Rehabilitation

Considerations in
Regenerative Medicine
Penny L. Head, PT, MS, SCS, ATC, CSCS

KEYWORDS
 Regenerative rehabilitation  Mechanotransduction  Mechanotherapy
 Physical therapy  Platelet-rich plasma  Stem cell therapy

KEY POINTS
 Regenerative rehabilitation pairs exercise principles with regenerative therapies to facili-
tate the regeneration and repair of bone, muscle, cartilage, ligaments, tendons, nerves,
and other musculoskeletal tissues.
 Mechanotherapies form one of the largest groups of interventions prescribed by physical
therapists with nearly every intervention used introducing mechanical forces.
 A basic understanding of mechanotransduction and the impact of mechanical loading on
cellular biology can guide the development of appropriate rehabilitation programs after
regenerative therapies.
 Regenerative rehabilitation guides protocols for when to start therapy, types of stimuli
administered, and graded exercise programs, taking into account biological factors and
technologies designed to optimize healing potential.

INTRODUCTION

Regenerative medicine is an emerging, interdisciplinary field that combines advances

in molecular biology, gene therapy, cellular therapy, and tissue engineering to replace
or regenerate human cells, tissues, or organs.1,2 The goal of regenerative medicine is
to restore or establish normal function after loss from any cause, including congenital
defects, injury, disease, or aging.2,3 Given that physical rehabilitation shares the same
goal, the combination of the 2 approaches may serve to enhance the desired treat-
ment outcomes and could be transformative for individuals with previously untreatable
injuries or disorders.3,4
Regenerative rehabilitation is defined by the American Physical Therapy Association
as “the integration of principles and approaches from rehabilitation and regenerative

Disclosures: None.
Department of Physical Therapy, University of Tennessee Health Science Center, 930 Madison
Avenue, Room 604, Memphis, TN 38163, USA
E-mail address: [email protected]

Phys Med Rehabil Clin N Am 27 (2016) 1043–1054

http://dx.doi.org/10.1016/j.pmr.2016.07.002 pmr.theclinics.com
1047-9651/16/ª 2016 Elsevier Inc. All rights reserved.
1044 Head

medicine, with the ultimate goal of developing innovative and effective methods that
promote the restoration of function through tissue regeneration and repair.”5 Regen-
erative rehabilitation pairs exercise principles (eg, loading, intensity, frequency, dura-
tion), with regenerative therapies to facilitate regeneration and repair of bone, muscle,
cartilage, ligaments, tendons, nerves, and other musculoskeletal tissues. This concept
requires an interdisciplinary approach between scientists, clinicians, and physical
therapists (PTs). In addition, it requires PTs to develop an understanding of the impact
of exercise on cellular and molecular biology.
After tissue injury, PTs use targeted exercise therapy to enhance the efficiency of
the body’s innate healing potential.6 Properly designed rehabilitation programs can
play a critical role in optimizing the incorporation of regenerative therapies into the
native tissues. The role of PTs should not be confined to restoring function after tissue
regeneration or repair has occurred, because we should also play an active role in
facilitating regeneration and repair during the healing process.1

MECHANOTHERAPY

The term “mechanotherapy” was initially coined in the 19th century, and defined in the
Oxford English Dictionary as “the employment of mechanical means for the cure of
disease.”7,8 In 2009, Khan and Scott7 proposed to update the definition to “the
employment of mechanotransduction for the stimulation of tissue repair and remodel-
ing” to highlight the cellular basis of therapeutic exercise prescription for tissue heal-
ing. This definition also recognized that injured and healthy tissues may respond
differently to mechanical loads.7
In 2016, Thompson and colleagues1 proposed to once again update the definition to
“any intervention that introduces mechanical forces with the goal of altering molecular
pathways and inducing a cellular response that enhances tissue growth, modeling,
remodeling, or repair.” This definition highlights the responsiveness to mechanical sig-
nals at a multisystem level (ie, molecular level, cellular level, and tissue level) and rec-
ognizes the influence of mechanical forces on the processes responsible for tissue
development, maintenance, healing, and regeneration.1
Mechanotherapies form one of the largest groups of interventions prescribed by
PTs. Nearly every intervention used in the practice of physical therapy introduces
mechanical forces.1 Such interventions, including but not limited to, exercise prescrip-
tion, joint mobilization, soft tissue mobilization, muscle stretching, and even neuro-
muscular electrical stimulation, provide mechanical stimulation at both the cellular
and tissue levels.7,9 Developing insight into the molecular and cellular responses to
the forces used in daily practice will allow PTs to increase understanding of therapeu-
tic dosing and potentially improve clinical outcomes in patients undergoing regenera-
tive therapies.

