treatment group having persistent
to 38.9% of 33 patients (limited to those with pain reduction, improvement in function, and
positive discography but without full thickness improvement in MRI appearance [69]. Yoshikawa
annular tears) followed to 1 year, most notably et al. [70] reported on two patients receiving
for those with higher initial pain [68]. intradiscal autologous MSCs with clinical
Autologous implanted intradiscal MSCs dem- improvement in lower back and lower extremity
onstrated clinical improvement by 3 months, and symptoms at 2 years and improvement in vacuum
when measured at 1 year, as reported by Orozco phenomenon on x-ray and CT imaging.
et al. [45]. At the last metric, this group found As referenced above, El-Kadiry et al. recently
improved discal hydration on MRI, but not published their findings in utilizing BMAC tar-
improved discal height. Another group performed geted delivery to either intradiscal (with positive
a similar study with culture-expanded MSCs for discography) or to the facet joints and their sur-
radicular pain, finding beneficial results as far as rounding structures (if discography was negative)
6 years after treatment [66]. Notable for this [19]. The intradiscally treated population exhib-
study was reduction in the size of disc “bulge” in ited improved disc height and canal space size,
a portion of the patients who underwent post- and clinically reduced pain (and reduced opioid
treatment MRI. The same group also had good use), from 1 to 12 months posttreatment and at all
results with hypoxic cultured MSCs [67]. metrics in between.
256 J. D. Gross

All of these relevant studies utilized bone logical structures is advised to be guided by fluo-
marrow-­derived stem cells. There are not yet any roscopy or tomographic scanning, although there
clinical studies identifiable reporting on adipose-­ are experienced ultrasonographers who can
derived stem cells, or pluripotent cells for intra- localize the intervertebral discs [79]. Until a
discal therapy, except as a combined therapy (see practical alternative replacement is identified,
below). However, Pang et al. described the intra- provocative discography remains the best method
discal use of amniotic MSCs in two patients with to confirm discogenic spinal pain and can be per-
discographically confirmed discal pain. The formed simultaneously with an intradiscal injec-
results included pain reduction and improved sig- tion procedure. However, one can theorize that
nal on T2-weighted MRI, although the study was even if in the presence of negative discography,
limited to two patients [71]. There is not yet preventative (and sealant) reasoning exists to
enough information to conclude as to the best support further investigation and applications of
source of naturally occurring stem cells for intra- intradiscal regenerative treatment.
discal efficacy. There is some evidence that a cell
population might best include notochordal lin-
eage, being the source of the nucleus of an inter- Regenerative Subchondral
vertebral disc; however, the studies identified and Intravertebral Injections
described herein are all MSC based.
Combined intradiscal therapies have also been Not yet published, but worthy of discussion here,
described. Kumar et al. injected adipose-derived is the vertebral endplate as treatment target.
stem cells plus hyaluronic acid to the interverte- Based upon the work of Hernigou, and stemming
bral discs [72] with results of clinical improve- from his study in following patients with knee
ment in six of ten patients sustained to 1 year (the osteoarthritis for 15 years, one can find refer-
end point of the study) and disc rehydration sug- ences to anecdotal analogous treatments of verte-
gested in half of six patients. Combined use of brae [80, 81]. The logic behind this approach is
stromal vascular fraction (SVF) and PRP for flu- that the disc receives its nutrients and health from
oroscopically guided intradiscal application was the vertebral endplate, mostly by diffusion.
reported by Comella et al. [73]. Improvement in Healthier vertebral endplates and nearby sub-
pain was seen in over 6 months; however, the pre-­ chondral bone marrow subserve a healthy condi-
procedural pain generator was not confirmed by tion for the intervertebral disc, and theoretically
discography, and there was no imaging metric in with that, less pain, and improved viscoelastic
this study. function of the disc/endplate complex. This
Although not yet clinically described, there is appears to be a strong candidate for the future
much discussion of growth factors and scaffold- direction in treating the symptomatic degenera-
ing to support intradiscal stem cell-based treat- tion of discs.
ments [74–76]. The disc is generally thought to
be inhospitable to cells, which is also a founda-
tion for intravertebral injections (see next sec- Conclusions
tion) [72, 75–77]. However, some authors
theorize that combined intradiscal biological The explosion of scientific advancements in bio-
therapies to the spine will be best form of deliv- medicine is coming back full circle to a more
ery [74, 75]. Although not yet clinically con- logically bioactive and less pharmaceutical
firmed, in an animal disc injury model, intradiscal approach, addressing cellular metabolism
delivery of MSCs prevented multifidus muscle directly, instead of the indirect downstream extra-
degeneration [78]. cellular and organismal effects of inflammatory
Broadly, clinical results appear promising as changes. The clinical observations catalogued
described herein. Intradiscal delivery being herein demonstrate a broad demonstration of rel-
deeper and requiring navigation around neuro- ative safety and success without prejudice for a
12 Spinal Regenerative Medicine 257

biological or anatomical treatment approach. 13. Wu J, Zhou J, Liu C, Zhang J, Xiong W, Lv Y, Liu R,
Wang R, Du Z, Zhang G, Liu Q. A prospective study
Although further studies are needed [82, 83] to comparing platelet-rich plasma and local anesthetic
more specifically address confirmed anato-­ (LA)/ corticosteroid in intra-articular injection for
physiological problems of spinal origin and to the treatment of lumbar facet syndrome. Pain Pract.
compare the differing available biologics, there is 2017;17(7):914–24.
14. Sanapati J, Manchikanti L, Atluri S, Jordan S, Albers
adequate support for further refining and main- AL, Pappolla MA, Kaye AD, Candido KD, Pampati
streaming the described treatment as a beneficial V, Hirsch JA. Do regenerative medicine therapies
step prior to considering more invasive, including provide long-term relief in chronic low back pain: a
surgical endeavors for many patients. systematic review and metaanalysis. Pain Physician.
2018;21:515–40.
15. Navani A, Manchikanti L, Albers SL, Latchaw RE,
Sanapati J, Kaye AD, Atluri S, Jordan S, Gupta A,
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 Part IV
Dentistry
 Regenerative Medicine
in Dentistry
13
Samia Elazab

Introduction progenitor cells, and possibly fibroblasts [7].

Thus, it is necessary to effectively classify and
Stem cell assortment from bone marrow, blood, purify these cells to prevent unexpected clinical
fetal material, and umbilical cords presents results.
exceptional practical and conflicting ethical chal- Stem cells that fit for regenerative medicine/
lenges [1, 2]. However, the discovery of postnatal dentistry must be exposed to complete control of
stem cell populations in the tooth pulp by cell fate in the body to ensure the safety of the
Gronthos et al. [3] about two decades ago opened patient. In this regard, only adult MSCs, as that
up new horizons to dental stem cell research and obtained from oral tissues, currently have faithful
pushed the dental profession further into the clinical potential. Certainly, the regeneration of
exciting field of regenerative medicine. bone and periodontal tissues by MSCs has been
Regenerative medicine research has exploded extensively evaluated, with some studies already
in the last few decades; in turn dentistry, as a applied in the dental clinic [8].
major segment of medicine, would have its fair With regard to accessibility, bone marrow
share of research attempting to make new scien- aspiration from the iliac crest and liposuction
tific breakthroughs in this field. In dentistry, adult from extra-oral tissue is not an easy operation for
mesenchymal stem cells (MSCs) have been dentists because of the limitations of the dental
detected in several oral and maxillofacial tissues. license and the dental specialization. In contrast,
These cells have participation in regenerative orofacial bone marrow, periosteum, salivary
therapies and consequently have attracted signifi- glands, and dental tissues are accessible stem cell
cantly increasing clinical interest [4]. sources for dentists. Thus, appropriate stem cells
Many research groups have therefore used for dental tissue engineering should not only be
dental stem cells (DSCs) to elucidate various bio- able to differentiate into the target tissue/organ
logical phenomena and to establish their poten- but also should be easily collected and prepared,
tial clinical applications [5, 6]. However, these and probable immunomodulatory properties have
cells are heterogeneous with various differentia- to be used to provide a further benefit. In this sce-
tion states as they may include true “stem” cells, nario, human oral tissue-derived MSCs have low
inherent immunogenicity [9].
A great number of patients all over the world
S. Elazab (*)
experience tooth loss due to irreparable damage
Galala University, Suez, Egypt
of the periodontium caused by deep severe peri-
Faculty of Dentistry, Cairo University, Giza, Egypt
odontal diseases or trauma. Inappropriately, con-
e-mail: [email protected]

© Springer Nature Switzerland AG 2022 263

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_13
264 S. Elazab

ventional therapies such as scaling and root pulp stem cells” (DPSCs) [16]. Afterward, three
planning are frequently only palliative. more types of DSCs populations were isolated
Consequently, the decisive goal of the treatment and characterized: stem cells from exfoliated
for periodontitis is to restore disrupted periodon- deciduous teeth (SHED) [17], periodontal liga-
tium to its original shape and function [10]. The ment stem cells (PDLSCs) [7], and stem cells
periodontium is a complex tissue composed from apical papilla (SCAP) [18, 19]. Recent
mainly of two soft tissues and two hard tissues; studies have identified a fifth dental-tissue-­
the former comprises the periodontal ligament derived progenitor cell population, referred to as
(PDL) tissue and gingival tissue, and the latter “dental follicle precursor cells” (DFPCs) [ (20)].
includes alveolar bone and cementum covering These cells had phenotypic characteristics simi-
the tooth root. PDL is a unique dynamic connec- lar to those of BMSCs [21].
tive tissue that is exposed to frequent adaptation Alternatively, it was reported that two types of
to maintain tissue size and width, as well as struc- adult stem cells have been characterized in dental
tural integrity of ligament fiber attachment in the tissues: epithelial stem cells and MSC-like cells.
alveolar bone. The primary function of PDL is to An adult epithelial stem cell niche in teeth was
retain the tooth within its bony socket and pro- first established in 1999 [22] through organ cul-
tecting it from injury by mechanical loading. ture of the apical end of the mouse incisor. The
Actually, reconstruction of PDL using stem cells niche is located in the cervical loop of the tooth
is valuable in regenerative dentistry [11]. apex and possibly contains dental epithelial stem
The new era in regenerative dentistry not only cells, which can notably differentiate into
constitute stem cells but also use ultrasound and enamel-producing ameloblasts [23].
law density laser for enhancing proliferation and Although the epithelial stem cell niche is valu-
bio-stimulation [12–14]. Herein this chapter, able for the fate of stem cells in tooth develop-
there will be emphasis on the characteristics, ment, no data is available for dental epithelial
preservation, and multiple roles of DSCs and its stem cells in humans. This niche may be specific
potential impact on clinical settings. These novel to rodents because their incisors differ from all
insights of the regenerative capacity of DSCs human teeth in that they erupt continuously
appear hopeful to explore their abilities in a wide throughout the life of the animal. On the other
diversity of pathologies. Besides, DSCs are hand, mesenchymal progenitor or stem cells have
becoming very related to tissue engineering and also long been assumed to exist in dental tissues
regenerative medicine. Moreover, the advantages [24, 25] and can regenerate or form reparative
of using DSCs over stem cells derived from other dentin to protect the pulp against invading irri-
parts of the body will be declared. tants [26, 27]. Ikeda et al. [28] identified distinc-
tive stem cells in the dental mesenchyme of the
third molar tooth germ at the late bell stage (tooth
Sources of Dental Stem Cells (DSCs) germ progenitor cells: TGPCs) with high prolif-
eration activity and the capability to differentiate
Recent stem cell studies in the dental field have in vitro into lineages of the three germ layers
recognized many adult stem cell sources in the including osteoblasts, neural cells, and hepato-
oral and maxillofacial region. These cells are cytes [15].
thought to present in a precise zone of mesenchy- DSCs are enormously nearby, prevail during
mal tissue, referred as “stem cell niche,” and all life, and own a remarkable multipotency. In
these cells are collectively referred to as multipo- the past decade, DPSCs and SHED have been
tent MSCs [15]. DSCs are MSC-like populations meticulously studied in regenerative medicine
with self-renewal capacity and multi-­and tissue engineering as autologous stem cell
differentiation potential. At present, there are five therapies and have shown amazing therapeutic
main DSCs, the first type was isolated from the abilities in orofacial, neurologic, corneal, cardio-
human pulp tissue and termed “postnatal dental vascular, hepatic, diabetic, renal, muscular dys-
13 Regenerative Medicine in Dentistry 265

trophy, and auto-immune conditions, in both hydroxyapatite/tricalcium phosphate were trans-

animal and human models, and lately some of planted [3]. These pools of heterogeneous DPSCs
them proceeded to human clinical trials [29]. form vascularized pulp-like tissue and are sur-
Interestingly, DSCs not only have potent capaci- rounded by a layer of odontoblast-like cells that
ties to differentiate into odontogenic cells but produces dentin with dentinal tubules mimicking
also have the ability to give rise to other distinct natural dentin that, over time, thickened [41].
cell lineages: osteo-/odontogenic, adipogenic, Moreover, if DPSCs are seeded onto human den-
and neurogenic as well as endothelial cell lin- tin surfaces and implanted into immunocompro-
eages [30, 31]. mised mice, reparative dentin-like structure is
Recent reports verified that DSCs also deposited on the dentin surface [42]. In addition
secrete nanoscale extracellular vesicles that to their dentinogenic potential, subpopulations of
may add to their therapeutic functions [32, 33]. DPSCs have adipogenic and neurogenic differen-
These vesicles transfer specifically packaged tiation capacities as well, by exhibiting adipo-
proteins, lipids, and small RNA species and are cyte- and neuronal-like cell morphologies and
taken up by, and capable of reprogramming, expressing their corresponding gene markers
target cells [34]. Yet, although stem cells from [40]. More recently, DPSCs were similarly found
early tooth buds can generate entirely new to undergo osteogenic, chondrogenic, and myo-
teeth, and while DSCs may remediate specific genic differentiation in vitro [43–45]. It was
lesions, growing any other replacement organs reported that DSC therapy primarily involves
from these accessible DSCs may yet be just out DPSCs found in the core of baby teeth and wis-
of reach [35, 36]. On the other hand, there are dom teeth. DPSCs are considered as naturally
the oral mucosa-derived stem cells (OMSCs), produced “raw materials” that can multiply, dif-
besides stem cells that could be harvested from ferentiate, and even grow to new tissue. They are
alveolar periosteum, salivary glands, as well as primarily intended to promote healing injuries in
oral adipose tissue [37]. the teeth or gums. However, current research
efforts are proposed to use DPSCs in healing
injuries throughout the human body [46].
Dental Pulp Stem Cells (DPSCs) Nowadays, so-called stem cell banking is a
flourishing business with several companies
Postnatal stem cells present in pulp could be everywhere in the world offering to extract and
obtained from adult premolar teeth extracted for cryogenically preserve children’s DPSCs. These
orthodontic purposes as well as surgically companies claim that stem cells could be effec-
removed impacted third molars (wisdom teeth). tively used after being stored for 22 years for a
One significant character of pulp cells is their diversity of applications. They additionally sup-
odontoblastic differentiation potential. Human pose that the donor could use the stocked cells for
pulp cells could be induced in vitro to differenti- medical problems including metabolic disorders,
ate into cells of odontoblastic phenotype with cardiovascular disease, multiple sclerosis, as well
polarized cell bodies and accumulation of miner- as cancer [47, 48]. Furthermore, DPSCs might be
alized nodules [38]. used autologously (extracted from and applied to
From the pulp tissues, DPSCs are extracted the same person); this means that immune
with enzyme treatment [39]. There are diverse response is extremely nil. A few studies over the
cell densities of the resultant colonies, supposing last decade have indicated that DPSCs could
that each cell clone may have a dissimilar growth serve in treating or aiding recovery from trau-
rate [40]. Inside the same colony, different cell matic spinal cord and brain injury, retinal dam-
sizes and morphologies might be observed. age, as well as glaucoma, stroke, and more [49].
Besides, ectopic pulp-dentin-like tissue com- Similarly, it’s reasonable to assume – and the tri-
plexes were formed in immunocompromised als appear to confirm – that because of their influ-
mice when ex vivo expanded DPSCs mixed with ential capabilities, DPSCs possibly will be used
266 S. Elazab

in tissue engineering to regenerate the liver, tumor recognition antigens. Regarding in vivo
esophagus, bladder, bone, and other body parts. engraftment into different tissues, 3 months fol-
Moreover, DPSCs have already shown promise lowing the injection of IDPSCs into the intraperi-
in preliminary trials to regrow teeth and may toneal space of nude mice, IDPSCs can be traced
shortly find their way into clinical practice for in various tissues and organs, including the liver,
this application. Collectively, DPSCs are consid- spleen, and kidney, suggesting their potent dif-
ered to be unique among other types of stem cells ferentiation plasticity [53].
in that they are present in body parts that are Under neurogenic conditions, cultured SHED
habitually removed for medical reasons or that readily express a variety of neural cell and glial
simply fall out in aged person [50]. cell markers, which may be related to the neural
crest cell origin of the dental pulp. Neural devel-
opmental potential was studied by the injection
Stem Cells from Human Exfoliated of SHED into the dentate gyrus of the hippocam-
Deciduous Teeth (SHED) pus of immunocompromised mice [54]. It was
reported that SHED could survive for more than
Significantly, it was reported that SHED could 10 days within the mouse brain microenviron-
precisely induce formation of a bone-like matrix ment and express neural markers such as neuro-
with a lamellar structure by recruiting host cells filament M. This finding is comparable to what
[51]. This distinct character of SHED may be was verified for BMSCs, which are capable of
explained by the nature of deciduous teeth, whose differentiating into neural-like cells subsequent
root resorption is associated with new bone for- to in vivo transplantation into the rat brain [55].
mation around the root. Although SHED could SHED also exhibit multicytoplasmic pro-
not differentiate directly into osteoblasts, they cesses instead of the typical fibroblastic morphol-
seemed to induce new bone formation by estab- ogy. Additionally, myogenic and chondrogenic
lishing an osteoinductive template to recruit potentials of SHED have been proved as well.
murine host osteogenic cells [17]. With the osteo-­ Allogeneic SHED, which is easily accessible,
inductive potential, SHED can repair critical-­ appears to be an attractive candidate for peri-
sized calvarial defects in mice with considerable odontium tissue regeneration and may be applied
bone formation [51]. These observations suggest to treat periodontitis in clinics in the near future.
that deciduous teeth may not only afford guid- Moreover, ex vivo expanded SHED transplanted
ance for the eruption of permanent teeth, as into immunocompromised mice yield human-­
mostly supposed, but may also be involved in specific odontoblast-like cells directly associated
inducing bone formation during the eruption of with a dentin-like structure. When single-colony-­
permanent teeth. Likewise, it was found that derived SHED clones were transplanted into
SHED have the capacity to undergo not only immunocompromised mice, only one-fourth of
osteogenic but also adipogenic differentiation the clones had the potential to generate ectopic
[17]. Furthermore, iPS cells have been generated dentin-like tissue equivalent to that generated by
from SHED where iPS cells may be of particular multicolony-derived SHED. However, all single-­
importance for developing innovative technolo- colony-­derived SHED clones tested are capable
gies to regenerate missing jaw bones, periodontal of inducing bone formation in immunocompro-
tissues, salivary glands, and lost teeth [52]. mised mice [17].
SHED appear to represent a population of
multipotent stem cells that are perhaps more
immature than other postnatal stromal stem-cell Periodontal Ligament Stem Cells
populations. Kerkis et al. (2006) isolated SHED (PDLSCs)
and termed the cells “immature DPSCs”
(IDPSCs), and they found that IDPSCs express The perception that stem cells may reside in the
the embryonic stem (ES) cell markers as well as periodontal tissues was first anticipated nearly
13 Regenerative Medicine in Dentistry 267

20 years ago. Since periodontal regeneration is SCAP also demonstrate the capacity to
principally a form of reconstrucion of periodon- undergo adipogenic differentiation following
tium growth including cytodifferentiation, mor- induction in vitro. Interestingly, without neuro-
phogenesis, extracellular matrix production as genic stimulation, cultured SCAP show positive
well as mineralization, this is supporting the staining for several neural markers. After stimu-
thoucht that PDLSCs are responsible for tissue lation, additional neural markers are also
homeostasis. PDLSCs can even be isolated from expressed by SCAP, including glutamic acid
extracted teeth. The periodontal ligament is an decarboxylase, neuronal nuclear antigen, neuro-
adult MSC source in dental tissues, and PDLSCs filament M, neuron-specific enolase, and glial
act as a source of renewable progenitor cells gen- markers [60].
erating fibroblasts, osteoblasts, and cemento-
blasts during adult life [56].
A recent report proposed that the characteris-  ental Follicle Precursor Cells
D
tics of the PDLSCs may depend on the harvest (DFPCs)
location because PDLSCs from the alveolar bone
surface exhibited superior alveolar bone regen- Dental follicle is an ectomesenchymal tissue sur-
eration compared with PDLSCs from the root rounding the enamel organ and the dental papilla
surface. PDLSCs were identified as a specific of the developing tooth germ prior to eruption.
MSC with expression of array of osteogenic This tissue contains progenitor cells that form the
markers like alkaline phosphatase, matrix extra- periodontium, i.e., cementum, PDL, and alveolar
cellular phosphoglycoprotein, bone sialoprotein, bone. Precursor cells have been isolated from
and osteocalcin as well as tendon marker scler- human dental follicles of impacted third molars.
axis [57]. Similar to other DSCs, these cells form low num-
Electron microscope radio-autography was bers of adherent clonogenic colonies when
utilized in an attempt to recognize any associa- released from the tissue following enzymatic
tion between the location and degree of differ- digestion [61].
entiation of progenitor cells in the periodontal Cells in dental follicles express markers, sug-
ligament (PDL). Accordingly, PDL fibroblasts gesting the presence of undifferentiated cells.
were classified on the basis of their nuclear/ After cells are released from the tissue, only a
cytoplasmic ratio and their distance to the clos- small number of single dental follicle cells are
est blood vessel measured. It was determined attached onto the plastic surface. DFPCs show a
that an undifferentiated paravascular progenitor typical fibroblast-like morphology and express
cell population exists and that the PDL also con- collagen type I, bone sialoprotein, osteocalcin,
tains progenitor cells displaying a range of cyto- and fibroblast growth factor receptor. DFPCs
differentiation. This demonstrated that postnatal demonstrate osteogenic differentiation capacity
stem cells can be retrieved from solid-frozen in vitro after induction. A membrane-like struc-
human PDL with promising clinical utility of ture forms in DFPC cultures after 5 weeks of
PDLSCs [58]. stimulation with dexamethasone [62].
Incubation with enamel matrix derivatives
(EMD) for 24 hrs. increases the expression of
Stem Cells from Apical Papilla (SCAP) bone morphogenetic protein-2 and protein-7
(BMP-2 and BMP-7, respectively) by DFPCs.
Apical papilla refers to the soft tissue at the api- Expression of cementum attachment protein and
cal part of the roots of developing permanent cementum protein-23, two putative cemento-
teeth where there is an apical cell-rich zone lying blast markers, has been detected in EMD-
between the apical papilla and the pulp. Stem stimulated whole dental follicle and in cultured
cells from the apical papilla (SCAP) are found in DFPCs stimulated with EMD or BMP-2 and
this apical papillary tissue [59]. BMP-7 [62].
268 S. Elazab

Transplantation of DFPCs generates a struc- ways that comprise direct cell replacement and
ture comprised of fibrous or rigid tissue. These also release of cytokines and chemokines mediat-
transplants expressed human-specific transcripts ing immunomodulation, vascular remodeling by
and collagen type I. However, there was no den- angiogenesis, synaptogenesis, and apoptosis in
tin, cementum, or bone formation observed in the target tissue [63]. In addition to tissue repair,
transplant in vivo. The authors explained that it these secreted mediators may allow local stem
could be due to the low number of cells in the cells to exert an immunomodulatory influence on
original cultures [15]. tissue response to oral pathogens in the progres-
sion of oral diseases such as periodontitis [15].
Unlike other mesenchymal stem cells, it looks
DPSCs vs SHED vs DPSCs vs SCAP clear now that DPSCs are derived from neural-­
crest tissue and that neural cells such as Schwann
Similar to DPSCs and SHED, ex vivo expanded cells and their precursors have the capacity to
SCAP can undergo odontogenic differentiation migrate into the pulp chamber and be able to pro-
in vitro. However, SCAP express lower levels of duce dentin matrix material [64]. In turn, isolated
matrix extracellular phosphoglycoprotein, trans- dental pulp cells – and other neural crest-derived
forming growth factor β receptor II, and dental stem cells such as PDLSCs, DFSCs, and
melanoma-­ associated glycoprotein in compari- gingiva-derived stem cells – can become func-
son with DPSCs. Significantly, CD24 is expressed tional neurons with SHED again having a greater
by SCAP which is not detected on DPSCs or capacity to do so than DPSC. In vivo studies have
BMSCs. The expression of CD24 by SCAP is demonstrated that implanted SHED can regener-
downregulated in response to osteogenic stimula- ate functional neurons, which is an exciting clini-
tion. However, the biological consequence of this cal prospect if successfully translated [65, 66].
outcome needs additional study. On the other Importantly, it was observed that SHED pro-
hand, both DPSCs and SHED possess definitive liferate faster than DPSCs and BMSCs (SHED >
stem cell properties, such as multi-differentiation DPSCs > BMSCs) and produce sphere-like clus-
and self-renewal [40]. Besides, DPSCs have the ters when cultured in neurogenic medium. The
specific ability to regenerate the dentin-pulp clusters either adhere to the culture dish or float
complex when transplanted into immunocom- freely in the culture medium and could be dis-
promised mice. Meanwhile, unlike DPSCs, sociated and subsequently grown on 0.1%
SHED is unable to regenerate a complete dentin gelatin-­coated dishes as individual fibroblastic
pulp-like complex in vivo. Furthermore, one cells. This phenomenon advocates a high prolif-
prominent character of SHED is that they have erative capability, analogous to that of neural
the capacity of inducing recipient murine cells to stem cells [17]. Concerning DPSCs and SCAP,
differentiate into bone-forming cells, which is the distinction between dental pulp and apical
not a property attributed to DPSCs following papilla is that apical papilla is the precursor tis-
transplantation in vivo [17]. sue of the radicular pulp. From this perspective,
Although it seems that there is little functional it may be speculated that SCAP are similar to
difference between DPSC and SHED, both of stem cells residing in the dental papilla that gives
them have the capability to recapitulate dental rise to the coronal dentin-­ producing odonto-
pulp tissue, regarding endothelial cells and dentin blasts. Once the apical papilla turns into pulp,
secreting odontoblasts, the critical constituents to whether the SCAP convert into DPSCs or the lat-
regenerate the integrity of a damaged tooth [63]. ter are derived from a different stem cell pool is
Therefore, under investigational conditions, currently unclear [67].
SHED and DPSC are able to reconstitute human Nonetheless, previous studies showed that
tissue in general and more complex dental tis- when SCAP and DPSCs are compared in vitro,
sues – such as pulp – specifically. DSCs in vivo there are some differences. Overall, SCAP are
seem to repair damaged tissue in a variety of derived from a developing tissue that may repre-
13 Regenerative Medicine in Dentistry 269

sent a population of early stem/progenitor cells the oral mucosa-derived stem cells is the oral epi-
which may be a superior cell source for tissue thelial progenitor/stem cells, which are a subpop-
regeneration. Additionally, these cells also high- ulation of small oral keratinocytes (smaller than
light an important fact that developing tissues 40 μm) [70]. Although these cells seem to be uni-
may contain stem cells distinctive from those of potential stem cells, i.e., they can only develop
mature tissues [68]. into epithelial cells, they possess clonogenicity
The capacity of SCAP to differentiate into and the ability to regenerate a highly stratified
functional dentinogenic cells has been verified by and well-organized oral mucosal graft ex vivo
the same approaches as for DPSCs. Likewise, a [71], which advocates that they may be valuable
typical dentin-pulp-like complex is generated for intra-oral grafting [72].
when SCAP are transplanted into immunocom- In 2009, Zhang et al. [10] first characterized
promised mice in an appropriate carrier matrix. human gingiva-derived MSCs (GMSCs) as other
As mentioned above, SCAP show characteristics stem cells in the oral mucosa that have been
similar to, but different from, those of DPSCs. identified in the lamina propria of the gingiva
SCAP appear to be the source of primary odonto- that attaches directly to the periosteum of the
blasts that are responsible for root dentin forma- underlying bone with no intervening submucosa.
tion, whereas DPSCs are likely the source of This gingival tissue overlying the alveolar ridges
replacement odontoblasts that form reparative and retromolar region is frequently resected dur-
dentin. Again, the apical papilla is different from ing routine dental surgical procedures and can
the pulp in terms of containing less cellular and often be obtained as a discarded biological sam-
vascular components than the pulp. Also, the ple [69].
cells in the apical papilla proliferate two- to Lately, Marynka-Kalmani et al. [73] reported
threefold faster than those in the pulp in organ that a multipotent neural crest stem cell-like
cultures [15]. population, termed oral mucosa stem cells
Compared with DPSCs, SCAP demonstrate (OMSCs), can also be reproducibly generated
better proliferation in vitro and better regenera- from the lamina propria of the adult human gin-
tion of the dentin matrix when transplanted in giva and can differentiate in vitro into lineages
immunocompromised mice. These findings sup- of the three germ layers. The inherent stemness
port that “developing” dental tissues may provide of gingival cells may therefore partly explain
a better source for immature stem cells than the high reprogramming effectiveness of gin-
“developed” dental tissues. In a pilot study with giva-derived fibroblastic cell populations during
minipigs as a model, the surgical removal of the iPS cell generation [74].
root apical papilla at an early developing stage The multipotency of GMSCs/OMSCs and
halted root development, despite the pulp tissue their ease of isolation, clinical abundance, and
being intact, whereas other roots of the tooth, rapid ex vivo expansion provide a great advan-
containing apical papilla, maintained normal tage as a stem cell source for potential clinical
growth and development [17]. applications. It was reported that iPS cell genera-
tion could be obtained from human gingiva as
well. These iPS cells, as in SHED, may be of pre-
Oral Mucosa Stem Cells (OMSCs) cise benefit to regenerate missing jaw bones,
periodontal tissues, salivary glands, and lost teeth
The oral mucosa is composed of stratified squa- [52]. In a mouse model, iPS cells combined with
mous epithelium and underlying connective tis- enamel matrix derivatives provided greatly
sue consisting of the lamina propria, which is a improved periodontal regeneration by promoting
zone of well-vascularized tissue, and the submu- the formation of cementum, alveolar bone, and
cosa, which might involve minor salivary glands, periodontal ligament. However, the scientific
adipose tissue, neurovascular bundles, and lym- understanding of iPS cells and how to control
phatic tissues dependent on the site [69]. One of their differentiation fate is still limited [75].
270 S. Elazab

 lveolar Periosteum Stem/Progenitor

A results in xerostomia and a compromised quality
Cells of life. Therefore, stem cells in the adult salivary
gland are expected to be useful for autologous
A comparative analysis of canine MSCs/progeni- transplantation therapy in the context of tissue
tor cells showed that the in vivo potential of peri- engineered salivary glands or direct cell therapy
osteum cells to form bone was higher than that of [15]. Even though existence of salivary gland
ilium-derived BMSCs [76]. The phenotypic pro- stem cells was proved [83], a single stem cell that
files of human maxillary/mandibular periosteum gives rise to all epithelial cell types within the
cells were analogous to those of maxillary gland has not yet been identified. Thus far, the
tuberosity-­derived BMSCs, and both cell popula- isolation of stem cells in the salivary glands has
tions formed ectopic bone after subcutaneous been attempted through the cell culture of disso-
implantation in mice [77]. Agata et al. reported ciated tissue. Kishi et al. [84] isolated salivary
that human periosteal cells proliferated faster gland stem/progenitor cells from rat submandib-
than marrow stromal cells, and subcutaneous ular glands and found that the cells are highly
transplants of periosteal cells treated with a com- proliferative and express acinar, ductal, and myo-
bination of recombinant growth factors formed epithelial cell lineage markers.
more new bone than BMSCs in mice [78]. Lombaert et al. [85] reported that an in vitro
Periosteal grafts have been shown to induce floating sphere culture method could be used to
cortical bone formation, whereas bone marrow isolate a specific population of cells expressing
grafting induced cancellous bone formation with stem cell markers from dissociated mouse sub-
a bone marrow-like structure in a rat calvarial mandibular glands. These cell populations could
defect model [79], which indicates that the source differentiate into salivary gland duct cells as
of the transplanted cells can impact the structural well as mucin- and amylase-producing acinar
properties of the regenerated bone. The robust cells in vitro. Progenitor/stem cells were also
osteogenic potential of periosteum-derived cells isolated from swine [86] and human [87] sali-
has inspired dentists to use the periosteum for vary glands. Moreover, the intra-glandular
orofacial bone regeneration. Indeed, the inverted transplantation of cells isolated from mouse
periosteal flap technique [80] has been suggested submandibular glands successfully rescued the
for alveolar bone augmentation in conjunction salivary function of irradiated salivary glands
with implant placement or in combination with [88]. These reports recommend that the salivary
bone graft surgery. gland is a promising stem cell source for future
Additionally, cultured periosteum-derived therapies targeting irradiated head and neck
cells have been used for alveolar ridge or maxil- cancer patients. However, primary cultures of
lary sinus floor augmentation that effectively dispersed cells will always contain a number of
proved enhanced bone remodeling and lamellar cells with different origins, such as parenchy-
bone formation with subsequent reliable implant mal cells, stromal cells, and blood vessel cells,
insertion [81] and reduced postoperative waiting which makes it difficult to select salivary gland
time after implant placement [82]. Therefore, the stem cells [15].
alveolar periosteum is a source of stem/progeni- Indeed, Gorjup et al. [89] isolated primitive
tor cells for bone regeneration, principally for MSC-like cells from the human salivary gland,
large defects. but possibly from stromal tissue, which expressed
embryonic and adult stem cell markers and could
be guided to differentiate into adipogenic, osteo-
Salivary Gland Stem Cells genic, and chondrogenic cells. To obtain a genu-
ine stem cell population that can be considered to
Patients aggrieved with head and neck cancer be a true stem cell for the salivary gland, it is nec-
who receive radiotherapy suffer from an irrevers- essary to select cells carrying a specific marker or
ible impairment of salivary gland function that labeled with induced reporter proteins [90].
13 Regenerative Medicine in Dentistry 271

 dipose Stem Cells (ASCs)

A regeneration of tissues from both ectochyme and
from Orofacial Tissues mesenchymal origin. Ease of tissue harvest, high
initial yield of cells, low population-doubling
Adipose-derived MSCs can be readily harvested time, plasticity, multipotential capabilities, and
via lipectomy or from lipoaspirate from areas immunomodulatory characteristics make them
such as the chin; ASCs exhibit robust osteogene- an appropriate candidate for tissue engineering
sis and are thus expected to be an alternative applications. Furthermore, immunoregulatory
source of MSCs for bone regeneration in den- properties of DSCs provide potential for both
tistry. Indeed, the feasibility of using autologous autologous and allogenic tissue engineering
ASCs for orofacial bone regeneration and implant approaches [98].
placement has been demonstrated [91]. Pieri To engineer and regenerate a complete tooth,
et al. demonstrated that the transplantation of the cell source may have to come from tooth buds
autologous ASCs with an inorganic bovine bone in which all the needed cell types are retained. To
scaffold enhanced new bone formation and repair partly lost tooth tissues such as PDL, den-
implant osseointegration following vertical bone tin, and pulp, one or two particular types of DSCs
augmentation of the calvarial bone of rabbits, could be satisfactory to fulfill the need [11].
which proposes that ASCs may be useful for ver- Tissue engineering is an emerging field of
tical alveolar bone augmentation for implant regenerative medicine, where during the past
insertion [92]. decade, it has progressed from the use of naked
Most recently, periodontal tissue regeneration biomaterials just replacing small area of dam-
using ASCs has been successfully verified in a rat aged tissue to the use of controlled three-­
experimental animal model [93]. Another in vitro dimensional scaffolds in which cells can be
study demonstrated that rat ASCs acquired seeded before implantation. These cellularized
cementoblast features when cultured in dental constructs intend to functionally regenerate large
follicle cell conditioned medium containing den- tissue defects [99].
tin non-collagenous proteins [94]. Furthermore, Scaffolds or matrices are specific materials
Ishizaka et al. [95] demonstrated that ASC trans- that provide mechanical support to the forming
plantation induced pulp regeneration in the root tissue and deliver the cells or signaling molecules
canal after pulpectomy in dogs. Additionally, to the appropriate anatomic site. The physical
Hung et al. [96] demonstrated that ASC implants and chemical characteristics of a scaffold play a
were able to grow self-assembled new teeth con- significant role in cell proliferation and tissue in-­
taining dentin, periodontal ligament, and alveolar growth. Cell-seeding scaffolds are either natural,
bone in adult rabbit extraction sockets with a synthetic, resorbable, or non-resorbable [100].
high success rate. Further studies on the isola- Among the settled scaffolds is the polymeric
tion, characterization, and application of ASCs to hydrogels that proved to be reasonable for jaws’
enhance their efficacy for bone and periodontal cartilage and bone repair [101]. In contrary,
regeneration will provide a significant protocol fibrin-based scaffolds have been used for soft tis-
for the use of waste fat tissues in future clinical sue engineering and the revascularization of den-
applications [97]. tal pulp as a result of odontoblastic differentiation.
For instance, platelet-rich fibrin was applied into
the root canal of a necrotic infected immature
 caffolds and Tissue Bioengineering
S tooth after total canal disinfection [102].
in Dentistry The use of biomaterial scaffolds and stem
cells can be safe and potent for the regeneration
In recent years, DSCs have gained in popularity of pulp tissue and re-establishment of tooth vital-
for tissue engineering. The highly proliferative ity. Natural and synthetic polymers have distinct
and self-renewing population of DSCs with the advantages and limitations, and in vitro and
neural crest origin expands their applicability for in vivo testing have produced positive results for
272 S. Elazab

cell attachment, proliferation, and angiogenesis being rich sources of stem cells, they are discarded
[103]. The type of biomaterial used for scaffold as biological samples. Consequently, dental spe-
fabrication also facilitates stem cell differentia- cialists must identify the promise of the emergent
tion into odontoblasts. Multiple methods of scaf- field of regenerative dentistry and the possibility of
fold design exist for pulp tissue engineering, obtaining stem cells during conventional dental
which demonstrates the variability in tissue engi- treatments. These cells could be banked for autol-
neering applications in endodontics [104]. ogous therapeutic use in the future [20].
Delivery of marrow mesenchymal stem cells Furthermore, it was found that bone marrow
(MSCs), with or without growth factor, from bio- stem cells (BMSCs) that obtained from the cra-
degradable hydrogel composites could be used niofacial area (membranous bone) for autologous
for the repair of osteochondral defects [105]. bone grafting provide better bone volume than
Alternatively, in a tooth slice model (horizontal bone harvested from the iliac crest or rib (endo-
section, 1 mm thick), it was shown that SHED chondral bone) [110]. This finding suggests that
seeded onto synthetic scaffolds seated into the different skeletal donor tissues have site-specific
pulp chamber space formed odontoblast-like regenerative properties that may depend on stem
cells that localized against the existing dentin cell type and its niche present in the graft.
surface (Cordeiro et al., 2008) [ (106)]. However, Embryologically, the maxilla and mandible bones
no orthotopic regeneration of pulp-like tissues in exclusively originate from cranial neural crest
the pulp space has been reported with this cells [111], whereas the iliac crest bone is formed
approach. by mesoderm. This variance in embryological
One concern is that implanting stem cells/ origin might consequence in functional pheno-
scaffolds into root canals that have a blood sup- typically differences between orofacial and iliac
ply only from the apical end may compromise crest human BMSCs. Additionally, Akintoye
vascularization to support the vitality of the et al. observed that orofacial BMSCs from the
implanted cells in the scaffolds. It has been pro- same individuals are of higher proliferation and
posed that, because of the concern of over vascu- osteogenic differentiation capacity forming more
larization, a stepwise insertion of engineered mineralized bone compared with the iliac crest
pulp may have to be implemented clinically to BMSCs. Also, the adipogenic potential of orofa-
achieve the desired pulp tissue regeneration [ cial BMSCs is less than that of iliac BMSCs,
(107)]. Recent in vitro studies demonstrated the which could decrease unfavorable fat formation
differentiation of mouse iPS cells into amelo- during bone regeneration [112].
blasts [ (108)] and odontogenic mesenchymal Interestingly, orofacial bone-derived BMSCs
cells, which may be useful approach for tooth can be obtained not only from young patients but
bioengineering strategies [109]. Most recently a also from relatively aged individuals, indicating
new approach was introduced in dentistry using that the age of the donor appears to have minute
pulsed low-intensity ultrasound displays with an consequence on the BMSC gene expression pat-
optimistic consequence on cell proliferation and tern and the clinical efficacy of bone formation
collagen deposition even without growth factor [113]. In contrary, several reports have demon-
supplements [13]. strated an age-related decline in the osteogenic
potential of BMSCs isolated from the human
iliac crest and femur [114, 115]. In addition, cul-
Regenerative Medicine Versus tured mesenchymal stem cells obtained from the
Regenerative Dentistry periodontium, PDLSCs, display almost 30%
higher rates of propagation compared to the
Growing evidence has revealed that regenerative growth of cultured BMSCs. It appears that these
medicine in dentistry is superior in many aspects. cells preserve this ability of higher growth poten-
For instance, many intra-oral tissues such as decid- tial beyond 100 population doublings before
uous teeth, wisdom teeth, and the gingiva, despite in vitro senescence is noticed. It was ­demonstrated
13 Regenerative Medicine in Dentistry 273

that putative stem cell marker, STRO-1, used to Tooth Banking

isolate and purify BMSCs, is also expressed by
human PDLSCs as well as dental pulp stem cells With the promise of cures for conditions as
(DPSCs) [116]. diverse as diabetes, autism, neural degeneration,
Besides, iPS cells have been generated from organ replacement, aging, addiction, as well as
several oral mesenchymal cells and found to cancer, long-term preservation of dental stem
have a higher reprogramming efficiency than cells is a growing market. Banks specialized in
the conventionally skin fibroblasts. This perhaps stem cells isolated from teeth are relatively new
is due to their high expression of endogenous in comparison to stem cell banks collecting bone
reprogramming factors and/or ES cell-associ- marrow and placental cord blood. In North
ated genes [117] along with their high prolifera- America, India, and the United Kingdom in par-
tion rate [52]. Accordingly, cells of oral origin ticular, dental stem cell banks are expanding in
are expected to deliver an ideal iPS cell source number. An English language Internet search of
for dental researchers [15]. The chondrogenic the first 100 hits for “tooth + stem + cell + bank”
potential of DPSCs appears weak, and both recovered 15 separate tooth-banking services.
DPSCs and SCAP are weaker in adipogenesis in Though this is not a comprehensive search, other
comparison with BMSCs [18, 19]. Conversely, tooth bank companies that work locally, in par-
the neurogenicity of DSCs may be more potent ticular in the United States, extend their banking
than that of BMSCs, most probably due to their facilities continentally and globally. It is worth
neural crest origin [54]. Furthermore, a similar noting that one of the first tooth banks looking at
level of gene expression between DPSCs and stem cell recovery was started in Hiroshima
BMSCs was found for more than 4000 known University in Japan as early as 2004 [119].
human genes, except a few differentially Tooth banking concentrates on the collection
expressed genes, including, for instance, insu- of a child’s baby teeth, as they are shed naturally
lin-like growth factor-2 and cyclin-dependent and it is noninvasive source of autologous stem
kinase 6, which are highly expressed in DPSCs, cells used for therapeutic purposes later on when
whereas insulin-­like growth factor binding pro- the child need. In turn, companies and dental
tein-7 and collagen type I α2 are more highly offices offer to collect extracted teeth and pre-
expressed in BMSCs. The cementum/PDL-like serve the DPSCs within teeth. Moreover, associ-
structures are totally different from typical ated oral tissue such as epithelium, gingiva
bone/marrow structures generated by BMSCs (gums), and salivary gland also house unique
and dentin/pulp-like structures generated by populations of stem cells [120].
DPSCs. Collectively, current evidence suggests On the other hand, tooth germ progenitor cells
that biochemical pathways involved in the dif- (TGPCs) and DFSC present in the tooth bud are
ferentiation of DPSCs into functional odonto- stem cells that contribute to the developing tooth
blasts are similar to differentiation pathways of and so are not readily accessible for therapeutic
BMMSCs into osteoblasts [4]. use [121]. Indeed, frequent studies have noted
DPSCs do share a similar pattern of protein that SHED have even greater proliferative prop-
expression with BMMSCs in vitro. Furthermore, erties than DPSC and may have a greater propen-
human GMSCs exhibited clonogenicity, self-­ sity for survival than their adult counterparts
renewal, and a multipotent differentiation capac- [122]. This property is significant when consider-
ity similar to that of BMSCs. However, GMSCs ing the small numbers of stem cells available
are uniformly homogenous, proliferate faster within the confines of a tooth pulp. One of the
than BMSCs, display a stable phenotype, main- primary services provided by dental stem cell
tain normal karyotype and telomerase activity banking companies is the expansion of the few
with extended passaging, and are not tumorigenic cells isolated from the pulp to a number that
and do not lose their MSC characteristics with could be therapeutically useful [123]. Regarding
extended passaging [118]. carious teeth as a source for banked stem cells
274 S. Elazab

where a percentage of extracted deciduous teeth trary, BioEden claim to use a process for collec-
are carious and so are bacterially infected, tooth-­ tion and transport augmented for naturally
banking companies are alienated over receiving exfoliated teeth. Indeed, their transport medium
of diseased teeth. Similarly, the scientific litera- for the tooth is pasteurized cow milk. For the
ture is split [51]. other services they are accepting teeth from home
Werle et al. proved that stem cells extracted extractions, just requiring the tooth to have an
from mutually carious and healthy deciduous existing blood supply – evidenced by post
teeth established equivalent capacity for tissue removal bleeding. However, for all the Indian
differentiation [124]. In similar manner, Tsai tooth banks and five of the US tooth banks,
et al. compared the efficiency of stem cell recov- extraction by a dental professional is required
ery from deciduous teeth in the presence or [127].
absence of caries regarding increasing levels of Indeed, professional extraction shortens the
disease severity [125]. They also concluded that time the tooth is out of physiological circum-
stem cells could be isolated from carious teeth stances possibly to preserve the pulp tissue.
nevertheless with numbers in inverse relation to Long-term success rates for re-implantation of
the clinical severity of the caries. Really, a greater avulsed teeth lost due to physical trauma range
than fourfold variance in fruitful stem cell isola- from about 20% to above 90% depending on how
tion from healthy versus carious teeth was estab- the tooth was handled and how the patient was
lished. Contrarily, Werle et al. noticed only a treated post implant [128].
10% difference in successful stem cell isolation Yet, the enthusiasm of an otherwise healthy
from carious versus healthy teeth [124]. Studies extracted tooth and the manner in which it is
of adult stem cells from healthy teeth and post-­ extracted are not the primary factors concerning
caries teeth with inflamed pulps confirmed that tooth-banking services. Once a tooth has been
cell recovery was inferior in the diseased teeth extracted or exfoliated, storage for transport has
but that both sources of stem cells retained com- the major impact on living pulp and consequently
parable differentiation abilities [125, 126]. stem cell survival [129].
Notably, Tsai et al. described an increase in
both inflammatory mediator expression and of
innate immune system molecules in stem cells Transporting of Dental Stem Cells
from the diseased teeth compared to healthy
ones. It is blurred how those alterations may A number of studies have assessed different
influence the long-term use of SHED or DPSC media for efficacious preservation of live teeth
banked for regenerative purposes; however it is though many are ex vivo models and have looked
reasonable to be cautious at the very least. The at the specific survival of periodontal ligament
questions around carious teeth obviously high- cells after tooth storage in the media. One of the
light the paucity of information regarding teeth as described transport media is the balanced salt
a source of banked stem cells [125]. solutions such as phosphate buffered saline.
Alternatively, there is Hank’s buffered saline
solution (HBSS) that is predominates with some
 ollection and Processing for Tooth
C undefined nutrients. As previously declared,
Banking BioEden calls for the use of bovine milk as the
transport medium [130].
Many collection protocols for DSC banks are Avulsed teeth are often recommended to be
comparable; so far there are some notable and transported to the dentist in milk or even held in
important differences in both sample require- the mouth with saliva acting as the carrier [131].
ments and sample processing. The majority of Significantly, tissue drying is the greatest enemy
services recommend that a dentist extracts the to successful tooth recovery, and similarly, the
deciduous tooth as soon as it is loose (174). In con- same is true for stem cell retrieval from banked
13 Regenerative Medicine in Dentistry 275

teeth. Times allocated for transportation vary I solation and Preparation of Dental
from overnight up to 48 hours as maximum con- Stem Cells
veyance times from tooth extraction to receipt by
the banking facility. So far, just keeping the tooth Magnificently gaining viable cells is the critical
hydrated, in water, for instance, is insufficient to step in banking process. Stem cells are extracted
that purpose instead an isotonic fluid mimicking from the pulp by mechanical and enzymatic
physiological conditions is compulsory [132]. preparation of single cell populations or alterna-
Bovine milk offers a number of appropriate tively by tissue outgrowth – where cells are per-
standards that are absent from many other media mitted to naturally migrate from the extracted
[133]. It is biocompatible, has neutral pH, and is pulp onto plastic culture surfaces. In early studies
naturally buffered, as well as it is commonly for isolation and characterization of DPSCs,
available. Accordingly, if milk is used as a car- Songtao Shi and Stan Gronthos enzymatically
rier, dental tissue obviously survives in it, and digested the pulp tissue with collagenase type I
teeth can be successfully re-implanted [134]. and dispase – to free cells from the extracellular
This is more imperative for the unplanned loss of matrix – then they passed them through a 70 μm
teeth by avulsion due to trauma, but still also, sieve. Single cells were able to grow in culture
conceivably to a lesser extent, for exfoliated teeth thereafter. This recovery protocol, with rapidity
where the tooth is shed at home, school, or any- of process, 24–48 h from start to finish, is likely
where other than the dental clinic. Notably, employed basically with no modification two
bovine milk is still the most widely recommended decades later [142, 143].
preservation media for avulsed tooth storage dur- The primary substitute method described fre-
ing transport to the dentist [135]. quently in the literature, tissue outgrowth, is a
Other biological media explored for tooth simpler yet lengthier protocol where the pulp tis-
preservation include propolis (a honeybee natural sue is macerated and then placed in a culture ves-
product), soymilk, almond milk, pomegranate and sel in balanced salt solution with suitable
other fruit juices, chicken egg white, coconut nutrients to maintain stemness. The cells migrate
water, green tea extract, Gatorade sports drink, out from the tissue and establish colonies on the
and the Brazilian plant extract dragon’s blood plastic culture surface. In both cases, the cell
Croton lechleri sap [136–139]. Nevertheless, with population surviving in culture is greatly enriched
the possible exception of Gatorade, these non- in stem cells following two or three rounds of
defined media have recognized to be viable as subculture [144].
tooth tissue preservation vehicles, yet none stand- The existence of stem cells needs both viabil-
ing out as consistently better than milk [140]. ity testing and flow cytometry. Regarding flow
Closely following bovine milk in frequency of cytometry, it requires only a few thousand cells
recommendation is HBSS, which is frequently out of the entire sample [145], yet this is critical
used for tissue and cell preservation and mainte- as pulp tissue volumes vary between incisors and
nance under in vitro experimental circumstances molars and are consistently small in deciduous
[129]. Remarkably, HBSS is the medium con- teeth. Cells can be concurrently labeled by fluo-
tained in the tooth preservation kit, Save-a-­ rescent molecular probes or antibodies, which
Tooth™ the kit officially used by the tooth bank could include markers for viability and stem cell-­
Store-A-Tooth [141]. The main apparent benefit specific markers as well. All tooth-banking ser-
of HBSS, and similar saline solutions, is that they vices test cell viability, though stem cell marker
are of a distinct and consistent formulation, rather testing may not be conducted unless explicitly
than milk [134]. Ideally, for tooth banking, it is noted. The reason for this is possibly that exces-
required to use their proprietary collection media sive handling of the pulp-derived cells in the
kits and preferred extraction by a dentist; it is this early stages of isolation could result in loss of
matter of consistency that drives the tooth preser- stemness or viability [146].
vation process.
276 S. Elazab

At least one company, the National Dental  ow-Level Laser Therapy (LLLT)
L
Pulp Laboratory tooth bank, states that they and Bone Bio-stimulation
adhere to the US Food and Drug Administration
(FDA) non-binding regulatory guidance on mini- Apart from using stem cells in regenerative den-
mal handling of cell and tissue-based products tistry, a recent study was designed to evaluate the
for homologous use. For extracted cells this effect of low-level laser therapy (LLLT) by means
means, in the words of the FDA, “… processing of diode laser bio-stimulation compared to tradi-
that does not alter the relevant biological charac- tional teriparatide therapy in induced osteoporo-
teristics of cells or tissues” [147]. sis (OP) in rats [14]. In 2002, FDA has approved
teriparatide (TPTD), the first anabolic agent that
stimulates osteoblastic bone formation to improve
Cryopreservation of Dental Stem bone quality and bone mass. To date, it is the only
Cells currently available therapeutic agent that
increases the formation of new bone and could
Once viable cells or pulp tissue have been iso- provide some remediation of the architectural
lated, they have to be effectively frozen and defects in the osteoporotic skeleton. However, it
stored. Cells are suspended in a preservation is restricted to second-line usage for OP treat-
medium, possibly containing growth factors and ment due to its higher cost than first-line less
a cryoprotectant, commonly dimethyl sulfoxide effective agents such as alendronate [153].
which inhibits the growth of ice crystals that may On the other hand, LLLT has gained accep-
disrupt the cell membrane and so reduce overall tance in both medical and dental practices in the
viability [148]. They are transferred to special- past few decades. The application of low inten-
ized cryo-vials generally constructed from high-­ sity impacts the cellular behavior through photo-
density polypropylene, and then the samples are physical, photochemical, and photobiological
frozen and placed in low-temperature storage effects on the irradiated cell tissues. Various stud-
containers filled with liquid nitrogen [149]. ies showed that LLLT could be an alternative, co-­
The majority of tooth banks store isolated, adjuvant, and noninvasive therapy with a
viable stem cells, but at least one, Store-A-Tooth, significant effect on the healing process with
mentions the preservation of at least some of the minimum side effects. Due to the several benefits
original pulp material along with the isolated of LLLT, researchers have attempted to deter-
cells. Although whole tooth storage for future mine its effect on the bone. However, scarce
recovery of stem cells has proven technically pos- investigations were accomplished to explore the
sible, the efficiency of stem cell recovery is highly osteogenic potential of LLLT on OP [154].
variable, and it is not in general use by commer- Accordingly, it was interesting to study the
cial banking services [150]. Indeed, both in vitro effect of LLLT on OP in rat lower jaws and com-
and in vivo functions are maintained if stem cells pare it to the widely approved TPTD, as well as
are recovered from frozen pulp tissue [151]. to study their combined effects, using a state-of-­
Interestingly, Lizier et al. settled a protocol for art techniques like computed tomography (CT),
greatly scaling up the numbers of extracted stem ordinary light microscope, and scanning electron
cells from pulp tissue prior to freezing in which microscope (SEM) to detect bone pores
the same piece of pulp tissue is transferred from (Fig. 13.1) and energy dispersive x-ray analyzer
culture plate to culture plate seeding each of them (EDAX) and enzyme-linked immunosorbent
in turn with stem cells over a number of days assay (ELISA) to detect procollagen type I N
[152]. Under these circumstances, cells preserved propeptide (PINP) concentrations. This study
stemness throughout the process indicating that was looking forward to widening the variety of
dental stem cells and pulp tissue are relatively the less invasive therapeutic options to improve
resistant to handling and manipulation if done the OP prognosis and enhance the quality of life
carefully. for humans, especially elderly patients [14].
13 Regenerative Medicine in Dentistry 277

a b c d

e f g h

Fig. 13.1 SEM images. (a) Normal control group show- small regular pores with few large ones (f) TPTD group
ing normal jawbone architecture with equal and uniform demonstrating at week 24 numerous uniform bone pores,
porosity. (b) Osteoporotic group displaying increased (g) LLLT group showing uniform regular bone pores at
large and irregular bone pores, (c) TPTD group revealing week 24. (h) Combination group presenting at week 24
at week 16 bone pores with variation in size. (d) LLLT uniform regular bone pores with some pores are getting
group illustrating at week 16 bone pores that get narrower. completely obscured
(e) Combination group presenting at week 16 numerous

The beneficial effect of LLLT on the bone is It was concluded that TPTD has osteogenic
attributed to its bio-stimulatory action, where it is potential and is capable to enhance bone archi-
capable of increasing mitochondrial activity, tecture by inducing the formation of new well-­
bone formation, osteocalcin and osteopontin organized bone with narrower bone pore
gene expression, as well as alkaline phosphate diameter. LLLT can be used as a good alternative
activity [155]. This is supported by Torstrick local treatment strategy with minimal side effects
et al. [156], who pointed out that LLLT could be and superior outcomes as it can improve bone
utilized to prevent fracture, improve healing, and strength by faster bone deposition and higher cal-
accelerate implant fixation. The osteogenic cium content. Additionally, combination of both
potential of LLLT is in harmony with the results TPTD and LLLT has a synergistic beneficial
of Scalize et al. [154] and Fallahnezhad et al. effect on bones of experimental rats with induced
[157], as they observed new bone formation and OP. This can possibly overcome systemic side
improved cell viability of the ovariectomized rat effects of a high dose of TPTD and the limita-
bone marrow mesenchymal stem cells, respec- tions of LLLT application, as well as giving max-
tively. Furthermore, through histopathological imum benefit of uniform and speedy new bone
examination, numerous reversal lines were formation [14].
observed of lased group that reflects the capabil-
ity of LLLT to induce rapid bone formation and
high bone turnover. In this regard, Matsumoto  ow-Intensity Pulsed Ultrasound
L
et al. [158] highlighted that experimental group Applications in Dentistry
irradiated by LLLT was able to induce woven
bone formation faster than the control group. In tissue engineering, mechanical stimulates are
Moreover, the recent study of Suzuki et al. [159] required for creating the circumstances appropri-
demonstrated that LLLT could independently ate for cell proliferation. In turn, low-intensity
accelerate the bone remodeling process and in pulsed ultrasound (LIPUS) improves cells by
turn accelerate tooth movement during orthodon- effective mechanical interaction. It was found
tic treatment. that the mechanical index parameter 0.20 has
278 S. Elazab

promoted collagen I expression and cell prolifer- only in regenerative dentistry but also for regen-
ation [160]. In dentistry, several applications of erating any tissue in the body.
LIPUS were tried. For instance, LIPUS was eval- Stem cells derived from oral and maxillofacial
uated to detect its possible effect on tooth move- region is superior on other body stem cells in sev-
ment and root resorption in orthodontic patients. eral aspects.
The study outcome revealed accelerated tooth Tissue engineering is among the latest tech-
movement and minimized orthodontically nologies that impacted the field of dentistry and
induced tooth root resorption at the same time is now being successfully applied in regenerative
[161]. Furthermore, there was a clinically signifi- surgery.
cant reduction in the overall orthodontic treat- Parents should think twice before throwing
ment duration indicating acceleration of new away their child’s avulsed or extracted tooth
bone formation around the moving teeth [162]. which may be a nidus for tooth banking which
Moreover, LIPUS therapy was investigated to will serve in autologous regenerative therapies.
detect whether it stimulates osteogenesis in man- New modalities other than stem cells could be
dibular distraction in a double-blind trial. It was utilized for regenerative medicine/dentistry
concluded that LIPUS matures the regenerated including low-level laser therapy and low-­
tissue by altering the microarchitecture of the intensity pulsed ultrasound for bio-stimulation
newly formed bone [163]. Besides, it was and new bone formation as well as dental sup-
observed that LIPUS accelerates impaired frac- porting tissues.
ture healing suggesting that the mechanism is by
increasing osteoid thickness, mineral apposition
rate, and bone volume, indicating increased References
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 Part V
Musculoskeletal Ultrasound
in Regenerative Medicine
 Regenerative Medicine Procedures
Under Ultrasound Guidance
14
Jeimylo C. de Castro

Introduction progress in the development of new approaches

in the preparation, isolation, administration of
Regenerative injection therapy is an evolving regenerative products, and the understanding of
interventional treatment that provides alternative its biologic mechanisms and molecular compo-
solutions for different musculoskeletal condi- nents shift the momentum in favor of its use as a
tions. Recent advances in research and scien- modern tool for treating different musculoskele-
tific knowledge regarding regenerative therapies tal injuries. The lack of long-term efficacy
for neuromusculoskeletal conditions have of existing therapies also contributes to why there
evolved from a mere alternative therapy to a more is an increasing interest in its use. In addi-
specific treatment of musculoskeletal conditions. tion, patients and healthcare providers alike raise
In fact, the surge in research on regenerative a common concern about the safety of oral medi-
medicine have shown the varied interest of differ- cations for prolonged use in the presence of
ent specialties on the potential of this treat- comorbidities. Thus, regenerative therapies,
ment. The gap between conservative and surgical being an autologous source have the potential of
options has been bridged with the advent of this providing the needed answer to these concerns
technology, allowing physicians to postpone an with an added advantage of minimal safety
operative procedure in favor of this intervention issues, ease of administration and less
with some operative procedures incorporating immune reactions. Additionally, the advent of
the use of regenerative therapies either to shorten musculoskeletal ultrasound complements the
the time of recovery or return to play espe- procedure by its portability and dynamic fea-
cially for some elite athletes. Although this treat- ture. A better view of the target site
ment modality has been challenged by some makes it a point of care modality assuring both
physicians and accepted by others, the amount of patients and physicians that the intended injec-
tion site with the regenerative solutions are pre-
cisely delivered. it also ensures that no vital
J. C. de Castro (*) structures were affected during the injection pro-
Chair, Physical Medicine and Rehabilitation
cedure. While it is true that regenerative injection
Department, The Medical City-South Luzon,
Sta. Rosa, Laguna, Philippines therapy is a modern intervention used in address-
ing musculoskeletal conditions, the use of ultra-
Medical Director/CEO, SMARTMD Center for
Non-Surgical Pain Interventions, Makati City, sound is a much needed tool to ensure that the
Philippines solution is delivered appropriately.

© Springer Nature Switzerland AG 2022 287

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_14
288 J. C. de Castro

General Guidelines million/μL) baseline from what is normally found

for Regenerative Intervention in the whole blood [12, 13, 16]. It is basically pre-
pared by centrifuging autologous, anticoagulated
Just like any procedure, it is always important to whole blood to separate its plasma components
provide safety procedures in the process of pre- based on their densities and to concentrate plate-
paring patients for the treatment procedure. Be it lets above their baseline levels [10, 11, 13].
platelet-rich plasma (PRP), bone marrow con- Depending on the systems used, the protocols
centrate (BMC), or lipoaspirate (LA), the value may include one or two-steps centrifugation to
of skill and safety cannot be overemphasized. separate the different layers of the whole blood,
Although each of these procedures has its unique based on their sedimentation rates [14]. The effec-
harvesting technique, it is important to be famil- tivity of PRP depends on the number of growth
iar with these techniques and ensure that patients factors and cytokines released from the alpha
are oriented as to the process of harvesting, the granules of platelets and the accuracy of the injec-
amount of time needed for the procedure, and tion sites, whether it be tendons, joints, muscles,
where exactly it will be injected and how it will nerves, or any part of the musculoskeletal system,
be injected. This information, therefore, sets the thus providing a regenerative stimulus to augment
expectation of patients before the actual proce- healing and repair in the target tissues [9, 10, 15–
dure is done. Several studies confirmed the accu- 17]. Thus, the “ideal” PRP concentration depends
racy and superiority of ultrasound-guided on various factors like the type of tissues being
procedures over palpation-guided procedures in treated and the stage of the disease (Fig. 14.1).
any part of the musculoskeletal system [1–4], The potential of PRP to enhance healing is
although some would also use and prefer fluo- due to the presence of growth factors and cyto-
roscopy [5] in doing procedures. Thus, to kines. The basic cytokines include insulin-like
enhance safety and accuracy, I would like to sug- growth factor-1 (IGF-1), transforming growth
gest that imaging must be done in any of these factor β (TGFβ), platelet-derived growth factor
procedures [6]. (PDGF), fibroblast growth factor (FGF),
epidermal growth factor (EGF), and vascular
­
endothelial growth factor (VEGF) [18, 19]. In
Platelet-Rich Plasma (PRP) vitro studies have shown that 1.5 × 106 platelets/
μL (5× to 7× baseline) was optimal in promoting
The use of platelet-rich plasma (PRP) in the mus- human umbilical vein endothelial cell prolifera-
culoskeletal system could be traced back to the tion, motility, and morphology with greater or
1990s when Marx et al. initially demonstrated an lower concentration causing lower angiogenic
improved density of mandibular defects with potential [17]. Depending on which tissues to
PRP-enhanced autografts versus autografts alone treat, the concentration of platelets has been
and has since stimulated other practitioners to observed to vary in its effectivity. For instance,
investigate its potential effects in driving an effec- in vitro platelet preparation containing 0.494 ×
tive and faster healing process [7]. Anitua demon- 106 platelet/μL can induce hyaluronic acid secre-
strated the application of PRP in dental tion in the joints among osteoarthritic patients
procedures to enhance bone regeneration in future [20]. No benefit however was observed in rotator
sites of tooth extraction site implants [8]. In sports cuff tears when the platelet concentration is
medicine, Mishra and Pavelko recognized the greater than 2.0 × 106 platelets/μL [21].
value of PRP in chronic lateral elbow tendinosis Leukocytes play a major role in the inflamma-
[9]. Since then, the use of PRP was expanded to tory process where growth factors from the plate-
include other musculoskeletal injuries [10, 11]. lets during the initial stage of healing attract and
PRP is an autologous plasma enriched with activate neutrophils and macrophages to the site
platelet and growth factors with varying concen- of injury. Thus, it may contribute to the pro-­
trations of 2.5 to 3× to about 5× to 7× (about 1.5 inflammatory effects in the tissues once it is
14 Regenerative Medicine Procedures Under Ultrasound Guidance 289

a b c

Fig. 14.1 Preparing a PRP solution. (a) Extracting 60 cc from plasma, 3800 rpm. (c) Platelet-poor plasma is
of anticoagulated peripheral venous blood. (b) Using a extracted initially from the topmost layer, and then the
swing-out centrifuge to separate the cellular components lower layer of plasma is the platelet-rich plasma

injected. Braun et al. have shown that a leukocyte-­ hemophilia and consequently may result in a
rich PRP (LR-PRP) with red blood cells (RBC) higher incidence of arthritis [25, 26].
formulations administered intra-articularly With varied methods used in the preparation of
resulted in cell death in the synovium and pro-­ PRP come different classification systems. This
inflammatory mediator production [22]. comes because of diligent research and while this
Consequently, there is a significant increase in technology is still evolving there will always be
other pro-inflammatory mediators such as change that will take place over the years. Part of
interleukin-1β (IL-1β), interleukin-6 (IL-6), standardizing the practices for PRP is the pro-
interferon-λ (IFN-λ), tumor necrosis factor-α posed classification system to enable practitioners
(TNF-α), and greater matrix metalloproteinases to identify what type of method to follow. The
(MMP-9), which lead to cartilage degeneration in classification systems have been proposed to
the joints [19, 22]. By releasing anti-­inflammatory improve practices and clinical results. In 2012,
mediators, namely IL-4 and IL-10, leukocyte-­ DeLong et al. proposed the PAW (Platelet-­
poor PRP and RBC-free formulations may be Activation-­ White Blood Cell) Classification
considered when injecting intra-articularly and System [27]. This classification is based on three
thus may be ideal for joint pathologies [22]. variables namely the absolute number of platelets,
LR-PRP, however, may be beneficial to tendinop- the manner of platelet activation, and the presence
athies [23]. Furthermore, Mirosnychenko et al. or absence of leukocytes or white blood cells [27].
showed in their studies that non-neutrophil-­ The PLRA System proposed by Mautner et al.
containing PRP or platelet-poor plasma (PPP), (Fig. 14.2) includes four variables which include
after an additional spin to remove platelets, stim- platelet count, leukocyte content, red blood cell
ulates myoblast differentiation, which is impor- content, and whether it is exogenously activated
tant in skeletal muscle regeneration [24]. or not [28]. In 2017, Lana et al. proposed another
Intentionally slowing and shortening the spin classification called MARSPILL which include
regimens when processing PRP can result in low- additional variables including the harvest method,
ering and excluding of the leukocytes. activation, red blood cells, number of spins,
Subsequently, the reverse is true when producing image guidance, leukocyte number, and the use
a higher concentration of leukocytes and red of light activation [29] (Fig. 14.3). Interestingly,
blood cells [15, 22]. the function of monocytes and all their plasticity
On a similar note, red blood cells in PRP have which is a potential property for regeneration of
a negative effect on chondrocytes with hemar- tissue are discussed in this classification system
throsis from either traumatic knee injuries or [29]. Other PRP classification includes the
290 J. C. de Castro

PLRA Classification
Criteria Final Score
P Platelet count ____________________ P ____________________ M
Volume injected Cells/µL
L Leucocyte count* >1% +
<1% –
R Red blood cell content >1% +
<1% –
A Activation+ Yes +
No –
Table created by Drs. Patrick Nguyen and Walter Sussman
* If white blood cells are present (+), the percentage of neutrophils should also be reported.
+
The method of exogenous activation should be reported.

Fig. 14.2 PLRA classification. (Used with permission from Dr. Kenneth Mautner; Source: Mautner et al [28])

MARSPILL Classification
Letter Relates to Type
M Method Handmade (H)
Machine (M)
A Activation Activated (A+)
Not activated (A-)
R Red blood cells Rich (RBC-R)
Poor (RBC -P)
S Spin One spin (Sp1)
Two spins (Sp2)
P Platelet number PL 2-3 PL 6-8
(folds basal) PL 4-6 PL 8-10
I Image guided Guided (G+)
Not guided (G-)
L Leukocyte concentration. Rich (Lc-R)
Poor (Lc-P)
L Light activation. Activated(A+)
Not activated (A-)
Lc: leucocyte concentration; PL: platelet concentration; RBC: red blood cell

Fig. 14.3 MARSPILL classification. (Used with permission from Dr. Joseph Purita; Source: Lana et al. [29])

Mishra Classification [11] and Dohan Ehrenfest During the pre-procedure instruction,
Classification [30]. patients must avoid any intake of non-steroidal
anti-­inflammatory medications (NSAIDs) for at
 reparation Methods for PRP
P least 2 weeks prior to the procedure. NSAIDs
It is very important that patients are properly are known to inhibit the prostaglandin pathway
instructed about the pre-procedure preparation, and thus reduce the release of growth factors
the procedure itself, and to orient them as to the [31]. The use of blood thinners must be noted,
level of expectation during the early stage of and it is prudent to obtain an International
healing after the procedure. Normalized Ratio (INR) to ensure that values
14 Regenerative Medicine Procedures Under Ultrasound Guidance 291

are within normal therapeutic levels. Patients mostly platelets and leukocytes, an intermediate
with bleeding tendencies and those with neo- layer known as the buffy coat which is rich in
plastic findings need to get medical clearance leukocytes, and the bottom layer which is mostly
from their physicians before undergoing this made up of red blood cells. A leukocyte-rich PRP
procedure. is obtained by extracting the topmost and inter-
In the beginning, a venipuncture is performed mediate layers and a second spin is performed.
from the patients usually at the brachial area of Once the second spin is done, about two-thirds of
the arm. To ensure easy blood extraction, espe- the upper layer are removed, which in this case is
cially for obese patients, an ultrasound-guided mostly made up of platelet-poor plasma (PPP),
extraction is suggested. Depending on what sys- and the lower third is extracted without getting
tem is used or the number of sites to be injected, the red blood cell that sticks at the bottom of the
blood extraction volume can vary from 20 cc to tube and is homogenized to obtain a PRP [33]. In
about 120 cc. Different systems come with their the second method, otherwise called the buffy
unique packaging kits. Some kits have pre-filled coat, whole blood collected is centrifuged (high
anticoagulants in their tubes. Others have sepa- spin) at a high speed. Similarly, the three layers
rate anticoagulants and must be filled into their of platelet-poor plasma (uppermost) and the mid-
respective tubes. The anticoagulant solution in dle (buffet coat layer) and the bottom (red blood
many prefabricated PRP kits that are commonly cell) layers can be seen. The uppermost portion is
used is acid citrate dextrose (ACD), sodium removed up to the level just above the buffy coat.
citrate (SC), or ethylenediaminetetraacetic acid And then the buffy coat is collected and trans-
(EDTA). These different anticoagulants may ferred to another sterile tube. Leukocytes can be
affect the normal physiologic tissue pH, platelet separated from the buffy coat using a leukocyte
count, and growth factor content [32]. The use of filtration filter or centrifuge at a low speed. This
EDTA resulted in higher platelet yield in whole method obtains a high concentration of leuko-
blood. However, it induced an increase in the cytes [33]. Platelet activation can be done by
mean platelet volume (MPV) when centrifuging using either calcium chloride or thrombin. This is
for PRP purposes. EDTA had the lowest overall referred to as exogenous activation. Thus, there is
growth factor release and can damage the platelet prompt release of 70–95% growth factors for
membrane [32]. When using SC, PRP obtained a about 10 minutes [10, 11]. In endogenous activa-
higher platelet recovery at 81% during the first tion, the collagen in the tissue where it is injected
centrifugation step as compared to EDTA (76%). activates the release of growth factors through
SC also showed the highest TGF release and is exposure [11, 33]. Whatever system is preferred,
suggested by the authors to be the preferred anti- despite their variations, the generic sequence of
coagulant for PRP purposes. ACD however blood collection, centrifugation (single- or dual
showed the highest VEGF concentration [32]. spin), and activation is followed prior to the
PRP is processed by means of differential cen- injection proper [33].
trifugation using a swing-out centrifuge rotor
instead of the fixed angle rotor [33]. The accel- I njection Procedure of PRP
eration force is adjusted to sediment certain cel- Once the PRP solution is ready, it is important to
lular constituents based on their respective identify the specific location of the approach on
specific gravity [32]. There are two methods of the patient so that patient can be positioned in
preparing PRP: the PRP method and the buffy-­ such a way that will be convenient for both the
coat method. The PRP method is a dual-spin cen- patient and the physician doing the procedure.
trifugation (soft spin) procedure, where the first Ideally, but not obligatory, the line of needle
spin separates the plasma from the red blood cells approach together with the position of the ultra-
followed by a second spin where the platelet is sound monitor should be in one place where the
concentrated. During the first spin, three layers physician is at one end and the ultrasound
will be seen: the topmost layer which contains machine on the direct opposite end with the tar-
292 J. C. de Castro

get on the patient at the middle, for as long as it is the needle path but at the same time provide you
ergonomically advantageous for both patient and with information about the existence of an
physician. inflammatory process [34] (Fig. 14.5).
Ultrasound scanning and ultrasound-guided A sterile movable table can be used to secure
injection (Fig. 14.4) allow the physician to see the PRP solution, alcohol-based chlorhexidine
and identify specific structures for injection with solution [35], needles, syringes, sterile gloves,
improved accuracy [4]. Pre-scanning of the area masks, sterile anesthetic ultrasound gel, and local
or regions to be injected prior to injection must anesthetics and must be in proximity with the
be performed. This allows the physician to plan physician during the procedure. Ensure that con-
their approach as to whether to perform an in-­ sent forms are properly read and signed by the
plane or out-of-plane approach and for uneven patient.
surfaces a stand-off approach. It is also important Draw up all the necessary medications needed
to determine what type of transducer to use, the for the procedure including the PRP solution and
length and size of the needle, and its trajectory local anesthetics. Determine appropriate ultra-
during the procedure. The use of Doppler will sound probes to be used and ensure to maintain
also help avoid neurovascular structures along sterile technique during the procedure. A sterile

a b c

Fig. 14.4 Ultrasound-guided PRP injection. (a) approach will ensure easy visualization of the target, the
Ultrasound-guided PRP injection allows every physician needle, and the track of the needle. (c) The out-of-plane
to plan his approach during an injection. (b) An in-plane approach uses the walk-down method toward the target

a b c

Fig. 14.5 Ultrasound images of the (a) in-plane approach Doppler is a very useful feature in ultrasound to visualize
during an injection procedure. An out-of-plane image the degree of inflammation in short-axis view (SAX). (c)
simply shows a dot in the ultrasound image. (b) Power Long-axis view of the image with power Doppler
14 Regenerative Medicine Procedures Under Ultrasound Guidance 293

condom cover for the ultrasound probe is an ered in the marrow through fibroblastic colony-­
excellent way for making sure that a sterile inter- forming unit (CFU-F) assays [40] and can
face during the procedure is assured [36, 37]. differentiate into multiple different musculoskel-
Skin preparations using alcohol-based chlorhexi- etal lineages (multipotent) in vitro and regenerate
dine must be used and a sterile drape on top of the bone in vivo (not multipotent) [39]. Over time as
area to be injected [35] be placed. we age, however, the MSCs’ proliferative capac-
ity and telomere length are diminished [41].
Conversely, hematopoietic stem cells (HSC) are
 one Marrow Aspirate Concentrate
B characterized by their positive expression of sur-
(BMAC) face marker CD34+ (cluster of differentiation)
which can differentiate into their respective blood
Bone marrow aspirate concentrate (BMAC) is cell types. HSCs were first identified in the 1980s
another method of regenerative injection therapy although bone marrow transplantation began
procedure (Fig. 14.6). Bone marrow has long around the 1950s primarily for patients suffering
been used as a primitive cell source for fracture from the effects of radiation and chemotherapy
healing and bone grafting dating back to the [42–44]. In contrast to MSCs, HSCs have been
1800s [38]. It is a major source of two major pro- considered exempt from the aging process,
genitor and adult stem cells namely mesenchy- although extensive studies in cycling kinetics
mal stem cells (MSCs) and hematopoietic stem [45], ontogeny-related studies [46], and ex vivo
cells (HSCs) [39]. IN 1960, MSCs were discov- expansion trials [47] strongly suggest a certain

ACH Classification:
Letter Relates to Classification
A BMA 1 – Collection and injection
2 – Description of harvesting
3 – Cell count
4 – Dosage of cytokines (GF and/or IL)
5 – CFU
6 – MSC and HSC phenotyping
7 – Differentiation evaluation
8 – Functional assays
C BMAC 1 – Collection and injection
2 – Description and harvesting
3 – Cell count
4 – Dosage of cytokines (GF and/or IL)
6 – HSC and/or MSC phenotyping
7 – Differentiation evaluation
8 – Functional assays
H BMA + BMAC used together 1 – collection and injection
2 – Description of harvesting
3 – Cell count
4 – Dosage of cytokines (GF and/or IL)
5 – CFU
6 – HSC and/or MSC phenotyping
7 – Differentiation evaluation
8 – Functional assays

