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Abstract
Tendon disorders are frequent, and are responsible for much morbidity both in sport and the workplace. Although the pres-
ence of degenerative changes does not always lead to symptoms, pre-existing degeneration has been implicated as a risk factor
for acute tendon rupture. The term tendinopathy is a generic descriptor of the clinical conditions in and around tendons aris-
ing from overuse. The terms "tendinosis" and "tendinitis/tendonitis" should only be used after histopathological examination.
Disordered healing is seen in tendinopathy, and inflammation is not typically seen. In acute injuries, the process of tendon heal-
ing is an indivisible process that can be categorized into three overlapping phases for descriptive purposes. Tendon healing can
occur intrinsically, via proliferation of epitenon and endotenon tenocytes, or extrinsically, by invasion of cells from the sur-
rounding sheath and synovium. Despite remodeling, the biochemical and mechanical properties of healed tendon tissue never
match those of intact tendon. Tendon injuries account for considerable morbidity, and often prove disabling for several months,
despite what is considered appropriate management1. Chronic problems caused by overuse of tendons probably account for
30% of all running-related injuries2, and the prevalence of elbow tendinopathy in tennis players can be as high as 40%3. The
basic cell biology of tendons is still not fully understood, and the management of tendon injury poses a considerable challenge
for clinicians. This article describes the structure of tendons, and reviews the pathophysiology of tendon injury and healing.
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P. Sharma and N. Maffulli: Tendon injury and healing
Collagen is arranged in hierarchical levels of increasing the tertiary bundles as the endotenon. The endotenon is a thin
complexity, beginning with tropocollagen, a triple-helix reticular network of connective tissue investing each tendon
polypeptide chain, which unites into fibrils; fibers (primary fibre17. Superficially, the epitenon is surrounded by paratenon,
bundles); fascicles (secondary bundles); tertiary bundles; a loose areolar connective tissue consisting of type I and III
and the tendon itself (Figure 1)12. Soluble tropocollagen collagen fibrils, some elastic fibrils, and an inner lining of syn-
molecules form cross-links to create insoluble collagen mol- ovial cells8. Synovial tendon sheaths are found in areas sub-
ecules, which aggregate to form collagen fibrils. A collagen jected to increased mechanical stress, such as the tendons of
fibre is the smallest tendon unit which can be mechanically the hands and feet, where efficient lubrication is required.
tested and is visible on light microscopy. Although collagen Synovial sheaths consist of an outer fibrotic sheath, and an
fibres are mainly oriented longitudinally, fibres also run inner synovial sheath, which consists of thin visceral and pari-
transversely and horizontally, forming spirals and plaits13. etal sheets12. The inner synovial sheath invests the tendon
The ground substance of the ECM surrounding the colla- body, and functions as an ultrafiltration membrane to produce
gen and the tenocytes is composed of proteoglycans, gly- synovial fluid18. The fibrous sheath forms condensations, the
cosaminoglycans (GAG), glycoproteins and several other pulleys, which function as fulcrums to aid tendon function19.
small molecules5. The strongly hydrophilic nature of proteo- At the MTJ, tendinous collagen fibrils are inserted into
glycans enables rapid diffusion of water soluble molecules and deep recesses formed by myocyte processes, allowing the
migration of cells. Adhesive glycoproteins, such as fibronectin tension generated by intracellular contractile proteins of
and thrombospondin, participate in repair and regeneration muscle fibres to be transmitted to the collagen fibrils20. This
processes in tendon13. Tenascin-C, another important compo- complex architecture reduces the tensile stress exerted on
nent of the tendon ECM, is abundant in the tendon body and the tendon during muscle contraction20. However, the MTJ
at the osteotendinous (OTJ) and myotendinous (MTJ) junc- still remains the weakest point of the muscle-tendon unit20.
tions14. Tenascin-C contains a number of repeating The OTJ is composed of four zones: a dense tendon zone,
fibronectin type III domains, and, following stress-induced fibrocartilage, mineralized fibrocartilage, and bone21. The
unfolding of these domains, it also functions as an elastic pro- specialized structure of the OTJ prevents collagen fibre
tein14. The expression of Tenascin-C is regulated by mechani- bending, fraying, shearing and failure22.
cal strain, and is up-regulated in tendinopathy15. Tenascin-C
may play a role in collagen fibre alignment and orientation16. Blood supply
The epitenon, a fine, loose connective-tissue sheath con-
taining the vascular, lymphatic, and nerve supply to the tendon, Tendons receive their blood supply from three main
covers the whole tendon and extends deep within it between sources: the intrinsic systems at the MTJ and OTJ, and from
182
P. Sharma and N. Maffulli: Tendon injury and healing
80
60
STRESS
40
20
2 4 6 8
MACROSCOPIC FAILURE
STRAIN (%)
Figure 2. Stress-strain curve demonstrating the basic physical properties of normal tendons.