MECHANOTRANSDUCTION

Mechanotransduction refers to the physiologic process by which cells convert me-

chanical stimuli into cellular responses.1,7,10 These cellular responses will, in turn, pro-
mote structural adaptation. Mechanotransduction consists of 3 distinct phases: (1)
mechanocoupling, (2) cell–cell communication, and (3) the effector response. Mecha-
nocoupling refers to a mechanical stimulus or load that causes physical perturbation
to cells.7 The perturbation may be direct or indirect and can trigger a variety of cellular
responses depending on the type, magnitude, frequency, and duration of the
load.11–13 Cells may be exposed to an array of mechanical forces, including tension,
compression, shear, hydrostatic pressure, vibration, and fluid shear. The tissue in
 Rehabilitation in Regenerative Medicine 1045

which a cell resides, as well as the location of the cell within that tissue, will influence
the types of mechanical stimuli to which the cell is exposed.1 The mechanical stimuli
are sensed by various mechanosensitive molecular mechanisms that transduce the
signal intracellularly. These mechanisms may include cell surface receptors, integrins,
focal adhesion complexes, stretch-activated ion channels, growth factor receptors,
and the extracellular matrix, to name a few.10,14–16
The cell–cell communication phase, sometimes referred to as the signal propaga-
tion phase, involves the recruitment of cell signaling pathways and other means of
signal spread (eg, cytoskeleton tension) for the biochemical conversion and propaga-
tion of the transmitted mechanical signal.7,17 Just as there are multiple mechanosen-
sitive mechanisms available to sense the mechanical stimulus, there are also multiple
signaling pathways that a cell may use to create a biochemical response.1 The cell
signaling pathways are composed of a cascade of multiple potential cytosolic medi-
ators that will transmit the biochemical signal from the cell surface to the effector
endpoint.9
The final phase of mechanotransduction is the effector response. Once the
biochemical signal is transmitted to the effector endpoint, changes in cellular biology
occur. If the endpoint is the nucleus, the signal may induce expression of mechano-
sensitive genes.1 If the endpoint is effector cells, changes may include an increase
or decrease in intracellular tension, changes in adhesive properties, cytoskeletal reor-
ganization, and/or modulation of cellular proliferation, differentiation, migration, and
apoptosis.18
Eccentric exercise provides an excellent example of the potential impact of mecha-
notransduction on muscle repair or regeneration. Muscle regeneration depends on a
functioning population of satellite cells.19 Eccentric exercise has been shown to stim-
ulate an array of cellular responses that have the potential to optimize the regenerative
process in muscle by stimulating the activation and proliferation of satellite cells.
Although the underlying mechanisms are still under investigation, recent studies
demonstrate that interstitial nonmyogenic, nonsatellite stem cells, including pericytes,
may play an important role in the regenerative process.20,21
Although nonmyogenic, pericytes have been shown to secrete a variety of beneficial
growth factors and antiinflammatory cytokines (eg, insulinlike growth factor-1, inter-
leukin-6, vascular endothelial growth factor, and hepatocyte growth factor) that acti-
vate satellite cells upon extraction from exercised muscle.22 Valero and
colleagues23 demonstrated an increase in the accumulation of pericytes and an in-
crease in satellite cell number in muscle after acute eccentric exercise in mice. Results
of the study suggest that the pericytes upregulate the expression of stem cell markers
when subjected to mechanical strain, potentially accounting for the significant in-
crease in the accumulation of satellite cells in muscle after exercise. In addition, the
authors demonstrated that pericytes indirectly stimulate new fiber synthesis after in-
jection of muscle-resident mesenchymal stem cells, particularly when recipient mice
are exercised immediately before injection. The results of this study provide evidence
that coordinated communication between pericytes and satellite cells positively influ-
ence muscle regeneration after eccentric exercise.23