Fig. 14.6 The ACH classification. BMA Bone marrow hematopoietic stem cell, A aspirate, C concentrated, H
aspirate, BMAC bone marrow aspirate concentrate, CFU hybrid. (Source: Purita et al. [398])
colony-forming unit, MSC mesenchymal stem cell, HSC
294 J. C. de Castro

degree of aging in the most primitive stem cell tissues while administered intravenously, there is
population. The HSC pool dynamics could be little data to support such a hypothesis, although
affected by programmed cell death within the MSCs may arrive and incorporate in the desired
HSC population and HSC pool size might be tissue to generate clinical benefits [51]. MSCs
feedback regulated [48]. In the bone marrow secrete a variety of cytokines inducing other
aspirate, around 0.001–0.01% of all nucleated MSCs to the area, promoting cellular differentia-
cells are MSCs and 0.01–1% are HSCs character- tion to target tissue sites, promoting new tissue
ized by CFU-F and CD34+ expression, formation and angiogenesis, reducing fibrosis
­respectively [39, 49]. While HSCs may be avail- and inflammation, preventing apoptosis, and sup-
able in the bloodstream by means of activation pressing catabolic activity [54]. Bone marrow
during a bone injury, transplantation, and stimu- and its concentrate contain several growth factors
lation with drugs like GCSF (granulocyte colony-­ like vascular endothelial growth factor (VEGF),
stimulating factor), MSCs are not inherently platelet-derived growth factor (PDGF), trans-
available in the bloodstream. Thus, when a forming growth factor β (TGF-β), bone morpho-
BMAC is delivered on the site of injury, direct genic proteins (BMP), interleukin-8 (IL-8), and
cellular therapy is performed [39]. interleukin-1 receptor antagonist [55]. Thus,
It was Arnold Caplan in 1991 who popular- bone marrow aspirate concentrate (BMAC) with
ized and coined “mesenchymal stem cells” to its MSCs has enormous potential as cell therapy
refer to the spindle-shaped plastic-adherent cells for tissue regeneration, immune modulation, and
isolated from bone marrow, adipose, and other anti-tumor agents [51].
tissue sources such as pericytes on the outside of Several bones in the body can be a source of
blood vessels with multipotent capacity in vitro these mesenchymal progenitor cells such as the
[49–51]. It is characterized in the literature in the vertebral body, iliac crest, tibia, and calcaneus.
1950s and isolated later by Friedenstein et al. The iliac crest yielded a higher mean concentra-
[52]. in 1970. Despite Caplan’s proposal that tion of osteoblastic progenitor cells compared
these cells can differentiate into bone, cartilage, with tibia and calcaneus [56]. Advanced age has
tendon, ligament, marrow stroma, adipocytes, been shown to reduce the colony-forming units
dermis, muscle, and connective tissue [50], con- (CFU-F), and hence, stem cells may have reduced
vincing data to support “stemness” of these cells efficacy in the elderly population [56, 57].
were not forthcoming and isolated MSCs are not The quality of iliac crest harvesting is
the homogeneous population of stem cells, technique-­dependent, and failures happen due to
although a bona fide stem cell may reside within inconsistent aspiration techniques. It is suggested
the adherent cell compartment of marrow. Thus, that targeting the posterior superior iliac spine
the International Society for Cellular Therapy yields more MSCs [58] than in any other site.
(ISCT) has recommended that MSCs be termed Further, the quality of MSCs decreases as you
“mesenchymal stromal cells” and that “mesen- increase the volume being aspirated. In fact, the
chymal stem cells” should be reserved for the first 4–5 ml contains MSCs of high quality, and
subset of mesenchymal cells that demonstrate withdrawal of bigger volumes leads to dilution
stem cell activity [53]. To use this term appropri- with peripheral blood [55]. Thus, it is suggested
ately, the single most characteristic feature of that drawing blood from multiple sites increases
MSCs is their capacity to differentiate between MSC yield rather than more volumes from a sin-
osteoblasts, adipocytes, and chondroblasts gle bone site [59–61]. This is since MSCs reside
in vitro [51]. Another characteristic feature of in the subcortical areas and pericytes reside
MSCs is that they escaped immune recognition around blood vessels, and so drawing from more
(immune-privileged) and may secrete immuno- sites and not necessarily from manipulating the
suppressive molecules while being recognized by trocar with one entry in different sites maximizes
an allogeneic immune system (immunosuppres- MSC yield and allows access to pericytes [62,
sive) [51]. As to its ability to home to diseased 63]. Pericytes around blood vessels can differen-
14 Regenerative Medicine Procedures Under Ultrasound Guidance 295

tiate into MSCs when injuries occur and are adhere to plastic, (2) express cell surface antigens
recruited from the bone marrow for neovasculo- (CD105, CD73, and CD90) and (3) not express
genesis [64, 65]. the cell surface antigens CD45, CD34, CD14,
Crisan and colleagues in their landmark study CD11B, CD79α, CD19, or HLA-DR, and (4) dif-
showed that MSCs are derived from perivascular ferentiate into osteoblasts, adipocytes, and chon-
cells (pericytes) from several human tissues such droblasts in vitro [76].
as fat, skin, heart, liver, and muscle [66–69] and
not from the connective tissue (stroma) of mar-  reparation Methods of BMAC
P
row or the stroma of other tissues [70, 71]. To ensure safety, informed consent must be
Furthermore, mesenchymal cells (pericytes) that required from all patients. It should detail the
exhibit the properties of MSC can be isolated name of the patient, date, time, home address,
between the tunica media and tunica intima of phone number, name of the procedure, name of
large blood vessels [71–73], small vessels, and physician and assists, and the involved risks and
capillaries. Each pericytes coming from different benefits of the procedure. A detailed state-
tissue origin are morphologically tissue- and ment regarding the procedure must be included
vessel-­specific and have shown to have different in the consent form, to allow time for the patient
chemistries and reactivities, although embryo- to read and understand the procedure. Once the
logically the vascular endothelial cells have not consent form is read and understood, the patient
been proven to be the progenitors of pericytes needs to sign at the bottom page to accede to the
[71]. Pericyte is expressed by its markers (CD146, given procedure. Since this is not a standard
PDGFRβ, NG2, αSMA) [74]. In addition, MSCs care procedure, the risks of the procedures must
secrete “trophic factors” that inhibit scar forma- be included in the statement, like hematoma,
tion, inhibit ischemia-caused apoptosis, stimulate fracture, or infection [77]. Caution as to the use
angiogenesis, stimulate the mitosis of tissue-­ of steroids and non-steroidal anti-inflammatory
specific, tissue-inherent stem cells, and guard drugs (NSAIDS) must be emphasized prior
against viruses and bacteria. Thus, Caplan would to the start of the procedure. Studies have shown
like to call MSC a “medicinal signaling cell” that these medications interfere with the results
[71]. Pericytes are sourced from the abluminal of the treatment and thus are best to be discon-
surface of the blood vessel, anchored at the base- tinued during the treatment period [78]. Patients
ment membrane through the PDGF-BB, and its with asthma using injectable steroids need to
sympathetic innervation is not associated with delay the procedure for about 8 weeks prior to
the vascular endothelial cell but with the the procedure while inhaled steroids should be
pericytes-­MSCs. In an injury, the pericytes dif- temporarily discontinued [79, 80]. Interestingly,
ferentiate into MSCs and can be squeezed in due short-term fasting (minimum of 12 hours) or
to its sympathetic innervation and contractile calorie restriction (20–40% reduction of calorie
apparatus and can respond accordingly [71]. It, intake) was shown to enhance stem cell function
therefore, plays a fundamental role in angiogen- in multiple tissues and slow the ravages of aging
esis, blood vessel homeostasis, regulation of with a high-­ fat diet reducing hematopoietic
blood vessel integrity, permeability, blood flow, stem cells activity. The ketogenic diet however
immune response, and their regenerative applica- did not show any effect on stem cell function
tion in the musculoskeletal system especially in [81–83].
wound healing and inflammation becoming col- Basic laboratory examination like complete
lagen type 1-producing fibroblasts and can dif- blood count could provide the adequacy of hema-
ferentiate into skeletal muscle [70, 71, 74, 75]. tocrit and hemoglobin levels. Prothrombin time/
In 2006, the Mesenchymal and Tissue Stem partial thromboplastin time (PT/PTT) together
Cell Committee of the International Society of with HBA1C may serve as useful references to
Cellular Therapy (ISCT) cited the following min- ensure the patient would not have bleeding ten-
imum criteria for defining MSCs: cells must (1) dencies. Patients under anticoagulants should be
296 J. C. de Castro

properly weighed in terms of benefits versus risks gluteal nerve and vessels. If the trocar is pushed
as withdrawing such drugs might cause more more than 6 cm, perforation of the bone might
harm than good [77]. occur. Thus, the safest sector to put the trocar is
When doing the posterior superior iliac spine around sector 6. Factors that may give rise to
approach, it is important that one is familiar complications include the thickness of the iliac
with the anatomy of the pelvis. The location of crest with subsequent breaching of the lateral
the following structures must be scanned care- and medial table of the ilium and injury to the
fully namely sacroiliac joint, sacral foramina, sciatic nerve and superior gluteal nerves and
sciatic nerve, superior cluneal nerves, lumbar blood vessels [85].
nerve roots, superior gluteal nerve, and blood In another study, Hernigou and colleagues
vessels and must be thoroughly marked out evaluated the size of the trocar in relation to the
using a pen [84]. To ensure a safe and reliable thickness of the ilium specifically the spongy
procedure, Hernigou and colleagues constructed bone in an iliac wing (transverse thickness
a sector system where the neural and vascular between two tables) on vertical sections relevant
structures are located. Six equal sectors or lines for bone aspiration to ensure safe placement of
were drawn between the anterior and superior the trocar between the two tables and to evaluate
iliac spines and converge at the center of the hip the risk of reaching vascular and neurologic
where sector 1 is anterior and sector 6 is the structures. For instance, when the spongious
most posterior (Fig. 14.7). The space between bone transverse thickness of the iliac wing is
the lines of the sector drawn is used as a refer- <3 mm, it would be difficult to use an 8- gauge
ence for the placement of the trocar. When the trocar (3.26 mm). Six equal sectors were drawn
trocar is placed in the most posterior superior as explained in the previous study above with
portion (sector 6), there is a possibility that it number 1 as the most anterior and 6 as the most
may puncture the sciatic nerve and the superior posterior. In between these sectors are lines with

a b c

Fig. 14.7 (a) The corresponding sectors can be found were approximately perpendicular to the curve of the iliac
and marked on the patient by using the same technique crest. Six sectors were defined by these lines. Sectors 1
and corresponding in clinical practice to different zones of and 2 are anterior parts of the iliac bone, sectors 3 and 4
bone marrow aspiration according to the position of the centers are part of the iliac bone, and sectors 5 and 6 are
patient. Three different approaches can be used to harvest posterior parts of the iliac bone. (c) Radial CT scan cuts of
bone marrow from the iliac crest: patient supine and ante- the hemipelvis. The transverse distance (T) of the external
rior crest approach (sectors 1, 2, and 3), patient prone and iliac artery from the inner pelvic table, the distance (D)
posterior iliac crest approach (sectors 4, 5, and 6), and between the iliac crest and external iliac artery, and the
patient in the left or right lateral position allowing easier angle (A) between the iliac wing direction and the line
middle iliac crest approach (sectors 3 and 4). (b) The iliac joining the external iliac artery to the iliac crest (Used
wing (three-dimensional construction) was divided by with permission from Springer); Source: Hernigou et al.
drawing lines from equidistant portions spaced along the [85])
rim of the iliac crest to the center of the hip. These lines
14 Regenerative Medicine Procedures Under Ultrasound Guidance 297

letter A between 1 and 2 sectors and letter E from the results of negative pressure from the
between 5 and 6 sectors. Pelvic CT scans were pull of the trocar during bone marrow aspiration
done to measure the transverse thickness of the [87].
iliac wing. Results of the study showed that sec- The use of local anesthetics in bone marrow
tor 6 had the greatest spongious bone thickness aspiration procedures is an acceptable method for
close to the entry point followed by sectors 2 and rendering the approach to bone marrow aspira-
3. The trocar of 3 mm can be safely penetrated up tion less painful if not totally anesthetized. In
to 9 cm as the thickness of the spongious is 2003, Vanhelleputte and colleagues reported 84%
>3 mm. There was no correlation between the of procedural pain which was less than antici-
thickness of the iliac crest in each sector and sex, pated but disappeared within 10 minutes after the
age, side (left or right), height, and BMI [86] procedure. Younger patients and longer proce-
(Fig. 14.8). dures, however, emerged as independent predic-
In Denmark, Gronkjaer and colleagues tors of pain [88]. Levels of local anesthetic
assessed two techniques of bone aspiration using toxicity are also one concern and physicians
either an R-technique or an S-technique. The should properly administer an acceptable thera-
R-technique is a quick pull, creating a high dif- peutic dose. There is no concern for anesthetics
ferential pressure for 1 second in a 10 ml syringe, to affect the cells of the bone marrow as it is out-
while the S-technique is a slow, low differential side the bone marrow. For lidocaine, 4.5 mg/kg is
pressure. The uniform pull of a 10-ml syringe for the maximum dose, up to 300 mg lidocaine with-
approximately 5–15 seconds in the posterior out epinephrine, or 7 mg/kg or 500 mg lidocaine
superior iliac spine provides for the extraction with epinephrine. The maximum recommended
of 1.5–3.0 ml of bone marrow under local anes- volume for a 70 kg male is between 32 ml and
thesia. The results of the study showed a better 45 ml of 1% lidocaine depending on the refer-
specimen quality of the R-technique as compared ence chosen [89].
to the S-technique, except for the pain intensity Contraindications to bone marrow procedure
which is higher in the R-technique. Thus, pain include infection at the graft site with its symp-
could be generated from inadequate anesthesia or toms, bleeding tendencies, hemophilia, dissemi-

a 3
2 B C 4 b
A D
1 5
35-40°
E
6

4-5 cm

Fig. 14.8 (a) Map of the ilium. The blue zone is the part <1 mm. The yellow, orange, and red zones are in sectors
of the ilium where the thickness of the spongios is always 1, 4, and 5. Line A is the border between sectors 1 and 2
>3 mm. The yellow area corresponds to the zone wherein and line B is the border between sectors 2 and 3, and so
50% cases of the thickness is <3 mm but >2 mm. The forth. (b) Trocars are introduced between the two tables of
orange area corresponds to the zone wherein 25% cases of the ilium. (Used with permission from Springer; Source:
the thickness is <2 mm but >1 mm. The red corresponds Hernigou et al. [86])
to the zone wherein 20% of cases of the thickness is
298 J. C. de Castro

nated intravascular coagulation, and neoplastic before the trocar is drilled through the bone. In
conditions [90]. Other relative contraindications this case, ropivacaine is safer in lower concentra-
may include the use of anticoagulant medica- tions [94]. The trocar to be used must be rinsed
tions, those with atrial fibrillations, and other thoroughly with 1000 IU/ml solution of heparin
blood dyscrasias [91]. together with the syringes to ensure that no clot is
formed, [89] as clots can trap stem cells and ren-
Injection Procedure of BMAC der them ineffective for their intended use [93].
Aseptic technique for any procedure applies for The syringes (10-ml) to be used for bone marrow
bone marrow aspiration. Sterile gloves, masks, extraction must also be thoroughly heparinized.
hair caps, drapes, and towels and other equip- Leave at least 1 ml of heparin inside the syringe
ment should be used to ensure that pathogens do to serve as an anticoagulant during bone marrow
not get in the way. It is preferable to use extraction.
chlorhexidine-­alcohol solution to clean the area The patient preparing for this procedure
of approach [35, 92] in this procedure. Other sup- should be lying in a prone position, with a head
plies should include a scalpel blade if a drill is to cut out. The area for bone marrow aspiration
be used to incise the skin prior to drilling at the must be cleaned using the chlorhexidine-alcohol
posterior superior iliac spine (PSIS). The choice solution. The target area at the PSIS must be
between 11-gauge Jamshidi trocars and a similar prepped and draped appropriately. A pillow under
power drill with a bit must be made depending on the abdomen is useful to minimize lordosis of the
the familiarity of the physician. Friedlis and spine. The table preferably must be stable and
Centeno suggested the use of 20 ml 0.5% ropiva- movable to allow it to move in different positions
caine, 27-gauge 0.5-in skin needle, 22-gauge [89, 93] (Fig. 14.9).
3.5–4.0 11-/16-in needle, 5 ml syringe with Image guidance either by means of ultrasound
5000 units of heparin in normal saline, Steri-­ or fluoroscopy allows the precision of the tar-
Strips (3 M, St Paul MN), gauze and tape [93]. geted areas during trocar placement. While ultra-
Alternative medication includes 1% lidocaine sound offers a convenient way of imaging with
without epinephrine that would be used through no exposure to radiation, fluoroscopy facilitates
the skin before the skin incision. Marcaine and placement of the trocar within the anesthetized
lidocaine however are toxic and should not be area and provides less soft tissue penetration due
used when injecting the periosteum of the ileum to its steeper approach with easier trocar manipu-

a b c d

Fig. 14.9 Fluoroscopic-guided aspiration of bone mar- car with a mallet until a give is felt and the trocar is
row aspirate. (a) The patient is positioned in a prone posi- inserted to a depth of about 4–5 cm. (d) Once the marrow
tion with the beam oriented to about 15° to 30° ipsilateral cavity is reached, unscrew the top portion of the trocar,
oblique and caudal tilt with PSIS as the target. (b) The insert a sterile 10 cc syringe and begin the aspiration of
trocar is inserted toward the PSIS between the two tables the bone marrow aspirate. (Courtesy of Dr. Joseph Purita)
of the ilium. (c) Once PSIS is reached, gently tap the tro-
14 Regenerative Medicine Procedures Under Ultrasound Guidance 299

lation [93]. Ultrasound however requires a larger radiopaque marker can help identify the area
area of local anesthetics as the trocar will have to 1 cm lateral to the PSIS, and a hub view is done
travel a longer distance through the soft tissue but once the needle is inserted for perpendicular
with no procedural suit needed [93]. When using approach [89, 93]. Care should be taken to avoid
an ultrasound, the location of the PSIS is scanned going beyond the superolateral area to avoid hit-
and marked first and then the iliac crest is marked ting the superior cluneal nerve. Conversely, avoid
all the way to about 4 cm toward the anterolateral going too inferior towards the sacroiliac joint to
portion from the PSIS. A linear probe may be avoid hitting the the superior gluteal ­neurovascular
sufficient for a thinner individual but a curvilin- structures [89]. Anesthetize the area in a circular
ear probe for obese patients is better for greater manner about 2 cm in diameter with about 7 ml
depth in any bony identification [89] (Fig. 14.10). of anesthetics for the injection point and the track
Three approaches are possible: the parallel, per- leading to the periosteum. The second target must
pendicular, and ultrasound-assisted approaches. be about 2 cm from the first one and 1 cm from
In a parallel approach, PSIS is drawn and marked the edge of the ilium and anesthetized like the
out as indicated above. The trocar is inserted first one [93] (Fig. 14.11).
from inferior to superior at a steep angle, in the The area of the target is spherical. Drilling on
plane to the probe. In the perpendicular approach, a curve surface is a bit challenging. Care should
the medial part of the probe is placed on the PSIS be taken to prevent the trocar from sliding down
and the lateral portion points to the greater tro- to areas that are not anesthetized as it may cause
chanter. The trocar is inserted from lateral to pain and complications. To prevent unnecessary
medial about 1–2 cm from the iliac crest for bone errors, approach the ilium at right angles to the
marrow aspiration. For the ultrasound-assisted surface of the curvature. If you are harvesting
parallel approach, the PSIS, medial and lateral, from different sectors, be conscious of the differ-
are thoroughly marked out on the skin but with ent neurovascular structures around it as each
no direct visualization with the trocar entry at the area will have a different curvature. Another
PSIS mark [89]. In all these approaches, a skin aspect of drilling is deciding on what type of
incision by a scalpel must be made on the target aspiration tool to use, whether a manual tool or a
entry point prior to the trocar insertion to enable power-driven rotary device. When using a man-
a smooth entry of the trocar into the PSIS. ual drill, firm pressure must be applied and 180°
If fluoroscopy is preferred, orient the beam to rotation must be applied at the target site in the
about 15°–30° ipsilateral oblique and caudal tilt PSIS, alternating in both clockwise and counter-
to help visualize the target site at the PSIS. A clockwise directions. A mallet could also be used

a b c

Fig. 14.10 Ultrasound-guided approach to the PSIS. (a) a correct approach. (c) Ultrasound-guided entry into the
Anesthetic is administered over the area of approach at the PSIS 30° lateral and about 15° cephalad. (Courtesy of
PSIS. (b) Ultrasound is used to pre-scan the area to ensure Zarah Francine de Castro)
300 J. C. de Castro

a b c

Fig. 14.11 Target sites for anesthesia. (a) Anesthesia is applied over the PSIS until the periosteum is reached using 2%
lidocaine (b) Then you may do other injection points in marked areas, as shown here (c) Sites for anesthesia injection

while the trocar is touching the target site to MSCs are found mostly in the trabeculae [60,
enable it to enter the marrow cavity [89, 93]. A 95]. Various studies note the advantage of smaller
moderate tap may be used in the beginning as it volumes of 2–4 ml of bone marrow aspirate over
allows entry into the PSIS and a sense of “give” bigger volumes which will cause peripheral
is felt indicating the entrance into the marrow blood dilution [60, 96]. A study by Hernigou and
(Fig. 14.9). Hernigou and colleagues [85] cau- colleagues examined the higher concentration of
tioned the practitioner about the risk when the tip MSCs using 10 ml syringes compared to that of
of the trocar (10 cm) is accessible to the sector 50 ml syringes [97]. Thus, for the purpose of
and a deviation of 20° from the plane of the iliac maximizing the quality of MSCs harvested, a
wing. Also, as the trocar enters the marrow, the smaller volume from multiple sites is ideal for
patient usually feels the pressure, but not the bone marrow aspiration than the bigger volumes.
pain, unless the trocar goes out of the anesthe- Furthermore, in the process of extracting the
tized area. In that case, redirect the trocar for bone marrow using a syringe, it is important to
appropriate direction and target [93]. When using pull gently in a pulse-wise fashion but not oblivi-
the powered rotary device, a specialized needle ous to the pressure that might be felt by the
fits into the battery-powered handle. This type of patient. After completing the extraction of bone
aspiration tool is more ideal for younger patients. marrow from at least 3 sites, remove the syringe
By using a smaller 15-gauge needle, less axial and cap it, and allow the syringe to be moved
force is required with associated less procedure continuously to prevent clotting. Then withdraw
time, and the chance of sliding is also reduced. the trocar quickly and apply pressure into the
Less pain was also observed using the power wound to prevent bleeding [93]. Tegaderm (3 M,
rotary device. It is suggested that it must be oper- St. Paul, MN) is an ideal dressing for the wound
ated continuously rather than by pulse to sense to be kept until the following day, after which the
the sound of the drill as it transitions from the patient can clean the area and replace it with a
cortex to the marrow cavity. Once it reaches the simple dressing or Band-Aid (Johnson & Johnson
marrow cavity, the trocar is usually stuck firmly Consumer Inc, New Brunswick, NJ). For post-­
in the bone. If it is loose, continuous drilling is procedural pain, 500 mg/tablet of paracetamol or
done until the trocar is solidly in the bone. You acetaminophen is taken once a day up to a maxi-
can test it by tapping gently showing a solid feel mum of thrice a day be taken until pain subsides.
which means that it has reached the bone. Take The patient can stay on the table for a sufficient
note of the 1-cm marking on the trocar to ensure period while the sample is being processed and to
that the depth is acceptable [93]. make it ready for injection. Repeat the same pro-
The purpose of bone aspiration is to get as cess if there is a need to get more samples at the
many nucleated cells as possible. Most of the opposite side of the ilium.
14 Regenerative Medicine Procedures Under Ultrasound Guidance 301

 dipose-Derived Stem/Stromal Cells

A benefits with a higher cell yield per unit of tissue
(ADSC) substrate than bone marrow MSCs. It is estimated
that a given adipose has a frequency yield of
Liposuction is a popular procedure among aes- about 1:100 to 1:1500, while bone marrow yields
thetic and plastic surgeons for a variety of clini- about 1:100,000 nucleated cells and their quan-
cal conditions (Fig. 14.12). Most of these tity decline over time as one ages [98, 101]. They
procedures are intended for aesthetic purposes are also genetically stable and relatively resistant
but only recently have they found it to be equally to senescence in culture as compared to bone
effective for degenerative musculoskeletal con- marrow MSCs [98]. Because of its stability, it
ditions. The isolation of adipose-derived stem can be cryopreserved and stored for long periods
cells is a novel therapy in regenerative medicine but with a finite lifespan and clinically is ideal for
that caught the attention of a lot of practitioners tissue repair and regrowth in several pathologies.
due to its potential regenerating capacity in an Thus, they can be called progenitor cells, which
aging musculoskeletal region. Adipose-derived reflects their ability to renew over a longer period
stem cells (ADSC) are a ubiquitous solution for while committed to a certain lineage. However,
aesthetic and reconstructive problems because of to date, stem cell research and clinical trials are
tissue volume loss secondary to aging or yet to be ascertained [98, 102].
radiation-­induced loss of tissue pliability and Adipose stem cells (ASC) then are mesenchy-
vascularity [98]. mal, adult stem cells that reside in the stromal
Adipose tissue, otherwise known as “white vascular component of adipose tissue, with a pri-
adipose tissue,” to distinguish it from infantile, mary function of tissue repair and expansion
thermoregulatory “brown adipose tissue,” is an [103]. Like bone marrow-derived stem cells, it is
energy store and an endocrine organ secreting immunosuppressive and upon systemic injection,
several adipokine hormones [99]. ADSC (white it can home to specific injured areas, in response
adipose tissue) is said to be multipotent as it can to hypoxia, apoptosis, or inflammation [100,
differentiate into a range of different adult cell 103]. The International Society for Cellular
types such as adipocytes, osteoblasts, myocytes, Therapy (ISCT) introduced a minimum criterion
and neurons but within the same lineage [98, for MSCs expressing the following cell surface
100]. Mature adipocytes are sensitive to ischemic markers CD70, CD90, CD105, and HLA-ABC
changes while their precursors (ADSC) are resis- but negative for the other markers such as the pan
tant to ischemia, a feature that makes it very ideal hematopoietic marker CD45; the monocyte/mac-
for tissue grafting. Their popularity stemmed rophage markers CD 11B or CD14; the B cell
from its potential to address a host of therapeutic markers CD79α and CD19; and primitive

a b c

Fig. 14.12 Simple liposuction procedure. (a) Simple (Tulip®) in different sizes to accommodate various
manual liposuction procedure using a 23-gauge needle to syringes. (c) Snap Lok device (Tulip®) inserted into the
harvest fat at the posterior pelvis. (b) Snap Lok device plunger to create a vacuum during the harvesting of fats
302 J. C. de Castro

h­ematopoietic progenitors and endothelial cell stromal cells by dissolving lipids and connective
markers CD34 and HLA-DR [98, 102, 103]. tissue from a lipoaspirate and may not be compli-
Other positive markers for ADSC-MSCs are ant with the US FDA, whereas Lipogems® and
CD10 [104], CD13 [104–106], CD29 [104–108], Puregraft® are closed systems, provide autolo-
CD44 [105–107], and CD166 [105, 106, 108]. gous fat for lipofilling and are delivered percuta-
They also secrete growth factors such as basic neously, do not extract from stromal vascular
fibroblast growth factor (bFGF), keratinocyte fraction, and are compliant with the US FDA
growth factor (KGF), transforming growth fac- [89]. As a word of caution, please do not rely on
tor-beta (TGF-β), hepatocyte growth factor a commercial company or its medical representa-
(HGF), and vascular endothelial growth factor tive without verifying such information as to the
(VEGF) [101]. US FDA guidelines.
Before we go any further to discuss some In the European Union, cell-based therapies
details regarding the harvesting procedures and are regulated as advanced therapy medical prod-
isolation of the ADSC, let me share the regulation ucts (ATMPs) and are subject to European
that governs this type of procedure. In the United Medicines Agency (EMA) regulation and require
States, adipose stem cells are regulated under the market approval. ATMPs are further subdivided
broader category Human Cells, Tissues, and into gene therapy medicinal product (GTMP),
Cellular and Tissue-Based Products (HCT/Ps). somatic cell therapy medicinal product (SCTMP),
Other countries prescribed their own regulation tissue-engineered product (TEP), or a combina-
after the United States. This is further subdivided tion. Cell-based products like ADSC may only be
into 361 or 351 products which determine how subject to public health legislation if they are
stringent the Food and Drug Administration homologous, not manipulated substantially, and
(FDA) allows their access into the markets. The not combined with any article. Interestingly,
351 products are considered drugs and as such there are products in the United States that fall
they are regulated like pharmaceutical products under non-ATMPs in the EU, thus causing some
subject to stringent clinical trials before gaining safety concerns if these products have unproven
market accessibility. In contrast, 361 products are effects for different indications. The approval
not regulated like pharmaceutical products but system therefore could be circumvented [100].
need to comply with the Public Health Services In Japan and much in Asia, they have their
Act and Current Good Tissue Practice own regulatory bodies which may be patterned
Legislations, under the Code of Federal after the US or EU regulations. In Japan, they fall
Regulations, Title 21, Part 1271 [100, 109]. A under a separate regulatory body called “cell/
361 product must be only minimally manipu- tissue-­engineered product.” To encourage the use
lated, intended for homologous use, and not used of new regenerative products, they provide incen-
in conjunction with another article. FDA defines tives during the clinical trials with conditional
minimal manipulation as cutting; grinding; shap- market approval. Data are collected for the next 7
ing; centrifugation; soaking in antibiotic solu- years for monitoring and reevaluation and for
tion; sterilization by ethylene oxide treatment or final market approval [100].
irradiation; cell separation; density gradient sepa- Rodbell and colleagues in the 1960s were the
ration; lyophilization; freezing; cryopreserva- first to isolate cells from adipose tissue using
tion; and selective removal of B cells, T cells, minced rat fat pads [110]. Subsequently, with the
malignant cells, red blood cells, or platelets. potential of this procedure, it was modified for
Except for autologous cells, the product must the isolation of cells from human adipose tissue
have no systemic effects or rely on the metabolic specimens. This procedure was minced using
effect of the patient’s living cells [100]. With this hands, but with the development of liposuction,
in view, ADSC is a 351 product, and a stromal this procedure has been simplified [111, 112]. In
vascular fraction (SVF) should be treated and humans, fat is usually harvested from the lower
regulated as a drug [100]. Adistem™ extracts abdomen, lateral gluteal region, medial and
14 Regenerative Medicine Procedures Under Ultrasound Guidance 303

l­ateral thigh, posterior hip, or flank with the the fat tissue; epinephrine causes vasoconstric-
greatest number of viable cells taken from the tion and decreased bleeding, and lignocaine
lower abdomen followed by the thigh [113]. Lim induces anesthesia [117, 118]. This tumescent
and colleagues together with the study by solution is infiltrated at the collection sites in the
Choudhery and colleagues did not show any dif- skin by creating a skin nick by a scalpel. A blunt
ference in the quality of MSCs from different cannula is used to deliver about 180–300 ml of
sites taken from the same donor showing unaf- the tumescent fluid into the subcutaneous fat
fected differentiation capacity [114, 115]. layer. After delivering the solution, 15–20 min-
Although previous studies indicate that abdomi- utes is allowed for the diffusion of the tumescent
nal sources are resistant to apoptosis, the arm has solution. Then, the cannula is inserted where the
the highest yield of cells and the inguinal area skin nick was made into the subcutaneous fat
has the greatest plasticity [116]. Ultrasound layer, and by using a 10-cc syringe with a locking
imaging can be used to assess the thickness of device to create a vacuum, begin the aspiration
adipose tissue prior to harvesting of the adipose process. Lipoaspiration using a 20 ml or 60 ml
tissue. syringe is more difficult. A total volume of about
20 ml of lipoaspirate is obtained. Repeat the aspi-
 reparation Methods for Adipose
P ration when necessary. Trivisonno and colleagues
Aspirate found higher stromal and vascular cells with
Usually, the patient is prepped by choosing the blunt microcannula (2 mm diameter, with 5
appropriate area for liposuction [113–115]. My rounded ports on each side, 1 mm in size each) as
personal preference is at the posterior hip and compared with 3 mm blunt cannula with a single
lower abdomen. When the area is chosen, the port on the side (3 × 9 mm) [119]. The lipoaspi-
patient is draped in an aseptic manner. An anes- rate is then transferred to a sterile test tube from
thetic solution of about 3 cc is delivered over the the syringes (Fig. 14.13). Other methods use
skin to form a wheal at the entry site. A derma- automated aspirating devices, but there are find-
tologist in California named Dr. Jeffrey Klein ings that it could damage the cells. No significant
described a tumescent solution for liposuction difference of cells aspirated was found though
which is composed of lignocaine, epinephrine, when comparing manual versus automated pro-
and large amounts of saline. The saline balloons cessing systems [120].

a b c

Fig. 14.13 Lipoaspirate. (a) Simple separation of the until the adipose tissue becomes homogeneous. (b) After
lipoaspirate to gravity separate without centrifugation to centrifugation, there is a clear delineation of the infrana-
remove excess fluid at the bottom admixed with blood. tant fluid at the lower layer of the tube. The adipose tissue
The middle portion is a concentrated adipose tissue. The remains at the top layer. (c) Sediments settle at the bottom
uppermost layer is made up of oil and lipid fractions. of the tube
Additional washing with sterile normal saline is done
304 J. C. de Castro

After the aspiration of fat, the cannula is with- plate after it is placed in a humidifier atmosphere
drawn, and pressure is applied in the area with a of 5% C02 at 37 °C [98, 111]. At present, this is
2 × 2 gauze and a Tegaderm patch. The area must not allowed by law and, therefore, is treated as a
be kept dry while the area is still healing. It might drug, subject to strict clinical trials before being
take not less than 2 days before the area of injec- allowed access to the market.
tion will fully recover. The patient must watch Four SVF isolation systems are identified:
out for any sign of infection or any untoward MultiStation (PNC International, Gyeonggido,
signs and symptoms [89]. Republic of Korea), Cytori StemSource 900/MB
As discussed earlier, there are regulations that System (Cytori Therapeutics, Inc., San Diego,
govern whatever the final product of the lipoaspi- California), LipoKit Platform (Medi-Khan Inc.,
rate would be. The use of enzymes such as colla- Irwindale, California), and GID SVF-2 Platform
genase in the processing of lipoaspirate with the (The GID Group, Inc, Louisville, CO). The
resultant stromal vascular fraction (SVF) is con- choice of which system is to be used depends
sidered a 351 product [89, 100, 109], while mini- upon the type of clinical practices of the physi-
mal manipulation for homologous use falls under cians [121]. To overcome the issue of enzymatic
a 361 product. Thus, the removal of red blood cells digestion which is not allowed by law, van
and oil that can interfere with healing is minimal Dongen and colleagues developed a technique
manipulation and is done with the goal of preserv- called the fractionation of adipose tissue (FAT)
ing the optimum amounts of multipotent cells and procedure. This procedure can be done within
growth factors. Adipose tissue cannot be kept at 10–12 minutes with isolation of 1 ml of SVF
room temperature for more than 24 hours [111]. from a 10 ml centrifuged adipose tissue. However,
A stromal vascular fraction (SVF) is done by based on histological stainings, interdonor varia-
collecting the lipoaspirate and mixing it with a tion exists which might result in different thera-
physiological solution. Adipose tissue is washed peutic effects. Thus, it is too early to say that this
repeatedly using phosphate-buffered solution could be effectively used for the treatment and at
(PBS) until a clear lipoaspirate without red cells the same time be allowed by the FDA [122].
and fat is removed. This then will be mixed with a Commercial kits for adipose tissue processing
digestion solution containing 2 mg/ml of collage- are also available. These include AdiPrep® from
nase A, with or without trypsin dissolved in (PBS) Harvest®, Adistem™, Lipogems®, Puregraft®,
solution (1:1 ratio). Digestion is done by agitation and Tulip®. The Lipogems® is a system that is
at 37 °C for 30 minutes. After this process, 1 vol- designed to harvest, process, and transfer refined
ume of PBS is added, and the solution is filtered adipose tissue without the use of enzymes.
through a 40-μm cell strainer. Then centrifugation Adipose tissue is micro fragmented gently and
is done at low speed (500 g) or at 2000 rpm for washed from pro-inflammatory oil and blood
5 minutes and then washed twice with PBS [111, residues, whose end-product contains pericytes
119]. Other methods include agitating the cells which are retained within an intact stromal vas-
after centrifugation, disrupting the pellet, and cular niche and thereby activated as MSCs as it
mixing the cells. This completes the separation of interacts with the target tissues [123]. Like
stromal cells from the primary adipocytes. Then Lipogems®, Puregraft® is a closed system and
repeat the centrifugation process again, and after provides autologous fat for lipofilling and is
the spin, remove all the solution above without delivered to the patient percutaneously.
disturbing the cells at the bottom of the tube. The Adistem™ uses enzymes in processing the
resultant cell pellet is called stromal vascular frac- lipoaspirate and thus its clinical use at this point
tion (SVF). The pellet is resuspended in a cell cul- may not be compliant with the US FDA [89].
ture medium and seeded into a culture plate. In Liposuction is not without any complications.
vitro differential adhesion cell culture technique Although rare, the list is extensive. It may
is used to isolate ADSC from SVF. ADSC is iden- include bleeding, hematoma, chronic edema,
tified as the spindle-shaped cells adherent to the depression, fat embolism, fibrosis, hyperpig-
14 Regenerative Medicine Procedures Under Ultrasound Guidance 305

mentation, scars, seroma, thromboembolism, Gauthier et al. in 1974, and then by Lebreton de
infection, lidocaine anaphylaxis and toxicity, Vonne and Mouray in 1974 [133]. It is a high
loose skin, necrosis, neurologic problems, injury
molecular weight homotetrameric glycoprotein
of vessels, perforation of a hollow viscus, pul-that can inhibit matrix metalloproteases (MMPs)
monary edema, and skin burns [124]. The most or any protease without the direct blockage of
common of this complication is sepsis due to protease active sites [134, 135]. It is one of the
necrotizing fasciitis. The mortality rate is about
members of protease inhibitors family (alpha1
19–20 per 100,000 [125, 126]. Tumescent lipo- antitrypsin or α1−AT, C1-inhibitor, alpha1-anti-
suction, however, is the safest method of fat chymotrypsin, etc.). It is synthesized by the liver,
removal with the fewest complications [127]. In astroglia, and blood cells in humans. It forms an
a review of literature done by Boni, there were irreversible complex and transports of cytokine
no reported fatalities in tumescent liposuction,interleukin-6 (IL-6) and growth factors [134,
while very rarely, fatalities were reported in 136]. Alpha-2-macroglobulin (A2M) has been
intravenous sedation or under general anesthesiaidentified in the luminal surfaces of the endothe-
[128]. The current FDA limit of 7 mg/kg lido- lial cells of arteries, veins, and lymphatics. It was
caine is a non-significant risk of harm to patients.
found to inhibit a broad spectrum of plasma pro-
Also, a dose of 55 mg/kg of tumescent lidocaine teases, thus having a protective role against inju-
is remarkably safe for liposuction, although therious plasma and cellular enzymes [137]. It is a
standard recommended dose of about 35 mg/kg 718-kDa protein and is found in the plasma and
as presented by Klein is recommended. With extracellular spaces at a concentration of about
liposuction, the dose range of epinephrine ranged
2–4 mg/ml [138].
from 1.2 mg to 4.3 mg, and with this dose, there Peptidases trigger a massive conformational
was no clinical evidence of epinephrine toxicityrearrangement of alpha-2-macroglobulin after
[129, 130]. Furthermore, the tumescent solution cutting in a highly flexible bait region such that
did not also alter the quality of fat grafts and did
A2M being a broad-spectrum endopeptidase
not influence the viability of the adipocytes inhibitor causes their entrapment described as
[131]. Bupivacaine was reported to show the “Venus flytrap” or “snap-trap” mechanisms. A
highest cell viability but has to be properly dosed
second action may take place among other homo-
to be safe and effective [129, 132]. logs that involve a highly reactive β-cysteinyl-γ-­
Lipoaspiration and tumescent liposuction areglutamyl thioester bond, which covalently binds
safe procedures when done under a controlled cleaving peptidases which further stabilizes the
environment where all precautions are put in enzyme–inhibitor complex. Although active,
place assuming also that this procedure is done trapped peptidases have limited access to their
mainly for healthy individuals. Although much ofsubstrates. This way, A2M (the active form is S;
the research done is derived from aesthetic and inactive form is F) homolog regulates proteolysis
cosmetic procedures, we can use their data to our
in complex biological processes such as nutri-
own advantage. Those patients taking anticoagu- tion, signaling, and tissue remodeling and at the
lants are advised to discontinue the medications 2
same time protects the host organisms against
weeks prior to the procedure. Ask for any aller-attacks by external toxins and other virulence
gies to medications so unnecessary reactions factors during infection and envenomation.
could be avoided [89]. Further, it can inhibit pro-inflammatory cyto-
kines, inhibits a broad spectrum of serine, threo-
nine, and metalloproteases, and modifies
Alpha-2-Macroglobulin (A2M) hormones and growth factors [139, 140].
Therefore, it has the potential to treat cartilage-­
The human ultrastructure of alpha-2-­based pathology, inflammatory painful arthritides
macroglobulin was first identified by Hoglund [140], alter the course of peripheral nerve injury
and Levin in 1965, by Bloth et al. in 1968, by [141], and has the potential to treat neuropathic
306 J. C. de Castro

pains [134]. A recent study in 2019 by Orhurhu pro-inflammatory cytokines like interleukin-6
and colleagues also showed that A2M is an active (IL-6), interferon-γ (IFN-γ), interleukin-10 (IL-­
inhibitor of joint degeneration and cartilage pres- 10), and interleukin-18 (IL-18) [134, 150–153].
ervation, and improves the quality of life for In fact, TNF-α is used as a biomarker of Wallerian
patients with knee osteoarthritis [142]. In fact, degeneration in an injured peripheral nerve [154].
early intra-articular A2M exerts an anti-­ Wallerian degeneration upregulates other factors
inflammatory effect and attenuates cartilage and such as chemokines and transcription factors in a
bone damage [143]. Huang and colleagues in peripheral nerve injury with both beneficial and
2019 have also demonstrated that supplemental detrimental effects in a regenerating nerve or
A2M has beneficial effects on cartilaginous end- neuropathic pain induction [155].
plates (CEP) that slow the progression of inter- Alpha-2-macroglobulin (A2M) can regulate
vertebral disk (IV) degeneration by inhibiting the distribution and activity of pro-inflammatory
effects of proinflammatory cytokines [144]. cytokines such as transforming growth factor-β
Vincenzetti and colleagues have observed that (TGF-β), TNF-α, platelet-derived growth factor
A2M in neuropathic pains is decreased and that (PDGF), IL-6, nerve growth factor (NGF), fibro-
treatment with gabapentin reverses the condition blast growth factor (βFGF), and IL-1β [156]. In a
[145]. Similarly, alpha-2 macroglobulin inhibits study, Arandjelovic [141] prepared three prepara-
proinflammatory cytokines such as interleukin-1, tions for A2M namely human A2M, activated
tumor necrosis factor-α (TNF-α), and interleu- A2M (methylamine-activated α2-macroglobulin –
kin-­6 [134] which are predominant in peripheral α2M-A), and MAC, where a native α2M was
nerve injury [141] and inhibits matrix metallo- treated with 0.6 mmol/L cis-Pt for 6 hours at
proteases and other proteases in addition to other 37 °C and then with MA (methylamine HCl), by
enzymes involved in joint pathologies [140]. It dialysis. Like TNF-α, IL-1β binds with increased
has also been found that A2M exhibited a protec- affinity with MAC [157] and has been reported to
tive effect against radiation injury in human bone play an important role in peripheral nerve injury
marrow mesenchymal stem cells and is a poten- [151]. Other proinflammatory cytokines such as
tial therapeutic agent for the prevention and treat- IL-6 and IL-18 have a close affinity with MAC as
ment of osteoradionecrosis of the jaws during compared with α2M-A and human α2M, with
radiation therapy [146]. IL-6 binding exclusively with MAC [152, 153].
Peripheral nerve injury, whether partial or Such α2M derivative (MAC) is very active in
complete, may result in a series of complicated suppressing inflammation and in altering the
responses. While it is true that regeneration fol- course of peripheral nerve injury by acting
lows an inflammatory process, fulminant inflam- against the proinflammatory cytokines, thereby
mation may cause unnecessary axonal damage directly addressing neuropathic pains [141].
and neuropathic pain [141, 147]. This peripheral Electron microscopy studies, however, suggest
nerve injury will in turn cause the release of that naturally occurring A2M conformational
tumor necrosis factor-α (TNF-α) and intermediates may be like MAC [158] with simi-
interleukin-1β (IL-1β) with associated infiltration lar effects when done in vivo, causing a direct
of neutrophils and pro-inflammatory M1 mono- anti-inflammatory activity in peripheral nerve
cytes/macrophages in the distal stump [134, 148]. injuries [134, 141], thus relieving neuropathic
In a study by Wagner and Myers, direct injection pains.
of TNF-α in an uninjured nerve causes demyelin- Known to be a non-inflammatory joint pro-
ation, macrophage infiltration, and pain mimick- cess, osteoarthritis presents however with
ing changes seen in an injury [149]. The activation ­significant joint inflammation as shown by the
of p38 mitogen-activated protein kinase (MAPK) presence of proinflammatory cytokines. Cells
by TNF-α in Schwann cells, consequently, leads originating from the synovium (synoviocytes),
to increased expression of IL-1β [147]. The cartilage (chondrocytes), and leucocytes partici-
peripheral nerve injury also leads to release of pate in the pathogenesis of the disease. During
14 Regenerative Medicine Procedures Under Ultrasound Guidance 307

the early stages of osteoarthritis, the synovial the G3 domain from aggrecan reduces the chance
cells release proinflammatory cytokines espe- of FAC formation, thus affording relief from pain
cially TNF-α, IL-1β [159, 160], IL-6, and several in the degenerative process [140]. With this infor-
other cytokines and chemokines [161]. These mation, the potential of α2-macroglobulin as a
proinflammatory cytokines, in turn, cause the multipurpose protease inhibitor and anti-­
release of lysosomal enzymes and matrix metal- inflammatory mediator is seen [140].
loproteinases (MMPs) from the synoviocytes, TNF-α is involved in acute phase reaction and
chondrocytes, and infiltrating leukocytes, which systemic inflammation and disrupts the normal
collectively degrade the cartilage proteoglycan, turnover of the extracellular matrix which
collagen, and matrix [162, 163]. These proin- degrades the cartilage and thereby causes pain
flammatory cytokines namely, TNF-alpha and [170, 171]. In fact, TNFα is also involved in
IL-1β stimulate the mRNA expression of cata- osteophyte formation and in muscle and tendon
bolic cytokines, such as MMP-1, MMP-3, MMP-­ damage in osteoarthritis [172, 173]. In addition,
9, and MMP-13 thus degrading structural these proinflammatory cytokines will also induce
components of extracellular matrix (ECM) such the release of other biologically active substances
as the aggrecan and collagen and causing changes such as prostaglandin E2 (PGE2) and nitric oxide
in chondrocyte viability and GAG (glycosamino- (NO) by inducing nuclear factor-κB (NF-κB) and
glycans) release [164–167, 174]. Further, cata- mitogen-activated protein kinase (MAPK), which
bolic factors such as disintegrin and then contribute to the pathogenesis of osteoarthri-
metalloproteinase with thrombospondin motifs tis [174]. Recently, there are findings seen in the
(ADAMTS), cathepsins, and receptor activator of subchondral bone area which may be due to an
nuclear factor κB ligand (RANKL) affect bone imbalance in remodelling between bone resorp-
and cartilage metabolism and ultimately erode tion and bone formation which may result in
the bone [168, 169] which are activated by TNF-α diminished tissue mineralization, loss of stiffness,
and IL-1β. Fragments of fibronectin and collagen and bone thickening [175, 176]. Certain neuro-
are reported to further stimulate the release of peptides from the synoviocytes such as Substance
proinflammatory cytokines and their production, P contribute to inflammation and pain inside the
chemokines, and MMPs, thus resulting in a joint. Growth factors such as TGF-1β and IGF-1
vicious cycle of increased protease production are also involved in the disease process [163].
[140]. Aggrecan, which is a large multidomain Another interesting finding in osteoarthritis is
proteoglycan component of articular cartilage, the release of exosomes from neutrophils and
provides cartilage compressibility and elasticity synovial fibroblasts which have been detected in
under normal circumstances, but it then deterio- OA and RA synovial fluid. Exosomes occur natu-
rates over time as one ages. In an osteoarthritic rally from many tissues and cells arising via the
condition, proteases that cleave to aggrecan can endocytic pathway from the endosomal cell com-
trigger the release of its G3 domain (MMP-2, partment where they are stored in multivesicular
MMP-7, MMP-9, and MMP-13) and which ulti- bodies of late endosomes and are released in
mately form the fibronectin-aggrecan complex short bursts by exocytosis upon fusion with the
(FAC). Loss of aggrecan is a critical event in an cell membrane. They are responsible for cell-cell
early degenerative process, beginning at the sur- communication and epigenetic modifications.
face and eventually affecting the deeper layers of Exosomes could modulate joint pathology espe-
the articular cartilage. FAC can then stimulate cially because their release is influenced by
cytokines and the release of MMPs. The by-­ senescence and hypoxia which are present in
product which is fibronectin-aggrecan complex osteoarthritis [175]. MSC-derived exosomes
(FAC) is a good indicator of a joint pathology, as stimulated repair of osteochondral defects in ani-
well as those patients undergoing microdiscec- mal models and cartilage damage in chondrocyte
tomy who are FAC+ prior to the operation. A cultures which involved increased cellular prolif-
therapeutic agent that can prevent the release of eration and infiltration [175, 177].
308 J. C. de Castro

 reparation and Clinical Application

P (HNP) has elevated levels of MMPs, nitric
of α2-Macroglobulin oxide (NO), prostaglandin-E, and IL-6 [181].
In a related study, the cartilage degration prod-
Several methods are available in the prepara- ucts FAC is found to be associated with pain
tion of autologous α2-macroglobulin. This is due to inflammation. The presence of FAC indi-
usually an office-based procedure approved by cates that lumbar epidural steroid injection will
the Food and Drug Administration for different respond positively to patients with radiculopa-
types of musculoskeletal conditions. It is thy secondary to a disc herniation. Similarly,
referred to as Autologous Platelet Integrated significant clinical improvements are also
Concentrate (APIC) protein-rich plasma observed following surgical microdiscectomy
(Cytonics) (Fig. 14.14). The system concen- [182]. In hip OA and femoroacetabular
trates α2-macroglobulin via centrifugation and impingement (FAI), FAC together with carti-
ultrafiltration with a tangential flow filter after lage oligomeric matrix protein (COMP) was
drawing 45 ml of peripheral blood [140]. also used as biomarkers with potential utility in
Treatment of α2-macroglobulin is based on its the clinical diagnosis and clinical management
multipurpose protease inhibiting ability. Wang [183]. With this inflammatory component
and colleagues have shown that α2M is a pow- in the joints and around it, autologous
erful inhibitor of many cartilages catabolic fac- α2-macroglobulin-rich concentrate injection
tors and it can attenuate posttraumatic OA has shown successful results, especially for
cartilage degeneration. It inhibits MMP-13 in a those positive with FAC, against proinflamma-
dose-dependent manner and further decreases tory cytokines especially TNF-α and IL-1β,
cartilage catabolic cytokines and enzymes IL-6, against metalloproteinases, and against
including IL-1β, IL-8, TNF-­α, GM-CSF, MMP- neurotrophic factors in the neuromusculoskele-
3, and MMP-9 [178]. Studies have also shown tal system [134, 140–145, 178–180].
that α2M inhibits ADAMTS-4, ADAMTS-5, Cytonics (Cytonics, West Palm Beach,
ADAMTS-7, and ADAMTS-12 which is upreg- Florida) Autologous Platelet Integrated
ulated by IL-1β [178–180]. ADAMTS-5 and Concentration (APIC™) System is an autolo-
MMP-13 specifically degrade collagen type II gous α2M treatment system with the intent of
where ADAMTS-5 is released during the early halting cartilage degeneration. The CYT-108 is
phase of an injury and MMP-13 shows a an α2M recombinant drug that can help slow the
delayed response. In the spine, Kang and col- progression of osteoarthritis in preclinical mod-
leagues found that herniated nucleus pulposus els [184]. A company named PuRxCell™

Fig. 14.14 Cytonics Corporation (Jupiter, FL, USA) processes alpha-2-macroglobulin (6× concentration) from autolo-
gous blood using an Autologous Platelet Integrated Concentration (APIC™) System
14 Regenerative Medicine Procedures Under Ultrasound Guidance 309

located at 200 Glades Road, Boca Raton, Florida I nterleukin-1 Receptor Antagonist
prepares PuRx-A2M kits. This company uses Protein (IRAP)
rapid platelet-poor plasma (PPP) ultrafiltration
processing kit to be able to extract Due to the proinflammatory cytokines that pre-
α2-macroglobulin (Fig. 14.15). This preparation dominate an inflammatory process, such as
is primarily used for peripheral nerve injuries TNF-α and IL-1β in the joints and peripheral
with associated neuropathic pains acting against nerves, there was a growing interest in addressing
the proinflammatory cytokines such as TNF-α, how these cytokines can be inhibited to counter-
IL-1β, and IL-6. This is also used for degenera- act a degenerative process. Interleukin-1 receptor
tive joint diseases [134]. Research is underway antagonist (IL-1ra) protein is a naturally occur-
to be able to understand better its specific mech- ring modulator of inflammatory and immune
anisms on peripheral nerve injuries and the dra- response and is an important therapeutic cytokine
matic success especially when it is injected in that acts as a receptor-binding antagonist against
affected nerves in an entrapment, age-related, IL-1a and IL-1b [185]. The amino acid sequence
and metabolic neuropathies using ultrasound-­ of IL-1ra is said to be 26% identical to IL-1β
guided hydrodissection procedures. [186]. By binding to the IL-1 receptor, IL-1 acti-

a b

c d

Fig. 14.15 Preparing an A2M solution (PuRxCell): (a) the next one is a protein filter that filters in the alpha-­2-­
Platelet-poor plasma (PPP) is extracted from about 40 cc macroglobulin (A2M) protein and filters out the smaller
of venous peripheral blood. (b) A total of about 8 cc of proteins. (d) After the filtration process, the stopcock in
A2M is extracted from PPP. (c) Using the PuRxCell tech- between filters is directed in such a way that the Plain
nology, PPP is filtered passing through two separate fil- NSS will push back the A2M trapped in the protein filter
ters: the first one is a cellular filter that filters out cellular back to the designated syringe and the process is
elements as it is gently pushed to the opposite side, and completed
310 J. C. de Castro

vates the nuclear factor kappa B (NFκB) path- from interacting with IL-1AcP, thus impeding the
way, triggering the transcription of genes for signaling capacity of the receptor [193, 197].
proteins involved in the inflammatory process Nature however has endowed IL-1 the advantage
such as cytokines and prostaglandins [187]. It is of transducing a signal to the cell even in an
also associated with activation of macrophages, extremely low concentration. It has been calcu-
monocytes, and stimulation of osteoclasts which lated that even with a 5% IL-1 availability, full
subsequently breaks down the bone and cartilage biological response can already be triggered.
matrix [188]. IL-1Ra is normally produced by This means that an excessively high amount of
monocytes or mononuclear cells which could be IL-1Ra must be available to inhibit the actions of
found at the synovial tissue and from keratino- IL-1, which is at least 10–100 times the concen-
cytes [189, 190]. In fact, the IL-1Ra of the periph- tration of IL-1 [193, 198].
eral blood mononuclear cells (PBMCs) may be a The therapeutic efficacy of a recombinant
useful marker for untreated early RA [187, 191]. molecule of IL-1Ra named anakinra, derived
There is an equilibrium that exists between IL-1 from Escherichia coli, has been evaluated to treat
and IL-1Ra which maintains a healthy balance in RA. It is available in combination with metho-
the tissues of the joints under normal circum- trexate and is approved by the US Food and Drug
stances. During an inflammatory process, TNF-α Administration for the treatment of rheumatoid
is thought to have a role in early RA, while IL-1, arthritis and is marketed as Kineret. It is self-­
being a more potent cytokine, will shift the equi- administered subcutaneously at a daily dose of
librium, and thus, a catabolic process ensues with 100 mg [199]. In the European Monotherapy
subsequent destruction of the cartilage inside the Study, which is a 24-week, placebo-controlled,
joint associated with bone erosion [192, 193]. randomized, double-blind, multicenter study, the
The IL-1 family consists of two inflammatory safety and efficacy of anakinra at 150 mg per day
agonists namely IL-1α and IL-1β and one natu- was examined. The study revealed that 43% of
rally occurring interleukin-1 receptor antagonist patients who took 150 mg/day achieved a clinical
(IL-1Ra). The two inflammatory agonists bind to response (ACR20) compared with 27% of the
the same signaling receptor and exert comparable placebo group. It showed a superior response in
biological effects on target cells. In vivo, how- RA for several indices of disease including the
ever, IL-1β is actively secreted and functions as number of swollen joints, number of tender
an extracellular cytokine while most of the IL-1α joints, Health Assessment Questionnaire, eryth-
is not processed to its mature form and remains rocyte sedimentation rate (ESR), and C-reactive
intracellular. Two different cell-surface receptors protein (CRP). Clinical responses (via ACR20)
are available for IL-1 – type I (IL-1RI) and type were noted to occur after 2 weeks of therapy
II (IL-1RII) [193]. IL-1RI is responsible for [200]. Radiologic images also confirmed a statis-
transducing the IL-1 signal to the cell [194]. With tically significant improvement in joint space
its long cytoplasmic tail, it binds with IL-1 by narrowing and several joint erosions as compared
forming a complex with IL-1 accessory protein to placebo at 24- and 48-week follow-up. Further,
(IL-1AcP). This bond activates a series of intra- the improvement was stable both clinically and
cellular phosphorylation events amplifying the radiologically even up to 76 weeks [193, 200] of
IL-1 signal and dictating the specific response of anakinra therapy. Consequently, the rate of bone
the cell [195]. On the other hand, the type II erosions is reduced as treatment is continued.
(IL-1RII) receptor with its short cytoplasmic tail This treatment can be singly or in combination
only serves as a decoy molecule that binds with with methotrexate is well tolerated and is safe for
IL-1 and locally titrates its activity [196]. As dis- patients with RA [201], although the frequency
cussed earlier, IL-1Ra is a competitive inhibitor of serious infection was slightly higher with its
of IL-1. IL-1Ra preferentially binds with type I use which is about 2.1% [202]. A newer drug
(IL-1RI) without the stimulatory activity we see such as canakinumab shares a similar effect with
in IL-1. Once bound, it simply prevents the IL-1 anakinra, and the safety and efficacy of both the
14 Regenerative Medicine Procedures Under Ultrasound Guidance 311

drugs on prolonged usage against RA remain elu- Osteoarthritis Outcome Score (KOOS) symptom
sive [203]. and sport parameters. However, at 12-month fol-
The possible beneficial effects of anakinra in low-­up, the expected clinical improvement was
osteoarthritis do not extend for more than a not achieved and thus the use of Orthokine could
month due to its limited persistence in the joint not be recommended [216]. In 2009, Baltzer and
space when injected intraarticularly. It could colleagues did a controlled clinical trial with an
however dampen pain and swelling in an erosive observer-blinded follow-up of 104 weeks after
OA of the hand [204–207]. treatment with Orthokine. In this study, Orthokine
showed a statistically significant improvement
Autologous Conditioned Serum (ACS) based on Patient Reported Outcome Measures
Autologous conditioned serum (ACS) has been (PROM) compared to saline and hyaluronic acid
developed in 1998 and used clinically to treat [217]. In 2010, an in vitro study was conducted
OA, RA, and spine disorders. ACS is prepared by Rutgers and colleagues to investigate the
from peripheral white blood cells by initially effect of Orthokine on cartilage proteoglycan
drawing 60 ml of peripheral venous blood and metabolism and cytokine production. The aim
then placed into a syringe containing glass beads was to evaluate possible disease-modifying and
with CrSO4 to initiate monocyte activation. The chondroprotective effects. The study showed no
specimen is incubated for 24 h at 37 °C and blood difference between Orthokine and saline admin-
is recovered, clarified by centrifugation, filtered, istration [215]. Although considered to be an
and returned to the patient. The resulting autolo- option prior to arthroplasty, Orthokine still
gous is now selectively enriched for anti-­ seemed to provide a potential treatment for
inflammatory cytokines IL-1Ra, IL-4, and IL-10 patients suffering from degenerative joint dis-
and returned to the patient. ACS is injected six eases. With the predominance of inflammatory
times over a 21-day period, with each 2 ml solu- cytokines in advance cases, there is a need to then
tion injected into the knee joints [199, 208–210]. modify the approach of therapy toward the early
For epidural use, 1 ml each for 3 injections was stage of OA [218]. Other options such as
injected over a 21-day period [199]. This product α2-macroglobulin and mesenchymal stem cells
is marketed as Orthokine (Orthokine, Dusseldorf, as discussed earlier may offer better results.
Germany) in a Good Manufacturing Process Strumper conducted an unblinded, uncontrolled
(GMP) facility [199]. Since IL-1β is active at low retrospective cohort study to evaluate the effect
concentrations, it is important that a minimum of Orthokine in 47 patients with pain diagnosed
ratio of 1:10 (IL-1β to IL-1Ra) is required to with meniscal lesions. Results showed a signifi-
inhibit IL-1β activity [193, 211]. This process cant reduction in knee pain but with no evidence
also produces other beneficial growth factors and of meniscal repair [219]. Another study was car-
cytokines embedded in ACS such as vascular ried out in 2015 with 118 patients suffering from
endothelial growth factors (VEGF), platelet-­ OA, whose chronic pain made them eligible for
derived growth factors (PDGF) AB, hepatocyte surgery, but who chose treatment with ACS and
growth factor (HGF), insulin-like growth factor-1 physiotherapy. By 24 months, all patients
(IGF-1), fibroblast growth factor-2 (FGF-2), and reported more than 60–80% improvement in pain
transforming growth factor (TGF) [199, 212]. with only one opting for a knee replacement
ACS is based on studies that revealed that macro- [220]. In a subgroup analysis, ACS was found out
phages and monocytes are endogenous sources to be effective regardless of age, weight, sex and
of IL-1Ra [199, 213, 214]. Other data showed disease grade highlighting its potential to address
however the presence of TNF-α in ACS [215]. different sets of patient population [221].
Three studies on ACS showed conflicting Patients undergoing ACL reconstruction of
results on OA. Auw Yang and colleagues formed the knee usually present with elevated pro-­
the current cohort and found statistically signifi- inflammatory cytokines, of which majority is
cant improvement of Knee Injury and IL-1β. In fact, there is evidence that IL-1β plays
312 J. C. de Castro

an important role in the pathogenesis of bone tun- Results showed gradual and sustained improve-
nel enlargement following ACL reconstruction. ment among those treated with ACS, while those
Studies have shown that IL-1β are elevated fol- receiving steroids showed improvement initially
lowing that procedure and continue to be elevated but then showed deterioration over the 6-month
several weeks thereafter [222–224]. In a study by study period [229]. A separate trial for patients
Darabos and colleagues, it has been observed that with lumbar disk herniation radiculopathy com-
IL-1β is increased up to 10 days postoperatively paring ACS against triamcinolone showed favor-
causing an osteoclastic activity following ACL able responses in the ACS group for both pain
injuries at the graft-bone tunnel interface. and disability over a 6-month study period [230].
Application of ACS intraarticularly showed a In a related study, Kumar and colleagues showed
healing effect on the ACL reconstruction of the improvement among patients diagnosed with
knee with a decreasing level of IL-1β concentra- lumbar radiculopathy treated with ACS present-
tion. After 10 days, the values of IL-1β become ing with a 6-week duration of painful radiculopa-
equal or even below the concentration compared thy but with absent motor deficits, no epidural
to the normal knee [222]. In a related study, injections done 3 months prior, and no opioids
Darabos and colleagues published a level 1 thera- given 6 months prior to intervention [231].
peutic randomized controlled trial study demon- One of the most common sport injuries is mus-
strating that ACS reduced bone enlargement with cle contusion followed by muscle strain. The
four injections after ACL reconstruction [225]. presence of a muscle strain, however, takes a toll
The incidence of Achilles tendon rupture is on an athlete, limiting his/her ability to return to
about 18/10,000 and is commonly seen among sports or if severe enough also affecting his/her
middle-aged men who exercise. Surgical inter- full recovery. In a study by Wright-Carpenter and
vention is very common to treat the tendon. Novel colleagues, the use of ACS was evaluated in
intervention however is available to treat such a second-­degree muscle strains based on MRI find-
condition. A study done by Genc and colleagues ings. Due to its inherent capacity to contribute
showed that injection of ACS showed positive his- specific growth factors which are essential for
topathological healing on day 15 and 30 and bio- muscle regeneration, ACS was used in this experi-
mechanical healing on day 15 in rat Achilles mental study using a control against Actovegin/
tendon. ACS treatment is said to lower the colla- Traumeel. Results showed a faster recovery time
gen type 3 density by day 30 [226]. In a related in the ACS group which was also confirmed by
study, Muller and colleagues showed the impor- MRI with an observed acceleration of the lesion
tance of paratenon in the Achilles tendon for the [232]. In another study, this time on muscle con-
effective healing of an injured tendon. Growth tusion done with mice, Wright-Carpenter and col-
factors cannot replace the absence of paratenon in leagues assessed ACS in stimulating growth
the healing process as it is limited in restoring factors to improve the proliferative activity of
blood supply nor providing local progenitor cells myogenic precursor cells. Mice were subjected to
[227]. Earlier studies by Majewski and colleagues experimental contusion injury at the gastrocne-
among rat Achilles tendons showed that ACS- mius muscle. One group received ACS at 2 hours,
treated tendons showed a thicker tendon with 24 hours, and 48 hours post-injury against a
more type 1 collagen and it presents with the ­control group that received saline injections. The
accelerated recovery of tendon stiffness and matu- histology results showed that satellite cell activa-
rity of repair tissue. However, it did not show any tion at 30/48 hours post-injury was accelerated
advantage as to its ability to withstand a load as and the diameter of the regenerating myofibers
compared to the untreated group [228]. was increased during the first week as compared
Goni described the effect of ACS among 40 with the saline control group. ELISA results con-
randomized patients with cervical disk herniation firmed an elevation of fibroblast growth factor
radiculopathy versus epidural application with (FGF-2) (460%) and transforming growth
methylprednisolone over a 6-month study period. factor-β1 (TGF-β1) (82%) as compared to con-
14 Regenerative Medicine Procedures Under Ultrasound Guidance 313

trols. The study concluded the advantage of ACS 60 years of age show a certain degree of symp-
in reducing the time of recovery from muscle tomatic knee [1, 234]. The total cost of total knee
injury [233]. arthroplasty is about US$57,000 with a mortality
rate of approximately 0.25% and post-op compli-
cations ranging from deep vein thrombosis,
 pecific Regenerative Interventions
S infection, and chronic pain [235]. With the pro-
uUnder Ultrasound Guidance jected increase of about 601% by 2030 annually
for a total knee replacement, it is imperative that
In this section, I will discuss which regenerative we have a clearer understanding of the different
interventions will be appropriate and for what factors contributing to its development together
indications. I will also include some techniques with an earlier and better detection to lower its
on how to approach it under ultrasound guidance. progression [236]. On the other hand, non-­
I will not include all musculoskeletal areas as surgical treatments such as physical therapy, anti-­
they will be discussed separately and elaborately inflammatory, and analgesics medications have
in some parts of this book. Hopefully, this all modest and short-term efficacy at best [237].
approach will help readers and practitioners Such is the need to find new, effective, and sus-
choose the right regenerative interventions based tainable ways of treating osteoarthritis.
on scientific clinical evidence. As this field is still Different regenerative treatments are available
evolving, I expect that some indications will con- for treating osteoarthritis, the most common of
tinue to change over the years as we continue to which is platelet-rich plasma (PRP) therapy
understand the specific roles of each regenerative (Fig. 14.16). Depending on the platelet concentra-
intervention with newer techniques and newer tion, it could be an autologous conditioned plasma
regenerative procedures discovered and studied. (ACP) where the platelet concentration is about
two- to threefold greater than baseline or a plate-
let-rich plasma where the platelet concentration is
Joints about four- to sixfold greater than baseline [238].
Leucocyte concentrations of the PRP are further
Among the most common indications for doing subdivided into leucocyte rich (LR) or leucocyte
regenerative injection therapy is osteoarthritis. poor (LP) depending on the concentration of
About 10% of men and 13% of women over granulocyte or neutrophil but with high mononu-

a b c

Fig. 14.16 Ultrasound-guided joint injection of the knee. Needle is slowly inserted into the suprapatellar recess
(a) Planning the approach for ultrasound-guided injection with the bevel of the needle facing upward. Ensure that
of the knee. (b) Ultrasound-guided injection of the knee, the ultrasound probe is parallel to the needle during the
in-plane to the probe but short axis to the knee at the level needle injection. QT quadriceps tendon, PF prefemoral fat
of the suprapatellar recess, lateral to medial approach. (c) pad, F femur
314 J. C. de Castro

clear cell concentration [238, 239]. Bone marrow ferentiating into cartilage tissue [247]. Therefore,
concentrate (BMC) and its MSCs with or without ASCs differentiate into cartilage cells and fill the
PRP is another option. Moreover, adipose-­derived defects in the cartilage as well as treat OA. Exosomes
stem cells (ADSC) with or without cellular expan- in the ASC acting as paracrine mediators help treat
sion or ADSC which requires collagenase for OA by downregulating TNF-­α, IL-6, PGE2, and
enzymatic digestion are an equally important nitrogen monoxide which cause inflammatory
option [238]. Autologous chondrocyte transplan- response and thus prevent cartilage degradation.
tation which is another option for a focal defect Cho and colleagues in their recent study on knee
OA has showed limitations in its effectivity and OA showed a decrease in pain, improved joint
necessitates the development of a new treatment range, and decreased defect size in the short term
paradigm for it to be useful [240]. after directly injecting the joint using a combina-
Chang and colleagues published a level 1 sys- tion of ASC and PRP. No enhanced recovery how-
tematic review and meta-analysis showing the ever was seen in a 1-year and 2-year follow-ups
effectiveness of PRP over hyaluronic acid (HA) [248]. Infrapatellar fat pad (IPFP)-derived stem
and the results showed that patients with less cell is also an excellent source for cartilage regen-
severe OA achieved a superior outcome than eration with an easy harvesting access [249].
those with advanced OA [241]. Riboh and col- Bone marrow stem cell (BMSC) is another
leagues in 2015 performed a level 1 meta-­analysis great source of treatment for OA. Shapiro and
comparing LR-PRP and LP-PRP. This study did colleagues in a randomized controlled trial com-
not show any statistical difference between pared the effects of BMAC with saline in OA
LR-PRP and LP-PRP, although LP-PRP treat- using VAS and ICOAP constant pain and ICOAP
ment is ranked the highest based on the WOMAC Intermittent pain scores during pre-injection,
(Western Ontario and McMaster Universities 1-week, 3-month, and 6-month period on the
Osteoarthritis Index) and IKDC (International knee. The study showed significant pain reduc-
Knee Documentation Committee) scores [242]. tion from pre-injection pain scores [250]. Bone
The decrease in pain and improved functional marrow stem cells were used in the knee by
status for knee OA because of PRP injection, Centeno and colleagues with signficant improve-
however, showed a consistent decline in improve- ment in pain as shown in the outcomes scores. No
ment 12 months after injection based on the sys- added benefit therefore was noticed when
tematic review done by Souzdalnitski and lipoaspirate was added. Females tend to benefit
colleagues adding that the decline is still better from pain and functionality and those with higher
than the pre-injection scores [243]. A combina- body mass index reported improvement in func-
tion treatment of PRP and injectable HA hydro- tion [251]. Thus, the most common source of
gel in a study done by Yan and colleagues showed MSCs right now is BMAC for OA. Adipose with
hyaline-like cartilage (type II collagen) without its enzymatic process producing SVF is not
formation of hypertrophic cartilage in a porcine allowed by the FDA [252]. Also, another advan-
model evaluated at 6-month period [244]. Dallari tage of BMAC is its low oxygen tension which is
and colleagues have shown favorable outcomes advantageous for bone marrow stem cell induc-
of PRP in hip joint OA as compared to HA, based tion activity for chondrocytes which is kept at
on the visual analog scale, WOMAC, and Harris 2–3% oxygen tension [253]. In a study by
Hip Score with 1-, 3-, and 6-month follow-ups Kokubo and colleagues, greater proliferation by
but not at 12 months [245]. Singh and colleagues chondrocytes in the joint was noted when the
in a retrospective analysis of 36 patients showed oxygen tension is at 2% which is the same envi-
that those with Kellgren-Lawrence grade 1 and ronment deep within the cartilage as compared
grade 2 hip OA responded to PRP at 6 months with the ambient environment (21% oxygen ten-
with 86% and 82% pain relief, respectively [246]. sion). Normally, the joint has an oxygen tension
Adipose stem cells (ASC) exhibit a superior of 10% at the surface and 2% at the deep layer
ability than bone marrow stem cells (BMSC) in dif- close to the bone [254].
14 Regenerative Medicine Procedures Under Ultrasound Guidance 315

Pro-inflammatory cytokines originating from degeneration with fibrocartilage tears and degen-
synviocytes of the synovial layer inside the joint, eration is warranted. Severe osteoarthritis associ-
chondrocytes in the cartilage, and leucocytes that ated with osteophyte formation causing bony
infiltrate during the inflammatory process may be impingement and osteocartilagenous loose bod-
found in OA. In the early stages of inflammation, ies with loss of range of motion is contraindi-
TNF-α and IL-1β cause a cascade of reactions cated [256]. Ideally, physical therapy should
which in turn release the chemokines and neuro- precede any regenerative procedures to improve
trophic factors that cause additional pain and the range of motion and muscle is reeducated. A
inflammation [161]. It is for this purpose that separate chapter in this book will discuss the
α2-macroglobulin is used to counteract the details of injection in every joint.
effects of pro-inflammatory cytokines [134, 141]
and inhibit matrix metalloproteinases from the
damaged cartilage [140]. Tendons and Ligaments
Among the exercise for the knee joint, joint
distraction seemed to be the most plausible tech- Tendons are tissues that are interposed between
nique for enhancing chondrocyte regeneration muscles and tendons containing highly special-
using a pull traction device. It was found out that ized cells and a unique structure composed of
it promoted cartilage repair of osteochondral long type 1 collagen fibrils (70–80%) and a few
defects in weight-bearing joints [255]. elastic fibers. Most of the cells are made up of
highly metabolically active fibroblasts called
tenoblast which over time mature into less meta-
Joint Injection Technique bolically active tenocytes [257]. Collectively,
these cells comprise 90–95% of the cells in the
The use of either ultrasound or fluoroscopy is a tendons. An abundant extracellular matrix made
vital tool in ensuring that the area being targeted up of glycosaminoglycans and proteoglycans
is correctly injected and that the solution reaches surrounds the collagen and tenocytes. Tendons
the area appropriately (Fig. 14.17). are maintained by a dynamic interaction between
For regenerative treatment to have its optimal matrix metalloproteinases (MMPs) and their
and beneficial effect, mild to moderate joint inhibitors. Cytokines, mechanical load, and sys-

a b

Fig. 14.17 Ultrasound-guided injection of the posterior needle. Needle is injected from lateral to medial approach,
glenohumeral joint of the shoulder. (a) Patient is posi- in-plane with the probe. (b) Needle is injected from lateral
tioned in lateral decubitus position with the shoulder to be to medial, in about 45° angle targeting the posterior gleno-
injected in adducted and retracted position. A linear ultra- humeral joint. D deltoid, IF infraspinatus muscle and ten-
sound is used and positioned just below the spine of the don, HH humeral head
scapula with the probe tilted to visualize the entry of the
316 J. C. de Castro

temic conditions affect the tendon environment components of the extracellular matrix. This col-
[258]. When this balance is disrupted due to inju- lagen synthesis continues up to the remodeling
ries or trauma, there is tendon inflammation, ten- phase. Type I collagen increased its production
dinopathy, or tendon injury, all of which can during the modeling phase which usually occurs
cause pain. Remodeling of tendon after an injury 6 weeks following the injury. It is aligned in the
usually takes 2 years to complete healing, but full direction of stress until it is fully matured and
tendon regeneration is never completed [259]. usually would last for a year [272]. Ligamentous
Sedentary individuals surprisingly have a higher laxity is part of the consequence of ligamentous
level of proinflammatory factors such as TNFα, injury during the healing phase. There is greater
IL-1β, VEGF, and low levels of collagen-1. This stress relaxation as was shown in an experimental
in turn stimulates an increase of MMPs (MMP-2, study of the medial collateral ligament and which
MMP-9, and MMP-13) activity with the onset of will ultimately lead to posttraumatic osteoarthri-
low state of inflammation resulting in a higher tis of the joint [268], especially among athletes.
risk of tendon rupture [260]. Inflammation The joint instability resulting from the ligament
appears to be strongly influenced by exercise in injury together with the shear motion in the joint
animal models [261, 262]. This highlights the surfaces is the primary factor that causes osteoar-
role of early mobilization (about 3–7 days) in thritis [273].
injured tendons. Without inflammation, the heal- Platelet-rich plasma (PRP) therapy is one of
ing process and the subsequent changes that the most common regenerative interventions
characterize chronic inflammation (>12 weeks) used for tendon and ligament injuries. PRP-­
cannot take place. Therefore, exercise still repre- treated structures showed better collagen organi-
sents one of the best ways to influence tendon zation and increased metabolic activity,
healing [263, 264]. Early physical therapy with histologically [274]. Sanchez and colleagues
eccentric and concentric exercise after tendon showed excellent results for midportion tendi-
injury or surgery is strongly recommended [259]. nopathy injection as compared to only good
Caution, however, should be observed when results in insertional tendinopathy [275]. A recent
stretching the tendons as their elasticity is lost meta-analysis by Hurley and colleagues exam-
and becomes more rigid because of inflamma- ined 18 randomized controlled trials comparing
tion, which is why exercise at this point becomes PRP to arthroscopic repair alone of a rotator cuff
more challenging [265]. The ruptured force of injury with 1147 patients. The study showed that
healed tendons is only 56.7% of normal tendons patients treated with PRP had significantly
[266]. Further, healed tendon also has 80% of decreased rates of incomplete tendon healing for
normal tendon strength, 80% of normal tendon small-medium and medium-complete tears. They
stiffness, 40% of normal tendon stress [267]. also found out that the visual analog scale for
Like tendons, ligaments are made up of type I PRP-treated patients was low at 30 days and final
collagen, which is usually densely packed and follow-up as compared to the control group
cross-linked and therefore provides stability and [276]. Liddle and colleagues in a systematic
strength to this structure [268]. It is also rela- review done on the patellar tendon showed an
tively avascular with little innate ability for heal- overall improvement in pain and function with
ing [269]. The ligament has a lower percentage of 81% of patients able to return to their pre-­
collagen as compared to tendon but has a higher symptom level of activity [277]. Lateral epicon-
percentage of elastin, proteoglycans, and water dylitis is one of the most common areas being
[270]. In a ligamentous injury, fibroblasts during studied for PRP treatments. In a recent system-
the proliferative phase synthesize collagen III atic review by Ben-Nafa and colleagues, PRP
rather than type I but with a lesser volume during showed a slower onset of efficacy as compared
this phase of healing [271]. Like tendons, the with steroids. PRP, however, showed a longer-­
fibroblast in ligaments is also responsible for the lasting clinical effect as compared with steroids
synthesis of collagen, proteoglycan, and other that lasted up to 2 years [278]. The kind of PRP
14 Regenerative Medicine Procedures Under Ultrasound Guidance 317

preparation also matters in this treatment. Mishra ways of isolating PRP from different vendors.
and colleagues found that leucocyte-rich PRP With its low risk during the treatment, it remains
yielded better long-term results than the local a viable conservative treatment [287].
anesthetic injection and dry needling for tendi- Mesenchymal stem cells (MSCs) from bone
nopathy [279]. In fact, Fitzpatrick and colleagues marrow or adipose tissue are another option for
in a systematic review and meta-analysis study tendon and ligament regenerative recovery. They
showed the advantage of using leucocyte-rich have been shown to indirectly stimulate tissue
PRP for tendinopathies under ultrasound guid- repair by secreting trophic factors which activate
ance with a single injection [280]. residual recipient cells or modulate local immune
No randomized controlled trial is available for response. MSCs rarely if ever contribute to tissue
injuries affecting the ulnar collateral ligament of regeneration [287, 288].
the elbow using PRP. Surgery provides 83–90% The more recent approach for tendon and liga-
success rate for a complete ulnar collateral liga- ment regenerative treatment is the use of tissue-­
ment injury and a return to play for 9–12 months engineered approach where MSCs are seeded
post-surgery [281]. Other than the conservative into a scaffold prior to implantation or the use of
treatments for partial ulnar collateral ligament culture method where MSCs are cultured on a
injury, PRP holds promise as a possible treatment scaffold in vitro to produce a neotendon before
for the elbow. In a study by Dines and colleagues, they are implanted into an injured tissue. This
PRP showed 73% success rate among baseball approach provides a mechanical support to the
players treated due to partial UCL injury and a injured structure. The scaffold provides mechani-
return to play in 12 weeks [282]. cal stability and 3D template for regenerative tis-
Sports injury on the knee with anterior cruci- sue growth. To augment ligament and tendon
ate ligament tear (ACL) is usually treated with healing, PRP or growth factors are incorporated
surgery to restore functionality. PRP can be into the scaffold. The following are parameters to
incorporated during an ACL surgery, but studies ensure an effective administration of regenerative
show that they found no significant effect with products through tissue engineering and this
no difference in healing at the intraarticular por- includes the choice of cells, quantity of cell deliv-
tion of the ACL on MRI at 12 months [283]. ered, type of growth factor, drug delivery system,
However, in a partial ACL injury, Di Matteo and and type of biologically active molecules and
colleagues in a systematic review that between scaffold. The goal of tissue-engineered substitute
70% and 85% of PRP-treated partial ACL injury is to provide a temporary functional tissue while
patients return to their previous level of activity awaiting the natural regenerative process to set in
without surgery [284]. In another recent study [272, 287]. Another good source of stem cells
by Walters and colleagues, there was no differ- comes from tendon-derived stem cells (TDSCs)
ence noted in kneeling pain after a bone-­patellar-­ or endogenous ligament-derived stem cells
bone-­tendon (BPTB) autograft ACL (LDSCs) [287]. Some studies refer to this as a
reconstruction with intra-­operative administra- resident tendon stem/progenitor cell (TSPCs).
tion of PRP [285]. There are varied results in But even if they have potential for tissue regen-
PRP efficacy in tendons and ligaments, and one eration in vitro, it is unclear why TSPCs do not
way to address this difference is to standardized regenerate tendon under normal conditions [289].
preparation of PRP, in terms of composition, They have been found out, however, to have
quantity, and frequency to optimize results to superior tenogenic capacity in vitro with superior
induce maximal amount of healing [286]. tendon healing as compared with MSCs. These
Despite its promise effect, we are yet to see a types of stem cells however have limited supply.
definitive proof of efficacy in ligaments and ten- Leong and colleagues in their review note that
dons healing when using PRP. Multiple factors despite this progress, the only accepted treat-
contribute to this issue such as varied formula- ments to date are still surgery and physical ther-
tions from different physicians and peculiar apy [287]. Previous studies by Mautner and
318 J. C. de Castro

Blazuk also confirmed conflicting results with treated by injecting into the tendon sheath
regard to the use of stem cell in muscle, liga- (Fig. 14.19). In the case of an A1 pulley where it
ments, and tendons [290]. is diagnosed with acute stenosing tenosynovitis
(trigger finger), the purpose of the injection is to
minimize inflammation and to reduce pain. For
Ultrasound-Guided Injection other solutions like steroids, it is important that
of the Tendon and Ligaments direct tendon injection must be avoided to pre-
vent secondary damage to the tendon [294].
Ultrasound-guided injection of the tendon and However, PRP solution can be injected directly
ligaments provides a precision-guided interven- through the intratendinous substance [295].
tion to ensure that the needle is correctly placed,
the injured tissues are accurately targeted, vital
structures are avoided and adverse side effects Muscle Injuries
are prevented (Fig. 14.18). Ultrasound plays a
major role in demonstrating the pathophysio- Muscle injuries are quite common among ath-
logic state of a tendon or ligament. A high-­ letes, the most common of which is muscle strain
resolution ultrasound can display the different representing 12–16% [296]. One-third of these
phases of healing with its detectable echo den- athletes will usually suffer any one of the muscle
sity and echogenic changes and can further injuries in their lifetime with the lower extremity
check the integrity of the tendons and ligaments representing 92% of all these injuries [1, 297]. In
by performing dynamic imaging [268, 291, 292]. a 12-year study of the European professional soc-
Often the use of power Doppler imaging can cer leagues, injuries occurred in these four mus-
help identify the inflammatory status of the ten- cle groups: the hamstrings, hip adductors,
dons with signs of hyperemia and color Doppler quadriceps, and calf muscles in decreasing order
during injection to avoid injecting vital neuro- [298]. Hamstring injuries being the most injured
vascular structures [293]. muscle of the lower extremity have a reinjury rate
When injecting a tendon under ultrasound of about 12–21% [299] with some studies report-
guidance diagnosed with tendinosis, patients are ing as high as 39% within the same season [1].

a b c

Fig. 14.18 Ultrasound-guided injection of the supraspi- (c) The shoulder of the patient is in modified Crass posi-
natus tendon. (a) The patient is in a sitting position with tion. An ultrasound probe is in a coronal oblique plane
her right shoulder in a modified Crass position. An ultra- with the needle approaching from superolateral to infero-
sound probe is positioned in a coronal oblique plane, a medial direction targeting the supraspinatus tendon. D
short axis to the supraspinatus tendon. (b) Normal long-­ deltoid, SS supraspinatus tendon, C cartilage, GT greater
axis ultrasound image of the supraspinatus tendon (SST) tuberosity, SD bursa subdeltoid bursa, BT biceps tendon
inserted into the greater tuberosity (GT) of the humerus.
14 Regenerative Medicine Procedures Under Ultrasound Guidance 319

a b

Fig. 14.19 Ultrasound-guided injection of the A1-pulley geal joint. (b) Ultrasound-guided injection of the
of the 4th digit. (a) Hypoechoic swelling of the A1 pulley A1-pulley and flexor tendon sheath, in-plane approach,
of the flexor tendon at the level of the metacarpophalan- long axis to the flexor tendon using PRP

