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Tendinopathy: injury, repair, and current exploration

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Drug Design, Development and Therapy

Kelsey Lipman 1 Abstract: Both acute and chronic tendinopathy result in high morbidity, requiring management
Chenchao Wang 2–4 that is often lengthy and expensive. However, limited and conflicting scientific evidence sur-
Kang Ting 2 rounding current management options has presented a challenge when trying to identify the
Chia Soo 4 best treatment for tendinopathy. As a result of shortcomings of current treatments, response to
Zhong Zheng 2 available therapies is often poor, resulting in frustration in both patients and physicians. Due to
a lack of understanding of basic tendon-cell biology, further scientific investigation is needed
1
David Geffen School of
Medicine, 2Division of Growth
in the field for the development of biological solutions. Optimization of new delivery systems
and Development, Section of and therapies that spatially and temporally mimic normal tendon physiology hold promise for
Orthodontics, School of Dentistry, clinical application. This review focuses on the clinical importance of tendinopathy, the structure
University of California, Los Angeles,
CA, USA; 3First Hospital of China of healthy tendons, tendon injury, and healing, and a discussion of current approaches for treat-
Medical University, Shenyang, ment that highlight the need for the development of new nonsurgical interventions.
China; 4Division of Plastic and Keywords: tendinopathy, tendon injury, tendon repair, healing
Reconstructive Surgery, Department
of Orthopaedic Surgery, Orthopaedic
Hospital Research Center, University
of California, Los Angeles, CA, USA Introduction
Though the incidence of tendinopathy is difficult to evaluate, it has been estimated
that approximately 30% of consultations for musculoskeletal pain in a general practice
setting are related to tendinopathy.1 While tendon injury remains an issue in the lives of
a variety of patients and commonly occurs in the workplace, it has been reported that up
to 30%–50% of sporting injuries involve tendinopathy.1,2 There is both an increase in
the prevalence of musculoskeletal disease and an increase in cost per person in recent
years, leading to rapidly rising economic impact of musculoskeletal conditions. The
most recent assessment of economic burden of musculoskeletal disease demonstrates
an increase in aggregate total expenditure for health care to have increased from
US$367.1 billion in 1996–1998 to $796.3 billion in 2009–2011.3
Tendon injuries are often multifactorial, and can be classified as tendonitis, char-
acterized by inflammation, and tendinosis, characterized by degenerative changes in
Correspondence: Chia Soo
Orthopaedic Hospital Research Center, tendon structure.4 More recently, the term “tendinopathy” has been adopted to encom-
University of California, 635 Charles pass the clinical aspect of pain and reduced function of tendons.1,4 In most cases of
E Young Drive South, Los Angeles,
CA 90024, USA tendinopathy, injury is due to the culmination of multiple pathological processes, rather
Tel +1 310 794 5479 than a single factor, that in combination lead to loss of tissue integrity and subsequent
Fax +1 310 206 7783
Email [email protected] rupture. Statistical analysis reveals that the rotator cuff, Achilles, tibialis posterior,
and patellar tendons are the most prone to pathology.4 Despite the use of currently
Zhong Zheng
Division of Growth and Development, available therapies, tendon injuries can result in disability that lasts for several months
Section of Orthodontics, School of and ultimately results in a weaker tendon that is susceptible to further injury.5
Dentistry, University of California,
10833 Le Conte Avenue, Los Angeles,
While extrinsic factors, such as sports and physical activity, are often associated
CA 90095, USA with tendon injury, additional intrinsic factors that can make an individual more or less
Tel +1 310 206 5646
Fax +1 310 206 7783
likely to suffer from a tendon injury include age, sex, disease (ie, diabetes, rheuma-
Email [email protected] toid arthritis), and genetic predisposition.4 Because tendon injury has a strong impact