CLINICAL INTEGRATION OF MECHANOTRANSDUCTION

Recent advances in the field of regenerative medicine, including the use of platelet-
rich plasma (PRP), stem cell therapy, and tissue engineering provide promising stra-
tegies to enhance tissue repair after musculoskeletal injury. The success of these
regenerative medicine technologies ultimately depends on the therapies being
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incorporated into the native tissue and creating a musculoskeletal tissue with
enhanced mechanical characteristics.1 Physical therapy has foundations in the use
of targeted mechanical stimuli designed to enhance the intrinsic healing potential of
tissue.3 A basic understanding of mechanotransduction and the impact of mechanical
loading on cellular biology can help to guide the development of appropriate rehabil-
itation programs after the application of regenerative therapies.
Eccentric exercise, as discussed, is 1 form of mechanotherapy that may serve to
facilitate tissue healing in conjunction with regenerative therapies. A more recent strat-
egy involving low-load resistance training with blood flow restriction (BFR), may poten-
tially play a role in regenerative rehabilitation. This form of exercise, also referred to as
strength training with vascular occlusion, has been shown to increase muscle hyper-
trophy and strength similar to heavy-load resistance training.24 BFR training involves
decreasing blood flow to a muscle using a wrapping device, such as a blood pressure
cuff or specially designed restrictive straps. Muscle hypertrophy has been demon-
strated during resistance exercises with intensities as low as 20% of 1 repetition
maximum with moderate vascular restriction (w100 mm Hg).25 In some studies,
BFR training has been applied with high frequency (1–2 sessions per day) and short
duration (1–3 weeks), resulting in significant increases in muscle size and strength.26,27
This form of training could potentially be quite beneficial to patients after regenerative
therapies that are unable to tolerate high-intensity resistance training (70% 1 repe-
tition maximum).
Although the underlying cellular mechanisms responsible for the adaptive changes
in muscle size and strength are largely unknown, recent studies show increased pro-
tein synthesis after acute bouts of BFR training, accompanied by posttranslation regu-
lation in the AKT/mammalian target of rapamycin pathway.27,28 Nielsen and
colleagues26 demonstrated marked proliferation of satellite stem cells and increased
number of myonuclei per myofiber with a short-term, high-frequency BFR training
program using low-load resistance.

Platelet-Rich Plasma
The use of PRP injections is one of the most common applications of regenerative
therapies for musculoskeletal injury. Although originally introduced in the 1970s, the
use of PRP injections has increased significantly in recent years, especially for the
treatment of sports-related ligament and tendon injuries.29,30 Rehabilitation protocols
after PRP therapy have not been well-outlined in the literature. Although physical ther-
apy is often used after PRP injections, there is little clinical evidence regarding the
optimal program design. Virchenko and Aspenberg31 examined the relationship
between mechanical stimulation and tendon healing after PRP injection in the trans-
ected Achilles tendons of rats. Results of this study indicated that although PRP
improved the material properties of the tendon callus, the effects were lost when
the tendon was unloaded mechanically. The authors concluded that mechanical stim-
ulation may be necessary for PRP therapy to be successful. In addition, the study
demonstrated that only the early phases of tendon regeneration were influenced by
the platelets, stressing the importance of mechanical stimulation early in the process
of healing.31
The results of the Virchenko and Aspenberg study have led to most rehabilitation
protocols endorsing early controlled loading of the tissue after PRP therapy for tendin-
opathy.32 Although several studies investigating the efficacy of PRP injection to pro-
mote tissue healing have demonstrated improvements in various outcome
measures,33–36 few have described the rehabilitation program or activity level of the
involved subjects after PRP therapy. Those that provide a detailed description of
 Rehabilitation in Regenerative Medicine 1047