In a muscle injury, two subsequent stages of ferentiate into myoblasts which are also stimu-
responses are observed at the muscle level. In the lated by IL-4 and Il-10 in vitro. These myoblasts
first phase, which is referred to as degeneration, a will eventually fuse with one another, replacing
given muscle injury leads to death at the cellular the injured muscle tissue [301]. Satellite cells are
level. There is increased permeability of the sar- usually found between the plasma membrane and
colemma of affected myofibers with subsequent the basal lamina surrounding the muscle fibers
release of cytokines. These cytokines can stimu- and this plays a crucial role in the regeneration
late immune and inflammatory cells into the area process. With each regeneration, these satellite
which is primarily made up of neutrophils during cells return to a stage of quiescence until such
the acute stage and subsequently followed by time that it is needed again [302]. Other non-­
macrophages (M1) after 48 hours. These early muscle stem cells are also capable of regenera-
macrophages (M1) stimulate inflammatory cyto- tion. Finally, when regeneration is fully
kines such as TNF-α, IL-1β, and interferon completed, which is usually within a month, the
gamma (IFN-γ). These cytokines increase cell new muscle cells are indistinguishable from
proliferation and satellite cell activation. This ini- existing mature muscle cells [303]. Interestingly,
tial inflammatory response is followed by the physical exercise promotes regeneration of mus-
proliferation of M2 macrophages. It is in this sec- cle tissue through rebalance of M1 and M2, but at
ond phase that these macrophages (M2) are asso- the same time increases their numbers by exer-
ciated with tissue repair and satellite cell cise [304, 305]. An exception to this type of
differentiation. It ultimately suppresses inflam- regeneration is during a volumetric muscle loss
mation and phagocytizes unwanted debris from (VML), which is usually secondary to combat
the necrotic muscles [300]. In the second phase, injury, trauma such as in car accidents, tumor
macrophages (M2) play an active role by secret- ablation, bone fracture fixation, and degenerative
ing cytokines that activate muscle cell precursors diseases [306]. This type of muscle injury is
to repair the damaged tissues. Examples of these caused by a persistent functional deficit, and
cytokines include fibroblast growth factor unlike other injuries which fully recover,
(FGFβ), transforming growth factor-β (TGF-β), untreated VML does not regain its full functional
IL-4, IL-10, and IL-6. These help in the growth capacity [307]. To date, vascularized skeletal
and differentiation of muscle stem cells or acti- muscle tissue engineering and neural regenera-
vated myogenic cells. These precursor cells may tion are used for VML treatment together with
include satellite cells and non-muscle stem cells. rehabilitative exercises [306]. A major deterrent
As it is activated, these cells proliferate and dif- in muscle regeneration is the predominance of
320 J. C. de Castro

fibrosis and dense scar formation which eventu- colleagues showed that the use of PRP did not
ally leads to muscle contracture and chronic pain. promote muscle healing, and although the return
Fibrotic lesion formations are stimulated by to sport is shorter in the PRP group than the con-
TGF-β of which its member, myostatin or other- trol group, there was no significant statistical dif-
wise called growth/differentiation factor-8, inhib- ference noted considering that the clinical trials
its skeletal muscle maturation and persistent were regarded as very low in quality. Thus, there
activation of inflammatory cells and cytokines is a need for a larger number of high-quality trials
[308]. A natural inhibitor of TGF-β including [311]. Although these studies support the poten-
myostatin referred to as follistatin was found in tial of PRP as a regenerative solution to treat
animal models which promotes an increased muscle injuries, no clear benefit was seen in this
muscle mass [309]. Another interesting case is a retrospective study done by Sateyeshi and col-
denervated muscle tissue where the satellite cells leagues [312]. Rossi and colleagues in a random-
begin to be depleted over 7 months post-injury. ized controlled trial however showed that a single
During the first few months after denervation, PRP injection shortened the time to return to play
satellite cells usually increased in number sug- after an acute grade 2 muscle injury when com-
gesting activation from the quiescent stage to a bined with physical rehabilitation [296].
proliferative stage. However, by the seventh A comparative study of bone marrow aspirate
month post-denervation, the satellite cells concentrate (BMAC) and PRP and its compo-
decreased significantly. This satellite cell deple- nents by Ziegler and colleagues has shown the
tion then exacerbates muscle atrophy and wors- high concentration of IL-1Ra which is ideal for
ens reinnervation. Wong and colleagues then muscle strain treatment [232] followed by
proposed a reinnervation process and satellite LR-PRP. They have suggested that in cases where
cell transplantation process following 3-month vascularity and healing are desired for pathologi-
denervation in mice models [310]. cal or injured tissues, LR-PRP is a good choice
PRP for muscle injuries to regenerate muscle due to the high concentration of PDGF, TGF-β,
tissue and speed return to play provides minimal EGF, VEGF, and soluble CD40 ligand [313].
support based on the clinical evidence The mesenchymal stem cell is a good source
(Fig. 14.20). In a systematic review, Grassi and of regenerative intervention. Intramuscular trans-

a b

Fig. 14.20 Ultrasound of the medial gastrocnemius mus- pain after landing on one leg while playing basketball. He
cle. (a) Normal ultrasound image of the medial gastrocne- complained of persistent discomfort over the medial side
mius muscle. Note the uniform “starry-night” appearance of the calf muscle. The patient was given two sessions of
of the muscle fibers. (b) Ultrasound appearance of the PRP 2 weeks apart with complete relief after 1 month
affected side of a 44-year-old male with a history of calf
14 Regenerative Medicine Procedures Under Ultrasound Guidance 321

plantation of human bone marrow-derived stem benefit as compared to physical rehabilitation

cells in dystrophic mice restored dystrophin alone to accelerate return to sport, improve mus-
expression, although it did not improve contrac- cle strength, or influence reinjury rates after 2
tile function [314]. Another source is the muscle-­ and 6 months among athletes after an acute ham-
derived MSCs that are administered string injury [321]. In a retrospective study in
intramuscularly. This technique shows an 2020, among National Football League Players
increase in Pax7 (marker of muscle satellite cells) with grade 2 acute hamstring injuries, Bradley
satellite cell quantity, myofiber hypertrophy, and and colleagues showed that athletes who received
arteriogenesis in mouse hindlimb muscle [301]. leukocyte-poor PRP showed a faster return to
Adipose-derived stem cells in contrast to human play, although there is no significant difference
bone marrow stem cells showed myogenic poten- in days missed or time to return to practice [322].
tial in vitro and have greater myogenic differen- Ultrasound-guided injection of the hamstring
tiation, and thus aid in muscle regeneration by muscle is very challenging because most of the
modulating the inflammatory and fibrotic pro- major structures are deeply situated. To visualize
cess. With all that has been recommended, a suc- the appropriate target muscle, a curvilinear probe
cessful strategy for muscle regeneration at is needed for better penetrance. It is also possible
present has yet to be found [315]. to initially use a curvilinear probe, and depending
on the depth of the pathology, a shift to a linear
high frequency probe could be used for superfi-
Ultrasound-Guided Injection cial lesions. Both short- and long-axis scanning
of the Muscles must be done first to ensure the dimension of the
muscle injury. In the case of a hamstring injury,
One of the most common muscle injuries that the most common area of pathology is usually
require ultrasound-guided regenerative injection found at the biceps femoris long head (BFlh)
therapy is the hamstring muscle. In one study by which usually happens during an eccentric con-
Hamid and colleagues, a single-blinded RCT has traction [323]. Initially, an examination of the
shown that PRP reduces pain over 10 weeks and affected part may not be possible due to the inten-
reduces time to return to sports by 16 days for an sity of pain, although a palpable defect distal to
acute hamstring partial tear [316]. A retrospec- the ischial tuberosity may be a clue. A large
tive study by Park comparing PRP and steroid ecchymosis may appear only about 2–4 days
for grade 2 proximal hamstring injuries favors after the injury [324]. When this occurs, it is
the efficacy of PRP in a short-term pain relief important to evaluate the patient sonographically.
[317]. A single injection of PRP for grade 2 More than half of the injuries are intramuscular,
hamstring injuries among National Football whose size and presence by ultrasound have not
League Players revealed a shorter time of retrun been shown to correlate with the prognosis of
to play [318]. A recent, single-blinded, random- return to sports activity. An increase of echo-
ized controlled trial among 20 injured athletes genicity combined with fiber rupture, hemor-
with grade 2 hamstring injuries showed that PRP rhage, and/or edema is the main sonographic
combined with physical rehabilitation has finding. Ideally, 1–10 days are required to exam-
reduced time to return to play and increased the ine by ultrasound the injury since no abnormali-
concentration of growth factors compared to ties may be seen if the timing is too soon or too
physical rehabilitation alone [319]. In another long [325]. Hall suggested a rational timing for
study, however, by Manduca and colleague, a lit- doing an ultrasound of between 2 and 48 hours
erature review showed no significant effect on post-injury [326]. Theoretically, the size of the
return to play when using PRP compared to edema and bleeding will be increased during the
rehabilitation alone [320]. Similarly, a larger, first few hours/days after an injury and gradually
double-blind RCT using single PRP injection normalized in subsequent days and weeks [325].
with physical rehabilitation did not show any The most common location for hamstring inju-
322 J. C. de Castro

ries is at the midsubstance [327] typically at the At least 90% of patients over 60 years old
proximal muscle-tendon junction of the long have degenerative disk change on imaging with a
head of the biceps femoris (BFlh) as seen in the small minority requiring spine surgery highlight-
setting of excessive lengthening of the ham- ing the ubiquitous nature of this condition [331].
strings [328]. In 2005, the self-reported functional limitations
due to neck and back pain are about 24.7% of the
US population which is like other developed
Regenerative Treatments for Spinal nations in Europe. In a recent report among
Conditions Americans who have reported work disability,
30.3% stated that their disability was a function
Spine conditions represent a significant burden of neck and back problems [332]. Although
upon aging populations. And even though they imaging studies have found an association
exist in the general population, a whole spec- between IVD degeneration and severity of low
trum of spine conditions can have an impact on back pain, not all individuals with IVD degenera-
the mobility and quality of life of everyone. An tion are symptomatic, and gradual progression of
injury of the intervertebral discs (IVD) may be IVD degeneration is part of the aging process
the beginning of the end of the spine described [330]. However, Jensen and colleagues observed
as an IVD degeneration cascade. This structural that 3% of disc bulges and 38% of focal protru-
wear alters the stability of the motion segment sions may resolve spontaneously. Broad-based
of the spine and consequently results in diseases disc protrusions, extrusions, and sequestrations
affecting the disks, facets, and nerves in between showed a better prognosis with approximately
the spine. As had been observed, this spine 75–100% resolving spontaneously [333].
degeneration (IVD) can lead to degenerative The intervertebral disk is composed of three
disk disease (DDD), spinal stenosis, radiculopa- structures namely the cartilaginous endplates, the
thy, disc herniation, facet joint arthropathy, nucleus pulposus, and the annulus fibrosus. It is
instability, degenerative spondylolisthesis, and the largest avascular tissue in the body and has a
sacroiliac joint pain. Symptoms arising from very extensive extracellular matrix with a paucity
these conditions may include axial back pain, of cells with which to regenerate that matrix. It
neuropathic pains, or neurologic symptoms with relies on passive diffusion from adjacent endplate
loss of sensory and/or motor function [329, 330] vessels for nutrition, with resultant poor healing
(Fig. 14.21). potential. The center of the disk has very low

a b c

Fig. 14.21 Ultrasound-guided lumbar spine injection. L4L5 level facet joint using a curvilinear probe in a lateral
(a) Anesthetic applied over the entry site prior to the injec- to medial approach, in-plane to the probe but short axis to
tion of the regenerative injection therapy. (b) Ultrasound-­ the lumbar spine. SP spinous process, TP transverse pro-
guided injection over the facet joint at the L4L5 level. (c) cess, ES erector spinae
Ultrasound image of the injection site (using A2M) at the
14 Regenerative Medicine Procedures Under Ultrasound Guidance 323

oxygen and glucose concentration and high lac- 337, 340]. The IL-1 and TNF-α expression
tate level resulting in a low pH [334–336]. The increase matrix-degrading enzyme production
IVD is made up of an outer annulus fibrosus and while TNF-α stimulates nerve ingrowth [337].
a central nucleus pulposus. The outer annulus The nerve endings’ ingrowth extends into the
fibrosus is composed of tough lamellae of fibrous annulus. They are unmyelinated nerve fibers and
ring made from type I collagen fibers while the are susceptible to stromal changes, inflammatory
central nucleus pulposus consists of hydrophilic mediators, and pain information along with the
proteoglycan, elastin fibers, aggrecan, and type II sensory nerve signals. Consequently, the abnor-
collagen. The former provides tensile force resis- mal spinal nerve can cause abnormal spastic pain
tance while the latter distributes the force radially signals inducing low back pains [341]. As IVD
during a compression [334, 337]. The functional degenerates, the disc space height diminishes,
cells within the nucleus pulposus produce the with loading more pronounced posteriorly and
extracellular matrix (ECM) that binds to water. It consequently leads to asymmetric deformity, and
is bounded superiorly and inferiorly by cartilagi- then spinal stenosis sets in [337].
nous endplates which are securely attached to the Factors that affect the degeneration process of
vertebral bodies [334]. Bioactive proteins and the IVD include genetic factors, environmental
growth factors participate in the maintenance of factors, cigarette smoking, and biochemical fac-
IVD. Transforming growth factor (TGF-β) is tors. Surprisingly, 70% of this is caused by
associated with the synthesis of collagen and pro- genetic factors [342, 343]. Studies indicate that a
teoglycans, playing an important role in ECM BMI > 25 mg/m2 was an independent risk factor
accumulation. In fact, TGF-β is needed for end- for degenerative disk disease (DDD), and obesity
plate (EP) growth at the postnatal stage [338]. at a young age was a strong risk factor for future
Bone morphogenetic protein (BMP), which increases in the number of degenerated disks
belongs to TGF-β superfamily, promotes the pro- [342, 344]. It was also shown in another study
liferation and differentiation of multiple cell that there is an increased IL-6 and ­proinflammatory
lines. Together with IVD cells, BMP increases cytokines among obese patients that could fur-
the synthesis of proteoglycan, upregulates the ther contribute to disk degeneration [336, 344,
mRNA expression of type II collagen, and serves 345]. From the biochemical standpoint, the
as the mitotic agent of IVD [338, 339]. early breakdown of aggrecan leads to loss of
Intervertebral disk degeneration (IDD) with hydration of the disk which eventually leads to
its non-healing annular fissures has been impli- structural damage of the IVD over time. As
cated as one of the major causes of chronic low degeneration progresses, the catabolic agents
back pain. With advanced aging, cartilaginous (MMPs, ADAMTS, HRTA1, etc.) and the inhibi-
endplates have decreased permeability and blood tors of anabolism (TGF-β) favor the extracellular
supply leading to alterations in the microenviron- matrix breakdown. This catabolic environment
ment of IVD that favors catabolism. Changes contributes to a degenerative cascade which in
characteristics of IDD include progressive loss of turn triggers the production of inflammatory
proteoglycans and water content leading to a less mediators leading to further matrix degradation
hydrated IVD and replacement of chondrocyte-­ products. As the severity worsens over time, pro-
like cells in the nucleus pulposus [336, 337, 340]. duction of MMPs 1, 3, and 13 and ADAMTS-4
Collagen type I fibers in the inner annulus fibro- also increased [336]. A by-product of cartilage
sus and nucleus pulposus replaced the normal degeneration is referred to as fibronectin-­
collagen type II. There is also an upregulation of aggrecan complex (FAC) and this can be used as
proinflammatory cytokines from the IVD cells, biomarkers for degenerative disk disease and
such as IL-1 and TNF-α, which leads to an radicular symptoms from herniated nucleus pulp-
increased sensitization of the rich network of osus [345]. FAC can further stimulate proinflam-
nerve fibers around the annulus fibrosus causing matory cytokines and release MMPs [140]. There
pain during normal activities of daily living [336, is a positive predictive value for response to lum-
324 J. C. de Castro

bar steroid injection when FAC is isolated in the matrix or inhibiting the inflammatory cytokines
epidural space [346]. that upregulate the matrix-degrading enzymes
Discogenic low back pain because of inter- [337]. An agent that inhibits the formation of
vertebral disc (IVD) degeneration is usually FAC will also be efficacious in the treatment of
chronic and persistent. IVD degeneration usu- low back pain [346].
ally represents ≥40% of chronic low back pain There is mounting evidence that PRP injected
[347]. Peng and colleagues in their prospective intradiscally for intervertebral disc degeneration,
clinical study of 4 years showed that 68.8% of with its rich content of growth factors, may help
patients with chronic back pain did not show any injured and degenerative discs during the early
change in pain and disability from their original stages of degeneration (Fig. 14.22). The remain-
pain. The study also showed a longer period of ing functional cells in the IVD once exposed to
low back pain [348]. For herniated and bulging these growth factors will respond with prolifera-
discs with signs of compressed nerves, a micro- tion and ECM accumulation, thus restoring the
discectomy is a favorable option. For patients function and preserving the structure of the
requiring a complete IVD replacement either by degenerated IVD. Several studies showed coher-
fusion surgery or by total disc arthroplasty, chal- ent evidence supporting the use of PRP intradis-
lenges are on the horizon [349]. In a retrospec- cally by fluoroscopic guidance, while at the
tive cohort study undergoing fusion surgery, the same time preventing surgery [351–353]. Further
return-to-­work rate was reported as 67% for non- studies also showed PRP to be effective in facet
treated patients compared to 26% of fusion- joint arthropathy, degenerative disc disease, and
treated patients. Moreover, 27% of the sacroiliac joint-related pain [354]. In a prospec-
fusion-treated patients required reoperation with tive, randomized, open-blinded endpoint study,
11% progressing to permanent disability com- they compare PRP with steroids among 40
pared to 2% in the non-surgical group [350]. patients with sacroiliac joint pain. The study
With this background, a more comprehensive showed that the PRP was more effective in 60%
option must be considered with the goal of and 90% of patients, while steroids were effec-
restoring and reestablishing a healthy IVD under tive in 75% and 25% of patients at 2 weeks and
a safe and effective intervention with long-term 3 months respectively [355]. A systematic review
pain alleviation results (>6 months). With regen- comparing PRP with posterior lumbar interbody
erative treatments, there is a need to focus on fusion versus posterior lumbar interbody fusion
either stimulating the production of extracellular in patients with low back pain showed lower low

a b

Fig. 14.22 Ultrasound-guided cervical spine injection. cle as the reference toward the C6 nerve root using
(a) Ultrasound-guided injection using PRP over the cervi- PRP. Note the needle tracking (white arrows) close to the
cal spine short axis to the spine, in-plane to the probe. (b) posterior tubercle. AT anterior tubercle, PT posterior
Ultrasound image of the injection with the posterior tuber- tubercle, TP transverse process, NR nerve root
14 Regenerative Medicine Procedures Under Ultrasound Guidance 325

back pain and faster bone union time among marker of axonal growth in a degenerated IVD
patients with PRP with autologous bone graft [363]. Interestingly, these proinflammatory cyto-
than autologous bone graft alone [356]. An kines are blocked by A2M and thus reversing the
in vitro study found that PRP can suppress the inflammatory process [134, 145, 148]. A2M also
proinflammatory degrading cytokines (TNF-α slows the progression of intervertebral disk (IV)
AND IL-1) and its mediators in the nucleus degeneration by inhibiting the effects of proin-
pulposus cells, thereby stabilizing nucleus pulp- flammatory cytokines [144]. Furthermore, A2M
osus cell differentiation [357]. Further, the prevents sensitization of nerve fibers in the IVD
growth factors in PRP have confirmed their and suppresses proinflammatory cytokines.
promising efficacy in the treatment of interverte- Limiting mobility in the spine in a discogenic
bral disc degeneration by preserving water con- low back pain will further help in pain control
tent, upregulating the expression of ECM, and [361] (Fig. 14.21).
maintaining disc height [338]. Percutaneous injection of stem cells is one of
Alpha-2-macroglobulin (A2M) is a protease the promising treatments to slow or reverse disc
inhibitor native to plasma that may help prevent degeneration or an alternative to disc arthroplasty
the formation of the fibronectin-aggrecan com- or spinal fusion procedures. Studies have shown
plex (FAC), which is a product of cartilage degra- that current surgical procedures fail to address
dation, thus relieving low back pain in patients the proinflammatory milieu of the discs, loss of
with degenerative disc disease (DDD) [346]. In functional cells and tissues, and the loss of matrix
the study by Montesano and colleagues, patients anabolism. The elimination of tissues or fixating
who are FAC+ within the disk, are more likely to it by surgery will alter spine biomechanics and
demonstrate clinical improvement following would not allow the opportunity for regeneration
intradiscal injection of autologous platelet-poor [364]. Studies have consistently shown that intra-
plasma rich in A2M [358]. This group of patients discal stem cell procedures can restore the
also responds with microdiscectomy from disc extracellular matrix of the disc, including the
­
herniation and epidural steroid injection [182]. proteoglycan content of the nucleus pulposus
Since pain generators in low back pain can [365–368]. One of the criteria for injecting stem
also arise from proinflammatory cytokines such cells intradiscally is to choose a cell carrier to
as TNF-α, IL-1, and nerve growth factor (NGF), effectively carry the progenitor cells into the
recent preclinical and clinical observations may nucleus pulposus to protect the cells from the
lead to the development of biologic agents target- harsh environment of the disc, promote engraft-
ing these specific cytokines [359]. Disc degener- ment, prevent cell leakage, and restore mechani-
ation with hypermobility or sometimes referred cal properties while regeneration is taking place
to as disc dynamic compression accelerates sen- [365]. An example of a cell carrier to support
sory innervation of lumbar IVD and increases the MSCs delivery into the disc is PRP/hyaluronic
levels of proinflammatory cytokines (TNF-α, acid/Batroxobin gel (PRP/HA/BTX) for cellular
IL-6, IL-8, IL-1, NGF), thereby initiating a cas- disc regeneration [369]. An undesirable migra-
cade of inflammatory reactions that causes low tion of MSCs can occur if the cell leakage is not
back pain [360, 361]. In addition, NGF promotes prevented. It could lead to an osteophyte forma-
nerve ingrowth into the disc, sensitizes dorsal tion. Thus, it is important to ensure a secured
root ganglion (DRG) neurons, and causes neuro- sealing technology in the annulus fibrosus and a
nal sprouting into the dorsal horn. In fact, NGF is stable cell carrier system [370]. Prior to the pro-
higher in painful discs [362]. The presence of cedure, the integrity of the IVD structure must be
nerve ingrowth into the pathological and degen- assessed to ensure that it is preserved as this kind
erated IVD is shown also by the presence of of interventional treatment will work only in mild
growth-associated protein (GAP-43), which is to moderate grades of disc degeneration [365].
under the influence of its key factor, the In some cases, it is also possible to home the
NGF. GAP-43 is recognized as the pathological MSCs to the IVD cells instead of injecting
326 J. C. de Castro

directly into the IVD to enhance the regenerative process of managing back pains. The surgical
capacity of the IVD cells as an alternative proce- option is not an immediate answer to an intrac-
dure to MSC injection. Using a Tie-2-positive table pain condition. There is a risk of adjacent
progenitor cell population, MSC homing level of degeneration as observed in spinal fusion
enhances the survival and regenerative capacity [374]. Regenerative medicine offers a great
of IVD cells. This Tie-2-positive progenitor cells alternative not only for those unwilling to
however decrease with aging and thus this strat- undergo surgery but also for those patients who
egy could be used instead to prevent the onset of are refractory to pain management. There is still
the degenerative cascade in IVDs [371]. a lot of work and research to do in regenerative
Intradiscal fibrin sealant is used as a function- medicine for degenerative disc disease, but to a
ing physical barrier between inflammatory con- large degree, a greater tendency is noted toward
stituents of the annulus fibrosus and the disc’s more conservative but effective regenerative
nociceptors [337]. It is also used as a treatment interventions [337].
for IVD-related symptoms in an injured annulus
fibrosus. Since the nucleus pulposus can leak
inflammatory cells into spinal nerves through a Regenerative Treatment
defective annulus fibrosus during a pathologic for Peripheral Nerve Injury
condition, fibrin sealant can serve as a barrier
limiting the outflow of these inflammatory con- Peripheral nerve injuries represent a major clini-
stituents into the dura, meninges, and spinal cal and public health problem that leads to func-
nerves. Further, while intradiscal biologic ther- tional impairment and permanent disability.
apy such as mesenchymal stem cells or PRP is Roughly 3% of all trauma patients have periph-
intended to treat and repair degenerated IVD, eral nerve injuries [375]. Unlike in the central
iatrogenic leakage may be incurred such that the nervous system where damaged neurons are
use of a fibrin is important to prevent such a sce- incapable of regenerating, axons in the peripheral
nario from happening [337, 370]. Fibrin there- nerves can regenerate after an injury though the
fore can act as a scaffold to prevent the leak from process is incomplete. This condition, however,
happening while the stem cells are injected to can lead eventually to neuropathic pains which
repair the degenerated IVD. Fibrin is a biocom- are characteristics of a fulminant inflammatory
patible composite hydrogel of fibrin and throm- process [376]. The terminal stump of the tran-
bin acting as a hemostatic agent, sealant, and cell sected peripheral nerve usually undergoes
carrier [337, 372]. Intradiscal fibrin injection is Wallerian degeneration which begins within 2–3
safe and effective for patients with low back pain days post-injury moving in both antegrade and
due to degenerative disc disease [373]. retrograde manner [377, 378]. Schwann cells in
Low back pain secondary to IVD degenera- the peripheral nervous system provide for a con-
tion is one of the most disabling conditions con- ducive microenvironment for the regeneration of
tributing to the number of days lost in work and an injured nerve [379]. The process involves
to the rising health conditions. The need to be dedifferentiation of the Schwann cells with pro-
prudent in diagnosing the problems and identify- liferation and migration to build the bands of
ing the most effective interventional treatment Bungner, which is a column of Schwann cells
with the goal of relieving the pain and address- within the endoneurial sheath, and then to redif-
ing the cause of the pain seems to be the most ferentiate again to form new Schwann cells
logical approach to do. Spine intervention target- around a regenerated unmyelinated peripheral
ing the painful annular fissures early will help a nerve [380, 381]. In fact, proliferating Schwann
long way in preventing the secondary effects of cells take the lead, and the regenerating axons
spinal deformities. A well-informed patient follow from the proximal terminal stump across
regarding possible treatments will help us iden- the injury into the distal nerve stump [382, 383].
tify which ones will have to be done first in the Myelin debris is also cleared by the Schwann
14 Regenerative Medicine Procedures Under Ultrasound Guidance 327

cells and together with macrophages are recruited terminal stump and thus the chances of the dis-
to the injury site and the terminal stump within tal stump recovery will decline over time, even
3 days to begin the complex process of axonal affecting the denervated skeletal muscle in its
regeneration and to release the growth factors, recovery [389].
chemokines, cytokines, and extracellular matrix Neuropathic pain represents 7–10% of the
(ECM) proteins [384, 385]. Other important population. It is secondary to metabolic diseases
growth factors also include the nerve growth fac- such as diabetes mellitus and degenerative
tor (NGF), glial cell line-derived neurotrophic peripheral neuropathy. Among diabetic patients,
factor (GDNF), and brain-derived neurotrophic neuropathic pain represents about 10–26% [390].
factor (BDNF) [386]. Peripheral nerve injury Among patients undergoing a surgical procedure,
regrowth continues at a rate of 1–3 mm/day pro- 73% of those complaining of persistent pain were
vided there are no deterrents during the process identified to be suffering from neuropathic pain
[378]. The inflammatory process in an injured [391]. Although this will not be fully discussed in
peripheral nerve will also release proinflamma- this chapter, the existence of this condition is of
tory cytokines including TNF-α, IL-1β, IL-6, primary consideration in pain discussions.
IFN-γ, and IL-18 [134, 141, 152, 377]. TNF-α Consequently, neuropathic pain, sensory loss,
serves as a biomarker of Wallerian degeneration and skeletal muscle denervation become a func-
in an injured peripheral nerve [134, 141]. tional impairment in patients with peripheral
Although peripheral nerve injury has different nerve injury. Thus, a novel interventional regen-
types, depending on whether one uses the Seddon erative procedure is a vital treatment option for
Classification or Sunderland Classification, it is patients with these conditions.
very important to know that types 1 and 2 of the In a study by Yu and colleagues on platelet-­
Sunderland Classification will show full recov- rich plasma, the use of PRP could promote nerve
ery, while the rest may need surgical intervention regeneration and repair in patients with p­ eripheral
for healing of the injured nerve to take place. nerve injury [392]. Also, in another study, PRP
Surgeons may need 8–10 weeks post-injury to do showed positive effects on healing in the nerve
a surgical intervention to ensure that healing does function as well as histological improvements in
not improve spontaneously [387, 388]. By that an injured peripheral nerve. However, more stud-
time, if no regeneration occurred, a surgical ies are needed to come up with more consistent
repair can be done to coaptate the nerve stump evidence-based conclusions [393]. The use of
that was severed. PRP on peripheral nerve injury together with
The time lapse for a nerve to fully regenerate appropriate rehabilitation exercises seems to
in the absence of surgical intervention will take have a promising future [394].
a toll on the regeneration process. Most likely, In a preliminary study by Lopez and col-
the regenerating axons will fail to reinnervate leagues using PRP among 45 patients with a
the denervated skeletal muscle with subsequent 3-month history of neuropathic pain, it showed a
fat infiltration. The consequence in the nerve pain reduction of 50% one-month post-PRP
could be any of the following: chronic axotomy injection and 70% at the end of the 3-month
of the neurons, which is a denervated axon iso- period. Half of the patients reported complete
lated from their neurons; chronic Schwann cell resolution of pain [395].
denervation, which is denervation of Schwann Alpha-2-macroglobulin (A2M) is a promising
cells in the distal nerve stumps; and chronic intervention for patients with peripheral nerve
skeletal muscle denervation, which is denerva- injuries with associated neuropathic pains. A2M
tion of the muscle due to a prolong severance of interacts with and neutralizes the pro-­
the peripheral nerve into the skeletal muscle inflammatory cytokines which are one of the
[389]. As a result of this observation, the delay causes of pain in peripheral nerve injuires as
in any treatment for the injured peripheral nerve shown in preclinical studies and reviews [134,
could be detrimental to the regeneration of the 141]. A2M can be safely delivered into an
328 J. C. de Castro

a b c

Fig. 14.23 Ultrasound-guided injection of the peripheral nective tissue and retinaculum of the median nerve. (c)
nerve. (a) Ultrasound-guided injection of the median The needle is redirected to hydrodissect the lower portion
nerve, medial approach, in-plane to the probe but short of the median nerve at the epineurium. MN median nerve,
axis to the nerve, using alpha-2-macroglobulin (A2M). FT flexor tendons, FR flexor retinaculum, the white arrow
(b) The needle initially hydrodissects the uppermost layer represents the needle track
of the perineurium to peel it off from the surrounding con-

affected peripheral nerve via an ultrasound-­ in ensuring the effectiveness of regenerative pro-
guided peripheral nerve hydrodissection proce- cedures in addressing musculoskeletal
dure [396] (Fig. 14.23). This technique is safe conditions.
and can deliver the solution for therapeutic pur-
poses [397]. Acknowledgment First and foremost, to the Faithful
Regenerative medicine is an evolving field God who allowed me to finish this manuscript during
these challenging times of COVID19 pandemic, who kept
that has attracted the attention of a lot of practi- me busy writing but at the same time keeping us safe from
tioners due to its potential to treat patients in a infection.
non-surgical way. But much to its promise of My family: my wife Kyna de Castro and two kids,
effective results, shorter recovery periods, and Rafael Bennett and Zarah Francine de Castro, for their
constant and unwavering support.
other breakthroughs, it is necessary for practitio- To my colleagues who inspired me to move on.
ners to provide patients with informed consent, a Psalm 84:11 – “For the Lord God is a sun and shield;
well-educated explanation of the procedures, the Lord bestows favor and honor. No good thing does He
and an end-point expectation of what the proce- withhold from those who walk uprightly.”
dure can offer. There is still a great need for hard
evidence-­based research such as determining the
length of the treatment, knowing the frequency References
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 Ultrasound-Guided Nerve
Hydrodissection for Pain
15
Management: From Anatomy
to Techniques

King Hei Stanley Lam, Yung-Tsan Wu,

and Kenneth Dean Reeves

Introduction this technique can safely and effectively treat car-

pal tunnel syndrome (CTS) [1–6]. Notably, the
The technique of ultrasound-guided hydrodissec- 20th edition of Harrison’s Principles of Internal
tion (HD) of peripheral nerves has become one of Medicine textbook now lists injection of 5% dex-
the commonly used methods to treat neuropathic trose as an alternative local treatment that does
pain in the pain, sports, and musculoskeletal med- not have the side effects of corticosteroid for CTS.
icine fields. There were randomized control trials The most extensively studied clinical condition
published in high impact journals showing that treated by ultrasound-guided HD of peripheral
nerves is CTS [1–10]. Other clinical studies have
also used this technique to treat neuropathic pain
Supplementary Information The online version con-
tains supplementary material available at [https://doi. related to deep nervous structures or neuro-axial
org/10.1007/978-3-030-98256-0_15]. spine [11], ulnar neuropathy at elbow [12], radial
nerve palsy [13], and meralgia paresthetica [14].
There was also review articles available which
K. H. S. Lam (*) summarize the rationale, methods, current litera-
The Hong Kong Institute of Musculoskeletal ture, and theoretical mechanisms of this technique
Medicine, Kowloon, Hong Kong [reference]. The aim of this chapter is to provide
Department of Family Medicine, The Faculty of an introduction and overview to this technique in
Medicine, The Chinese University of Hong Kong, order to assist physicians in better utilizing this
New Territory, Hong Kong ultrasound-guided HD for the treatment neuro-
Department of Family Medicine, The Faculty of pathic or nerve-related pain. However, it is by all
Medicine, The University of Hong Kong, means not a replacement of hands-on fresh
Hong Kong, Hong Kong
cadaver workshops which the author believe is the
Y.-T. Wu best way to learn and practice this technique
Department of Physical Medicine and Rehabilitation,
Tri-Service General Hospital, School of Medicine, before using it to treat real patients.
National Defense Medical Center, Nerve HD is a technique which uses high-­
Taipei, Taiwan resolution ultrasound-guided fluid injection to
Integrated Pain Management Center, Tri-Service separate nerves from a surrounding or adjacent
General Hospital, School of Medicine, National structure, usually the fascia, which is believed to
Defense Medical Center, Taipei, Taiwan constrict or irritate the nerve either during move-
K. D. Reeves ment or at rest [15, 16]. The vulnerability of
Private Practice of Physical Medicine and mixed sensory/motor nerves for circumferential
Rehabilitation, Roeland Park, KS, USA

© Springer Nature Switzerland AG 2022 343

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_15
344 K. H. S. Lam et al.

compression was demonstrated by Bennett [17], ing in abnormal friction/compression during

who developed the most commonly used animal nerve movement, altered gait patterns because
model of neuropathic pain by placing self-­ of limited ability to bear weight or antalgia,
dissolving ligatures about the sciatic nerve of and formation of scars or fibrosis about a sur-
rats. A key aspect of his approach was the exclu- gical/fracture site.
sive use of light constriction to prevent the 4. Idiopathic acute or chronic neuropathic pain
restriction of epineural blood flow; moreover, the without an apparent cause.
ligatures could be moved up and down the nerve
to ensure minimal indentation [18]. This light Neuropathic pain is defined as pain caused by
constriction led to prominent and rapid reactive a lesion or disease of the somatosensory system
morphological changes, and development of allo- [19, 20]. It usually has the following
dynia and hyperesthesia, therefore, provided a characteristics:
reliable animal model. Additionally, this model
provided a rationale to suspect that in humans, 1. Deep-seated pain with poor localization of the
the peripheral nerves may be more vulnerable to source of pain.
light compression and entrapment effects at mul- 2. The degree of pain is usually not proportional
tiple locations than that previously reported. to the degree of tissue/nerve damage.
Nerve HD techniques can be used to treat neu- 3. The pain can be sore, numb, or with electric
ropathic pain, or pain caused by nerve entrap- shock; presence of hyperalgesia and/or
ment/ injuries in the following conditions. These allodynia.
are listed alongside their proposed, but as yet, 4. A sensation of cold or heat can be felt on the
unconfirmed mechanisms. affected region, and the skin on the affected
area may appear bluish, similar in appearance
1. Sports injuries: sudden nerve elongation dur- to venous stasis.
ing sprain or strain injuries, which exceeds the
stretch limit of the semi-elastic nerve compo- A potential benefit of separation of nerves
nents of a nerve or forced nerve movement from the surrounding soft tissue with fluid and
through areas of fascial constrictions or with the fluid flushing, or enclosing the nerve to
through the bony prominences, e.g., forced treat neuropathic pain, is the release of pressure
movement of the common peroneal nerve on the “free nerves supplying the main nerves,”
about the fibular head during an inversion which are called “nervi nervorum” [21–25], out-
sprain injury. side the epineurium. These “nervi nervorum”
2. Osteophytosis/tendinosis/other degenerative innervate and regulate the function and discharge
changes with osteophytic changes which of the main nerves.
alters the course of a nerve or causes friction Additionally, “vasa nervorum,” which are
or nerve irritation within the areas of chronic small blood vessels on the surface of the nerves
tendinosis, ligamentosis, or osteophytosis are also present; the arteries supply nutrients to
which subsequently sensitizes the innervating the main nerve, and the veins drain away the
peripheral nerves or alters the free movement metabolites from these main nerves [26–28].
of the related nerves because of reduced flex- Entrapment of the vasa nervorum would likely
ibility when innervating through areas of result in stasis and ischemia and the potential
degenerated tissues. accumulation of toxins at the affected part of
3. Post-fracture or post-surgical pain: uncon- the nerve. In addition, it is postulated that lym-
trolled pain leading to central and/or periph- phatic drainage might be present outside the
eral sensitization; stretching of nerves to epineurium (Fig. 15.1). Therefore, the primary
facilitate surgical access or to avoid inadver- objective of HD is to release the entrapment of
tent nerve lysis, contusions at the time of the peripheral nerves by hydrodissecting the
injury with secondary nerve swelling result- nerves.
15 Ultrasound-Guided Nerve Hydrodissection for Pain Management: From Anatomy to Techniques 345

Fig. 15.1 Diagram

shows “nervi
nervorum,” “vasa Nervi
nervorum,” outside the Nervorum
epineurium [21]
Perineurium
Vasa
nervorum
Epineurium

Artery
Vein Endoneurium

Myelin sheath
of schwann cell

Current Methodology Normal part

of the nerve

Ultrasonography (US) is usually used in nerve

HD to guide needles and fluid (hydro) used to Swollen part
of the nerve
separate (dissect/ release) the nerves from the
surrounding entrapped soft tissues.
There are two methods of US-guided HD of
the nervous systems [29, 30].

 ethod 1 (In-Plane Approach, Needle

M
Perpendicular to the Long Axis
of the Nerve)
Fig. 15.2 Illustrates the needle position for method 1 of
hydrodissection of nerves. With “in-plane” technique,
Generally, when using method 1 for HD of first, the inferior surface of the nerve is hydrodissected
nerves, the needle is perpendicular to the long with the needle bevel positioned up; and thereafter, the
axis of the nerve, and the probe is perpendicu- superior surface of the nerve is hydrodissected with the
needle bevel positioned down
lar to the short axis of the nerve. The needle
is in-­plane to the transducer, and the tissues
above and below the nerves are hydrodissected. nerve looks oval and surrounded by anechoic
The needle first approaches the inferior surface fluid on US. A 25-gauge, 2-inch needle or a
of the nerve, with the needle bevel positioned 22-gauge, 2¾-inch needle is typically used, or
up, and the pressure of the injectate is used to a 22-gauge, 4-inch needle is used especially for
open the soft tissues around the nerve layer by performing hydrodissections of deeply seated
layer until the epineurium is surrounded by the nerves.
injectate. The same process is repeated with
the needle approaching from the superior sur-  eal Practice of This Technique
R
face of the nerve, with the needle bevel posi- The following links shows the real practice of
tioned down (Fig. 15.2). The hydrodissected this technique in clinical situations.
346 K. H. S. Lam et al.

https://www.dropbox.com/s/320rd6ncih6e73w/ 3. If the bevel of the hypodermic needle is posi-

RN%20HD%20combine%20%2B%20%20 tioned down, the injectate points and flows
name%20.mp4?dl=0 downward and the tracking of the needle is
The following link shows the real practice of upward, especially if a long and thin needle is
ultrasound-guided hydrodissection of the radial used (Fig. 15.4).
nerve, using method 1. 4. Usually, HD of the nerve is initiated from the
https://www.dropbox.com/s/kszoldfrkmjtkx8/ site where the nerve is most severely damaged
CPN%20HD%20new%20with%20name%20. or trapped. If the diseased nerve or the dam-
mp4?dl=0 aged/entrapped part of the nerve is long, the
The following link shows the real practice of same entry point can be used, with the trans-
ultrasound-guided hydrodissection of the com- ducer and needle pivoted to the proximal part
mon fibular nerve, using method 1. of the nerve and, thereafter, to the distal part of
the nerve to repeat the HD process (Fig. 15.5).
Clinical Pearls
1. The basic principle of US-guided HD of ner-
vous structure is that the fluid/injectate but not Direction of jet
the needle is the actual tool used to separate
the soft tissues. Therefore, after administering
local anesthetics at the superficial entry point Tracking of needle
of the needle, it is essential to visualize the
needle at all times during the procedure, par- Fig. 15.3 Illustrates the effect of bevel up position on the
direction of flow of the injectate and tracking of the
ticularly during needle advancement, during needle
which time the physician will continually
inject the fluid. The injectate separates the soft
tissues in front of the needle, and the needle
Tracking of needle
just moves through and into the space sepa-
rated by the fluid.
2. Pay special attention to the beveling of the
Direction of jet
needle; if the bevel of the hypodermic needle
is positioned up, the injectate points and flows
upward, whereas the tracking of the needle is
Fig. 15.4 Illustrates the effect of the bevel down position
downward, especially if a long and thin nee- on the direction of flow of the injectate and tracking of the
dle is used (Fig. 15.3). needle

Fig. 15.5 Shows the 1st step

sequence of HD of the 3rd step 2nd step
diseased nerve using
method 1. First, HD is
initiated from the site
where the nerve is most
severely damaged or
trapped; thereafter, using
the same needle entry
point, pivot the probe Proximal
and the needle to the Distal
more proximal and/or
distal part of the nerve Needle entry Nerve to be
and repeat the HD hydrodissected
15 Ultrasound-Guided Nerve Hydrodissection for Pain Management: From Anatomy to Techniques 347

5. This method can be used for HD of 2–3 nerves back to the top of the nerve, and the probe is
running parallel to each other and if all nerves turned “in-plane” toward the nerve to inject the
require treatment simultaneously (Fig. 15.6). fluid above it, with the bevel positioned down
when approaching the nerve to avoid making
https://www.dropbox.com/s/qqmmmk9atl- accidental contact with the nerve (Fig. 15.7). The
5ghpv/HD%20TN%20to%20CPN%20com- injected fluid should be visualized to be tracking
bine%20%2B%20name%20.mp4?dl=0 above and below the nerve.
The above link shows the use of method 1 to The real clinical practice of method 2 for HD
treat 2 or 3 diseased nerves running parallel to of nerves shown in the following link:
each other in real clinical practice. https://www.dropbox.com/s/9uchgjfwfskgsrp/
MN%20HD%20SAX%20to%20LAX%20
with%20Name.mov?dl=0
 ethod 2 (Out-of-Plane
M
with Subsequent In-Plane Approach) Clinical Pearls
1. Method 2 for HD of nerves requires good “out-
The needle is parallel to the long axis of the of-plane” and “in-plane” techniques. Therefore,
nerve; the probe is first perpendicular and there- we suggest extensive practice of this technique
after parallel to the long axis of the nerve. First, on fresh cadavers. A doctor is not proficient in
an “out-of-plane” technique is used for HD of the method 2 but with good method 1 skill can still
nerve from the surrounding tissues. The nerve perform in-plane HD perpendicular to the
should be confirmed to be freed from the sur- short-axis of the nerve first, followed by HD of
rounding soft tissues by visualizing the anechoic the nerve in-plane with the needle and trans-
fluid surrounding the nerve (both above and ducer parallel to the long axis of the nerve
below the nerve). Thereafter, the needle is guided through another needle entry point.

Fig. 15.6 Showing the Normal part

method for using 1 of the nerve
needle entry for HD of 2 Nerves
two nerves running need to be
Swollen part
parallel to each other, treated
of the nerve
when both need to be
treated simultaneously,
e.g., the common Swollen
peroneal nerve lateral to fascicle
the tibial nerve, at the
level of the distal
hamstring

Fig. 15.7 Diagram Hydrodissection direction when

shows the relative using the in-plane technique
direction and movement
of the needle with the
nerve with method 2 for
HD of nerves Needle
Nerve to be
hydrodissected

Hydrodissection direction when

using the out-of-plane technique
348 K. H. S. Lam et al.

2. Generally, method 2 for HD can separate a The following link shows the tracking of
comparatively longer length of nerves from common peroneal nerve (CPN) from the dis-
the surrounding soft tissues. The end target is tal to proximal end and shows a swollen
the separation of the nerve from the surround- fascicle.
ing soft tissues and visualization of the
anechoic injectate above, below, proximal, Normal part
and distal to the hydrodissected nerve. of the nerve

I dentification of Nerve(s) Indicated

for Treatment Swollen part
1. The pathologic nerves/entrapped nerves are of the nerve
usually more swollen compared to the
healthy counterpart. The cross-sectional
areas of the entrapped nerves are usually
found to be double or even triple in size in
comparison to the healthy nerves (Figs. 15.8,
15.9, and 15.10).
2. One of the fascicles of the entrapped/diseased
nerve is swollen and much bigger than the rest
of the fascicles within the same nerve
Fig. 15.8 Illustrates a swollen pathologic nerve with
(Figs. 15.11, 15.12, and 15.13). twice the cross-sectional area of the healthy nerve

Fig. 15.9 Shows normal common fibular nerve with a normal cross-sectional area of 9 mm2

Fig. 15.10 Shows an abnormal/swollen common fibular nerve with a cross-sectional area of 22 mm2
15 Ultrasound-Guided Nerve Hydrodissection for Pain Management: From Anatomy to Techniques 349

Normal or sligtly
swollen nerve

Swollen
fascicle

Fig. 15.13 Shows slightly swollen nerve with swollen

nerve fasicle with a cross-sectional area of 3 mm2

The following link shows direct transducer

Fig. 15.11 Shows one or more of the fascicles with a palpation and snapping of the superficial radial
cross-sectional (CSA) of more than 2 mm2; the whole
nerve may have a normal CSA or may be slightly nerve against the first compartment wrist exten-
swollen sor and reproduce the neuropathic pain the patient
is usually experiencing with the proximal inter-
section syndrome.
https://www.dropbox.com/s/nnfjt0idvb7e32g/
Proximal%20intersection%202%20no%20
sound%20.mp4?dl=0
Dynamic US of the nerves shows lost relative
movement of the some of the nerves to the sur-
rounding structures. The major example is the
loss of the “seesaw sign” of the tibial nerve and
common peroneal nerve in the sciatic nerve
sleeve during the ankle-planter flexion and dorsi-
flexion [31, 32].
The following link shows the dynamic US
Fig. 15.12 Shows the normal nerve with normal visualization of the loss of the “seesaw sign” of
fascicles the tibial nerve and the CPN in the sciatic nerve
sleeve during the ankle-planter flexion and
https://www.dropbox.com/s/igv46w- dorsiflexion.
gl8qch3cc/CPN%20from%20distal%20 https://www.dropbox.com/s/q586l7wjpa6aynj/
to%20proximal%201.mp4?dl=0 Seesaw%20sign%20combine%201.mp4?dl=0
3. Direct digital/ transducer palpation of the sus- Elastography may show the whole or part of
pected swollen nerve or suspected nerve with the nerve with fibrosis or the hardened nerve
swollen fascicles reproduces the neuropathic (Fig. 15.14) [10, 33].
pain experienced by the patient. If the patient has no phobia of needles,
4. Using continuous dynamic US, a snapping/ US-guided dry needling can be utilized. The dry
sudden motion of a nerve against a surround- needle is placed as close as possible to the dis-
ing bone, ligament, muscle, or tendon is eased part of the nerve and stimulate by vibration
observed, and it reproduces the neuropathic or electricity to assess the reproducibility of neu-
pain experienced by the patient. ropathic pain experienced by the patient.
350 K. H. S. Lam et al.

Fig. 15.14 Elastography image of the swollen radial under the present scanning conditions, corresponding to
nerve after injury with scar tissues. (a) Shows the left-side the B mode image on the left; the brown regions show that
B-mode image; the yellow circle outlines the swollen the scanned structure has a high density, and the green
radial nerve with the swollen fascicles in red circle; the regions represent soft tissues. (b) The red circular part of
panel on the right is the elastography image showing the the radial nerve shows similar hardness as compared to
relative hardness of the tissues enclosed in the square the scar tissue near the swollen radial nerve

The following link shows the dry needle stim- thetic solution are used for HD of nerves [7, 9].
ulation of the pathologic lateral sural cutaneous Recently, other injectate such as 5% dextrose,
nerve under US guidance; both of the two maneu- platelet-rich plasma (PRP), and hyaluronic acid
vers reproduced patient’s usual neuropathic pain were also used for HD [34].
over the lateral gastrocnemius. HD alone appears to be beneficial, as shown
https://www.dropbox.com/s/pney930r- in a clinical trial of patients with mild-to-moder-
bj15j64/Dry%20needle%20stimmulation%20 ate CTS, which compared the effect of HD with
of%20LSCN1.mp4?dl=0 saline injected to the intracarpal region (inter-
ventional group) and to the subcutaneous area
Injectate for HD beyond carpal tunnel (sham group). The results
Traditionally, a large volume of normal saline show significantly improved the Boston Carpal
and a small volume of steroids and local anes- Tunnel Syndrome Questionnaire score and
15 Ultrasound-Guided Nerve Hydrodissection for Pain Management: From Anatomy to Techniques 351

cross-­sectional area (CSA) in the interventional Downregulation of the Transient

group [4]. Wu et al. compared HD with 5% dex- Receptor Potential Vanilloid Receptor-1
trose and HD with saline in patients with CTS (TRPV1) Ion Channel
and found 5% dextrose to be more effective in The TRPV1 ion channel has been postulated to
treating median nerve entrapment [2]. In addi- be associated with chronic neuropathic pain [38].
tion, Wu et al. showed that HD with 5% dextrose Its upregulation is directly associated with persis-
is more effective than HD with steroid for treat- tent of chronic neuropathic pain, and dextrose
ing CTS [1]. Hence, the 20th edition of may directly or indirectly antagonize the TRPV1
Harrison’s Principles of Internal Medicine text- upregulation effects. The TRPV1 ion channel
book lists HD of 5% dextrose as an alternative was previously called the capsaicin receptor
local treatment that does not have the side effects (Fig. 15.15) because it is the only capsaicin
of corticosteroids for CTS. Moreover, Shen et al. receptor-containing TRP ion channel [39].
[5] revealed a single HD with PRP was more Capsaicin causes characteristic burning sensation
effective in reducing the CSA of the median by upregulating the TRPV1 channel. Mannitol, a
nerve than HD of single 5% dextrose for moder- 6-carbon-atom sugar, has been found to reduce
ate CTS. the burning sensation after exposure to capsaicin,
Su et al. [35] also reported HD with hyal- suggesting an antagonistic (calming) effect on
uronic acid has more short-term efficacy than HD TRPV1 upregulation. Dextrose, similar in struc-
with saline for CTS. ture to mannitol, has empirically been observed
Other studies have supported the use and effi- to have similar effect, although it has not been
cacy of dextrose solution to treat neuropathic formally tested using the capsaicin model devel-
pain [36]. Injection of 5% dextrose into the cau- oped by Bertrand et al. [40].
dal epidural space has been demonstrated by Chronic neuropathic pain may signify glyco-
Smigel et al. to result in prompt and consistent penia around the corresponding nerve(s).
multi-segmental post-injection analgesia and a Injecting dextrose may promptly correct this gly-
cumulative analgesic effect in patients with copenia and consequently reduce neuropathic
chronic low back pain with radiation to buttock pain. Moreover, 40% of our peripheral somato-
or leg [37]. In a retrospective data collection of sensory nervous system are small capsaicin-­
consecutive patients with severe neuropathic sensitive nerves (nerves with the TRPV1 ion
pain, Lam et al. demonstrated both the safety and channels on their surface), which are predomi-
efficacy of 5% dextrose solution without the use nantly C fibers, and have an apparent homeostatic
of lidocaine to treat neuropathic pain caused by role in monitoring the level of systemic dextrose
nerve roots or plexi in consecutive patients [11]. [41]. Both the brain and peripheral nerves have
Chen et al. [12] show HD with 5% dextrose was high and constant requirement for glucose [16].
as effective as HD of steroid for ulnar neuropathy When isolated C fibers are exposed to a hypogly-
at elbow. Two case reports also revealed HD with cemic environment by substituting D-glucose
5% dextrose was effective for treating radial with non-metabolizable L-glucose, it demon-
nerve palsy [13] and Meralgia paresthetica [14]. strated a dramatic (653 ± 23%) increase in dis-
This is of particular interest as in the absence of charge frequency, within 5 minutes and
lidocaine, optimal HD volumes can be utilized maximized after 15 minutes [42]. Hypoglycemia
without the concern for lidocaine toxicity [11]. results in the reduction of high energy substrates,
Given the benefit of injection at the nerve root e.g., ATP, leading to reduced activity of the ATP-­
and plexi level, a mechanism of action of 5% dependent Na + -K+ pump, resulting in progres-
dextrose injection at the somatosensory system at sive nerve depolarization and hyperexcitability.
the dorsal root level has been proposed [37]. Replacement of D-glucose can rapidly correct
Several hypotheses have been proposed to the above-said effects [42].
explain the effect of dextrose solution on treating Dextrose injection may hyperpolarize nerve
neuropathic pain such as the following. cells responsible for neuropathic pain and reduce
352 K. H. S. Lam et al.

Perceptions in brain: Thermal injuries:

Mechanical injuries: Extreme hottnes/ burn,
Pain, Stinging, and Contusion,
Itching Sensations or Extreme Cold/ice
Entrapment,
Pulled injuries etc
Acidosis
of different causes

Ca2+
Capsaicin
Na+

Fig. 15.15 Figure showing different stimuli, including cause influx of sodium and calcium and thence depolar-
mechanical stimuli (which include entrapment, pulled ization of the nerves, leading to signal perceived in the
injuries, direct trauma), heat, ice, acidosis, capsaicin, will brain

their depolarization and pain generating ability. ment ceases just outside the epineurium, and the
There are both potassium channels and TRVP1 injectate dissects and releases the entrapped soft
channels localized on capsaicin-sensitive nerves tissues around the nerves. It is crucial to have the
[43]. These potassium channels have receptors nervi nervorum and vasa nervorum fully released
for dextrose. The attachment of dextrose to the from the entrapment or abnormal external stimuli
receptor leads to opening of the potassium chan- and to be surrounded by the injectate. Therefore,
nel and thence transports potassium out from the the soft tissues surrounding the nerve will be
cell and hyperpolarizes the nerve cell [43]. hydrodissected layer by layer until the epineu-
In summary, when performing HD of nerves, rium has no further layers of fascia surrounding
the needle is guided by US to approach the it. A key observation here is that the nerve should
nerves. The skin is anesthetized by skin bleb by appear rounded rather than fusiform and is free
administering local anesthetics. Once the needle floating. Along with the release of the nerve, the
is under the skin, the patient usually does not feel injection of dextrose is expected to induce a
the needle movement if continuous HD with 5% calming effect on the effects of TRPV1 upregula-
dextrose solution is maintained. A key feature of tion and improves the vascular supply and venous
the technique is that the advancement of the drainage (may be lymphatic drainage as well) of
injectate/solution dissects the soft tissues in front the main nerves.
of the needle, without the involvement of the
needle. It is the injectate that opens the fascia or Acknowledgments The authors need to acknowledge Dr.
spaces in front of the needle. Needle advance- Dick Hui for drawing the illustrating pictures.
15 Ultrasound-Guided Nerve Hydrodissection for Pain Management: From Anatomy to Techniques 353

Conflicts of Interest Declare conflicts of interest or state domized double-blind trial. Arch Phys Med Rehabil.
“The authors declare no conflict of interest.” 2020;101(8):1296–303.
13. Chen SR, et al. Ultrasound-guided perineural injection
with dextrose for treatment of radial nerve palsy: a case
report. Medicine (Baltimore). 2018;97(23):e10978.
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 High-Frequency Peripheral
Nerve Ultrasound
16
Jeffrey A. Strakowski

Introduction significant advantage over other types of imaging

modalities. Another advantage of ultrasound over
High-frequency ultrasound has become the conventionally used imaging modalities is that
modality of choice for visualizing most periph- the peripheral nerve inspection is continuous and
eral nerves. It has a number of advantages over does not require the use of the reconstruction of
other imaging modalities that include its relative sliced images [65].
portability, low cost, lack of ionizing radiation, One limitation to the assessment of peripheral
and dynamic capabilities that facilitate seeing nerves with ultrasound includes substantial
moving tissue in real time [42]. In addition, ultra- dependence upon the skill of the operator. This is
sound has higher resolution for superficial struc- a factor with all types of peripheral nerve imag-
tures than conventional magnetic resonance ing; however, ultrasound requires considerable
imaging. The more recent development of ultra-­ training for both image acquisition and interpre-
high-­frequency transducers has led to unprece- tation. This also serves as an advantage with
dented visualization of superficial nerves [8]. highly skilled practitioners because with ultra-
Another advantage is that the ultrasound systems sound, the clinical assessment can be performed
are generally portable and can be used in an simultaneously with the imaging. This alleviates
office setting. This allows convenient and rapid the need from adhering to a very strict imaging
acquisition of information. Evaluations do not protocol and allows on-the-spot changes in the
have to be performed in imaging centers, and the regions visualized as needed, including side-to-­
point-of-care imaging results in the ability to side comparisons. This is particularly advanta-
obtain a diagnosis without delay. There are no geous when the findings are different than the
problems with patient claustrophobia such as is initial expectations.
often experience with magnetic resonance imag- Other limitations of conventional ultrasound
ing (MRI). There is also no limitation due to include the inability to penetrate bone and
metallic prosthesis, fragments, or medical decreased resolution with deeper structures
implants [31, 38]. The use of Doppler imaging including anatomic structures in patients with a
for assessing vascular structures also provides a higher body mass index [24]. Ultrasound is not
effective for visualization of the spinal cord or
the portions of the spinal nerves that are encased
J. A. Strakowski (*) in bone. It can be used effectively, however, for
Department of PM&R, The Ohio State University, the identification of anatomic landmarks as the
OhioHealth Riverside Methodist Hospital,
spinal nerves exit the spinal foramen. Improving
Columbus, OH, USA

© Springer Nature Switzerland AG 2022 355

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_16
356 J. A. Strakowski

technology has also allowing progressively better disorders of peripheral nerve over history and
imaging for deeper peripheral nerves. physical alone. Techniques are available that can
Electrodiagnosis has traditionally been the provide relatively good localization of abnormal-
modality of choice for peripheral nerve assess- ities of most nerves and examination of even very
ment for both focal and generalized neuropathies distal segments of nerves [22]. When used in
[21]. The value of ultrasound in this role and proper context, electrodiagnosis should be used
increasingly more apparent and its use has to refine and narrow a differential diagnosis that
become routine in many centers for this purpose. has already been established with the history and
The modalities are complementary when used to physical.
diagnose peripheral nerve disease. Conventional nerve conduction studies (NCS)
Successful sonographic imaging of peripheral are of primary importance for the assessment of
nerves requires an in-depth knowledge of periph- focal neuropathies [34]. When possible, the nerve
eral nerve anatomy as well as the surrounding tis- being examined should be stimulated on both
sue. Image optimization and proper scanning sides of a suspected lesion to assess for both focal
techniques are needed for appropriate visualiza- slowing and change in the duration and ampli-
tion. Ability to accurately measure nerves is tude of the waveform. This provides the most
needed for distinguishing normal and abnormal sensitive measure for the identification of both
anatomy [58]. Other visible internal characteris- the presence of a neuropathy and the best indica-
tics can be used to help distinguish normal and tion of relative severity [41]. Distinguishing the
diseased peripheral nerve. Ultrasound can be extent of neurapraxia versus axonotmesis of a
valuable for the assessment of both focal and gen- focal neuropathy should be considered one of the
eralized neuropathies. The dynamic capability of most valuable contributions of electrophysiologic
ultrasound also makes it the ideal imaging modal- testing. This is a distinction that cannot be reli-
ity for guided peripheral nerve procedures [27]. ably provided by imaging modalities. A relative
Electrodiagnostic techniques and high-­weakness of electrodiagnostic testing is that it is
frequency ultrasound provide complimentary not able to reliably distinguish between neurot-
diagnostic information for assessing focal neu- mesis and a complete functional axonotmesis.
ropathies. Electrodiagnosis provides primarily When NCS abnormalities are discovered, suf-
physiologic information about nerve function. ficient testing should be performed to localize the
Ultrasound is primarily an anatomic assessment. lesion with the most precision possible. When
Both together can provide detailed information possible, the nerve should always be tested above
that in summation has more practical value in and below the level of the lesion to assess sever-
many cases than either one alone. Both modali- ity. The most valuable prognostic information is
ties require extensive training and reasonable often the compound muscle action potential and
experience for an appropriate interpretation of sensory nerve action potential amplitudes distal
the findings. The testing, in all cases, should be to the level of the lesion. Enough sampling of
performed as an extension of an appropriately both normal and abnormal nerves should also be
detailed history and physical. done to determine if there is a more generalized
polyneuropathy present [15, 43].
Needle electromyography (EMG) provides
Integrating Electrodiagnosis the advantage of allowing investigation with
and Ultrasound for Diagnosis additional techniques of the physiologic function
of Peripheral Neuropathies of motor nerves, including those that are less
accessible for conventional nerve conduction
Electrodiagnosis studies [19]. Features of the EMG findings can
often provide a general sense of the chronicity of
The proper use of electrodiagnostic techniques nerve disease and sometimes help distinguish
can improve localization, define relative severity, neurogenic atrophy from other sources of muscle
and provide additional objective information in atrophy. The electrodiagnostic information
16 High-Frequency Peripheral Nerve Ultrasound 357

should never be used independently from the

clinical presentation, but instead integrated with
the clinical scenario to derive the correct
diagnosis.

Peripheral Nerve Ultrasonography

Virtually all peripheral nerves that can be evalu-

ated with electrophysiologic techniques can be Fig. 16.1 Ultra-high-frequency (70 MHz) sonogram of a
visualized with high-frequency ultrasound [53]. short-axis view of an injured saphenous nerve at the level
The exception to this is peripheral nerve struc- of the proximal foot demonstrating enlargement and dis-
tures that are obscured by bone such as spinal ruption of the internal fascicles and scarring of the epineu-
rium. This level of resolution facilitates inspection of
nerves. Ultrasound cannot effectively penetrate changes within portions of a millimeter. Note that the
bony cortex. Ultrasound can serve as an adjunct depth of the entire image is 6 mm
to electrophysiologic testing as an aid in both
performing the test and providing unique diag- facilitates recognition of structural nerve changes
nostic clues. Ultrasound can be used to facilitate over portions of millimeters (Fig. 16.1).
accuracy of needle placement in needle EMG as Electrodiagnostic techniques do not provide
well as assist in the localization for NCS for less localization with anywhere near that level of pre-
commonly tested nerves [7]. It is also helpful for cision for most nerves.
identifying anatomic variants as well as surgical By contrast however, electrodiagnostic studies
or traumatic alteration. can more easily provide a better overview of the
Whereas electrodiagnostic techniques provide health of the peripheral nervous system and
information on nerve function in focal neuropa- therefore more effectively localize the neuropa-
thies, high-frequency ultrasound provides ana- thy to a certain region of the limb. The meticu-
tomic information. Identification of changes in lous nature of ultrasound scanning for anatomic
peripheral nerves in pathologic conditions as nerve abnormalities makes this more challenging
well as surrounding anatomic structures can often if the general site of the lesion is not readily
provide more precise localization of an injury apparent from the history and physical. For this
than other methods. It additionally can provide reason, it is recommended to perform electrodi-
anatomic detail that explains the source of neu- agnostic testing prior to ultrasound scanning
ropathy. Ultrasound can be used to assist in the when it is anticipated that both modalities will be
diagnosis of focal neuropathies due to compres- used.
sion, trauma, and tumors. In some situations, it Electrodiagnosis is more effective for assess-
can provide information about the type and sever- ing the severity of a neuropathy. Despite some
ity of the injury. tendencies of appearance in axonal injury and
neurapraxic lesions previously mentioned, this
has not been consistently shown to be a reliable
Comparison of Electrophysiology indicator. There is significant variation seen with
and Peripheral Nerve peripheral nerves displaying conduction block.
Ultrasonography There can be focal swelling of the entire nerve at
the site of the injury, enlargement of a single fas-
Ultrasound has some strengths and weaknesses cicle, or even a subtle fusiform enlargement
relative to electrodiagnosis in the assessment (Fig. 16.2). In general, distinction between neura-
focal neuropathies. Ultrasound is often better for praxic and axonal injuries are much more reli-
more precise localization of a focal neuropathy ably made with electrodiagnostic techniques than
with resolution in the order of microns. This ultrasound.
358 J. A. Strakowski

Fig. 16.2 Sonogram of side-to-side comparisons of a is shown on the right. The symptomatic side has both
short-axis view of the fibular nerve at the fibular head. The enlargement of the entire nerve and internal fascicular
normal asymptomatic (ASX) side is shown on the left, enlargement (yellow arrow)
and the abnormal symptomatic side (SX) with neuropathy

Fig. 16.3 Sonogram of a long-axis view of a complete

neurotmesis of the median nerve in the forearm. Note the
enlarged appearance of the proximal stump and the
“empty bed” appearance of the residual sheath void of
nerve tissue (arrowheads)

The distinction between complete functional Fig. 16.4 Integration of electrophysiology and
ultrasonography
axonotmesis and neurotmesis cannot be made
with electrodiagnostic techniques prior to re-­
innervation in an incomplete lesion. This abnormalities. This knowledge can be invaluable
­differentiation is an important role of ultrasound when contemplating treatment options. There is
of traumatic injuries. The distinction is not clear value in both modalities, and many authors
always easy to make with imaging, but an “empty have concluded that ultrasound should be consid-
bed” appearance with retracted endings occurs in ered an integral part of routine testing in an elec-
neurotmesis (Fig. 16.3). Ultrasound generally trophysiological assessment [57]. Some of the
can also be used more effectively immediately electrophysiologic instruments are now being cre-
after an acute injury than electrodiagnostic tech- ated to have integrated ultrasonography (Fig. 16.4).
niques. Electrodiagnostic findings are typically
less conclusive until after enough time has
elapsed for Wallerian degeneration to occur. This  eripheral Nerve Anatomy
P
can be in the realm of 10–21 days depending on and Sonographic Appearance
the severity of the injury and other factors [61].
The clear advantage of ultrasound in focal neu- Peripheral nerves have an uninterrupted fascicular
ropathies is that it can demonstrate the anatomic pattern on ultrasound (Fig. 16.5). This differs from
source of the neuropathy. It can demonstrate areas the intercalated fibrillar pattern typical of tendons
of constriction, focal mass lesions, post-traumatic [10] (Fig. 16.6). The dark (hypoechoic) nerve fas-
scarring, anatomic variability, and even vascular cicles are intermixed with brighter (hyperechoic)
16 High-Frequency Peripheral Nerve Ultrasound 359

Fig. 16.7 Ultra-high-frequency (48 MHz) sonogram of a

short-axis view of the median nerve in the forearm. The
Fig. 16.5 Ultra-high-frequency (48 MHz) sonogram of a fascicular pattern and epineurium are highly conspicuous
long-axis view of the median nerve overlying the flexor and in contrast to the hypoechoic surrounding muscle.
tendons. Note the uninterrupted fascicular pattern of the The hypoechoic fascicles and hyperechoic epineurium
of the nerve in contrast to the intercalated fibular pattern give the nerve a “honeycomb” appearance
of the tendons

Fig. 16.8 Ultra-high-frequency (48 MHz) sonogram of a

short-axis view of the median nerve in the forearm. The
fascicular pattern and epineurium are highly conspicuous
Fig. 16.6 Ultra-high-frequency (48 MHz) sonogram of a
and in contrast to the hypoechoic surrounding muscle.
short-axis view of the median nerve overlying the flexor
The hypoechoic fascicles and hyperechoic epineurium
digitorum superficialis tendons. Note the fascicular pat-
give the nerve a “honeycomb” appearance
tern of the of the nerve in contrast to the fine fibular pat-
tern of the tendons
surrounding tissue [9]. It also assists to understand
connective tissue creating what is often referred to the relationship to adjacent structures (Fig. 16.9).
as a “honeycomb” appearance when viewed in Longitudinal views also provide valuable informa-
short axis [47] (Fig. 16.7). The fascicles consist of tion but are more difficult to obtain as they fre-
bundles of individual nerve fibers that are each quently curve out of the field of view (Fig. 16.10).
enveloped by the endoneurium. The perineurium Slight movement of the transducer should be per-
surrounds the bundle of nerve fibers creating the formed with this view, including medially and lat-
fascicle [49]. The size and number of fascicles erally to visualize the entire width, as well as
seen in nerves are highly variable depending on heel-to-toe rocking to remain reduces anisotropic
the nerve size and its location in the body [5, 42], artifact.
(Peer, 2008) (Fig. 16.8). The external sheath of the Peripheral nerves are accompanied by an
nerve is the outer hyperechoic epineurium. The tis- extensive vascular supply. The surrounding arter-
sue that lies inside the outer epineurium between ies and veins are relatively easy to identify, par-
the fascicles is often called the “inner epineurium” ticularly in larger nerves. Power and color
[12]. The short-­axis view of the nerve is typically Doppler can be used to assess flow (Fig. 16.11).
the best orientation to differentiate it from other Nerves also have an internal network of vessels
360 J. A. Strakowski

Fig. 16.9 Sonogram of a short-axis view of the tibial (hyperechoic) and surrounding muscle (hypoechoic), and
nerve at the level of the tarsal tunnel. The short-axis per- overlying flexor retinaculum can be easily identified. The
spective allows detailed inspection of all of the surround- fascicular pattern and epineurium are highly conspicuous
ing tissue and structures. In this view, the entire width of and in contrast to the hypoechoic surrounding muscle.
the nerve (which has begun to split into medial and lateral The hypoechoic fascicles and hyperechoic epineurium
plantar nerves) and position of the neighboring posterior give the nerve a “honeycomb” appearance
tibial artery and veins, flexor hallucis longus tendon

contained within their internal epineurium with

endoneurial vessels that traverse into the ­fascicles
[62]. The veins are compressible with alternating
transducer pressure, and the arteries can be iden-
tified by their pulsations (Fig. 16.12).

Imaging Strategies

Goals of imaging include reliably identifying the

nerve and distinguishing it from other tissue.
Fig. 16.10 Sonogram of a long-axis view of a nerve with
Learning effective scanning techniques to
surrounding muscle. Long-axis views are somewhat more
challenging for creating still images, and movement of the improve nerve conspicuity will enhance the iden-
transducer is required to visualize the width of the nerve, tification of normal and abnormal nerve. The
as well as add clarity to the proximal and distal ends if the image should also be optimized for reliable
nerve curves away from a 90-degree relationship to the
assessments and measurements as well as assess-
incident sound waves from the transducer
ment of the fascicular architecture. The nerve,
along with the surrounding tissue, should also be
compared in both short- and long-axis views. The
examiner should be familiar with the often more
conspicuous surrounding bony, soft tissue, and
vascular landmarks. Doppler imaging can be
helpful for distinguishing vessels from small
nerves [46]. Nerves are generally more conspicu-
ous when they are surrounded by tissue with dif-
ferent echogenicity. When a nerve is surrounded
Fig. 16.11 Color Doppler sonogram of a short-axis view by other hyperechoic structures, it is often more
of the tibial nerve at the level of the tarsal tunnel. The difficult to identify. In that circumstance, it is
Doppler flow is seen in the posterior tibial artery. The helpful to follow the nerve to a location where it
hypoechoic veins are seen surrounding the artery. Flow
can be demonstrated in the veins by alternating transducer is readily visible and trace it back to the region of
pressure interest (Fig. 16.13).
16 High-Frequency Peripheral Nerve Ultrasound 361

a b

Fig. 16.12 Sonograms demonstrating short-axis views collapse of the vein. Veins are often more conspicuous
of the great saphenous vein in the medial leg with varying than the smaller nerves. In this case, the great saphenous
transducer pressure. Veins will collapse with increased vein can be used to identify the less conspicuous neigh-
transducer pressure. (a) Light transducer pressure. (b) boring saphenous nerve
Slightly increased transducer pressure showing partial

a
b

Fig. 16.13 Sonograms demonstrating the relative con- alis (FCR) tendons, which are relatively isoechoic relative
spicuity of a nerve in different locations. Short-axis views to the median nerve. (c) The median nerve at the level of
of the median nerve are shown. (a) Unlabeled at the carpal the mid-forearm. At this location, the nerve is much more
tunnel inlet. Because the nerve is neighboring relatively conspicuous because it is surrounded by hypoechoic mus-
isoechoic tendons, the median nerve can be more chal- cle. When faced with a scenario in which the nerve is chal-
lenging to identify for a less experienced observer. (b) lenging to distinguish from the surrounding tissue, it can
Labeled structures at the carpal tunnel inlet including the be identified in a more conspicuous region and then fol-
flexor digitorum superficialis (FDS) and flexor carpi radi- lowed to the area of interest

Developing skill with the ultrasound transducer surrounding tissue more than moving the trans-
will also increase success with peripheral nerve ducer slowly [13]. Tracing back and forth rapidly
scanning. The transducer should be held with a when looking at branch points, smaller nerves, and
comfortable grip at the base that allows easy move- focal abnormalities within the nerve also improves
ment and good control and prevents fatigue visualization. A liberal use of conduction gel can
(Fig. 16.14). Scanning quickly but with good con- facilitate rapid movement of the transducer while
trol can enhance the contrast between the nerve and maintaining a clear image (Fig. 16.15).
362 J. A. Strakowski

termed anisotropic artifact [11]. It can be chal-

lenging at times to minimize anisotropic artifact
when moving the transducer because body tissue
is rarely completely in a straight line. Movements
of the transducer termed “toggling” and “heel-to-­
toe rocking” can be used to create a perpendicu-
lar incident sound beam through the tissue.
Toggling can be used in some circumstances
to distinguish nerve from other tissue. A nerve
can sometimes be difficult to distinguish from
surrounding highly reflective tendons. Tendons
Fig. 16.14 Demonstration of appropriate grip on the
base of the transducer for optimum control.
generally have a greater amount of anisotropic
artifact. Because of this property, toggling can be
used to help distinguish similar-appearing tendon
from a neighboring nerve. As the incident beam
is directed away from a perpendicular position to
the tissue, the nerve tends to maintain its appear-
ance better than the tendons [30] (Fig. 16.16).
The examiner should be attentive to the
amount of transducer pressure that is being
placed on the tissue. It is generally preferable to

Fig. 16.15 Demonstration of the use of a liberal amount

of transducer gel to facilitate rapid scanning for nerves of Fig. 16.16 Sonograms demonstrating the effect of tog-
the forearm. gling the transducer and anisotropic artifact. This is a
short-axis view of the median nerve at the carpal tunnel
also demonstrating the highly reflective tendons of the
Changing the direction of the incident sound flexor digitorum superficialis (FDS). (a) The transducer is
waves from the transducer has significant impact orthogonal to the carpal tunnel revealing the details of
on the appearance of the tissue. The underlying both the nerve and the tendons. Both tissue types are rela-
tively isoechoic, creating some challenge in reliably dis-
tissue is seen in the greatest detail when the inci- tinguishing the border of the outer epineurium of the
dent sound waves are orthogonal to the tissue. median nerve. (b) The transducer is toggled to cause the
Any deviation from that leads to increased refrac- incident sound waves to approach at a less than orthogo-
tion of the returning sound waves away from the nal position resulting in anisotropic artifact. The tendons
are prone to more anisotropy than the nerve. This, there-
transducer and therefore less detail. The loss of fore, results in greater conspicuity of the outer epineurium
clarity of the image resulting from a deviation of the median nerve. This shows the potential value of tog-
from perpendicular incident sound waves is gling when assessing the borders of peripheral nerves
16 High-Frequency Peripheral Nerve Ultrasound 363

use liberal coupling gel and light pressure. mapping. These concepts are discussed in more
Excessive pressure will deform the nerve as well detail in other portions of the book. Some ultra-
as the surrounding tissue. This is important when sound machines have a general setting for nerves,
assessing the shape of a peripheral nerve, particu- and some allow these features to be adjusted with
larly when performing measurements and assess- high precision.
ing flattening ratios in tunnel entrapments [17]. The frequency is measurement in millions of
The effect of the pressure can be even more pro- hertz (cycles per second) designated megahertz
nounced when the nerve is pressed against (MHz). High-frequency waves allow better reso-
unyielding bone such as the radial nerve at the lution of superficial structures but do not pene-
spiral groove (Fig. 16.17). In some circum- trate tissue as deeply as low-frequency waves
stances, greater transducer pressure can improve [24]. Most peripheral nerves should be assessed
the visualization of the nerve by compressing the at the highest transducer frequency available that
overlying tissue. This is particularly true of still provides adequate depth of penetration. A
deeper nerves [49]. Actively moving the sur- comprehensive assessment might involve visual-
rounding muscles and tendons can also be help- ization at different frequencies to inspect the sur-
ful for improving nerve conspicuity. rounding tissue in detail (Fig. 16.18).
Detailed knowledge of the ultrasound machine The depth should be set so the structures of
is also critical for optimizing the image. This interest encompass the majority of the screen.
includes applying the appropriate frequency, Having the depth set too high can leave wasted
image depth, focal zone, grayscale gain, and space and decrease the resolution of the nerve.

a b

Fig. 16.17 Sonograms demonstrating the effect of trans- compressed. The veins surrounding the artery are col-
ducer pressure on the image. This is a short-axis view of lapsed and the nerve displays flattening. (c) High trans-
the radial nerve at the level of the arm. (a) Light trans- ducer pressure brings the nerve even closer to the surface
ducer pressure results in the nerve being further from the as the tissue is flattened. The effect of the transducer pres-
surface. There is no deformation of the nerve and the sur- sure also slightly changes the position of the nerve and
rounding vascularity. (b) Medium transducer pressure neighboring muscle. The examiner should be vigilant
shows the nerve is closer to the surface and a greater about the extent of transducer being applied and the effect
amount of the underlying humerus is seen as the tissue is on the image
364 J. A. Strakowski

a affects the depth of the screen. The grayscale

gain is more analogous to the loudness of a radio.
It is used to affect the brightness of the image,
and its setting is often personal preference for the
degree of contrast between tissues (Fig. 16.21).
Grayscale mapping can be altered to affect the
b contrast between tissues and is also typically a
matter of personal preference.