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on patient quality of life and health care system spending, believed that tenoblasts are stimulated to differentiate into
it is crucial to investigate further the molecular mechanisms terminally differentiated tenocytes in response to a variety
involved in tendon repair in order to encourage the develop- of stimuli, including exercise and trauma, in order to induce
ment of novel therapies for treatment. proliferation and matrix remodeling.4,8
It has also been demonstrated that tendons contain TSPC
Tendon physiology niches capable of self-renewal and clonogenicity.7 Prior to
Tendons are composed of a highly organized structure to identification of TSPCs by Bi et al in 2007, the development
allow for the transmission of large-magnitude forces between of fibrocartilage and ossification in response to injury and
muscle and bone during daily activities. The structure relies the expression of adipogenic, osteogenic, and chondrogenic
on highly regulated interplay between the activity of local cell differentiation pathways within tendon-derived immortal-
types and the regulation of extracellular matrix (ECM) com- ized cell lines suggested the presence of an stem cell (SC)
position (Figure 1). The ECM is composed of parallel col- population within tendons.7,9–11 Bi et al7 also identified two
lagen fibers that can be further divided into fascicles, fibrils, ECM small leucine-rich proteoglycans (SLRPs) – fibromodu-
subfibrils, microfibrils, and tropocollagen components.6 lin (Fmod) and biglycan (Bgn) – as critical organizational
Collectively, the bundled fibers are surrounded by connec- components of the niche that act through modulation of
tive tissue layers – epitenon and endotenon – that allow for BMP signaling.
frictionless movement and supply blood vessels, nerves, The regulation of differentiation of these SCs within
and lymphatics to deeper tendon structures. Regulation of the niche is not precisely known, but proposed mechanisms
this highly organized structure by tenocytes, tenoblasts, and include a combination of mechanical loading, composition/
tendon stem/progenitor cells (TSPCs) is crucial to maintain microstructure of the ECM, vascular input, and metabolic
proper mechanical properties and prevent injury.6,7 activity.12,13 For example, culturing TSPCs with an aligned
nanofibrous scaffold encouraged tenogenic lineage com-
Tendon-cell niche mitment compared to an osteogenic lineage commitment
Tenoblasts and tenocytes are tendon-specific cell types that associated with a randomly oriented scaffold, supporting the
comprise the vast majority of the cellular content within notion that TSPCs receive topographical information from
tendons.4 Tenocytes are considered fibroblast-like cells the surrounding ECM.12,14 FMOD has previously been used
between collagen fibers and the endotenon capable of pro- to reprogram human fibroblasts into a multipotent stage15,16
ducing necessary components, such as type I collagen and and elicit a fetal-like phenotype in adult fibroblasts during
other ECM molecules during growth and healing (Figure 1). wound healing via delegate modulation of transforming
Although the signaling process is not fully understood, it is growth factor (TGF)-β signal transduction,17 demonstrating

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Figure 1 Hierarchical structure of tendon.

Notes: Collagen alignment is based on organization into fascicles, fibers, and fibrils. Tenocytes, terminally differentiated from tenoblasts, are the main cellular component of
tendons. Though the exact location of tendon stem cells is unknown, their presence has been confirmed. Blood vessels and nerves are also present within the structure, but
are not shown. Data from Docheva et al4 and Nourissat et al.5

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Dovepress Tendinopathy and current therapies

its ability to regulate cell fate within endogenous cell to be crucial for mechanical properties of tendons. As a
niches.15,18 Further research is needed fully to characterize result, research efforts are aimed at understanding the role
the signaling that coordinates properties of the SC niche with of growth factors, transcription factors, and mechanical
TSPC differentiation and self-renewal. forces related to regulation of type I collagen-fibril spatial
distribution. For example, TGFβ and FGFs have been shown
Tendon extracellular matrix to regulate collagen-architecture formation within tendons
Although extensive subdivisions exist within tendons, col- during development.23,24 In addition, the transcription factors
lagen fibers are considered the force-transmitting unit of the scleraxis, Mohawk homeobox protein, and zinc-finger protein
tendon.19,20 The ability of tendons to transmit force between early growth response protein 1 (EGR1) regulate the forma-
the myotendinous junction and the osteotendinous junction tion of type I collagen within tendons through modulation of
is dependent upon the structural integrity between individual COL1A1 and COL1A2 gene expression (Figure 2).25–27
muscle fibers, as well as ECM composition and the fibrillar In addition to the highly ordered collagenous matrix
structure of the tendon.19 Most importantly, tissue strength within tendons, research is increasingly focusing on the
depends on the ability of the collagen molecules to form an roles of the noncollagenous matrix.28 The noncollagenous
organized and cross-linked structure.21 matrix is primarily composed of the fibrous protein elastin,
Type I collagen predominates within the ECM of ten- glycoproteins, proteoglycans, and other molecules, such as
dons, with type III collagen being the next-most abundant collagen oligomeric matrix protein (COMP), lubrican, and
and critical in pathologic tendons and tendon-healing pro- tenascin C (Figure 2).29 Elastin fibers provide flexibility
cesses (Figure 2).22 Type I collagen alignment is recognized for distention during unidirectional elongation and provide

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Figure 2 Representation of the interaction between tendon extracellular matrix and cellular signal transduction.
Note: With a predominance of type I in the healthy tendon, collagens interact with growth factors (such as TGFβ) and proteoglycans (such as SLRPs and COMP) that regulate
their synthesis and architectural organization. Data from references.22–33
Abbreviation: SLRPs, small leucine-rich proteoglycans.