the extrinsic system via the paratenon or the synovial insertion23. However, laser Doppler flowmetry has demon-
sheath23. The ratio of blood supply from the intrinsic to strated substantially reduced blood flow near the Achilles
extrinsic systems varies from tendon to tendon. For example, tendon insertion, with an otherwise even blood flow
the central third of the rabbit Achilles tendon receives 35% throughout the tendon27. A similar zone of hypovascularity is
of its blood supply from the extrinsic system24. At the MTJ, present on the dorsal surface of the flexor digitorum profun-
perimyseal vessels from the muscle continue between the dus tendon subjacent to the volar plate, within 1 cm of the
fascicles of the tendon23. However, blood vessels originating tendon insertion28. In general, tendon blood flow declines
from the muscle are unlikely to extend beyond the proximal with increasing age and mechanical loading27, and peak exer-
third of the tendon23. The blood supply from the OTJ is cise peritendinous blood flow reaches only approximately
sparse, and limited to the insertion zone of the tendon, 20% of the maximal blood flow capacity in that area29.
although vessels from the extrinsic system communicate with
periosteal vessels at the OTJ5,23. Tendon innervation
In tendons enveloped by sheaths to reduce friction,
branches from major vessels pass through the vincula Tendon innervation originates from cutaneous, muscular,
(mesotenon) to reach the visceral sheet of the synovial and peritendinous nerve trunks. At the MTJ, nerve fibres cross
sheath, where they form a plexus12. This plexus supplies the and enter the endotenon septa. Nerve fibres form rich plexus-
superficial part of the tendon, while some vessels from the es in the paratenon, and branches penetrate the epitenon.
vinculae penetrate the epitenon. These penetrating vessels Most nerve fibres do not actually enter the main body of the
course in the endotenon septae, and form a connection tendon, but terminate as nerve endings on its surface.
between the peri- and intra-tendinous vascular networks. Nerve endings of myelinated fibres function as specialised
In the absence of a synovial sheath, the paratenon pro- mechanoreceptors to detect changes in pressure or tension.
vides the extrinsic component of the vasculature. Vessels These mechanoreceptors, the Golgi tendon organs, are most
entering the paratenon course transversely, and branch numerous at the insertion of tendons into the muscle30.
repeatedly to form a complex vascular network25. Arterial Golgi tendon organs are essentially a thin delicate capsule of
branches from the paratenon penetrate the epitenon to connective tissue that enclose a group of branches of large
course in the endotenon septae, where an intratendinous myelinated nerve fibres. These fibres terminate with a spray
vascular network with abundant anastomoses is formed5,26. of fibre endings between bundles of collagen fibres of the
Tendon vascularity is compromised at junctional zones tendon31.
and sites of torsion, friction or compression. In the Achilles Unmyelinated nerve endings act as nociceptors, and sense
tendon, angiographic injection techniques have demonstrat- and transmit pain. Both sympathetic and para-sympathetic
ed a zone of hypovascularity 2-7 cm proximal to the tendon fibres are present in tendon32.
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P. Sharma and N. Maffulli: Tendon injury and healing
184
P. Sharma and N. Maffulli: Tendon injury and healing
matory mediators, fluoroquinolones, and matrix metallopro- with no statistically significant elevation of the pro-inflamma-
teinase imbalance have all been implicated as mechanisms of tory prostaglandin PG E278. However, the levels of PG E2
tendon degeneration6,63-70. were consistently higher in tendinopathic tendons compared
Histologically, tendinopathy shows a picture of disordered to controls, and the results possibly lacked statistical signifi-
haphazard healing with absence of inflammatory cells, poor cance due to the small sample size of the study.
healing response, non-inflammatory intratendinous collagen Substance P functions as a neurotransmitter and neuromod-
degeneration, fibre disorientation and thinning, hypercellu- ulator, and is found in small unmyelinated sensory nerve fibres79.
larity, scattered vascular ingrowth, and increased interfibril- A network of sensory innervation is present in tendons80. Senso-
lar glycosaminoglycans12. Frank inflammatory lesions and ry nerves transmit nociceptive information to the spinal cord,
granulation tissue are infrequent, and are mostly associated and increased levels of substance P correlate with pain levels in
with tendon ruptures71. rotator cuff disease and medial and lateral epicondylopathy81,82.