Nerve Measurement

Nerves can be precisely measured with most

ultrasound systems. This is an important tool
when assessing nerve enlargement or compres-
sion in pathologic circumstances. Cross-sectional
Fig. 16.18 Sonograms demonstrating the effect of fre-
quency differences on the appearance of a short-axis view area measurement of the nerve in short axis with
of the tibial nerve at the tarsal tunnel. (a) 12 MHz image perimeter tracing is generally considered to be
demonstrating the nerve and some of the surrounding the most reliable and reproducible method for the
anatomy. (b) Ultra-high-frequency (48MH) image. There detection of enlargement [2] (Fig. 16.22). This
is considerably better visualization of the detail of the
nerve with the higher frequency. The lower-frequency has been shown to also correlate well with mea-
image demonstrates a broader view of the tissue surround- surements in cadaveric studies. This technique is
ing the nerve performed by tracing around the margin of the
hypoechoic nerve fascicles and inside the hyper-
echoic border of the outer epineurium with an
electronic caliper [36, 37, 45].
The transducer must be placed perpendicular
to the nerve to obtain an accurate cross-sectional
area measurement. An oblique view will result in
an inaccurately large measurement. Generally,
the smallest cross-sectional area measurement
that can be obtained in short axis reflects the
Fig. 16.19 Ultra-high-frequency (70 MHz) sonogram of
greatest accuracy [37, 51, 60].
the median nerve with an early bifurcation. Note that the
depth is set so that the nerve of interest encompasses a Cross-sectional area can be performed by an
large portion of the screen indirect method with the use of digital calipers.
With this method, an ellipse is created to pro-
With most peripheral nerves, the depth setting is duce the measurement. This method has good
very superficial (Fig. 16.19). The focal zone inter-­
rater reliability; however, many nerves
refers to the location where the ultrasound beam have an irregular circumference, particularly at
converges and is typically the site of the clearest entrapment sites, making them difficult to fit
image. This feature is not present on every type perfectly into an ellipse. The manual tracing
of ultrasound machine, but when available, it method is recommended for greater precision
should be placed at the level of the nerve being and accuracy [29].
inspected (Fig. 16.20). The diameter of the nerve can also be mea-
The grayscale gain affects the brightness of sured in long axis. This view and measurement
the image. This term is not to be confused with should always be included and compared to the
the gain on EMG machines, which essentially short-axis view when performing clinical assess-
16 High-Frequency Peripheral Nerve Ultrasound 365

a b

Fig. 16.20 Sonograms demonstrating the effect of the cantly deep to the level of the nerve with relatively poor
focal zone position on the appearance of a peripheral clarity. (b) The focal zone is placed at the level of the
nerve. A short-axis view of an ulnar nerve in the forearm nerve with significantly improved clarity
is shown. (a) The focal zone (yellow arrowhead) is signifi-

a b

Fig. 16.21 Sonograms demonstrating the effect of and surrounding muscle. (b) The gain is excessively low,
changes in the grayscale gain on the appearance of the with poor clarity as the image to too dark. (c) The gain
short-axis view of nerve and muscle. (a) The image with setting to create the optimum contrast between the nerve
the gain slightly high with less contrast between the nerve and muscle

ments. It is sometimes more challenging to surement obtained in long-axis view reflects the
obtain, particularly in smaller nerves. A tech- most accurate (Fig. 16.23).
nique of first localizing the nerve in short axis The surrounding tissue should be inspected in
and then slowly rotating the transducer to a long detail, and it should be confirmed that only nerve
view can be used to make this easier. tissue is being measured. The long-axis diameter
Because the diameter measurement should measurements should be correlated with the
reflect the center of the nerve, the largest mea- short-axis measurements to confirm accuracy.
366 J. A. Strakowski

a b

Fig. 16.22 Sonograms demonstrating the direct-tracing at the inner border of the outer epineurium. From this
method for obtaining cross-sectional area. (a) Short-axis measurement, the cross-sectional area is calculated
view of the median nerve. (b) Direct tracing of the nerve

used to localize focal injury with good accuracy

and precision, even within millimeters [23]. It
also provides anatomic information that can help
to identify the source of the neuropathy. This can
include nerve distortion in tunnel entrapments,
surrounding tissue injury, scarring, and com-
pressive masses [3, 25, 32] (Fig. 16.24). The
dynamic capabilities of ultrasound provide an
advantage over other imaging modalities.
Dynamic compression or subluxation of nerves
can be seen in circumstances where no abnor-
Fig. 16.23 Sonograms demonstrating the diameter mea-
mality would be identified in a static image
surement (yellow line) of a nerve in long axis. The mea-
surement is made from the inner border of the outer (Fig. 16.25).
epineurium Although ultrasound can provide some infor-
mation about relative severity of a focal neuropa-
Nerve size generally decreases when imaged thy, electrodiagnosis is generally the most
from proximally to distally as the branches leave effective modality for this role. Proper use of
the main nerve trunk. The cross-sectional area of nerve conduction studies, with stimulation both
nerves tends to be larger in taller individuals and proximally and distally to a lesion, can be used to
smaller in women. Nerve cross-sectional area distinguish a neurapraxic injury versus one with
also generally increases with age. For this reason, axonal loss. Ultrasound has an advantage over
the nerve should be investigated over sufficient electrodiagnosis in some traumatic injuries. It
length and different levels for adequate compari- can be used to differentiate a functionally com-
son when focal enlargement is suspected. plete axonotmesis from neurotmesis (Fig. 16.3).
­Side-­to-­side comparisons are also helpful in uni- These conditions cannot be distinguished with
lateral disease. electrodiagnosis. In addition, some electrodiag-
nostic clues, such as fibrillations and distal sen-
sory nerve action potential (SNAP) and
Evaluation of Focal Neuropathies compound muscle action potential (CMAP)
amplitude loss, are not present until the develop-
Ultrasound can provide valuable information ment of Wallerian degeneration, which can often
when assessing focal neuropathies and is an take many days after an acute injury. Ultrasound
excellent complement to the physiologic infor- findings are rarely limited by temporal factors to
mation provided by electrodiagnosis. It can be a significant extent.
16 High-Frequency Peripheral Nerve Ultrasound 367

a b

c d

Fig. 16.24 Sonograms demonstrating examples of fibular nerve at the knee tunnel being compressed and dis-
sources of peripheral nerve compression. (a) An ultra-­ torted by post-traumatic laceration tissue injury. (c)
high-­frequency (48 MHz) sonogram of a long-axis view Sonogram of a long-axis view of the median nerve at the
of the median nerve at the carpal tunnel being compressed carpal tunnel being compressed at the level of the carpal
at the level of the carpal tunnel outlet by the overlying tunnel outlet by post-surgical scar. (d) Short-axis view of
transverse carpal ligament. (b) An ultra-high-frequency the dorsal branch of the ulnar nerve being compressed by
(48 MHz) sonogram of a long-axis view of the common a neighboring ganglion cyst (mass)

a b

Fig. 16.25 Sonograms demonstrating short-axis views ulnar groove with the elbow in relative extension. (b) The
of the ulnar nerve dislocating over the medial epicondyle ulnar nerve has dislocated anterior to the medial epicon-
(ME) with elbow flexion. (a) The ulnar nerve is in the dyle with elbow flexion

I dentifying Focal Nerve mal to that area [23] (Fig. 16.26). Median neu-
Abnormalities ropathy at the carpal tunnel is the most common
focal entrapment neuropathy and has been stud-
The appearance of focal nerve injury is typically ied to the greatest extent. Measuring the nerve for
a result of the nature of the injury. Peripheral abnormal swelling is the most reliably way to
nerves often display changes in size at levels of identify abnormality [16]. The precise
focal neuropathy. Entrapment neuropathies usu- pathophysiology behind the enlargement is a
­
ally present with narrowing or deformation at the source of ongoing debate, but theories include
site of compression and focal swelling just proxi- the blocking of axoplasmic flow at the entrap-
368 J. A. Strakowski

(Fig. 16.29) [52]. This can be the sole imaging

abnormality in some neuropathies. The destruc-
tion of the normal fascicular pattern is often asso-
ciated with more severe injuries and can reflect
axonal injury [6, 26]. Demyelinating lesions fre-
quently will appear enlarged without loss of the
fascicular architecture. In stretch injuries, the
nerve abnormalities can be relatively inconspicu-
ous or notably more diffuse. As with looking for
Fig. 16.26 Sonogram of a long-axis view of an abnormal enlargement, techniques of inspecting the nerve
median nerve with compression at the carpal tunnel. Note proximally and distally with side-­to-­sides com-
the narrowing of the nerve at the site of compression (3
and 4) and also the enlargement of the caliper of the nerve
parisons should also be incorporated for investi-
proximal to the site of compression (2) gating areas for echotexture change.
Color and power Doppler imaging can be used
to assess for increased intraneural vascularity.
The endoneurial and epineurial vessels accompa-
nying most nerves have slow flow velocities and
are ordinarily not seen with conventional ultra-
sound imaging. Detectable flow signals should be
considered to represent increased vascularity,
associated with neuropathy [4]. This increased
flow has been shown in some entrapment neu-
Fig. 16.27 Sonogram of a long-axis view of an abnormal ropathies including median neuropathy at the
sural nerve with focal injury. The site of neuropathy is carpal tunnel and even polyneuropathies [1, 18].
identified by the focal enlargement (yellow arrows). This Care should be used to avoid confusion of normal
region can be compared to the caliper at other areas of the vessel flow with pathologic increased vascularity
nerve to help identify the abnormality
(Fig. 16.30).
Relative mobility and excursion of the nerve
ment site and resulting endoneural edema [14]. should also be noted. Anatomic variants should
Cross-sectional areas of nerves can be compared also be identified. In post-operative or post-­
to standardized normal measurements to deter- trauma situations, the region should be assessed
mine abnormal enlargement. There is consider- for scarring or other potential sources of nerve
able variation in the literature, particularly with compression [48]. The course of the nerve
less commonly studied nerves. The enlargement should also be inspected for intraneural or extra-
should always be assessed in both short- and neural tumors when a neuropathy is suspected
long-axis views. Use of diameter measurement in (Fig. 16.31).
short axis is preferred in smaller nerves in which
a reliable cross-­sectional area cannot be obtained.
Comparison of the unaffected course of the Evaluation of Generalized
nerve can be used to help with this assessment Neuropathies
(Fig. 16.27) [63]. This should be performed with
caution in more severe injuries as the enlarge- As with focal neuropathies, ultrasound is gaining
ment can potentially extend over greater lengths an increasing role in the assessment of more gen-
of the nerve. In such cases, it can be helpful to eralized neuropathies [59]. Ultrasound is a rela-
compare the neighboring unaffected nerves or tively practical and effective imaging modality to
use side-to-side comparisons (Fig. 16.28). distinguish anatomic features to correlate with
Loss or change of normal fascicular architec- clinical and electrodiagnostic findings. Additional
ture is another clue for peripheral neuropathy historical and laboratory data are often needed to
16 High-Frequency Peripheral Nerve Ultrasound 369

Fig. 16.28 Sonograms of side-to-side comparisons of side (SX), and the normal comparison from the asymp-
the deep branch of the radial nerve (yellow arrow) in (a) tomatic side (ASX) is shown for comparison. Side-to-side
short-axis and (b) long-axis in the area of the radial tunnel comparisons are helpful for distinguishing differences,
between the superficial and deep heads of the supinator. particularly with nerves that are less frequently scanned
The enlarged abnormal nerve is seen on the symptomatic

reliably determine the source of neuropathy. thies includes determining the relative severity,
Despite this, sonographic appearance of periph- distribution of abnormality, and extent of con-
eral nerves can often provide valuable clues duction blocking, conduction slowing, and axo-
toward the nature of the neuropathy, the areas of nal loss. To reliably do this, sufficient testing of
involvement, and even the identification of focal sensory and motor nerve conductions should be
neuropathies in the context of more generalized performed in multiple limbs to establish the pat-
disease. tern of abnormality [44]. Identification of con-
Ultrasound should be considered an adjunc- comitant nerve entrapments at common sites,
tive tool that can be used to enhance the diagnos- including radiculopathies, should be considered
tic information provided by clinical and in this assessment.
electrophysiologic assessments. A goal with clin- Sonographically, identified morphologic char-
ical and electrodiagnostic testing is to determine acteristics of peripheral nerves can potentially be
if the neuropathy is hereditary or acquired and used to help characterize the neuropathy, but this
assess the relative effect on sensory and motor has some limitations. The peripheral nerve
nerves and in some cases autonomic function. appearance in many generalized peripheral neu-
Efforts should be made to determine if the neu- ropathies is non-specific and does not reliably
ropathy is acute or chronic, symmetrical or asym- identify the underlying condition [28]. Despite
metrical, and axonal or demyelinating. this, there are patterns of changes typically seen
A role of electrodiagnostic testing in the in some neuropathies that can provide clinical
assessment of generalized peripheral neuropa- clues [40]. Demyelinating neuropathies, such as
370 J. A. Strakowski

a b

Fig. 16.29 Sonograms demonstrating examples of focal of short-axis views of the medial and lateral sural cutane-
neuropathies with severe axonal loss, identified by the dis- ous nerves. In this case, there is a selective injury to the
ruption of the normal internal fascicular architecture. (a) medial sural cutaneous nerve reflected by the loss of the
An ultra-high-frequency (48 MHz) sonogram of a short-­ normal internal echotexture. A preserved fascicular pat-
axis view of the median nerve in the forearm injured by tern is seen in the healthy lateral sural cutaneous nerve. (c)
trauma. Note the enlargement of the fascicles as well as An ultra-high-frequency (70 MHz) sonogram of a long-­
the hyperechoic change in some, reflecting loss of normal axis view of an injured sural nerve showing complete loss
axons. (b) An ultra-high-frequency (70 MHz) sonogram of the normal fascicular architecture

a b

Fig. 16.30 Sonograms demonstrating examples of nor- median artery more proximally at the level of the pronator
mal vascularity that could potentially be confused with quadratus. Following the Doppler flow outside of the
pathologic neovascularization. (a) Short-axis view of a region can confirm that the signal is arising from a healthy
bifid median nerve at the carpal tunnel shows increased vessel as opposed to neovascularization at a focal entrap-
vascular flow. This represents flow from a persistent ment site. Suspected abnormal vascularization should also
median artery, which is a normal anatomic variation. (b) ideally be identified within the outer epineurium of the
Short-axis view of the same median nerve and persistent nerve in both short- and long-axis views
16 High-Frequency Peripheral Nerve Ultrasound 371

a b

Fig. 16.31 Sonograms demonstrating a schwannoma of entrapments. Ultrasound facilitates the rapid inspection of
the common fibular nerve in both (a) long axis and (b) large segments of peripheral nerves to enable screening
short axis. Tumors can develop at sites that are atypical for for unusual sources of neuropathy

acute inflammatory demyelinating polyradiculo- interventional procedures [7]. Ultrasound allows

neuropathy (AIDP) and chronic inflammatory live guidance throughout the procedure while
demyelinating polyradiculoneuropathy (CIDP), using high-resolution imaging of the peripheral
have a tendency toward nerve enlargement to a nerve. Details of various ultrasound-guided pro-
much greater extent than predominantly axonal cedures are discussed throughout the book in
neuropathies [20, 64]. other chapters.
Patients with chronic inflammatory demyelin- The general guidelines for all ultrasound-­
ating polyradiculoneuropathy have shown dra- guided injections should be used for peripheral
matic enlargement of multiple peripheral nerves nerves. Peripheral nerve procedures require spe-
at sites that are not typical for entrapment, includ- cial consideration because of the vulnerability of
ing the brachial plexus and cervical roots [33, 55]. the target. It is recommended that peripheral
This can include nerve enlargement greater than nerve procedures should be performed with a
two times normal size. Studies of these conditions short-axis view of the nerve and in-plane view of
have shown good correlation with abnormal nerve the needle. The needle tip should be visualized at
sizes measured with ultrasound compared to MRI all times throughout the procedures as should the
and autopsy evaluations [35, 56]. Some studies flow of the injectate [50] (Fig. 16.32). In some
have demonstrated that cross-sectional area circumstances, it can be helpful to assess the pro-
enlargement frequently correlates with nerve con- cedure in both short and long axis to gain full
duction slowing, but rarely other measures of appreciation of the movement of the injectate.
electrophysiologic assessment. Limited studies This is particularly helpful in higher-volume
have been performed to qualify the extent of hydrodissections. The introduction of the injec-
peripheral nerve internal derangement which is tate should stop while rotating the transducer to
often more characteristic of axonal neuropathies. view a different plane.
Further work is needed in this area to better define The image of the peripheral nerve should be
morphologic characteristics seen with ultrasound optimized with guided procedures in the fashion
in comparison to electrophysiologic findings. as when performing diagnostic assessments [39].
The goal is to accurately identify the border of
the outer epineurium to allow the injectate to be
Ultrasound-Guided Peripheral placed close to the nerve but avoid an inadvertent
Nerve Procedures intraneural injection. In general, the highest-­
frequency transducer that will still allow suffi-
In addition to use in diagnosis of peripheral nerve cient penetration should be used for greatest
disorders, ultrasound is an ideal modality for per- resolution, but consideration should also be given
forming guided nerve procedures. This includes to needle conspicuity. An exception to using
anesthetic and therapeutic blocks, nerve ablation higher resolution is deeper peripheral nerves in
techniques, hydrodissections, and other guided which bony landmarks are used for identification.
372 J. A. Strakowski

Fig. 16.32 Sonograms demonstrating an in-plane injec- and the injectate can be seen creating a hypoechoic halo
tion with a short-axis view of the lateral cutaneous nerve around the nerve
of the thigh. The needle tip is seen with the in-plane view,

Pre-scanning of the region around the nerve resolution with development of ultrasound scan-
should also be performed prior to the injection. ning symptoms, including ultra-high-frequency
Doppler imaging can be used to assess for sur- transducers, have led to unprecedented visualiza-
rounding vascularity. tion of both normal nerve and pathologic condi-
During the injection, caution should be used to tions. Advancements in the understanding of the
avoid obliquity of the needle relative to the trans- nature of focal and more generalized neuropa-
ducer. This can give the false impression that the thies will lead to more effective management
portion of the needle crossing the transducer is the decisions.
needle tip. The flow of the injectate should con-
stantly be monitored to establish that the injectate
is moving into the desired area [54]. Doppler References
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Adapinar B. Value of power Doppler and gray-scale
duce a small amount of the injectate to increase US in the diagnosis of carpal tunnel syndrome: con-
the conspicuity of the border of the nerve prior to tribution of cross-sectional area just before the tun-
proceeding with the entire injection. nel inlet as compared with the cross-sectional area at
the tunnel. Korean J Radiol. 2010;11(6):632–9. Epub
2010 Oct 29
2. Alemán L, Berná JD, Reus M, Martínez F, Doménech-­
Summary Ratto G, Campos M. Reproducibility of sonographic
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ing modality of choice for most peripheral nerve Khoury V. Ultrasonographic evaluation of peripheral
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as dynamic capabilities make it highly practical Bone Spine. 2008;75(6):643–9.
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and effective as a diagnostic and therapeutic tool. skeletal system. Heidelberg: Springer-Verlag; 2007.
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 Dextrose-Based Perineural
Injection Treatment,
17
and Ultrasound Hydrodissection

Liza Maniquis-Smigel, Paschenelle Celis,

and Dean Reeves

Introduction use of acetaminophen, nonsteroidal anti-­

inflammatory drugs, opioids, or in combination,
Anyone in pain will say that it needs no definition. with the expectation of pain resolution once the
It takes over one’s whole being and affects activi- injury is resolved. Despite addressing and cor-
ties of daily living, so much so as to make it recting risk factors, many patients report they
impossible to be productive in even the simplest have “tried everything,” but pain persists and
of tasks. Throughout the world, one in five adults becomes a chronic problem.
suffers from severe chronic pain [1]. It affects mil- With the impact of chronic pain, opiate addic-
lions of Americans, hindering many from work- tion has become a nationwide epidemic in the
ing, attending school, socializing, and enjoying United States, with drug overdose deaths that con-
life [2]. “If all chronic pain conditions were tinue to increase by twofold in the last decade [4].
lumped together and considered to be a single dis- National organizations have called for new thera-
ease, as many pain researchers view the problem, pies to address underlying pathologies and to pro-
it would be the most common, disabling, and duce improved non-opioid treatment regimens.
expensive health problem in the world” [3]. Neuropathic pain is a commonly overlooked
Traditionally, much of our attention and edu- cause of painful conditions, resulting in pain lit-
cation in clinical setting is looking at musculo- erally from head to toe. A recent systemic review
skeletal problems, as it is considered to be the of epidemiological research on neuropathic pain
most common cause of chronic pain in the United across the world suggests the prevalence lies
States, with a 54% proportion of chronic pain between 6.9% and 10% in the general population
related to musculoskeletal conditions [3]. These [5], which in our opinion is a very low percentage
include osteoarthritis, rheumatoid arthritis, tendi- given that their criteria only includes specific
nitis, and chronic low back pain. The medical neurological conditions. Not only is neuropathic
field has classically addressed pain through the pain overlooked, but severity of neuropathic pain
can be high. Observational studies in the United
L. Maniquis-Smigel (*) States and Europe alone suggest that between
Hilo, HI, USA 70.0% and 96.0% of patients with neuropathic
P. Celis pain seeking care experience moderate to severe
Physical Medicine & Rehabilitation Department, pain [6].
Clinica OS Habitares, Quezon City, Philippines Centralization of pain concepts has dominated
D. Reeves the mechanistic explanations for initiation and
Private Practice of Physical Medicine and perpetuation of chronic neuropathic pain, which
Rehabilitation, Roeland Park, KS, USA

© Springer Nature Switzerland AG 2022 375

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_17
376 L. Maniquis-Smigel et al.

Somatosensory pathway

First order neuron

Third order Unmyelinated C & A delta Dextrose Sensory
neuron TRPVI nociceptors works here nerve

DRG

Modulators Second order

opiates, antidepressant, neuron
anticonvulsants

Fig. 17.1 Somatosensory pathway

is thought to result from changes in the properties of the somatosensory system” [8] (Fig. 17.1).
of neurons in the CNS. The classic explanation of This new definition reflects a general movement
refractory neuropathic pain states that pain sig- to reconsider the importance of peripheral ner-
nals originating in the periphery migrate cen- vous system autonomy as a mechanism for
trally, “burn their way” into the CNS, and in time chronic pain [9]. Most clinicians may not be
create a permanent trace that is independent of aware that peripheral small fiber nerve abnormal-
peripheral drive [7]. In other words, it is a state in ities can lead to debilitating pain, mimicking
which neurons in the CNS become hyperexcit- headaches, adhesive capsulitis, cardiac disease,
able. Treatments have focused on decreasing cen- intra-abdominal pathology, hernia, CRPS, or
tral sensitization with antidepressants, plantar fasciitis [10]. Localization and effective
antiseizure, and opiate medications, which has treatment of these chronic small fiber nerve inju-
proven to be unsatisfactory, due to incomplete ries can prevent unnecessary and expensive diag-
pain relief and considerable medication side nostic testing and treatments and help to avoid
effects. unnecessary pain and suffering.
PIT is an injection-based treatment for neuro-
pathic pain that has rapidly increased in popular-
 hange in Neuropathic Pain
C ity over the last several years, empirically
Definition and Introduction changing the lives of patients worldwide and
of Perineural Injection directly addressing the peripheral nervous sys-
Therapy (PIT) tem. Clinically, physicians and patients alike
report reduction of pain within seconds after an
In 2011, the International Association of the isotonic dextrose solution (5% dextrose in water;
Study of Pain proposed a new definition of neuro- D5W) is injected adjacent to painful peripheral
pathic pain, as “pain caused by a lesion or disease nerves in the subcutaneous tissues or deeper,
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 377

using a 27G 1/2 inch needle. Repeated treatments 4. To discuss findings, benefits, and advantages
have a cumulative effect [11, 12]. Clinical of ultrasound-guided nerve hydrodissection
improvement is hypothesized to be due to a sen- (HD) using dextrose to release peripheral
sorineural effect of dextrose on neuropathic pain nerves from their encasing fascia in order to
generators [13]. provide a decompressive and dextrose senso-
Somatosensory Pathway starts with the free rineural effect
nerve endings under the skin as unmyelinated C
fibers and the A delta fibers, also known as
TRPV1 nociceptors, that travel through the Differentiating Dextrose-Based
whole length of the C fiber nerve with the cell Treatments
body in the dorsal root ganglion, then enters the
spinal cord through the dorsal rami and dorsal Although the focus of this chapter is on the peri-
horn of the gray matter, then crosses over to con- neural injection therapy (PIT), it is important to
tralateral side and ascends up to the thalamus differentiate this from traditional prolotherapy,
and to the somatic sensory cortex of the brain to two very different dextrose-based treatments.
perceive pain. Dextrose is postulated to work on Dextrose prolotherapy (DPT) uses hypertonic
the first order neuron/ unmyelinated C fiber (12.5–25% dose) dextrose solution for regenera-
nerves. tive repair of weakened structural tissues. The
Many factors have converged to accelerate the proposed mechanism is regenerative repair. DPT
growth of PIT worldwide: use began in the 1930s and was originally used in
the treatment of ligamentous laxity [14]. In the
1. The lack of long-term efficacy of standard of 1950s, George S. Hackett, a general surgeon in
care for chronic pain, including steroid injec- the United States, began performing injections of
tions and the rise of the opioid epidemic. irritant solutions in an effort to repair joints and
There is a push to produce non-opioid treat- hernias [15]. Prolotherapy technique utilizes a
ment that is economical, safe, and effective. combination of palpation and ultrasound scan-
2. Advancements in the scientific understanding ning to assess anatomical structures that are not
of neurogenic inflammation and peripheral routinely emphasized in conventional musculo-
sensitization. skeletal medicine (generally ligaments, tendons,
3. A clearer understanding of dextrose and its and small joints). It is dependent on a highly
role in chronic pain at its molecular and cel- refined knowledge of neuromusculoskeletal and
lular level. surface anatomy. Dextrose is predominantly
4. The subsequent escalation of nerve hydrodis- injected in enthesis and intra-articularly in the
section ultrasound techniques that have fur- performance of prolotherapy. One of the pearls of
ther enhanced the effects of neural dextrose prolotherapy is to always inject on bone as weak-
injections. ness occurs on the enthesis,where the tendon or
ligament attaches to the bone160. It consists of
The focus of this chapter is: microinjections into the enthesis whose primary
intent is to encourage repair of damaged tissues.
1. To differentiate dextrose-based treatments The hypertonic dextrose is hypothesized to cause
2. To review some of the historical and relevant a mild osmotic irritation [9, 13, 16, 17]. This irri-
documentation of neurogenic inflammation tation along with needle microtrauma initiates
and its relationship to pain the healing cascade (inflammation, proliferation,
3. To explain our current theory of the sensori- and remodeling), with eventual laying down of
neural therapeutic effect of D5W at its molec- collagen by fibroblasts and repair of damaged
ular and cellular level targeting small fiber structures, correcting biotensegrity, and relieving
sensory peripheral nerves in reducing neuro- pain [9, 13, 16, 17]. However, an immediate ben-
genic pain, hyperalgesia, and allodynia efit after injection of dextrose has been noted fre-
378 L. Maniquis-Smigel et al.

quently, raising questions about whether caine toxicity [12]. This is gaining ground as
­therapeutic mechanisms of dextrose other than ultrasound technology achieves higher resolu-
proliferative are at work, such as a neurogenic tion, allowing better visualization of small sen-
effect (see below). sory cutaneous nerves (Fig. 17.4).
Perineural injection treatment (PIT) (formerly There are many advantages of ultrasound
known as superficial prolotherapy or neural pro- guidance (USG). It allows accurate identification
lotherapy) is different from DPT. It uses 5% dex- of the nerve to facilitate the precise approach
trose (D5W), an isotonic concentration, injected required for HD. USG allows visualization of
subcutaneously, for the treatment of neuropathic potential areas to avoid, such as vascular struc-
pain [18–21]. It first appeared in the medical lit- tures. One can appreciate pathological nerves
erature in 2006 [22]. The proposed mechanism is which are usually swollen or with thickened epi-
a sensorineural effect of dextrose. Dr. John neurium and perineurium compared to healthy
Lyftogt was the first to observe that injection of nerves. In normal-sized nerves, individual fasci-
subcutaneous dextrose without local anesthetic cles can be enlarged, signifying pathology as
over painful sensory nerves resulted in relief of well. Dynamic ultrasound of nerves can show
pain within seconds of injection of areas of pain. snapping of the nerve against surrounding bone,
Precise anatomical knowledge of the sensory ligament, or tendon, reproducing pain that is
cutaneous innervation of the body provides the experienced by the patient There is less percent-
guide to utilize skin gliding palpation technique age of error, as compared to palpation-guided
of the suspected swollen nerves, termed chronic needle injection alone, increasing efficiency, and
constrictive injuries (CCIs) [23] or Valleix points in most cases, this equates to a faster procedure.
[24], which reproduces the neuropathic pain Ultrasound visualization improves patient com-
experienced by the patient. Every treatment aims fort and confidence, which increases compliance.
to extinguish the pain and has a cumulative effect. Ultrasound documentation, before, during, and
Repeated sessions [2, 3, 5–7] may be required, after the procedure, can serve as a record of
with the aim of complete resolution and to allow improvement and as a reference for future proce-
return to full function [18] (Figs. 17.2 and 17.3). dures and plans. Furthermore, use of ultrasound
is safe for most patients, including pregnant
women or patients with implants [27].
Perineural Hydrodissection While ultrasound guidance enjoys all these
With Ultrasound Guidance benefits, there are obvious limitations when com-
pared to the palpation-guided PIT. There is a
In recent years, nerve hydrodissection (HD), steep learning curve which makes gaining com-
employing high-resolution ultrasound, has been petency a time-intensive training process on the
used for continuous visualization to inject fluid to part of the physician. Use of technology will
separate the nerves from fascial layers. The tech- limit the access to patients that can be treated vs
nique is explained in detail in a different chapter PIT, which is palpation-based and can be per-
of this book (Chap. 13: Peripheral Nerve formed anywhere in the world including third-­
Hydrodissection by Dr. Stanley Lam). world countries where ultrasound machines are
Traditionally, a large volume of normal saline inaccessible.
and a small volume of steroids and anesthetic are With current standard ultrasound machines
used for HD of nerves [25]. Since a recent publi- being used today in the clinical setting, even
cation evidencing that stand-alone dextrose has with extensive training and experience in the
an analgesic effect [26], D5W is becoming the part of the physician, the larger nerves are appre-
solution of choice for USG nerve hydrodissec- ciated, but smaller sensory cutaneous fiber
tion, as it offers a dual advantage of mechanical nerves cannot be effectively visualized.
hydrodissection and sensorineural effects with- Therefore, a combination approach combining
out the side effects of steroids or the risk of lido- hydrodissection and injection by palpation guid-
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 379

3rd occipital
Trigeminal I Lesser occipital
Greater occipital
Trigeminal II
Great auricular
Trigeminal III
Dorsal branches
Great auricular of cervical nerves
Cut. cervical Supraclavicular
Supraclavicular Medical branches
of dorsal rami of
Axillary
thoracic nerves
Ant.div.of thoracic
Axillary
Intercostobrachial Posterior cut. nerve
Lateral brachial of arm
cutaneous Intercostobrachial n.
Med.brachial cut and medial cut. nerve
Lat.div.of thoracic of arm
Radial Inferior lateral cut. n.
of arm
Lat.antebrachial
Lat.cut.branches of
cut
the thoracic N
Medical antebrachial
Lat.cut. nerve of
Iliotypogastic forearm
Medical cut
Radial nerve forearm
Iliohypogastric
Median
Supracluneal
Median
Ulnar Ulnar
Genitofemoral Middle cluneal
Ilioinguinal Genitofemoral
Lat.femoral Lat.cut nerve of thigh
cut. Posterior cut. nerve of
thigh
Femoral
Obturator
Obturator
Lateral sural
Saphenous
Saphenous
Lateral cutaneous Superficial fibular
nerve of the calf
Sural
Superficial fibular Tibial nerve via medial
Sural calcaneal branches
Lateral plantar Lateral plantar
Deep fibular Medial Plantar
Medial Plantar

Anterior Posterior

Fig. 17.2 Cutaneous innervation of peripheral nerves provides the guide to identify the area of neuropathic pain region
of suspected swollen cutaneous nerves

ance is commonly utilized by clinicians. In the ments, and the current theory continues to evolve.
future, as higher-resolution ultrasound technol- However, it is important to understand the histori-
ogy becomes more available and affordable, cal context in which this theory is based. We will
improving visualization of small sensory cutane- review several concepts that are pertinent to our
ous nerves, will allow us to be more accurate, understanding of how glucose works in the
effective, and faster in our procedures. peripheral nervous system to reduce pain.

 istorical Relationship Between

H Early Concepts of Pain
Neurogenic Inflammation and Pain
Neurogenic inflammation is the inflammation
We are just beginning to understand the scientific that is produced through the release of substances
rationale for sensorineural effect of dextrose treat- from the sensory neurons from the periphery, in
380 L. Maniquis-Smigel et al.

Nervi
nervorum

Inflammed Healthy

Fig. 17.5 On the right is a normal nerve with nervi ner-

vorum that arises from the nerve trunk itself and branches
and extends into the epi-perineurium of nerve trunk. The
nervi nervorum, when activated, will result in inflamma-
tory exudates and, ultimately, neural swelling
2

Fig. 17.3 Perineural injection treatment (PIT): 1. Skin

gliding palpation over the suspected swollen nerve with
Victor Horsley In December 15,1883. In their
tips of fingers; characteristic and localized pain and swell- Bradshaw Lecture on Nerve Stretching, they postu-
ing are present. 2. With the use of the two-finger tech- lated that the nervi nervorum (the small nerve fila-
nique, buffered D5W without local anesthetic is injected ments innervating the sheath of a larger nerve) are
perineurally with a 27-gauge, 0.5 inch needle, which
results in the relief of pain within seconds of injection
the cause of neuralgia or neuropathic pain [30, 31].
Their illustration of the healthy nerve shows
small nerve endings that arise from the nerve
trunk itself (Fig. 17.5). These nerve endings are
Median nerve
the nervi nervorum which are intrinsic small fiber
nerves that supply the nerve itself and the con-
nective tissue that surrounds the nerve. Nervi ner-
Needle vorum “ramify” in the epi-perineurium of nerve
trunks and beyond, and these small fiber nerves
can trigger pathological neurogenic inflamma-
tion which may result in inflammatory exudates
and, ultimately, neural swelling [31].
In the publication “Nerve stretching for the
relief or cure of pain,” Marshall has inferred that
Fig. 17.4 Ultrasound image demonstrating hydrodissec- nervi nervorum would participate in pain genera-
tion of the median nerve at the carpal tunnel in short-axis,
in-plane approach tion mechanisms observed in cases of peripheral
nerve compression. Together with Horsley, he
particular, from A delta and unmyelinated C has shown that nervi nervorum were sensitive to
afferent fibers [28]. In addition to the classic pain, especially to pressure. Dr. Marshall also
afferent functions of the sensory peripheral nerve, postulated that “The pain of neuralgia is more
it is now well established that the peripheral ner- severe at certain apertures where the nerve passes
vous system also participates in the regulation of out the osseous or fibrous framework of the body,
efferent actions on cell proliferation, expression or passes around given points of bone.” These
of cytokines and growth factors, inflammation, neural swellings, which occur at certain small
immune responses, and hormone release. This is apertures where the nerves pass through, restrict-
called the paradoxical “efferent” role of nocicep- ing axonal flow and activating the nervi nervo-
tive sensory fibers and was suggested already by rum, he called chronic constrictive injury (CCI).
Baylis in 1901 [29]. When a nerve is subjected to 30 mmHg, there is
Neuralgia and chronic constrictive injury (CCI) consistent inhibition, which was even more
were first described by Dr. John Marshall and Sir marked at 60 mmHg and still more at 90 mmHg
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 381

[32]. The activated nervi nervorum may, in turn, subcutaneous nerve cell endings that initiate the
cause dilation of blood vessels, an increase in perception of pain. They are receptors that
blood flow, and swelling which results in respond only to noxious stimuli and generate
neuralgia. impulses through nerve pathways along nerve
The concept of CCIs is reinforced by Bennett’s fibers to target centers in the brain, which pro-
experimental observation that a peripheral neu- cess the signals to produce the experience of
ropathy is consistently produced when lightly pain [33, 34].
constrictive ligatures are placed around a rat sci- In 1894, Maximilian von Frey made another
atic nerve. This results in functional nerve disrup- critical addition to the specificity theory that
tion and an hourglass appearance of nerve, with served to advance the concept. His contribution
swelling on either side of the ligature [23]. This assigns different types of sensations to different
sciatic ligature model, commonly used to create specific pathways. These sensations include cold,
neuropathic pain (hyperalgesia and allodynia) in pain, heat, and touch [33, 34] (Fig. 17.6). There is
research settings, supports the concept that even a unique receptor for each type of sensation. Frey
minimal compression of nerves in fascial layers explained that nociceptors are specialized cells
can result in clinically important neurogenic that sense pain or noxious stimuli with no addi-
inflammation and neuropathic pain [18]. tional influences. He argued that the body has a
separate sensory system for perceiving pain, just
as it does for hearing and vision. The free nerve
Valleix Points endings subserve the pain modality [28, 29].
Thus, it is based on the assumption that the free
In the early 1800s, François Louis Isidore Valleix, nerve endings are pain receptors and that the
a French pediatrician, already described the sites other types of receptors are also specific to a sen-
of these peripheral nerve swellings, similar to sory experience. This theory considers pain as an
CCIs described by Marshall and Horsley. “Valleix independent sensation, with specialized periph-
points” are various points in the course of a nerve, eral sensory receptors (nociceptors), which
at which applied pressure causes pain in cases of respond to damage and send signals through
neuralgia [24]. These points are enumerated as nerve fibers to target centers in the brain, which
where the nerve emerges from the bony canal, produce the experience of pain [34] (Fig. 17.7).
where it pierces a muscle or aponeurosis to reach We now know that peripheral nociceptors (A
the skin, where a superficial nerve rests on a delta and C fibers) sense three types of noxious
resisting surface where compression is easily impulses: mechanical, mechanothermal, and
made, where the nerve gives off one or more chemical. The A delta fibers are lightly myelinated
branches, and where the nerve terminates in the and respond to intense mechanical or mechano-
skin [24]. PIT practitioners use Valleix points as thermal stimuli, while the C fibers are the unmy-
guide on where to focus palpation to find the elinated and respond to thermal, mechanical, and
swelling of nerves in the subcutaneous tissue. chemical stimuli and are therefore polymodal [35].
Sir Charles Scott Sherrington elaborated on the
specificity theory of pain. Sherrington’s law states
Concept of Nociceptors “Every nerve can influence the proper and specific
activity of a tissue it innervates and has a trophic
The specificity theory of pain, initially presented influence on that tissue” [34, 36]. In other words,
by Charles Bell (1774–1842), is one of the first sensory nerves have a trophic reparative influence
modern theories of pain. It holds that specific on the tissues that it innervates. In normal physio-
pain receptors transmit signals to a “pain center” logical conditions, the efferent effect of the sen-
in the brain that produces the perception of pain sory system is responsible for tissue maintenance
[33, 34]. Nociceptors are special cutaneous or and renewal and has trophic activity [36].
382 L. Maniquis-Smigel et al.

VALLEIX POINT 1841

where the nerve where a superficial nerve

emerges from rests on a resistingsurface
the bony canal where compression is
easily made

where it
pierces a
muscle or
aponeurosis to
where it is reach the skin
Cama
turnel entrapped b/w
Liganent Tanson fibrous tissue
Medai nerve aheetha
Tondens

Fig. 17.6 Valleix points are various points in the course of the nerve, about which, when pressure is applied, causes
pain in cases of neuralgia

Hilton’s Law For what we are doing, it is applicable to under-

stand Hilton’s law. John Hilton was the foremost
anatomist and surgeon of his day. He developed
many anatomical principles culminating in a
series of lectures on On Rest and Pain [32, 33].
He described the organization of peripheral
nerves. Hilton’s law states “The nerve trunk sup-
plying a joint also supplies the overlying skin
and the muscles that move that joint” [37, 38].
This law suggests that in clinical setting, subcu-
taneous near nerve injections will affect the
underlying joint and muscles that they supply
(Figs. 17.8 and 17.9).
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 383

Strong
Pressure
Cold FREE NERVE
ENDINGS (PAIN)
Light Touch
Heat

Pain

MERKEL’s DISC
(TOUCH)

THERMORECEPTORS
(HEAT & COLD)

PASCINIAN
CORPUSCLES
(TOUCH)

Nerve Connective Hair

Tissue Movement

Fig. 17.7 Nociceptors are specialized cells that sense pain or noxious stimuli with no additional influences. The four
sensory nociceptor modalities are cold, heat, pain, and touch [29, 34]

PIT subcutaneous injections without intra-­ may facilitate our understanding of why dex-
articular injections have been empirically trose has an instant calming effect on pain sen-
reported to relieve pain and improve function of sation. We believe that pain relief has to do with
arthritic patients. This may also explain rapid these ion channels through impulse generation
pain reduction after deeper (enthesis or intra-­ (APs), which are heavily influenced by glucope-
articular) injection in dextrose prolotherapy, nia and corrected by perineural injection of dex-
since the same pain-producing C fibers are also trose (Fig. 17.10).
found in high density on bony cortex [39]. Ion channels expressed by immune system
cells (e.g., P2X7) have been shown to play a piv-
otal role in changing pain thresholds, while chan-
 wenty-First Century: Pain
T nels involved in sensory transduction (e.g.,
As a Channelopathy TRPV1), the regulation of neuronal excitability
(potassium channels), action potential propaga-
Neuroscientists in the twenty-first century iden- tion (sodium channels), and neurotransmitter
tified complex ion channels on nociceptor mem- release (calcium channels) have all been shown
branes. These ion channels found on the sensory to be potentially selective analgesic drug targets
axons have an efferent function. This contra- to control pain [34].
dicts the classic theory of the unidirectional Two ion channels and one transport protein
afferent pathway of sensory nerves, and a bidi- system which are of particular importance in
rectional function for the same side of the sen- neuropathic pain initiation and maintenance,
sory nerve is now favored [40]. These recent include TRPV1 and potassium ion channels, and
advances of the role of ion channels in neurons the glucose transporters (GLUTs).
384 L. Maniquis-Smigel et al.

Articular branches of the anterior

and posterior hip joint
MUSCLE
SKIN
JOINT
BR
ULAR AN
ARTIC H CH
BRANC

a
K

a
N
TRU

b
b
SOURCE

“The same trunks of nerves whose

branches supply the groups of muscles
moving the joint furnish also a
distribution of nerves to the skin over the a. Sacral plexus a. Femoral nerve
same muscles” b. Obturator nerve b. Obturator nerve

Figs. 17.8 and 17.9 Hilton’s law states “The nerve trunk that in clinical setting, subcutaneous near nerve injections
supplying a joint also supplies the overlying skin and the will affect the underlying joint and muscles that they
muscles that move that joint” [37, 38]. This law suggests supply

(d) 2-pore (f) acid-sensing

(b) Voltage-gated
K+ channel Ion channels (ASIC)
Na+ channel
• TREK-1
• TASK

(c) Voltage-gated (e) TRPV (g) Ligand gated

(a) Transduction
K+ channel channels channel
channels
(e) Signal gated
channel

Na+

K+

Cytosol Na+ K+ Ca2+

Fig. 17.10 Complex ion channels on nociceptive mem- rotransmitters and hormones (ligand-gated channels). For
brane: Neuroscientists have discovered and identified instance, direct depolarization of neurons by electrical
complex ion channels on nociceptor membranes. The stimuli will open voltage-gated Na+, Ca2+, and K+ chan-
direct activation of most ion channels is triggered by nels [34]
changes in either voltage (voltage-gated channels) or neu-
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 385

TRPV1 releases neuropeptides: substance P (SubP) and

calcitonin gene-related peptide (CGRP) [43, 44].
The TRPV1 ion channel (formerly known as the Neurogenic inflammation, in this context,
“capsaicin receptor”) has been postulated to be refers to the inflammation that is produced
associated with neuropathic pain [41]. TRPV1 is through the release of neuropeptides from the
a member of the vanilloid family of channel small-diameter unmyelinated C fiber nerves that
receptors that, when stimulated, allow calcium have TRPV ion channels embedded on their
and sodium ions to enter the neuron. There are membrane [45, 46]. This action is by far the most
about 28 TRPV channels that play a role in sen- important source of pathological pain in humans
sory physiology [42]. TRPV1 is the most studied. [46] (Fig. 17.11).
It is sensitive to noxious heat; endogenous pro-
inflammatory molecules, such as arachidonic acid  hat Are the Effects of CGRP
W
metabolites; nerve growth factors; bradykinins and Substance P That Produce Signs
and protons (tissue acidification). As a result, the and Symptoms of Chronic Pain
neuron becomes depolarized, and if the depolar- Syndromes and Degeneration?
ization passes a certain threshold, it triggers action Calcitonin gene-related peptide (CGRP), a 37
potentials producing pain. The nociceptor then amino acid peptide, is the most potent microvas-
cular vasodilator currently known. It has a

TRPV1
Mechanical Injuries:
Confusion, Entrapment,
Pulled Injuries etc
Thermal Injuries:
Extreme Hotness / Burn, Acidosis of
of Extreme Cold / Ice different causes Perception
Ca2+ of pain
Capsaicin
Na+

Sensory
neuron

CGRP & SubP

in vesicles
Spinal cord
Na+
Depolarization &
Action potential
initiation
Ca+

Exocytosis of CGRP & SupP

By depolarization

Fig. 17.11 TRPV1 ion channel: TRPV1 is sensitive to influx causes depolarization of the membrane potential
mechanical injuries; noxious heat; endogenous pro-­ producing pain. Ca influx causes the release of neuropep-
inflammatory molecules, such as arachidonic acid metab- tides: SubP and CGRP from microvesicles within the cell
olites; nerve growth factors; bradykinins; and protons which are pro-inflammatory mediators of sensory nerves,
(tissue acidification). When TRPV1 ion channel is acti- causing changes in sensory neuron function brought about
vated, there is an influx of Na and Ca into the cells. Na by these inflammatory transmitters
386 L. Maniquis-Smigel et al.

potency nearly 10-fold higher than the most why it was originally termed the “capsaicin
potent prostaglandins and 10–100 times greater receptor” for years. Dr. Lyftogt observed that
than other vasodilators such as acetylcholine and that both dextrose (glucose) and a similar 6 car-
substance P [47]. It results in increased vascular bon atom monosugar, mannitol, reduce burning
permeability and plasma extravasation, produc- pain after capsaicin is applied to the human lip
ing edema formation in skin and joints. It has (personal communication). This was followed
been known for a long time that arthritic patients by an RCT by Bertrand et al. which demon-
have increased levels of CGRP in their plasma strated that mannitol application (compared to
and synovial fluid, and CGRP may be a very control) reduced the burning pain effect of cap-
early mediator in the disease process. CGRP can saicin on human lips [52]. Their conclusion was
cause cytokine production from whole blood that topical mannitol reduces the effects of
cells and fibroblasts seen in rheumatoid arthritis TRVP1 channel activation by a downstream
(RA) and osteoarthritis (OA) patients. It upregu- mechanism, since mannitol has no receptor on
lates vascular endothelial growth factor (VEGF), the TRPV1 channel. This study has not been rep-
which leads to neovascularization and neo-­ licated with glucose, which also has no receptor
neurogenesis. VEGF in turn, increases matrix on the TRPV1 channel. The current postulate for
metallopeptidase (MMPI), leading to collagen- further mechanistic research is that there is a
olysis and tendon and ligament degeneration. It class effect of certain monosugars, including
blocks the uptake of calcium by osteoblasts, dextrose, that antagonizes the effects of TRPV1
increasing tissue calcium levels, leading to calci- activation.
fication changes. It stimulates osteoclasts to
eventually produce breakdown of bone (dystro-
phic bone) [47]. Potassium Channels
Substance P (SubP) is a neuropeptide contain-
ing 11 amino acids and belonging to the tachyki- Potassium (K+) channels are pertinent to our dis-
nin family. Substance P is a key first responder to cussion as they have receptors for dextrose and
most noxious stimuli and is regarded as an imme- have a role in energy homeostasis and glucose
diate stress repair-survival system [48]. SubP is sensing. This may further clarify the mystery of
also a potent vasodilator in post-capillary venules why dextrose provides instant analgesia.
causing increased vascular permeability and pro- Ion channels are critical in regulating the
tein extravasation [49, 50]. SubP activates the membrane potential of neurons [53]. The activa-
immune cells to produce cytokines; it binds to tion of a specific ion channel will either activate
mast cells causing degranulation. It is related to or inhibit a neuron depending on the resting
the transmission of pain information into the cen- membrane potential (RMP) and the ion’s equilib-
tral nervous system. SubP is particularly excit- rium. Typically, neurons have RMP of −55 mv.
atory to cell growth and multiplication [49]. SubP Activation of the ion channel will depolarize the
has been associated with the regulation of mood cell as cations will rush into the cell membrane
disorders and anxiety symptoms [51]. It affects which results in the depolarization of the mem-
the hypothalamus to stimulate the corticotropin-­ brane potential (i.e., Na+ channels, Ca+ ­channels).
releasing hormone which leads to adrenal fatigue By contrast, anions rush in or cations rush out to
and exhaustion [51]. It also impairs propriocep- hyperpolarize the membrane potential when
tion by delaying antagonist muscle reflex inhibi- RMP is more positive than the equilibrium poten-
tion [39]. Increased SubP can explain the tial of an ion (e.g., K+ channels and CL- chan-
significant negative impact on those afflicted nels) [53].
with chronic pain, including decreased activity, Sensory nerves, like all nerves, are high
fatigue, insomnia, and mood changes such as energy users, which is supplied by glucose. A
depression [51]. large proportion of energy requirements is
The TRPV1 ion channel is the only ion chan- used to support neuronal resting membrane
nel known to respond to capsaicin [43], which is potential [53].
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 387

To date, glucose sensors in the periphery have most important mover of life [51]. The ability to
been found in the pancreatic β-cell intestine, hep- import and metabolize glucose at the cellular
atoportal vein, and carotid body [54]. The portal level is by a process of facilitative diffusion medi-
vein sensory afferents contain CGRP since they ated by members of the GLUT family of mem-
are capsaicin sensitive. However, chemosensitiv- brane transport proteins. The well-established
ity to CO2 and O2 hampers the interpretation of glucose transporter isoforms, GLUTs 1–4, are
glucose-sensing afferent signals. known to have distinct regulatory and kinetic
Recent evidence suggests that specialized tan- properties that reflect their specific roles in cel-
dem pore potassium (K2P) channels are sensitive lular and whole-body glucose homeostasis.
to glucose [55]. Glucose-sensing neurons are GLUT3, specifically, is the major neuronal glu-
responsible for regulating energy and glucose cose transporter, present in both dendrites and
homeostasis. The attachment of dextrose to the axons. GLUT3 has a high affinity for glucose and
K2P receptor leads to its activation, which opens has the highest number of calculated turnovers of
the potassium channels, transports potassium GLUT isoforms, thus ensuring efficient glucose
outside the cell, and hyperpolarizes the cell mem- uptake by neurons [57] (Fig. 17.12).
brane. Hyperpolarization of the membrane poten- According to GLUTs in the twenty-first-­
tial inhibits neuronal activity (associates with century article by Thorens et al. [58], activation
pain reduction) [55, 56]. of GLUT3 occurs by glucose-sensing neurons. A
We can therefore hypothesize that the clinical decrease in extracellular glucose concentration or
instant relief we observe with perineural dextrose hypoglycemia (cellular glucose deprivation) acti-
injection has to do with this inhibition of neuro- vates ATP-sensitive (KATP) glucose-sensing K
nal activity and restoration of perineural glucose channel neuron, and glucose is transported within
levels. This will result in repolarization and the cell by a glucose transporter, which then goes
hyperpolarization mediated by tandem pore through the glycolysis for ATP production,
potassium channels, eliminating neuropathic needed to regulate gene transcription, enzyme
pain and reducing neurogenic inflammation [53]. activity, hormone secretion, and the activity of
glucoregulatory neurons. This has been evidence
tested with KATP channel activation with channel
Glucose Transporter 3 (GLUT3) opener diazoxide which amplifies counterregula-
tory hormone responses to hypoglycemia in nor-
The significance of glucose transporters in biol- mal and recurrently hypoglycemic patients [57]
ogy is apparent as they are the gateways for the (Fig. 17.13).

Fig. 17.12 Glucose 2. Transport protein

transporter (GLUT): The shifts to alternative
conformation
ability to import and 1. Glucose binds to 3. Glucose is
metabolize glucose at binding site open released
the cellular level is by a To outside. to the inside and
process of facilitative protein returns to
its original
diffusion mediated by confirmation
members of the GLUT
family of membrane
transport proteins
Glucose
Glucose

Glucose Transporter
388 L. Maniquis-Smigel et al.

Mechanism of Glucose Sensing in Glucose Neurons action potential frequency within 15 min, with
prompt reversal to a normal baseline firing rate
Glucose
when dextrose was reintroduced [60, 61].
GLUT3
Dextrose injections may provide analgesia
through correction of local glycopenia. However,
confirming that the perineural environment is
Glucokinase (GK) relatively glycopenic will require microdialysis
P
(Glucose-6-phosphate) or other analysis methods for confirmation [62]
(Figs. 17.14 and 17.15).
Glycolysis

ATP/ADP
 euronal Energy Deprivation
N
suppression of
the counteregulatory
Theory of Pain/Lyftogt Theory
Vm response of Pain
K+ ATP Neuronal to hypoglycemia
firing
channel Dr. John Lyftogt has postulated a “neuronal
energy deprivation theory of pain” (personal
Fig. 17.13 A simplified model of glucose-sensing neu-
ron via ATP-sensitive K+ channels: Glucose sensing in communication). He hypothesizes that neuro-
glucose-excited (GE) neuron requires glucose uptake via pathic pain reflects problems with tissue homeo-
glucose transporters (GLUTs), glucose phosphorylation stasis and that pain is due to hypoglycemia,
by the rate-limiting enzyme glucokinase, and subsequent ischemia, or low pH, supported by the Maclver
metabolism of glucose to increase the intracellular ATP-­
to-­ADP ratio. In the setting of glucose sufficiency, ATP-­ study on the effect of glucose and oxygen level
sensitive K+ channels are closed, the membrane is manipulation effects on C fiber firing rate. He
depolarized, and neuronal firing occurs, which suppresses postulates that neuropathic pain is an energy fail-
the counterregulatory response while glucose levels are ure syndrome due to an oxygen/glucose depriva-
not low. Thus, a rise in plasma glucose increases neuronal
activity in GE neurons. However, when glucose levels fall tion state. This triggers C fiber firing through
as would occur during hypoglycemia, the decreased direct or indirect effect through TRPV1 channel
metabolism of glucose leads to the opening of K-ATP activation, triggering release of SubP and CGRP,
channels and hyperpolarization of these glucose-excited and subsequent neurogenic inflammation and
neurons [59]
neuropathic pain. Buffered glucose may resolve
neuropathic pain in the absence of hypoxia
The Basic Science on Dextrose through correcting local tissue hypoglycemia and
Algesia Efficacy acidosis.

The Maclver study “Activation of C fibers by

Metabolic Perturbations” [60] is probably the  arly Clinical Evidence of PIT
E
most important published research study support- Efficacy Using Dextrose
ing PIT. According to Maclver, the presence or
absence of glucose can be detected by small Dextrose injected around nerves in reducing neu-
fibers and has been tested by in vitro study in a rogenic pain is being supported by a growing
corneal model of small fibers. Perineural glyco- number of small but methodologically rigorous
penia results in progressive depolarization and clinical studies across many pain conditions [33].
hyperexcitability of nociceptive nerve fibers, pre- Results of several case studies suggest pain
sumably through reduced effectiveness of the reduction with injection of subcutaneous dex-
ATPase pump, which depends on dextrose for trose over related sensory nerve pathways in
ATP production [40]. In this study, nociceptive C shoulder, elbow and knee tendinopathies, also in
fibers exposed to a temporary glycopenia envi- cases of Achilles tendinopathy and low back
ronment demonstrated a 653% ± 23% increase in pain. [19–21].
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 389

a b
50
CONTROL

SPIKES/SECOND
40

30 D-GLUCOSE

20
L-GLUCOSE 15 min
10

0
0 10 20 30 40 50 60
TIME (min)
L-GLUCOSE 1 Hour

50
L-GLUCOSE

SPIKES/SECOND
40
0.1 mV
RECOVERY 30
20

10

0
0 10 20 30 40 50 60
TIME (min)

Fig. 17.14 a and b. Activation of C fibers by metabolic 653% ± 23% increase in action potential frequency within
perturbations: Nociceptive C fibers exposed to a tempo- 15 minutes, with prompt reversal to a normal baseline fir-
rary hypoglycemia state, by substitution of D-glucose ing rate when dextrose was reintroduced. (With permis-
with L-glucose, increases C fiber discharge activity by a sion from Bruce MacIver)

800 post-injection were consistent, and clinical bene-

% CONTROL FREQUENCY

fits were cumulative and clinically significant to

600 1-year follow-up [11, 26] (Fig. 17.17). This is the
first study that proves that dextrose is analgesic
400
(Fig. 17.18).
200
Epidural D5W injection in the absence of
anesthetic resulted in consistent post-injection
0 analgesia and clinically significant improvement
CONTROL HYPOXIA HYPO BOTH in pain and disability through 12 months for most
GLYCEMIA
participants. The consistent pattern post-injection
Fig. 17.15 Bar graph comparing cumulative effects of analgesia suggests potential sensorineural effect
hypoxia and hypoglycemia (L-glucose) on C fiber firing. of dextrose on neurogenic pain [57]
Hypoglycemia > hypoxia produced statistically signifi-
Another RCT assessing perineural dextrose
cant increase in discharged frequency greater than control.
Combined hypoxia and hypoglycemia did not produce a injection has been performed. Yelland et al.
significantly greater increase in discharge frequency com- compared subcutaneous dextrose injection to
pared to hypoglycemia alone. With permission from eccentric lengthening exercise (ELE) in Achilles
Bruce MacIver
tendinopathy and showed non-inferiority of
dextrose injection to the evidence-based ELE
The primary author of this chapter published a approach to Achilles tendinopathies and poten-
double-blind RCT comparing D5W to saline tial additive benefit from combining both treat-
injection in the caudal epidural space in partici- ments [63].
pants with back and either buttock or leg pain, Recently published RCTs consistently report
resulting in significant analgesia of 15 minutes to clinical benefits compared with injection control,
48 hours duration [11, 26] (Fig. 17.16). Upon including an RCT comparing dextrose to anes-
continued open-label treatment, analgesic effects thetic in the treatment of temporomandibular dis-
390 L. Maniquis-Smigel et al.

Fig. 17.16 Results of Short term analgesic effects of 5% dextrose epidural

short-term analgesic injection for chronic low back pain RCT
effects of 5% dextrose
Improvement in 0-10 NRS Pain Scores over two weeks
epidural injection for
chronic low back pain 6
RCT. Change in 0–10
Dextrose
NRS over 2 weeks.
5 Saline
Results show significant
analgesic effect of
dextrose that endured for
48 hours, suggesting a 4
short dextrose-specific
biological and clinical
effect. Compared with 3
blinded saline, D5W
caudal epidural injection
resulted in substantial 2
analgesia within
15 minutes that persisted
for more than 48 hours 1
among chronic
non-surgical LBP
patients with buttock 0
and/or leg pain [26] 0 15Min 2Hrs 4Hrs 48Hrs 2 Wks

Analgesic pattern upon repeated 5% dextrose

caudal epidural injection every 2 weeks
7

6
Improvement in NRS Score

0
0 2 Wks 4 Wks 6 Wks

Figs. 17.17 and 17.18 Analgesic response to 5% dex- treatment, analgesic effects post-injection were consis-
trose caudal epidural injection and long-term pain course. tent, and clinical benefits were cumulative and clinically
NRS, numerical rating scale. Upon continued open-label significant to 1-year follow-up [11]
17 Dextrose-Based Perineural Injection Treatment, and Ultrasound Hydrodissection 391

Analgesic pattern upon repeated 5% dextrose caudal epidural

injection and long term pain course.
Post injection analgesic pattern NRS improvement over 1 year.
All participants (n = 32)
7
Improvement in NRS Score

0
0 2 4 6 3 Mo 6 Mo 12 Mo
Wks Wks Wks

15 minutes post injection 4 hours post injection

2 hours post injection 48 hours post injection

Figs. 17.17 and 17.18 (continued)

order [64], providing increasing evidence of a system at the level of the dorsal root/dorsal root
sensorineural effect of dextrose injection. ganglion.
Wu et al. demonstrated that hydrodissection of
the median nerves in the carpal tunnel with dex-
trose was clinically effective in reducing symp- Discussion
tom of carpal tunnel syndrome compared to
saline injection [65]. Wu et al. also demonstrated The rapid analgesic effect of dextrose on pain-­
in other RCTs that hydrodissection with D5W producing C fibers following subcutaneous injec-
was superior to either hydrodissection with saline tion is stunning empirically but has not been
[66] or hydrodissection with triamcinolone in formally timed except in a study on epidural
saline [67]. Thus, dextrose hydrodissection injection of dextrose versus saline, which has an
appears to offer both mechanical hydrodissection effect within minutes, slower than that seen with
and sensorineural effects in carpal tunnel superficial injection of dextrose [26]. The num-
syndrome. ber of clinically based publications related to the
To emphasize the potential generalizability of effects of D5W on neuropathic pain is growing.
benefit of hydrodissection for neurogenic pain, We are just beginning to understand the scientific
Lam et al. hydrodissected a variety of nerves or rationale for PIT, and we propose that neuro-
ganglia in the upper body (stellate ganglion, bra- pathic pain is, at least in part, a neuronal energy
chial plexus, cervical nerve roots, and paraverte- deprivation disorder. Potential research areas are
bral spaces) in participants with severe myriad; e.g., a substantial percentage of those
neuropathic pain, and pain reduction exceeded with painful idiopathic neuropathy have empiri-
50% in 26 consecutive participants [12]. This cally benefited clinically from PIT.
high-volume hydrodissection used only dextrose, In current clinical practice, regenerative/mus-
and so had no lidocaine toxicity risk. This study culoskeletal physicians who are proponents of
supports an effect of D5W on the somatosensory sensorineural mechanism of dextrose find that
392 L. Maniquis-Smigel et al.

adding PIT and US nerve hydrodissection aug- and training programs provided by the Hackett
ments the effects of other regenerative injection Hemwall Patterson Foundation. The use of high-­
therapies such as prolotherapy, platelet-rich resolution ultrasound is an added and invaluable
plasma (PRP), and stem cell therapies. It com- asset in DPT because it is accurate, efficient, and
prises an intriguing and potentially effective more comfortable for patients and in PIT because
approach to pain and degenerative issues. it offers the visualization required for hydrodis-
Acquisition of procedural skills for PIT section of deeper nerves. Workshops on DPT/
requires continuing medical education, through PRP injection and hydrodissection are focusing
PIT conferences and master workshops by Dr. on the development of skill in the use of high-­
John Lyftogt or workshops and medical mission resolution ultrasound.

Free
Nerve
Thermoreceptor Ending
(Heat) (pain)

Merkel’s
Krause’s Disc
Corpuscles (touch)
(Cold)

Blood
vessels

Conclusion addition, although the peripheral nervous system

has the capability for regeneration, much research
PIT is a simple, extremely effective, and safe still needs to be done to optimize the environment
treatment for chronic pain and other degenerative for maximum regrowth potential.
conditions. Given the current level B evidence for
efficacy of DPT in the treatment of multiple con-
ditions, such as rotator cuff tendinopathy [9, 13, References
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 Ultrasound-Guided Spinal
Procedures
18
Jonathan Kirschner and Aditya Raghunandan

 egenerative Medicine for Spinal

R lumbar epidural injections, there were one high-
Procedures quality RCT, multiple relevant moderate-­quality
observational studies, and a single-arm meta-
Evidence analysis, and the qualitative evidence was only
assessed as a Level IV. For lumbar facet joint PRP
“Regenerative” and novel orthobiologics in the injections, assessment was based on one high-
treatment of spine-related disorders is a relatively quality RCT and two moderate-­quality observa-
new but growing field. The recent guidelines pub- tional studies with an assessment as Level
lished by the American Society of Interventional IV. Finally, for sacroiliac joint injections, there
Pain Physicians provide the most current data on were only one high-quality RCT, one moderate-
safe and efficacy of use of the biologics for low quality observational study, and one low-quality
back pain [61]. The studies were included based case report, and the qualitative evidence has been
on the PRISMA flow diagram and graded from I assessed as Level IV. Studies addressing cervical
to V as described by the Agency for Healthcare spine-related disorders were not evaluated in this
Research and Quality (AHRQ). For lumbar disc publication, and a search of PubMed reveals a
platelet-rich plasma (PRP), there were one high-­ paucity of studies for cervical spine-related ortho-
quality randomized controlled study (RCT), mul- biologic interventions.
tiple moderate-quality observational studies, a
single-arm meta-analysis, and one systematic
review, and the qualitative evidence was assessed Contraindications
as Level III. For lumbar disc medicinal signaling/
mesenchymal stem cell (MSCs), there were also “Regenerative” or biologic treatments are not
only one high-quality RCT, multiple moderate-­ without risk; the following contraindications
quality observational studies, a single-arm meta-­ should be kept in mind when selecting appropri-
analysis, and two systematic reviews, with the ate patients for spinal procedures. These include
qualitative evidence also assessed as Level III. For blood dyscrasias, platelet dysfunction, septice-
mia or fever, cutaneous infections in the area to
J. Kirschner (*) · A. Raghunandan be injected, anemia (hemoglobin less than 10 g/
Department of Physiatry, Hospital for Special dl), malignancy (particularly with hematologic or
Surgery, New York, NY, USA
bony involvement), allergy to bovine products if
Department of Rehabilitation Medicine, UT Health bovine thrombus is to be used, severe psychiatric
San Antonio, TX, San Antonio, USA
impairment, or unrealistic expectation [61].
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2022 397

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_18
398 J. Kirschner and A. Raghunandan

Peri-procedural Considerations main advantage of utilizing ultrasound for needle

placement is that critical blood vessels can be
Ideally, platelet concentration in the injectate visualized, preventing inadvertent puncture [57].
should be at least 2.5 times greater than the base- The important vascular anatomy to be aware of is
line plasma concentration [27]. In the USA, the as follows: in a cadaveric study, it was found that
FDA requires “minimal manipulation” and 20% of cervical foramina contained either the
“homologous use.” Cells should be used within deep or ascending cervical artery within 2 mm of
24 hours of thawing from a frozen medium [25]; the needle target for standard fluoroscopic
use of 19G needle (or larger bore) is ­recommended approach and 33% of the time these arteries
to reduce the incidence of apoptosis of tri-lineage entered the posterior foramen [36], radicular
capabilities, differentiation, and viability of artery branches from the ascending or deep cervi-
MSCs [25]; and a 2 mL syringe is recommended cal arteries traverse the foramen as the course
to avoid overinflation [25]. Intra-procedural rec- medially [34], and a small study found that there
ommendations are similar to most other proce- is a small incidence of arteries found in the poste-
dures in that cell material, patient, joint location, rior aspect of the foramen or posterior supply that
and affected side should be verified prior to injec- coursed medially into the foramen [34]. Using
tion and performed under direct image-guided the Doppler mode allows optimal visualization of
visualization. Following the injection, patients the vasculature and aids in avoiding inadvertent
should be instructed to rest, and some clinicians vascular injury [40]. Other complications due to
partially immobilize the injected body part; to cervical transforaminal injections range from the
date, there are no specific validated protocols that more common and relatively benign like vasova-
have been published regarding specific timelines, gal reactions, central steroid response, and tran-
but about 1 week of activity restriction is a rea- sient increase in pain to the rare but serious
sonable timeframe to avoid potential sequelae. complications such as spinal cord infarcts, epi-
Patients should also be counseled on avoiding dural hematomas, quadriparesis, stroke, and even
anti-inflammatory medications for at least 1 week death [70]. These risks are higher with particulate
pre- and 4 weeks post-­injection, since the bio- injectates [48], so caution with orthobiologics
logical basis of these injections hinges on the uti- must be taken.
lization of the patient’s inflammatory cascade.
The risks and benefits for aspirin should also be
reviewed with the patient [23, 38, 39]. Scanning Technique and Important
Anatomy

Cervical Spinal Nerves The affected side should be exposed by either

lying the patient in the lateral decubitus position
Indications with the affected side toward the ceiling or lying
the patient supine with the head rotated away
The incidence of cervical radiculopathy is rela- from the affected side. The prominent posterior
tively common with an estimated incidence of tubercle and rudimentary anterior tubercle are
107.3 per 100,000 for men and 63.5 per 100,000 identified by placing the transducer in short axis
for women [68]. Fluoroscopic and CT-guided at the C7 level. As the transducer is moved crani-
epidural injections are commonly used to treat ally to C6, the anterior and posterior tubercles of
cervical radiculitis; however, in a randomized the cervical vertebrae as well as the two-humped
blinded controlled study, there were found to be camel sign become more prominent [50]. Tracing
no difference outcomes in an ultrasound-guided the vertebral artery, which lies anterior to C7 and
versus fluoroscopy-guided transforaminal injec- enters the C6 foramen 90% and further cranial
tion in the lower cervical spine [40], and similar 10% of the time, is another method for identify-
findings were confirmed by Zhang et al. [78]. The ing the correct cervical level [51]. It is important
18 Ultrasound-Guided Spinal Procedures 399

a b

c d

Fig. 18.1 (a) Transverse (axial) view over C7; note the prominent anterior and posterior tubercles. (d) Dashed
prominent posterior tubercle. (b) Dashed orange line out- orange line outlines posterior tubercle, dashed purple line
lines posterior tubercle, yellow indicates C7 spinal nerve, outlines anterior tubercle, yellow indicates C6 spinal
and arrows with stops indicate carotid artery and internal nerve, and arrows with stops indicate carotid artery and
jugular vein. (c) Transverse (axial) view over C6 with internal jugular vein

to keep the transducer perpendicular to the cervi- alizing the rudimentary anterior tubercle and
cal level of interest to prevent angling the trans- prominent posterior tubercle.
ducer toward an unintended level. The power • Markings: Identify the transverse process and
Doppler feature should be utilized to identify the tubercles of C7 as they differ from the other
significant vascular structures including the cervical vertebrae, marking the C7 level. If
carotid artery, vertebral artery, and smaller radic- more than one level injection is planned, use a
ular vessels in and around the foramen (Fig. 18.1). marker to identify the probe position at the
desired vertebral levels and the needle entry
site. Mark any vessels that are identified on
Injection Technique Doppler to avoid inadvertent injury.
• Needle position: Plan your needle path prior
• Patient positioning: Lay the patient in the lat- to insertion to avoid any feeding vessels or
eral decubitus position with the affected side ones located in the posterior foramen. A blunt
facing upward with a pillow placed between needle should be inserted from a posterior to
the patient’s legs and one under the arm to anterior direction. The needle should be kept
facilitate comfort. The patient can also lay in-plane directed toward the desired nerve
supine with the head rotated and side bent root.
away. • Safety considerations: Care should be taken to
• Probe positioning: Place the transducer trans- avoid contact with a blood vessel or spinal
verse (short axis) over the C7 vertebrae, visu- nerve.
400 J. Kirschner and A. Raghunandan

Pearls C2–3 joint), the shoulder, or the interscapular

• The anterior spinal artery may receive some region (C5–6, C6–7) [15]. Each cervical facet
blood flow from the ascending and deep cervi- joint is innervated by two medial branches, and
cal arteries. anesthetizing these nerves can provide specificity
• Keep the transducer perpendicular as you scan and a diagnostic benefit [4]. Injection of the joint
to keep your desired vertebral level in site. with corticosteroid may provide therapeutic ben-
Angling the transducer may cause you to view efit, but may not be as helpful diagnostically [11].
up or down a level. Always inject from a pos- Cervical medial branch blocks have convention-
terior to anterior direction to avoid the internal ally been performed via fluoroscopic guidance;
jugular vein, vagus nerve, common carotid however, ultrasound guidance presents some
artery, and 80% of anterior located radicular unique advantages [16]. The main advantages of
arteries in the cervical foramen. using ultrasound guidance are the direct real-time
• Doppler mode may help to identify feeding visualization of vessels and nerves and needle
vascular structures in the posterior foramen. advancement which decreases the number of nee-
dle passes and trauma to adjacent structures [16,
Equipment Needed 17, 73], as well the lack of radiation exposure.
• High-frequency linear array transducer Longer-term treatment for cervical facet-­
• 22- or 25-gauge spinal needle mediated pain can be achieved by radiofrequency
• Non-particulate steroid preparation neurotomy, and ultrasound guidance to perform
• 1–2 mL of local anesthetic or normal saline the procedure has been shown to be a viable
(Fig. 18.2) option [18, 43].

 ervical Medial Branch Blocks

C Scanning Technique and Important
and Third Occipital Nerve Anatomy

Indications The patient should be placed in a lateral decubitus

position with the transducer placed in long axis;
Axial neck pain can arise from the cervical zyg- the superior end should be positioned on the mas-
apophyseal or facet joints. This pain can radiate toid process. The articular pillars of the cervical
to the posterior occipital region (commonly the vertebrae (C2–7) appear as hills and valleys, the

a b

Fig. 18.2 (a) Example of transverse (axial) probe posi- out of the field of view to allow for easier needle trajec-
tion over C6 level with in-plane needle position. (b) tory); arrowhead indicates needle tip, and arrow indicates
Example of in-plane axial injection toward the C6 spinal needle
nerve (probe angled slightly to position posterior tubercle
18 Ultrasound-Guided Spinal Procedures 401

joint being the hills and the troughs where the • Probe positioning: Place the transducer coro-
medial branches lie, the valleys. The first hill rep- nally over the mastoid process and view the
resents the C2–3 zygapophyseal joint. There are articular pillar, identifying the levels as you
two ways to confirm your level, either by visual- move caudally.
izing the transverse process of C1 on the cephalad • Markings: Identify and mark the desired cer-
portion of the screen or via use of the Doppler to vical levels.
identify the vertebral artery traversing anteriorly • Needle position: The needle is inserted in-
into the C2 foramen [58]. The superficial medial plane toward the medial branch if identified. If
branch of C3 differs from the other ­ cervical the nerve is not visualized, direct straight
medial nerves, because it sits on top of the “hill” down between the articular pillars toward the
at the C2–3 zygapophyseal junction as it travels deepest point, touching down on bone. For the
enroute to becoming a cutaneous nerve; this nerve TON, the needle is inserted in-plane toward
is also referred to as the third occipital nerve the apex of the C2–3 joint.
(TON) and also has smaller contributions from • Safety considerations: Keep the transducer
the C2 medial branch. The TON can be identified and injection posterior and lateral to avoid the
by placing the transducer in long axis, starting at anterior vasculature and spinal cord.
mastoid process and scanning caudally from the
transverse process of C1 to the vertebral artery as Pearls for CMBB
it traverses into the C2 foramen, and ultimately
identified at the top of the “hill” of the C2–3 zyg- • Aim at the deepest point between the articular
apophyseal junction [73]. The remainder of the pillars.
cervical medial branches (C4–8) are identified by • The medial branch may be difficult to visual-
scanning caudally and visualized as they traverse ize in an obese patient.
dorsally in the troughs of the articular pillars to • The cervical medial branch becomes more
innervate the facet joint at the levels above and difficult to identify as you proceed caudally.
below [24] (Fig. 18.3).
Pearls for TON

Injection Technique • Aim at the convexity of the C2–3 joint.

• The C2 level is also identified as having the
• Patient positioning: Lay the patient in the lat- first bifid spinous process [23]. The transducer
eral decubitus position with pillows under- can be placed axially over the spinous process
neath the head, between the legs, and under of C2, and the lamina of C2 can be traced lat-
the arm. erally until the C2–3 joint appears.

a b

Fig. 18.3 (a) Coronal view of the cervical articular pillars. (b) Black arrowhead indicates TON, black arrow indicates
C3 medial branch, and asterisk indicates C2–3 and C3–4 zygapophyseal joint
402 J. Kirschner and A. Raghunandan

a b

Fig. 18.4 (a) Example of coronal view over the cervical medial branches with in-plane needle position. (b) Arrowhead
indicates needle tip adjacent to medial branch; white arrow indicates needle; articular pillar labeled

Equipment Needed Scanning Technique and Important

• High-frequency linear array transducer Anatomy
• 22 or 25G 2.5–3.5′′ spinal needle
• 0–1 mL of steroid preparation per level The patient should be placed prone with the
• 0.5–1 mL of local anesthetic per level transducer placed in long axis in the midline sag-
(Fig. 18.4). ittal plane over the cervical spinous processes.
The C2 level can be identified as the most cranial
cervical vertebra with a bifid spinous process
Cervical Zygapophyseal Joint [15]. Each cervical level can be identified by
scanning caudally and counting the midline
Indications superficial hyperechoic spinous processes. In
order to view the desired zygapophyseal joint,
The cervical zygapophyseal or facet joints are identify the corresponding spinous process, and
formed by the articulation of the superior and move the transducer laterally to bring the saw-
inferior articular pillars of contiguous vertebrae. tooth image of the zygapophyseal joint into view.
Intra-articular zygapophyseal joint injections It should be noted that zygapophyseal joints
have been shown to have both diagnostic and become more vertical as the scan progresses cau-
therapeutic benefits [6, 71], but the evidence is dally [65, 69] (Fig. 18.5).
less robust than for MBB and RFA. These proce-
dures are usually performed under either fluoro-
scopic or CT guidance; however, Injection Technique
ultrasound-guided cervical facet joint injections
have been found to have the advantages of • Patient positioning: Lay the patient in the
requiring fewer needle repositions, shorter pro- prone position with a pillow underneath the
cedure time, and better pain scores at 1-month chest to allow for slight cervical flexion.
follow-up [63]. The main hindrance for using • Probe positioning: Place the transducer in the
ultrasound guidance compared to fluoroscopy is sagittal plane over the cervical spinous pro-
difficulty in the identification of the correct tar- cesses and move laterally until the facet joints
get and level [22]. at the desired levels are in view.
18 Ultrasound-Guided Spinal Procedures 403

a b

Fig. 18.5 (a) Sagittal view of the cervical facet joints. (b) Asterisk indicates cervical facet joints

a b

Fig. 18.6 (a) Example of sagittal probe position over indicates needle; IAP inferior articular process, SAP supe-
cervical facet joint with in-plane injection technique. (b) rior articular process
Arrowhead indicates needle tip entering facet joint; arrow

• Marking: Identify and mark the desired cervi- • Keeping the needle angle shallow will help to
cal levels. mimic the angle of the facet joint and ease the
• Needle position: The needle is inserted in- approach and needle placement for an intra-­
plane from caudal to cephalad toward the facet articular injection.
joint. • The C2 vertebra has the first bifid spinous
• Safety considerations: Keep the transducer process.
and injection posterior to avoid the anterior
vasculature. Equipment Needed
• High-frequency linear transducer
• 22-gauge, 1.5–3.5′′ needle
Pearls • 0.5–1 mL of steroid preparation per level
• The cervical facets appear as shingles on a • 0.5–1 mL of local anesthetic per level
roof with the probe in the sagittal plane. (Fig. 18.6).
404 J. Kirschner and A. Raghunandan

Stellate Ganglion recurrent laryngeal nerve; and anterior to the ver-

tebral artery and longus colli muscle [35].
Indications Dimensions of the stellate ganglion are usually
2.5 cm long, 1 cm wide, and 0.5 cm thick [59].
The stellate ganglion block (SGB) is the oldest
and most common sympathetic block. It has many
indications including complex regional pain syn- Scanning Technique and Important
drome (types I and II), postherpetic neuralgia, Anatomy
intractable angina, post-traumatic stress disorder,
hyperhidrosis, arrhythmias, hot flashes, and The patient should be placed in supine position
Raynaud’s disease [1, 2, 31, 33, 45, 47, 64]. The with the head placed in slight extension and
original procedure was described as being per- rotated away from the affected side. Start by plac-
formed under palpation guidance in which the ing the transducer over the cricoid cartilage in the
needle target was the anterior aspect of the C6 axial plane, and scan laterally until the prominent
transverse process, named Chassaignac’s tubercle anterior tubercle of the C6 transverse process is
[44]. Various imaging-guided techniques for SGB visualized. It is important to identify and avoid the
have also been described including fluoroscopy, following structures: carotid artery, internal jugu-
computerized tomography, magnetic resonance lar vein, cricoid cartilage, and longus colli mus-
imaging, and radionucleotide tracers. The main cle. The Doppler should be utilized to identify and
issue with these techniques, however, is that they avoid the inferior thyroid artery and a vertebral
may not be practical in a clinical setting, due to artery. To confirm the level, identify the C7 level,
increased time, cost, and radiation exposure. Use which has a prominent posterior and rudimentary
of ultrasound guidance provides the benefit of anterior tubercle; this differs from the more cra-
direct visualization of the needle path, vasculature nial C6 level which has prominent posterior and
close to the stellate ganglion, as well as important anterior tubercles [67] (Fig. 18.7).
adjacent soft tissue structures [26]. The stellate
ganglion, or cervicothoracic ganglion, is the
fusion of the inferior cervical ganglion and the Injection Technique
first thoracic ganglion. It lies posterior and lateral
to the trachea, esophagus, and thyroid; medial to • Patient positioning: Lay the patient supine
the common carotid artery and internal jugular with the neck in slight extension and slight
vein; just lateral to the inferior thyroid artery and rotation away.

a b

Fig. 18.7 (a) Transverse (axial) view of the stellate gan- indicates longus colli, black arrow indicates location of
glion with Doppler. (b) Magenta indicates sternocleido- stellate ganglion, and arrow with stop indicates carotid
mastoid, purple indicates anterior scalene, orange artery; IJ internal jugular vein
18 Ultrasound-Guided Spinal Procedures 405

a b

Fig. 18.8 (a) Example of axial probe position over stel- vertebral fascia; white arrow indicates needle; SCM ster-
late ganglion at the level of C6 with in-plane injection nocleidomastoid, Th thyroid; vertebral body labeled
technique. (b) Arrowhead indicates needle tip in the pre-

• Probe positioning: Start by placing the probe • A nerve stimulator can help to identify the
at C7 in the axial plane. As you scan cephalad, phrenic nerve and avoid inadvertent diaphrag-
the anterior tubercle of C6 comes into view. matic paresis.
Now at the level of C6, visualize the anterior
tubercle of C6, longus colli muscle and pre- Equipment Needed
vertebral fascia, carotid artery, and thyroid • High-frequency linear array transducer
gland. • 25G 1.5–3.5′′ needle
• Markings: There are a number of significant • 1–3 mL of short-acting anesthetic for local
anatomical structures to mark and note in this anesthesia
region. Identify the esophagus, trachea, • 10–20 mL of long-acting anesthetic for the
carotid artery, internal jugular vein, and infe- block (Fig. 18.8).
rior thyroidal artery.
• Needle position: The needle is inserted in-
plane from lateral to medial aiming at the pre- Greater Occipital Nerve
vertebral fascia just anterior to the longus colli
muscle. Plan out the course of the needle to Indications
avoid puncturing important structures. If the
needle path can cause injury to these struc- Greater occipital nerve (GON) blocks are indi-
tures, adjust the probe position or insert the cated for the treatment of occipital neuralgia and
needle with a more oblique trajectory. have been used for a variety of headache disorders
• Safety considerations: Avoid the esophagus including cluster and cervicogenic, acute and
and trachea medially and the carotid artery, chronic migraines, post-dural puncture, and even
internal jugular vein, inferior thyroid, and ver- a case report for spontaneous intracranial hypo-
tebral arteries laterally. A phrenic nerve block tension headache [3, 7, 55, 56, 62, 75]. The origi-
can occur and cause diaphragmatic paresis. nally described procedure uses palpation of the
occipital artery at the level of the superior nuchal
Pearls ridge and injecting just medial [29]. The chal-
• The stellate ganglion lies medial to the scalene lenge with this method, however, is that palpation
muscles. of the occipital artery can be difficult and there
• Stellate ganglion is formed by the fusion of can be variability in the course of both the occipi-
the inferior cervical and first thoracic tal artery and GON. In most cases, the GON arises
ganglion. from the C2 dorsal ramus and courses around the
406 J. Kirschner and A. Raghunandan

inferior aspect of the inferior oblique muscle • Probe positioning: Start by placing the trans-
(IOM) and ultimately between the IOM and the ducer transverse (axial) over the bifid spinous
semispinalis capitis (SSC) muscle [53]. The GON process of C2. The posterior arch of C1 will
can become irritated and entrapped at a number of appear smooth. The inferior obliquus capitis
locations including where the GON emerges from muscle attaches to the spinous process of C2
the C2 dorsal ramus between C1 and C2, where and transverse process of C1. Follow the infe-
the nerve courses between the IOM and SSC mus- rior obliquus capitis in-plane as it moves later-
cles, where the nerve pierces the belly of the SSC, ally and cranially. The GON sits in the fascial
and as the nerve exits from the tendinous aponeu- plane between the inferior obliquus capitis
rosis of the trapezius [46, 60]. and semispinalis capitis muscle.
• Markings: Use Doppler to identify any
branches of the occipital artery to avoid inad-
Scanning Technique and Important vertent puncture.
Anatomy • Needle position: The needle is inserted in-
plane from lateral to medial. Advance until the
The patient should lie prone with slight cervical needle is close to the nerve sheath. If the nerve
flexion to expose the suboccipital region. The cannot be clearly visualized, then place medi-
ultrasound transducer should be placed over the cation in the fascial plane between IOM and
bifid C2 spinous process and moved one level SSC.
cephalad to C1. The IOM is located just superficial • Safety considerations: Prior to placing the
to C1 and the SSC just superficial to the IOM. The needle, Doppler may help to identify the
GON is a hyperechoic round or elliptical structure occipital vessels.
that lies within the plane between the IOM and
SSC before it pierces superficially through the Pearls
SSC [10]. Doppler should be utilized to visualize • The C2 spinous process is bifid which distin-
and avoid the occipital artery (Fig. 18.9). guishes it from the smooth posterior arch of
C1.
• Placing the neck in slight flexion will help to
Injection Technique clear room for the ultrasound transducer.
• Rotate the probe slightly (lateral end more
• Patient positioning: Lay the patient prone with cranial than medial end) to help bring the
the neck in slight flexion. A pillow can be ­inferior obliquus capitis muscle parallel to the
placed under the chest. probe.

a b

Fig. 18.9 (a) Axial view of the GON with Doppler. (b) Orange indicates IOM, SSC and inion labeled; arrow with stop
indicates occipital artery; yellow indicates GON
18 Ultrasound-Guided Spinal Procedures 407

a b

Fig. 18.10 (a) Example of axial probe position over GON with in-plane injection technique. (b) Arrowhead indicates
needle tip adjacent to GON; white arrow indicates needle; SSC, inion, and inferior oblique labeled

Equipment Needed blocks compared to fluoroscopic guidance pro-

• High-frequency linear array transducer vides the advantage of avoiding radiation expo-
• 25G 1.5′′ needle sure while being just as accurate [28, 32, 37, 41].
• 0.5–1 mL of steroid preparation
• 1–3 mL of local anesthetic (Fig. 18.10).
Scanning Technique and Important
Anatomy
 umbar Medial Branch Blocks
L
and Zygapophyseal Joint The patient should be placed in the prone posi-
tion. The transducer should be placed longitudi-
Indications nally to identify the correct level and then rotated
axially to obtain the “crown sign.” Alternatively,
Facet-mediated low back pain is very common it can be placed axially over the upper aspect of
and accounts for up to 45% of axial lumbar pain the sacrum to start and then translated cephalad
[8, 52]. The zygapophyseal or facet joints are as the hyperechoic midline spinous processes are
diarthrodial and formed by the superior and infe- counted until the desired level is reached. Move
rior articular processes (SAP and IAP). In the the transducer laterally and center it over the
lumbar spine, these joints are innervated by the junction of the SAP and transverse process (TP)
medial branches of the dorsal rami of the level (Fig. 18.11).
involved and the level above. For example, the
L4–5 facet joint is innervated by the L3 and L4
medial branches. It is important to note that the Injection Technique
L5 dorsal ramus does not have a medial branch,
so the dorsal ramus itself is targeted [12, 14]. • Patient positioning: Lay the patient prone with
Lumbar facet-mediated pain is usually described a pillow under the pelvis.
as dull/achy in nature and typically localized to • Probe positioning: Start by finding your
the axial lower back, but can occasionally radiate desired level as above. Keep the probe in an
into the buttocks and proximal thigh [8]. Loading axial view and identify the “crown” sign,
the facet joint with oblique extension may repro- transverse process deep, z-jt in the middle,
duce symptoms; however, the gold standard is and spinous ­process superficial, all in the same
image-guided comparative anesthetic medial view. Center the probe over the z-jt.
branch blocks [14, 54]. The use of ultrasound • Markings: Mark the spinal levels beginning at
guidance for performing diagnostic medial the sacrum as you scan cephalad. This can be
408 J. Kirschner and A. Raghunandan

a b

c d

Fig. 18.11 (a) Axial view over sacrum. (b) Dashed elements; SP spinous process, ZJ zygapophyseal joint, TP
orange line outlines dorsal sacrum. (c) Axial view over L5 transverse process; paraspinal muscle labeled
vertebrae. (d) Dashed orange line outlines L5 posterior

done by scanning axially or sagittally from the Equipment Needed

midline using the sacrum as a landmark. • Curvilinear transducer or a wide-footprint lin-
• Needle position: The needle is inserted in- ear transducer with a low-mid frequency
plane from lateral to medial toward the base of • Spinal needle 22–25G 3.5–5″
the SAP and the transverse process for the • 0.5–1 mL of steroid preparation per level
medial branches and toward the cleft formed • 0.5–1 mL of local anesthetic per level
by the IAP and SAP for the z-jt. (Fig. 18.12).
• Safety considerations: Prior to placing the
needle, Doppler may help to identify any ves-
sels. If the needle is too caudal or cephalad, it Caudal
may enter the epidural space.
Indications
Pearls
• Fine-tuning or toggling the probe once it is in Caudal epidural injection is one of the oldest
position over the facet joint in the axial plane interventional procedures for treating pain due to
will help to visualize the joint opening. lumbar spinal stenosis or disc herniation. This
• After the target is reached, turn the probe sag- approach may be preferred for patients who have
ittally to view the needle tip on the upper part undergone previous surgery or have difficult
of the transverse process to confirm it is in anatomy whereby lumbar transforaminal access
proper position for the medial branch block. is difficult. It also has a lower risk of inadvertent
18 Ultrasound-Guided Spinal Procedures 409

a b

Fig. 18.12 (a) Example of axial probe position over L5 z-jt joint with in-plane injection technique. (b) Arrowhead
indicates needle tip at z-jt, arrow indicates needle tip, and asterisk indicates z-jt; spinous process labeled

intrathecal injection [42]. Caudal injections are Injection Technique

typically performed under fluoroscopic guidance
and can be performed with either a shallow or • Patient positioning: Lay the patient prone
steep angle approach depending on the patient’s comfortably on the table.
specific anatomy [72]. Even under image guid- • Probe positioning: Start by placing the trans-
ance, there can be inadvertent needle placement ducer short axis (transverse) to the mid-
25.9% of the time [74]. Ultrasound-guided nee- sacrum and scan caudad until the sacral cornua
dle placement provides a reasonable alternative appear. Rotate the probe 90° to give a sagittal
to fluoroscopy with 96% accuracy [67]. Use of and longitudinal picture, and center the sacral
Doppler to avoid vasculature has shown very hiatus on the screen.
high accuracy rates as well [77]. It has also been • Markings: Mark the placement of the probe
shown that there is no statistically significant dif- and needle entry site once the ideal position is
ference in terms of pain or disability between found so that the area can be sterilized and
fluoroscopic and ultrasound-guided caudal injec- found quickly again. You can also mark the
tions [66]. distance between S2 and S4 so you know the
distance to the thecal sac.
• Needle position: The needle is inserted in-
Scanning Technique and Important plane from caudal to cephalad aiming at the
Anatomy sacral hiatus. The needle should be inserted
deep to the dorsal aspect of the sacrum. Some
With the patient in a prone position, palpate the resistance by the sacrococcygeal ligament and
sacral hiatus with a sterile gloved hand. Place a “pop” may be appreciated.
the transducer axially across the sacrum, mid- • Safety considerations: Carefully aspirate to
line and proximal to the sacral hiatus. Scan dis- ensure no blood or cerebrospinal fluid is
tally until the sacral cornua appear as an returned.
inverted U-shape structure and the sacrococcy-
geal ligament is seen as a horizontal hyper- Pearls
echoic line just deep to them. Rotate the • Once the needle advances through the sacro-
transducer 90 degrees to obtain a long-axis coccygeal ligament, begin aspiration and
view to visualize the sacrum and sacral canal injection. Do not advance the needle too far as
[9] (Fig. 18.13). the dural sac typically ends at S2 and the nee-
410 J. Kirschner and A. Raghunandan

a b

c d

Fig. 18.13 (a) Axial view over sacral cornua. (b) Green hiatus. (d) Dorsal sacrum (left); green indicates sacrococ-
indicates sacrococcygeal ligament; SC sacral cornua; cygeal ligament; asterisk indicates sacral hiatus
asterisk indicates sacral hiatus. (c) Sagittal view of sacral

a b

Fig. 18.14 (a) Example of sagittal probe position over sacrum with in-plane injection technique. (b) Arrowhead indi-
cates needle tip traversing toward sacral hiatus; arrow indicates needle

dle cannot be visualized anterior to the dorsal • 0–4 mL of local anesthetic

bony aspect of the sacrum. • 0–6 mL of normal saline (Fig. 18.14).
• Injection volume of 20 mL can reach S1
100%, L5 89%, L4 84%, and L3 19% of the
time. Sacroiliac Joint

Equipment Needed Indications

• High-frequency linear array transducer
• 22 or 25G 3.5′′ spinal needle The diagnosis of sacroiliac joint (SIJ)-mediated
• 2 mL of steroid preparation pain is based on a combination of history of low
18 Ultrasound-Guided Spinal Procedures 411

back/buttock pain and physical exam; however, the level of the sacral hiatus. Move the probe
there are no reliable imaging studies or specific lateral and cephalad until the cleft between the
physical exam maneuvers to accurately diagnose sacrum and ilium is centered on the screen.
SIJ dysfunction. SIJ injections provide both The probe should be positioned 1 cm above
­diagnostic and therapeutic value and can confirm the lower end of the joint.
the SIJ as the pain generator [5, 21, 49, 76]. The • Markings: No significant vascular or neural
precise innervation of the SIJ is complex and not structures need to be marked.
fully understood. Some authors argue a combi- • Needle position: The needle should be
nation of anterior and posterior innervation, inserted in-plane from medial to lateral paral-
whereas others suggest innervation entirely pos- lel to the transducer for optimal needle
terior from the lateral branches of the dorsal visualization.
rami [13, 19, 20, 30]. • Safety considerations: Prior to placing the
needle, Doppler may help to identify any ves-
sels. Take care in osteoporotic individuals to
Scanning Technique and Important not advance the needle through bone.
Anatomy
Pearls
The patient should be placed in the prone posi- • The injection can be performed in the lower
tion with the transducer placed transversely over third of the SIJ which is synovial, while the
the posterior superior iliac spine (PSIS) and upper portion is fibrous and not a true joint.
translated medially to identify the S1 foramen. • Target the most inferior portion of the joint.
Translate the transducer caudally to identify the • Push the needle through the posterior liga-
inferior SIJ recess/capsule, located lateral to the ment, and feel a pop to help confirm joint
S2 foramen (Fig. 18.15). entry rather than a periarticular injection.