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capabilities related to deformity and elastic recoil. However, and fascicle sliding, thereby regulating tendon viscoelastic
the relatively low concentration of elastin simultaneously properties.39,40
prevents excessive stretching during muscle contraction such Noncollagenous matrix components not only demonstrate
that force is properly translated into articular movement.21 roles in ECM assembly but also participate in the regulation
Most of the proteoglycans found within tendon are catego- of cell fate. As discussed previously, SLRPs are thought to
rized as SLRPs, with decorin (Dcn) accounting for 80% of regulate cell growth and differentiation through modulation
the total proteoglycan content and lower levels of Bgn, Fmod, of TSPC niches.34,41,42 The ability of Fmod to reprogram
and lumican (Lum).30 human fibroblasts into multipotent cells supports the idea
The role of noncollagenous matrix proteins during that Fmod regulates cell fate through alterations in the cell
growth and development has been well characterized. Many niche microenvironment. Because Fmod is a 59 kD ECM
of these proteins have the ability to regulate fibrillogenesis proteoglycan, it is unlikely that the molecule freely penetrates
in terms of fibril diameter, alignment, and stability.31–33 the membrane for reprogramming. Rather, Fmod most likely
For example, BGN- and DCN-knockout mice contain thin, modulates expression of growth factors and cytokines in the
disorganized collagen fibrils and areas of calcification ECM microenvironment that can lead to altered cell fate.15
within the tendon.33,34 Interestingly, Bgn synthesis can be In addition, it is likely that the various SLRPs in the non-
upregulated in DCN-null mice, suggesting the proteins have collagenous matrix work as a unit to induce temporally and
similar functions and may be able to play compensatory roles spatially specific signaling cues for cell differentiation during
for each other.32 In a less severe manner compared to Bgn tendon development and tendon healing. Detailed character-
and Dcn, Fmod- and Lum-deficient mice also demonstrate ization of each component of the noncollagenous matrix at
increased cellularity and larger, irregularly shaped fibers.35 hierarchical levels of tendons is needed to understand fully
Similarly, knockout mice for various SLRPs have been the structure–function relationship and apply the knowledge
shown to have disorganized dermal collagen architecture to tendon-injury treatment.
in the context of wound healing, leading to delayed wound
closure and increased scar formation. 36–38 For example, Growth factors
14-day scars of Fmod-deficient mice demonstrate a wider Tendon injury involves the production of multiple growth
range of fibril diameters, decrease in the orderly packing of factors at various stages of healing that increase cellularity
fibrils with increased interfibrillar space, and contain scal- and attempt to regenerate tissue (Table 1). Though the
loped edges with lateral fusion.36 In mature tendon, noncol- roles of specific growth factors vary, they typically work
lagenous proteins have been proposed to modulate fiber synergistically with other signaling molecules and are

Table 1 Summary of tendon-healing process

Duration Inflammation* Proliferation* Remodeling*
Days Weeks Months–years
Overall Formation of hematoma Deposition of randomly organized Decrease in cellularity and matrix
changes proteoglycans and collagen production
Invasion of cells for phagocytosis Increased cellularity Transition from type III to type I collagen
Release of proinflammatory cytokines Activation of TSPCs Increase collagen-fiber cross-linking
Cellular Neutrophils, macrophages Fibroblasts increase type III collagen Fibroblasts regulate type III–I collagen
mediators transition
Molecular IGF1 Stimulation of proliferation and IGF1 Stimulation of proliferation and IGF1 Stimulation of proliferation and
mediators migration migration migration
TGFβ Stimulates collagen production and TGFβ Stimulates collagen production and TGFβ Stimulates collagen production and
cell migration, regulates proteinases cell migration, regulates proteinases cell migration, regulates proteinases
PDGF Stimulates DNA and protein PDGF Stimulates DNA and protein FGF2 Regulates angiogenesis and cellular
synthesis synthesis migration
FGF2 Regulates angiogenesis and cellular VEGF Promotes neovascularization
migration MMPs Collagen degradation and
VEGF Promote neovascularization reorganization
BMPs Regulate differentiation of stem cells
Note: *Inflammatory, proliferative, and remodeling phases are characterized by structural changes regulated by cellular and molecular mediators that work synergistically to
promote healing and increase tendon strength after an injury.4,6,43–46,49–55,85,86
Abbreviation: TSPCs, tendon stem/progenitor cells.