post-PRP rehabilitation are often case reports or case series versus randomized
controlled trials.37,38 Although a common recommendation after PRP injection for
the treatment of tendon pathology is the use of eccentric exercise, the timing of exer-
cise implementation varies widely.38–41
Kaux and colleagues38 described a standardized rehabilitation program based on
submaximal eccentric exercise after PRP injection for patients with patellar tendinop-
athy. The protocol used 1 week of relative rest before initiating a progressive regimen
of closed kinetic chain eccentric quadriceps strengthening performed 3 times per
week.38 Progression of eccentric exercise was based on pain threshold as recommen-
ded by Stanish.42 Results of this case series indicated significant improvements for
pain and function, as measured by the visual analog scale, the International Knee
Document Committee scale, and the Victorian Institute of Sport Assessment scale.38
van Ark and colleagues41 described a 5-phase rehabilitation program after PRP
injection for patients with patellar tendinopathy. The goal of the initial 3 phases was
to create conditions to optimize recovery. The final 2 phases focused on loading to opti-
mize return to sport/activity. Gradual progression of the intensity of the exercise pro-
gram was based on correct execution of exercises and a visual analog scale score
of 50 or less on a scale of 0 to 100. Eccentric exercises were implemented in the third
phase of the program and were initially performed only twice a week to allow the tendon
to adapt to the load.41 The protocol described by van Ark and colleagues incorporates
both concentric and eccentric training, because the combination of both types of
training may promote collagen synthesis.43 In addition, the protocol integrated core
stability exercises, because core muscle strength has been found to be important in
the load distribution on the patellar tendon.44 Results of this case-series demonstrated
improvements in both pain and function as measured by the visual analog scale and
Victorian Institute of Sport Assessment. The results also indicated a potential relation-
ship between patient compliance and improvement in pain and function; the 3 patients
with the highest self-reported program compliance demonstrated the greatest
improvement in Victorian Institute of Sport Assessment scores, and the 1 patient
who did not improve had the lowest self-reported compliance.41
Based on the study by Virchenko and Aspenberg,31 it seems that tendon healing
requires a combination of biological and mechanical factors. Rehabilitation after
PRP therapy is necessary to provide the mechanical loading component. There are
a number of important factors to consider when designing a rehabilitation program af-
ter PRP injection. In addition to addressing specific impairments the patient may have,
interventions should facilitate the potential synergistic effects of mechanical loading
and PRP therapy. Factors to be considered include timing of the initiation of physical
therapy after PRP injection, type of exercise (eg, concentric vs eccentric loading), in-
tensity, duration, and frequency. Although treatment should be individualized for each
patient after PRP therapy, general guidelines are provided in Table 1 for rehabilitation
after PRP or stem cell therapy for tendon, ligament, and/or articular cartilage. In addi-
tion, the rehabilitation protocol after PRP injection for patellar tendinopathy as
described by van Ark and colleagues41 is detailed in Box 1.

Stem Cell Therapy

The use of stem cell injections for the purpose of tissue regeneration has received
considerably more attention in the last decade.45,46 Use of stem cells for this purpose
is appealing because of their ability to differentiate into a variety of specialized muscu-
loskeletal tissues including bone, cartilage, tendon, ligament, and muscle.47,48 Key
features determining the success of stem cell therapy once injected into the host tis-
sue include the ability of the stem cells to survive and divide, migrate to the site of
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Table 1
General guidelines for platelet-rich plasma/stem cell therapy

Phase I—(0–3 d)
Goals  Protection of affected tissue/joint
 Pain control
Precautions  Limited immobilization and/or unloading of affected joint
 Consider sling for shoulder/elbow pathologies
 Consider unloading brace for knee osteoarthritis cellular therapies
 Consider partial weight-bearing with crutches for lower extremity
pathologies
 Consider walking boot for ankle/foot pathologies
Suggested  Begin gentle PROM and AROM exercises out of the immobilizing
interventions device
 Perform short duration (2–3 min), multiple times per day (3 times/d)
 Taping techniques for tendon unloading
Criteria for Minimal pain/discomfort (<50 on VAS) with AROM
progression
Phase II—(3–14 d)
Goals  Increase tissue tolerance to loading
 Discontinue immobilization/unloading
Precautions  Prevent overstressing affected tissue
 Avoid shear stress if articular cartilage pathology
 Gradually wean from immobilization
 Gradually progress weight-bearing
Suggested  Continue PROM and AROM activities for 3–5 min/session, 3–5 times
Interventions a day
 Begin submaximal isometric exercises for affected tendons/joints;
maximal isometrics if ligament
 Begin progressive loading for lower extremity pathologies (eg,
weight shifting, aquatic exercise, zero-gravity treadmill)
 Unloaded cycling/upper body ergometer
 Well leg/arm conditioning exercises
 Core stability exercises
 Continuation of taping techniques to unload if tendon pathology
Criteria for  Minimal pain (<50 on VAS) during exercise and ADLs
progression  Pain should decrease after completion of exercise
 Normal gait if lower extremity pathology
Phase III—(2–8 wk)
Goals  Full ROM of affected joint
 Increase tissue tolerance to loading
 Improve strength/endurance
Precautions  Avoid impact, high-intensity, or high-velocity activities (eg,
jumping, running, throwing, heavy weight lifting)
 Avoid postexercise/activity pain
Suggested  Joint mobilization as needed to restore normal joint
interventions arthrokinematics
 Stretching of affected muscle–tendon unit (holding 30 s for 3–5
reps)
 Progress to isotonic strengthening
 Initiate eccentric strengthening with tendon pathology if symp-
toms allow (<50 on VAS); pain should subside within 24 h; 3–4 d/wk
 Dynamic neuromuscular control drills
 Cardiovascular exercise with progressive loading (eg, stationary
bike, upper body ergometer, elliptical trainer, deep water running,
zero gravity treadmill)