Equipment Needed
Injection Technique • Curvilinear or linear array 6–10 mHz
transducer
• Patient positioning: Lay the patient in the • 22G 3.5′′ spinal needle
prone position with a pillow under the pelvis. • 1–2 mL of steroid preparation
• Probe positioning: Start by placing the trans- • 1–2 mL of local anesthetic (Fig. 18.16).
ducer short axis (transverse) to the sacrum at

a b

Fig. 18.15 (a) Axial view of the SIJ. (b) Dashed orange line outlines the sacrum, dashed purple line outlines the ilium,
and asterisk indicates joint space; subcutaneous fat labeled
412 J. Kirschner and A. Raghunandan

a b

Fig. 18.16 (a) Example of axial probe position over SIJ with in-plane injection technique. (b) Arrowhead indicates
needle tip entering SIJ, arrow indicates needle, and asterisk indicates joint space; sacrum and ilium labeled

ceeding with caudal epidural injections. Arch Phys

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 Musculoskeletal
Ultrasound-­Guided Regenerative
19
Medicine

Angela N. Cortez
and Rhoel James Timothy O. Dejano

 he History of Ultrasound
T mum function lost through injury illness or
and Physiatry ­disabling conditions [6]. The physiatrist’s under-
standing of functional anatomy and biomechan-
Physiatry was one of the first fields to take on the ics lends itself to wanting accurate information in
ultrasound in its scope of practice, starting with the patient room, in real time, to guide clinical
the founding of the American Institute for decision-making and management. By 1999,
Ultrasound in Medicine (AIUM) among a group Primack demonstrated musculoskeletal ultra-
physiatrists in 1951 [1]. Its use in the field has sound as an extension of the clinical exam, an
evolved as ultrasound technology has evolved, idea that largely gained momentum among phys-
starting initially with therapeutic ultrasound as a iatrists in the twenty-first century with improve-
heating modality [2]. By 1958, Dr. Karl Dussik ments in technology [7]. Just as electrodiagnostic
published the first report on musculoskeletal testing has long been thought of as an extension
ultrasonography, heralding a movement in mus- of the clinical exam in the physiatrist, the ultra-
culoskeletal applications in physiatry that has sound has taken arguably equal importance with
escalated in the twenty-first century [2–4]. the physiatrist as a diagnostic tool.
Physiatrists’ role in the history of ultrasound has
uniquely positioned the field in guiding its appli-
cations and evolution [5].  he Ultrasound as an Extension
T
The American Academy of Physical Medicine of the Physiatrist
and Rehabilitation describe physiatrists as physi-
cians who are “muscle and bone experts who The musculoskeletal ultrasound has now been
treat injuries or illnesses that affect how you coined the “stethoscope” of the physiatrist, as its
move.” Specifically, goals of the field involve many current advantages (e.g., convenience, por-
diagnosing and treating pain and restoring maxi- tability, high resolution, dynamic real-time prop-
erties) facilitate prompt diagnosis, functional
A. N. Cortez (*)
information, and interactive imaging of musculo-
Department of Physical Medicine & Rehabilitation, skeletal conditions [8]. Nearly half of the publi-
University of California at Davis, cations on musculoskeletal ultrasound were in
Sacramento, CA, USA the field of physical medicine and rehabilitation
R. J. T. O. Dejano over a 25-year period, and its integration into
Department of Internal Medicine, University of Cebu physiatric education has been seen globally [2,
Medical Center, Cebu City, Philippines

© Springer Nature Switzerland AG 2022 417

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_19
418 A. N. Cortez and R. J. T. O. Dejano

9]. Simultaneously, the evolution of musculo- Individuals over age 35 experience higher risk
skeletal ultrasound has produced alongside it the of overuse tendinopathies, and tendinopathies
development of interventional ultrasound in are the most common cause of chronic shoulder
physiatry. Insomuch as a trained practitioner can pain in the general population [15, 16].
now both identify pathology in real-time and Optimizing function and improving perfor-
accurately provide an ultrasound-guided inter- mance can be difficult in the context of chronic
vention, its use in physiatry is expansive. tendinopathies, as treatment is often protracted
and requires careful adherence from the patient.
Physiatrists are optimized at assessing biome-
Ultrasound in Physiatric chanical abnormalities that predispose their
Musculoskeletal Medicine patients to tendinopathy and at developing a
realistic rehabilitation program [15]. Identifying
Joint Injections calcific tendinopathies especially of the supra-
spinatus, enthesophytes, tendon thickening
Musculoskeletal-related conditions are a primary indicative of tendinopathy, and dynamic assess-
source of worldwide disability, with osteoarthri- ment of snapping tendons are within the capa-
tis one of the leading causes [10]. Hip and knee bilities of musculoskeletal ultrasound [17].
osteoarthritis account for 17 million years lived Within this framework, musculoskeletal ultra-
with disability globally [11]. Physiatrists use a sound allows for direct visual participation of
multitude of interventions to decrease pain and the patient and in-office reassurance of their
improve function due to joint pain, and diagnosis and treatment plan [18].
ultrasound-­guided interventions allow for accu- The ability to directly visualize tendon struc-
rate and convenient in-office treatment options. tures increases accuracy of established proce-
For osteoarthritis, several studies have confirmed dures and has also allowed for interventional
the accuracy of ultrasound-guided interventions procedures not previously available 10 to 15
to various joints, and intervention accuracy can years ago [14]. Subacromial and greater trochan-
maximize the efficacy of the desired injectate, teric hip injections have been mainstays for the
such as PRP, prolotherapy, hyaluronic acid, or treatment of common musculoskeletal patholo-
corticosteroids [12–14]. gies, but direct visualization of the tendon has
Commonly performed joint injections include allowed for the development of procedures such
hip joint injections, glenohumeral joint injec- as needle tenotomy of the gluteus medius and
tions, and subtalar joint injections. Deeper joints minimus tendons for chronic tendinopathy. Other
and small joints are particularly useful under interventional examples include high-volume
ultrasound guidance. The accuracy of ultrasound-­ injection of the paratenon to disrupt neovessel
guided interventions allows for therapeutic abnormalities in Achilles tendinopathy and bar-
options to diminish pain, in addition to diagnostic botage of a calcific rotator cuff tendon [19].
options via anesthetic infiltration to differentiate
pain generators from nearby structures (e.g., hip
joint and iliopsoas tendon). Joint effusions and Injections in Soft Tissue
Baker’s cysts are quickly visualized and fully
aspirated to improve mobility via ultrasound. Within the scope of the physiatrist are periph-
eral nerve disorders, including carpal tunnel
syndrome and Morton neuromas. Available
Tendon and Bursa Injections studies have shown ultrasound-guided Morton
neuroma injections to be highly accurate and
Tendinopathies have seen increasing prevalence comparable to MRI in diagnostic accuracy [14,
with an increase in recreational sports [15]. 20]. Carpal tunnel syndrome, a common disor-
19 Musculoskeletal Ultrasound-Guided Regenerative Medicine 419

der among adults, can be treated with cortico- Spinal Cord Injury Considerations
steroid injection as an alternative to splinting. A
critical review of the literature has found In patients with spinal cord injury, rehabilitation
ultrasound-­guided carpal tunnel injections to be can include the use a manual wheelchair to regain
less painful and more efficacious than land- independent mobility. Increased loads into the
mark-based injections [14]. Given those find- upper limb from manual wheelchair use have
ings, the physiatrist, armed with electrodiagnostic been associated with a high prevalence of shoul-
machine and an ultrasound as “stethoscopes,” der and wrist pain in this population due to over-
can be a patient’s single point of contact from use [24]. Correspondingly, treating upper limb
diagnosis to treatment of various compressive pain can be critical for those who rely on their
focal mononeuropathies. upper limbs for independent mobility and activi-
ties of daily living [24, 25]. Pathologies include
rotator cuff tendinopathy, shoulder impingement,
Ultrasound in Rehabilitation biceps tendinopathy, ulnar neuropathy at the
elbow, and carpal tunnel syndrome [21, 26].
Musculoskeletal injuries are a prominent focus Heterotopic ossification is another common
for physiatrists in musculoskeletal ultrasound, complication after spinal cord injury with inci-
but its use can be conveniently applied in reha- dence ranges of 10–53% and approximately
bilitation settings, within the backdrop of brain 20–30% of these patients with clinically signifi-
injury, spinal cord injury, and amputation [21]. cant disease [27]. Symptoms include decreased
joint range of motion, swelling, and pain.
Bisphosphonates have been found effective at
Post-stroke Shoulder Pain halting the progression of heterotopic ossifica-
tion, though the medication was found most
Stroke is a common syndrome and the second effective when used prior to positive findings on
most common cause of disability worldwide. In radiographs which can take 4 to 6 weeks [28–30].
spastic hemiparesis, post-stroke shoulder pain is Triple-phase bone scan is currently the mainstay
a frequent complication with likely multiple for early diagnosis, though its low specificity can
pathologies, including shoulder subluxation, be problematic at differentiating the disease from
shoulder impingement, adhesive capsulitis, and other potential sources such as deep venous
rotator cuff and biceps tendinopathies [21, 22]. thrombosis, infection, and tumors [27].
Hemiparesis in stroke begins with a flaccid Ultrasound has long demonstrated to be superior
stage, which is the most common period for the to plain radiographs at the early detection of het-
emergence shoulder subluxation [23]. It is char- erotopic bone formation [29, 30]. In contrast to
acterized by the inferior displacement of the triple-phase bone scan, ultrasound is more spe-
humeral head due to impaired muscle tone, cific and highly sensitive for the early detection
which can predispose the shoulder to other dis- and intervention of heterotopic ossification, with
orders including tendinopathy. Ultrasound has increased portability to allow for bedside appli-
been found useful in the measurement of post- cations [27, 29, 30].
stroke shoulder subluxation and can easily be
performed bedside for those with mobility
impairments [23]. In the same manner, ultra- Botulinum Toxic Injections
sound-guided diagnostic and therapeutic inter-
ventions for rotator cuff and biceps pathologies Common to both stroke and spinal cord injury is
in post-stroke shoulder pain can be performed spasticity, which is velocity-dependent muscle
with good specificity and accuracy to the benefit tone that has the potential to limit function in
of the patient [14, 21]. patients. Botulinum toxin injections are com-
420 A. N. Cortez and R. J. T. O. Dejano

monly used for targeted treatment of spasticity Conclusion

and can be guided via electromyography, elec-
trical stimulation, and ultrasound [21]. Injection Musculoskeletal ultrasound has seen substantial
accuracy is crucial for treatment efficacy and growth among physiatrists over several decades
avoidance of neurovascular structures, which to aid both the diagnostic evaluation and the
makes ultrasound well-suited for this role. interventional treatment of various disorders. The
Electromyography, although widely available, musculoskeletal ultrasound can be thought of as
requires the patient to activate muscle, a task an extension of physiatrist. Applications in physi-
that can be limited in those with stroke or spinal cal medicine and rehabilitation are immense and
cord injury, and both electromyography and only briefly surveyed in this chapter. Physiatrists
electrical stimulation can be painful for the should anticipate continued development in mus-
patient [31]. Musculoskeletal ultrasound, in culoskeletal ultrasound applications within their
contrast, allows for precise localization of the practice as the technology advances.
targeted muscle, avoidance of neurovascular
structures, and arguably improved efficacy and
safety [31]. References
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2003;22(4):675–92. 29. Cassar-Pullicino V, McClelland M, Badwan D,
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 Part VI
Sports Medicine
 Ultrasound-Guided Exercises
20
Michael Francis Obispo

 istory of Ultrasound Use

H phragm, and lumbopelvic muscles particularly in
in Exercise patients suffering from low back pain. In particu-
lar, Julie Hides [21] was able to detect atrophy of
In 1958, Dussik et al. [12, 32] measured the the lumbar multifidus via ultrasound at the spinal
acoustic attenuation of articular and periarticular level corresponding to the symptoms of acute low
tissues including the skin, adipose tissue, muscle, back pain. She also noted that there was no
tendon, articular capsule, articular cartilage, and immediate recovery of the lumbar multifidus
bone, which, thereafter, became the first pub- once pain subsided [22] and that specific exer-
lished article on the use of musculoskeletal ultra- cises reduced the frequency of recurrence of low
sound. The initial publication detailing the back pain [23]. Also of significance was a paper
application of diagnostic ultrasound scanning for by Hodges and Moseley [26] which was able to
physical rehabilitation was done in 1968 by Ikai note the altered neuromuscular control and pre-
and Fukunaga [29], who made a correlation paratory recruitment of the diaphragm and trans-
between the size of upper limb muscles on ultra- versus abdominis muscles in patients with low
sound and the strength they generate. McDonald back pain. In May 2006, the term “rehabilitative
and Leopold [38] published one of the earliest ultrasound imaging” or RUSI was coined at a
uses of ultrasound for the musculoskeletal sys- symposium in San Antonio, Texas. The objective
tem in 1972 when they conducted scans to dif- of this meeting was to develop the best practice
ferentiate a Baker’s cyst from thrombophlebitis. guidelines for the use of ultrasound imaging for
In 1980, Archie Young [64] made a comparative the abdominal, pelvic, and posterior spine mus-
measurement of atrophy through the use of tape cles and to develop an international collaborative
measure and ultrasound scans. research agenda related to the use of ultrasound
The practice of integrating the use of ultra- imaging [53]. The consensus from this meeting
sound in therapeutic exercises began with a series illustrated the use of ultrasound not just as a
of papers between 1993 and 2006 which docu- means for assessment but also as an instructional
mented core muscle activity of the transversus tool in the conduct of therapeutic exercise. It was
abdominis, lumbar multifidus, pulmonary dia- agreed that RUSI would be defined as a sono-
graphic procedure utilized by physiotherapists to
evaluate muscle and other soft tissues, along with
M. F. Obispo (*)
their respective functions during exercise and
Department of Physical and Rehabilitation Medicine,
De La Salle Medical and Health Sciences Institute, physical tasks, to assist in the formulation of
Dasmariñas, Cavite, Philippines therapeutic interventions aimed at improving
e-mail: [email protected] neuromuscular function [61].
© Springer Nature Switzerland AG 2022 425
Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_20
426 M. F. Obispo

injury involved and the symptoms are a result of

Box 20.1 RUSI Benefit behavior and habits that have formed in a period
Jackie Whittaker [60] enumerated the fol- of time. While it is easy to modify overt activities
lowing benefits of using ultrasound for like shooting a basketball, where an individual’s
exercise as derived from the 2006 RUSI sensory processes are mostly adequate enough to
consensus: be aware and cognizant of the activity at hand,
including any faults in carrying out the action, it
• Ultrasound imaging enhances the obser- is not the same for ambiguous activities like
vation, palpatory, and instructional modifying the contraction of trunk muscles. This
skills of a clinician in order to confirm is a recurring problem among therapists instruct-
or negate their findings. ing patients and who are challenged to properly
• Ultrasound imaging is a tool for teach- visually elucidate how the activity is to be done.
ing which allows a clinician to explain According to Scmidt and Wrisberg [47], an
and demonstrate the subtleties of the intrinsic feedback is information provided by an
specific motor control impairment. individual’s sensory system, which is usually
• Ultrasound imaging is an invaluable adequate to refine a task performance. An extrin-
form of biofeedback when attempting to sic or augmented feedback information, on the
increase or decrease a specific muscle other hand, is provided by an external source
tension or to coordinate activity of mus- (i.e., an instrument or another individual) when
cle groups. sensory responses fail. Intrinsic feedback deficit
resulting in altered proprioception and muscle
response may come from a disrupted paraspinal
muscle spindle input and/or an imprecise central
Biofeedback in Exercise processing leading to an impaired position sense
[5]. This may be compensated by extrinsic feed-
Exercise has long been recognized as a mainstay back strategies through the mechanism of (a)
in facilitating proper physiologic healing of vari- central nervous system facilitation to provide an
ous conditions for more than a century. While optimal sensory-motor loop; (b) patient aware-
various surgical and interventional procedures ness, confidence, and volitional control over spe-
have progressed in alleviating pain in many neu- cific physiological processes; (c) motivation; and
romusculoskeletal conditions, exercise is consis- (d) reinforcement of repetition of successful
tently included in all long-term rehabilitation action of tasks [44]. Ribiero et al. [44] recom-
planning. A randomized controlled trial by Jielile mend using extrinsic feedback in therapy at
et al. [30] comparing cast immobilization and reduced frequency or to avoid constant cueing to
early post-operative rehabilitation for the treat- avoid dependency and to focus on providing
ment of neglected Achilles tendon rupture information on general movement patterns with
showed better clinical outcomes and faster over- attention to its effect after a number of trials.
all tendon healing with early rehabilitation com- Giggins et al. [18] classified the most fre-
prising weight bearing exercises. Additionally, a quently used biofeedback tools used in physical
meta-analysis conducted by Hayden et al. [19] rehabilitation as either biomechanical or physio-
showed that exercise therapy reduced average logical. Biomechanical feedback measures
pain and functional limitations in individuals movement, forces, and posture through the use of
with persistent low back pain. inertial sensors, force/pressure plates, electrogo-
One of the ways exercises are conducted at a niometers, and camera systems. The physiologi-
rehabilitation setting is through the use of bio- cal biofeedback measurements are conducted for
feedback to facilitate adaptive responses for nor- the neuromuscular and cardiorespiratory systems
mal or near-normal movement patterns after an in rehabilitation. The neuromuscular biofeed-
injury [52]. But there are times that there is no back, which involves the use of electromyogra-
20 Ultrasound-Guided Exercises 427

phy or ultrasound, is of particular interest to this eliminating any hypertonic activity of the super-
chapter as it is involved in refining movement or ficial trunk muscles, followed by the isolated and
action for tasks. then coordinated co-activation of the deep core
muscles to be done cognitively and as indepen-
dently as possible from the superficial muscles.
Ultrasound-Guided Lumbar Core She adds that ultrasound scanning has a major
Exercise role in this motor relearning process during the
cognitive and associative stages of learning.
With a number of researches pertaining to the use The cognitive stage is described as providing
of ultrasound to assess the trunk muscles, there has real-time information to educate a patient regard-
been a renewed interest in applying ultrasound ing their precise problem, as well as providing
scanning for low back pain especially in the area the specifics of the task at hand [60]. Ultrasound
of training the core muscles. According to Fatoye scanning comes into play when it is used to iden-
[16], the prevalence of low back pain in 2019 is at tify hypertonic or atrophied muscle groups in the
1.4–20.0% with an incidence ranging from 0.024% resting state, as well as the onset, speed, and
to 7.0% in Canada, the USA, Sweden, Belgium, duration of the contraction of the muscle on
Finland, Israel, and the Netherlands. dynamic testing. The goal here is to provide
The lumbar “core” muscles, which include the awareness to the patient as to what is happening
diaphragm as the roof, the pelvic floor muscles as internally by providing a visual anatomical anal-
the floor, and the abdominal muscles and paraspi- ogy to augment their proprioceptive and kines-
nals as the cylindrical covering, all serve as a form thetic perception of the activity to be carried out.
of muscular corset to stabilize the trunk regardless The associative stage is mainly comprised of
of movement or position [2, 45]. Maintaining lum- the biofeedback function upon which motor con-
bar spinal stability involves (1) a passive support trol performance can be modified. Ultrasound
system, which relies on the patency of joints, liga- imaging is invaluable in providing biofeedback
ments, and fascia; (2) an active contraction system, in a patient with low back pain through minimiz-
in which lumbar spinal movement and stability are ing hypertonicity and/or through facilitating
maintained by coordinated co-contraction of the activity of hypotonic muscles. Superficial core
core muscles; and (3) a discerning central nervous muscles like the obliquus abdominis externus,
system [1]. Porterfield [42] described this mecha- the obliquus abdominis internus, and the superfi-
nism as akin to a tent where the lumbar spine cial multifidus are usually hypertonic in low back
serves as the central pole, the core muscles as the pain. Some strategies suggested by Whittaker to
guy wires, and the thoracolumbar and abdominal help reduce the hypertonicity of these muscles
fascia as the tent canvass. It is the coordinated co-­ are through positional changes and breathing pat-
contraction of the core muscles as well as the ten- tern modifications while monitoring these
sigrity of the surrounding fascia that minimizes changes on real-time ultrasound scans [60]. For
lumbosacral instability. As previously mentioned hypotonic functioning deep core muscles, tar-
early on this chapter, the trunk muscles in an indi- geted facilitation strategies like performing
vidual with low back pain exhibit (1) altered neu- abdominal drawing-in maneuvers [20, 54] and
romuscular control presenting as loss of modified forms of Kegel’s exercise [59, 62] are
anticipatory contraction of the deep core muscles some of the activities that can be taught to patients
(transversus abdominis, deep multifidus, dia- first under ultrasound guidance to help refine the
phragm, pelvic floor muscles) [26] and (2) deficits proper action before these are integrated to func-
in muscle control that do not immediately resolve tional tasks.
with resolution of pain and are not addressed with Ultrasound evaluation for the anterior trunk
traditional strengthening exercises [23]. muscles is done in a supine position with the hips
The treatment, as proposed by Whittaker [60], and knees slightly flexed to lessen the tension to
is primarily to address motor control by first the pelvis. For the assessment of the transversus
428 M. F. Obispo

abdominis, external obliques, and internal muscles is also done in supine with hips and
obliques, the transducer is placed on the lumbar/ knees slightly flexed and with a full bladder to
flank region in a transverse orientation (Fig. 20.1). improve visualization of the pelvic floor. The
Preferential activation of the transverse abdomi- transducer is placed midline and superior to the
nis is performed by instructing the patient to per- pubis and is examined at both the sagittal and
form an abdominal hollowing or a drawing-in transverse planes (Figs. 20.2 and 20.3, respec-
maneuver. The examination of the pelvic floor tively). Preferential activation of the pelvic floor

Fig. 20.1 Placement of ultrasound transducer over the anterior abdominal wall for sonographic assessment of the
transversus abdominis (TrA), abdominal internal oblique (IO), and abdominal external oblique (EO) [60]

Fig. 20.2 Ultrasound transducer placement for evaluation of pelvic floor muscles (PfM) in longitudinal or long-axis
view [60]. Pr prostate

Fig. 20.3 Ultrasound transducer placement for evaluation of pelvic floor muscles (PfM) in transverse or short-axis
view [60]. Pr prostate
20 Ultrasound-Guided Exercises 429

muscles may be done by providing instructions performing abdominal drawing-in maneuvers or

on how to simulate a Kegel’s exercise. For abdominal hallowing activities with lesser num-
examination of the multifidus muscle at the pos- ber of repetitions to perform effectively as com-
terior trunk, the patient is placed either in prone pared to just using the verbal and tactile feedback
or side-­lying. Transverse plane examination of done in most clinics. However, the data on both
the ­multifidus is done with the transducer in studies was inconclusive as to the retention of the
midline over the vertebra of interest (Fig. 20.4). skill. Teyhen et al. [54] had contrasting findings
Sagittal plane examination of the multifidus is of no improvement of preferential activation of
performed at the paraspinal region approxi- the transversus abdominis in a 4-day period. A
mately visualizing the area of the lumbar facet systematic review of 36 articles by Ghamkar
joints (Fig. 20.5). Preferential activation of the et al. [17] revealed that ultrasound imaging had
lumbar multifidus muscle may be carried out good reliability and validity in differentiating a
through the use of visualization instructional healthy subject from one suffering from low back
techniques of the action to be performed to pain, as well as in monitoring rehabilitation out-
induce a near isolated contraction of the muscle come measures. However, the ability of ultra-
at the desired segment [60]. sound imaging to provide a diagnosis (i.e., spinal
The studies done by Henry [20] and that of stenosis, disc herniation, soft tissue pathology,
Worth [63] were able to note that the use of ultra- etc.) of the low back pain based on pathological
sound imaging showed better reproducibility in features on sonoanatomy did not allow for defini-

Fig. 20.4 Ultrasound transducer placement for evaluation of the multifidus muscles (Mf) in transverse or short-axis
view [60]. Sp lumbar spinous process

Fig. 20.5 Ultrasound transducer placement for evaluation of the multifidus muscles (Mf) in longitudinal or long-axis
view [60]. S1 sacral vertebra, L3–L5 lumbar vertebra levels 3–5
430 M. F. Obispo

tive conclusion because of the very low diagnos- The treatment of nerve impingement using
tic capability at the spinal area [55]. The varying ultrasound in recent years has mostly been done
results on the benefits of ultrasound scanning in through nerve hydrodissection or hydrorelease,
patients with low back pain may be attributed to which is a process of separating the nerve from
the heterogeneity of sample population as well as the surrounding fascia and tissues [8]. Prior to the
the differences in the testing or scanning advent of nerve hydrodissection, physiothera-
protocols. pists have long been employing a similar concept
The challenge with engaging on core muscle through a series of mobilization and exercise to
training is taking into consideration the complex help relieve the symptoms of nerve impingement
nature of trunk control, stability, and mobility. in patients who are averse to surgical intervention
There may be a paradox involved when a patient [4, 35, 36]. Michael Shacklock [49] defines neu-
is instructed to relax the internal and external rodynamics as a form of mobilization, exercise,
abdominal obliques while at the same time trying and positional treatment mostly for pain manage-
to contract the transversus abdominis muscle. ment by addressing the interaction between neu-
Also, an individual may also be disoriented if a ral tissue and its surrounding structures by
coordinated contraction of the different muscle evoking both a mechanical and physiological
groups is required to be done. Eyal Lederman response that affects neural sensitivity. The
[37] has warned that core exercises may contrib- mechanical responses include changes in neural
ute to the development of continuous and abnor- movement or sliding, neural tension, intraneural
mal patterns of trunk muscle use resulting in the pressure changes, viscoelastic function, and
development of symptoms. There is strong evi- alterations in the cross-sectional shape of the
dence to support that stabilization exercises help nerve. The ­physiological responses involve sym-
in the short-term management of low back pain pathetic activation and alterations in intraneural
as compared to regular exercises, but is not par- blood flow, impulse traffic, and axonal transport.
ticularly beneficial with regard to addressing The advent of the use of ultrasound imaging in
long-term disability [11, 50, 57]. It should there- dynamic, real-time assessment of the nerves has
fore be stressed that core programs should be provided a means by which to document the
used judiciously and only as an adjunct to other nerve excursion through neurodynamics. A sys-
interventions in addressing a patient with low tematic review of 18 studies which was done by
back pain. Kasehagen et al. [33] revealed moderate reliabil-
ity in using ultrasound imaging to measure the
excursion of the median, sciatic, and tibial nerves;
Ultrasound in Neurodynamics high to very high reliability in measuring the
common fibular nerve excursion; and moderate
Special tests in physical examination such as the to high reliability for assessing the radial nerve
slump test, the straight leg raise test, and even the excursion. The clinical implications of this paper
brachial plexus tension test have pointed to the show that ultrasound imaging can help assess and
concept of “neural tension” as a biomechanical document impingement of specific nerves as well
source of pain especially during nerve impinge- as suggest the type of neural mobilization to be
ment as suggested by David Butler [6]. Ellis and undertaken.
Hing [14] state that it is vital that the nerves are in Treatment with neurodynamics is initially car-
a position to adapt to mechanical loads by under- ried out passively through limb or body position-
going mechanical processes like elongation, slid- ing and through mobilizations carried out by a
ing, cross-sectional change, angulation, and therapist. These mobilization techniques have
compression. Otherwise, the nerves would be been classified as either “tensioners” or “sliders”
susceptible to neural edema, hypoxia, ischemia, [9]. Neural “tensioner” acts to lengthen the nerve
and fibrosis in the event of failure of the dynamic bed. It is performed very similarly to the various
protective mechanisms to function. limb tensioning tests where the sensitivity of the
20 Ultrasound-Guided Exercises 431

nerve is reproduced by placing both ends of a neural edema and improvement in pain and
joint, through which the nerve in question tra- function.
verses the limb, away from each other in a • No definite recommendations could be derived
stretched position. A neural “slider” is performed on performing neural mobilization for lateral
by placing one joint end into a stretched position, epicondylalgia, although one study with low
while the other joint end is in a slack position. risk of bias showed improvement of pain with
The alternating stretch-slack of both joint ends cervical lateral glide technique.
going to the same direction would produce an • Straight leg raise technique for neural mobili-
excursion or gliding motion of the nerve which is zation is recommended for tarsal tunnel syn-
also called “neural flossing.” Moksha et al. [40] drome and plantar heel pain based on two
conducted a study on 60 patients with non-­ studies with low risk of bias.
specific low back pain who underwent neurody-
namic mobilization. It was revealed that neural Ultrasound imaging is able to monitor the
sliders produced a significant reduction in pain neural excursion in real time especially when a
severity and disability scores as compared to per- patient is progressed to actively perform the neu-
forming neural tensioner techniques. ral mobilization movements themselves. The
In a meta-analysis conducted by Basson et al. imaging is carried out with the transducer placed
[3] pertaining to the effectiveness of performing in a longitudinal or long-axis orientation in rela-
neural mobilizations for neuromusculoskeletal tion to the level of interest of the nerve to be
conditions, it was found that: examined, and the extremity chain is moved
accordingly while monitoring for nerve excur-
• Slump and straight leg raise techniques for sion (Fig. 20.6). A study conducted by Richard
neural mobilization are recommended in Ellis [13] noted that the excursion of the sciatic
improving nerve-related low back pain sever- nerve was greatest toward the mid to late ranges
ity and disability scores (level A evidence). of performance of the neural mobilization. An
• Cervical lateral glide techniques for neural in vivo cross-sectional study conducted by
mobilization are recommended for improving Coppieters et al. [10] revealed markedly different
nerve-related neck and arm pain severity sciatic nerve excursions for neurodynamic tech-
(level A evidence). niques combining movements for the hip and the
• There were no significant positive effects for knee. In another in vivo study to determine if spi-
conducting neural mobilization for patients nal posture had an effect on sciatic nerve excur-
with carpal tunnel syndrome (level A evi- sion, it was found that changes in spinal posture
dence). It was noted, however, that sliding have little effect on sitting-based neural mobili-
techniques resulted in the reduction of intra- zation exercises for the sciatic nerve in healthy

Fig. 20.6 Sonologist positioning and ultrasound probe placement while conducting neural flossing of the median nerve
(left) and neural mobilization of the sciatic nerve (right)
432 M. F. Obispo

subjects [15]. These are the few studies which nosis as there is still no objective measure to
provide an insight on ultrasound as an imaging document the so-called myofascial trigger points.
tool in monitoring the treatment of a patient espe- The studies of Stecco et al. [51] and of Turo and
cially when adjusting the manner in which the Otto [56] have started to foray on using elastog-
neural mobilization is to be carried out. However, raphy to map out muscles where the trigger points
it is highly advised that further research is may be present. This has the potential to aid in
required before definitive recommendations on the monitoring and planning for intervention of
its feedback utilization can be made. these muscles which would include tension con-
trol as well as relaxation techniques. The use of
elastography is not limited to the musculoskeletal
Other Applications of Ultrasound system as a systematic review conducted by Wee
in Exercise and Simon [58] showed that peripheral neuropa-
thies have presented with increased stiffness
The chapter has mainly focused on ultrasound-­ regardless of the etiology. This, in turn, has gen-
guided exercises for the core trunk muscles as erated studies on its application to monitor neu-
well as for its application in neurodynamics due rodynamic treatments to the median nerve [48]
to the growing number of researches in the field. and sciatic nerve [41].
Nevertheless, it must be noted that there are
other emerging areas in rehabilitation and phys-
iotherapy where ultrasound imaging is slowly Conclusion
gaining recognition. Jopowicz et al. [31]
reviewed some papers addressing scapular dys- It can be deduced by conventional analysis that
function in shoulder pain through the assessment the most common symptom for patients who
of the involved scapular muscles. Rosińska et al. undergo a musculoskeletal ultrasound scan is
[46] proposed a post-operative Achilles tendon the symptom of pain. The International
rehabilitation through the assessment of tendon Association for the Study of Pain (IASP) defines
gliding and of feedback on gastrocnemius mus- pain as “an unpleasant sensory and emotional
cle activity. Khoshkhoo et al. [34] conducted experience associated with actual or potential
sonographic examinations on the effect of tissue damage, or described in terms of such
strength training to the vastus medialis obliquus damage” [39]. It can be inferred that pain does
(VMO) of the knee. The application in most of not necessarily require an injury to precede the
these studies is similar to how ultrasound is occurrence of symptoms. It also means that
applied to the core trunk muscles where the char- pain, especially in non-traumatic conditions, is
acteristic of the muscle contraction is monitored more likely to be multifactorial in origin which,
and adjusted accordingly. at times, may not be necessarily reflected by
The development of shear-wave elastography imaging procedures like ultrasonography [7].
to grade soft tissue tension or stiffness has The fact that pain is also considered a form of
recently been gaining popularity in rehabilitation “experience,” it is paramount that contextual
[27]. Elastography not only has the potential to factors around any treatment options to be
monitor tendon healing, but it may also predict employed are considered carefully. It is, there-
the active and passive forces that a muscle gener- fore, in the patient’s best interest to carry out an
ates as derived from its stiffness [28]. It is no individualized, multi-­modal, and biopsychoso-
wonder that elastography has already undergone cial form of treatment in which ultrasound guid-
a study to monitor the activity of the transversus ance is just one of the options to be considered
abdominis during exercises [24]. One area of to provide variation, novelty, and engagement in
focus on research on elastography is on the diag- the performance of exercises, as well as to
nosis of myofascial pain syndrome, where enhance the therapeutic alliance between the
Quintner et al. [43] argue the validity of the diag- patient and the clinician.
20 Ultrasound-Guided Exercises 433

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[25]. The evidence to date is still inconclusive on imaging findings for identifying subacromial pain.
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Acknowledgment Peter Esselbach, BPhty, BSc (Hons), nerve during neural mobilisation: ultrasound imag-
Assoc Dip App Sc (Med US) ing assessment of sciatic nerve movement and the
Rodiel Kirby Baloy, PT, EdS, DPT, MS clinical implications for treatment (PhD thesis,
Franklin Domingo, MD, FPARM, RMsk Auckland University of Technology, Auckland, New
Paolo Belleza Zealand). 2011. Retrieved from http://hdl.handle.
Capt. Danilo Obispo net/10292/3402.
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 Evolution of Sports Ultrasound
21
Jeffrey Smith, Allison N. Schroeder,
Alexander R. Lloyd, and Kentaro Onishi

Introduction netic resonance imaging (MRI), both of which

became the advanced imaging technologies of
The history of ultrasound (US) in sports medicine choice for the evaluation of MSK and sports medi-
dates back to the 1940s when it was first used as a cine conditions. CT was most useful in identifying
diagnostic imaging modality by Karl Dussik to bony pathology typically missed on plain films
image brain tumors [1]. That application expanded including stress fractures and small intra-articular
into musculoskeletal (MSK) evaluation in 1958 fractures. MRI became popular for its ability to
when US was used to measure the attenuation of delineate soft tissues better than any existing imag-
articular and periarticular tissues [2]. The technol- ing technique [5–12]. Despite its early promise, the
ogy and image quality further improved over the subpar spatial resolution and operator dependency
following decade, eventually leading to a paper of US during this period relegated it to a few spe-
documenting the ability to differentiate a Baker’s cific applications outside of the MSK system.
cyst from thrombophlebitis [3]. From here, the However, further technological progress in the
use of US in athletes expanded beyond the MSK 1980s and 1990s led to renewed interest in apply-
system. Echocardiography was first used in the ing US to the MSK system, particularly for mus-
1970s to measure left ventricular end-diastolic cle, ligament, and tendon pathology [13–16].
volume and ventricular wall thickness and mass in Rheumatologists were the first to widely adopt
an effort to diagnose athletic heart syndrome [4]. diagnostic US use and were the first to deploy it
Ultrasound’s progress was eclipsed in the 1970s for procedural guidance during joint aspiration
and 1980s by computed tomography (CT) and mag- [17, 18]. Orthopedic surgeons soon recognized the
value of US after several papers correlated sono-
graphically identified rotator cuff pathology with
J. Smith · A. R. Lloyd arthrography [19] and postoperative function [20].
University of Pittsburgh Medical Center, Subsequent studies documenting the superiority of
Department of PM&R, Pittsburgh, PA, USA
US compared to standard radiographs in the diag-
e-mail: [email protected]
nosis of transient synovitis of the hip in children
A. N. Schroeder
also strengthened the case for its utility [21, 22].
University of Pittsburgh Medical Center,
Pittsburgh, PA, USA The publication of the first MSK US textbooks
e-mail: [email protected] in the 1990s led to broader awareness of the ways
K. Onishi (*) US could be used for diagnostic evaluation and
University of Pittsburgh Medical Center, Department interventional procedures in sports medicine and
of PM&R and Orthopedic Surgery, orthopedics [23, 24]. US was subsequently shown
Pittsburgh, Pennsylvania, USA

© Springer Nature Switzerland AG 2022 437

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_21
438 J. Smith et al.

to make injections more accurate than similar Table 21.1 Advantages of diagnostic US
injections done with landmark guidance for most Advantages of diagnostic US
peripheral joint and soft tissue injections, further Portable
boosting its popularity [25]. With increased inter- Superior spatial resolution over MRI for soft tissue and
est, US imaging evolved in the early twenty-first neurovascular imaging
Cost-effective
century as spatial resolution improved and porta-
Real-time, dynamic imaging
bility increased [26]. Between 2000 and 2009, Ease of side-to-side comparative study
there was a 316% increase in procedural use of Less ionization compared to radiographs and CT
MSK US [27]. Lack of artifact or distortion near metal hardware
Today, the term “sports US” refers to the use of Movement artifact does not impede evaluation
US for both diagnostic and therapeutic indica- Real-time vascular imaging (Doppler, SMI)
tions in sports medicine and includes the diagnos- Tissue characterization (shear wave elastography, strain
elastography, US tissue characterization)
tic and interventional use of US for MSK
MRI magnetic resonance imaging, CT computerized
conditions as well as the diagnostic use of US to tomography, SMI superb microvascular imaging, US
evaluate non-MSK conditions in athletes [28–32]. ultrasound
The recent development of US-guided procedures
indicates the ongoing interest in applying this machines which only reach 450 μm [43]. One
technology to improve upon current procedural study compared MRI and US in detecting periph-
techniques [33–35]. This chapter will describe the eral nerve pathology and found better sensitivity
current utility of diagnostic and interventional US with US, while the two were equivalent in speci-
in sports medicine. It will also review uses of US ficity [44]. Because of this high resolution, ultra-
in procedures and emerging technologies address- sound has proven to be a cost-effective diagnostic
ing current limitations in US imaging. tool for sports injuries, and if utilized for appro-
priate indications, it has been shown to poten-
tially save billions of dollars [45–49]. Its
 iagnostic Ultrasound in Sports
D real-time assessment allows for dynamic imag-
Medicine ing of pathology that may be missed using static
imaging such as CT or MRI [50, 51]. It has the
 dvantages of Diagnostic Ultrasound
A benefit of providing imaging of the healthy con-
in Sports Medicine tralateral side providing a control for compari-
son [52, 53].
There are a number of advantages of diagnostic Chronic musculoskeletal diseases such as
US compared to other imaging modalities such knee OA, which are more prevalent in athletes,
as x-ray, MRI, and CT (see Table 21.1). With often require imaging to assess severity of dis-
increasing portability, US can be brought to the ease [54, 55]. As the association of ionizing radi-
training rooms, injury clinics, or even athletic ation exposure and cancer risk has become better
events to assist in a timely diagnosis and proper understood, the potential for significant radiation
triaging for sports injuries from every organ sys- exposure over athletes’ lifetimes has raised con-
tem [36–40]. Advances in telecommunications, cern [56–58]. Ultrasound can provide equivalent
such as fifth-generation (5G) wireless, allow imaging for the assessment of disease progres-
ultrasound scanning to be remotely guided by an sion, such as OA-associated pathology, without
experienced practitioner and real-time dynamic any of the risks from ionizing radiation exposure
imaging for faster diagnosis [41, 42]. [59–61].
US also offers high spatial resolution of soft Due to higher prevalence of chronic musculo-
tissue and neurovascular pathology. A 10 Mhz skeletal diseases, athletes are more prone to joint
US probe can achieve axial in-plane resolution replacement during their lifetime than in the gen-
of approximately 150 μm, significantly more eral population [55, 62, 63]. Evaluation of peri-­
than the resolution of common clinical MRI prosthetic soft tissue can be difficult using CT or
21 Evolution of Sports Ultrasound 439

MRI due to metal artifact obscuring structures use in imaging abdominal complaints highlights
[64, 65]. US is effective in detecting peri-­ the technology’s utility beyond evaluation of the
prosthetic infections which are a leading cause of MSK system.
cause for revision of THAs and TKAs [66, 67].
Early identification of these infections to avoid
revision due to septic loosening could reduce risk  S in Sports Medicine: Organ System
U
of prolonged postoperative pain due to septic Evaluation
joint replacement [68].
Ultrasound has the advantage of avoiding Significant literature exists regarding the use of
interference from motion artifact which are noted US for the evaluation of sports-related injuries.
issues with CT and MRI assessment [69, 70]. It This section will highlight relevant organ sys-
also has superior vascular imaging capability tems and diagnoses for which US evaluation
such as color and power Doppler which allow the can be used in sports medicine and will include
identification of pathology such as muscle, ten- a discussion of the ways in which US evalua-
don, and bone injury and permit the identification tion can facilitate a more rapid and accurate
of vessels during ultrasound-guided procedures diagnosis.
to limit complications [71, 72]. Neovasculariza-
tion has been identified as a key finding in tendi- HEENT
nosis, and advances in ultrasound technology
such as superb microvascular imaging (SMI) Ocular Evaluation
have improved the identification of this pathol- Ocular examination with US is routinely used by
ogy compared to color or power Doppler [73– radiologists, ophthalmologists, and emergency
75]. Other advances such as elastography or medicine physicians as a rapid, radiation-free,
tissue characterization go beyond standard imag- and accurate way to evaluate structures of the eye
ing with B mode and allow for a more thorough [82, 83]. Sports-related eye injuries account for
assessment of mechanical properties of soft tis- approximately 1.5% of all sports injuries with
sues [76, 77]. higher rates in baseball, basketball, and racquet
sports [84–87]. For some athletes, these injuries
can lead to long-term vision loss [88]. US can
Broad and Expanding Applicability serve as a triage tool on the sidelines to screen for
of US Beyond Traditional MSK severe eye injuries after trauma and is not hin-
Applications dered by hyphema or lid edema often present in
these injuries.
As discussed elsewhere in this book, US can be Frequent pathologies seen in sports settings
used to evaluate ligaments, muscles, nerves, ten- amenable to US evaluation include retinal detach-
dons, and vessels at the point of care [78–80]. ment, retinal hemorrhage, and lens dislocation or
However, the use of US in the diagnosis and subluxation (Fig. 21.1). Retinal detachment
treatment of athletes has expanded beyond the requires rapid diagnosis and referral for interven-
MSK system. In a study of ultrasonography at the tion and can be readily visualized with US89.
2008 Beijing Olympics, US was found to be the Untreated, symptomatic retinal detachment can
imaging modality of choice in the Olympic vil- progress to complete detachment within days and
lage polyclinic and was most commonly used to can result in complete loss of vision. Given the
evaluate abdominal complaints (41% of US low incidence of retinal detachment among eye
exams performed) [81]. US’s portability, real-­ injuries in athletes, US is especially useful for
time results, and accuracy made it an ideal tool ruling out a detachment in the setting of acute
for initial imaging at a large sporting event where vision changes [90–92]. Research has shown that
transportation to local imaging facilities may be non-radiology specialists can be trained to reli-
complicated or lead to delayed diagnosis. The ably use US for the identification of retinal
440 J. Smith et al.

Fig. 21.1 Ocular US:

globe on the left reveals
a detached retina which
is visualized as a
hyperechoic line anterior
to the posterior wall; the
right is normal

detachment with sensitivity ranging from 97 to breathing complaints in sport [98, 99]. The pre-
100% and specificity from 83 to 100% [89, 93, cise etiology is not well understood and is
94]. Retinal hemorrhage and lens dislocation or believed to have multiple independent causes
subluxation can also be visualized during the that result in partial obstruction of the airway
same examination, facilitating rapid triage for during exercise [99–101]. The presenting symp-
emergent care and early warning to the ­emergency toms of EILO are very similar to those of
department if urgent ophthalmologic evaluation exercise-­induced asthma, resulting in frequent
is needed [82]. misdiagnosis [99, 101]. These symptoms include
Ocular US can also be used for an assessment difficulty breathing, chest discomfort, wheezing,
of elevated intracranial pressure (ICP) after head dry cough, and a feeling of throat constriction
trauma. The optic nerve sheath is contiguous that doesn’t respond to standard asthma treat-
with the dura mater and expands when ICP is ment [102]. Fiber-optic video laryngoscopy is
elevated. This expansion can be seen on US [95, the gold standard for diagnosis, but requires spe-
96]. A meta-analysis reviewing studies that com- cialized clinical space and equipment, which is
pared optic nerve sheath diameters on US to CTs often not available to sports medicine physi-
with findings suggestive of intracranial compres- cians, especially when symptoms are occurring
sion suggested a cutoff of sheath diameter of [101]. Since symptoms may be context depen-
5mm in adults was 95.6% sensitive and 92.3% dent and are transient, US offers the possibility
specific for elevated ICP [97]. of sideline evaluation and possible diagnosis
while the athlete is symptomatic. One study
Exercise-Induced Laryngeal Obstruction demonstrated the ability to differentiate para-
Exercise-induced laryngeal obstruction (EILO), doxical vocal fold motion from normal vocal
often referred to as vocal fold dysfunction, is an fold motion with US, but additional research is
uncommon and likely underrecognized cause of needed for confirmation [101].
21 Evolution of Sports Ultrasound 441

Chest diastolic interventricular septal thickness, left

ventricular diameter, left ventricular wall thick-
Echocardiography ness, and aortic root diameter [110, 114, 115].
While rare, the most common cause of death in Initial studies on this protocol have shown simi-
sport is sudden cardiac death [103]. These deaths lar rates for the detection of anomalies between
are often preventable with adequate screening, cardiologists and non-cardiologists [110, 116].
but the type of screening and population to screen The role of screening echocardiography is still
is debated [104, 105]. The history and physical being debated and should not replace the H&P or
exam (H&P) with or without electrocardiogram EKG until more comprehensive and systematic
(EKG) are typically used as screening tools in the research has been performed.
preparticipation evaluation (PPE) of athletes, but
their effectiveness in disease identification is Rib Fracture and Pneumothorax
questioned [106]. A comprehensive review by The etiology of chest pain after trauma can be
Harmon et al. found that the pooled sensitivity difficult to determine acutely. Blunt trauma to the
for the history was 20% (range 7–44%) and 9% thorax can result in rib fracture, which is conven-
for the physical exam (range 3–24%). Both were tionally diagnosed with radiographs. However,
more specific at 94% and 97%, respectively, but US has been shown to be equivalent or superior
sole use of the H&P will likely omit athletes to radiographs for rib fracture diagnosis, and its
potentially at risk [106]. While EKG is both sen- portability allows for rapid evaluation on the
sitive and specific at 94% (79–98%) and 93% sideline or in the training room [117, 118]. On
(90–96%), respectively, it lacks portability and US evaluation, fracture is seen as a discontinuity
comes at a monetary cost [106]. Additionally, in the usually smooth, hyperechoic contour of the
EKG may have a high false-positive rate, partly rib [117].
as a result of physiologic cardiac changes that Pneumothorax is a common sequelae of rib
occur in athletes and the variability in criteria fractures and can be evaluated and diagnosed
used to define pathology in those settings [106, with US using several techniques [119]. The
107]. These false positives can exclude healthy absence of lung sliding, absence of B lines, and
athletes from play while subjecting them to pro- presence of A lines indicate pneumothorax [119–
longed and expensive workups [108, 109]. 121] (US findings described in Table 21.2)
US has a long history of use in cardiology set- (Fig. 21.2). The absence of lung sliding and pres-
tings. While current data is insufficient to report ence of A lines have a sensitivity and specificity
well-defined sensitivity and specificity, some of 94 and 95%, respectively, for the diagnosis of
research has shown that echocardiography com- pneumothorax [119]. Evaluation can be per-
bined with EKG might decrease the false-­positive
rate and reduce the need for subsequent cardiol-
ogy referrals [110–112]. One study of 3100 male Table 21.2 US findings in the lung exam for pneumo-
thorax. US, ultrasound
soccer players who were screened with echocar-
diography found several cardiac anomalies US in the lung exam for pneumothorax
US
missed by H&P and EKG, although most were
findings Description of finding
mild valvular abnormalities with unclear clinical A lines Repetitive reverberation artifact of the
significance [113]. Severe abnormalities were pleural line
rare in the study, and all that were present had an B lines Wide bands of hyperechoic artifact that
abnormal EKG [113]. originate at the pleural line and traverse the
entire US screen in vertical orientation
The Early Screening for Cardiac Abnormalities
Comet tail Short hyperechoic artifacts that originate at
with Preparticipation Echocardiography artifact the pleural line and only traverse a portion
(ESCAPE) protocol was developed specifically of the screen in vertical orientation
to screen for the most concerning cardiac anoma- Lung Parietal pleura sliding against visceral
lies in athletes using US. It examines the end-­ sliding pleura with breathing
442 J. Smith et al.

to triage athletes, do not increase the time to

intervention in the emergency department, and
may decrease the number of missed life-­
threatening injuries [127]. However, further
research is needed to support its use in sports-­
specific environments [29].

Splenomegaly Monitoring
in Mononucleosis
Infectious mononucleosis is the clinical mani-
festation of Epstein-Barr viral infection. While
common symptoms include fatigue and malaise,
transient splenomegaly is the most concerning
effect of mononucleosis for athletes [129, 130].
Splenic rupture is a rare, but potentially fatal,
complication of return to sport in the setting of
splenomegaly [130]. While contact sports are
Fig. 21.2 Lung US: comet tail artifact in the upper right
extending downward from the pleura; A lines are notable most commonly associated with reports of
throughout the image; no B lines are present splenic rupture, rupture can rarely occur with
significant Valsalva in non-contact sports [130].
formed by non-radiologists where x-ray equip- As a result, athletes are often prevented from
ment may not be readily available or ambient returning to play for 3 to 4 weeks after disease
noise may be too loud to permit auscultation onset to ensure resolution of their transient sple-
[121–123]. The diagnostic sensitivity and speci- nomegaly [130].
ficity of US evaluation are superior to upright US evaluation of the spleen has been proposed
anterior to posterior chest x-ray and similar to CT as a possible method to monitor splenomegaly
scan of the chest, which is the gold standard for and determine timing for safe return to play.
the diagnosis of pneumothorax [90, 124]. The However, there is significant interindividual
portability of US allows for point-of-care pneu- sonographic variability of spleen size, making
mothorax evaluation and rapid referral for care if normal values difficult to establish [130, 131].
present. Without consistent baseline measurements, true
splenomegaly is difficult to define and cannot
Abdomen guide return-to-play decisions as a result. It is
possible that baseline measurements followed by
Extended FAST (eFAST) serial scans would prove useful, but this is
The Focused Assessment with Sonography in resource-intensive and likely impractical in many
Trauma (FAST) was developed in the 1990s to settings. More research is needed to determine
identify abnormal intraabdominal fluid or solid the role of US in the evaluation of splenomegaly.
organ injury in the setting of blunt thoracoab-
dominal trauma [125, 126]. It includes evaluation Abdominal Muscle Evaluation
for hemoperitoneum, liver injury, hemopericar- Abdominal muscle pathology can often be visu-
dium, pericardial or cardiac injury, and splenic or alized with US. Pathology can include herniation
renal injury and should take the operator 5 min- of abdominal musculature through its fascial
utes or less to perform [125, 127, 128]. The FAST plane or injury to the musculature itself with a
examination was expanded to include the evalua- resulting defect and herniation of fat or abdomi-
tion for pneumothorax and hemothorax and nal contents. Spigelian hernias are rare, occur at
termed the extended FAST (or eFAST) examina- the edge of the rectus abdominis along the linea
tion. These exams can be performed rapidly, help semilunaris, and may be difficult to identify with
21 Evolution of Sports Ultrasound 443

static imaging modalities [132, 133]. These her- tion of abdominal contents into the femoral canal
nias commonly contain fat, but can contain bowel medial to the femoral neurovasculature and ven-
and are seen on US protruding ventrally through tral to the pectineus muscle [133, 144].
the linea semilunaris with Valsalva [133].
Epigastric, umbilical, and incisional hernias can Hernia Mimickers: Groin Pain
all be visualized as an outright defect in the in the Athlete
abdominal wall or with ventral protrusion of Evaluation of groin pain in the athlete should
abdominal contents with Valsalva [134]. Care include examination of pain generators in the
should be taken to apply light transducer pressure area, particularly if a true hernia is absent. “Sports
when attempting to visualize herniation in these hernia” and “athletic pubalgia” are ambiguous
areas since it may be prevented or reduced with terms often used to describe groin pain in athletes
heavy pressure [135]. and generally do not reflect a hernia of any kind.
Injury to the abdominal musculature can also Instead, they encompass the broad differential of
be visualized with US, including injury to the gastrointestinal, MSK, or neurologic pathologies
rectus abdominis, internal and external obliques, that may cause groin pain, including intraarticu-
and transversus abdominis [136–139]. These lar and periarticular hip joint pathology, muscu-
injuries are often seen in throwers, who generate lotendinous injuries (including abdominals, hip
significant rotational forces in order to properly adductors, and iliopsoas), inflammatory bowel
execute the throw [140]. These injuries appear on disease, or nerve entrapment syndromes [146,
US as disruption of the fibrillar architecture of 147]. US can help narrow this broad differential
the muscle and areas of hypoechogenicity at the diagnosis through its ability to evaluate the
site of pain and are thought to represent hemor- abdominal wall musculature (as described
rhage, edema, and muscle fiber disruption [137]. above), the rectus abdominis/adductor plate, and
the adductor tendon origin dynamically at high
Inguinal and Femoral Hernia Evaluation resolution [141, 146] [148]. Additionally, the
US evaluation is often used to visualize hernias iliopsoas can be scanned dynamically to evaluate
because they can be dynamically imaged during for snapping iliopsoas tendon [149, 150]. Nerves
provocation maneuvers. Hernias may cause dif- that can contribute to groin pain, including geni-
fuse and nonspecific pain in the groin and lower tofemoral nerve, obturator nerve, or medial fem-
abdomen, making it difficult to differentiate from oral cutaneous nerve, can also be evaluated
other pain generators and difficult to diagnose [151–153].
based on physical exam alone [141, 142].
Inguinal hernias are most common in men and MSK
can be either indirect or direct [143]. Indirect her- US evaluation of the MSK system is covered in
nias involve herniation of abdominal contents extensive detail in Chaps. 5, 6, 7, 8, 9, 10, and 11
through the deep inguinal ring and are visualized of this book. US is effective for the evaluation of
on dynamic US as tissue extension lateral to the a wide variety of MSK complaints, including
external iliac vessels or inferior epigastric vessels major joints, muscles, tendons, and ligaments in
[133, 144]. Direct hernias involve herniation of the extremities [28].
abdominal contents directly through Hesselbach’s
triangle in the abdominal wall, and dynamic US  eripheral Nerve Injuries
P
evaluation will show abnormal anterior move- Peripheral nerve injuries are believed to be rare in
ment of tissue medial to the inferior epigastric athletes but may just be underrecognized by cli-
vessels [133, 144]. nicians [154]. Peripheral nerve injuries can con-
Femoral hernias are the most common type of tribute to significant pain and inability to return
hernia in women [145]. They occur below the to play [155, 156]. While electrodiagnostic test-
level of the inguinal ligament, and dynamic US ing (EDX) is the most common method to local-
evaluation will reveal superior to inferior hernia- ize and determine the nature of these lesions,
444 J. Smith et al.

diagnosis is often delayed by the one to several [178–183]. CSA of the median nerve at the inlet
weeks it takes for EDX to be positive [157]. of the carpal tunnel has been found to be most
During this time, athletes may be symptomatic sensitive and specific in diagnosing CTS [184].
and unable to return to play without an accurate While normal nerve size can vary and exact cut-
diagnosis to guide effective treatment. While US offs are still debated, median nerve CSA between
is not a substitute for EDX, it can assist in local- 9.0 and 12.6mm2 measured at the inlet has been
izing nerve injury and facilitate diagnosis and shown to have sensitivity of 81% and specificity
early management [158, 159]. The development of 84% [184]. The color Doppler, power Doppler
of high-resolution US (HRUS), typically defined sonography, and contrast-enhanced ultrasonogra-
as 12 MHz or greater depending on the depth of phy can be used to identify median nerve hyper-
evaluation, allows for the evaluation of nerve or emia in the acute stage of CTS [185–187]. Superb
fascicle enlargement indicating compression or microvascular imaging (SMI) is a novel technol-
irritation and visualization of small nerves that ogy which allows improved visualization of flow
would be difficult or impossible to evaluate with of both small and large vessels without requiring
EDX and that may not be adequately visualized contrast enhancement and may be more sensitive
on MRI [158, 160–164]. US examination is also to detecting blood flow changes due to CTS [188,
less painful than EDX testing and may be better 189].
tolerated than EDX. Finally, US can supplement
EDX since EDX is a physiologic test that evalu- Ulnar Nerve
ates the strength and speed of nerve conductions, The second most common upper extremity neu-
while US evaluates other characteristics such as ropathy is ulnar entrapment, often at the ulnar
morphology of the nerve and nerve fascicles or groove of the cubital tunnel, less frequently
nerves’ relationship to surrounding structures caused by the humeroulnar arcade [190]. This
that might contribute to nerve irritation occurs with compression or recurrent subluxation
[165–172]. of the nerve. While entrapment at the elbow
Characteristics of nerve injury seen on US occurs most commonly in baseball players, it can
include increased nerve or fascicle cross-­sectional occur at the hand or wrist, especially in Guyon’s
area due to edema, increased connective tissue canal between the pisiform and the hook of
formation from scarring, thickened and hyper- hamate in wheelchair athletes, cyclists, and ski-
echoic epineurium, or a hypoechoic internal ers [191, 192]. While EDX remains the gold stan-
appearance [169, 173, 174]. A study of nerve dard for the localization of ulnar neuropathy,
characteristics in peripheral nerve compression diagnostic accuracy improves when US is per-
found increased transverse cross-sectional area formed concomitantly [193, 194]. The normal
(CSA) was most reliable for the diagnosis of ulnar nerve size varies between individuals and
nerve injury [175]. Several neuropathies that can anatomic location, but some suggest a cutoff of
be identified on US are described below, but this 10 mm2 or greater as a diagnostic of cubital tun-
is not a comprehensive list, and research on nel syndrome [195]. One study of patients in
peripheral nerve evaluation with US is ongoing. whom EDX was unsuccessful in localization
found all injury locations were identifiable with
Median Nerve HRUS [196].
Carpal tunnel syndrome (CTS) is the most com-
mon mononeuropathy in the general population Sciatic Nerve Branches
and is also common among wheelchair athletes The common fibular nerve is frequently injured
[176, 177]. US has been used in the diagnosis of through direct trauma in football, hockey, and
CTS and has shown sensitivity and specificity soccer players as it is superficial and prone to
similar to EDX in several studies while also trauma at the lateral knee near the fibular head
allowing immediate therapeutic injection or [197]. It is also susceptible to repetitive stress in
US-guided transverse carpal ligament release runners [198, 199]. The tibial nerve can be
21 Evolution of Sports Ultrasound 445

injured in combination with the fibular nerve in can cause brachial plexus compression and
acute ligamentous knee injuries, dislocations, occurs more frequently among overhead athletes
fractures, or entrapment in tarsal tunnel syn- compared to the general population [220].
drome at the medial ankle [200]. Both nerves can Ultrasound can identify the entrapment and guide
be visualized at the posterior distal thigh and can anesthetic injection to the anterior scalene mus-
be traced to determine if and where injury cle to promote relaxation which correlates with
occurred, providing diagnostic value comparable good surgical outcomes [221, 222]. EDX can
to that of MRI [201–205]. identify lesions that result in prolonged symp-
toms, but abnormalities will only appear after
Lateral Femoral Cutaneous Nerve several weeks of persistent symptoms. US is
Meralgia paresthetica, or neuropathy of the lat- capable of immediately visualizing nerve roots
eral femoral cutaneous nerve, is another com- from the vertebral foramina through the trunks,
monly discussed focal mononeuropathy divisions, cords, and branches to the axillary
described in gymnasts, baseball players, and soc- region, potentially providing earlier visualization
cer players [206–210]. Diagnosis of this injury of significant pathology and more rapid subse-
with EDX is possible, but can be technically dif- quent intervention although the clavicle can
ficult and may be significantly limited by body interrupt visualization from the supraclavicular
habitus [211]. Multiple reports have demon- area to the subpectoral area [223].
strated HRUS is useful in identifying nerve
entrapment at the lateral end of the inguinal liga- Vascular Injuries
ment and for performing guidance diagnostic While vascular injuries are uncommon in sports,
blocks and pain relief [212, 213]. they can cause significant symptoms in all
extremities and should be considered when clau-
Brachial Plexus dication symptoms are present. Vascular causes
The brachial plexus is a common area for neuro- of exertional lower leg pain include external iliac
pathic injury in sports, especially those involving artery endofibrosis and popliteal artery entrap-
blunt trauma [214]. While most brachial plexus ment syndrome. External iliac artery endofibrosis
injuries are “stingers” that cause transient motor results from intimal fibrosis of the arterial wall
and sensory symptoms, others like neurogenic resulting in progressive stenosis and subsequent
thoracic outlet syndrome (nTOS) result can also ischemic pain during exercise [224]. It is typi-
result in injuries to brachial plexus structures cally seen in endurance athletes such as cyclists
[215]. nTOS is the most common type of thoracic and marathon runners [225]. Untreated, endofi-
outlet syndrome comprising more than 95% of brosis can lead to arterial dissection or thrombo-
cases and can result from cervical trauma or from sis [226, 227]. US can be used to identify
repetitive overhead activities that result in rela- endofibrotic lesions, which appear as a segmental
tive hypertrophy of muscles such as the pectora- thickening of the intimal arterial wall with
lis minor that can compress the brachial plexus increased echogenicity of the arterial wall [228].
and cause symptoms consistent with lower trunk Doppler studies are normal at rest but show a
brachial plexopathy [216]. While still under decreased ankle brachial index (ABI) following
debate, US may be useful in identifying anoma- exercise [229].
lous fibromuscular bands, sometimes referred to Popliteal artery entrapment occurs due to the
as “Roos ligaments,” compressing the lower compression of the artery by the anatomy of the
trunk of the brachial plexus and causing nTOS gastrocnemius or popliteus muscles or dynamic
[217]. It can also be useful in evaluating pectoral compression by the soleus and can cause claudi-
muscles for compression and tension placed cation symptoms [230, 231]. If undiagnosed, it
upon the medial and lateral cord [218, 219]. can progress functional occlusion during activity,
Nerve compression between the clavicle, first rib, aneurysm, or thrombosis [232]. According to a
and scalene muscles due to muscle hypertrophy meta-analysis, US Doppler ABI has a sensitivity
446 J. Smith et al.

of 90%, but specificity data is limited and may stimuli and assist with nutrition decisions. This
result in a high number of false-positive sono- might subsequently help prevent fatigue and
graphic findings as a result [233]. This is sup- overtraining syndrome while helping athletes and
ported by a study that found arterial occlusion coaches optimize competition, training, recovery,
induced with knee extension and subsequent and nutrition strategies [246–248]. Currently,
plantarflexion and dorsiflexion in up to 50% of muscle biopsy is the gold standard for determin-
asymptomatic individuals [234]. ing glycogen quantity, but this is an invasive and
Overhead athletes can also incur vascular uncomfortable procedure that is unrealistic for
injuries, especially aneurysms of the axillary use during training. An application called
artery and its branches including the posterior MuscleSound (MuscleSound LLC, Denver, CO)
circumflex humeral artery (PCHA). This can lead has been developed using US to quantify and cor-
to thrombosis or emboli causing subsequent digi- relate the water content of muscles with glycogen
tal ischemia [235–237]. Both symptomatic and content. Two studies funded by MuscleSound
asymptomatic volleyball players have been found LLC have shown a strong correlation between
to have PCHA aneurysms with a high prevalence muscle biopsy and MuscleSound measured gly-
of symptoms of digital ischemia thought to be cogen content [249, 250]. An independently
secondary to microemboli [238, 239]. US has funded study found poor correlation between
shown promise in the recognition of a PCHA glycogen quantity measured by MuscleSound
aneurysm, which appears as a segmental vessel when compared to muscle biopsy [251]. More
dilatation of greater than 50% compared to the research is needed on the validity of this technol-
closest normal-appearing vessel segment [240]. ogy before the utility of noninvasive measure of
Overhead athletes are also susceptible to vas- muscle glycogen content can be established.
culogenic thoracic outlet syndrome, which can be
of two forms: arterial thoracic outlet syndrome Body Composition
(aTOS) due to compression of the subclavian Many athletes, especially those in weight-­
artery and venous thoracic outlet syndrome sensitive sports, monitor and attempt to modulate
(vTOS) due to compression of the subclavian body composition to improve performance [252].
vein [241]. vTOS presents with fatigue or numb- US has been identified as a tool to assist in deter-
ness that worsens when the arm is abducted and mining body fat measurements by measuring the
externally rotated [242, 243]. US has proven to thickness of adipose tissue [253]. This could
have a role in diagnosis as episodes of occlusion replace the traditional use of fat calipers, which
have been identified by Doppler US, especially lack accuracy due to tissue compression during
while observing during provocative maneuvers measurement [254, 255]. US was shown to have
of the extremity [244, 245]. a better inter-rater reliability than the use of cali-
pers for measuring body fat composition, but US
scanning protocols for body composition are still
 S in Sports Medicine: Physiologic
U under development [256].
Measures
Tendon Stiffness
US has been used experimentally to monitor Prior muscle or tendon injury has been identified
physiologic parameters in an attempt to opti- as one of the major risk factors in the recurrence
mize training regimens and improve sports of injury and thus has been examined as a factor
performance. in determining return to play. Identifying weak-
ened tissue is important in both diagnosing injury
Muscle Glycogen and determining timing for safe return to play
Evaluation of muscle glycogen content, an without risking reinjury. Elastography estimates
important source of energy for athletes, may help tissue hardness and can be used to estimate the
athletes evaluate their body’s response to training mechanical properties of tissues. This may, in
21 Evolution of Sports Ultrasound 447

turn, help with early identification of at-risk indi- measure of density using Young’s modulus [280].
viduals, outcome tracking, and treatment moni- SWE produces a more objective and quantitative
toring [257]. There are three types of elastography: assessment compared to strain elastography since
acoustic radiation force impulse elastography, the operator is not involved in stressing the tis-
compression (strain) elastography, and shear sues. Shear wave has been used to evaluate mus-
wave elastography. Unfortunately, technical cle, ligaments, and tendons [281, 282]. Findings
issues such as a lack of standardization and insuf- have largely paralleled those seen with SE includ-
ficient data on the characteristics of normal ver- ing softening of tendinopathic tendons [283, 284]
sus diseased tissues still limit the wide use of and stiffening of post-surgical tendons [285].
elastography [257]. The types of elastography SWE has also been used to monitor gastrocne-
and their respective utility in sports medicine are mius, soleus, and Achilles tendon injuries and
highlighted below. may be useful in guide return to play [286, 287].
Acoustic radiation force impulse (ARFI) elas- As with SE, further studies on SWE are needed to
tography uses focused acoustic beams to convert validate inter- and intra-rater reliability and
acoustic compression waves to shear waves by determine its role in the diagnosis of tendon
absorbing acoustic energy [258]. The reaction of injury, ability to monitor recovery, and usefulness
tissue to this process is monitored within the in guiding return to play.
range of excitation, and images are generated US tissue characterization (UTC) was devel-
from sequential data collection with lateral move- oped to provide a standard assessment of tissue
ment at given positions. The speed of shear wave stiffness [77]. UTC utilizes a motorized device
propagation outside the range of excitation is that guarantees a fixed US transducer position
used to estimate the tissue shear modulus [259]. that obtains 600 contiguous transverse images in
While ARFI elastography has been used exten- 45 seconds at intervals of 0.2 millimeters over a
sively in hepatic imaging, it has only recently 12 centimeter distance to render a 3D block of
received investigation in musculoskeletal evalua- US images [288]. After images are obtained, a
tion [258, 260, 261]. complex algorithm characterizes each area of
SE uses US imaging to measure the amount of tendon into one of four echotypes based on pixel
deformation following manual compression. stability which is correlated to stiffness [288].
Software then converts tissue hardness into a UTC has primarily been used for large tendons
color map on the US machine. It has been used to and ligaments, such as the Achilles tendon and
evaluate tendon pathology including Achilles patellar ligament [289–293]. Of note, the device
tendon [262–264], patellar tendon [264], epicon- used for standardized image acquisition in UTC
dylar tendons of the elbow [265–270], rotator has to be built specifically for each tendon.
cuff tendons [268, 271–274], and biceps tendon Similar to strain elastography (SE) and shear
[275]. Most studies have found that pathologic wave elastography (SWE), the role of UTC in the
tendons are softer than normal tendon, with only diagnosis of pathologic conditions and guiding
one study finding that pathologic Achilles ten- return to play is yet to be determined, but shows
dons are stiffer than normal tendons [276]. promise in its ability to monitor the effect of load
Additionally, SE has been used to show that heal- or treatment on tendon structure [77].
ing Achilles tendons postoperatively are stiffer
than normal tendons [277, 278]. Further studies
are needed to validate the inter- and intra-rater  S in Sports Medicine: Guiding
U
reliability of SE and determine its role in the Return to Play
diagnosis of tendon injury and its use for moni-
toring recovery [279]. As discussed above, the improving portability of
SWE uses an acoustic radiation force pulse to US and the ability to perform serial examinations
generate shear waves that propagate perpendicu- make US an ideal imaging modality for guiding
lar to the US beam and can be converted to a return-to-play decisions. Many physicians utilize
448 J. Smith et al.