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Dovepress Tendinopathy and current therapies

upregulated throughout the tendon-repair process. The main lead to tendinopathy or tendon rupture, and the injury can
growth factors involved in tendon healing that have been the be due to a combination of both acute and chronic trauma.
focus of new repair therapies include IGF1, TGF, VEGF, For example, tendon ruptures may occur in the setting of
PDGF, FGF2, and BMPs.4,43 acute overload or laceration, but are often secondary to
IGF1 and TGFβ become active almost immediately after intrinsic pathology.56 Participating in a sporting activity is
tissue injury and remain active throughout most phases of the most common etiologic factor for Achilles tendon rup-
tendon healing. Multiple studies have demonstrated upregu- ture, but biopsies have shown degenerative changes in most
lation of IGF1 mRNA, protein, and receptors during and ruptured Achilles tendons.57–59 As such, this type of injury
after soft-tissue injuries.44–46 IGF1 is postulated to stimulate is classified by some authors as acute trauma of chronically
proliferation and migration of fibroblasts at the injury site degenerated tendons.56
and to promote the production of ECM components during In addition to damage induced by stresses that are outside
remodeling. Tsuzaki et al demonstrated that proliferation of physiological limits, such as rupture or laceration, repetitive
tendon fibroblasts reached maximum levels when IGF1 was microtrauma that occurs within physiologic limits can induce
administered with PDGF, rather than as an individual applica- tendinopathy and increase risk of acute and chronic injury.
tion, supporting the idea that growth factors are synergistic in Repetitive loading can be detrimental to tendon structure, as
nature.45 PDGF is mainly involved in early stages of healing the repair mechanism has less time to heal the microtrauma
and induces synthesis of IGF1, subsequently stimulating DNA before subsequent stresses.60–62 Also, microtears can be
synthesis.47,48 PDGF also stimulates collagen and noncollagen induced by nonuniform force production and muscle acti-
protein production in the area of injury in a dose-dependent vation that results in nonuniform loading of tendons. This
manner.43 TGFβ has been shown to have a wide variety of indicates that both load magnitude and distribution are critical
effects in all stages of healing, including stimulation of colla- factors in the determination of tendon-injury etiology.60,61
gen production, regulation of fibronectin-binding patterns and Several ideas have been proposed to underlie the etiology
proteinases, and stimulation of extrinsic cell migration.43,59 of tendinopathy, including hypoxia, ischemic damage,
Unlike IGF1 and TGFβ, which are active throughout the oxidative stress, induction of apoptosis, and production of
entirety of healing, VEGF is most active during the prolifera- inflammatory cytokines.63–68 For instance, following ischemia
tion and remodeling phases.50 Increases in VEGF correspond induced by maximal tensile load, relaxation and subsequent
to subsequent vascular ingrowth from epitendinous and generation of free radicals may play a role in tendinopathy.63
intratendinous blood sources toward the area of injury.51 This Supporting this idea is the upregulation of peroxiredoxin 5,
neovascularization serves to provide nutrients and additional an antioxidant enzyme present in human tenocytes, in cases
growth factors to the injured site. FGF2 serves as a regulator of tendinopathy.64 In addition, localized hypoxia may result
of angiogenesis within wounded tissue. In a rabbit flexor- in failure to maintain necessary ATP levels and contribute
tendon wound-healing model, Chang et al demonstrated an to degeneration.65
increase in FGF2 mRNA expression in tenocytes within It has also been demonstrated that strain application
epitenon and infiltrating fibroblasts after transection and induces the production of protein kinases that regulate
repair.52,53 BMPs stimulate mitogenesis and regulate differ- apoptosis of tenocytes. 66 Furthermore, protein-kinase
entiation of multipotent SCs in vitro and in vivo.54,55 activity demonstrates a magnitude-dependent rather than
Because growth factors interact with one another to regu- frequency-dependent response. Animal models have shown
late the tendon-healing environment, understanding the time that administration of harmful inflammatory mediators,
course and function of growth factors in an individual sense such as prostaglandin E2 and IL6, induces tendinopathy
has limited clinical applicability. As research progresses, histologically.67,68 Physiologic levels of cyclic stretching have
the interplay between multiple growth factors will likely be also been shown to induce secretion of IL6 in tenocytes.67
a focus of therapeutic strategies, rather than administration Although the relative contribution of each of these biologic
of a single factor. processes requires further investigation, tendinopathy is most
likely due to a combination of these propositions. Although
Tendon injury and repair tendons have some regenerative capacity, their mechanical
Overview of tendon injury properties and highly ordered structural organization will not
As tendons transmit forces between muscle and bone during return to preinjury levels even after extended periods.69–71
repeated motion, they become susceptible to acute and Khan et al proposed the “biochemical hypothesis”
chronic injury.56 There are many mechanisms of injury that to explain the pain associated with tendinopathy as it relates