Macroscopically, the affected portions of the tendon lose An opioid system exists in the Achilles tendon of rats83.
their normal glistening white appearance and become grey- Under normal conditions, a balance probably exists between
brown and amorphous. Tendon thickening, which can be dif- nociceptive and anti-nociceptive peptides84. However, this
fuse, fusiform or nodular, occurs72. Tendinosis is often clini- balance may be altered in pathological conditions84.
cally silent, and its only manifestation may be a rupture, but
it may also co-exist with symptomatic paratendinopathy64. Tendon healing following acute injuries
Tendon rupture Tendon healing studies have predominantly been per-
formed on transected animal tendons or ruptured human
Tendon rupture is an acute injury in which extrinsic factors tendons, and their relevance to human tendinopathy with its
predominate, although intrinsic factors are also important. In associated healing failure response remains unclear85.
Achilles tendon rupture, an acceleration/deceleration mech- Tendon healing occurs in three overlapping phases. In the
anism has been reported in up to 90% of sports-related initial inflammatory phase, erythrocytes and inflammatory
injuries73. Malfunction of the normal protective inhibitory cells, particularly neutrophils, enter the site of injury. In the
pathway of the musculo-tendinous unit may result in injury74. first 24 hours, monocytes and macrophages predominate,
The aetiology of tendon rupture remains unclear10. Degener- and phagocytosis of necrotic materials occurs. Vasoactive
ative tendinopathy is the most common histological finding in and chemotactic factors are released with increased vascular
spontaneous tendon ruptures. Arner et al. first reported permeability, initiation of angiogenesis, stimulation of teno-
degenerative changes in all their 74 patients with Achilles cyte proliferation, and recruitment of more inflammatory
tendon rupture, and hypothesised that these changes were cells86. Tenocytes gradually migrate to the wound, and type
due to intrinsic abnormalities present before the rupture75. III collagen synthesis is initiated87.
Kannus and Jozsa found degenerative changes in 865 of 891 After a few days, the remodeling stage begins. Synthesis of
(97%) spontaneous tendon ruptures, whilst degenerative type III collagen peaks during this stage, which lasts for a few
changes were only seen in 149 of 445 (34%) of control ten- weeks. Water content and glycosaminoglycan concentrations
dons9. Tendon degeneration may lead to reduced tensile remain high during this stage87.
strength and a predisposition to rupture. Indeed, ruptured After approximately 6 weeks, the modeling stage com-
Achilles tendons have a histological picture of greater degen- mences. During this stage, the healing tissue is resized and
eration than chronic painful tendons from overuse injuries76. reshaped. A corresponding decrease in cellularity, collagen
and glycosaminoglycan synthesis occurs. The modeling phase
Pain in tendinopathy can be divided into a consolidation and maturation stage88.
The consolidation stage commences at about 6 weeks and
Classically, pain in tendinopathy has been attributed to continues up to 10 weeks. In this period, the repair tissue
inflammation. However, chronically painful Achilles and changes from cellular to fibrous. Tenocyte metabolism
patellar tendons show no evidence of inflammation, and remains high during this period, and tenocytes and collagen
many tendons with intratendinous pathology detected on fibres become aligned in the direction of stress89. A higher
MRI or ultrasound are not painful72. Pain may originate from proportion of type I collagen is synthesized during this
a combination of mechanical and biochemical causes72. Ten- stage90. After 10 weeks, the maturation stage occurs, with
don degeneration with mechanical breakdown of collagen gradual change of fibrous tissue to scar-like tendon tissue
could theoretically explain the pain, but clinical and surgical over the course of one year89. During the latter half of this
observations challenge this view72. Chemical irritants and stage, tenocyte metabolism and tendon vascularity decline91.
neurotransmitters may generate pain in tendinopathy. Micro- Tendon healing can occur intrinsically, via proliferation of
dialysis sampling revealed a two-fold increase in lactate levels epitenon and endotenon tenocytes, or extrinsically, by invasion
in tendinopathic tendons compared to controls77. Patients of cells from the surrounding sheath and synovium92. Epitenon
with chronic Achilles tendinopathy and patellar tendinopathy tenoblasts initiate the repair process through proliferation and
show high concentrations of the neurotransmitter glutamate, migration93. Healing in severed tendons can be performed by
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P. Sharma and N. Maffulli: Tendon injury and healing
cells from the epitenon alone, without relying on adhesions for phonuclear leukocytes, macrophages and other inflammatory
vascularity or cellular support94. Internal tenocytes contribute cells104. These growth factors induce neovascularization and
to the intrinsic repair process and secrete larger and more chemotaxis of fibroblasts and tenocytes and stimulate fibrob-
mature collagen than epitenon cells95. Despite this, fibroblasts last and tenocytes proliferation and synthesis of collagen105.