US both to immediately assess ability to return to detail below), which could not be performed
play on the field (i.e., triage) and to help deter- accurately without US guidance [302–304].
mine when an athlete is sufficiently healed to Some US-guided interventions have additionally
resume play. However, imaging criteria and shown shorter recovery times with less post-­
­published guidelines are lacking, and clinicians procedural pain than open surgical procedures
generally rely on a combination of clinical exam- with similar clinical outcomes [305, 306]. Many
ination and functional performance measures peripheral nerve procedures exist and can relieve
correlated with imaging findings when returning pain; however, they all require perineural needle
athletes to sport. A few studies on muscle injuries placement which increases risk of nerve injury
in athletes have shown that evidence of disorga- through intraneural injection or nerve penetration
nized fibrous tissue, intramuscular hematoma, [307, 308].
intermuscular hematoma, and power Doppler The American Medical Society for Sports
signal on US examination predict longer time to Medicine (AMSSM) has suggested that
return to play [294–296]. US-guided procedures can be divided into three
different generations [309]. First-generation
techniques are those that apply US guidance to
I nterventional Use of Ultrasound improve accuracy of established procedures.
for Procedural Guidance Second-generation techniques are those that have
been developed primarily as a result of US guid-
 dvantages of Interventional US
A ance and utilize commonly available needles.
in Sports Medicine Examples include needle tenotomy for chronic or
calcific tendinosis, neovessel ablation and tendon
Ultrasound also has multiple advantages when scraping, fenestration of the transverse carpal
used to assist with sports medicine procedures ligament, A1 pulley fenestration, and nerve
(see Table 21.3). If an interventional treatment is hydrodissection. Third-generation techniques
determined to be needed following diagnostic utilize specially designed surgical tools or devices
US, it can often be performed immediately after to duplicate well-established surgical procedures
evaluation without the additional time delay under US guidance. These include A1 pulley
required when obtaining an MRI or CT for diag- release using a hook knife, carpal tunnel release
nosis [80]. Injection accuracy is improved with using Guo wires or specially designed devices,
the utilization of ultrasound for needle guidance and tenotomy or fasciotomy using meniscotomes,
for most structural targets [297, 298]. Doppler Guo wires, or hook knives [25].
US can also be used to visualize blood vessels to
evaluate vascular malformations as well as vas- First-Generation Procedures
cularity of soft tissue masses which can contrib- Since the initial use of US by Karl Dussik to eval-
ute to diagnosis [299–301]. The use of US uate the MSK system, US’s ability to visualize
guidance is even more important for advanced both soft tissue and neurovascular structures has
procedures such as barbotage and percutaneous made it popular for procedural guidance. The use
fasciotomy and tenotomy (described in more of US for diagnosis affords an easy transition to
performance of US-guided procedures with supe-
rior accuracy to palpation guidance [302]. In a
Table 21.3 Advantages of interventional US
position statement on US-guided procedures, the
Advantages of interventional US AMSSM concluded that there is high-quality evi-
Immediate intervention following diagnosis
dence that US-guided injections are more accu-
Improved accuracy of most injection procedures
rate than landmark-guided injections in large
Visualization of nearby vascular and neural structures
to avoid inadvertent injuries joints (accuracy 91–100% for US-guided and
Conversion to less invasive interventions for 64–81% for landmark-guided), intermediate
traditionally operative interventions joints (approximately 95% for US-guided and
21 Evolution of Sports Ultrasound 449

78% for landmark-guided), small joints (accu- [314]. Repeat barbotage may be required to fully
racy 94–100% for US-guided and 0–96% for address some calcific lesions [315] and may be
landmark-guided), and tendon sheaths (accuracy combined with subacromial corticosteroid injec-
87–100% for US-guided and 27–60% for tion for greater relief [316]. Several reviews and
landmark-­guided), though the difference in effi- meta-analyses describe calcific barbotage as safe
cacy and cost has not yet been determined [309]. and effective for the treatment of calcific rotator
Individual joint procedures are discussed in more cuff tendinosis [313, 316–318]. Compiled results
detail in Chaps. 5, 6, 7, 8, 9, 10, and 11. show up to 55% improvement in pain and indi-
Historically, corticosteroid injection near the cate that it can be used as a first-line treatment
target structure was believed to be sufficient to [313, 316–318]. Calcific barbotage may also be
provide therapeutic benefit. The local and sys- used to treat calcific tendinopathy of the gluteal
temic effects of corticosteroid allowed for thera- tendons [319] and the common extensor tendon
peutic benefit even if the injection was not at the elbow [320].
precisely placed. As corticosteroid use has fallen
out of favor due to its toxic effects on tendon and Neovessel Ablation
cartilage, newer agents have arisen that are Neovessel ablation procedures include tendon
thought to require precise placement at the site of scraping and high-volume image-guided injec-
injury for maximum efficacy. These include tion (HVIGI) that can be performed together or in
autologous blood products, bone marrow, adi- isolation under US guidance. The goal of these
pose tissue, allogenic amniotic membrane, or procedures is to disrupt the neovessels and neo-
dextrose solutions [309]. As a result, it is recom- nerves that grow from fat pads like Hoffa’s or
mended to perform these injections under US Kager’s fat pad that lie deep to large tendons.
guidance to achieve the highest injection accu- These neonerves and neovessels are thought to
racy and best outcomes [309]. Further informa- contribute to pain associated with patellar [321]
tion on and discussion of regenerative medicine and Achilles [322] tendinopathy. US with color
injectates can be found in Chaps. 1, 2, and 3, and Doppler allows for the visualization and targeting
procedures are reviewed in Chaps. 12 and 13. of these neovessels pre-procedurally with the
hope of subsequently disrupting the accompany-
Second-Generation Procedures ing neonerves. A significant advantage of these
Greater spatial resolution has made it possible to extra-tendinous procedures is that the integrity of
perform procedures that require detailed needle the tendon is not compromised. This results in a
visualization beyond mere guidance to a target. more rapid return to activity after the procedure
This includes using needles to fenestrate or cut a than what is recommended for intra-tendinous
pathologic calcification, ligament, tendon, or procedures.
retinaculum. The tendon scraping procedure can be per-
formed entirely under US guidance through an
Calcific Barbotage 11-blade stab incision with an 18-gauge needle or
Calcific barbotage is used for the treatment of meniscotome inserted perpendicular to the ten-
calcific tendinopathy [310, 311] and is most don under US guidance. This is then passed back
effective for intratendinous calcification rather and forth in a sweeping motion deep to the ten-
than osseous extension [312]. The goal of the don at the area of neovascularization. While the
procedure is to break up the painful calcifications utility of open and mini-open surgical tendon
within the tendon. This involves lavage of the cal- scraping to treat Achilles tendinosis is well docu-
cific particles using injection of normal saline mented, only one study has examined percutane-
and a needle (commonly 18-gauge) to repeatedly ous Achilles tendon scraping under US guidance.
inject and aspirate the calcification under direct In that study, percutaneous scraping of 19 ten-
US guidance [313]. Soft and middle-sized calci- dons showed similar efficacy to an open proce-
fications generally respond best to this treatment dure [322]. One case has been published on the
450 J. Smith et al.

use of tendon scraping to treat patellar tendinopa- Ligament or Retinaculum Release

thy that resulted in complete resolution of symp- Ligament or retinaculum release can now be per-
toms and full return to play at 4 weeks with no formed under US guidance through a very small
recurrence at 11-month follow-up321. incision. This has been demonstrated with release
HVIGI typically consists of a 40–50mL injec- of the transverse carpal ligament (TCL) in carpal
tion of normal saline and aims to separate the ten- tunnel syndrome, release of the A1 pulley in trig-
don from the deep fat pad while disrupting ger finger, release of the flexor retinaculum in
neovessels and neonerves [323–331]. HVIGI has tarsal tunnel syndrome, and release of the first
been shown to improve pain and physical func- dorsal compartment of the wrist to treat de
tion in multiple case reports, case series, one ran- Quervain’s tenosynovitis.
domized controlled trial (RCT), and a Release of the TCL under US guidance to treat
retrospective cohort study, but rates of return to carpal tunnel syndrome has evolved from a pro-
sport varied [323, 325–330, 332]. When com- cedure done with US assistance to one done com-
pared to PRP or eccentric exercises alone, HVIGI pletely under US guidance through needle
had better results at 6 weeks than PRP and eccen- fenestration [337–339], use of a wire to cut the
tric exercises alone, and both PRP and HVIGI TCL [340–342], use of a hook knife to cut the
were superior to eccentric exercises alone at 24 TCL [305, 343–347], or use of commercially
weeks [324]. HVIGI to treat greater trochanteric available devices such as the SX-ONE device
pain syndrome [333] and shoulder impingement [348–351]. US guidance allows for the direct
[331] have been studied by one author, but found visualization of pertinent anatomy that must be
either no benefit or only short-term benefit, avoided during the procedure. This includes the
respectively. transverse safe zone (bordered radially by the
median nerve and ulnarly by the hook of the
Third-Generation Procedures hamate or ulnar artery), palmar cutaneous branch
More recently, specific tools have been devel- of the median nerve, Berrettini branch, recurrent
oped to perform procedures under US guidance motor branch of the median nerve, and other neu-
that were historically performed by open or rovascular anomalies [352]. Overall, studies on
arthroscopic surgery. US-guided procedures US-guided carpal tunnel release with the
allow for smaller incision sites that are associated SX-ONE device report successful release of the
with reduced post-procedure pain and improved TCL in over 600 wrists with minimal complica-
function with a more rapid return to baseline tions and a 95% success rate [348].
activity. These procedures are also likely less Trigger finger release with a needle can be per-
costly with lower complication rates and formed under US guidance with improved cosme-
increased patient satisfaction [334–336]. sis and fewer days absent from work than open
However, if these procedures are performed by surgical release [306, 353, 354]. This is commonly
practitioners with inadequate anatomical and performed after failure of a corticosteroid injec-
procedural competence, they carry significantly tion. Trigger finger release under US guidance can
higher risk for injury to surrounding structures. also be accomplished with use of a hook knife or
Correct identification of the anatomy and pathol- wire to cut in a retrograde direction (intra or extra
ogy is central to any US-guided procedure, and sheath) or use of a needle or needle knife (Nokor
most third-generation procedures should be prac- needle) to cut in an anterograde direction [355].
ticed on cadavers prior to use in patients. Use of Cadaveric and clinical data have shown a higher
cutting devices without adequate experience complete pulley release rate when using a hook
could lead to severe and irreversible injury to knife instead of a needle [355–358]. When com-
critical structures. Therefore, these procedures pared to surgery, US-guided trigger finger release
are best performed by experienced sonographers has a shorter procedure time, lower cost, and more
and proceduralists. rapid return to normal activities [306, 359].
21 Evolution of Sports Ultrasound 451

US-guided tarsal tunnel release with a hook Although many of these procedures are still in
knife [360] and first dorsal compartment release development, the use of US to guide procedures
with a needle have also been described. These offers a promising method to minimize the inva-
procedures theoretically afford less pain, are siveness of surgical procedures, decrease recov-
lower cost, and have a more rapid recovery than ery time, and decrease cost. However, additional
their respective surgical procedures, but more research is needed to develop specific tools to
research is needed [361]. improve the ease of US-guided procedures and to
directly compare outcomes between surgical and
Tendon, Muscle, or Fascial Release non-surgical procedures. The next step in the
Tendon, muscle, and fascial release can be per- development of US-guided procedures is to
formed under US guidance and is most beneficial determine if repair of tissues performed under
for those who are poor surgical candidates or need US guidance has similar outcomes to open or
a more rapid return to activities than that afforded arthroscopic surgical procedures and what differ-
by surgery. To date, several cadaveric and a few ences in complications and rehabilitation proto-
patient studies of these techniques have been pub- cols and timeline are noted. A protocol outlining
lished. Current limitations to these procedures US-guided repair of the lateral ligament complex
include operator skill and lack of procedure-­ of the ankle has been published and shows prom-
specific tools. The procedures are highlighted ise [369].
below, although a full description of these tech-
niques is beyond the scope of this chapter.
Biceps tendon release using different devices US in Orthopedics: Use of US
(hook knife, scalpel, banana blade, retractable in Preoperative Planning
blade, serrated blade) with retrograde cutting of and in the Operating Room
the biceps tendon at various locations (rotator
interval, bicipital anchor, and bicipital groove) In addition to assisting with diagnosis, US can
have been described [362–364]. Cases performed be used to assist orthopedic surgeons during pre-
in the bicipital groove using a scalpel or hook operative planning and intraoperatively to aug-
knife were most successful in releasing the long ment visualization of relevant structures. Several
head of the biceps in cadavers. studies have shown that preoperative sono-
Plantaris tendon release using a hook knife graphic measurements of the patellar tendon
[365] and adductor release using a Guo cutting [370], quadriceps tendon [371], and gracilis and
wire [366] in a retrograde direction under US semitendinosus tendons [372–374] predict ACL
guidance have been described in cadavers and are graft size. Preoperative US mapping of periph-
thought to be safe. eral nerves targeted for surgical intervention has
Plantar fascia release under US guidance also been used to speed identification and access
using a hook knife to cut in a retrograde medial to to the target, minimize tissue destruction, and
lateral direction [367] in cadavers or a beaver decrease operating time [375]. US can also be
blade to cut in a deep to superficial direction in utilized preoperatively to tag nerves commonly
patients [368] have been found to be successful. injured during certain procedures that are diffi-
Fasciotomy of the anterior and lateral com- cult to localize intraoperatively. This includes
partments of the lower leg for treatment of avoiding sensitive structures during Achilles ten-
chronic exertional compartment syndrome has don repair [376], plantar fascia repair [377], and
also been successfully performed on cadavers medial elbow arthroscopy [378] and localizing
under US guidance using a meniscotome and the lateral femoral cutaneous nerve for operative
anterograde release [34]. decompression [379].
452 J. Smith et al.

 urrent Limitations and Future

C tery life (although alternative battery sources,
Directions such as solar power, are also in development)
[382]. In spite of that, technological progress
In spite of the dramatic expansion of US tech- continues to move toward a world where side-
nology over the last several decades, US still line US evaluation could be as simple as pulling
has several limitations (Table 21.4). Overcoming out a durable, pocket-sized probe that syncs
these limitations is the topic of ongoing wirelessly with a mobile device or laptop.
research, and promising methods are discussed The “operator dependency” of US is fre-
below. quently cited as a weakness, but this is likely
While US is often touted as a portable imag- improving as US training increases. US training
ing modality, especially compared to x-ray, is being incorporated into medical school, resi-
MRI, and CT, companies continue to push the dency programs, fellowships, and national work-
limits of portability to make US truly “pocket- shops to improve and standardize operator skill
portable.” The first US machine small enough to [383, 384]. The number of articles cited in
be used on the battlefield was developed in 1996 PubMed that utilize US to evaluate MSK condi-
[380], and portable US machines have contin- tions has increased exponentially since the 1970s
ued to demonstrate utility in field clinics after with over 2800 articles published in 2018 alone.
natural disasters [381]. Transducers that attach Despite this, inter-rater reliability in MSK and
to phones and tablets are now commonplace. nerve evaluation still varies based on the site
Transducers the size of a pen are actively in examined, whether the tissue is healthy or patho-
development, but several disadvantages and bar- logic, and how much training the examiner has
riers to production remain for these small received [385–389]. New technology, such as
devices. Smaller probes and US machines often UTC, attempts to standardize US evaluation by
compromise image resolution, field of view, removing the human operator, but remains
ability to employ multiple scanning modes impractical for widespread implementation as
(such as Doppler), machine durability, and bat- described previously.
Additionally, US evaluation is limited by
Table 21.4 Limitations of US and research addressing
beam attenuation caused by superficial structures
these limitations. US, ultrasound that impede deeper visualization. B-mode US
Limitation Future direction/research relies on high-frequency sound waves to provide
Lack of high-quality Technological improvements sufficient spatial resolution for tissue differentia-
portable images and improved resolution of tion, but these high-frequency waves are attenu-
small US machines with ated when they pass through tissue layers,
transducers the size of a pen.
especially subcutaneous fat. This makes sono-
Transducers that attach to
phones and tablets graphic imaging of obese patients difficult. While
Operator dependent Access to education. deeper penetration can be achieved by using a
Standardization of image lower-frequency transducer, this results in
acquisition decreased resolution [390]. Tissue harmonic
Inability to visualize Tissue harmonic imaging,
imaging (THI) is one attempt to overcome this
deep structures spatial compound imaging,
(particularly in obese speckle reduction, and tissue problem. It utilizes higher-frequency harmonic
patients) due to beam aberration correction sound waves produced by the original US wave
attenuation interacting with nonlinear tissues of deep struc-
Inability to penetrate Development of tools for tures. These higher-frequency waves reflected
bone and visualize in-office arthroscopy such as
inside joints MiEye from deep structures are captured by the probe,
Limited field of view Extended view imaging allowing for higher-resolution visualization of
Conventional US is in 3D US imaging deep structures that would not be possible with
two dimensions standard B-mode US [391, 392]. In addition to
21 Evolution of Sports Ultrasound 453

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 Use of Musculoskeletal Ultrasound
and Regenerative Therapies
22
in Sports

Jeimylo C. de Castro

Musculoskeletal Ultrasound all the challenges in the healthcare industry, the

in Sports use of ultrasound provides a less costly alterna-
tive to MRI scan, with one notable drawback,
Musculoskeletal ultrasound has significantly which is its operator-dependency [2]. A well-­
improved over the years as a primary tool for trained and competent sonologist is needed for
diagnosing musculoskeletal injuries in the sports consistent and reliable imaging studies.
activity. As technology improves coupled with its With regard to sports injuries, there is always
unique dynamic feature of looking at tissues, the the question of which comes first – the need for
ability to provide real-time information is precision and diagnostic sensitivity of the
enhanced. High-quality diagnostic ultrasound, machine to be able to deliver the appropriate
however, cannot be done without an accurate treatment or the upgrading of the machine itself
clinical history of the injury, knowledge of to get the advantage of the market? In profes-
gender-­specific injuries, and an understanding of sional sports, one feature in ultrasound, for
the mechanism of injuries especially in diagnos- instance, that stands out is tissue harmonic imag-
ing defects and determining appropriate treat- ing (THI). This provides greater contrast in reso-
ment among amateur and professional athletes lution for tendons and muscles with similar
alike [1]. Several technological features were impedance [3]. For instance, the use of THI at
added in the ultrasound such as higher resolution 7.5 MHz will collect the information at 14 MHz,
linear array probes, tissue harmonic imaging, thus enabling the image to be shown at greater
extended field of view, two-dimensional matrix resolution even at deeper structures. Further, it
probe technology, power Doppler sonography, reduces most of the artifacts such as reverbera-
and elastography. All these features make it eas- tion, and improves the signal-to-noise ratio [3].
ier for the sonologist to detect and characterize a Some studies show that this feature is best for
variety of musculoskeletal pathologies [2]. With diagnosing shoulder lesions, especially subscap-
ular tendons [4, 5]. Another feature that enhances
visualization of the image is an extended field of
J. C. de Castro (*) view technique or panoramic view. With this,
Chair, Physical Medicine and Rehabilitation large lesions can be viewed easily, especially
Department, The Medical City-South Luzon, those involving the knees and thigh muscles [3].
Sta. Rosa, Laguna, Philippines To improve the lateral resolution of the image,
Medical Director/CEO, SMARTMD Center for and improve the images of deeper planes, a real-­
Non-Surgical Pain Interventions, time compound ultrasound system can be used
Makati City, Philippines

© Springer Nature Switzerland AG 2022 469

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_22
470 J. C. de Castro

[6]. Also, the use of power Doppler enables dict the outcome of previously large supraspina-
images to be obtained in painful tendinopathies tus (SSP) tear sustaining retear after surgical
and inflammatory conditions which correlate repair. In the past, MRI-based parameters like
well with MRI scans [3]. Recently, Afandi and tear size, fatty infiltration, and tendon retraction
Astawa did a 10-year systematic review of ath- are measured pre-operatively together with the
letes suffering from tendinopathies using elastog- demographic data of the patient. Similarly, the
raphy ultrasound (EUS) between 2009 and 2019 postoperative morphologic changes seen in the
using 59 articles. The study showed that both MRI scan can hardly be used to predict outcomes,
strain and shear-wave elastographies are reliable and thus has weak to moderate predictive
techniques in musculoskeletal ultrasound and strength. This was observed in a number of
have shown higher sensitivity, specificity, and patients at risk for poor functional outcome or
accuracy in diagnosing early tendon pathologies failed tendon healing because of the inability of
than the B-mode conventional ultrasound. EUS is the lesion to be detected by MRI imaging. In this
also used as a tool to evaluate and guide ongoing study, muscle perfusion assessment by CEUS is
treatments in post-op rehabilitation monitoring used postoperatively reflecting the regenerative
and to predict a return to play especially in high-­ potential of the SSP muscle/tendon system rather
level professional athletes. Various tendons are than the morphologic parameters in MRI. Results
amenable to this technique such as rotator cuff showed that preoperative CEUS-based assess-
and rotator cuff tendons, common extensor ten- ment of SSP perfusion significantly correlated
dons of the elbow, patellar tendons, Achilles ten- with early postoperative shoulder function and
don, and the plantar fascia [7]. Of particular tendon retear after surgical repair. Therefore, it
interest and unique feature of ultrasound also is helps identify patients who are at low or high risk
dynamic imaging. Dynamic ultrasound is for tendon retear by assessing microcirculation as
affected, however, by the field of view, which is a surrogate parameter for tissue vitality and
typically 40–60 mm wide, and the frame rate. metabolism [13].
The field of view can be improved by using either Wengert and colleagues compared the use of
an extended field of view feature or probes with a high-resolution ultrasound and magnetic reso-
larger field of view. The frame rate refers to the nance arthrography (MRA) in sports-related
number of images the ultrasound can acquire in 1 shoulder injuries. Usually, MRA is used to
second [8]. In one study, dynamic ultrasound of a assess intraarticular abnormities and rotator
lateral ankle injury involving calcaneofibular lig- cuff injuries by application of contrast agent
ament (CFL) showed that ultrasound has a sensi- with better visualization of intraarticular shoul-
tivity of 90% and a specificity of 100%, with a der injuries as compared to conventional MRI
positive predictive value (PPV) of 100% and a scan. This study has shown that high-frequency
negative predictive value of 91.7% as compared ultrasound is a reliable modality for the rotator
to MRI [9]. Dynamic imaging in ultrasound can cuff, long head biceps (LHB) tendon, and acro-
be used to evaluate multidirectional laxity of a mioclavicular joint over MRA based on its
structure, assess tendon subluxation, and support diagnostic accuracy, comfortability, cost-effec-
the clinical decision of a referral [10, 11]. It can tiveness, and availability. However, for other
also be used for ultrasound-guided interventional structures, MRA remains the gold standard of
procedures to aid the practitioner in optimal nee- diagnosis [14]. It is also recommended that in
dle placement [12]. Contrast-enhanced ultra- any sports injury, musculoskeletal ultrasound
sound (CEUS) is another feature in ultrasound should be used as an initial study for patients
which is used to visualize other organs in the with acute and chronic shoulder pain [15, 16].
body, but recently it has been found useful for Conventional radiographs should always be
visualizing musculoskeletal injuries. In a study used as a baseline imaging modality for any
by Kunz and colleagues, CEUS was used to pre- shoulder injuries [14].
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 471

The use of musculoskeletal ultrasound will be structures, MRI provides better imaging with
much simple with the advent of capacitive micro- deeper structures like muscle injuries [18].
machined transducer (CMUT). It is a break-
through in ultrasound technology where a single
probe instead of various probes for different Musculoskeletal Ultrasound/
ultrasound examinations can be applicable. In Regenerative Therapies in Upper
contrast to conventional ultrasound, CMUT does Extremity Sports Injuries
not utilize crystals. Instead, it makes use of the
new generation silicon wafer technology com- Shoulder
posed of innumerable tiny vibration drum cells The shoulder is one of the most affected areas in
formed in the micrometer scale. These cells are swimming and water sports. This is by far the
arranged in a matrix array that improves spatial most frequent chronic injury in swimmers repre-
resolution where the frequency bandwidth is in senting about 40–90% of limiting shoulder pain
the range of 2–22 MHz. Its e-focusing feature among swimmers [19]. Generally, the symptoms
allows better penetration with less focus-­ are caused by overuse injuries and affect the sub-
dependency. It has the ability to image all or most acromial region, rotator cuff, long head of the
of the image fields during each transmission by biceps, subcoracoid and subacromial-subdeltoid
its fast parallel beam-forming ability. CMUT bursae, which are best diagnosed by ultrasound
delivers one probe for all ultrasound examina- [1, 20, 21]. Lengthy swimming careers may lead
tions. Moreover, with all its fancy development, to a reduction in the mechanical properties of the
there is a need to improve in terms of the resolu- supraspinatus muscle and tendon with an
tion of the superficial tissues and Doppler signal increased likelihood of rotator cuff pathology
to validate its claim over the lead-based piezo- over the years [22]. Surprisingly, the pathological
electric linear probes [17]. changes that lead to pain among elite swimmers
An emerging development in the diagnosis of are not known, although ultrasound findings sug-
sports injury is the fusion of MRI-US technology. gest overuse tendinopathy and glenohumeral lig-
Although it technically requires fusion imaging amentous laxity [19]. In water polo sports, a
hardware, it is a good choice for sports-related complex combination of shoulder pathologies is
injuries such as partial- or full-thickness tendon seen in the early asymptomatic stage. As a result,
tears, nerve entrapments, muscle strains, liga- the use of ultrasound is useful in the quick man-
mental sprains, joint effusions, and other soft-­ agement of and regular follow-up of shoulder
tissue injuries. This is usually done by using modifications in regular practice in sports medi-
previously acquired MRI scans and is then fused cine [23].
with real-time US. The linkage is made possible Generally, the patient with rotator cuff tears
by the fusion imaging hardware whereby an elec- (Fig. 22.1) usually presents with pain and weak-
tromagnetic sensor attached to the US probe ness of the lateral deltoid. Pain is usually felt at
sends positional data to the fusion US machine. night when the patient sleeps on that side affected.
By selecting two or more recognizable land- The most effective examination tests are the
marks, locking a plane, and then registering the active painful arc test, drop arm test, and weak-
images on each of the two studies, this linkage is ness on external rotation [24]. A study by Wengert
done. US fusion technology allows simultaneous and colleagues, comparing US to MRA to assess
viewing of the MRI which corresponds with real-­ shoulder pathology, showed that US is superior to
time US images on the US monitor on any plane. MRA in assessing rotator cuff, long head of the
This combination of imaging techniques can lead biceps, posterior labrum, and the AC joint with
to a more accurate diagnosis and better clinical the additional feature of dynamic examination of
decisions during a sports injury. While the US US in conjunction with clinical examination [14].
provides imaging studies for the more superficial Also, muscle degeneration as the consequence of
472 J. C. de Castro

a b

Fig. 22.1 (a) A longitudinal view of the supraspinatus serves as the attachment of the supraspinatus tendon. (b)
tendon showing full-thickness tear with hypoechoic Short-axis view of the supraspinatus tendon full-thickness
swelling of the subdeltoid bursa. Note the cortical irregu- tear with some hyperechoic changes indicative of calcium
larity of the greater tuberosity of the humerus which deposits

supraspinatus tendon tear could be best visual- ence of pain in the shoulder among athletes do
ized by contrast-enhanced ultrasound (CEUS) not correlate with the presence of shoulder
examination rather than by MRI scan. CEUS pathologies such as tendinopathies or tendon
assesses muscular vitality by assessing microvas- tears as these findings may be present in asymp-
cular perfusion of the muscle tissue after rotator tomatic individuals [26]. Moreover, among base-
cuff repair and thus serves as a quantitative ball pitchers experiencing shoulder pain, an
method to evaluate rotator cuff muscles [25, 26]. ultrasound study detected an increase in width of
Asymptomatic rotator cuff tears are common the infraspinatus and long head of biceps tendon
among overhead and throwing athletes, and with as early as 50 pitches as a response to overload
particular interest are the baseball pitchers [26]. experience with no associated decrease in echo-
The increased risk of tendinopathy occurred dur- genicity [27]. In a study by Takenaga and col-
ing the late cocking phase of throwing causing an leagues on healthy college baseball players with
internal shoulder impingement [28]. Most of a career length of at least 10 years, shear-wave
these asymptomatic patients surprisingly do not ultrasound elastography was used to measure
develop symptoms of pain even up to 5 years elasticity. The study showed that the posterior
follow-up of ongoing, competitive play [29, 30]. and postero-inferior capsules of the shoulder
Most of them showed articular-sided tears of the were stiffer and thicker in the throwing shoulder
supraspinatus and infraspinatus muscles without than in the non-throwing shoulder. Further, pos-
any symptoms at all [30]. In fact, some of them in terior capsule elasticity has greater effect on gle-
a repeat MRI scan may show resolution of the nohumeral internal rotation deficit (GIRD) than
tendinopathy or partial tears of the rotator cuff, did posterior capsule thickness, and thus this
years after retirement from sports activity, and non-invasive procedure will help identify players
does not progress to full tears [31]. So, the ques- who are at risk for shoulder injuries [34].
tion is what is the cause of the shoulder pain? Moreover, pitchers with GIRD usually show
Among non-athletes, Yamaguchi sonographically dominant humeral retro torsion [35]. Humeral
found that enlargement of the tears in 50% of retro torsion is also seen as an adaptive change
patients may be the cause of pain [31], while among young healthy baseball athletes
other ultrasound studies showed that shoulder (8–14 years old) during throwing activities and
pain with partial- and/or full-thickness tears is could influence shoulder motion at a young age
associated with increasing age [32, 33]. The pres- [36].
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 473

Shoulder injuries might in some way affect the The use of ultrasound to diagnose shoulder
brachial plexus nerves. In a systematic review by conditions in sports medicine could not be over-
Chin and colleagues on traumatic brachial plexus emphasized. In undifferentiated shoulder pain, a
injury studies up to July 2016, covering seven bedside ultrasound showed a change in diagnosis
studies, the use of ultrasound as a diagnostic tool in 53% of cases and a change in management in
was most sensitive in lesions in the upper and 60% of cases. It also resulted in a new order of
middle (C5-C7) than in the lower spinal nerves MRI in 28% of cases and an elimination of an
(C8, T1). However, the window for ultrasound MRI order in 21% of patients [43]. Arthroscopic
examination in these studies was up to about a techniques remain the gold standard for treating
27-month period. Identifying surgical candidates most rotator cuff tears providing similar func-
is most needed within the 3- to 6-month period tional results to open and mini-open surgery with
and as such the question of whether the US is sen- an additional advantage of lesser postoperative
sitive enough to diagnose cases in the acute stage complications [44]. Pain in post-arthroscopic sur-
is raised. The value of the US as a first-line diag- gery, however, was more significant in smaller
nostic tool for traumatic brachial plexus injuries tears than in larger tears because of more vigor-
needs further standardized studies. However, this ous healing in smaller tears from 6 weeks to
does not preclude the fact that this tool has a great 6 months after surgery [45]. Regenerative injec-
potential for such cases [37]. Unless there is an tion therapies are becoming popular as an alter-
indication of a peripheral nerve injury, the use of native treatment to surgery due to their potential
ultrasound as a screening modality for athletes to provide healing and shorter recovery as in the
with suspected peripheral nerve entrapment due case of platelet-rich plasma (PRP) (Fig. 22.2).
to atrophy of supra- and infraspinatus muscles The use of PRP therapy in rotator cuff conditions
with or without pain is not warranted [38]. did not show any improvement when used in an
Pectoralis muscle injuries occur when the ath- interstitial supraspinatus tear as compared with
lete is eccentrically contracted, with the shoulder saline injections [46]. Ultrasound-guided periten-
extended, abducted, and externally rotated. dinous subacromial hyaluronic acid (HA) injec-
Patients often complain of pain, swelling, and tion over the supraspinatus tendon combined
weakness [39, 40]. While this is rare, this is com- with physical therapy showed high efficacy in the
mon among weightlifters and occurred during the treatment of supraspinatus tendinopathy result-
eccentric phase of bench press [39]. Ultrasound ing in an earlier return to play and with lesser
is a valuable modality for assessment but has its rehabilitation sessions [47]. Cai and colleagues
limitations. MRI scan remains the diagnostic did a study combining PRP and sodium hyaluro-
imaging of choice. Surgical intervention is rec- nate (SH) to treat partial-thickness rotator cuff
ommended for complete tears of pectoralis mus- tear and compared the results with either PRP
cles with a return to play at about 6 months [41]. alone or SH alone. A study showed that the com-
Ultrasound can also be used to evaluate bination of PRP + SH as compared with either
whether a certain exercise modality provides the PRP alone or SH alone yielded a better clinical
promised effect on a particular muscle being outcome in terms of healing and showing a
trained. Sachdeva and colleagues assessed differ- cumulative effect after repeated injections. This
ent strength training for the supraspinatus mus- combination treatment enhanced the recovery of
cle. Their study showed that strength training small- to medium-sized bursal-sided tears by
using prone horizontal abduction was effective alleviating pain and decreasing tear size over a
for maintaining fiber bundle length (FBL) and 12-month period (pretreatment AP
facilitating increases in strength in multiple size = 7.38 ± 1.06; 1-year post-treatment AP
modes allowing the muscle to produce greater size = 1.52 ± 0.62) [48]. PRP was also used as an
forces over a larger range of motion of the shoul- adjunct treatment for post-arthroscopic supraspi-
der joint. Thus, this is a more effective exercise natus repair. A midterm evaluation was done to
for supraspinatus strengthening [42]. see any effect of PRP on the healing tissues. This
474 J. C. de Castro

a b c

Fig. 22.2 (a) Ultrasound-guided LR-PRP injection of the using both B-mode and power Doppler to ensure that no
supraspinatus tendon. (b, c) Short axis ultrasound vital structures are hit during the approach
approach to the torn supraspinatus tendon using LR-PRP

a b

Fig. 22.3 (a) A 51-year-old female complaining of lat- sistent with tendinosis. (b) Ultrasound image with power
eral elbow pain for more than 6 months with prior history Doppler showed mild inflammatory reaction over the
of repetitive wrist extension activities showed the follow- inner layer of the common wrist extensor tendon with pos-
ing ultrasound findings. Note the hypoechoic lesion over sible involvement of the lateral ulnar collateral ligament.
the inner layer of the common wrist extensor tendon with Also note the thickening of the common wrist extensor
the absence of a distinct fibrillar pattern of the tendon con- tendon

study showed that there is significant pain-free machines will help establish a clinical diagnosis
abduction strength on the shoulder treated with and at the same time guide practitioners to find the
PRP but no difference in terms of tendon repair most appropriate medical and surgical manage-
and durability and resistance to tendon reinjuries ment. Lateral elbow pain has an incidence of
as compared to the control group [49]. An 1–2% and is due to an overuse injury of the com-
ultrasound-­guided PRP injection post-­mon wrist extensor origin of the lateral epicon-
arthroscopically also does not improve early dyle of the elbow [51]. Lateral elbow tendinopathy
tendon-­bone healing or functional recovery [50]. (Fig. 22.3) is one of the most common patholo-
gies affecting the elbow both in sports and occu-
Elbow pational settings. Pain in this area is usually
Elbow ultrasound is a very useful modality both exacerbated by wrist extension as this is the origin
for diagnosis and for guided procedures. The use of common wrist extensor tendons. For lack of
of unique and novel features in ultrasound inflammatory findings, this is often referred to as
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 475

tendinosis. Ultrasound findings are characterized elbow flexion valgus stress minus resting elbow).
by structural changes such as tendon thickening, The anterior bundle of the UCL is the primary
hypo echogenicity, intrasubstance tears, and neo- stabilizer of the medial elbow against valgus
vascularity [52]. Of these features, the most sig- stress [59]. A recent study by Park and colleagues
nificant clinical findings relating to a poor showed that stress ultrasound can be used to
prognosis are the presence of lateral collateral diagnose complete medial UCL tears in athletes
ligament (LCL) tear and the size of the largest when joint gapping is greater than 0.5 mm at 30°
intrasubstance tears which may require either sur- of elbow flexion and greater than 1 mm at 90° of
gical intervention or regenerative therapies [52]. elbow flexion [60]. It was also found out that
Early tendon pathology can be assessed by elas- increasing the pitch velocity by 10 km/hour
tography to avoid further degeneration of tendons would increase the risk of medial epicondyle
which otherwise cannot be seen when using con- abnormality and medial elbow pain by three
ventional ultrasound [7]. Moreover, sonopalpa- times, together with the number of practices per
tion to induced tenderness over the lateral week [61]. Thus, valgus stress stabilization exer-
epicondyle in an ultrasound examination showed cises involving the flexor digitorum superficialis
that maximum tenderness corresponds to the (FDS), especially of the middle and index fin-
exact site of pathology, rules out other differential gers, provide medial elbow support for UCL
diagnoses, and guides ultrasound-guided intrale- [62]. In fact, hand gripping reduces medial elbow
sional injections [53]. In one study, recalcitrant joint gapping compared with rest as shown in
lateral elbow tendinopathy responds favorably elastography measurements [63]. For partial
with ultrasound-guided percutaneous tenotomy UCL tears, ultrasound-guided PRP injection is an
which was followed up after 3 years [54]. effective treatment [64] with an added benefit of
Ultrasound-guided tenotomy has the benefits of early return to play [65].
pain relief, improved physical function, and high Among adolescents, repetitive throwing activi-
patient satisfaction [55]. In a randomized con- ties in sports may put a strain over the immature
trolled trial study, the use of platelet-rich plasma capitellum of the elbow and may cause capitellar
for chronic lateral epicondylitis led to pain relief osteochondritis dessicans (COCD) [66]. This con-
earlier than autologous whole blood [56]. dition may cause fragmentation of the osteochon-
Among young professional baseball pitchers, dral bone that may be unstable and may cause
one of the first changes sonographically in the pains. The evaluation of the stability of the lesion
medial elbow is the increase in ulnar collateral is important so that practitioners can decide
ligament (UCL) thickness, which increases over between operative and nonoperative options.
time professionally [57] but is not seen among Stable lesions tend to heal with simple elbow rest,
young high school pitchers [58]. It is measured at but unstable lesions require surgery [67]. In the
the midportion of the UCL without stress at the past, preoperative MRI scans play an important
elbow [57]. As you can see, injury to the UCL role in the diagnosis, with a sensitivity of 84% and
can be a career-threatening defect for elite specificity of 70% [68]. In this study, ultrasound
overhead-­ throwing athletes causing pain, was a useful tool in evaluating fragment instabil-
decreased control, and velocity to the pitcher [57, ity in COCD. It is superior to MRI with a sensitiv-
59]. And as such, assessing this structure can pro- ity of 92% and a specificity of 100% [67].
vide essential guidance as to the best possible
training and treatment. In a cadaveric study, the Wrist and Hand
release of the anterior bundle of UCL results in Approximately 25% of all sports-related injuries
the greatest increase in joint gapping as measured involve the wrist and hand [69]. With its intricate
by medial elbow stress ultrasound (SUS), which structural makeup, The unique demand of sports
is measured by the greatest distance of the ulno- upon the hands and wrists of athletes makes this area
humeral valgus joint gapping (difference of 90° very susceptible to injuries. The mechanism of injury
476 J. C. de Castro

a b

Fig. 22.4 (a) Short-axis view of the first dorsal compart- plaining of radial wrist pain for 10 months. (b) The long-­
ment of the wrist with abductor pollicis longus (APL) and axis view showed the extent of swelling of the sheath of
extensor pollicis brevis (EPB), with a relatively swollen the first dorsal compartment of the wrist with an active
sheath and mild effusion of a 51-year-old female com- inflammatory process

and an ideal, quick, available, and reliable diagnostic tendon sheaths at the intersection [75, 76]. Given
imaging tool are important factors for decision-mak- its low prevalence rate of 0.20%, ultrasound is
ing in the management of these injuries. useful for patients who are refractory to conser-
The most common tendinopathy affecting the vative therapy, and planning for surgical inter-
wrist and hand is De Quervain’s tenosynovitis vention is an option. Ultrasound imaging is also
[70]. This is brought about by repetitive thumb needed to identify anatomical variants and guide
extension and abduction with thickening of the interventional procedures [76]. Among volleyball
abductor pollicis longus (APL) and extensor pol- and water polo players, repetitive wrist flexion or
licis brevis (EPB) tendons under the first dorsal overstretching of the wrist can cause tendenitis of
compartment of the wrist (Fig. 22.4). the flexor carpi radialis (FCR) tendon. Pain
A positive Finkelstein test confirms the site of develops as this tendon thickens which run right
the problem [71]. Ultrasound findings showed adjacent to the flexor retinaculum of the carpal
marked hypoechogenic thickening along the tunnel [77]. FCR tenosynovitis is characterized
­tendon of EPB due to thickened extensor retinac- sonographically by effusion and/or thickening of
ulum with associated hypervascularity and effu- the synovial membrane surrounding the FCR ten-
sion by power Doppler signal [72, 73]. don. Tenosynovitis of mechanical origin is char-
Intersection syndrome or Oarsman’s wrist is a acterized by effusion prevails [78]. In contrast,
friction between the first dorsal compartment ten- tenosynovitis associated with RA or chronic
dons passing over the tendons of the second dor- inflammatory disorders and thickening of the
sal compartment of the dorsal wrist which synovial membrane (pannus) prevail [79].
sometimes could be mistaken for De Quervain’s Tendinopathy, on the other hand, is characterized
tenosynovitis. The site of the pain and tenderness as tendon thickening and heterogeneous
are more proximal with intersection syndrome hypoechogenicity with or without superficial
[74]. It is usually located 4–8 cm proximal to the tearing [78].
Lister’s tubercle where these groups of tendons Extensor carpi ulnaris (ECU) injuries are usu-
intersect. A distal intersection syndrome also ally seen among players in golf, baseball, hockey,
exists where the third dorsal wrist compartment tennis, and other racquet sports. The mechanism
intersects with the second dorsal wrist compart- of injury is characterized by repetitive micro-
ment but not as common. Ultrasound findings trauma or a sudden traumatic event during wrist
showed effusion within the sheath by power flexion, supination, and ulnar deviation as seen in
Doppler and with peritendinous edema within the tennis or in the leading hand in the downward
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 477

phase of a golf stroke [71]. There is typically ten- sheath and thus ECU tendon subluxation [80].
derness over the ECU groove and pain is initiated ECU synergy test has been shown to be specific
during resisted wrist extension and ulnar devia- for ECU tendinosis [81]. Ultrasound findings for
tion. Supination with ulnar deviation of the wrist tenosynovitis showed anechoic, easily compress-
might uncover subluxation of the ECU [71]. ible fluid surrounding the tendon with minimal or
There is about an 8.9% incidence of a wrist injury absent vascularity on power Doppler [80].
which may affect ECU. The common features of However, for tendinopathy, tendon thickening
injury that might affect ECU are a combination may be subtle during the early stages and so it is
of forces such as wrist flexion during supination important to do a side-to-side comparison. Over
and ulnar deviation or sudden lateral force time, as the disease progresses, tendon thicken-
applied when the tendon is engaged in strong iso- ing will be more pronounced with neovascular-
metric contraction such as in tennis, golf, or ization on power Doppler [80, 82].
rugby sports. In tennis, it usually occurs in Sports injury over the ulnar side of the wrist
double-­ handed backhand stroke. In golf, it can involve the triangular fibrocartilage complex
­usually affects the leading wrist, which is the (TFCC) (Fig. 22.5) such as in athletes who rotate
wrist that faces the target. In traumatic ECU sub- and grip baseball bats, racquets, and golf clubs.
luxation, the leading wrist moves from radial As you know TFCC is a soft tissue complex that
deviation to a neutral position at impact. supports and stabilizes the distal radioulnar and
Subsequently, the momentum puts the leading ulnocarpal joints [83]. In an acute injury of the
wrist toward ulnar deviation, with the ECU con- wrist, TFCC may be injured because of hyperex-
tracting isometrically to counteract the ulnar tension and pronation of the axially loaded ulnar-­
deviation, which then brings the club through the deviated wrist. Patient will usually complain of
end of the golf swing with an impact. This reac- deep aching pain or pain with gripping associated
tion together with the body’s reaction can result with clicking during pronation and supination of
in the failure of the subsheath with ECU sublux- the wrist [71]. Although attempts to diagnose
ation. In rugby, the attempt of player to clutch the TFCC lesions using high-resolution ultrasound
ball on the chest with the forearm in maximal have been proposed, no agreement has yet been
supination, with the wrist in flexion and ulnar made as to the lesions in TFCC [84]. The sensi-
deviation, and his/her attempt to increase the iso- tivity, specificity, and accuracy of MRI and USG
metric contraction of the ECU may tear the sub-

a b

Fig. 22.5 (a) Ultrasound image of a normal triangular bones with the TFC between the ulna and lunate bones.
fibrocartilage (TFC) of the ulnar wrist showing the exten- (b) Ultrasound image of the dorsal scapholunate ligament
sor carpi ulnaris (ECU) tendon on top with bony acoustic (SLL) with the bony acoustic landmark of the scaphoid
landmarks of the ulnar (U), lunate (L,) and triquetral (T) (S) and lunate (L) bones
478 J. C. de Castro

for TFCC tear were 75%, 100%, 87.5% and 0%, between the torn-off UCL and the proximal pha-
50% and 50%, respectively [85]. lanx insertion [71]. The adductor pollicis
Scapulolunate (SL) ligament (Fig. 22.5) tears ­aponeurosis normally lies superficial to the UCL
can occur following a position of impact in con- [94]. Ultrasound imaging of the UCL is done
tact sports such as football and rugby. The mech- orthogonally in the coronal plane relative to the
anism of injury is wrist hyperextension, ulnar metacarpal bone. Correct transducer placement
deviation, and supination [71]. Tenderness is consists of finding the shallow groove or concav-
induced between the third and fourth dorsal ity at the ulnar aspect of the distal first metacarpal
extensor wrist compartments. A radiographic PA between the apex of the lateral tubercle and artic-
clenched fist view may show greater than 5 mm ular surface, and a similar but smaller groove in
widening between the scaphoid and lunate (Terry the ulnar aspect of the proximal phalanx near the
Thomas sign), which is diagnostic of a complete phalangeal collateral tubercle where the UCL is
tear of the SL ligament [86]. Ultrasound scanning attached [95–97]. A displaced UCL is character-
begins at the Lister’s tubercle of the dorsal wrist ized by the absence of UCL fibers spanning the
in the transverse plane and then slowly advances first MCP joint and well-defined heterogeneous
distally with the proximal pole of the scaphoid mass-like abnormality proximal to the apex to the
bone in view distal to the radiocarpal joint space. metacarpal lateral tubercle [95]. A displaced full-­
Adjust the probe to visualize both the scaphoid thickness tear of the UCL is characterized by
and the lunate and avoid anisotropy. The SL liga- retraction of the proximal UCL to the proximal
ment fibers which connect the scaphoid and edge of the adductor aponeurosis which is
lunate are characterized by a triangular echogenic referred to as the Stener lesion [98]. To ensure
structure with a compact and fibrillar hyper- correct imaging, passive flexion of the first IP
echoic echotexture [87]. The dorsal portion of joint causes isolated movement of the adductor
this ligament is visualized up to 78% of normal aponeurosis but not the UCL (Martinolli tech-
wrists [88]. Tears in the SL ligament are inter- nique) [95]. For complete tears, reconstruction
preted as a loss of the normal echogenic appear- surgery is needed. For partial tears, hand-based
ance, disruption or absence of the normal thumb spica is recommended [71].
ligament, or presence of concurrent fluid or an Sagittal band ruptures (Boxer’s knuckles) rep-
associated ganglion [89]. Dynamic ultrasound resent zone 5 extensor tendon injuries [99]. As
examination for SL ligament instability assess- the primary lateral stabilizer of the tendon over
ment has a high specificity and accuracy but a the MCP joint, the sagittal band attaches to the
low sensitivity. Thus, other diagnostic modalities extensor hood and runs to the volar part of the
may be used in conjunction with ultrasound to finger to insert at the volar plate [100]. The injury
establish a diagnosis [90]. occurs when there is a direct force toward a flexed
The injury to the ulnar collateral ligament digit with the wrist in flexion and ulnar deviation
(UCL) of the thumb is quite common and is often [101]. A typical radial-sided sagittal band rupture
seen in skiing, basketball, and football [91]. occurs resulting in pain and swelling with ulnar
Injury to the UCL happened in an abducted subluxation of the extensor tendon with MCP
thumb as in a fall of an outstretched hand at the flexion [99]. The index and middle fingers are
thumb metacarpophalangeal joint (MCPJ) [71]. commonly affected among professionals with the
An acute injury is what is referred to as a skier’s ring and little fingers among amateurs. Overall,
thumb [92] in contrast to a chronic attritional the middle finger is affected in 48% of sagittal
insufficiency injury of the same structure which band injuries [102]. Rayan and Murray proposed
is referred to as a gamekeeper’s thumb [93]. The a classification for closed sagittal band injuries
thumb UCL has two portions: the proper which is depending on the degree of structural abnormal-
more dorsally located and the accessory which is ity [103]. Dynamic ultrasound is extremely use-
volarly located. A Stener lesion occurs when the ful in assessing the extent of the injury with
adductor pollicis aponeurosis is interposed subluxation of the extensor tendons seen during
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 479

MCP joint flexion [104, 105]. A transverse scan but with a tendency to anisotropy [108]. High-­
of the dorsal finger is done with finger extension frequency ultrasound provides the diagnostic
and 30° MCP flexion. The sagittal band appears ability for A2 and A4 ruptures. The threshold
as a hypoechoic band on both sides of the com- value was determined to evaluate the optimal
mon extensor tendon. The transverse and oblique tendon-bone distance for pulley rupture diagno-
bands are not visible by ultrasound. A sagittal sis in an ultrasound cadaveric study. For A2 pul-
band rupture is shown as a discontinuity in the ley rupture, the threshold distance is 1.9 mm and
alignment of the sagittal band. Dynamic scanning 1.85 mm for A4 pulley rupture [109]. Bodner and
will help in evaluating the stability of the exten- colleagues in a comparative study between high-­
sor tendon with ulnar deviation in the index, mid- frequency ultrasound and MRI found that a com-
dle, and ring fingers but not with the little finger plete ruptured pulley showed a distance of 3 mm
even if the fingers are stressed in flexion [106]. between tendon and bone in an extended finger,
Splinting in full finger extension with PIP joint-­ and a distance of 5 mm during finger flexion con-
free is done if there is no subluxation or firmed the diagnosis [110]. The sensitivity of
dislocation. Operative treatment is done for a
­ ultrasound for depiction of pulley injuries is
ruptured sagittal band with dislocation or sublux- about 98% with 100% specificity [111].
ation [71]. Finger injuries represent 38% of all upper
Among basketball and volleyball players, extremity injuries [112]. Jersey finger or sweater
boutonniere deformity may occur because of finger is an avulsion of the flexor digitorum pro-
volar dislocation or forced flexion of the PIP joint fundus tendon at the volar aspect of the distal
with rupture of the triangular ligament at the dis- phalanx due to forced hyperextension of the DIP
tal end of the central slip. Boutonniere deformity joint while the finger is actively flexed. The FDP
is described as PIP joint flexion and hyperexten- of the ring finger is more commonly involved. It
sion of the DIP joint with the lateral bands is commonly seen during football and rugby
migrating volarly [71]. The patient is tested by sports [113]. Physical examination showed loss
flexing the PIP to 90° and asking the patient to of active DIP joint flexion of the involved digit
actively extend the DIP in this position. A patient with the inability to make a full fist [113]. A
with disrupted central slip will demonstrate rigid related condition where there is loss of terminal
DIP hyperextension or a positive Elson test. extension function of the DIP joint of the fingers
Isolated central slip will not result in Boutonniere is referred to as mallet finger. A jamming force at
deformity and may appear innocuous if not care- the fingertip while the DIP joint is in active exten-
fully assessed [99]. High-frequency ultrasound sion results in avulsion of the extensor tendon.
can be used to assess central slip injuries. Mallet fingers can occur in softball, baseball,
Rock climbing is becoming common nowa- football, basketball, or soccer. The patient usu-
days and it does not go without injury. The pres- ally presents with an inability to fully extend the
sure imposed upon the finger pulley system DIP joint [113]. A high-frequency ultrasound is
during frequent climbing causes ruptures at the placed at the volar area of the distal phalanx of
A2 and A4 pulley systems usually at the middle the involved finger in long-axis view. In Jersey
and ring fingers [71]. Such lesions result from finger, ultrasound shows an irregular hyperechoic
overuse injuries with anterior displacement of the fragment located at the proximal metaphysis of
flexor tendons (bowstringing) and reduced digital the middle phalanx just distal to A3 pulley of the
performance. High-frequency ultrasound shows flexor tendons. The common synovial tendon
a gap detected between the bone and flexor ten- sheath contained a small hypoechoic effusion
dons in the injured area and can be elicited by [114]. In partial tears, ultrasound demonstrates
active forced flexion. There is also an associated hypoechoic, fusiform swelling of the tendon and
effusion inside the sheath of the flexor tendon focal discontinuity of the internal fibrillar pattern.
[107]. Annular pulleys are usually hyperechoic For complete tears, the ruptured tendon cannot be
relative to the tendons with fibrillar appearance seen at the injury site, and the distal, retracted
480 J. C. de Castro

tendon presents as a hypoechoic and irregular 56%, and NPV 90%, and thus ultrasound is not
lesion with posterior acoustic shadowing [115]. recommended for early diagnosis based on their
The accuracy of ultrasound is noted when it is studies [123]. Recently, Kwee and Kwee (2018)
done after 1 day but within 7 days of injury as the in their systematic search found that radiographi-
immediate hematoma of the area might obliterate cally occult scaphoid fracture using ultrasound
the structures being imaged. If done after 1 day, has a sensitivity of 77.8–100% and a specificity
the accuracy of ultrasound is 100%, 88% if done of 71.4–100%, adding the presence of cortical
on the same day of the injury, and 85.7% when disruption as the sole diagnostic criterion, which
done after 7 days. Overall, the sensitivity of diag- might be the reason for the high sensitivity and
nostic ultrasound is 96% and specificity is 95% specificity. Most of the fractures in the scaphoid
[116]. In the surgical management of Jersey fin- bone are seen in the scaphoid waist and thus are
ger, the use of ultrasound helps in identifying the very accessible to ultrasound imaging [122]. In
proximal end of the ruptured tendon in 72% of cases where an ultrasound confirmed the pres-
cases and to decide as to whether to do a direct ence of scaphoid fractures, additional CT or MRI
repair or not [116]. Return to play is expected is requested to identify the location and extent of
between 8 and 12 weeks post-treatment [113]. the fracture [122]. In another study, Malahias and
Mallet finger appears on the ultrasound as an colleagues in 2019 showed that ultrasound has a
irregular, hypoechoic soft tissue lesion at the dis- sensitivity of 90% and a specificity of 85.7% in
tal shaft of the middle phalanx, after it has diagnosing occult scaphoid fractures and has
retracted. When an avulsion fracture accompa- noted that ultrasound can be used only under
nies the mallet finger, a retracted bone accompa- strict circumstances for early diagnosis of occult
nies the retracted tendon [115]. Splinting for both scaphoid fracture. Moreover, the presence of sub-
conditions may serve as conservative interven- periosteal hematoma and cortical discontinuity
tions for these athletes for 6 weeks [71]. confirmed its presence. Further, if the ultrasound
Scaphoid fractures are the most injured carpal is negative and symptoms persist, MRI or CT
bones seen among college football players [117] scan is required for definitive diagnosis [124]. In
representing about 10.6–29 per 100,000 per year contrast, CT and MRI have a sensitivity of 72%
or 2% of all fractures [118, 119]. It also repre- and 88%, respectively [125].
sents 60% of carpal fractures and 11% of hand Scaphoid fracture is a very critical condition
fractures [120]. This is a hyperextension injury that needs timely and appropriate treatment
that occurred in a pronated and radially deviated where the aim of the treatment is the union of
hand. Pain is felt at the radial side of the wrist scaphoid fracture [119]. In Sweden, the risk of
(snuffbox), especially during pincer grasp and diagnosed nonunion after a diagnosed scaphoid
axial loading of the thumb [71]. An early correct fracture was 2.4% [126] with serious conse-
diagnosis is important to avoid “overtreatment” quences after prolonged immobilization referred
with unnecessary immobilization or “undertreat- to as scaphoid nonunion advanced collapse
ment” which carries the risk of nonunion, delayed (SNAC) wrist [127]. As previously mentioned,
union or osteonecrosis, carpal instability, and there is a need to avoid “overtreatment” or
osteoarthritis [121, 122]. Ultrasound assessment “undertreatment” as both cases carry sequelae of
is considered positive when one of the four of the risk. In a recent study by Commandeur and col-
following criteria is seen: a fracture line, a sub- leagues, a graduated and guarded immobiliza-
periosteal or subcapsular hematoma, a ridge or a tion using below elbow cast where the thumb is
contour crossing the cortex of the scaphoid, and not immobilized and the wrist is in a slightly
displacement of the deep branch of the radial extended position is suggested. A 6-week period
artery from the radial cortex of the scaphoid of immobilization is done with intermittent clini-
[123]. In a previous study, Munk and colleagues cal and radiological evaluation. If no consolida-
(2000) showed that the accuracy of ultrasound tion occurs, immobilization is extended with 2
was 84%, sensitivity 50%, specificity 91%, PPV weekly evaluations, with no agreed extent of
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 481

immobilization period. There is no evidence that complicate the presentation of the problem and
other conservative treatments like electromag- as such a comprehensive neurologic test must
netic field therapy or pulsed low-intensity ultra- always be performed to identify the specific
sound therapy work [128]. In Europe, cast nerve involved. Electromyographic tests can aid
immobilization is reported to have 90–95% heal- in the diagnosis of neuropathies. However, it
ing [119], and CT before and CT after the immo- takes 2–3 weeks before the nerve injury before
bilization are recommended to ensure optimal fibrillation potentials and positive sharp waves
results [129]. CT investigation is needed to can be observed. With Wallerian degeneration,
determine whether fractures are displaced or significant motor amplitudes change may only be
non-displaced. Conservative treatment usually detected after a week. For the sensory ampli-
has been reported to result in a nonunion rate of tudes, the change may be significant after 10 days
10–14% for non-­displaced fractures and 50% for of injury [135]. Following trauma, high-­
displaced fractures. Persistent pain, however, frequency ultrasound can determine the type of
may indicate incomplete or delayed union or injury, localize the proximal and distal nerve
may be a­ ssociated with other injuries [120, 130]. stumps, and differentiate between acute and
Proximal scaphoid fractures with their tenuous chronic peripheral nerve injuries. Compared to
blood supply should be treated operatively to MRI, high-frequency ultrasound provides quick,
maximize union rates [131], while distal pole reliable, dynamic, and cost-effective diagnostic
scaphoid fractures should be treated nonopera- imaging devices [136]. Kullmer and colleagues
tively with predictably high union rates [132] in tracking down the changes after muscle dener-
due to its well-vascularized region. A minimally vation found out that there is a decrease in muscle
displaced or non-displaced waist scaphoid frac- diameter and an increase in overall echogenicity
ture will heal successfully (90%) after conserva- on ultrasound by day 14 after denervation, while
tive management at 6 weeks, while unstable and MRI showed a decrease in muscle diameter with
severely displaced fracture must be treated oper- associated increased signal intensity indicating
atively [120]. Return to work is assessed by CT its first sign of denervation by day 21. Then,
scan when the scaphoid fracture is united with 28 days post-denervation, the ultrasound findings
more than 50% trabecular bridging across the of muscle atrophy because of denervation are
fracture site, and wrist range and grip strength detectable on day 28 and are characterized by an
should be within 20–40% of the contralateral increase in echogenicity, while the same atrophic
side [120, 133]. An ultrasound-guided PRP treat- changes in the muscle as a result of denervation
ment was reported on a nonunion scaphoid frac- are detectable on MRI on day 35. EMG showed
ture with complete healing after doing an MRI spontaneous activity more than 11 days after
and CT scan [134]. denervation [137]. This study recommends the
use of ultrasound and EMG for complete func-
 eripheral Nerve Injury Secondary
P tional and anatomical assessment of the sequelae
to Sports in the Upper Extremity of early denervation [137]. In another study
Sports injury affecting the peripheral nerves is focusing on detecting focal peripheral nerve
usually secondary to compression, traction, isch- pathology, ultrasound is more sensitive than MRI
emia, and laceration [135]. Unlike the musculo- (93% vs 67%), has equivalent specificity (86%),
skeletal system, peripheral nerve injuries may and better identifies multifocal lesions than MRI
develop in an insidious manner with subtle clini- [138]. High-resolution ultrasound shows good
cal signs and symptoms. Pain is not always pres- diagnostic utility and management of peripheral
ent and gross muscle atrophy may be seen over nerve lesions [139]. Ultrasound has been found
time as nerve injury progresses. Muscle strength to aid in the decision-making regarding conserva-
testing may not be reliable during the acute stage tive or surgical treatment and is an ideal diagnos-
as athletes may compensate for the movement by tic complement to clinical electrophysiological
using muscle substitution. Referred pain may testing for peripheral neuropathies [140].
482 J. C. de Castro

Jacobson and colleagues noted the earliest sign spontaneous recovery. A damaged axon with
of nerve entrapment as decreased echogenicity of associated Wallerian degeneration is an injury
the connective tissue layers of a nerve trunk, with referred to as axonotmesis. It commonly
the nerve appearing globally hypoechoic. Later, involves C5 and C6 levels. With an intact epi-
it will show a hypoechoic enlargement. neurium, it could slowly recover but longer than
Sonopalpation can also be done to elicit pain over neuropraxia for several months. There is pain,
the site of nerve distribution. Denervation burning, or tingling sensation, such that it is
changes as described above will be noted in the referred to as “burner” or “stinger.” Muscle
muscle being innervated characterized by abnor- weakness is seen over the deltoid, supraspina-
mally increased echogenicity. Muscle atrophy tus, and coracobrachialis muscles [146].
will be shown over time as significant evidence Electrodiagnostic studies, MRI scans, and high-­
of peripheral nerve injury [141]. Overall, high- frequency ultrasound are useful to localize the
frequency ultrasound is a useful complementary lesion, define an appropriate treatment, and
tool for assessing peripheral nerve lesions in the monitor functional prognosis [148]. Chin and
context of finding the exact location, course, con- colleagues in a systematic review on the value
tinuity, and extent of traumatic nerve lesions and of ultrasound for traumatic BPI noted that high-­
for assessing nerve entrapment and tumors if frequency ultrasound is an effective diagnostic
there is any [142]. High-frequency ultrasound tool for traumatic adult BPI. The sensitivity of
can also identify different degrees of peripheral lesion detection is higher in the upper and mid-
nerve injury from mild hypoechoic swelling, dle levels (C5 is 93%; C6 is 94%; C7 is 95%)
continuity of epineurium, the absence and/or than in the lower spinal nerves (C8 is 71%; T1 is
swelling of the fascicles, and whether there is 56%) with an overall ultrasound sensitivity of
continuity in the epineurium in the case of neu- 87%, while MRI has an overall sensitivity of
rotmesis. It cannot, however, show the myelin 81% [37]. High-frequency ultrasound (Fig. 22.6)
sheath and axons; thus, current damages to this can very well visualize the cords of the brachial
structure are indistinguishable [143]. While EMG plexus and the level of the root avulsion, and, if
provides the physiological status of the nerve, the there is any rupture of the cord, it can detect any
concurrent use of US can complement it by pro- disruption of the nerves [149].
viding morphological information [143].
Spinal Accessory Nerve
Brachial Plexus Injury or “Stingers” Spinal accessory nerve (SAN) injury occurs sec-
Brachial plexus injury (BPI) is common among ondary to blunt trauma of the posterior triangle of
athletes who play football or other collision the neck or a traction injury when a blow
sports. It is sometimes referred to as “stingers.” depresses the shoulder while the head moves in
Stinger is referred to as a transient episode of the opposite direction [150]. This is commonly
shooting or electric pain with acute onset after seen in football, lacrosse, and hockey. The trape-
an impact to the head and/or shoulder [144]. zius muscle is paralyzed but the sternocleidomas-
The most affected nerve is the brachial plexus toid is spared since the injury happened distal to
followed by radial and ulnar nerve, and then by its innervation [150]. The location of the SAN in
the axillary nerve in that order of frequency this area is very superficial and covered only by
[145]. This type of injury affects about 49–65% the skin and subcutaneous fascia. There is an
of college football players and with a recurrence obvious drooping of the shoulder, loss of shoul-
rate of about 87% [146, 147]. The mildest and der elevation, and pain [151]. High-frequency
most common form of brachial plexus injury is ultrasound showed the nerves at the posterolat-
referred to as neuropraxia. It is characterized by eral border of the SCM (Fig. 22.6) and the ante-
a loss of sensation and motor function due to rior border of the trapezius [152]. However,
focal demyelination which could last for actual transection of the nerve may not be seen by
6 weeks without any treatment followed by ultrasound. That is why it is important to evaluate
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 483

a b

Fig. 22.6 (a) The brachial plexus nerves are found in scanned proximally in the neck. Also shown here is the
between the anterior scalene (AS) and middle (MS) mus- fourth cervical nerve (C4) root in between the anterior (A)
cles as shown here in this ultrasound image. (b) The spinal and posterior (P) tubercle and the internal carotid artery
accessory nerve (SAN) is found in the fascial sheath in the (ICA)
middle of the sternocleidomastoid muscle (SCM) when

the status of the trapezius to check for fatty infil- musculature, and not all patients with anatomical
tration or echogenicity which confirms denerva- entrapment will present with symptoms. Also, in
tion of the muscle [153]. this same study, only 86.5% pierced the middle
scalene muscles [156]. Since there is no cutane-
Long Thoracic Nerve ous distribution coming from the long thoracic
Sports-related injuries affecting the long thoracic nerve to explain the sensation of pain, the pain
nerve (LTN) are usually associated with extreme could arise from the increased sensitization of the
hyperabduction movements such as what is seen nerve fibers resulting from nerve trunk injuries
in archery, wrestling, soccer, boxing, tennis, referring to pain into the neck or from the tho-
bowling, hockey, gymnastics, and weightlifting. racic posterior rami with its cutaneous branches
When serratus anterior muscle undergoes wing- because of stretching from scapular winging
ing, it is minimal in resting position and is only referred to as interscapular pain [156]. High-­
accentuated during forward flexion and while frequency ultrasound will show at least four areas
pushing with arms extended forward [154]. to scan the long thoracic nerve: at the cervical
Serratus anterior basically serves as the primary region, at the supraclavicular level, at the infra-
stabilizer of the scapula. Inman noted that serra- clavicular level, and at the midaxillary line beside
tus anterior is important in sustaining primary the lateral thoracic artery [158].
scapulohumeral function [155]. Patients with
long thoracic nerve impingements usually pres- Suprascapular Nerve
ent with pain, paresthesia, and weakness of the Suprascapular nerve (Fig. 22.7) injury could be
serratus anterior [156]. Only with severe cases injured in sports with compression at the level of
will it present with medial winging and medial the suprascapular notch associated with back-
translation or rotation of the scapula, or projec- packers, volleyball players, weightlifters, and
tion of the medial scapular border may concur- baseball pitchers [135]. It is considered the most
rently take place [157]. It is not unusual however injured brachial plexus peripheral nerve branch
to see long thoracic nerve entrapment not associ- among athletes [159]. The nerve arises from the
ated with trauma and this is usually due to ana- upper trunk or sometimes directly from C5 nerve
tomical variations, especially within the scalene root. It provides motor branches to the supraspi-
484 J. C. de Castro

a b

Fig. 22.7 (a) Ultrasound image of the suprascapular at the superior portion of the shoulder underneath the
nerve (SN) at the level of the spinoglenoid notch at the supraspinatus tendon. IST Infraspinatus tendon, H
posterior shoulder. (b) Ultrasound image of the supra- humerus, GL glenoid labrum, S scapula
scapular nerve (SN) at the level of the supraspinous fossa

natus and infraspinatus muscles. The sensory the lesion at the spinoglenoid notch affecting the
branch innervates the acromioclavicular joint, suprascapular nerve is usually incomplete show-
glenohumeral joint, and subacromial bursa. The ing some function of the muscle and thus most
most frequent site of injury is at the suprascapu- athletes are asymptomatic with teres minor com-
lar notch where the nerve travels under the supe- pensating for the infraspinatus dysfunction [162].
rior transverse scapular ligament. It does not High-frequency ultrasound can demonstrate the
injure the nerve at the spinoglenoid notch except suprascapular nerve at the suprascapular notch
in sports involving overhead activities [160]. appearing as a thin, hypoechoic structure lying
Contemori and Biscarini reported the higher over the echogenic bony floor of the groove,
shoulder position during overhead activities especially for lean individuals. However, in cases
where the hitting shoulder incurred isolated where it is not visualized due to the thick muscu-
infraspinatus atrophy due to injury of the supra- lature, a color Doppler may provide a clue to the
scapular nerve at the spinoglenoid notch [161]. In location of the nerve as it visualizes its neighbor-
fact, it was reported that up to 20–45% of vol- ing vascular bundle. In 96%, the superior trans-
leyball players had evidence of isolated infraspi- verse suprascapular ligament could be visualized
natus muscle impairment [162, 163]. There is and in 86% the vascular bundle which is the
also a subsequent reduction of position sense in suprascapular artery can be shown demonstrating
the affected shoulder suggesting an impairment the location of the suprascapular nerve [164].
of the shoulder sensorimotor control system
resulting from reduced afferent proprioceptive Axillary Nerve
information. Overall, this results in reduced The axillary nerve is commonly injured in wres-
shoulder functional stability and increased risk of tling, weightlifting, rugby, hockey, and football
injury. This study highlights the fact that the pro- players. It is the most injured peripheral nerve in
prioceptive system serves a very important role in 9–18% of anterior shoulder dislocations. The
the preservation of functional joint stability. mechanism of injury is usually a direct blow to
Athletes with this type of isolated nerve injury the lateral deltoid usually seen during hockey
can benefit from a specific proprioceptive and collisions or in football or rugby [135, 165]. Its
neuromuscular preventive training program nerve fibers originate from the upper trunk and
[161]. In other studies, it was also reported that C5 and C6 cervical roots. Before innervating the
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 485

deltoid and teres minor muscles, it courses poste- (Fig. 22.8) syndrome is a chronic compression
riorly through the quadrangular space [135]. syndrome of the axillary nerve in athletes whose
Neurological complications following shoulder sports require repetitive throwing motions.
dislocation occur more often in patients aged Fibrous bands developed at the inferior border of
more than 40 or 50 years, with an associated the teres minor eventually compress the posterior
increased risk if it remains dislocated more than humeral circumflex artery and axillary nerve with
12 hours. The axillary nerve is susceptible to subsequent complete denervation of the deltoid
stretch injury after a shoulder dislocation due to and teres minor. Compression of the structures is
its numerous attachments with the deltoid muscle more severe in shoulder abduction and externally
and thus more often associated with infraclavicu- rotated positions [166]. High-frequency ultra-
lar brachial plexus injury [165]. Moreover, most sound can image the quadrilateral space
of the axillary nerve injuries are part of the com- (Fig. 22.8). The probe is positioned in the long
bined brachial plexus injury and only 0.3–6% are axis of the humerus 2 cm below the posterolateral
isolated axillary nerve injuries [162]. Athletes border of the acromion at the dorsal aspect of the
with axillary nerve injury may be asymptomatic, arm. With the aid of the color Doppler, the poste-
regardless of whether it is complete or incom- rior humeral circumflex artery could be detected,
plete lesions. Only when they exercise will they and the axillary nerve is right next to it. Also,
show easy fatigabilities such as when they do an note any sign of denervation and atrophy of the
overhead activity or heavy lifting. These present deltoid [167]. Ultrasound is also preferred as a
with reduced abduction strength or inability to first-line diagnostic modality for axillary nerve
raise the arms. There is a sensory deficit at the trauma [168].
lateral arm. Sometimes, it is possible to have
intact sensation with complete deltoid muscle Musculocutaneous Nerve
weakness. In the later stage, there is atrophy of The musculocutaneous nerves may be injured by
the deltoid and teres minor, unless the lesion is a stretch with anterior shoulder dislocations or
beyond the quadrilateral space, in which case, compressed with hypertrophied coracobrachialis
these two muscles are spared [162]. A unique in weightlifters [135]. The musculocutaneous
syndrome referred to as quadrilateral space nerve arises from the lateral cord together with

a b

Fig. 22.8 (a) Ultrasound image of the axillary nerve minor (TMI), lateral head of the triceps muscle and the
(AN) at the axillary shown beside the posterior circumflex deltoid (D) muscle, and the humeral bone as a bony acous-
humeral artery (PCHA). This is otherwise known as an tic landmark or otherwise referred to as quadrilateral
anterior view of the axillary nerve. (b) The posterior view space. CB coracobrachialis, TMAJ teres major, Subscap
of the axillary nerve (AN) together with the posterior cir- subscapularis
cumflex humeral artery (PCHA) seen in between teres
486 J. C. de Castro

a b

Fig. 22.9 (a) Ultrasound image of the musculocutaneous musculocutaneous nerve (Musc N) at the level of the pec-
nerve (Musc N) at the level of the axillary fossa using the toralis major (PECT MAJ) tendon attachment to the mid-
axillary artery (AA) as the reference in short-axis view. humeral (H) bone. Also seen are the tendons of the short
The musculocutaneous nerve perforates through the cora- head (SHBT) and long head of the biceps tendon (LHBT).
cobrachialis muscle (CB). (b) Ultrasound image of the TMAJ teres major

the median nerve and lateral pectoral nerve. They with a mixed motor and sensory deficit, with
come from C5, C6, and C7 spinal nerve roots. It associated weakness of the elbow flexors and
pierces the coracobrachialis at the level of the sensory deficit at the lateral forearm, while the
axilla and then descends in between the biceps distal lesion is a purely sensory deficit with
brachii and brachialis muscles. In a unique way, accentuation of symptoms during elbow exten-
the coracobrachialis muscle is supplied by this sion and forearm pronation [169, 173]. Ultrasound
nerve before it enters the muscle, while the biceps is a useful tool for diagnosing traumatic injury of
and brachialis are supplied after it enters the mus- the musculocutaneous nerve complementing
cle. In the elbow, the nerve perforates the fascia MRI and EMG tests. Two positions are suggested
lateral to the biceps tendon and continues to the in imaging this nerve: one is tracing the nerve
forearm as the lateral antebrachial cutaneous while the arms is at the side of the trunk. The
nerve [169]. Among weightlifters, the most com- musculocutaneous nerve is at the anatomical
mon injury is the injury to musculocutaneous position but located deep in the muscle. The other
nerve at the level of the coracobrachialis position is when the hand is placed behind the
(Fig. 22.9) as well as in between the biceps bra- head and in this way the musculocutaneous nerve
chii and brachialis leading to ischemic injury of becomes more superficial [174]. High-resolution
the nerve with focal demyelination and variable ultrasound shows a fusiform stretching neuroma
axonal degeneration [170]. Traction mechanism located between the long head and the short head
can also injure this nerve when the elbow is in of the biceps brachii or between the biceps and
full extension as in the case of skydiving where coracobrachialis muscles. Color Doppler did not
the arms are in abduction, extension, and exter- show any increased flow on the site of the neu-
nally rotated position [171]. The second mecha- roma [174].
nism of musculocutaneous nerve injury involves
the distal branch at the level of the superficial Median Nerve
antebrachial fascia and the biceps tendon. In The median nerve injury can occur in different
about 10% of such injury is iatrogenic in nature segments of the upper extremity. The median
and is induced by the the displacement of the nerve arises from the lateral cord (C5-C7 roots)
humeral shaft fracture when using Russell-Taylor and from medial contributions (C8-T1 roots)
splints. It usually affects the lateral antebrachial [135]. Repetitive movements of the elbow and
cutaneous branch of the musculocutaneous nerve forearm can cause impingement of the median
[172]. Clinically, a proximal lesion will present nerve at the level of the pronator teres muscle.
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 487

The median nerve is entrapped in between the rum profundus of the second and third digits, and
two heads of the pronator teres muscle or under pronator quadratus in the forearm. Or it can also
the proximal edge of the flexor digitorum super- be compressed at the FCR, FDS origin deep into
ficialis arch or at the lacertus fibrosus of the the pronator teres head, or by an accessory head
elbow. Resisted elbow flexion with the forearm of the FPL (Gantzer muscle). There is an inability
supinated can be used to test if the entrapment to make an “OK” sign (weakness of the FPL and
occurred in the lacertus fibrosus [175]. This is FDP of the second digit) with no sensory deficit
common among baseball players, archers, pitch- [176, 179]. Carpal tunnel syndrome is a common
ers, tennis players, and weightlifters. There is entrapment of the median nerve at the volar wrist
usually associated pain in the volar forearm and especially seen among wheelchair users repre-
numbness of the first three fingers including the senting about 8% among disabled athletes [180].
radial half of the fourth digit much like the carpal Recently, with the advent of gaming in electronic
tunnel syndrome but with peculiar numbness of sports or e-sports, there is a growing incidence of
the thenar eminence without nocturnal pains. symptoms related to carpal tunnel syndrome. A
Pain is elicited during pronation and supination competing athlete in e-sports would regularly
motion. Resisting the pronation motion could spend 12–15 hours a day practicing dynamic and
reproduce the symptoms [150, 176]. The second repetitive movements using a mouse and a key-
entrapment takes place at the forearm affecting board [181]. Among long-distance cyclists,
the motor branch of the median nerve, referred to numbness over the palmar hand was reported,
as anterior interosseous nerve syndrome (syn- and although in most cases, the deep branch of
drome of Nevin and Kiloh). Entrapment of this the ulnar nerve to the first dorsal interossei was
nerve occurs superior to the elbow at the ligament affected, the median nerve is also compressed
of Struther where it forms part of the median especially exacerbating symptoms of carpal tun-
nerve. It may also be entrapped at the site where nel syndrome [182]. High-frequency ultrasound
the median pierces the two heads of the pronator is an effective tool for diagnosing median nerve
teres. The anterior interosseous nerve (motor) entrapment syndromes in the upper extremity.
passes deep to the tendinous bridge connecting Although EMG/NCS is a common test to confirm
the humeroulnar and radial heads of the flexor carpal tunnel syndrome, the sensitivity of NCS
digitorum superficialis muscles (sublimis bridge) has only a range of 49–84% and the specificity is
[177]. The anterior interosseous nerve (AIN) more than 95% [183]. In fact, 25% of clinical
innervates the pronator quadratus, FPL, and FDP CTS revealed a normal NCS study [184, 185]. An
of the second and third digit [178]. The AIN is ultrasound diagnostic test (Fig. 22.10) has a sen-
deep to the flexor pollicis longus, flexor digito- sitivity of 77.6% and a specificity of 86.8% for

a b

Fig. 22.10 (a, b) Ultrasound images of the short and lon- of numbness for more than 6 months duration. It showed
gitudinal views of the median nerve (MN) at the level of a swollen median nerve with associated minimal loss of
the wrist of a 62-year-old male patient who is complaining fascicular pattern. FR, flexor retinaculum
488 J. C. de Castro

CTS and can be useful in clinical CTS which c­ ausing neuritis. The subtle laxity and stretching
might reveal a normal CTS [186]. Although ultra- of the medial elbow structures due to VEO syn-
sound can provide morphologic abnormality in drome may also injure the ulnar nerve [192]. In a
CTS, it cannot provide information about axonal cadaveric study by Mihata and colleagues, the
loss or coexisting neuromuscular conditions greatest strain in the UCL and ulnar elongation at
which the electrodiagnostic test can do [187]. the medial elbow occurs during 60° and 90° of
The work of Cartwright and colleagues will sig- elbow flexion, thus causing cubital tunnel syn-
nificantly alter the way peripheral nerve injuries drome [194]. It is important though to determine
can be diagnosed when using an ultra-high fre- whether the injuries primarily affect the UCL
quency ultrasound such as in a median nerve by without the presence of ulnar neuritis or whether
counting the number of fascicles in the nerve the ulnar neuritis is secondary to a deficient or lax
[188]. In the pronator teres median nerve entrap- UCL [192]. The first stage of ulnar neuritis
ment, a high-frequency ultrasound study showed includes medial elbow pain and muscle weakness
that a CSA of 4.9–12.9 mm2 is considered normal without numbness [195]. The clinical diagnostic
and is suggested when the normal side-to-side criteria for ulnar neuritis include the following:
comparison is not available. However, an upper medial elbow pain or numbness at the ulnar side,
limit of side-to-side difference of >3.0 mm2 is tenderness or Tinel sign at the site of the ulnar
considered abnormal [189]. Ultrasound of the nerve around the elbow, and weakness of the
AIN is inconclusive due to its deep location in the intrinsic muscle strength of the abductor digiti
forearm and its size unless there is a mass [177]. minimi, adductor pollicis, or positive elbow flex-
Transverse high-resolution ultrasound can visu- ion test. All three criteria must be satisfied to
alize the anterior interosseous nerve by assessing come up with the diagnosis [195]. Other entrap-
the echogenicity of the innervated muscles such ment sites of the ulnar nerve are found at the
as the FPL, FDP of the second and third digit, and Arcade of Struthers in the arm. This thin aponeu-
pronator quadratus [190]. In a systematic review, rotic band extends from the medial head of the
Malahias and colleagues reported that PRP treat- triceps to the intermuscular septum. This area is a
ment is recommended for mild to moderate CTS confluence of structures made up of the medial
but not in severe CTS patients [191]. head of the triceps, medial intermuscular septum,
and the internal brachial ligament. It is approxi-
Ulnar Nerve mately 6–8 cm proximal to the medial epicon-
Ulnar nerve injury at the elbow is the second dyle of the elbow and the ulnar nerve passes
most common injury in the upper extremity seen underneath the arcade in about 70–80% of indi-
in throwing athletes after “burner” or “stinger.” viduals. The second entrapment is what is
Valgus instability which causes traction on the described above, the cubital tunnel. Compression
ulnar nerve at the medial elbow makes it very of the ulnar nerve by the Osborne ligament may
susceptible to injury and pain [192]. The strain of diminish the gliding of the ulnar nerve during
overhead throwing on the medial elbow of the elbow flexion and extension [192, 196]. When
baseball pitcher occurs at the acceleration phase Osborne’s ligament has a pathologic fusion of the
where the large rotational moments of the elbow layers, it can reduce the cross-sectional area of
produce a large amount of force in all parts of the cubital tunnel by as much as 40% during
elbow articulations [192]. In fact, Andrews called elbow flexion [197]. The third entrapment site for
this combination of forces in the elbow causing a the ulnar nerve occurs as the nerve enters the two
spectrum of disorders as valgus extension over- heads of the flexor carpi ulnaris at the deep fascia
load syndrome (VEO) [193]. The repetitive of the anterior forearm. Lastly, ulnar nerve
nature of this activity may drive the tissue to entrapment can occur at the confluence of fascia
eventually absorb the stress. As a result, the ante- from the flexor digitorum superficialis to the ring
rior bundle of the UCL may eventually fail. finger [192]. Hand numbness on the ulnar side,
Subsequently, it will injure the ulnar nerve ulnar nerve subluxation, and UCL injury are
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 489

strong predictors of poor outcome after a period the common digital branch to the fourth web
of conservative treatment, and surgery provides space at the lateral and an ulnar (medial) proper
an excellent result [195]. Described as the digital nerve to the medial side of the finger
“cyclists’ palsy” or “handlebar palsy,” this ulnar [200]. A rare ulnar nerve injury may occur at the
neuropathy is quite common among bicyclists. It thumb among bowlers referred to as bowler’s
is characterized by a gradual onset of numbness thumb. Patients with this condition will usually
and tingling sensation at the little and ring fingers complain of a painful nodule found at the volar
and/or weakness of the ulnar-innervated muscles surface of the hand between the first and second
of the hand and fingers. Recently, cyclists’ palsy web space. It is described as a posttraumatic neu-
usually occurs as an isolated deep motor branch roma of the thumb due to a repetitive friction
lesion. At the Guyon’s canal in the palmar wrist, affecting the thumb ulnar digital nerve [201].
the ulnar nerve can be entrapped anywhere along At the level of Arcade of Struthers, which is
the course of the nerve in which case the signs about 8 cm proximal to the medial epicondyle, an
and symptoms vary as to whether it is a mixed ulnar nerve entrapment in this area shows a
sensory and motor (proximal), a pure sensory hypoechoic enlargement of the ulnar nerve with
(middle), or a pure motor (distal) ulnar neuropa- evidence of fascial thickening. Normally, the
thy. The floor of this canal is formed by the piso- ulnar nerve will appear normal distal to the FCU
hamate ligament and transverse carpal ligament, during an entrapment in this site [196]. High-­
the roof by volar carpal ligament, the radial wall frequency ultrasound is a reliable tool for evalua-
by the abductor digiti minimi and hook of the tion of the ulnar nerve at the elbow and its related
hamate, and the ulnar wall by the pisiform bone. structures around the elbow and to diagnose any
In the hand, the ulnar nerve divides into a super- pathological conditions [202]. The main ultra-
ficial sensory branch that supplies the palmar sur- sound finding at the medial elbow is an increase
face of the little finger and the ulnar half of the in the cross-sectional area (CSA) diameter at the
ring finger and the deep motor branch which sup- affected side (Fig. 22.11). This method is the
plies all the small muscles of the hand except the most accepted means of diagnosing entrapment
radial two lumbricals and the median innervated neuropathies of the ulnar nerve. Ultrasound
thenar muscles, except the deep head of the FPB showed a sensitivity of 93.1% and a specificity of
[198, 199]. The superficial sensory branch divides 50% using nerve conduction studies as reference
into two branches after it gives off a branch to the [203]. Thickening of the epineurium was
palmaris brevis. These two branches consist of observed with patients with dislocating nerves at