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to the release of noxious stimuli and subsequent nociceptor characterized by disorganized deposition of granulation tissue
stimulation.72,73 It has been demonstrated that tenocytes have and a peak in relative concentrations of type III collagen and
the ability to produce signal substances that are typically con- DNA, setting the stage for further collagen synthesis and
fined to neuronal transmission, including substance P (SP), eventual transition from type III to type I collagen in sub-
catecholamines, glutamate, and acetylcholine (ACh).73,74 sequent stages.6,86
Deeper investigation showed upregulation of tyrosine Remodeling involves a slowing of ECM deposition, lon-
hydroxylase, the rate-limiting enzyme in catecholamine gitudinal organization of collagen fibers within the tendon,
synthesis, and choline acetyltransferase, the biosynthetic and normalization of type III:I ratio of collagen-fiber types.6
enzyme for ACh, in chronically injured tendons compared In addition, it has been shown that MMPs are key regulators
to control.74–78 Furthermore, immunohistochemical analysis of ECM remodeling after tendon injury.83,87 Specifically,
and in situ hybridization have shown an increase in both MMP9 and MMP13 play a role in collagen degradation,
protein and mRNA levels of SP and vesicular glutamate while MMP2, MMP3, and MMP14 participate in collagen
transporter 2, an indirect marker of glutamate release.79,80 remodeling.87 The concentration of various MMPs varies
It has also been shown that tenocytes themselves upregulate throughout the healing process. Although the remodeling
expression of receptors for catecholamines, ACh, and SP in phase generates a tendon that is structurally similar to
chronic injury, suggesting that nonneuronal local substances the original, the injured tendon will remain mechanically
may function in an autocrine or paracrine manner.74,76,78,79,81,82 inferior and have increased susceptibility to damage in the
However, further development is needed in regard to the bio- future compared to the uninjured tendon.43 The remodeling
chemical hypothesis to determine if the signaling substances phase continues years beyond the original injury, and
are causative in nature or merely a byproduct of disease, in continuously tries to enhance the response of the tissue to
order to determine the potential for treatments that target the applied forces.88
biochemical milieu. It is worth noting that tendon healing occurs by both
intrinsic and extrinsic healing. Intrinsic healing results from
Tendon-healing physiology proliferation of tenocytes within the epitenon and endotenon,
Though the impact of mechanical and chemical stress while extrinsic healing results from invasion of cells from
depends on location and severity, response typically involves the surrounding sheath and synovium.89–91 The contribution
either inflammation of surrounding sheath, degeneration of of these healing mechanisms to repair may depend on the
collagen and ECM, or a combination of both.83 Subsequent particular location and type of injury, but it has been dem-
tendon healing typically occurs through a sequential series onstrated that intrinsic healing optimizes the repair process.
of hemostasis, proliferation, and remodeling (Table 1). Intrinsic healing preserves gliding within the tendon sheath,
Although these phases can be described distinctly, they often leading to fewer complications compared to the formation of
overlap and vary in duration according to location and type adhesions associated with extrinsic healing.92 The differences
of injury.6 Immediately after acute injury to tendons, changes in healing outcomes from intrinsic vs extrinsic healing can
in surrounding vascular structures and release of signaling most likely be attributed to variability in tenocyte function
molecules from intrinsic cells promote the formation of a according to site of origin. While tenocytes from tendon
hematoma for primary hemostasis. This initial step induces sheaths produce less collagen than epitenon/endotenon teno-
the release of growth factors and potent proinflammatory cytes, they have been shown to proliferate at an increased
cytokines that draw inflammatory cells to the site of injury rate.93,94 Further investigation is needed to understand this
for the breakdown of the blood clot and surrounding necrotic variation and apply this concept to repair therapies.
tissue. The macrophages responsible for phagocytosis of sur-
rounding fragments play a role in the proliferation of fibro- Current tendon-repair therapies
blasts and angiogenesis to provide a means for delivery and Several therapies exist to modulate the tendon-healing
synthesis of DNA, glycosaminoglycans, type III collagen, process, but no single therapy has been reported to be con-
and other factors to begin generation of a new ECM.6,84,85 sistently more effective than the others.95 Because the patho-
Extrinsic cells, including neutrophils and macrophages, genesis of tendinopathy is so complex and involves a variety
that are key regulators in removing debris release a second of biological phenomena, current physical and biologic thera-
generation of cytokines that transitions the healing pro- pies attempt to modulate the repair process through a variety
cess into a subsequent phase.83 The proliferative phase is of pathways in hopes of mimicking complex native tissue.95