in the epitenon and tenocytes synthesize collagen during Nitric oxide is a short-lived free radical, with many biolog-
repair, and different cells probably produce different collagen ical functions: it is bactericidal, can induce apoptosis in
types at different time points. Initially, collagen is produced by inflammatory cells, and causes angiogenesis and vasodilata-
epitenon cells, with endotenon cells later synthesizing colla- tion106,107. Nitric oxide may play a role in several aspects of
gen96. The relative contribution of each cell type may be influ- tendon healing. Nitric oxide synthase is responsible for syn-
enced by the type of trauma sustained, anatomical position, thesizing nitric oxide from L-arginine. Experimental studies
presence of a synovial sheath, and the amount of stress induced have shown that levels of nitric oxide synthase peak after 7
by motion after repair has taken place97. days and return to baseline 14 days after tenotomy of rat
Tenocyte function may vary depending on the region of ori- Achilles tendons108. Inhibition of nitric oxide synthase
gin. Cells from the tendon sheath produce less collagen and reduced healing and resulted in decreased cross-sectional
GAG compared to epitenon and endotenon cells. However, area and a reduced failure load108. In that study, the specific
fibroblasts from the flexor tendon sheath proliferate more isoforms of nitric oxide synthase were not identified. More
rapidly98. The variation in phenotypic expression of tenocytes recently, the same group has demonstrated a temporal
has not been extensively investigated, and this information expression of the three isoforms of nitric oxide synthase109.
may prove useful for optimizing repair strategies. The inducible isoform peaks at day 4, the endothelial isoform
Intrinsic healing results in improved biomechanics and peaks at day 7, and the neuronal isoform peaks at day 21109.
fewer complications. In particular, a normal gliding mecha- Interestingly, in a rat Achilles tendon rupture model, peak
nism within the tendon sheath is preserved99. In extrinsic nerve fibre formation occurred between weeks 2 and 6, in
healing, scar tissue results in adhesion formation which dis- concert with peak levels of the neuronal isoform of nitric
rupts tendon gliding100. Different healing patterns may pre- oxide synthase110. These nerve fibres presumably deliver neu-
dominate in particular locations, and, for example, extrinsic ropeptides, which act as chemical messengers and regula-
healing tends to prevail in torn rotator cuffs101. tors, and may play an important role in tendon healing. Sub-
stance P and calcitonin gene-related peptide (CGRP) are
Remodeling responses pro-inflammatory and cause vasodilation and protein
extravasation111,112. In addition, Substance P enhances cellu-
The histopathological process as the basis of the clinical lar release of prostaglandins, histamines and cytokines113.
manifestations of tendinopathy then can be viewed as a fail- Peak levels of substance P and CGRP occur during the pro-
ure of cell matrix adaptation to a variety of stresses, due to liferative phase, suggesting a possible role during this phase.
an imbalance between matrix degeneration and synthesis102.
Remodeling plays an important role in responding to micro- Limitations of healing in acute tendon injuries
trauma from repetitive loading. This repair mechanism is
probably mediated by resident tenocytes, which maintain a Adhesion formation after intrasynovial tendon injury
fine balance between ECM production and degradation. poses a major clinical problem114. Synovial sheath disruption
Modeling is also involved in the physiological response of at the time of injury or surgery allows granulation tissue and
tendon to resistance training. In such situations, modelling tenocytes from surrounding tissue to invade the repair site.
adapts the tendon to the mechanical loads placed on it, and Exogenous cells predominate over endogenous tenocytes,
prevents the tendons from incurring injuries. An increase in the allowing the surrounding tissues to attach to the repair site
tendon mass and cross-sectional area occurs during modeling. resulting in adhesion formation.
Despite remodeling, the biochemical and mechanical
Modulators of healing properties of healed tendon tissue never match those of
intact tendon. In spontaneously healed transected sheep
MMPs are important regulators of ECM remodeling, and Achilles tendons, rupture force was only 56.7% of normal at
their levels are altered during tendon healing70. In a rat flexor 12 months115. One possible reason for this may be the absence
tendon laceration model, the expression of MMP-9 and of mechanical loading during the period of immobilization.
MMP-13 (Collagenase-3) peaked between days 7 and 14.
MMP-2, MMP-3, and MMP-14 (MT1-MMP) levels increased Conclusion
after surgery, and remained high until day 28103. These find-
ings suggest that MMP-9 and MMP-13 participate only in col- Tendon injuries give rise to substantial morbidity, and
lagen degradation, whereas MMP-2, MMP-3 and MMP-14 current understanding of the mechanisms involved in tendon
participate in both collagen degradation and collagen remod- injury and repair is limited. Further research is required to
eling. Wounding and inflammation also provoke the release improve our knowledge of tendon healing. This will enable
of growth factors and cytokines from platelets, polymor- specific treatment strategies to be developed116.
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P. Sharma and N. Maffulli: Tendon injury and healing
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P. Sharma and N. Maffulli: Tendon injury and healing
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P. Sharma and N. Maffulli: Tendon injury and healing
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