Fig. 22.11 Side-to-side comparison of the ultrasound (MHT) seen at the medial side of the elbow. Some patients
images of the ulnar nerve (UN) where the left elbow may experience instability of the ulnar nerve while being
showed an abnormal hypoechoic swelling at the level of pushed by the MHT during a dynamic flexion-extension
the cubital tunnel. Note the medial head of the triceps motion. E epicondyle, O olecranon
490 J. C. de Castro

the medial elbow which is a similar finding cause ulnar nerve entrapment. The first one is
among leprosy patients. Among baseball pitch- between the fibro-osseous tunnel formed by the
ers, for instance, there is a significant increase in tendon origin of the hypothenar muscles (roof)
the distance of the ulnar nerve from the elbow as and the pisohamate ligament (floor). The other
it approaches 120° flexion in the throwing arm as one is between the tendinous arch of the trans-
compared to the non-throwing arm, thus an verse and adductor heads of the adductor pollicis
increased tendency for nerve subluxation and muscle [206]. Other studies identified five areas
nerve irritation [204]. Interestingly, Scheidl and of ulnar nerve entrapment in the palmar wrist and
colleagues have found that ultrasound can distin- hand among the cyclists [199].
guish between axonal loss and demyelination. In
their study of the ulnar neuropathy at the elbow Radial Nerve
(UNE), diagnosed by electrodiagnostic studies, a The radial nerve arises from the posterior cord at
larger CSA of ulnar nerve at the medial epicon- C5-T1 spinal nerve roots. It usually runs poste-
dyle correlates with axonal loss, as opposed to rior to the axillary artery at the axilla and then
demyelinating lesions (mean CSA 10.1 mm2 in courses through the long and medial heads of the
demyelinating versus 15.2 mm2 in axonal loss) biceps brachii muscles to go posterior up to the
[205]. level of the humeral groove, (Fig. 22.12a) which
High-frequency ultrasound of the ulnar digital is a common entrapment site for the radial nerve.
nerve of the thumb in bowler’s thumb is placed at The radial nerve then perforates through the
the level of the MCP in long-axis view. It shows intermuscular septum laterally and then it enters
a gradual hypoechoic enlargement of the ulnar the anterior compartment of the arm distally.
digital nerve with enlarged hypoechoic fascicles Before it goes beyond the elbow, it innervates
with hyperechoic epineural thickening [201]. In the following muscles: extensor carpi radialis
the cyclists’ palsy, where the ulnar nerve is longus and brevis, triceps, and brachioradialis
injured at the area around Guyon’s canal, the muscles. From the elbow, it gives off two
nerve appears thickened in a high-resolution branches: superficial radial nerve (sensory) and
ultrasound in the proximal side of the lesion. For posterior interosseous nerve (motor), which is
the deep branch of the ulnar nerve, two sites can the branch that goes beneath the supinator mus-

a b

Fig. 22.12 (a) Ultrasound image of the radial nerve (RN) the supinator muscles at the level of the proximal elbow,
at the level of the humeral (H) groove where it is common which is on top of the radius (R). The superficial radial
to see radial nerve impingement, due to its proximity to sensory nerve (SRSN) splits from the main radial nerve
the humerus and is most superficial at this level. The deep branch at this level. LoHT long head triceps muscle, LHT
brachial artery (DBA) is right beside the radial nerve (RN) lateral head triceps muscle, MHT medial head triceps
in this image. (b) The deep radial nerve (DRN), beside the muscle, BR brachioradialis (BR) muscle
radial artery (RA) it perforates through the two layers of
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 491

cle at the Arcade of Frohse (Fig. 22.12b) and is 9.5% of humeral fractures. Also, an avulsion
thickened in 30% of individuals. This is the most fracture of the distal humerus at the origin of the
common site of entrapment of the radial nerve in brachioradialis muscle has sustained an associ-
the radial tunnel. The other area of entrapment of ated superficial radial nerve injury in a lacrosse
the posterior interosseous nerve is the fascial player in this case report [211]. Ultrasound over
bands connecting the brachioradialis and bra- the humeral groove shows hypoechoic swelling
chialis muscles, the leash of Henry, an arcade of of the radial nerve with loss of fascicular pattern.
anastomosing branches of the radial recurrent In the presence of fracture, the radial nerve may
artery, and the tendinous edge of extensor carpi be displaced at the edge of fracture fragments or
radialis brevis muscle. The superficial radial be pinched in between them [177]. Radial nerve
nerve runs over the posterolateral aspect of the entrapment can also occur at the radial side of
forearm, to the wrist and the hand to innervate the wrist just above the first dorsal compartment
the first, second, third, and radial half of the of the wrist. As the superficial radial nerve
fourth digits except the distal phalanx, which is a courses forward from the proximal forearm, it
median-innervated area. The posterior interosse- runs beneath the brachioradialis and perforates
ous nerve runs distally to innervate the muscles through the antebrachial fascia of the distal fore-
namely the extensor pollicis longus and brevis, arm. It moves superficially over the APL and
extensor carpi ulnaris, and finger extensors EPB tendons of the radial wrist [212]. High-
[207]. Radial tunnel syndrome is commonly frequency ultrasound can visualize the nerve in
observed in tennis and Frisbee players, weight- this area as in the case of Wartenberg Syndrome
lifters, and rowers. It is usually due to hyperex- (or cheiralgia paresthetica). Patients complain of
tension injuries of the elbow, or repetitive pain and paresthesia along the distal forearm,
pronation and supination of the forearm, or thumb, and index finger, much like a De
direct compression of the nerve [207–209]. This Quervain’s tenosynovitis [213].
is characterized by pain mimicking a tennis
elbow in contrast with a posterior interosseous
nerve (PIN) syndrome (supinator syndrome) Musculoskeletal Ultrasound/
which is characterized by weakness of the exten- Regenerative Therapies in Lower
sor muscles of the forearm without pain. The Extremity Sports Injuries
boundary of the radial tunnel includes the
humeroulnar joint and deep layer of the supina- Lower extremity sports injuries are becoming com-
tor muscle posteriorly; the fibrous attachments mon regardless of the status of an individual. In the
between brachialis and brachioradialis, and past, some sports activities are only played by the
ECRB laterally; the superficial layer of the supi- upper-class people, but recently with sports activity
nator muscle anteriorly; and the biceps brachii becoming an exercise activity or lifestyle, it has
medially [209]. Ultrasound of the radial nerve become accessible to all people. And so, it goes
inside the tunnel shows a hypoechoic swelling of with sports injuries. In a study by Brant and col-
the deep branch of the radial nerve with the leagues among US high school athletes, they
Arcade of Frohse being the most common site of described the epidemiology of lower extremity
entrapment [177, 209]. In fact, ultrasound con- sports injuries over a 10-year period from 2005 to
firms 83% of abnormal electrodiagnostic find- 2016. The study showed that the highest injury rate
ings of the posterior interosseous nerve with among both genders was seen in soccer, followed
additional information such as PIN enlargement by basketball, cross-country, track and field, volley-
nerve continuity or laceration in trauma [210]. In ball, softball/baseball with the lowest injury seen in
a sports injury involving the arm, the radial nerve tennis, swimming, and diving. In each individual
is the most injured peripheral nerve occurring in sport, girls have a higher rate of lower extremity
492 J. C. de Castro

injuries as seen in soccer. Regardless of sports activ- that these injuries made up 10.6% of all hip and
ity, the highest injury was an ankle sprain, with the groin injuries [218]. Among professional basket-
anterior talofibular ligament being the most strained ball players like the NBA, groin pulls and sports
ligament for both genders [214]. Moreover, the hernias are the most common hip and groin pains,
most common ligament injured among boys is the but this condition responds well with conserva-
patellar tendon, and for girls, it is the anterior cruci- tive treatments. However, a third of them con-
ate ligament [214]. In another study, it was reported tinue to experience hip pain after retirement and
that athletes with moderate to high sport specializa- 16.7% of them may soon require total hip arthro-
tion or those athletes specializing in a single sport plasty [219]. This rate is higher than that found in
have a higher risk of lower extremity injuries [215]. the population older than 50 years, which is 15%
[220]. Among soccer players, they have reported
Hip that a decreased hip range of motion (HROM) is
Groin pain is such a broad term that initially has associated with more hip and groin-related symp-
caused many physicians to describe this condi- toms independent of a cam hip deformity [221].
tion to refer to non-specific sports injury affect- Serner and colleagues characterized athletes with
ing the hip. It was not until 2015 that an impressive groin injuries in the hip flexor muscles using an
group of leaders in this field met in Doha during MRI study among 156 athletes with groin inju-
the First World Conference on Groin Pain in ries. The study showed that athletes with hip
Athletes and subsequently published their con- flexor injuries predominantly involve rectus fem-
sensus report. The result of this meeting provided oris and iliacus but rarely in combination.
four new subcategories of groin pain: Moreover, rectus femoris injuries are usually sec-
­adductor-­related, pubic-related, inguinal-related, ondary to kicking and then sprinting, whereas
and iliopsoas-­related groin pain [216]. Sports hip iliacus injuries took place during a change in
injuries account for about 6% of all sports inju- direction. Also, the indirect tendon is usually
ries and counting. It is usually seen in athletes involved in most proximal rectus femoris injuries
who require pivoting and cutting associated with while a distinct iliacus and psoas major injuries
rapid acceleration and deceleration. These inju- occurred at the muscle-tendon junction [222].
ries consist of adductor strains, osteitis pubis, and
athletic pubalgia, or core muscle injury previ- Anterior/Medial Hip
ously described as “sports hip triad” [217]. There In adductor strains, the adductor longus is the
is also an associated range of motion limitation usual source of symptoms and pathology in ath-
due to femoroacetabular impingement [217]. letes, commonly seen among soccer players and
This categorization of sports hip injury, however, ice hockey players and representing 23% of all
could be outdated, although many sports physi- muscle injuries. There is a reinjury rate of 18%
cians still use this. To our discussion, we will with a mean time lost in the play of about 2 weeks
describe this as objectively as possible referring [217, 223]. Reinjuries are higher in professional
to a particular and specific condition. The “core” ice hockey with a recurrence rate of 23.5% [223].
also was coined by exercise and fitness experts to Usually, the reinjuries take a longer time to
refer to the entire body from the chest to the mid-­ recover as compared to the original injury which
thigh. And this is also further subdivided into is why it is important that appropriate and timely
four categories namely muscular, hip, back, and rehabilitation must be performed. Athletes usu-
everything else. Thus, a core muscle injury is an ally report medial thigh pain aggravated by
injury of any structure from the chest to the mid-­ resisted adduction and passive stretching of
thigh [216]. adductors. Injuries over the myotendinous area
Hip flexor strain was the most common diag- are usually located more distally [217].
nosis with intraarticular injuries taking a toll on Surprisingly, the mechanism of injury of adduc-
days lost in competition (94.2 days) [216]. In a tor tears is non-contact in 77% of cases followed
study by Epstein and colleagues, it was reported by overuse injury which has a rate of 12.8%.
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 493

Such injury resulted in a time loss of 7–13 days. injury, then the pain will return when resuming
However, surgery is not required for such injury athletic activities [216]. Depending on the MRI
[224]. Moreover, it was reported by Ralston and findings, the plate detachment because of the
colleagues among NCAA Women’s Soccer injury could be found in the midline, right, or left
Players that the most common tears are found in lateral or there may be a posterior extension of
adductor and iliopsoas/sartorius muscles with a the injuries of the fibrocartilage plate from the
rate of about 81.5%. These injuries occurred dur- pubis. Chronic plate detachment may occur in a
ing practice and were sustained during the pre- long-standing injury without any treatment,
season [224]. where spicules of granulation tissue occupy
Core muscle injury, sometimes referred to as between the fibrocartilaginous plates and the
athletic pubalgia or “sports hernia,” is an injury pubic bone. Degenerative detachments may
about the chest and the mid-thigh. The muscles occur because of repetitive motion simulating a
attaching through the fibrocartilage covering the chronic plate detachments with a lytic appear-
pubic bone stabilize the pelvis and thus form a ance. Peripubic and bone marrow edema may
harness that allows the trunk to move with the signify a plate detachment [216]. The patient
legs. The following muscles are important in sta- responds well with conservative therapies like
bilizing the core: rectus abdominis, the three rest and physical therapy, although the pain can
adductors such as the pectineus, adductor longus, recur once athletic activity resumes. Steroids are
and adductor brevis, which serve a primary role. prescribed by some to relieve pain. Platelet-rich
Other muscles such as the iliopsoas and rectus plasma is also prescribed by other practitioners,
femoris may secondarily get involved [216]. The but with an increased incidence of heterotopic
rectus abdominis, adductor longus, and brevis ossification at the site of injection, caution is
muscles and pectineus muscles are attached to needed in considering such treatment. The defini-
the fibrocartilaginous plate at the anterior pelvis tive treatment for core muscle injuries is surgical
close to the pubic symphysis and pubic tubercles repair. The presence of an indirect hernia must be
[216, 225]. This injury is seen in sports that fixed as well, as this can contribute to the imbal-
require pivoting and cutting as in the case of ice ance of forces of the abdominal musculature and
hockey, soccer, or American football [217]. A the hip joint. Treating this laxity contributes to
classic symptom is pain over the pubis, abdomi- the complete restoration of the muscle acting on
nal obliques, rectus abdominis, adductor longus the pubic bone and hip [216, 228]. In fact, except
insertion at the pubis. Resisted sit-ups cause pain for core endurance, the core strength, core pro-
over the distal rectus abdominis and with resisted prioception, and neuromuscular control of the
adduction [226]. Core injuries can be unilateral, core contribute to lower extremity injuries if not
bilateral, or midline in location [225]. Ultrasound addressed appropriately [229].
can be an inexpensive and effective first step in There are lots of debate on the nomenclature
diagnosing this injury. The presence of edema as to whether osteitis pubis is part of the “sports
around the pubic bone or evidence of laxity or hernia” injuries or could be an altogether sepa-
atrophy of the abdominal musculature is an indi- rate entity. The incidence is about 0.5–8% with a
cation that an MRI is needed to confirm the higher incidence with distance runners or those
pathology [216]. MRI showed cleft sign over the athletes involved in kicking such as in male soc-
rectus abdominis/adductor aponeurosis at the cer players [230]. In fact, in another study, it was
anterior pelvis [227]. A poor MRI image, how- reported that 86% of patients suffering from
ever, might show diffuse haziness around the groin pain, treated for osteitis pubis and/or sports
pubic bone which may be interpreted as a pubic hernia, had radiographic evidence of femoroace-
bone stress fracture and the patient might unnec- tabular impingement (FAI) [231]. In contrast,
essarily be told to rest and be non-weight-bearing there is a prevalence rate of about 1.8–2.6% of
for months. Moreover, if this injury is related to symphysis pubis abnormality in patients with
muscle detachment in the case of core muscle FAIs [232]. As part of the groin pain in sports
494 J. C. de Castro

injury of the anterior pelvis, there is evidence to than 7 mm of the pubic symphysis is pathogno-
say that athletes could suffer from this condition. monic for this condition [230]. In contrast, MRI
This is described as a painful overuse injury of shows subchondral bone edema with bilateral
the symphysis pubis causing lower abdominal involvement, although it is more visible on the
pain and/or groin pain [217]. The pubic symphy- affected side [217]. There is a hyperintense signal
sis acting as a fulcrum balances the forces com- on the T2-weighted images around the pubic
ing from two antagonists muscles: the rectus symphysis on cases with less than 6 month dura-
abdominis acting to elevate the pelvis and the tion of symptoms. For patients with a longer
three adductors (pectineus, adductor longus, and duration of symptoms, there is usually subchon-
brevis) acting to depress it during core rotation dral sclerosis, subchondral resorption, with bony
and extension. When these muscles are imbal- irregularity, pubic beak-like appearance [230].
anced which may be subsequently injured, the This condition is usually self-limited and may
symphyseal biomechanics are altered with subse- respond to conservative treatments such as rest,
quent injury to the pubic bone and later degenera- ice, inflammatory conditions, and physical reha-
tion of the cartilage in the symphysis pubis [217]. bilitation with the goal of correcting muscle
This is where an overlap of signs and symptoms imbalance around the pubic symphysis, stretch-
is observed between osteitis pubis and athletic ing, and strengthening of pelvic musculature
pubalgia. The one distinguishing mark is pain [233]. Ultrasound imaging can show tendon,
elicited by palpation over the pubic symphysis or muscle, and aponeurosis abnormalities around
pain on resisted sit-ups (positive spring test) at the pubic symphysis together with cortical irreg-
the lateral edge of the rectus abdominis [217]. ularities, but MRI can show deep and intraosse-
The bilateral adductor test also has been found to ous abnormalities [234]. MRI is the preferred
be a sensitive test for this condition [230]. As this imaging modality, but ultrasound provides a
is a chronic condition, the radiographic findings dynamic assessment of soft tissue abnormality
may show lytic changes over the pubic symphy- and guided intervention. When used for guided
sis, sclerosis, and widening of the symphysis intervention, it is placed sagittally over the pubis
pubis [217]. A “flamingo view” where the patient and the needle is introduced superior to inferior
stands on one leg on an AP view will show the approach. It has a limited role in the diagnosis of
instability of the pelvis where a vertical sublux- symphysial dysfunction and in osteitis pubis
ation of more than 2 mm or a widening of more [235].

Fig. 22.13 Side-to-side comparison of the anterior hip showed a cortical step-off sign over the anterior femoral
joint of a 50-year-old male patient complaining of anterior head, typical of the cam type femoroacetabular impinge-
right hip pain, the left being asymptomatic and the right ment with associated hypoechoic swelling of the anterior
hip showing pains during >60° of hip flexion. Ultrasound recess. IP iliopsoas, L labrum, H femoral head
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 495

Labral tears of the anterior hip are quite com- nally rotated indicating a posterior labral tear
mon among athletes manifested as a dull anterior when pain is present during the maneuver [241].
hip or groin pain with signs of clicking and buck- Interestingly, Fukushima and colleagues reported
ling [236]. It is often the result of trauma or injury the severity of synovitis and chondral injury to be
which subsequently causes subluxation or dislo- more important pathologies for the origin of hip
cation of the femoral head and is associated with pain than labral tears or instability. Moreover, the
chondral injuries either at the acetabular or at the pain is due to inflammatory cytokines such as
femoral side [237]. Femoroacetabular impinge- TNF-α and IL-6 [242]. There is an increase of
ment (FAI) (Fig. 22.13) is the most common fibronectin-aggrecan complex (FAC) and COMP
cause of labral tear [238]. It is estimated that (cartilage oligomeric matrix protein) in FAI and
there is a prevalence rate of 38% of labral tears in is seen among young athletes. Thus, FAI instead
young asymptomatic athletes and 56% in profes- of the aging process causes hip OA. There is also
sional and adult collegiate athletes. Most of the a consistent increase of IL-6 in hip OA but with
labral tears (84%) are found in the anterosuperior varied results in TNF-α and IL-1 [243].
portion of the hip [236]. Rankin and colleagues Ultrasound of the anterior hip around an
reported a higher prevalence rate of FAI in men abnormal labral morphology usually showed a
(45%) and labral tears among women (47.7%) hypoechoic labral cleft with a detachment of the
[239]. It has three basic types:, the cam-type, labrum from the acetabular rim confirming a
where there is a bony protrusion at the anterolat- labral tear [236]. Usually the presence of paral-
eral head-neck junction and therefore this col- abral cyst by ultrasound is an indication of a
lides with the acetabular rim during motion labral tear. Filling a labral cleft with fluid in the
disrupting the chondrolabral conjunction and case of a hip effusion improves the detection of
eventually delaminating the articular cartilage the labral tear [244]. MRA arthrography however
and labrum; the pincer type, where the acetabu- has better sensitivity than ultrasound for the
lum creates an over coverage of the femoral head detection of labral tears [245]. Labral tears can
causing a breakdown of the cartilage and labrum initially be treated using rest, ice, NSAIDs, activ-
during motion; and the mixed type [240]. It was ity modification, and physical rehabilitation
reported that 83.7% had a cam deformity and [236]. In a prospective study, the use of
28% had a pincer deformity and the average ultrasound-­guided platelet-rich plasma injection
alpha angle was 66.7° [231]. Aiba and colleagues showed a significant effect in terms of pain and
use multiplanar reconstruction computed tomog- function for hip labral tear treatment in patients
raphy (mCT) for the detection of subclinical who are refractory to conservative treatments for
coincidence of hip OA and FAI with a labral tear. an 8-week period follow-up [246].
They reported the 2-mm rule narrow joint space The rectus femoris is the most common injury
which was previously used radiographically and of the anterior hip and comes second after ham-
applied it using mCT to detect poor outcomes of string injuries among athletes [247]. The injuries
hip arthroscopy in favor of hip arthroplasty sur- could be attributed to their biarticular nature, the
gery [240]. Patients with FAI complain of gradu- predominance of fast-twitch muscle types, and
ally developing anterior hip pain (Fig. 22.13) powerful eccentric and concentric contractions.
radiating to the knee and in most cases occurring Athletes sustain these injuries with the hip in
at night and can be aggravated by walking, pivot- extension and knee in flexion such as in football
ing, running, and prolonged sitting. An anterior and rugby [236] during kicking and sprinting
hip impingement test where the hip and the knee [222]. The indirect head is the most common site
are flexed to 90° and then adducted and internally of injury affecting the central aponeurosis of the
rotated confirms that the labral tear is anterior. musculotendinous part of the structure. The
For posterior hip impingement test, the patient injury has an insidious onset with athletes com-
lies prone with hip and knee extended. The hip plaining of only mild pain and spasms at the ante-
and knee are then extended, adducted, and exter- rior thigh [222, 236]. Acutely injured indirect
496 J. C. de Castro

head of the rectus femoris appears in the ultra- power Doppler ultrasound. Partial-thickness
sound as ill-defined, thickened, and heteroge- musculotendinous tears appear as focal disconti-
neous central tendon with a bull’s eye pattern on nuity of the fibrillar patterns with associated
transverse view due to its edema formation [248]. anechoic focal fluid on transverse view, while
Chronic injuries of the indirect head appear in full-thickness tears appear as full discontinuity of
ultrasound as a thickened hypoechoic form with the fibers, with a fluid-filled gap with its distal
loss of fibrillar pattern and a posterior acoustic fibers retracted [236, 252].
shadowing due to scar formation. Acute, high-­ Internal snapping hip syndrome was once
grade strains of the indirect head of the rectus described as a snapping of the iliopsoas tendon
femoris appear in ultrasound as a complete dis- over the iliopectineal eminence or the lesser tro-
ruption with bizarre tendon retraction mimicking chanter [253]. This condition is reported among
a soft tissue mass. Myofascial injuries are a dis- ballet dancers and football players. Moreover,
tinct abnormality in the muscle tissue which is this is observed in patients when climbing stairs
better visualized by MR imaging [236]. or when one gets out of the car or stands up from
Iliopsoas muscle strain and tendon tears were a chair [254]. Tatu and colleagues have found out
commonly seen secondary to a sports injury that the most medial fibers of the iliacus muscle
especially among men although they were rarely merged with the psoas muscle as an accessory
found in the normal population (prevalence of tendon making up the iliopsoas tendon, while the
0.66%) [236]. The injury is usually associated most lateral fibers of the iliacus muscle ended up
with age and gender rather than with specific without any tendon on the anterior portion of the
activity. Patients with a mean age of 53 years lesser trochanter and infratrochanteric region.
were seen suffering from partial tendon tears of The most inferior fibers of the iliacus muscle
the iliopsoas and patients under 65 years were joined the main iliopsoas tendon from the arcuate
more often found to have only muscle strains and line. Another muscle overlying on its anterolat-
partial tears. Those beyond 65 years usually pres- eral surface reached the anterior aspect of the
ent with complete iliopsoas tendon tear with lesser trochanter and infratrochanteric area with-
associated hip flexion weakness [249]. Iliopsoas out a tendon, called an ilio-infratrochanteric mus-
disorders are shown to be the cause of chronic cle [255]. Guillin and colleagues, deriving their
groin pain in about 12–36% of athletes and in knowledge from the cadaveric studies of Tatu,
25–30% of acute groin pain [250]. Trauma in the made the first attempt to study the dynamic
psoas is associated with team sports and canoe- movement of the iliopsoas muscle and tendon by
ing. It was also associated with sports involving sonographic examination. Under ultrasound
kicking and jumping such as football, basketball, imaging, in a dynamic movement of hip flexion,
and gymnastics [236]. This may lead to any of abduction, and external rotation (frog-leg posi-
the three distinct lesions in the iliopsoas, such as tion), the psoas major tendon (PMT) moved lat-
the fleshy part of the muscle, the myotendinous erally and followed an externally oriented
junction (small), and the lower part of the tendon rotational course around the medial fibers of the
insertions in the lesser trochanter. Of the three iliacus (MFI) (Fig. 22.14B). The rotating move-
lesions, this is the most disabling and is associ- ment was clockwise on the left hip and counter-
ated with hip flexion weakness [251]. Iliopsoas clockwise on the right hip. None of the tendon
tendinopathy was reported after acute and over- glides on the superior pubic ramus without any
use injuries. It has also been found to be associ- muscular interposition of the PMT and
ated with internal hip snapping, osteophyte MFI. Thus, as the PMT glides around the MFI,
formation, and post-arthroplasty impingement. the MFI was then entrapped between the PMT
This is shown in ultrasound as the hypoechoic and the superior pubic ramus. The snap created
heterogeneous appearance of the tendon with occurred during the last phase of external rotation
loss of fibrillar pattern, hypertrophic changes of at the vicinity of the anterior inferior iliac spine.
the iliopsoas tendon, and neoangiogenesis by When the hip is brought back to extension, the
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 497

a b

Fig. 22.14 (a) Ultrasound image of the greater trochan- subgluteus maximus or trochanteric bursa is seen way
ter in short axis view showing the bony apex (*), serving posterior between the gluteus maximus and posterior
as the key landmark between the lateral (L) and anterior facet. (b) Ultrasound image of the anterior hip in short-­
(A) facets. The gluteus minimus (Gmin) is seen attaching axis view at the level of the anterior inferior iliac spine
to the anterior facet and the gluteus medius (Gmed) (AIIS) shows the psoas tendon (PT), medial iliacus (MI),
attaching to the lateral facet. Also shown are the gluteus and lateral iliacus (LI)
max (Gmax) and the iliotibial tract (ITT). Usually, the

PMT and MFI followed a reverse course until the external rotation motions followed by extension
initial position is reached. Moreover, the MFI and adduction. The probe is adjusted more later-
was distinguished from the lateral fibers of the ally during the initial motion and moves a little
iliacus (LFI) by a thin echoic interface named medially toward the later part of the rotation of
“intramuscular fascia of the iliacus muscle” the hip to visualize the presence of a snap [258].
[256]. In another study, Deslandes and colleagues Interestingly, Audenaert and colleagues refuse to
have debunked the snapping of the iliopsoas ten- fully agree with Guillin and Deslandes that the
don against the iliopubic eminence. The sudden snapping exclusively does not involve the ilio-
tendon snap, therefore, is created between the pectineal eminence but further added his obser-
psoas tendon and the medial iliacus as described vation in the increase in tendon excursion with a
by Guillin [256, 257]. This dynamic maneuver as decreasing ischiofemoral distance, the presence
observed in ultrasound is present in up to 40% of of femoral malrotation, and its association with
normal subjects where even the athletes with this female sex [259].
physiological phenomenon may not be aware Snapping of the hip is usually classified as
[256]. The repetitive snapping may then cause intra-articular or extra-articular depending on the
inflammation with subsequent pain [257]. The appropriate location. Intra-articular snapping hip
other causes of painful snapping hip were is caused by any impingement occurring at the
between the two components of the bifid psoas hip joint such as due to labral tears, synovial
major tendon at the level of the anterior inferior chondromatosis, ligamentum teres tears, fracture
iliac spine while in the frog-leg position [257], at fragments, or any loose bodies inside the joint
the postoperative period of total hip arthroplasty space. Extra-articular hip snapping is the most
where there is an overlap of the prosthetic cup at common form and is further subdivided into
the anterior acetabular rim [258]. The ultrasound internal or external snapping hip [260].
procedure is done by putting the probe in a trans- Additionally, a posterior snapping caused by the
verse oblique plane between the anterior inferior proximal hamstring origin may also occur [261].
iliac spine and superior pubic ramus with the ilio- The previous one was just described above
psoas complex at the middle of the image. The lengthily. In the external form of snapping, the
patient is asked to perform hip flexion-abduction-­ thickened posterior portion of the iliotibial band
498 J. C. de Castro

(ITB) or the thickened anterior edge of the glu- trant trochanteric tendinopathies [266, 267].
teus maximus muscle. Surgical lengthening of the ITB by Z-plasty or
Posterior portion of the iliotiband band (ITB) endoscopic IT tract release is reserved for those
or the thickened anterior edge of gluteus maximus unresponsive for any treatment mentioned above
muscle snaps over the greater trochanter during [260, 268]. The open IT release showed a recur-
flexion and extension of the hip or by mere walk- rence rate of 11% compared to an arthroscopic IT
ing producing a “click” or a snap-on motion release with very minimal complication [269].
(Fig. 22.14A). Moreover, snapping cannot be
induced when a patient walks with the leg in Posterior Hip
external rotation since the thickened band moves Hamstring injuries are one of the most common
anterior to the greater trochanter. With the repeti- injuries involving athletes. Their prevalence
tive motion of the hip like running and ballet, it among professional baseball players is 12–15%
may cause inflammation and pain. Women are [270] The spectrum of these injuries can be as
often more affected than men. To some patients, simple as a hamstring strain to severe ruptures,
the snapping may not cause any pain at all [260, occurring either proximally, at the mid-substance,
262, 263]. The prevalence of this condition in or distally [271]. Acute hamstring strain is the
both symptomatic and asymptomatic cases are most common muscle strain with a high rate of
unknown [264]. Clinically, the snapping can be recurrence, with some studies reporting that one
elicited when the patient lies on the side with the in three hamstring strains will recur within the
affected leg passively extended or flexed in a neu- first 2 weeks of return to sports [272–274]. The
tral position [265]. The ITB lies posterior to the most common hamstring injuries affect the prox-
greater trochanter when the hip is extended, and it imal tendons following a history of forceful hip
moves anteriorly when the knee and hip are flexion and knee extension. It is characterized by
flexed. Thus, when the posterior part of the thick- sudden and acute onset of pain with ecchymosis
ened portion of the proximal ITB moves forward over the posterior thigh distal to the ischial tuber-
on a flexed knee in an abrupt motion, the snapping osity [275]. It is usually measured 2.3 cm distal
occurs [264]. In some cases, it is also possible that to the ischial tuberosity [276] and there is an
the distal gluteus maximus muscle may snap dur- associated difficulty in sitting and weight-­
ing hip flexion over the greater trochanter [260]. bearing. The ecchymosis can after a few days
MRI is the standard imaging diagnostic tool, but extend to the distal posterior thigh and posterior
ultrasound imaging can help also in the assess- leg. To some extent, the posterior cutaneous
ment. Ultrasound usually showed an increased branch of the sciatic nerve could impinge because
thickness of the iliotibial tract/band with hetero- of the hematoma and the retracted tendon can
geneous echogenicity indicating tendinopathy. cause numbness and neuropathic pains. In the
Dynamic imaging will demonstrate the transla- early phase of injury, walking and running could
tion of the IT tract over the gluteus medius tendon be very challenging [271]. Proximal hamstring
which is connected anteriorly with tensor fascia strains and avulsions are more common with the
lata and posteriorly by the gluteus maximus mus- long head of the biceps femoris most often
cle/tendon while the hip is being extended and injured, and the musculotendinous tendinous
then flexed [260]. Treatment for this condition junction is a possible location. Moreover, the
includes rest, NSAIDs, physical therapy, and injury involving the long head of the biceps fem-
stretching of the iliotibial band. Patients who are oris tendon occurs during high-speed running,
refractory to this treatment may undergo injection especially during the late swing and early stance
with steroid, platelet-rich plasma, or local anes- phases of gait [277] and semimembranosus being
thetic with steroids providing short-term relief. the next commonly injured muscle happens dur-
Platelet-rich plasma as a possible treatment has ing extensive stretching [278]. Proximal ham-
not been thoroughly investigated for external hip string avulsions occur predominantly in the
snapping, although it has been used for recalci- middle-aged patient and rarely in patients below
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 499

30 years of age with older female affected during shorter return to play in those athletes with grade
activities of daily living [279]. Regardless of 2 hamstring injuries [287]. As mentioned earlier,
whether the hamstring injury is distal or proxi- sciatic nerve impingement whose main symptom
mal, the patient usually presents with a feeling of is pain may be secondarily affected in proximal
snap at the posterior thigh and knee flexion weak- hamstring avulsion injuries but is underrecog-
ness with associated pain and stiffness, making nized. However, Wilson and colleagues have
weight-bearing a difficult task. In an isolated reported that with surgery, these symptoms are
biceps femoris rupture, pain can be felt at the lat- likely to improve and thus should be taken into
eral or posterolateral aspect of the thigh [271]. consideration when discussing the risks and ben-
Recent biomechanical studies also revealed that efits of operative repair [288]. Subbu and col-
hamstring muscle-tendon complex has a signifi- leagues in their study found that the meantime of
cant role in the rotational stability of the knee. In 22 days post-injury provides the best timing for
fact, hamstring is an ACL agonist and thus it pro- surgery with a quicker return to preinjury level of
tects the ACL from an added injury [280]. MRI play to about 16 weeks. The greater the delay to
and ultrasound are the modalities of choice for surgery, the wider the retraction of the proximal
hamstring injuries with MRI showing better sen- hamstring complex [289]. Surgical treatment of
sitivity for proximal hamstring tendinopathy. proximal hamstring tendon avulsions results in
Ultrasound findings of tendinopathy showed good clinical outcomes with early return to
hypoechoic thickening of the tendon with sports. Furthermore, surgical repair of partial and
­associated peritendinous fluid. There is also an complete tears provides similar clinical outcomes
echogenic focus of calcific tendinopathy with but with higher complication with complete avul-
cortical irregularity and tender on sonopalpation sions [290]. Return to play (RTP) is usually based
[281]. Partial-thickness tears are better visualized on any of these three grading systems derived
by MRI than ultrasound especially if there are from the MRI findings. It includes the Modified
subtle lesions involving the semimembranosus Peetrons, Chan Grading, or the BAMIC
muscle. For complete hamstring avulsion, an ini- Classification of hamstring injury [291], the
tial radiographic study is needed to rule out any Chan [292] or the BAMIC Classification [293] of
bony avulsion injury. Ultrasound is useful in this hamstring injury. Wangensteen and colleagues
type of injury to identify complete avulsion did a prospective study of these different classifi-
injury especially in a setting where MRI is not cation systems to assess their ability to predict
practical to use. But once surgery is being consid- time to return to sports. Their study concluded
ered, MRI is useful to characterize the details of that these MRI classification systems cannot be
the injury including the extent of muscle retrac- used alone to predict return to sports after ham-
tion and the number of tendons involved [282]. string injuries. Instead, the specific MRI system
Most hamstring strains, tendinopathy, or partial- must be specified to avoid misinterpretation when
thickness tears can be treated conservatively but using it [294]. Eggleston and colleagues in their
proximal hamstring avulsions or injury of the study among Australian Football Players reported
entire hamstring muscle complex requires sur- a longer RTP in intramuscular injuries >5 cm of
gery. Moreover, surgical treatment may be indi- the longitudinal length of intramuscular disrup-
cated for partial thickness tear after a failure of tion or 50% of intramuscular cross-sectional area
conservative treatment, involving two tendons based on MRI findings. Furthermore, the intra-
with a retraction of >2 cm or complete with three muscular injuries of the proximal long head of
tendon injuries [282–284]. Conservative treat- the biceps femoris with concomitant injuries of
ment may include physiotherapy, extracorporeal the biceps femoris/semitendinosus muscles had
shock wave therapy, and PRP injections [284]. the longest RTP [295]. There are mixed results in
There are no significant results to recommend the the recoveries among athletes with hamstring
use of PRP in recent studies [285, 286] for ham- injuries as shown in this study when using PRP
string injuries, although one study reported a treatment as compared to physical rehabilitation
500 J. C. de Castro

alone [286] with one study saying that PRP with the primary restraint to anterior tibial translation
physical rehabilitation showing good growth fac- during flexion, while the posterolateral bundle is
tor concentration with early return to play to pre- taut in extension and is restraint during anterior
injury level in 21 days for grade 2 hamstring tear tibial translation in extension and it assists in rota-
than physical rehabilitation alone [296]. tory control [303, 304]. These bundles originate
Reinjuries post-PRP, however, are common and from the medial aspect of the lateral femoral con-
are usually reported within the first 4 weeks and dyle within the intercondylar notch and course its
100 days in 53% and 70% of cases, respectively, way anteriorly to insert into the anterior aspect of
after return to play. Based on the MRI findings, the intercondylar eminence of the tibia [304].
the site for reinjuries is located where the initial With its distinct attachment, ACL can stabilize the
injury happened [297]. It was reported that rein- knee in different angles. For instance, the antero-
juries remain high at 12–63% [280]. Exercise- medial bundle stabilizes the knee when it is flexed
based interventions decreased hamstring injury to >30° knee flexion. But when the knee is in <30°
risk with no added benefits on load progression flexion including knee extension, the posterolat-
and frequencies in preventing further injury eral bundle of ACL assumes the role of stabilizing
[298]. Flexibility and strength though remain an it. Interestingly, both bundles exhibit identical
important clinical parameter during rehabilita- loads when the knee absorbs valgus stress and
tion in ensuring a decrease in acute hamstring internal tibial torques while flexed to 15° (pivot
injuries as depicted by MRI scans. Moreover, shift test) [304]. Non-contact injuries involving
flexibility testing by means of passive straight leg the ACL happen when there is an anterior tibial
raise test instead of active knee extension test was translation coupled with either varus or valgus
independently associated with recovery times loading in a planted foot (pivot shift injuries)
after hamstring injuries [299]. Also, medical staff which usually occur in a soccer game due to
like physicians and physiotherapists were con- abrupt changes in direction. This makes up most
sulted for deciding on the return to play (RTP), ACL injuries [305]. Whereas contact injuries
instead of the sports science staffs, coaches, and affecting the ACL happen whereby a valgus force
players as they are the gatekeepers of the RTP is applied on a partially flexed knee or in a hyper-
decision [300]. extended knee. This injury could simultaneously
involve the medial meniscus and medial collateral
Knee ligament as it is bound together structurally [303].
ACL tears present with a large hemarthrosis in
Anterior Cruciate Ligament about 41–75% of acute knee injuries [306].
Sports injury involving the knee remains the most Among the tests used for evaluating ACL injuries,
common injuries among athletes. In a 10-year the following tests have better sensitivity –
study by Gage and colleagues assessing different Lachman’s, anterior drawers, and pivot shift tests
knee impairments in the emergency room, about [307]. For definite diagnostic purposes, MRI is
50% of knee injuries are due to sporting or recre- still the imaging of choice [304]. Recently, a sys-
ational activities with soft tissue injuries account- tematic review on the use of ultrasound was
ing for most cases [301]. Around 90% of those reported by Lee and Yun which showed that ultra-
seeking medical help end up undergoing ACL sound is an excellent tool for diagnosing ACL
reconstruction [302]. One of the most injured lig- with a sensitivity of 88% and a specificity of 96%
aments in the knee is the anterior cruciate liga- provided it is performed by experienced musculo-
ment (ACL). It usually arises from the medial skeletal radiologists [308]. One caveat to note
margin of the lateral femoral condyle. It is com- here is the presence of fats. The extent of ACL can
posed of two bundles which are the longer antero- be seen in patients with a low proportion of fat
medial bundle and a shorter posterolateral bundle, around the knee, adding that the femoral attach-
and each is functionally distinct. The anterome- ment of the ACL is only partially visualized [309]
dial bundle is functionally taut on flexion and is (Fig. 22.15). Anteriorly, the patient’s knee is
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 501

a b

Fig. 22.15 (a) Ultrasound image of the anterior knee in (MFC) and lateral femoral condyle (LFC) as bony land-
90° knee flexion showed the anterior cruciate ligament marks to locate for the anterior cruciate ligament seen at
(ACL). Also shown are the patellar tendon (PT) and the lateral aspect (*) of the intercondylar notch. P popli-
Hoffa’s fat pad. (b) Ultrasound image of the posterior teal artery
knee in short-axis view with medial femoral condyle

flexed to 90° and the probe (7–10 MHz) is posi- positive, the sensitivity was at 86.8% and the
tioned parallel to the tibia in the sagittal plane just specificity was at 87.5%. In addition, a thick-
below the inferior pole of the patella. The probe is ened PCL compared to the normal side is con-
moved to 30° counterclockwise so that the probe sidered a positive sign for ACL rupture. Partial
is parallel to the ACL fibers. Posteriorly, in a midsubstance tears can be missed using this
prone position, the probe is positioned in a poste- indirect sign [312]. Most ACL tears can be prox-
rior intercondylar view (transverse view with lat- imal at the femoral attachment (43%) or mid-
eral and medial femoral in view) to assess the substance (52%) of the ligament [314]. Surgical
ACL attachment (Fig. 22.15). The normal appear- treatment is the preferred mode of treatment for
ance of ACL is a small oval-shaped, hypoechoic young, active individuals and athletes with high
structure. A tear appears as a hypoechoic collec- physical demands and those patients who remain
tion along the lateral wall of the femoral intercon- symptomatic after a trial of conservative treat-
dylar notch (femoral notch sign), representing ments with physical rehabilitation [313]. A
hematoma at the proximal attachment of the ACL, return to pre-injury sports after a unilateral ACL
where most tears appear. injury post-reconstruction procedure is about
Furthermore, these findings were confirmed 53–83% and return to pivoting sports is about
by MRI and arthroscopy. It is not clear when 83% [315, 316]. Return to pre-­injury sports is
hematoma can resolve, but it can last for as long about 40% in bilateral ACL post-­reconstruction
as 10 weeks post-injury [310]. Other indirect procedure. Interestingly, fear of reinjury was
signs by ultrasound include PCL wave sign and cited as the most common cause for failure to
capsular protrusion sign [311]. Moreover, to return to sport after the second reconstruction
enhance better diagnosis, the patient must be [315, 317], which is why it is important to make
scanned in prone, rather than in supine, position a psychological readiness assessment of athletes
and must be compared to the contralateral knee regarding treatment plans and physical rehabili-
all the time [308]. Mautner and colleagues tation process to prepare them for their return to
found out that the PCL wave sign had the high- sports activity [318, 319]. In another study, the
est sensitivity at 84.9% and the femoral notch rate of return to sports is 50% after a year post-
sign had the highest specificity at 93.8%, but a reconstruction and about 67% 2 years after that,
sensitivity of 56.6%. If 2 or 3 of the signs were with rates of second ACL injury affecting
502 J. C. de Castro

younger athletes up to 35% [320]. This same reported a reduction of post-­traumatic osteoar-
study however showed that 23% of athletes thritis following ACL reconstruction, for ana-
passed the return-to-play test batteries which tomic ACL reconstruction versus non-anatomic
provided a 60% decrease in the risk of graft rup- techniques. Anatomic ACL reconstruction is
ture but with a surprisingly 235% risk for con- defined as AARSC (Anatomic ACL
tralateral ACL injury. Thus, it would be difficult Reconstruction Scoring Checklist) score of ≥8
to apply these data clinically [320]. In a recent and is associated with a lower prevalence of OA
review, an isokinetic strength protocol with con- in long-term follow-up [327]. Maximal medical
centric tests at 60°/s was found out to be the improvement is no longer detectable 1 year after
most reliable assessment method for return to ACL reconstruction [328]. Several studies show
sports [321]. In another study, return to sports in that the use of PRP as a treatment for ligament
an ACL-deficient knee treated with conservative healing did not show any significant effect [329,
therapy consisting of quadriceps strengthening 330]. In fact, increasing PRP concentration neg-
and dynamic stability training and not recon- atively affected ligament strength and histologi-
structive surgery showed that 89% of them led cal characteristics [329].
an active sporting life with one-third of them
returning to pivoting sports [322]. However, it is Posterior Cruciate Ligament
also observed that there is a high rate of The posterior cruciate ligament is the largest
OA-related changes in MRI among young adults intra-articular ligament. It originates from the
during the first 1–5 years post-ACL reconstruc- medial femoral condyle within the intercondylar
tion with two-thirds showing some joint deterio- notch and inserts in between the two tibial plateau
ration. There is also an accelerated degenerative posterior to the tibial spine at the posterior inter-
change observed among older and overweight condyloid fossa [331]. Posterior cruciate ligament
patients especially affecting the patellofemoral injuries of the knee represent about 38–44% [332]
cartilage [323]. In fact, ACL injury alone, of acute knee trauma with hemarthrosis with iso-
regardless of age, was observed to increase the lated tears representing about 1–5% [306, 333].
inflammatory markers which subsequently led The most common mechanism of injury is a pos-
to the development of osteoarthritis, and ACL teriorly directed force against the tibia or knee
reconstruction did not reverse this process. hyperflexion with a plantarflex foot, but without
However, ACL reconstruction can improve knee the “pop” that you commonly encounter in ACL
kinematics and reduce secondary damages to injury. This is what commonly occurred in a
the cartilage and meniscus [324]. Wellsandt and “dashboard injury” where an individual seated on
colleagues compared the existence of osteoar- the front seat of a car in an accident had been hit
thritis between those treated operatively and by a dashboard with the proximal tibia absorbing
those treated non-­operatively under a progres- the posteriorly directed force. In sports injury, it
sive criterion-based rehabilitation 5 years after may occur when the athletes fall on the knee in a
an ACL injury. Results showed that 5% of those plantarflex foot [334]. With this given mechanism
treated non-operatively had tibiofemoral osteo- of injury, it can also involve other structures such
arthritis in contrast to 23% of those treated oper- as the posterolateral corner (PLC), of which 60%
atively. These findings are not statistically of PCL cases are found which includes the lateral
significant [325]. Smith and colleagues showed collateral ligament and the medial collateral liga-
similar results 10 years after an ACL injury was ment following a high energy trauma or accident.
treated non-operatively versus operative treat- The medial peripheral lesion is more common
ment, although the post-ACL reconstruction among biking and skiing accidents [335]. Other
knees have a higher likelihood of developing structures of the PLC that may be involved
degenerative processes [326]. One study though includes coronary ligament, popliteofibular liga-
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 503

ment, popliteus tendon, and arcuate ligament knee. Grade III injuries are defined as those with
[336]. The PCL usually prevents the posterior more than 10 mm posterior tibial translation and
translation of the tibia while the PLC is the most grade II injuries are the ones in between. For
important restraint in varus stress and is acting as complete PCL tear, a quadriceps active test can
a secondary restraint against posterior tibial trans- be used. Patient is placed in supine position while
lation on the lateral tibiofemoral compartment, the knee is flexed to 90°. The patient is asked to
but both are restraints to external rotation of the contract the quadriceps isometrically while the
tibia [337, 338]. Both PCL and PLC restrain the examiner stabilizes the foot. In a complete PCL
knee in high flexion angles while PLC is the main tear, the quadriceps contraction will reduce the
restraint in low flexion angles [338]. Posterior posteriorly subluxed tibia [341]. Hematoma from
cruciate ligament may also be injured because of the back of the knee confirms the presence of
multiligament injuries of the knee such as what PCL tear [334]. A dimple sign in the medial knee
occurred in an ACL type of injury with hyperex- is pathognomonic of a non-reducible knee dislo-
tension or hyperflexion of the knee with a rota- cation [342].
tional component and varus/valgus stress [339]. MRI remains the gold standard for the diagno-
Thus, combined injuries are more common than sis of a suspected PCL injury with 100% specific-
isolated PCL injuries [335] and sports is the most ity and sensitivity but needs to be correlated with
common cause for surgically treated PCL injuries the history and physical examination especially
except handball [340]. in acute cases [334]. In chronic PCL cases, how-
Physical examination for patient with sus- ever, the sensitivity is only up to 62.5%. So, to
pected PCL injuries includes posterior drawer increase diagnostic sensitivity in diagnosing
test. For isolated PCL injuries, posterior tibial chronic PCL tear, a 2.0 mm posteromedial tibial
translation will be decreased with internal tibial translation is performed to increase the sensitiv-
rotation due to the restraints exerted by the super- ity of MRI to 80% and the specificity to 89%. For
ficial medial collateral ligament and posterior revision cases, MRI has a sensitivity of 18.1%,
oblique ligament. With the amount of posterior but with 3.66 mm of posterior tibial translation
tibial translation during the posterior drawer test, (PTT) in the medial compartment, it shows a sen-
a grading system is used for determining severity sitivity of 92% and a specificity of 72% [343]. As
of PCL injuries. Grade I injuries are defined mentioned previously, combined injuries are
when the amount of posterior tibial translation is more common than isolated PCL injuries. In an
about 0–5 mm as compared to the contralateral isolated PCL injury, 25% shows an associated

a b

Fig. 22.16 (a, b) Sagittal ultrasound imaging over the terior tibia. The posterior cruciate ligament is hypoechoic
posterior medial knee shows the anechoic structure of the as a result of anisotropy. Thickness is usually <1 cm
posterior cruciate ligament (PCL) as it attaches at the pos-
504 J. C. de Castro

meniscal injury. Usually, 69% of the isolated acute or chronic injury. An acute and isolated but
PCL injury may occur in the midsubstance with uncommon PCL tear can be managed by conser-
27% occurring proximally and can be partial or vative treatment, while a chronic PCL tear with
complete tear [344]. Another modality for diag- knee instability will usually require surgical
nosis is the use of ultrasound. A 2D ultrasound intervention [334]. An acute PCL tear has good
technique with sonoelastography introduced by intrinsic healing capability when treated conser-
Wang and colleagues hold promise in the diagno- vatively, although it heals in an elongated and
sis of PCL injuries. The transducer is placed lon- attenuated condition with 62–75% of cases show-
gitudinally at the inferomedial aspect of the ing good continuity by MRI findings [349–351].
popIiteal fossa at the posterior intercondylar area The MRI is evaluated between 2 months and
of the proximal tibia. The PCL attachment is 17 months after a PCL injury showing good con-
measured 2 cm proximal to the tibial insertion tinuity [350, 351]. However, another study
(Fig. 22.16). A sprain is identified when there is a ­suggests surgery for those with grade II or grade
hypoechoic swelling as compared to the contra- III PCL injuries [352]. Under usual clinical con-
lateral knee. A partial tear is defined as a ditions, it is reported that more than 50% of PCL
hypoechoic gap with preserved partial continuity is seen by clinicians after more than a year of
and a complete disruption is defined as a com- injury [343]. If it is part of the multi-ligament
plete discontinuity of the ligament. It was injuries, prompt treatment and management are
reported in that study that a minimum thickness very important [334]. Conservative treatment
of PCL to ≥6.5 mm yielded a sensitivity of 90.6% may for a time provide certain relief, but there is
and a specificity of 86.7% in the diagnosis of a high rate of arthrosis in the medial and patello-
PCL strain injury. Thus, hypoechoic swelling femoral compartments due to altered kinematics
(increased thickness) and softening (by elastog- and loads. These arthritic findings can also be
raphy) are compatible with PCL injury and can used to determine the chronicity of the knee
be used as a screening tool for diagnosis [309, injury. Recent findings showed that avoiding pos-
345]. A torn PCL appears in ultrasound as hetero- terior tibial translation forms part of the conser-
geneously hypoechoic with an indistinct and vative management of patients with PCL injury
wavy posterior margin [309] or a focal disruption to optimize ligament healing. It includes also
of the ligament [346]. Lee and Yun in their study strengthening of the quadriceps and core muscu-
reported that knee ultrasound in the diagnosis of lature with a progressive range of motion exer-
PCL has a sensitivity and specificity of 99% pro- cises. At 12 weeks, interval training may
vided the examiner performs side to side com- commence followed by agility work and sports-
parison of the images, and dynamic ultrasound is specific exercises to prepare athletes for return to
performed by a competent and experienced mus- sports. This protocol has a high rate of return to
culoskeletal radiologist [308] (Fig. 22.16). sport [341]. Chronic PCL injuries with less than
Ultrasound can image the PCL using a posterior 8 mm posterior tibial subluxation have the poten-
longitudinal approach to the knee. A ruptured tial to heal with ligament fiber restoration as
PCL in ultrasound is characterized by an inter- shown in MRI findings [353]. For proximal or
ruptions close to its insertion into the intercondy- distal avulsion type PCL tears, it is recommended
lar fossa [347]. Dynamic ultrasound stress test that arthroscopic primary repair may be per-
was also shown to have a sensitivity of 83% and formed in which the ligament can be reattached
a specificity of 100% for injury of the lateral col- to its original insertions and origins. The advan-
lateral ligament and posterolateral corner struc- tage of this procedure is faster rehabilitation and
tures and thus can predict the need for surgery in preservation of the native tissue with a return to
100% of patients who required posterolateral their pre-­injury competitive level and with a full
repair or reconstruction [348]. range of motion [354]. There is no evidence that
The initial approach in the management of PRP works for PCL injuries [329].
PCL injuries is by determining whether it is an
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 505

Lateral (Fibular) Collateral Ligament Injury ion [356]. Varus laxity in an extended knee can
A blow to the medial side of the knee or hyperex- otherwise provide clues to an associated injury of
tension stress across the knee in non-contact either or both cruciate ligaments [361]. Claes and
injury can injure the lateral collateral ligament colleagues [362] proposed a term called lateral
(LCL). Sports like gymnastics and tennis contrib- collateral ligament complex (LLC) to include
ute to the increased incidence of lateral knee LCL and anterolateral ligament (ALL) which is
trauma. In a study of more than 200,000 knee commonly observed to be specific in Brazilian
injuries from different sporting events, isolated jiu-jitsu (BJJ) injuries occurring in about 25.9%
LCL pathology is represented by <2% [355]. As of athletes [363]. The mechanism of injury in BJJ
a primary varus stabilizer of the knee, failure to is described as a varus injury on a flexed knee
recognize its pathology in a multiligamentous with varying degrees of external rotation [364].
trauma can result in instability and unsatisfactory Care should also be noted in patients with LCL
outcome after a cruciate ligament reconstruction injury presenting with radiographic signs of avul-
[356]. The lateral collateral ligament also acts as sion injury of the fibular head otherwise referred
a secondary restraint to external rotation together to as arcuate sign or arcuate fracture. This could
with the popliteofibular ligament (PFL). The point to the possibility of posterolateral corner
LCL, PFL, arcuate ligament, and fabellofibular injury. Undiagnosed PLC injury could give rise
ligament are the static stabilizers of the postero- to recurrent instability, failed anterior cruciate
lateral corner (PLC), and together, they resist ligament reconstruction, and early onset of osteo-
posterior displacement of the tibia, varus instabil- arthritis [365]. Shekari and colleagues have found
ity, and external tibial rotation [357, 358]. an association between LCL injuries and ALL
Furthermore, it also provides stability to the PLC injuries [366].
of the knee, together with the popliteus muscle-­ The assessment of varus laxity regarding the
tendon unit and the PFL [359]. An angle of 30° LCL knee injury is done with the knee at 30°
knee flexion is observed to have the highest flexion. A varus opening of ≤5 mm indicates a
degree of varus laxity and thus is important in the low-grade injury and >10 mm a high-grade
clinical assessment of LCL laxity [360]. As the injury. Anything in between is a moderate grade
knee is further flexed, the control of the LCL on varus injury. Athletes with high-grade injuries
the knee is increasingly less and, therefore, the should be assessed further for possible multiliga-
LCL is loaded at the early range of the knee flex- mentous injuries [356]. Warren has noted an

a b

Fig. 22.17 (a) Ultrasound of the longitudinal axis view view of the iliotibial band as it inserts into the Gerdy’s
of the lateral collateral ligament (LCL) of the lateral knee tubercle of the tibia. Fib fibula, F femur, T tibia
as it inserts into the fibular head. (b) Longitudinal axis
506 J. C. de Castro

increase in varus opening to about 5–9° for com- grade III injuries have good outcomes with surgi-
bined LCL-popliteus injury which was confirmed cal intervention. Semitendinosus graft for grade
arthroscopically to an opening of 9–10 mm [367]. III LCL injuries is reported to have good subjec-
MRI remains the imaging of choice for LCL tive and objective results [356]. There are limited
injury with a sensitivity of about 58% [368]. studies regarding the use of PRP in ligament inju-
Grade I is the least severe characterized by sub- ries. No evidence of its effects on healing was
cutaneous fluid around the midsubstance or in observed on ligaments [372] except in decreasing
any of the insertions. Grade II indicates partial pain in both the short and long terms [373].
tears in the LCL in any part of the ligament with
associated edema formation. Grade III is a com- Medial Knee Ligaments
plete tear of the LCL with edema formation Medial collateral ligament (MCL) injuries result
[369]. Ultrasound of the lateral knee is a useful from a valgus force from a direct force to the lat-
modality for both static and dynamic imaging eral knee in a planted foot associated with sudden
(Fig. 22.17a). Sekiya and colleagues reported pain and a popping sound [374] usually seen in
that static ultrasound of the LCL has a sensitivity sports like hockey, football, and skiing. About
of about 92%, specificity of 75%, and accuracy 43% to 52% accounts for this injury which is
of 88%; popliteus has a sensitivity of 33%, speci- considered the most injured ligament of the knee
ficity of 100%, and an accuracy of 50%; and pop- occurring more among contact than non-contact
liteofibular ligament has a sensitivity of 67%, sports activities [375]. The medial knee is made
specificity of 75%, and an accuracy of 69%. up of static and dynamic structural stabilizers.
Dynamic ultrasound stress imaging is used to Among the static stabilizers, it includes the
measure the lateral joint space width which is superficial and deep MCL or medial capsular
normally <10.5 mm. The need for posterolateral ligament and posterior oblique ligament. The
corner surgery is based on a value >10.5 mm. dynamic medial knee stabilizers include the mus-
This dynamic stress testing has a sensitivity of culotendinous unit of semimembranosus, quadri-
83% and a specificity of 100% for injuries of the ceps, and pes anserinus [376]. There are three
LCL and PLC. This has a positive predictive layers of the MCL, namely the superficial sarto-
value of 100%, a negative predictive value of rial fascia layer, the middle superficial MCL with
75%, and an accuracy of 88% [348]. Anterolateral the posterior oblique ligament (POL), and the
ligament (ALL) is found in 97% of cadaveric deep MCL with the knee capsule [377]. A bursa
studies [362] such that it shares a common origin exists between the middle superficial and deep
with LCL of the lateral femoral condyle and then MCL which is not seen unless there is a fluid col-
runs deep and oblique to the ITB and finally lection in between [378]. Although rare, medial
inserts 2 cm posterior to the ITB insertions. By knee pain can be due to MCL bursitis due to the
flexing the knee to 90 degrees, a better view of osteophytes of knee OA [379]. The superficial
ALL is visible by ultrasound [370]. MCL originates from the medial femoral condyle
Conservative treatments for LCL injuries are and inserts underneath the pes anserine 4–5 cm
reserved for grade I or II injuries. Surgical repair from the medial joint line. Its anterior fibers are
and interventions are done for grade III midsub- taut in flexion and lax in full extension
stance tears and in chronic lateral instability due (Fig. 22.18). The deep portion of the MCL is
to LCL injury [371]. The same holds true for made of different confluence of ligaments namely
PLC injuries where grades I and II are treated the meniscofemoral, meniscocapsular, and
conservatively with good responses to treatment. meniscotibial. Posterior to the MCL is the pos-
High suspicion of PLC injuries must be made in teromedial corner (PMC) called posterior oblique
the presence of arcuate fractures involving the ligament (POL), which is a condensation of the
fibular head and such condition is best diagnosed capsule, together with semimembranosus and
by MRI and treated during the first 3 weeks post-­ medial meniscus. This complex is tight in exten-
injury with improved outcomes [365]. Thus, PLC sion [376]. As a primary restraint to valgus stress,
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 507

a b c

Fig. 22.18 (a) Ultrasound image of the longitudinal (MM) and the superficial layer is free. (c) Ultrasound
view of the medial collateral ligament (MCL) as it inserts image of the distal insertion of the medial collateral liga-
from the femoral condyle (F). (b) Ultrasound image of the ment (MCL) in longitudinal view deep to the pes anserine
medial collateral ligament (MCL) in relation to the medial structures made up of sartorius (S), gracilis (G), and semi-
meniscus (MM), where the inner fiber of the medial col- tendinosus (ST) in the tibia (T)
lateral ligament (MCL) is attached to the medial meniscus

MCL exerts 78% of resistance at 25° knee flex- the MCL. The presence of an effusion is a warning
ion. In full extension, the PMC with ACL con- sign of an intraarticular injury [383]. Three differ-
tributes to valgus stress with MCL still restraining ent grading systems are used for MCL injuries
57% of the force. Thus, valgus laxity in flexion is based on MRI findings and clinical findings. Grade
highlighted with an isolated MCL injury but with I injury refers to an intact fiber with surrounding
an additional laxity in knee extension when PMC edema, grade II injury shows partial disruption,
and ACL are injured. Moreover, in full extension, and grade III injury shows complete fiber disrup-
the greatest strain is at the posterior part of the tion and avulsion [384]. Stress testing of the MCL
MCL, while strain at the anterior fibers is con- is done with the knee in 0-30 degrees flexion while
stant in all flexion angles [380]. Recently, the applying valgus force at the medial joint line. The
study of Kramer and colleagues confirmed prior grading is based on AMA and is as follows: grade
research by Gardiner regarding injuries affecting I, 0–5 mm opening with painful/firm endpoint,
the proximal portion of the MCL in its posterior grade III, with >10 mm opening with soft or absent
origin when the knee is in full extension among endpoint, and grade II, in between with firm end-
pediatric and adolescent athletes [381]. Moreover, point [385]. Although rare, distal superficial MCL
Wierer and colleagues reported that the superfi- lesion could occur and appear in the MRI as a
cial MCL capsuloligamentous structure is the “wavy” lesion, described as fibers with a serpen-
most important restraint in anteromedial instabil- tine morphology. Also, when the proximal stump
ity with the deep MCL and POL playing minor of the superficial MCL is located superficial to the
roles. Thus, the superficial MCL is the key medial pes anserine and sartorius fascia, it is referred to as
restraint to valgus rotation, anteromedial transla- Stener-like lesion (SLL). Further, a distal lesion of
tion, and external tibial torsion [382]. the superficial MCL is characterized as an injury
The mechanism of injury is either a direct blow inferior to the medial joint line [386]. This type of
to the lateral knee on a planted foot or pivoting lesion is always accompanied by other structural
activity that produces a valgus moment in the knee injuries. Boutin and colleagues reported a con-
[377]. Although most athletes are injured by direct comitant tear of ACL at 82%, PCL tear of 22%,
contact, they will typically complain of pain with deep MCL tear of 61%, and lateral compartment
weight-bearing characterized by wobbling gait osseous injury of 94% with or without SLL-
and instability due to pain. Local swelling is usu- associated findings [387]. Injury of the PMC and
ally seen at the femoral origin (most common) of oblique popliteal ligament gave rise to pain, func-
508 J. C. de Castro

tional genu recurvatum instability, and failed ACL flare of the distal femur 31.4 mm proximal to the
reconstruction [388]. Ultrasound of the MCL of lateral epicondyle. The superficial lateral genicu-
the knee is an acceptable modality in showing the late artery can serve as the reference as it is found
anatomical detail of the superficial structures of just distal to the distal Kaplan fibers with the
the knee which may be difficult when using other capsulo-osseous layer of the ITB attached proxi-
diagnostic modalities. Skill and experience though mally to the lateral gastrocnemius tubercle [391].
define the best results for diagnosing an MCL Capsulo-osseous layer is also sometimes referred
injury [388]. to as the ALL and other different names were
An isolated MCL injury, whether sprains or made to refer to it like short lateral ligament,
tears (grades I and II), is treated conservatively mid-third lateral capsular ligament, and lateral
with good functional outcomes. However, capsular ligament [392]. Recently, Landreau and
when a grade III or complete MCL injury with colleagues [392] identified another distinct struc-
concomitant major ligament tears is diagnosed, ture after doing a cadaver dissection via a poste-
surgical intervention is always indicated. rior approach, but a previous study by Terry and
Moreover, the rare distal superficial MCL colleagues used anterior approach [393]. This
injury at or near the distal tibial attachment is structure was identified as “condylar strap” of the
always an indication for surgery because of ITB, and this is attached to the deep ITB and the
poor anatomic ligament healing and chronic femoral epicondylar area, which plays a role in
valgus instability with any conservative inter- anterolateral knee rotatory stability [392]. The
ventions [387]. Kaplan fibers earlier described by Godin and col-
The use of platelet-rich growth factors in leagues [391] could very much be seen in a rou-
MCL injuries is beneficial for early return to ath- tine MRI scan in an ACL-intact knee. With its
letic activities as shown in one study [389]. Three important role as a secondary stabilizer in the
case studies were reported showing recovery of ACL-deficient knee, its identification plays an
the damaged MCL, indicating that PRP hastened important role in the non-pathologic state.
the healing process of ruptured ligaments of both Moreover, it is suggested that the best plane to
superficial and deep layers of the MCL [390]. identify the Kaplan fibers in both normal and
pathologic states is in the sagittal plane with the
Iliotibial Band Injuries coronal plane being the worst. The identification
The iliotibial band (ITB) is a vital structure in the of the superior geniculate artery, lateral gastroc-
knee that provides restraint in internal rotation nemius origin, and lateral joint line has a good
together with the anterolateral ligament. The dis- correlation with cadaver studies and thus are
tal insertion of the ITB at the Gerdy’s tubercle of appropriate references for MRI identification of
the proximal tibia (Fig. 22.17b) may appear sim- such structures [394]. In a related study, Batty
ple at first, except for the fact that the cadaveric and colleagues reported a rate of 23.7% in diag-
study of Godin and colleagues provides us a nosing Kaplan injuries by MRI when done before
complex and comprehensive understanding of 90 days as compared to the 6.4% rate when per-
how it is attached both at the distal femur and formed after 90 days. Moreover, there is an
proximal tibia. Two separate bundles at the distal increase in associated injury by radiological find-
femur were identified referred to as Kaplan fibers. ings involving lateral meniscal injury, postero-
The proximal deep bundle (proximal Kaplan medial tibial bone marrow edema, and injury to
fibers) arises from the undersurface of the ITB the lateral and medial collateral ligament in a
and attach to the proximal ridge of the proximal Kaplan fiber injury. Due to its role in providing
femoral diaphysis, 53.6 mm proximal to the lat- anterolateral rotatory knee stability, its injury
eral epicondyle, while the distal deep bundle implies a high energy level of injury to the lateral
(distal Kaplan fibers) goes from lateral to distal knee. It is, however, reported that only about
and then medial and inserts at the supracondylar 18.6% of patients with an ACL injury show inju-
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 509

ries involving the Kaplan fibers [395]. Herbst and of related structures including the iliotibial band
colleagues, however, noted that the rotatory knee shows an effect with a return to dancing within
stability is provided by the anterolateral complex 6 months of therapy [401].
of the knee which is composed of the three
Seebacher layers and capsule-osseous layer of Patellar Tendon Sports Injuries
the ITB and the anterolateral joint capsule (ALC) Patellar tendinopathy otherwise referred to as
[396]. Getgood and colleagues with the ALC “jumper’s knee” is an overuse injury of the patella
Consensus Group Meeting included the antero- associated with sports such as running, jumping,
lateral ligament (ALL) as part of the ALC [397]. and kicking due to its repetitive and explosive
Iliotibial band syndrome (ITBS) is an inflam- activities. It is found in 55% of male basketball
mation of the distal part of the ITB and is second players. The pathology in the tendon is usually
only to patellofemoral pain as the most common characterized by microinjury to the tendon fibers,
chronic pathologies of the knee among runners, local mucoid degeneration, necrosis, and loss of
with females twice as much as males being transitional fibrocartilaginous tissue at its inser-
affected. Aside from runners, it also affects tion site to the bone but often with no sign of
cyclists and field hockey, basketball, and soccer inflammation [402]. This problem could take a
players [398]. Sinclair and colleagues have toll on the athlete’s performance, especially with
reported that the peak ITB strain and strain veloc- continuous sports activity, and develop into par-
ity alongside the impingement duration are high- tial patellar tendon tears (PPTT). This can even-
est during the run and cut movements compared tually lead to prolonging recovery time, reduced
to the hop and that the medial and off the shelf performance, and increased time off from sports
orthosis attenuates the mechanism linked to the and with a foreseeable unnecessary retirement
cause among female runners [398]. from their sports. Golman and colleagues
Ultrasound of the knee provides excellent reported that PPTT usually occurred at the poste-
visualization of the structures of the knee includ- rior and posteromedial portion of the patellar ten-
ing ITB. Under normal conditions, it appears as a don in 91% of cases which could be explained by
linear fibrillar structure from the lateral femoral its poor vascularity in that region [402]. The
condyle to the Gerdy’s tubercle of the tibia. A cadaveric findings of Pang and colleagues have
dynamic imaging technique can be done over the reported that the anterior patella is supplied by
femoral condyle during flexion and extension of three blood vessels namely inferolateral genicu-
the knee to detect any snapping [399]. Iliotibial late, anterior tibial recurrent, and inferomedial
band syndrome in ultrasound shows soft tissue geniculate while the posterior patellar tendon
edematous swelling, discrete fluid collection receives its blood supply from the smaller arter-
between the iliotibial bands, and lateral femoral ies of the retropatellar anastomotic arch in the
condyle suggestive of adventitial bursitis with Hoffa’s fat pad [403]. In fact, the collagen con-
thickening of the iliotibial band at the Gerdy’s tent and turnover of the entire patella are the
tubercle as an inconsistent finding [399]. same in all its length, although the glycosamino-
Sometimes, cortical irregularity may be seen at glycans (GAG) content is higher in the insertion
the lateral femoral condyle. Note the presence of and distal regions [404]. The patellar tendon
the fluid effusion at the lateral recess of the supra- thickness as measured by axial MRI scans of
patellar bursa which may be confused for the >8.8 mm has a high correlation of tear of the
fluid deep to the ITB [399]. It is possible that the patellar tendon. In fact, athletes with >11.5 mm
fluid collection deep to the ITB can be due to fat thickness or >50% tear thickness were less likely
pad compression and not to the actual ITB itself to improve with conservative interventions [402].
during running [400]. The use of PRP in the treat- On the other hand, patellar tendinopathy may be
ment of the iliotibial band has not been studied either symptomatic or asymptomatic. These
lengthily, although ultrasound-guided injection observations are important in predicting which
510 J. C. de Castro

a b

Fig. 22.19 (a) Ultrasound image of the longitudinal axis fat pad and the hypoechoic hyaline cartilage (C). (b)
view of the fibrillar pattern of the patellar tendon (PT) Short-axis view of the proximal portion of the patellar ten-
from its attachment in the patella (P) and inserts distally at don (PT) where most of the pathology can be seen
the tibia (TIB). Deep to the patellar tendon is the Hoffa’s

athletes are at risk for tendon pain, which is found Meniscal Injuries
in 45% in volleyball and 32% in basketball play- Meniscal injuries are common among athletes
ers [405]. Ultrasound imaging is a useful tool in and are usually caused by a combination of axial
determining which athletes will develop tendon loading and rotational forces that is translated on
pain or not in asymptomatic athletes. For instance, the meniscus. It could be injured in isolation or in
if an asymptomatic athlete does not show evi- a combination of other related structures such as
dence of structural changes such as thickening, the ligaments and articular cartilages. One of the
hypoechogenicity, and neovascularization, symptoms felt by an injured athlete is character-
asymptomatic athletes are at low risk for devel- ized by pain, swelling, and a peculiar locking,
oping any patellar tendon pain. In fact, an athlete buckling, and catching sensation [408]. Medial
can continue competitive sports activity even up meniscal tears are more common than lateral
to 3 years without any problem. Of those ultra- tears with males more commonly affected than
sound characteristics providing the highest asso- females with a ratio of 2:1–4:1 [409]. Moreover,
ciation to pain, neovascularization followed by meniscal root tears were reported to occur in
hypoechogenicity emerges as consistent findings association with multi-ligament knee injuries
[26] (Fig. 22.19). (less than 2%) because of compressive forces,
Platelet-rich plasma therapy reported good with valgus injury patterns seen associated with
results for patellar tendinopathies by Di Matteo lateral root tears and varus injury patterns seen in
and colleagues in a systematic review, although medial root tears. Meniscal root injuries are asso-
there are limited studies available to recommend ciated with rapid extrusion of the meniscus and
its use for such patients. It is therefore recom- rapid deterioration of the articular cartilage which
mended as a second line of treatment when other when left untreated leads to poor function and
conservative measures fail [406]. Le and col- subsequent surgery [410].
leagues recommend the use of LR-PRP for patel- In a recent study by Vaishya and colleagues,
lar tendinopathy showing good results in 6-month elite athletes of Indian and Brazilian origin
and 12-month follow-up [407]. showed that a quarter of them undergo surgery
such as partial arthroscopic meniscectomies with
lateral meniscectomy showing poorer prognosis
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 511

a b

Fig. 22.20 (a) Ultrasound image of a 51-year-old male and degenerated medial meniscus (MM) deep to the semi-
complaining of medial knee pain showed a bulging medial membranosus tendon (SM). Also seen are the medial gas-
meniscus (MM) deep to the medial collateral ligament trocnemius (MG) muscle and semitendinosus (ST)
(MCL). (b) Ultrasound image of a 52-year-old female tendon. F femur, T tibia
complaining of a posterior knee pain showing a bulging

than the medial side. The poor prognosis is asso- enced clinicians using tests such as Thessaly’s,
ciated with a return to the previous level of play, McMurray’s, and Apley’s to make a correct diag-
longer recovery, more problems post-surgery, nosis of meniscal injuries equal or even better
and a need for further arthroscopy [411]. In addi- than MRI [414].
tion, a peculiar observation is seen among side Up until the present, arthroscopic partial men-
midfielders showing the shortest recovery period iscectomy (APM) remains very popular among
with the goalkeepers showing the longest recov- orthopedic surgeons for the treatment of menis-
ery period reflecting the dynamic activity cal injuries. However, recent studies reported that
assigned to these players. Football has the high- meniscal repair is a more viable and more effec-
est knee injury during the summer Olympics tive alternative for such conditions. This proce-
while Alpine skiing showed the greatest knee dure aims to achieve meniscal healing while
injuries during winter [411]. MRI remained as avoiding the early onset of degenerative change
the imaging of choice for meniscal tears. It has a of partial meniscectomy, especially among young
sensitivity and specificity of 93% and 88% for and active athletes. Moreover, this procedure
medial meniscal tears and 79% and 95% for lat- does not come without a long-term failure rate of
eral tears, respectively. The low sensitivity of lat- less than 10% at a 2-year follow-up and a long-­
eral meniscal tears can however be complemented term failure rate (5 years) of 30%. Thus, there is
by a confirmatory arthroscopic finding [408]. a need to look for other alternative procedures
Similarly, ultrasound as a diagnostic tool such as meniscal allografting which shows an
(Fig. 22.20) was sensitive and specific and com- 89.2% 10-year follow-up survival rate [415]. The
parable to MRI in diagnosing meniscal injuries technique of meniscal allograft transplantation is
as reported by Xia and colleagues, and its use for becoming the standard of care for total meniscal
routine examination of meniscal injuries of the insufficiency. Further, artificial scaffold-based
knee is recommended [412]. Although MRI meniscal substitution although still evolving for
remains to be the imaging of choice for meniscal the treatment of irreparable partial meniscal inju-
knee injuries, ultrasound can be used to diagnose ries is becoming a feasible procedure in improv-
meniscal injuries in acute knee injuries as con- ing outcomes, especially for patients with
firmed by an arthroscopuc examination in acute post-meniscectomy syndrome. This progress in
knees [413]. Of special note, however, is the abil- treatment is due to more comprehensive tissue
ity of rigorous physical examination by experi- engineering [416]. A recent systematic review by
512 J. C. de Castro