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Table 2 Benefits and drawbacks of currently available treatment options

Treatment method Advantages Shortcomings
Low-energy laser therapy • Nonpharmacologic therapy • Unknown mechanism of action
• Reduction of inflammatory markers • Heterogeneous results of clinical trials
• Pain relief has been found when used in • Lack of optimized protocol for administration
addition to exercise therapy (ie, timing of treatment, exposure-area size)
Shock-wave therapy • Complications are negligible • Unknown mechanism of action
• Convenient and cost-effective • Lack of standardized application parameters
Steroid injection • Short-term pain relief and increased • Increased possibility of tendon rupture
functionality (,6 weeks) • Conflicting data regarding efficacy
Growth-factor therapy • Injection is simple • Short half-life requiring repeated injections
• Well-studied targets • Cost of protein production and purification
• Lacks spatiotemporal distribution of normal healing
Gene therapy • Avoids immunogenicity • Expensive and complicated manufacturing of viral vectors
• Allows localized production of gene products • Use of staging delivery is in its infancy
Note: Highlights the need for randomized control trials to provide consistency in results, a deeper understanding of tendon-cell biology, and the development of novel
therapies that can better mimic natural physiology in a spatial and temporal manner.69,88–94,97–100,103–114,117,118,121,122

Such therapies include low-energy laser stimulation, injection for the delivery of growth factors and nutrients to the site of
of steroids, growth-factor injection, and newer gene-therapy damage. It has been proposed that LLLT stimulation induces
developments. Table 2 provides a summary of the therapies the release of cytokines, FGF2, VEGF, and additional factors
discussed in this section. typically associated with neovascularization.98,100 Casalechi
et al demonstrated that LLLT increases mRNA expression
Low-energy laser therapy of the angiogenic factor VEGF in irradiated tissues.100
Although low-level laser therapy (LLLT) was first used to Not only is the choice to use LLLT for specific musculo-
target soft-tissue injuries and inflammation, its applications skeletal conditions a topic of debate, but there are also con-
have expanded to address a multitude of musculoskeletal tradictory suggestions regarding treatment parameters, such
injuries, including tendinopathy.96 The main mechanism as power density, timing of treatment, and size of exposure
by which LLLT promotes regeneration postinjury remains region (Table 2). Because several literature reviews have
unclear, and current results of clinical trials suggest distinct not separately analyzed results based on laser wavelength or
mechanisms of action as possibilities. While some studies doses, it is possible that LLLT has a larger effect on tendon
place an emphasis on the ability of LLLT to reduce inflam- healing than is reported.101–103 Detailed analysis including
mation and stimulate collagen production,96,97 other research consideration of administration parameters may help to
suggests its primary role in healing to be ATP production, explain the currently heterogeneous results among contra-
increased protein synthesis, and angiogenesis.98 dictory reviews. For example, Bjordal et al demonstrated
The anti-inflammatory effect of LLLT in humans has that LLLT modulates biological mechanisms of tendon
been analyzed through microdialysis, a minimally invasive repair in a dose-dependent manner, but an optimum dose
sampling technique that provides continuous measurement has yet to be determined.101,102 As more studies emerge that
of peritendinous fluid. Through this technique, LLLT has effectively demonstrate the validity of LLLT as a therapy
been shown to reduce levels of the inflammatory marker for injury repair and investigate ideal application methods,
prostaglandin E2 post-injury, supporting the relation of this LLLT has the potential to become more widely accepted
therapy to inflammation suppression.96,99 It has been shown for clinical use.
in animal models that the production of collagen is modu-
lated by photostimulation with LLLT through an increase Shock-wave therapy
in neutral salt-soluble collagen and insoluble collagen and a Shock waves (SWs) are typically biphasic and involve a peak
decrease in pepsin soluble collagen. These changes support pressure that is approximately 1,000 times that of ultrasound
the indication that LLLT-treated tendons have a higher waves.104,105 In addition to high peak pressure, SWs have a
turnover rate of collagen and higher mechanical integrity fast initial rise in pressure, low tensile amplitude, short life
compared to controls.97 LT has also been shown to increase cycle, and broad-frequency spectrum.104 They are generated
vessel numbers after injury, promoting neovascularization through a fluid medium, typically water, and a coupling