(continued on next page)

 Rehabilitation in Regenerative Medicine 1049

Table 1
(continued )
Criteria for  Full ROM
progression  No pain with ADLs
 Minimal pain with exercise activity
Phase IV—(8 wk)
Goals  Increase tolerance of tissue to loading
 Good neuromuscular control with activity
 Return to sport/work
Precautions  Minimal pain with activity
 Postactivity soreness resolves within 24 h
Suggested  Progressive strengthening with increased load
interventions  Daily eccentric exercises if tendon pathology
 Progress neuromuscular control drills
 Initiate and progress walk/run program if lower extremity
pathology
 Initiate and progress plyometric program is applicable to patient
 Sport-specific training
Criteria for return  Full ROM
to sport/work  Strength within 85% of contralateral extremity
 Good neuromuscular control with activity
 No pain with activity

Abbreviations: ADL, activity of daily living; AROM, active range of motion; PROM, passive range of
motion; ROM, range of motion; VAS, visual analog scale.

tissue injury, and ultimately differentiate into the targeted tissue of interest.3 Although
rehabilitation protocols after stem cell therapy have not been well-outlined in the liter-
ature, a number of studies provide evidence that exercise and physical activity are
linked to the activation, mobilization, and differentiation of various types of stem
cells.49–51
Tissues and cells in the human body are constantly exposed to a mechanical envi-
ronment. This environment is significantly influenced and changed by exercise
training.52 The integration of exercise after stem cell therapy helps to recruit trans-
planted stem cells to the site of interest,53 as well as stimulate activity of endogenous
stem cells.54 Ambrosio and colleagues55 investigated the effect of exercise on stem
cell transplantation to heal injured skeletal muscle in mice. Results of the study
demonstrated that 5 weeks of daily treadmill running significantly increased the num-
ber of transplanted stem cells. In addition, the majority of the donor cells terminally
differentiated toward a myogenic lineage. In the absence of mechanical loading via
treadmill running, the transplanted stem cells failed to rapidly divide.55
Yamaguchi and colleagues56 investigated the histologic effect of treadmill exercise
on osteochondral defects in rats after intraarticular injection of stem cells. Using the
Wakitani cartilage repair scoring system, results of the study demonstrated that exer-
cise after stem cell injection significantly improved cartilage repair, especially at the
4-week timeframe. This study highlights the importance of exercise after stem cell
therapy for the treatment of articular cartilage defects.56
Aoyama and colleagues57 demonstrated the feasibility and safety of a 12-week
rehabilitation program after mesenchymal stem cell transplantation augmented by
vascularized bone grafting for the treatment of idiopathic osteonecrosis of the femoral
head. Program design focused on improving hip joint function, avoiding collapse of the
femoral head, and promoting bone formation from the transplanted stem cells. The
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Box 1
Physical therapy program after platelet-rich plasma therapy for patellar tendinopathy

Phase 1—Inflammation/proliferation phase (0–2 weeks)