Belk and colleagues reported that an additional fessional football players have suffered from
PRP treatment after meniscal repair did not show ankle sprain [421]. However, with an improved
any difference in outcomes at midterm follow-up preventive rehabilitation strategies and stricter
[417]. games rules, the incidence rate decreased to
10–15% [422]. It has now become the fourth
 nkle and Lower Leg
A most common injury in sports. In one study, half
Ankle and lower leg injuries remain one of the of those with acute injuries may lead to chronic
most common sites of sports injuries. In a recent ankle sprain in their lifetime. Most often, an
study by Lucasti and colleagues among profes- inversion ankle injury may affect the lateral ankle
sional baseball players, covering 2011–2016, the ligament (ATF ligament), with 30% to 40% pro-
most common injuries included leg contusions, gressing into chronic ankle injury because of
anterior talofibular ligament sprains, unspecified non-healing. Recent findings point to the injury
ankle sprains, ankle contusions, and gastrocne- of the intra-articular superior fascicle of the ante-
mius strains. A review of the epidemiological rior talofibular ligament which is commonly
data showed that ligamentous sprains (37%) fol- affected during an inversion ankle injury
lowed by muscle strains (13%), bone problems (Fig. 22.21). The intra-articular location of the
(6%), and tendon injuries (6%) were noted [418]. superior fascicle could be the reason for its
Of this, the ankle lateral collateral ligament impaired healing [423]. The inferior fascicle of
(LCL) complex takes precedence as one of the the ATFL is attached to the calcaneofibular liga-
most injured areas in the ankle. This complex ment (CFL) through the arciform fibers. Together,
includes anterior talofibular ligament (ATFL), they form what is referred to as the lateral fibulo-
calcaneofibular ligament (CFL), posterior talo- talocalcaneal ligament (LFTCL) complex, which
fibular ligament (PTFL), and anterior tibiofibular is present in 100% of cases studied by Vega and
ligament (injured in high ankle sprain) [419]. colleagues. Moreover, the inferior fascicle of the
ATFL and the anterior border of the CFL are
Ankle Inversion Sprain attached to the subtalar joint capsule [424]. Injury
Ankle sprain used to be the most common injury to the superior fascicle of ATFL leads to ankle
among athletes [420]. In the past, 10–36% of pro- microinstability and is a subtle form of a lateral

a b

Fig. 22.21 (a) Ultrasound image of the longitudinal ment (CFL) deep to the peroneus longus (PL) and pero-
view of the anterior talofibular ligament (ATFL) with its neus brevis (PB) tendons. Typically, the deep layers of
superficial (intra-articular) and deep (extra-articular) lay- ATFL are attached to the anterior border of the CFL
ers. The superficial layer of the ATFL is commonly through the arciform fibers which form a complex referred
injured. (b) Ultrasound image of the calcaneofibular liga- to as lateral fibulotalocalcaneal ligament (LFTCL)
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 513

ankle injury. The LFTCL complex is an extra-­ Surgery and arthroscopy are said to be the high-
articular structure and as such can heal when est quality standard of reference. Chen and col-
injured. This is the main lateral ankle joint stabi- leagues have shown that ultrasound has a 93.8%
lizer and is an isometric structure. Injury to this sensitivity and 90.9% specificity for chronic lat-
ligament complex could lead to classical lateral eral injuries involving CFL with intraoperative
ankle instability [423]. Injury to the inferior and surgical findings as the standard of reference
superior ATFL however will result in chronic [426].
ankle instability [424]. Presently, no studies can The initial focus of treatment and rehabilita-
confirm whether an intra-articular lateral ankle tion with ankle sprain includes reducing pain
injury or its hidden pathology could be the reason while at the same time effort should be made to
for its instability and chronic involvement. Other restore the range of motion and strength of the
residual symptoms include chronic pain and patient. Persistent pain and instability even in the
muscular weakness. A study has shown that pre- absence of fracture may be an indication for sur-
vious history of ankle sprains increases the gery. The use of orthobiologics however showed
chance of incurring a recurrent ankle sprain up to promise in this case, although no large-scale
2 to 5 times compared to those with no history of studies have been reported. There are reported
ankle injury regardless of the severity [420]. cases of a faster return to play and greater func-
In a typical ankle inversion sprain, the supe- tional improvement with platelet-rich plasma
rior fascicle of ATFL being the weakest absorbed injections, especially in high ankle sprains [427].
the initial brunt of the injury and became the first However, for a lateral ankle sprain, there is no
to be affected (Fig. 22.21). With an additional significant difference in effect using an LR-PRP
force during an ankle inversion injury, the infe- for acute ankle injury [407].
rior fascicle together with the CFL is impaired. Return to play for a lateral ankle injury is a
Finally, an added and continuous force will even- more challenging task with several variables to
tually damage the posterior talofibular (PTFL) be considered in the process. These variables
ligament that could possibly lead to lateral ankle include clinical, functional, sport-specific, psy-
dislocation [424]. chosocial, and decision-modifying. In a recent
MRI remains the modality of choice for diag- study, it was advised not to include a time-­
nosing ligamental injuries with a sensitivity of contingent approach as each variable can change
92–100% and a specificity of 100% for ATFL as the patient moves to its return to sports pro-
injuries. In comparison with arthroscopy, how- cesses [428].
ever, MRI can correctly identify the injured part
of the ATFL in 93% of cases in contrast to ultra- High Ankle Sprain
sound at 63% [420]. In a meta-analysis reported High ankle sprain or otherwise called syndes-
by Seok and colleagues, the diagnostic capability motic sprains are not as common as ankle inver-
of ultrasound has a sensitivity of 99% and a spec- sion sprains but is three to four times more severe
ificity of 92% for ATFL injuries. It has a sensitiv- than lateral ankle sprains. It is usually seen in
ity and specificity of 95% and 99%, respectively, men’s football, ice hockey, and wrestling. It usu-
for CFL injuries. In subgroup analysis, ultra- ally affects the syndesmosis of the distal tibio-
sound has a sensitivity and specificity of 95% and fibular joint causing significant chronic pain and
82% for complete ATFL tears and a sensitivity ankle instability. A recent systematic review
and specificity of 90% and 82% for partial ATFL reported by Prakash showed that sporting popu-
tears, respectively, and thus is recommended as lation especially during the second or third
the first line of diagnostic modality replacing decade of life are more prone to this injury with
stress radiography [419]. This data was con- the highest risk during the competition [429].
curred by the systematic review studies on ultra- Traumas involving this joint may injure the ante-
sound of the ankle done by Lee and colleagues, rior inferior tibiofibular ligament (AITFL), poste-
which are recently published in 2020 [425]. rior inferior tibiofibular ligament (PITFL), and
514 J. C. de Castro

a b

Fig. 22.22 (a) Ultrasound image of the anterior inferior proper. (b) Ultrasound image of the distal component of
tibiofibular ligament (AITFL) which is commonly injured AITFL referred to as Bassett’s ligament. This structure
in a high ankle sprain or what is referred to as AITFL can also cause anterior ankle impingement

the interosseous ligament. The AITFL has two Misdiagnosed syndesmosis injury is a usual
components: the AITFL proper and the distal source of disability and delayed return to sport.
Bassett’s ligament which can cause anterior ankle Although MRI is considered the imaging of
impingement (Fig. 22.22). The most stable liga- choice for a suspected high ankle sprain, it has a
ment, PITFL, is also made up of two compo- lower chance of diagnosing it correctly after
nents: superficial and deep, which is also referred 6 weeks post-injury, with 12 weeks post-injury
to as transverse ligament. The interosseous liga- showing a normal MRI scan despite the ankle
ment is contiguous with the proximal interosse- instability. In fact, posterior malleolar edema is
ous membrane [430]. the only sign of a complete syndesmosis injury
Syndesmotic injuries are usually caused by with a surprisingly normal appearance of PITFL
excessive rapid-pivoting ankle rotation or com- [433]. In a recent study, Calder and colleagues
bined ankle dorsiflexion in a pronated foot with a identified in MRI scans, a subcircumferential
forceful external rotation of calcaneo-talar-­fibular edema, 4–6 cm above the ankle joint in patients
complex on a fixed forefoot [431]. The ligaments with syndesmosis injury which they coined as
of the ankle are injured in this order of frequency broken “ring of fire.” It has a specificity of 97%
from the most to the least common: AITFL, inter- and a sensitivity of 49%. This finding is seen
osseous ligament, and rarely the PITFL [430]. when there is substantial trauma to disrupt part of
The deep deltoid ligament may also be conse- the interosseous membrane leading to bleeding
quentially affected by this injury. Recent biome- around that area [434]. Ultrasound can provide
chanical studies reveal a multidirectional excellent visualization of the syndesmotic liga-
instability with anteroposterior translational and ments of the ankle and differentiate the pathology
rotational instability of the distal fibula relative to of each ligament (Fig. 22.22). It can provide
the tibia. What eventually separates the distal stress maneuvers and dynamic evaluation to
tibia and fibula is the rotation of the talus in the ensure whether a particular ligament is partially
mortise, with the fibula rotating externally and or completely torn [435]. In fact, ultrasound has a
moving posteriorly and laterally [431]. In a sensitivity of 66% and a specificity of 91% for
related study, this injury when accompanied with detecting AITFL pathology using a 13 MHz
tibial periosteal stripping by the avulsion of probe as compared to MRI [436]. Recent studies,
extra-osseous vasculature may lead to osteone- however, showed 100% sensitivity and specific-
crosis in about 3–4 weeks following the initial ity for AITFL pathologies using dynamic stress
injury [432]. ultrasonography, but this study had a very small
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 515

sample size [437]. Moreover, Fisher and col- injury mechanism is the key to effective rehabili-
leagues noted that a supination external rotation tation and prevention protocols. In a kinematic
(SER) stress ultrasonography test with 25% of analysis, Wade and colleagues have reported that
AITFL fibers intact will be able to sustain the a combination of ankle dorsiflexion during heel
force and will have a tibiofibular space widening strike followed by a rapid eversion is associated
of up to about 5.4 mm and thus can be treated with a non-contact ankle eversion sprain [443].
conservatively. However, in complete tears, stress Medial ankle sprains represent 15% of all ankle
ultrasonography was reported to show a tibiofib- sprains. The incidence of this injury increases in
ular space widening of 6 mm (normal is 4.5 mm). the presence of associated trauma such as lateral
Therefore, dynamic stress ultrasonography is a ligament injuries, malleolar fractures, or syndes-
useful evaluation of the extent of AITFL injuries motic disruptions [444]. In fact, in an arthroscopic
[438]. Becciolini and colleagues recently pub- study reported by Hintermann and colleagues,
lished a paper detailing the technique for imaging 40% of patients with chronic ankle instability
the PITFL using ultrasound where both the revealed a different type of injury involving the
superficial and deep components are visualized deltoid ligament [445].
[430]. In another recent study, a sagittal transla- The deltoid ligament is made up of three con-
tion was done in ankle syndesmotic injury using sistent ligaments (tibiospring ligament, tibiona-
ultrasound with significant and reliable results vicular ligament, and deep posterior tibiotalar
[439]. ligament) and three variable ligaments (superfi-
There are several approaches for treating these cial posterior tibiotalar ligament, tibiocalcaneal
injuries which include physical rehabilitation, ligament, and deep anterior tibiotalar ligament).
bracing, neuromuscular training, use of non-­ These ligaments are recognized as an important
steroidal anti-inflammatory drugs, manual ther- stabilizer of the medial tibiotalar joint [444].
apy, and surgery. Orthobiologics treatment was Furthermore, the ankle ligaments can be divided
reported in two studies [427], with one study into superficial and deep structures. The deep
using a single injection of platelet-rich plasma in ligaments of the deltoid are the deep posterior
syndesmosis injuries of the ankle involving the tibiotalar ligament (major ligament) and deep
AITFL and tibiofibular joint showing a faster anterior tibiotalar ligament. The rest of the liga-
return to play [440]. Samra and colleagues in a ments on the medial side of the ankle comprising
related study showed similar results [441]. The the deltoid ligament are superficial in location
only limitation for both studies is the small sam- [446]. The rich vascularity of the deltoid liga-
ple sizes [427]. ment is one reason why injury to this structure
Poor outcomes for acute ankle sprains are heals with conservative treatment; otherwise, any
affected by several factors. However, none of disruption to the blood supply during an ankle
them seemed to be consistent. Of these factors, trauma may predispose it to delayed or inade-
early surgical intervention is suggested for the quate ligament healing [444]. Moreover, when
following group of athletes/patients: high level/ the injury to the ligaments involves the superfi-
high demand athletes, severe injuries which cial ligaments, and the deep ligaments are intact,
include bone bruise, multi-ligament involvement, the medial clear space (MCS) of the medial ankle
persistent pain, and sprain recurrence, and lastly, is not altered, and thus conservative management
the presence of associated injuries like bony can be used to treat such patients. However, when
avulsion or cartilage injury [442]. a combination of superficial and deep ligaments
is injured, the medial clear space is significantly
Medial Ankle Sprains altered and thus this type of injury requires a sur-
Unlike lateral ankle sprains, medial ankle sprains gical approach for treatment, regardless of
have more severe pathomechanism of injury. It is whether there is a bony fracture or not [446].
associated with comorbidities, requiring longer Magnetic resonance imaging (MRI) scans
treatment and recovery times. Understanding the remain as the gold standard imaging modality to
516 J. C. de Castro

diagnose deltoid ligament injuries including sis is often seen in overuse injuries and usually
other associated abnormalities like bone edema, responds with conservative treatments. When no
intra-articular lesions, and joint effusions. improvement is seen in 6 months trial of conser-
However, it cannot provide any assessment on vative treatment, surgical debridement is consid-
ankle stability due to its static images. An ered. Acute Achilles tendon ruptures are observed
arthroscopic examination may show the integrity to be increasing due to a more active older popu-
of the medial ankle. However, it is an invasive lation engaging in exercise and sports activities.
procedure. Ultrasound proves to be a potential Thus, the pathology of the Achilles tendon can be
imaging modality that can assess for ankle stabil- acute or chronic or could be a spectrum of tendi-
ity due to its dynamic capability, portability, and nosis to actual tears, affecting both athletes and
non-invasiveness. Rosa and colleagues have nonathletes alike [449].
reported using ultrasonography that an intact del- Being the largest and strongest tendon in the
toid ligament (DL) had a medial clear space human body, the Achilles tendon is a confluence
(MCS) of 2.7 +/− 0.5 mm, a partial DL tear had of the gastrocnemius and soleus muscles inserted
an MCS of 5.2 +/− 2.4 mm, and a complete DL into the posterior calcaneal bone. From its origin,
tear had an MCS of 9.9 +/− 5.8 mm. Those with it spans three joints and is therefore actively
superficial DL tear had a mean MCS of 4.2 +/− involved in knee flexion, ankle dorsiflexion, and
0.3 mm, those with deep tears had a mean MCS hindfoot inversion. The etiology of Achilles ten-
of 4.5 +/− 0.6 mm, and those with tears in the don injuries can be due to any of the two possible
two layers had a MCS of 6.2 +/− 3.6 mm [447]. theories, namely, the chronic and degenerative
Thus, ultrasound showed 100% sensitivity and changes that come by age, or can be secondary to
90% specificity in this study. Arthroscopic exam- medications such as fluoroquinolones or cortico-
ination using gravity stress views, an MCS steroids or due to acute healthy traumatic inju-
greater than 5 mm had complete ruptures, those ries. Other factors that could possibly predispose
with less than 5 mm, but greater than 4 mm MCS injury include biomechanical malalignment such
is either intact or partial DL tear [446]. As frac- as hyper-pronation or inappropriate footwear
ture is commonly associated with deltoid liga- [450]. This hyper-pronation causes the rotation
ment injuries, there is always a need to surgically of the tendon to be accentuated which conse-
repair the ruptured ligament and its associated quently decreases the blood flow to the Achilles
fracture or d­islocation. Failure to surgically tendon, a phenomenon referred to as “whipping
repair the deltoid ligament tears may lead to early action” [451]. Arner and colleagues [452] have
osteoarthritis due to malalignment during weight- postulated that the tendon that has undergone
bearing. There is a relatively safe zone for surgi- degenerative changes could be coming from an
cal repair in the medial ankle without injuring the aging process and thus deprived itself of a normal
saphenous nerve or vein in the ankle [447]. blood flow which leads to hypoxia and altered
Salameh and colleagues have confirmed that a metabolism. This represents about 25% of
surgical repair of tibial fractures with the concur- Achilles tendon injuries [453]. In fact, this injury
rent repair of the deltoid ligament has shown a is difficult to diagnose and is more demanding in
better anatomical reduction of the ankle with terms of treatment and management. It is more
reduced MCS, lower pain scores, and lower com- challenging to diagnose it in the early stage [453].
plication rate [448]. No studies about orthobio- Moreover, Achilles tendon rupture is not always
logic treatment for deltoid ligament were reported preceded by tendinous degeneration and is com-
at present. mon among patients with non-sports-related inju-
ries and those with low sports activity [450].
Achilles Tendon Injuries However, Barfred and colleagues have observed
Achilles tendon pathologies are very common in a rat model, that what occurs among healthy
among athletes and their involvement from any subjects happened in a push-off type activity
trauma in sports is debilitating. Chronic tendino- where an obliquely loaded tendon at a short ini-
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 517

a b

Fig. 22.23 (a, b) Ultrasound images of the Achilles ten- (RCB) and superficial to it is the retroachilles bursa
don in longitudinal views show the Achilles tendon fiber (RAB). The Kager’s fat pad is shown anterior to the
as it inserts into the posterior calcaneal (c) bone. Deep to Achilles tendon
the Achilles tendon is shown the retrocalcaneal bursa

tial length is under a maximum muscle contrac- because of its portability. It has the capability of
tion. This asynchrony is common among athletes diagnosing tear, partial or complete, tendinosis,
who do not train consistently before engaging in type, and level of the rupture and can monitor the
a challenging sports activity [454]. Most tears changes during the healing process. Because of
occur about 3–6 cm proximal to the insertion at its dynamic capability, an ultrasound-­ guided
the calcaneus and usually this is because of a Thompson test has a sensitivity of 86% and a
paucity of vascularity by the posterior tibial specificity of 91% when compared with static
artery and this decreases over time and age [455] ultrasound imaging alone [459]. It is, however,
(Fig. 22.23). The ruptures usually occur between user-dependent and requires a great deal of
30 and 50 years, with older ones taking more familiarity and training to be able to make an
time for healing after any intervention is done accurate diagnosis [455]. Ultrasound changes,
[455]. Among the different types of sports, bas- however, maybe also seen in asymptomatic
ketball takes the lead for acute Achilles tendon patients and may be worth mentioning especially
rupture, followed by soccer and tennis [456]. since these are athletes who are engaged in active
There are systematic ways to identify an sports, such as among runners and soccer play-
Achilles tendon tear in a patient. A typical ers. The presence of neovascularization followed
patient will report a pop at the time of injury, by focal hypoechogenicity had a direct correla-
with immediate pain and an inability to plan- tion with the development of tendon pain.
tarflex the ankle or bear weight [455]. During a Caution however must be observed when inter-
physical examination, a defect can be palpable preting such findings [26]. Moreover, elastogra-
along the length of the Achilles tendon. The phy ultrasound is another feature in ultrasound
most widely used test is Thompson’s or that can make an early diagnosis for tendon
Simmond’s test. It has a sensitivity of 96% and a pathologies such as in Achilles tendon where
specificity of 93% [457]. Diagnostic modalities tendon stiffness is being assessed as well as
can further confirm your diagnosis by using monitoring post-op rehabilitation to evaluate and
either MRI or ultrasound. MRI is the gold stan- guide on-going treatments [7].
dard for a suspected Achilles tendon tear. It has a There are varied techniques of treatment in an
sensitivity of 94%, a specificity of 81%, and an Achilles tendon rupture with competing results
overall accuracy of 89% [458]. However, diag- of interventions, with each intervention showing
nostic ultrasound is a readily available modality its own benefits and disadvantages. In the past, it
518 J. C. de Castro

is common to have an immediate surgical inter- romusculoskeletal conditions. Aside from its
vention for an Achilles tendon rupture. However, unique feature of dynamic imaging, it has sev-
there are issues that come with operative inter- eral features that are now being included like
ventions such as infections, and devastating ultrasound elastography, ultrasound tissue char-
wound complications [455, 460]. Presently, non-­ acterization (UTC), and contrast-enhanced ultra-
operative treatment finds its way among clini- sound (CEUS). Ultrasound elastography is very
cians which consists of early mobilization and useful for identifying at-risk tendons among ath-
functional rehabilitation with significantly good letes. In a study of asymptomatic foot players,
outcomes such as reduced re-rupture rate. preseason softening of the Achilles tendon on
However, this approach may take several weeks strain elastography (SE) has a direct correlation
of intensive physiotherapy to achieve optimal for the development of symptoms postseason
results [455]. Aufwerber and colleagues under- [467]. Moreover, shear wave elastography
scored the importance of accelerated postopera- (SWE) or otherwise called dynamic elastogra-
tive protocol with immediate loading and ankle phy quantifies the stiffness of the tendons. It
motion in 6 months in Achilles tendon rupture however requires a depth of at least 0.4 cm for
[461]. From the surgical standpoint, the more the SWE to be generated. A depth of 9 cm from
conventional operative care appears to be evolv- the surface of the skin cannot be assessed prop-
ing where most surgeons prefer the less invasive erly due to pulse attenuation [467]. To bypass the
surgical technique such as minimally invasive depth limitation, especially for shallow struc-
and percutaneous surgical technique over the tures, applying a 5-mm layer of coupling gel
open technique with the advantages of lesser risk may serve as a stand-off [468]. It also has limited
for wound complications and infections but carry capability in assessing fluid-filled structures and
with it a more challenging learning curve for sur- soft tissue embedded in harder and incompress-
geons [460, 462, 463]. ible tissues [467]. SWE has shown great utility
Orthobiologic interventions such as platelet-­ in rotator cuff conditions as they correlate with
rich plasma (PRP) therapy have shown signifi- functional scores. In one study, it was shown that
cant benefits in an Achilles tendon injury. Neph long years of participation in sports revealed a
and colleagues have recently noted that PRP decrease in stiffness of the supraspinatus tendon
injection can be further potentiated for tendon which corresponds to increased thickness in
regeneration when mechanical loading rehabili- ultrasound and a self-­reported decline in func-
tation protocols are incorporated in Achilles tion [469]. Compared to SE, SWE is more objec-
­tendinopathy [464]. For Achilles tendon rupture tive, quantitative, and reproducible. This
(ATR), however, Boesen and colleagues in a ultrasound feature can also be used to monitor
recently published randomized, double-blinded the progress of the rehabilitation program. For
prospective study have not shown tendon healing instance, a postoperative Achilles tendon shows
or improved patient-reported outcomes and func- a progressive increase in stiffness in SWE after
tional and clinical outcomes in the first 12 months completing a rehabilitation program indicating
after an ATR by using PRP [465]. an improved functional score. The increase in
Athletes sustaining an ATR faced a challeng- stiffness can be due to the physiological healing
ing year ahead with 30.6% of them unable to process which shows a disorganized collagen
return to play. In fact, functional deficits are not fiber. The same holds true with eccentric loading
evident until after a year post-operatively. in an Achilles tendon which shows an increased
Moreover, the level of play akin to their previous tendon stiffness in SWE [467]. In general, SWE
performance can only be achieved 2 years post-­ showed that tendinopathic tendons and fasciae
operatively [466]. were heterogeneous and had reduced stiff pat-
terns or are softer than normal tendons and tissue
New Features in Ultrasonography elasticity decreased [470]. Thus, ultrasound elas-
Musculoskeletal ultrasound is a very useful tool tography is an important technique to promote
as a quick and convenient way to diagnose neu- an early diagnosis long before a conventional
22 Use of Musculoskeletal Ultrasound and Regenerative Therapies in Sports 519

ultrasound shows any changes, to identify the of echo type II does not necessarily mean an
risk of injury, and to evaluate rehabilitation abnormality but instead is a necessary morpho-
interventions [471]. In fact, the combination of logical, histological, and functional requirement
elastography and conventional ultrasound is with an increased level of glycosaminoglycans
more powerful than power Doppler and conven- (GAG) in the region. This finding showed that
tional ultrasound. Thus, it is recommended that UTC can quantify subtle differences in tendon
before further evaluation with MRI, ultrasound structure that may precede the development of
elastography can make a difference in diagnos- symptoms in an abnormal tendon [474].
ing early tendon pathology both among athletes Contrast-enhanced ultrasound (CEUS) is a
and non-athletes alike such that it can predict an technique using micro-bubble-based intravenous
ongoing pathology in what otherwise may contrast agents that can enhance the vascular
appear as normal in a conventional ultrasound flow of a particular structure being imaged and
and preclude further injury [7]. It has also been allow the assessment of microcirculation during
reported to have very good applicability in nerve ultrasound imaging. It can show microvascularity
entrapments. In fact, the loss of elasticity of and blood perfusion in real time and can detect
either the nerve itself or the carpal tunnel in the neovascularization at the capillary level [475]. In
case of carpal tunnel syndrome or both can pre- this case, a second-generation contrast agent used
cede any change in conventional neural cross-­ is sulfur hexafluoride (Sonovue®, Bracco
sectional measurements. And that is why with all Imaging, Milan, Italy), and this solution has
these advancements in ultrasound techniques, shown a good safety profile with no reported
new guidelines might emerge as to the current fatalities so far. In fact, it was reported to have a
diagnostic practice [472]. better safety profile than the MRI contrast agent
Ultrasound tissue characterization (UTC) is gadolinium [476]. Other contrast agents used in
used both in research and in clinical practice to the past include Levovist and Sonazoid. The 2017
quantify the structure specifically of the tendons. guidelines of the European Federation of
A conventional ultrasound has limited capability Societies for Ultrasound in Medicine and Biology
to detect minimal intratendinous changes and to (EFSUMB) introduced CEUS for non-hepatic
quantify tendon structure and as such is simply applications. It was initially intended for inflam-
using gross description like hypoechogenic zone matory joint diseases and eventually was applied
or tendon diameter and cross-sectional area. for microperfusion assessment for bone and mus-
UTC, therefore, converts a tendon structure into a cle tissue [475]. CEUS, however, has a specific
three-dimensional data block and then calculates window of time that corresponds to the phase of
the stability of the brightness of the pixels over contrast for ideal ultrasound scanning [475].
contiguous transverse images [473]. Wezenbeck Other advanced ultrasound techniques include
and colleagues did a study [474] on the Achilles microvascular imaging or superb microvascular
tendon of 70 physiotherapy students, with 26 imaging (SMI) wherein an extremely subtle
males and 44 females with no history of Achilles blood flow detects inflammation and malignancy
tendon injury. By using UTC, the study reported without the use of contrast agents and any inva-
that normal, healthy individuals showed a pre- sive procedures. In traditional color and power
dominance of echo type I in males and echo type Doppler technologies, the clutter is removed by
II among female counterparts at both the inser- suppressing low-velocity components, with loss
tion and midportion, which could be due to the of visibility and data. The SMI works by sup-
estrogen hormone in the females. Moreover, pressing low-flow signals and separating these
there is a predominance of echo type I at the mid- low-flow signals from overlaying the artifacts of
portion and a predominance of echo type II at the tissue motion while at the same time preserving
insertion site of the Achilles tendon. Echo types the low-flow components and enhancing detail
II, III, and IV represent alterations in tendon bun- and definition. It was reported to be better than
dles, with echo type IV showing the most altera- power Doppler ultrasound in assessing hypervas-
tions in tendon architecture. The predominance cularity in median nerve neuropathy such as in
520 J. C. de Castro

CTS. It can also identify neovascularization asso- sus conventional US of the shoulder. Radiology.
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available in selected high-resolution ultrasound S. Comparison of conventional sonography, real-­
machines like the Aplio 500 US system by time compound sonography, tissue harmonic sonog-
Toshiba (Toshiba Medical Systems, Tokyo, raphy, and tissue harmonic compound sonography
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With all these exciting developments, it can be generating large compound ultrasound images.
assured that musculoskeletal ultrasound can U.S. Patent 5575286; 1996. Available at: www.
freepatentsonline.com/5575286.html.
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culoskeletal sports diagnosis, a guide to prevent sound in diagnosing tendinopathy related sport
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any interventional procedure. Its optimal use by a T, Yamada S, Ohuchi H. Dynamic high-resolution
trained and experienced physician will enable ultrasound in the diagnosis of calcaneofibular liga-
quick and prompt diagnosis of an injury and pro- ment injury in chronic lateral ankle injury: a com-
vide a precision-guided ultrasound interventional parison with three-dimensional magnetic resonance
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nostic modalities that can provide better sensitive tion of the peroneal tendons in an asymptomatic elite
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Study to shew thyself approved unto God. 2 Med. 2020;185(Supplement_1):420–2.
Timothy 2:15 (KJV) 12. Murray T, Roberts D, Rattan B, Murphy D, Cresswell
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injection. Skeletal Radiol. 2020;49:1155–8.
13. Kunz P, Mick P, Gross S, Schmidmaier G, Zeifang F,
Acknowledgment Special thanks to the Almighty God
Weber M, Fischer C. Contrast-Enhanced Ultrasound
for providing me the inspiration and guidance in prepar-
(CEUS) as predictor for early retear and functional
ing this chapter and to my wife Kyna and my two kids:
outcome after supraspinatus tendon repair. J Orthop
Rafael Bennett de Castro and Zarah Francine de Castro.
Res. 2020;38(5):1150–8.
14. Wengert G, Schmutzer M, Bickel H, Sora M,
Polanec S, Weber M, Schueller-Weidekamm
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 Part VII
Future of Regenerative Medicine
 Regenerative Medicine:
Challenges and Opportunities
23
Susan Plummer and Yasser El Miedany

Introduction siasm about regenerative medicine and its wide-­

ranging potential of disease management created
Regenerative medicine encompasses innovative a gap between anticipations and the authenticities
interdisciplinary strategies which principally of transforming technology into standard clinical
involves both cell and gene therapies, tissue engi- practice [2]. In mid-2020, the European
neering and non-biologic constructs and aims at Academies’ Science Advisory Council (EASAC)
tissue repair and regeneration. With its potential and the Federation of European Academies of
to create living and functional cells, the created Medicine (FEAM) published their report on
living tissues can be used to replace or repair ‘Challenges and Potential in Regenerative
those which have sustained potentially irrepara- Medicine’ [3] to highlight the challenges and
ble damage due to disease, injury, trauma, age or opportunities of regenerative medicine for the
attained through genetic and congenital defects scientific community, health services, regulating
[1]. Broadly, regenerative medical approaches authorities, as well as policy-makers, and to
include harnessing, guiding, stimulating or deliver recommendations on the principles and
replacing endogenous repair or developmental options for change to inform the EU strategy.
processes. With the potential facility to produce For several years tissue engineering therapy
life-saving therapies for some genetic diseases was mostly confined to bone marrow transplanta-
affecting skin or blood, regenerative medicine tion for epidermis transplantation for large burns
represents a substantial hope for managing obsti- as well as haematological disorders. On their
nate disorders. path to clinical translation, stem cell and gene
So far regenerative medicine has only proved therapies were confronted by enormous chal-
itself and shown efficacy in just a few specific lenges—a status that started to change by the end
clinical conditions such as haematopoietic and of the 1990s. The past two decades have wit-
dermatology conditions. Consequently the enthu- nessed an exponential progress in experimental
therapies as tissue engineering therapy started to
enter the clinical arena. However, the outcomes
S. Plummer (*)
Faculty of Medicine, Health and Social Care, of these clinical studies varied from unequivocal
Canterbury Christ Church University, clinical efficacy for formerly intractable and
Canterbury, Kent, UK incurable conditions to (more often) a modest or
e-mail: [email protected] null effect. Elaboration of the underlying causes
Y. El Miedany of such broad variation in the studies’ outcomes
Institute of Medical Sciences, Canterbury Christ
Church University, Canterbury, Kent, UK

© Springer Nature Switzerland AG 2022 539

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0_23
540 S. Plummer and Y. El Miedany

has further highlighted the challenges facing But although it is tempting to insist that all
regenerative medicine. new therapeutics should be evaluated in rigorous
This chapter will address some critical scien- RCTs, this may not actually be possible for rare
tific issues for evidence-based implementation diseases that have few or no effective treatment
and regulation of regenerative medicine. It will options available [8]. It is therefore important to
start by addressing the challenges facing regen- consider other measures that can help to improve
erative medicine, followed by the available the strength of evidence for cell and gene thera-
opportunities and how to respond to these chal- pies [9]. For example, systematic reviews and
lenges. The chapter will conclude by a trial to meta-analyses pool data from multiple studies
answer the question: is there a bright future for and registries and can be used to provide more
regenerative medicine? precise estimates of effect or risk, particularly
when results from individual trials are
inconclusive.
Challenges Fortunately there are emerging methods of
evidence synthesis designed to support decision-­
Clinical makers facing heterogeneous data. Evidence
mapping is one such method which systemati-
 he Evidence Crisis
T cally depicts a broad (often heterogeneous) evi-
There is a main hurdle in the regenerative medi- dence body in order to identify knowledge gaps
cine field in that stem cell-based protocols are and opportunities for future research. In contrast
often applied to patients with very weak experi- to traditional systematic reviews and meta-­
mental base or understanding of the pathophysi- analyses, whose results are typically presented in
ology. Furthermore, the fact that the cells lack a the form of dense tables and figures, evidence
precisely identifiable molecular and chemical maps are most often designed to be user-friendly
structure makes its comparison to chemical com- and interactive [10].
pounds unapplicable. This has led to the conclu- The considerably limited supporting clinical
sion that it is very difficult to standardise the evidence for long-term safety and efficacy make
research methodology [4]. This is further compli- it impossible to distinguish between ‘good’ and
cated by the finding that medicinal products used ‘bad’ clinical activity [1]. Furthermore, the
in regenerative research may vary when prepared absence of reliable clinical knowledge from tri-
in the variable research centres and even within als makes it very difficult for both health-care
the same centre if prepared at different times [5]. professionals and patients who cannot be
This data reflected on the smart trial designs informed adequately of the risks and benefits of
and uniformity in reporting in regenerative medi- a certain treatment approach. Therefore more
cine research. Whilst randomised control trials comprehensive reporting might be the clue to
(RCTs) are considered the most commonly rec- facilitate the development of rapid and reliable
ognised as showing the most reliable evidence evidence and to promote valid pooling of data. In
when assessing the safety and efficacy of a new addition in a trial to tackle such challenge, inno-
therapeutic intervention and for gaining regula- vative tools such as interactive and dynamic evi-
tory body sanctions [6], in the year 2019, only dence maps could be used to track the evidence
half of the 12 approved advanced therapy medici- in real time and allow the field to make better
nal products (ATMPs) in Europe were tested in sense of the heterogeneity across the total evi-
RCTs, and many of these used small sample sizes dence landscape. In fact, combining these
(ranging from 99 to 512). The other half were approaches would represent a significant step
carried out only in single-arm studies (this is forward increasing confidence in the existing
according to the European public assessment evidence and paving the way to a smooth inte-
reports (EPAR) on the European Medicines gration of these innovative treatments into main-
Agency (EMA) website) [7]. stream clinical practice [7].
23 Regenerative Medicine: Challenges and Opportunities 541

Augmented Access to find approaches to unlock these products’

Another challenge results from the premature potential [9].
marketing approval and commercialisation of Another challenge that remains unabated is
expensive approaches, facilitated by regulatory the unregulated products and services which are
authority initiatives for accelerated access [5]. offered in the commercial clinics, bringing high
There is concern that schemes for conditional hopes of a broad range of positive outcomes but
marketing approval lead to medicinal products use poorly recognised therapies; ambiguous sci-
with limited evidence of clinical benefit. entific rationale, with poor or low effectiveness
Distinguishing between the ‘good’ and the evidence; and potential concerns regarding its
‘bad’ clinical activity can be difficult. The bio- safety concerns. This is presented in association
medical companies might start working based on with the primary intention of making financial
a rational hypothesis, gather some evidence and profits [12]. In a trial to combat these issues,
publish in reputable journals, but data can be some principles have been suggested by the
inflated and inadequately replicated, whilst risk EASAC-FEAM who endorsed vibrant and avail-
and benefit are inadequately ascertained [6]. able clinical efficacy evidence and to keep the
Furthermore, granting conditional (accelerated) patients who are contemplating such therapies
access transfers financial costs and the burdens of fully informed. A vital criterion that should be
medical uncertainty from drug developers to highlighted, particularly for the patients making
health-care systems and consequently from trial their decision whether to share in a novel clinical
participants (who should be required to undergo a trial, is that they should not be expected to pay for
rigorous informed consent process) to health-­ clinical research [3].
care consumers (who are not) [4].
One partial solution could be the adoption of
novel regulatory models such as limited approval Ethical and Governance Crisis
with intensive collection of new clinical evidence
before a drug becomes universally available. As a On engaging with the public, contacting the press
further step, drugs that have not yet shown clini- and decision-making bodies in the variable
cal outcome benefit could be made available at national health systems, scientists face many eth-
just the cost of production, or most profits could ical and governance issues. Political agendas
be kept in escrow, until adequate trials are com- may not match the public expectations. In some
pleted [8, 9]. centres, a novel therapy authorisation might be a
The EASAC-FEAM report [3] advises that in politically hot issue, even when effectiveness is
an era of international competitiveness when unverified, and the cost to taxpayers means other
some regulatory frameworks have become patients may get deprived of effective and estab-
increasingly permissive, it is essential that the EU lished treatments. Furthermore, there is evidence
does not lower its regulatory threshold without that some national regulatory systems have
assessing the consequences for patient safety, become too permissive, and there are examples
health-care budgets and public trust in science (such as in Asia) where regulatory review path-
[10, 11]. ways have been amended specifically to encour-
age approval of regenerative medicine [11, 13].
Commercial Clinics In other instances the regulatory authority
Several new ATMPs face challenges particularly allowed stem cells, if minimally manipulated and
regarding manufacturing know-how, reimburse- homologous, not to be subject to the same regula-
ment and prices as well as having access to the tory mechanism as drugs [14]. In addition it has
market. This reflects the difficulties such compa- been observed in the context of the recent contro-
nies face to make the leap from laboratory sense versy about synthetic trachea transplantation that
to commercial reality. Therefore many of these part of the World Medical Association’s Helsinki
companies working in this field are trying hard Declaration might be misinterpreted and merits
542 S. Plummer and Y. El Miedany

revision to provide better safeguards against paper; while reserving a final decision for when
experimentation at the physician’s own discre- current investigations are completed’ [19].
tion [15]. Ethical problems are raised by conflicting val-
The controversy about synthetic trachea ues and by interests that pull in different direc-
transplantation is a very good example of the tions. If and when interests or values clash (when
ethical and governance crisis that is worth men- certain values or interests can only be achieved at
tioning to learn from. In January 2016 a docu- the expense of others), principles are available
mentary was aired on the public Swedish that can guide the decision-making [2]. The
television [16, 17], telling the story of a thoracic Lancet commission published in 2018 [1] high-
surgeon (PM) at the Karolinska Institute in lighted the different ways in which stem cell
Stockholm and his trials to develop an innova- therapy can be accessed: ‘Patients can access
tive approach to replace parts of the trachea by stem cell and regenerative therapies in four ways.
growing stem cells on a synthetic scaffold, which First, and most straightforwardly, when a therapy
was then implanted into a patient. The first oper- has been tested and received marketing approval
ation, carried out in 2011 at the Karolinska for the indication for which the clinical team
University Hospital, was broadcasted as a intends to use it. Second, in the context of a clini-
groundbreaking attainment, published in presti- cal trial. Third, through permitted non-research
gious medical journals and hailed by the press. access to a treatment that does not have market-
Five years later a different picture was drawn. A ing approval for that indication—including hos-
3-hour documentary called The Experiments pital exemption within the EU, and also off-label
(Experimenten) was aired on the Swedish public or compassionate use. Fourth and more crucially,
television (SVT) [18] and presented follow-up of through direct recruitment (usually through the
surgeries performed implanting the synthetic tra- internet) from commercial entities whose activity
chea in both Sweden and similar surgeries in is not scrutinised or approved by any regulatory
Russia. The documentary showed interviews body’.
with the patients’ close relatives who believed Though such challenges can be difficult to
that the operations contributed to the patients’ address and solve, a strategy to tackle such hurdle
premature deaths. In addition the documentary can rely on coordinated approach based on four
shared data revealing that the surgeries lacked main pillars: better science, better governance
proper scientific support and regulatory approval better funding models and better public and
[19]. The magnitude of the crisis can be illus- patient engagement. Together with warranting
trated by the reaction of the Royal Swedish regulatory procedures which are transparent,
Academy of Science as reported in The Lancet robust and evidence-based and the expectation to
[20]. Several inquiries on issues ranging from be speedy and accurate, there is much else to be
research fraud to criminal misconduct were done. The academies’ consensus has highlighted
commenced following the airing of the docu- specific priorities including reinvigoration of EU
mentary [19] (Karolinska Institute 2016: research infrastructure, particularly for transla-
Karolinska Institute (2016) ‘ACTREM’ <http:// tional and clinical research [20], support for new
ki.se/en/clintec/actrem> (the site was removed models of partnership between academia and
in late March 2016). Four members of the Nobel industry whilst ensuring ethical development
Prize committee in physiology or medicine [14], inserting regenerative medicine in curricula
resigned. The vice-chancellor of the Karolinska for medical education and professional training
Institute, Professor Hamsten, resigned after for- [21], alerting against non-peer-reviewed ‘preda-
merly defending the thoracic surgeon PM. In tory’ journals [22], developing health services’
April 2016, The Lancet published an expression institutional readiness in relation to regenerative
of concern, noting the ‘ongoing uncertainty medicine research and engaging with the public
about the integrity of the work reported in this and patients to counter misinformation [2].
23 Regenerative Medicine: Challenges and Opportunities 543

Demand Over the past 2 years during the COVID-19

epidemic, an escalating demand for stem cell
The global stem cell therapy market is projected research products has been reported. This has
to reach USD 401 million by 2026 from USD been attributed to several factors including (1) the
187 million in 2021, at a compound annual use of stem cells in the treatment of COVID-19
growth rate (CAGR) of 16.5% during the forecast complications, such as immune and respiratory
period. Growth in this market is majorly driven complications; (2) promise of mesenchymal cells
by the increasing investment in stem cell research (MSCs) for ameliorating COVID-induced respi-
and the rising number of GMP-certified stem cell ratory distress, such as ARDS; (3) accelerated
manufacturing plants. The stem cell therapy mar- pathways for regulatory approvals during
ket is segmented into North America, Europe and COVID-19; (4) surging funding for stem cell
Asia Pacific, followed by rest of the world. The research due to support from BARDA, CIRM,
stem cell therapy market in the Asia Pacific NIAID and other groups; (5) increased interest
region is expected to grow at the highest CAGR among pharmaceutical companies in stem cell
during the forecast period. Factors such as the R&D programs related to COVID-19; and (6)
growing adoption of stem cell-based treatment in potential for stem cells to support the manage-
the region and the growing approval and com- ment of the global COVID-19 pandemic [24].
mercialisation of stem cell-based products for Such growing demand on stem cell therapy
degenerative disorders drive the growth of the and its potential to change the future of medicine
stem cell therapy market in the region [23]. represents a major challenge particularly to
One of the key factors boosting the growth of ensure patients’ safety. The general public must
this market is the limitations of traditional organ be cautious of clinics that exploit people’s des-
transplantation such as the risk of infection, peration for a cure. On the other hand, whilst
rejection and immunosuppression risk. Another researchers are working to use stem cells to
drawback of conventional organ transplantation improve health care, they have to make sure that
is that doctors have to depend on organ donors it is carried out safely with some form of
completely. All these issues can be eliminated by oversight.
the application of stem cell therapy. Another fac-
tor which is helping the growth in this market is
the growing pipeline and development of drugs Finance
for emerging applications. Increased research
studies aiming to widen the scope of stem cell Research into biomedical innovations has the
will also fuel the growth of the market. Scientists potential to yield economic and health benefits.
are constantly engaged in trying to find out novel However, noteworthy financial investment is
methods for creating human stem cells in mandatory to bring these innovations from
response to the growing demand for stem cell ‘bench to bedside’ [1, 2]. As such it is no surprise
production to be used for disease management. that several funding agencies as well as govern-
This has been supported by the results of research ments considered that fostering commercialisa-
studies revealing successful translation of stem tion is vital to make the economic and medical
cell therapies to patients that have augmented the potential of biomedical research a reality and to
hope that such regenerative strategies may one deliver on promised targets and benefits
day become a treatment for a wide range of vex- [25–28].
ing diseases (2). This is of particular interest for Commercialisation is defined as ‘links
those patients who have no other therapeutic between both publicly funded researchers and
option but to resort to stem cell clinics or prod- industry; and efforts to turn university - based
ucts given conditional marketing status on the research into marketable products and services’
basis of inadequate evidence. [29, 30].
544 S. Plummer and Y. El Miedany

The field of stem cell research has been sub- Media

ject to significant commercialisation pressure.
Scientists are facing pressure to develop stem cell Public views can significantly influence govern-
therapies that will reach the clinic within a short mental policy and consequently can have a large
period, from both the funding agencies as well as impact on regenerative medicine and stem cell
the public [22, 31, 32]. To date, there has been research. Therefore it is vastly important for the
only limited progress in translating stem cell public to be informed of scientific advancements
research into clinical therapies, but this has not and what they mean. Additionally it is vital that
lowered the expectations or enthusiasm for the researchers are in tune with how the public per-
field, as the phenomenon of ‘stem cell tourism’ ceives regenerative medicine research. In gen-
attests [32]. The commercialisation pressures eral, news media is the primary way the public
facing stem cell researchers are likely to continue learns about scientific and medical break-
into the foreseeable future. throughs. However, several questions have been
A major challenge comes to the surface on raised and await answers. These include the fol-
evolving the financial models. For some novel lowing: How does the media portray regenerative
approaches, limited experimental evidence may medicine and stem cell research? Do the articles
be existing based on a rational starting research available in the media promote unrealistic expec-
hypothesis, published in reputable journals and tations? And what topics about regenerative med-
involving expert scientists. But the data are icine research does the media focus on?
then endorsed in an unbalanced way by com- In their study [34], Kalina Kamenova and
pany sources with the consequence that the dis- Timothy Caulfield tried to answer these questions.
tinction between validated and replicated or Of the 307 newspaper articles analysed, 37.1%
premature and unsubstantiated therapeutic focused on clinical translation, and 22.8% dis-
claims may become harder. That is, instead of cussed new scientific discoveries. Only 1.6% of the
the initial simple scenario where ‘good’ and articles focused on the ethical issues of regenera-
‘bad’ clinical centres could easily be contrasted, tive medicine and stem cells. The majority (57.7%)
there is now a continuum from one extreme to of all newspaper articles between 2009 and 2014
the other without clear boundaries. Lack of presented the future of regenerative medicine and
published information may indicate a more stem cell research in a positive and optimistic tone.
general lack of evidence, for example, on cell
characteristics and clinical effects, and an
intention to claim beneficial properties in mul- Responding to the Challenges:
tiple indications [3]. The Opportunities
Such financial challenges highlight the need
for regulatory authorities to build good scientific In spite of the fact that research in regenerative
links with the companies and their regulatory medicine next generation cell and gene therapies
advisory committees to ensure the presence of an has been going on for years and the hype around
appropriately robust evidence base, even when stem cell therapies, tissue engineering and its
encouraging early access to innovation by potential value, it has only recently started to
patients who may have few or no other options. become commercially available, and relatively
There are also related issues for what should be few patients have benefited to date. Worldwide, 64
allowed in terms of promotional medical claims ATMPs have been reported including 34 cell ther-
on company websites when no marketing authori- apies, 20 gene therapies and 10 tissue engineering
sation has yet been granted and the use by com- products. Whilst not a relatively small figure, it is
panies of selected patient results when other far eclipsed by the number of products that have
information is not supportive [33]. entered clinical development and stalled there [3].
23 Regenerative Medicine: Challenges and Opportunities 545

The path to the market is rather complex, cial gaps in early product development. Sustained
expensive, time-consuming and highly regu- funding provided by either professional authority
lated. Even for those products that are success- such as EU as well as national organisations is
ful, not that many of them have the potential to also central to indorse networks able to bring
become blockbusters. In February 2021, one of together multiple regenerative medicine disci-
the biotech companies ‘Humacyte’ broadcasted plines (e.g. EuroStemCell). This will not only
its decision to go public, inaugurating its move help to explore the clinical potential but also to
from a clinical-stage company to a commercial set up the fundamental research base that pro-
one. The company, which develops regenerative vides the initial resource for any future pipeline
human tissues that can be implanted in any in regenerative medicine [38].
patient without the need for immunosuppressive Tackling the gaps in health-care education on
drugs, is expected to hit the market with a value regenerative medicine is also vital to endorse
of $1.1bn [34]. such innovative development. Unfortunately so
Endorsing the conversion of science to clini- far in most medical schools at either undergradu-
cal application necessitates strong ethical ate or postgraduate level, little mention is made
review and commitment of the sponsors of about regenerative medicine although there are
research. Clinical research is not cheap, and some cases of good practice represented by
EU-level funding mechanisms are warranted, in courses on haematological stem cell approaches
particular to advance from limited phase [21]. Efforts to progress medical education need
research to academic investigator-led, clini- to consider two main factors: first, tackling the
cally based studies, including clinical trials gaps in training on ethical, legal and societal
(and active comparator designs). Funding pro- issues in regenerative medicine, including how to
vided by professional organisations such as EU involve other stakeholders, especially patients, in
can help to coordinate and build initial critical research design and review [39] and second,
mass in clinical research [35]. training for primary care professionals to advise
Participation of the patients in the study design patients on how to access and assess good evi-
and follow-up can be beneficial particularly for dence. This was supported by the findings of a
the new models of regenerative medicine transla- recent research which highlighted the need to
tion [20]. There is also scope for public invest- improve information for these professionals
ment, at the EU level, in evolving platform about regenerative medicine [40].
technologies which can be implemented in mul- Tackling the publication practices is vital to
tiple applications, e.g. gene therapy vectors. ensure the integrity of the published research. The
Furthermore, there is also an opportunity for a development of guidelines/recommendations for
closer relationship between the clinical and social clinical trial registration/study design, data analy-
sciences and humanities. This would enable sis and reproducibility, as well as reporting, is
researchers to get better understanding of the important to ensure that the outcomes of failed tri-
social and ethical implications and public expec- als are documented, particularly as most journals
tations of regenerative medicine [36]. This will give priority to successful trials or trials claimed
also enable social scientists to better understand as such. Furthermore, there should be strategies
about the clinical trials’ practicalities. supporting the open accessibility of negative data
Building new links between academia and to enable independent analysis as part of strong
industry in regenerative medicine is vital to make and comprehensive procedures to track and coor-
such partnership a reality [37]. Such partnership dinate evidence development [3]. On another
paves the way for several potential roles, for gen- front, the scientific community should carefully
erating tools, promoting applications and clinical consider the issue of appraising the quality of
translation. It may also help in bridging the finan- journal publications. The launch of predatory,
546 S. Plummer and Y. El Miedany

non-peer-reviewed open access journals and the variable directions. To move forward, decisions
paucity of expert reviewers for the increasing can be taken and even changed as the scientific
manuscript numbers represent a major challenge evidence and value landscape change. These
that require tackling in the publication practices include (1) importance of objective (the targets,
issue. Therefore there is a role for medical whether theoretical or practical, should be of sig-
research charity patient groups to provide nificant value), (2) relevance of means (the means
resources, whereby patients can seek advice. should achieve or at least help to achieve the tar-
get), (3) most favourable option (there is no other
less risky or controversial means to achieve the
I s There a Bright Future target(s)) and (4) non-excessiveness (the means
for Regenerative Medicine? used should not be excessive in relation to the
intended target) [3].
Since the birth of the biotechnology industry in the
late 1970s, many transformational technologies
and new therapies have been announced improv-  pportunity: Emergence of iPSCs
O
ing medical care and benefitting patients. Further, as an Alternative to ESCs
in many areas of medicine exciting progress con-
tinues. However, there are many areas where stan- Induced pluripotent stem cells (iPSCs) are adult
dard of care is fundamentally limited and stem cells that have been genetically repro-
significant challenges highlighted. So, it is natural grammed back to an embryonic stem cell-like
to ask: What advances will the next decade bring? state. iPSCs function similarly to embryonic
How will the landscape evolve in light of key stem cells (ESCs), having the ability to differ-
health-care and technology trends? And is there a entiate into specialised tissue cells according to
bright future for regenerative medicine? This will the gene expression; this makes iPSCs an effec-
be stratified and discussed briefly below as the tive alternative to ESCs. As ESCs are derived
main pillars of modern regenerative medicine. from early-­stage embryos, they are associated
with socio-ethical issues and laws related to
contraception, abortion and in vitro fertilisa-
 river: Availability of Funding
D tion. The use of iPSCs bypasses the need for
for Stem Cell Research human embryos, thus avoiding socio-ethical
objections.
The need for newer and better therapies for the
treatment of autoimmune, neurological and car-
diovascular diseases has resulted in an overall  he Allogeneic Stem Cell Therapy
T
increase in research activities and the availability Segment Dominated the Stem Cell
of funding for cell-based research. In November Therapy Market in 2020
2019, the Australian government released a
10-year roadmap for stem cell research in Based on type, the global stem cell therapy
Australia—The Stem Cell Therapies Mission. market is broadly segmented into allogeneic
stem cell therapy and autologous stem cell ther-
apy. In 2020, the allogeneic segment accounted
 estraints: Ethical Concerns Related
R for the largest share of the stem cell therapy
to Embryonic Stem Cells market. The growth of the allogeneic segment
is attributed to the ease of manufacturing and
Several ethical issues are associated with the use production processes and the increasing avail-
of stem cells. Ethical problems are raised by con- ability of novel stem cell products across major
flicting standards and by interests that pull in geographies.
23 Regenerative Medicine: Challenges and Opportunities 547

 he Inflammatory and Autoimmune

T References
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Commission: stem cells and regenerative medicine.
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 Index

A American Medical Society for Sports Medicine

Abdominal muscle pathology, 442, 443 (AMSSM), 448
Accelerated access, 541 Amniotic membrane and umbilical cord (AMUC), 251
Acetaminophen, 375 AMPK pathway, 52
ACH classification, 293 Amputee limb complications, 420
Achilles tendinopathy (AT), 207 Amyotrophic lateral sclerosis (ALS), 9
Achilles tendon, 208 Ankle, 195
injuries, 447 Ankle anatomy
and patellar ligament, 447 ligamentous, 196
rehabilitation, 432 muscle, 197
Acoustic radiation force impulse (ARFI) elastography, osseous, 196
447 tendon, 197
Acromioclavicular joint Ankle brachial index (ABI), 445
anatomy and ultrasound evaluation, 86–87 Ankle inversion sprain, 512, 513
interventional procedures, 88 Ankle joint, 196
pathology, 87, 88 Anterior cruciate ligament (ACL), 29, 177, 317, 500–502
procedural protocol, 88–90 Anterior inferior tibiofibular ligament (AITFL), 196
Rockwood classification with ultrasound correlation, Anterior talofibular ligament (ATFL), 196, 213
88 Anterior tibialis (AT), 211
Acute tears, 75 Anterolateral ligament (ALL), 180–182
A delta fibers, 381 Anti-inflammatory therapy, 4
Adductor/rectus aponeurosis, 154 Arcuate ligament (AL), 192
Adhesive capsulitis, 93 Articular and periarticular tissues, 425
AdiLight, 50 Articular cartilage
Adipose stem cells (ASC), 271, 301, 314 deep zone, 36
Adipose-derived stem cells (ADSC) extracellular matrix, 35
adult cell types, 301 intermediate layer, 36
ATMPs, 302 lubricin, 35
clinical trials, 301 superficial zone, 35
harvesting procedures and isolation, 302 tidemark, 36
incentives, 302 Articular process (AP), 225
liposuction, 301 Asymptomatic rotator cuff tears, 472
minced rat fat pads, 302, 303 Athletic pubalgia, 493, 494
preparation methods, 303–305 ATP-sensitive K+ channels, 388
stem cell research, 301 Autologous chondrocyte implantation (ACI), 11
tissue repair and expansion, 301, 302 Autologous conditioned serum (ACS), 311–313
US/EU regulations, 302 Autologous platelet integrated concentrate (APIC), 308
Adipose tissue stem cells, 10 Avascular necrosis (AVN), 48
Advanced therapy medical products (ATMPs), 302 Axial neck pain, 400
Allogenic cell products, 51
Alpha-2-macroglobulin (A2M), 42, 305–309
American Academy of Physical Medicine and B
Rehabilitation, 417 Beam attenuation caused by superficial structures, 452
American Institute of Ultrasound in Medicine, 62 Berberine, 52

© Springer Nature Switzerland AG 2022 549

Y. El Miedany (ed.), Musculoskeletal Ultrasound-Guided Regenerative Medicine,
https://doi.org/10.1007/978-3-030-98256-0
550 Index

Biceps tendon release, 451 Chronic pain related to musculoskeletal conditions, 375
Biofeedback, 426 Colony-forming unit (CFU-F) assays, 293
in exercise, 426–427 Color and power Doppler imaging, 368
tools used in physical rehabilitation, 426 Common extensor tendon injection
Bio-stimulation, 264 Golfer’s elbow
BMAC injection, 28 anatomy, 112
Bone marrow, 47 cause, 113
Bone marrow aspirate concentrate (BMAC), 195, 320 equipment needed, 113
ACH classification, 293 injection indications, 113
characteristic feature, 294 injection technique, 113, 114
iliac crest, 294 tennis elbow
injection procedure, 298–300 anatomy, 111
overview, 293, 294 cause, 112
pericytes, 294, 295 equipment needed, 112
preparation methods, 295–298 injection indications, 112
Bone marrow concentrate (BMC), 251 injection technique, 112, 113
Bone marrow stem cells (BMSCs), 272, 273, 314 Complex ion channels on nociceptive membrane, 384
Botulinum toxic injections, 419–420 Compound annual growth rate (CAGR), 543
Bowler’s thumb, 489 Compound muscle action potential (CMAP) amplitude
Brachial plexus, 445 loss, 366
Brachial plexus injury (BPI), 482, 483 Compression (strain) elastography, 447
Brachial plexus tension test, 430 Compressive focal mononeuropathies, 419
Brazilian jiu-jitsu (BJJ) injuries, 505 Conservative approaches, 25
Contrad, 52
Contrast-enhanced ultrasound (CEUS), 470
C Conventional nerve conduction studies (NCS), 356
Calcaneofibular ligament (CFL), 196 Core muscle injury, 493–498
Calcific barbotage, 449 Core muscle training, 430
Calcitonin gene-related peptide (CGRP), 385, 386 Costotransverse joints (CTJ), 229
Capacitive micromachined transducer (CMUT), 471 C-reactive protein (CRP), 310
Carpal tunnel syndrome (CTS), 343, 418, 444, 487 Cross-sectional area (CSA), 351
Cartilage tears, 30 Curcumin, 53
Caudal epidural injection, 408–410 Cytokine therapy, 51, 52
Cell-based therapies, 15
Cell/tissue-engineered product, 302
Cellular and whole-body glucose homeostasis, 387 D
Centralization of pain concepts, 375 Deep gluteal pain, 167
21st Century Cures Act, 3 Deep gluteal syndrome, 161
Cervical articular pillars, 401 Deeper and small joints, 418
Cervical facet joint with in-plane injection technique, Degenerative tears, 75
403 Dehydrated human amnion/chorion membrane
Cervical facet joints, 228, 403 (dHACM), 205
Cervical facet mediated pain, 400 Deltoid ligament, 215
Cervical lateral glide techniques for neural mobilization, Dental follicle precursor cells (DFPCs), 264, 267
431 Dental pulp stem cells (DPSCs), 265
Cervical medial branch blocks and third occipital nerve, Dental stem cells (DSCs)
400–402 cryopreservation, 276
Cervical medial branches with in-plane needle position, isolation, 275
402 low-intensity pulsed ultrasound, 278
Cervical radiculopathy, 398 low-level laser therapy, 276, 277
Cervical spinal nerves, 398–402 preparation, 275
Cervical zygapophyseal or facet joints, 402, 403 scaffolds, 271, 272
C fibers, 381 sources, 264–271
CH-Alpha, 53 tooth banking, 273, 274
Channelopathy, 383, 384 transporting, 275
Cheiralgia paresthetica, 491 De Quervain’s tenosynovitis, 476
Chondrocytes, 35, 195 Dextrose-based therapies, 392
Chronic constrictive injury (CCI’s), 380, 381 Dextrose injections, 388
Chronic narcotic therapy, 5 Dextrose prolotherapy (DPT), 377, 378
Chronic pain, 195 Direct-tracing method, 366
Index 551

Dorsal sacrum, 408 G

Duchene muscular dystrophy (DMD), 14 Gemelli–Obturator internus syndrome, 164
Generalized neuropathies, 368, 369, 371
Generalized polyneuropathy, 356
E Gingiva-derived MSCs (GMSCs), 269
Early Screening for Cardiac Abnormalities with Glenohumeral (GH) joint
Preparticipation Echocardiography (ESCAPE) anatomy and ultrasound evaluation, 91, 92
protocol, 441 interventional procedures, 93, 94
Elastography, 349, 432, 446, 447 pathology, 92, 93
Elbow joint injection procedural protocol, 94, 95
anatomy, 109 static stabilizers, 91
common cause, 110 Glenohumeral internal rotation deficit (GIRD), 472
equipment needed, 110 Glenohumeral joint injections, 418
injection indications, 110 Glucose transporter (Glut), 387
patient positioning, 110 isoforms, 387
needle direction and approach, 110, 111 transporters, 383
radio-capitellar joint, 112 Glucose transporter 3 (Glut3), 387, 388
transducer position, 110, 111 Gluteus medius bursitis, 159, 160
Electrodiagnostic Glycosaminoglycans (GAG), 519
studies, 357 Gold Induced cytokines (GOLDIC), 28
techniques, 356, 357 Gray scale mapping, 364
testing, 369 Greater occipital nerve (GON) blocks, 405, 406
Electrophysiology vs. peripheral nerve ultrasonography, with Doppler, 406
357, 358 with in-plane injection technique, 407
Embryonic stem cells (ESCs), 10, 43, 546 Groin pain in the athlete, 443
Enamel matrix derivatives (EMD), 267
Endoneurium, 359
Epidural spaces, 250 H
European Academies Science Advisory Council Hand disorder, sonoanatomy and interventional
(EASAC), 539 techniques, 129–138
European public assessment reports (EPAR), 540 Hanks buffered saline solution (HBSS), 274
Exercise-induced laryngeal obstruction (EILO), 440 Hematopoietic stem cells (HSCs), 10, 46–47, 539
Extended FAST (or eFAST) examination, 442 Hernia mimickers, 443
Extensor carpi ulnaris (ECU) injuries, 476, 477 Hernias, 443
External iliac artery endofibrosis, 445 Heterotopic ossification, 419
Extra-articular ligamentous problems, 48 High frequency peripheral nerve ultrasound
Extracorporeal shock wave therapy (ESWT), 49 abnormal median nerve with compression, 368
Extrose on pain-producing C fibers, 391 abnormal sural nerve with focal injury, 368
Color Doppler sonogram, 360
complete neurotmesis of the median nerve, 358
F Doppler imaging, 360
Fabellofibular ligament (FFL), 191 fibular nerve, 358
Facet mediated low back pain, 407 flexor digitorum superficialis tendons, 359
Facetogenic structures, 250 focal neuropathies with severe axonal loss,
Feedback utilization, 432 370
Femoral hernias, 443 focal zone position on the appearance of a peripheral,
Femoroacetabular impingement (FAI), 493, 495 365
FHL longus (FHL), 198 gray scale gain, 364
Fibronectin-aggrecan complex (FAC), 324, 325, 495 great saphenous vein, 361
Fibrous/fibrovascular bands, 165 median nerve
Flexor digitorum longus (FDL), 198 with an early bifurcation, 364
Flexor digitorum superficialis (FDS), 475 in the forearm, 359
Focal nerve abnormalities, 367–368 nerve with surrounding muscle, 360
Focal neuropathies, 366 normal vascularity, 370
Focused assessment with sonography in trauma (FAST), relative conspicuity of a nerve, 361
442 scanning techniques, 360
Food and Drug Administration (FDA), 17 short-axis view of nerve and muscle, 365
FOXO family of forkhead transcription factors, 52, 53 superficial structures, 363
Full thickness tears, 75 tibial nerve, 360, 364
Functional axonotomesis, 358 transducer for optimum control, 362
552 Index

High frequency peripheral nerve ultrasound (cont.) fibrous/fibrovascular bands, 165

transducer gel, scanning for nerves of the forearm, 362 Gemelli–Obturator internus syndrome, 164
transducer pressure, 363 hamstring origin, 165, 167
ulnar nerve dislocating over the medial epicondyle, ischio femoral space/peri sciatic hydrodissection,
367 166
uninterrupted fascicular pattern on ultrasound, 358 pathology, 164
vascular supply, 359 piriformis pain syndrome, 161, 164
High volume image guided injections (HVIGI), 450 procedures, 165, 166
High volume injection (HVI), 207 quadricep femoris and ischiofemoral
Hilton’s law, 382–384 impingement, 164
Hip and knee osteoarthritis, 418 ultrasound, 162–164
Hip joint injections, 418 See also Thigh
Hip History and physical exam (H&P) with or without
anterior, 141 electrocardiogram (EKG), 441
acetabulum of pelvis, 142 Hyaluronic acid (HA), 27, 199, 473
anatomy, 142–146 Hyperbaric oxygen therapy, 49–50
at femoral head neck junction, 148 Hypoglycemia, 389
diagnostic anesthetic intra-articular hip injections, Hypoxia, 389
149
extra-articular, 142
femoral head, 142 I
hip joint/labrum injection/aspiration, 148–150 Iliolumbar ligament (ILL), 235, 243
hyaluronic acid, 150 Iliotibial band (ITB), 498, 508, 509
hydrodissection on lateral femoral cutaneous Iliotibial band syndrome (ITBS), 509
nerve, 152 Implant durability, 25
iliofemoral (Y ligament of Bigelow), 142 Induced pluripotent stem cells (iPSCs), 43, 44, 546
iliopsoas bursal injection, 151 Infectious mononucleosis, 442
iliopsoas tendon, 143 Infraspinatus
intra articular, 142, 145, 146 anatomy and ultrasound evaluation, 81, 82
ischiofemoral ligaments, 142 interventional procedures, 82, 83
labrum injection, 150 pathology, 82
pathologies, 144 Inguinal and femoral hernia evaluation, 443
procedures, 147 Inner epineurium, 359
pubofemoral ligaments, 142 Interleukin-1 receptor antagonist protein (IRAP),
rectus femoris, 143, 144 309–313
snapping hip, 146, 147 Internal snapping hip syndrome, 496, 497
sonopalpation, 144 International Association of the Study of Pain, 376
suction-seal mechanism, 142 Intersection syndrome, 476
transverse approach, 149 Interventional ultrasound
ultrasonography, 142 in physiatry, 418
clinical indications, 142 in sports medicine
differential diagnosis, 141 advantages, 448–451
lateral hip region, 141 corticosteroid injection, 449
anatomy, 156, 157 first generation procedures, 448, 449
corticosteroids, 160 second generation procedures, 449–450
gluteus medius bursitis, 159, 160 soft tissue and neurovascular structures, 448
pathology, 158, 159 third generation procedures, 450, 451
procedures, 160 Intervertebral discs (IVD), 322–324, 326
ultrasound technique, 157–158 Intervertebral disk degeneration (IDD), 323
medial hip region, 141 Intra-articular fractures, 437
adductor/rectus aponeurosis, 154 Intradiscal targets, 250
groin pain, 152 Intrinsic feedback, 426
osteitis pubis, 154, 155 Intrinsic feedback deficit, 426
procedure, 154–156 Investigational New Drug (IND), 51
pubic symphysis, 153
rectus abdominus, 153
MRI arthrography, 141 J
posterior hip region, 141 Jamshidi needle, 48
anatomy, 161, 162 Joint injections, 418
deep gluteal syndrome, 161 Jumper’s knee, 509, 510
Index 553

K Meniscus, 185
Knee injury and Osteoarthritis Outcome Score (KOOS), Meralgia paresthetica, 445
28 Mesenchymal cells (MSCs), 8, 9, 45, 46, 196, 294, 317,
Knee OA, 27–29 543
Knee pain, 177 Mesenchymal stromal cells, 294
anterior region, 177, 178, 180 Metformin, 52
ligament-capsule-menisci complex, 191, 192 MicroRNA, 49
medial region, 180, 181 Minimally clinically important difference (MCID), 28
posteriomedial corner, 183, 184 Modified-Crass position, 73
posterior region, 184, 186 Morton neuromas, 418
posterolateral corner, 190, 191 MSK system, 439, 443
Multiplanar reconstruction computed tomography
(mCT), 495
L Musclesound, 446
Lateral collateral ligament (LCL), 190, 505, 506 Musculoskeletal ultrasound, see Sports ultrasound
Lateral collateral ligament complex (LLC), 505 Musculoskeletal ultrasound-guided regenerative
Lateral epicondylitis, 27 medicine, 417–420
Lateral femoral cutaneous nerve, 445 Musculoskeletal-related conditions, 418
Ligament or retinaculum release, 450 Muse cell, 44
Ligaments and tendons, 36 Myopathies, 14
Limb amputation, 420
LL-37, 45
Local anesthetics, 297 N
Long head of the biceps brachii (LHBB) Neck pain, 223–225, 227
anatomy and ultrasound evaluation, 69–71 Needle electromyography (EMG), 356
injection approach, 72, 73 Neo-40, 53
interventional procedures, 72 Neovessel ablation procedures, 449
tendon pathology, 71 Nerve conduction studies (NCS), 356
Long thoracic nerve (LTN), 483 Nerve hydrodissection, 343, 346, 347
Low back pain, 235 injectate, 350, 351
anatomy and sonoanatomy, 236, 237, 239 neuropathic pain, 344
Iliolumbar ligament, 244 osteophytosis, 344
lumbar facet joints, 241, 242 post-surgical pain, 344
sacroiliac joints, 244, 245 sports injuries, 344
thoracolumbar fascia, 242, 243 technique, 343
Low level light therapy (LLLT), 50 ultrasonography, 345, 346
Low-intensity pulsed ultrasound (LIPUS), 277 Nerve hydrodissection (HD), 378
Low-level laser therapy (LLLT), 276 Nerve impingement using ultrasound, 430
Lubricin, 35 Nerve measurement, 364–366
Lumbar “core” muscles, 427, 429 Nerve size, 366
Lumbar facet joints, 241 Nervi nervorum, 344, 345, 380
Lumbar facet mediated pain, 407 Neuralgia and chronic constrictive injury (CCI’s), 380,
Lumbar interfascial triangle (LIFT), 235 381
Lumbar medial branch blocks and zygapophysial Joint, Neurapraxia, 358
407, 408 Neurodynamics, 430–432
Lumbar multifidus, 425 Neurogenic inflammation, 379, 385
Lumbar zygapophyseal joint injection, 402 Neuronal energy deprivation theory of pain, 388
Lyftogt theory of pain, 388 Neuropathic injury in sports, 445
Neuropathic pain, 343, 344, 375
Neuropathy of the lateral femoral cutaneous nerve, 445
M Nociceptors, 381, 383
Magnetic resonance arthrography (MRA), 470 Non-embryonic stem cells (NESC), 10
Manual tracing method, 364 Non-opioid treatment regimens, 375
Matrix metalloproteases (MMP), 42 Non-steroidal anti-inflammatory drugs (NSAIDs), 4, 25,
Matrix-assisted ACI (MACI), 11 375
Medial collateral ligament (MCL) injuries, 506–508
Medial fibers of the iliacus (MFI), 496
Median neuropathy, 368 O
Meniscal injuries, 510–512 Oarsman’s wrist, 476
Meniscal tears, 29, 30 Oblique popliteal ligament (OPL), 187
554 Index

Olecranon bursa injection, 114, 115 Physical medicine and rehabilitation, 417, 425
Operator dependency of US, 452 Piriformis pain syndrome, 161, 164, 167
Opiate addiction, 375 Plantar fascia release under US guidance, 451
Opioids, 375 Plantar fasciopathy (PF), 204
Opioid therapy, 5 Plantaris tendon release, 451
Oral mucosa stem cells (OMSCs), 265, 269 Platelet rich plasma (PRP), 195, 196, 199, 392
Organ system evaluation, 439–446 alpha granules, 36
Orthobiologics, 26 classification, 38
ACL tears, 29 clinical evidence, 39
adverse events, 30 dense granules, 36
basic science, 26 growth factors, 36, 37, 40
cartilage tears, 30 lysosomes, 36
clinical outcomes, 30 macrophages, 40–42
knee OA, 27–29 preparation, 38
lateral epicondylitis, 27 Platelet-activation-white blood cell (PAW) classification
meniscal tears, 29, 30 system, 289
MSC-mediated immunomodulatory activity, 26 Platelet-poor plasma (PPP), 291
orthobiologic medicine harnesses, 26 Platelet-rich plasma (PRP), 204, 211
patient-reported outcome measures, 30 classification systems, 289, 290
platelet-rich plasma results, 26 cytokines, 288
primary studies, 26 effectivity, 288
regenerative treatment methods, 26 growth factors, 288, 289
rotator cuff tear, 29 injection procedure, 291–293
rotator cuff tendinopathy, 27 leukocytes, 288, 289
safety and efficacy, 30 preparation methods, 290, 291
Orthopedics, 451 PRP-enhanced autografts vs. autografts, 288
Osteitis pubis, 154, 155 sedimentation rates, 288
Osteoarthritis (OA), 11, 25 Platelet-rich plasma (PRP) therapy, 316, 317
Osteochondral defects (OCD), 200 PLRA system, 289, 290
Osteophytosis, 344 Pneumothorax, 441, 442
Osteoporosis, 11, 14 Point-of-care pneumothorax evaluation, 442
Overhead athletes, 446 Polyneuropathies, 368
Ozone therapy, 51 Popliteal artery entrapment, 445
Popliteal fibular ligament (PFL), 190, 191, 505
Post procedure rehabilitation protocols, 215
P Posteriomedial corner (PMC), 181
Painful idiopathic neuropathy, 391 Posterior cruciate ligament (PCL), 502–504
Paraspinal myofascial structures, 250 Posterior interosseous nerve (PIN) syndrome
Patellar tendinopathy, 509, 510 anatomy, 117
Patient acceptable symptom state (PASS), 28 cause, 117
Pectoralis major, 99–100 equipment needed, 118
Pericytes, 26 injection indications, 118
Perineural glycopenia, 388 injection technique, 118
Perineural hydrodissection with ultrasound guidance, Posterior meniscofemoral ligament (PMFL),
378, 380 191, 192
Perineural injection treatment (PIT), 376–378, 380 Posterior superior iliac spine approach, 296
medical education, 392 Posterior talofibular ligaments (PTFL), 196
efficacy using dextrose, 388–391 Posterior tibial translation (PTT), 503
subcutaneous injections without intraarticular Posterior tibialis tendon (PTT), 196
injections, 383 Posterior tubercle, 399
Periodontal ligament stem cells (PDLSCs), 267 Posterolateral corner (PLC), 502, 503
Peripheral nerves, 343 Post-stroke shoulder pain, 419
compression, 367 Potassium (K+) channels, 386, 387
injury, 326–328, 443, 444 Potassium (K2P) channels, 387
ultrasonography, 357 Potassium ion channels, 383
Peripheral nociceptors (A delta and C fibers), 381 Power and color Doppler, 359
Peri-prosthetic soft tissue, 438 Preferential activation of the pelvic floor muscles,
Peroneus longus (PL), 211 428–429
Photo biomodulation (PBM), 50 Preparticipation evaluation (PPE) of athletes, 441
Physiatry, 417 Progenitor cells, 270
Index 555

Prolotherapy, 50, 77, 205, 206, 392 remodeling phase, 7

Proprioceptive and kinesthetic perception, 427 RM advanced therapy, 3
Prothrombin time/partial thromboplastin time (PT/PTT), scientific community, 539
295 self-regeneration, 6
Psoas major tendon (PMT), 496 for spinal procedures, 397–398
PurebredTM technique, 47 spine conditions, 322–326
standard pharmacotherapy, 4–5
standard treatment modalities, 4
Q stem cell-microenvironment communication,
Quadratus lumborum (QL), 235 9, 10
Quadricep femoris and ischiofemoral impingement, 164 and surgery curriculum, 18
Quadrilateral space, 97–99 tendons and ligaments
ACL, 317
early mobilization, 316
R healed tendon, 316
Randomized control trials (RCTs), 540 joint instability, 316
Regenerative injection, 223, 225 MSCs, 317
Regenerative medicine, 539, 540, 545, 546 PRP therapy, 316, 317
A2M, 305–309 stability and strength, 316
ADSC (see Adipose-derived stem cells) type 1 collagen fibrils, 315
augmented access, 541 ultrasound-guided injection, 318, 319
BMAC (see Bone marrow aspirate concentrate) Regenerative and novel orthobiologics, 397
cell sources, 10, 11 Rehabilitation, 426
cell therapies, 7, 8 Rehabilitation and physiotherapy, 432
clinical trials, 16, 17 Reinnervation process, 320
commercial clinics, 541 Respiratory burst, 47
controversies, 16 Retinal hemorrhage and lens dislocation/subluxation,
curriculum for next-generation physicians, 17, 18 440
definition, 3 Rib fracture and pneumothorax, 441–442
demand, 543 RM advanced therapy (RMAT), 3
evidence crisis, 540 Rotator cuff tear, 29
finance, 543, 544 Rotator cuff tendinopathy, 27
goal of, 19
governance crisis, 541, 542
health services, 539 S
image guidance, 7 Sacroiliac joints (SIJs), 235, 244
informed consent, 17 injections, 397, 410, 411
initial injury debridement, 6 with in-plane injection technique, 412
interventions, 16, 17 mediated pain, 410, 411
IRAP, 309–313 Sagittal band ruptures (Boxer’s knuckles), 478, 479
joints Salivary gland stem cells, 270
ASC, 314 Sarcopenia, 14
BMSC, 314 Satellite cell transplantation process, 320
indications, 313 Scaffolds, 271, 272
non-surgical treatments, 313 Scaphoid fractures, 480, 481
pro-inflammatory cytokines, 315 Scaphoid non-union advanced collapse (SNAC) wrist,
systematic review and meta-analysis, 314 480
ultrasound-guided injection, 313–315 Scapulolunate (SL) ligament, 478
local tissue metabolic changes, 5 Schwannoma of the common fibular nerve, 371
media, 544 Sciatic nerve branches, 444–445
mesenchymal stem cells (MSCs), 8, 9 Screening echocardiography, 441
metabolic balance, 5 Seesaw sign, 349
muscle injuries, 318–322 Senescent cells, 53
to musculoskeletal injuries, 3 Sensorineural effect of dextrose, 377, 378
phases of, 6 Sensory nerve action potential (SNAP), 366
peripheral nerve injury, 326–328 Sensory nerves, 386
proliferative healing phase, 7 Sensory-motor loop, 426
PRP (see Platelet-rich plasma) Shear wave elastography (SWE), 432, 447, 518
regulating authorities, 539 Sherrington’s law, 381
and rehabilitation, 14, 15 Short head of the biceps brachii (SHBB), 69
556 Index

Shoulder joint Spinal cord injury

acromioclavicular joint rehabilitation, 419
anatomy and ultrasound evaluation, 86–87 spasticity, 419
interventional procedures, 88 Spinal regenerative medicine, 249
pathology, 87, 88 epidural injections, 252–254
procedural protocol, 88–90 intradisal injections, 254–256
Rockwood classification with ultrasound paraspinal injections, 250–252
correlation, 88 subchondral intravertebral injections, 256
glenohumeral joint Spinoglenoid notch, 95–96
anatomy and ultrasound evaluation, 91, 92 Splenomegaly monitoring in mononucleosis, 442
interventional procedures, 93, 94 Sports hernia, 493, 494
pathology, 92, 93 Sports injuries, 344
procedural protocol, 94, 95 Sports medicine
static stabilizers, 91 advantages of diagnostic US, 438, 439
infraspinatus applicability of US, 439
anatomy and ultrasound evaluation, 81, 82 limitations, 452, 453
interventional procedures, 82, 83 ultrasound, 437
pathology, 82 Sports ultrasound
long head of the biceps brachii CEUS, 470
anatomy and ultrasound evaluation, 69–71 CMUT, 471
injection approach, 72, 73 diagnosis, 471
interventional procedures, 72 elbow, 474, 475
tendon pathology, 71 lower extremity
pectoralis major, 99–100 Achilles tendon pathology, 516–518
quadrilateral space, 97–99 ACL, 500–502
SASD bursa ankle inversion sprain, 512, 513
anatomy and ultrasound evaluation, 84, 85 anterior/medial hip, 492–498
interventional procedures, 85 features, 518–520
pathology, 85 groin pain, 492
procedural protocol, 85, 86 high ankle sprain, 513–515
spinoglenoid notch, 95–96 hip flexor strain, 492
sternoclavicular joint, 90, 91 ITB, 508, 509
subscapularis tendon LCL, 505, 506
anatomy and ultrasound evaluation, 79–80 MCL injuries, 506–508
interventional procedures, 81 medial ankle sprain, 515, 516
pathology, 80, 81 meniscal injuries, 510–512
suprascapular notch, 96, 97 patellar tendinopathy, 509, 510
supraspinatus tendon PCL, 502–504
anatomy and ultrasound evaluation, 73–75 posterior hip, 498–500
calcific disease classification systems, 76 MRA, 470
injection technique, 77–78 precision and diagnostic sensitivity, 469
interventional procedures, 76, 77 referral clinical decision, 470
one needle technique, 78 shoulder, 471–474
pathology, 75, 76 strain and shear-wave elastographies, 470
two needle technique, 79 technological features, 469
teres minor upper extremity
anatomy and ultrasound evaluation, 83–84 axillary nerve, 484, 485
interventional procedures, 84 BPI, 482, 483
pathology, 84 functional and anatomical assessment, 481
Sir Charles Scott Sherrington, 381 LTN, 483
Sirtuins, 52 median nerve injury, 486–488
Slump and straight-leg-raising techniques, 431 musculocutaneous nerve, 485, 486
Slump test, 430 myelin sheath and axons, 482
Snapping hip, 146, 147 radial nerve, 490, 491
Sodium hyaluronate (SH), 473 referred pain, 481
Soft tissue injections, 418–419 SAN injury, 482, 483
Soft tissue tension/stiffness, 432 suprascapular nerve, 483, 484
Somatosensory pathway, 377 ulnar nerve injury, 488–490
Specificity theory, 381 wrist and hand, 475–481
Spigelian hernias, 442 Sports US, 438
Spinal accessory nerve (SAN) injury, 482, 483 Stabilization exercises, 430
Index 557

Standard pharmacotherapy, 4–5 T

Stellate ganglion at level of C6 with in-plane injection Tendinopathy, 204, 418
technique, 405 Tendinosis, 4, 71
Stellate ganglion block (SGB), 404, 405 Tendon and bursa injections, 418
Stellate ganglion with Doppler, 404 Tendon scraping procedure, 449
Stem cell active cytokine C-kit ligand (SCF), 49 Tendon, muscle, and fascial release, 451
Stem cell-based injection therapy, 29 Tendons, 198
Stem cells Tenocytes, 195
cluster of differentiation, 42 Tension control and relaxation techniques, 432
embryonic stem cells, 43 Teres minor
induced pluripotent stem cells, 43, 44 anatomy and ultrasound evaluation, 83–84
mesenchymal stem cells, 45 interventional procedures, 84
Muse cell, 44 pathology, 84
niche, 43 Therapeutic exercises, 425
sources of, 42 Thigh
therapies, 392 anatomy, 168, 169
types of, 42 contusion, 168
V cells, 44 hematoma/seroma aspiration, 169–171
Stem cells from human exfoliated deciduous teeth Morel Lavalle lesions/seroma, 170
(SHED), 264, 266, 268 muscle injections, 171, 172
Stem cells from the apical papilla (SCAP), 267 muscle injuries, 168–170
StemXCell, 53 muscle trauma, 168
Stener-like lesion (SLL), 507 sonography, 168
Sternoclavicular (SC) joint, 90, 91 Thoracic back pain, 234
Steroid injection therapy, 4 anatomy, 229, 230, 232, 233
Stingers, 482, 483 costotransverse joint, 234
Straight leg raise test, 430 thoracic facet joints, 234
Straight-leg-raising technique, 431 Thoracolumbar Fascia (TLF), 242
Strain elastography (SE), 447 Toggling, 362
Stress fractures, 437 Tooth banking, 273, 274
Stroke, 419 Tooth germ progenitor cells (TGPC), 273
Stromal vascular fraction (SVF), 256, 304 Transducer, 345
Subacromial and greater trochanteric hip injections, Transient receptor potential vanilloid receptor-1
418 (TRPV1), 351, 352
Subacromial/subdeltoid bursa (SASD bursa), 73 Transverse process (TP), 225
anatomy and ultrasound evaluation, 84, 85 Triangular fibrocartilage complex (TFCC), 477
interventional procedures, 85 Trigger finger release, 450
pathology, 85 Trochanteric bursal swelling, 159
procedural protocol, 85, 86 Trochanteric bursitis, 159
Subcoracoid impingement, 80 TRPV ion channels, 385
Subscapularis tendon TRPV1 ion channel, 383, 385, 386
anatomy and ultrasound evaluation, 79–80
interventional procedures, 81
pathology, 80, 81 U
Substance P (SubP), 386 Ulnar collateral ligament (UCL), 475, 478
Subtalar joint injections, 418 anatomy, 115
Superb microvascular imaging (SMI), 519, 520 cause, 115
Supination external rotation (SER) stress, 515 equipment needed, 115
Supplements, 53 injection indications, 115
Suprascapular nerve, 483, 484 injection technique, 115, 116
Suprascapular notch, 96, 97 Ulnar entrapment, 444
Supraspinatus tendon Ulnar nerve at the elbow
anatomy and ultrasound evaluation, 73–75 anatomy, 116
calcific disease classification systems, 76 cause, 116
injection technique, 77–78 equipment needed, 116
interventional procedures, 76, 77 injection indications, 116
one needle technique, 78 injection technique, 116, 117
pathology, 75, 76 Ulnar neuropathy, 444
two needle technique, 79 Ultra Cur, 53
Surgical and interventional procedures, 426 Ultra-high frequency (70MHz) sonogram, 357
Syndesmotic sprain, 513–515 Ultrasonography, 345
558 Index

Ultrasound (US) V
depth, 60, 61 Valleix points, 382
Doppler function, 62 Vasa nervorum, 344, 345
evaluation for the anterior trunk muscles, 427 Vascular causes of exertional lower leg pain, 445
in exercise, applications of, 425–426, 432 Vascular injuries, 445, 446
findings, 366 Vastus medialis obliquus (VMO) of the knee, 432
in focal neuropathies, 358 Very small embryonic like stem cells (V Cells), 44
focal zone setting, 61 Vocal fold dysfunction, 440
frequency, 60 Volumetric muscle loss (VML), 319
gain setting, 61
needle visualization, 62
compression maneuver/manoeuvere, 64 W
ergonomics, 64–66 Wallerian degeneration, 366
heel toe maneuver/manoeuvere, 62 Wartenberg syndrome, 491
long axis linear slide, 62 Western Ontario and McMaster Universities
rotating the transducer, 63, 64 Osteoarthritis Index (WOMAC), 28
short axis linear slide, 62, 63 Whipping action, 516
tilting the transducer, 63 White adipose tissue, see Adipose-derived stem cells
transducer planes of manipulation, 62 (ADSC)
in neurodynamics, 430–432 Wrist disorder
orientation marker, 62 functional limitations, 119
in physiatric musculoskeletal medicine, 418, 419 sonoanatomy and interventional techniques
Piezoelectric effect, 59 acute/chronic instability of carpal bones,
in rehabilitation, 419–420 125
in sports medicine, 437 distal radio-ulnar joint, 120
in therapeutic exercises, 425 dorsal scapholunate ligament, 124, 127
transducers, 60 dorsal transverse approach, 123
Ultrasound guidance (USG), 200, 378 extensor carpi radialis brevis and longus tendons,
aspiration of fluid collections, 420 119
lumbar core exercise, 427–430 extensor carpi ulnaris tendon, 120
Morton neuroma injections, 418 extensor digiti minimi tendon, 120, 121
nerve hydrodissection, 377 extensor indicis proprius and extensor digitorum
spinal procedures communis tendons, 119
injection technique, 399–400 extensor pollicis longus tendon, 119
in-plane injection technique, 409, 410 hourglass sign, 128, 130
sacral cornua, 410 in-plane technique and distal to proximal
scanning technique and important anatomy, approach, 120, 121
398–399 in-plane technique and dorsal to volar approach,
subtalar joint injection 122, 123
anterolateral, 203 intra-tendinous injections, 120
posterior subtalar, 201 Lister’s tubercle, 119, 120
posteromedial, 203 longitudinal dorsal approach, 124, 127
Ultrasound tissue characterization (UTC), 519 out-of-plane technique and dorsal to volar
Ultrasound transducer placement approach, 123
for evaluation of pelvic floor muscles, 428 patient positioning, 119
for evaluation of multifidus muscles, 429 radiolunotriquetral ligament, 123, 126
Ultrasound-guided peripheral nerve procedures, 371, 372 scaphoid and pisiform for proximal carpal tunnel,
Unidirectional afferent pathway of sensory nerves, 383 126, 128
Upper extremity neuropathy, 444 sonographical navigation, 119
Urban legends of PRP, 39 transverse (palmar) approach, 126, 128
US Food and Drug Administration (FDA), 3 trapezium and hamate for distal carpal tunnel,
US guided tarsal tunnel release, 451 126, 129
US in sports medicine US-guided interventions, 122
Guiding return-to-play, 447, 448 US-guided peri-neural injections, 127
organ system evaluation, 439–446 US-guided (regenerative) injection, 120
physiologic measures, 446–447 ultrasound (US) imaging, 119
body composition, 446
tendon injury, 446, 447
muscle glycogen content, 446 Y
US tissue characterization (UTC), 447 Young’s modulus, 447