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gel to direct transmission to biologic tissues when used for (.6 months) outcomes were shown to be statistically
medical applications.104 equivalent for corticosteroid injections compared to placebo
In reference to orthopedic injury, the most important and other conservative treatments.119 The ability of corticos-
physical parameters of SW therapy include pressure distribu- teroid injections to modulate healing and reduce pain in the
tion, energy density, and total acoustic energy.106,107 Though short term may partially explain their popularity as a treat-
extracorporeal SW therapy (ESWT) was originally used for ment, despite lack of supportive evidence.
the treatment of renal calculi, ESWT is now used for several Whether administration is local or systemic, corticoster-
orthopedic applications.108 The exact mechanism by which oid injection has previously been associated with increased
ESWT promotes tendon healing is unknown, but several risk of tendon rupture (Table 2).120–122 However, in reported
hypotheses have been proposed, including induction of teno- cases involving systemic administration secondary to primary
cyte proliferation and collagen metabolism, increased col- disease, it is difficult to determine whether the tendon injury
lagen turnover, and enhanced neovascularization of injured is directly due to corticosteroid therapy or the primary dis-
tissue.109–111 Wang et al demonstrated that the induction of ease, making the investigation into the exact mechanism of
neovascularization at the site of injury was associated with rupture particularly challenging.120 Recent research indicates
the release of endothelial nitric oxide, VEGF, and proliferat- that corticosteroid injection may temporarily induce a com-
ing cell antinuclear antigen.112 In addition, Zhang et al showed bination of apoptosis and increased expression of MMP3, a
that ESWT at both high and low doses increased the expres- potent proteoglycan-degrading enzyme that plays a role in
sion of lubricin, a lubricating glycoprotein that facilitates collagen degradation.123
tendon gliding.113 Most likely as a result of a combination Due to the association with tendon rupture, techniques
of these proposed effects, ESWT has shown efficacy for the are being investigated to increase the safety of using corti-
treatment of Achilles tendonitis and calcific tendonitis of the costeroid injections, specifically aimed at optimizing drug
rotator cuff.114,115 However, in order to optimize application delivery. The use of fluoroscopy for corticosteroid injection
parameters, better understanding is needed of the precise involves the identification of peritendinous space using con-
cellular and molecular changes that are induced by ESWT. trast medium. Once the contrast medium is injected and the
space identified, a separate syringe is attached to the prop-
Steroid therapy erly placed needle to inject the steroid. This administration
Despite the questioned efficacy and poorly understood technique has been shown to reduce major complications
therapeutic mechanism, injection of corticosteroids remains associated with corticosteroid injection, including tendon
a commonly used therapy for tendinopathy.116 Traditionally, rupture, possibly because of reduced fibrosis, and vascular
corticosteroids are thought to regulate healing through regula- proliferation, limiting access of inflammatory mediators.124–126
tion of anti-inflammatory transcription factors.117,118 However, Further research is needed to optimize injection-visualization
several studies have reported an increase in inflammatory techniques and for the accumulation of more consistent data
mediators after injection, most likely in response to gluco- demonstrating efficacy.
corticoid-induced damage, revealing the “anti-inflammatory”
postulation to be an oversimplification in the case of tendon Growth-factor therapy
injury.116 While some studies have demonstrated that gluco- Because tendon injury promotes the production and release
corticoids result in increased collagen disorganization and of multiple growth factors during the healing process,
collagen necrosis, some have demonstrated a positive effect recombinant growth factors remain an area of investigation
on mechanical properties.116 For example, Dean et al inves- for potential tendon-healing therapies.95 Although no human
tigated mechanical properties of tendons after steroid injec- studies investigating this method have been published, in vivo
tion in 18 studies, and found that six showed a decrease in and in vitro experiments have demonstrated their efficacy
mechanical properties, three showed an increase, and nine and potential impact in the field. The involvement of growth
showed no significant change.116 Smidt et al demonstrated factors in tendon healing has focused on IGF1, TGFβ, VEGF,
that the effects of corticosteroid injection differ in the short PDGF, and FGF2.43,127
term compared to the long term. Corticosteroid injection The application of growth factors to the site of injury can
improved short-term outcomes (,6 weeks), including pain be performed via local injection, operation, coated sutures,
reduction and an increase in global improvement. By con- or implanted scaffolding material. Although there have been
trast, intermediate (6 weeks to 6 months) and long-term fewer studies on coated sutures and scaffolding methods,