Inform and advise patient, rest, low load (1 week physical therapy)
Days 1 to 3: Inform and advise patient
 Rest
 Low load (walk with 2 crutches)
 Reduce pain (cryotherapy)
Days 4 to 7: Inform and advise patient
 Optimize ROM if necessary, combined with isometric exercises for m. quadriceps
 Increase activities of daily living with VAS pain score of less than 50
Days 7 to 14: Exercise
 Optimize knee flexion and extension combined with unloaded cycling (hometrainer)
 Walking: 100% load without crutches
 Home exercise program: m. quadriceps isometric contraction, active straight-leg raise,
abduction side-lying (2 day, 3  20 reps, rest interval 30–60 s)
Pain score must not exceed 50 on the VAS scale during all exercises and activities of daily living
Phase 2—Proliferation phase (weeks 2–4)
More dynamic and active exercises (1  2 weeks physical therapy)
 Higher cycling intensity (build up load), goal: 20 to 30 minutes
 Home exercise program
 Squats, calf extensions, single-leg squat with arm swing, abduction side-lying, cycling on
home trainer (3  20 reps, rest interval 30–60 s)
 Exercises have to be possible (need to be executed) in complete ROM
 Closed chain exercises, mainly coordination and strength endurance; stability plays no
major role yet
 Light pain (VAS <50) allowed during exercises; however, the pain must decrease after the
exercise
Phase 3—Remodeling phase (weeks 5–6)
Active exercises are expanded (2 week physical therapy)
 Eccentric exercises are integrated into the program
Home exercise program (on days without supervised physical therapy): 2 days per week
Single-leg squat on decline board (25 )
 Various exercises (strength endurance) to increase load capacity of lower extremity
Including hometrainer warm-up, core stability exercises, lunges, abduction side-lying, squats
and step-downs (3  15 reps, rest interval 30 s)
 Integrate core stability exercises (eg, prone bridge, side bridge)
A pain increase within 48 hours is allowed (VAS <50) but the pain must have disappeared after
48 hours. No leg extension in open chain.
Phase 4—Integration phase (weeks 7–8)
Exercises progressing to higher percent of 1 repetition maximum, 3  8 to 15 reps, rest interval
30 s, more muscular hypertrophy (2 week physical therapy)
 Daily eccentric training (2 day, 3  20 reps)
 Run-and-walk exercises of increasing intensity and difficulty (starting with interval walking/
jogging, advancing to multidirectional, acceleration and deceleration running)
 Jump exercises with increasing difficulty (correct execution with controlled landing
important; start with height jumps, progress to long jumps)
 Core stability with greater difficulty
 Sport-specific exercises at maximal and speed strength
 Rehabilitation in Regenerative Medicine 1051

Phase 5—Sport-specific phase (After 8th week)

 Daily eccentric training continues (2 day, 3  20 reps) until end of supervised physical
therapy program (12 weeks)
 Advance to more sport-specific exercises, for example, plyometric, a-lactic, multidirectional
running, acceleration and deceleration

Abbreviations: ROM, range of motion; VAS, visual analog scale.

Data from van Ark M, van den Akker-Scheek I, Meijer LT, et al. An exercise-based physical
therapy program for patients with patellar tendinopathy after platelet-rich plasma injection.
Phys Ther Sport 2013;14(2):124–30.

rehabilitation program used a combination of passive and active range of motion, pro-
gressive weight-bearing, resistance training, and aerobic training, and used evidence
from the literature for the progression of these interventions.57
Research indicates that implementation of targeted rehabilitation programs after
stem cell therapy is necessary to maximize outcomes. Similar to the development
of a rehabilitation program after PRP injection, there are a number of important factors
to consider when designing a program after stem cell therapy. As stated, in addition to
addressing specific impairments the patient may have, interventions should facilitate
the potential synergistic effects of mechanical loading and stem cell therapy. Factors
to be considered include timing of the initiation of physical therapy after stem cell in-
jection, type of exercise (eg, concentric vs eccentric loading), intensity, duration, and
frequency. Refer to Table 1 for general rehabilitation guidelines after stem cell therapy.

SUMMARY

Rehabilitation coupled with regenerative medicine therapies has shown improved out-
comes for tissue regeneration.6 Regenerative rehabilitation seeks to guide protocols in
terms of when to start therapy, types of stimuli administered, and graded exercise pro-
grams, while taking into account biological factors and technologies designed to opti-
mize healing potential.6 Although there are currently no evidence-based guidelines for
rehabilitation after regenerative therapies, some fundamental physical therapy princi-
ples most likely apply. Immobilization after injury tends to have deleterious effects on
musculoskeletal tissues, whereas mechanical loading promotes tissue healing and
regeneration.58–61 Integration of common physical therapy interventions such as pas-
sive and active range of motion, joint mobilization, soft tissue mobilization, and exer-
cise prescription may provide beneficial effects after the application of regenerative
therapies. Further research is needed to determine optimal rehabilitation protocols
to enhance tissue healing and regeneration.

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