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Dovepress Tendinopathy and current therapies

it has been suggested that growth factors using these methods methods for gene delivery, including injection of naked DNA,
are cleared from the site of injury at a slower rate compared electroporation, and sonoporation.132,133
to local injection.4 Studies investigating the role of growth In vivo and ex vivo delivery are the two gene-delivery
factors have demonstrated their abilities to regulate differen- strategies used for both viral and nonviral vectors. In vivo
tial expression of collagens and increase cell proliferation.4 gene delivery involves the introduction of the vector directly
Administration of multiple growth factors allowed for lower via injection or other methods, including the use of gene-
dosing requirements and showed increased potency compared activated matrices. By contrast, ex vivo delivery involves
to individual factors.128 genetic modification of cells prior to injection, providing
The interplay between multiple growth factors throughout a higher level of safety by avoiding direct introduction of
the healing process helps to explain the proposed efficacy virus into the system. Experiments in small-animal models
of clinically used concentrates of autologous growth fac- have demonstrated efficacy using both viral and nonviral
tors, such as platelet-rich plasma. Investigations on the use methods to introduce marker genes to ligaments and tendons
of autologous growth factors remain contradictory, because using in vivo and ex vivo methodology.88 Because of the
of the poorly characterized nature of the concentrate and various factors that contribute to the tendon-repair process,
variety of devices used to generate platelet-rich plasma.129 investigators have approached introducing genes that affect a
This variability creates an inconsistency in the composi- wide variety of biologic processes. For example, while some
tion of growth factors and additional cytokines contained investigators focus on delivery of growth factors to promote
in the mixture, making results challenging to analyze and differentiation of PCs into tenocytes, others focus on growth
compare (Table 2).130 factors that enhance cellular and vascularity of the injured
Growth-factor therapy has shown some success for pro- region. There is an interest in introducing multiple growth
moting tendon regeneration. However, it remains unlikely factors using a staged approach or polycistronic vector to
that a single growth factor will be able to regenerate normal mimic the multistep process of natural tendon healing. Other
tendons. One possible area for potential research involves approaches are focused on driving multipotent PCs toward
the use of growth-factor combination therapy that involves tenogenesis by introducing tenogenic cDNAs that prevent
administration of multiple growth factors in a temporal and the formation of fat or bone during tendon repair.
spatial distribution that mimics normal physiology. This Although gene therapy holds the enticing ability to
“growth-factor cocktail” may be able to modulate healing manipulate the healing environment to generate favorable
through a variety of processes and at various time points conditions for repair, its development in regard to the tendon
postinjury for more controlled regulation of healing. In addi- is still in its infancy. The application finds challenges in iden-
tion, investigation into biomaterials that can deliver growth tification of targets, tissue heterogeneity, host heterogeneity,
factors in a spatiotemporally defined manner has shown and delivery systems.88 This technique will likely become a
promise for mimicking the healing cascade.131 balance between searching for a single gene-therapy target
and the development of a mixture of several targets for a
Gene therapy multifactorial approach.
By allowing a localized and focused production of gene Gene therapy remains an appealing approach for the
products in the area of injury, gene therapy permits sustained production of growth factors in situ, modulating natural
and targeted production of growth factors and additional healing and avoiding immunogenicity. However, new gene-
molecules that can undergo authentic posttranslational therapy approaches have investigated the use of nonviral
modification and avoid immunogenicity (Table 2).4 Because methods for the introduction of SLRPs as an alternative
of the ability of viruses to infect cells with their genetic to growth factors for modulation of healing. For example,
components, viruses are often manipulated to incorporate liposome-based gene delivery of FMOD, a key regulator
genes of choice while maintaining their ability to infect, of collagen fibrillogenesis in injured tendons, has been
simultaneously removing sequences needed for virulence. demonstrated to promote rat Achilles tendon repair in vitro
Currently, the recombinant viruses that have been investi- and in vivo.134
gated for delivery to tendons include adenovirus, lentivirus,
retrovirus, and adenoassociated virus.4 Because viral vectors Exercise
are expensive, complicated to manufacture, and have raise Though this review focuses on potential biologic therapies to
safety issues, there is an interest in using nonviral vector modulate tendon healing, it remains crucial to acknowledge

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the importance of tendon loading and its influence on it will take substantial research to optimize them and direct
repair.135 Rehabilitation regimens depend on the anatomy of the research toward clinical applications.
the injured tendon, and require a delicate balance between
the risk of adhesion and stiffness associated with immobi- Disclosure
lization and risk of injuring repaired tissue associated with The authors report no conflicts of interest in this work.
too much loading. For example, passive motion exercises
after flexor-tendon injury improve tendon gliding and repair
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