Biology of Tendon Injury: Healing, Modeling and Remodeling

J Musculoskelet Neuronal Interact 2006; 6(2):181-190

Review Article Hylonome

Biology of tendon injury: healing, modeling and remodeling

P. Sharma1 and N. Maffulli2

1Salisbury District Hospital, Wessex Deanery, United Kingdom; 2Department of Trauma and Orthopaedic Surgery, Keele University School of Medicine, Stoke-on-Trent, UK

Abstract

Tendon disorders are frequent, and are responsible for much morbidity both in sport and the workplace. Although the presence 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 healing 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 surrounding 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.

Keywords: Tendon Injury, Tendinopathy, Rupture, Recovery

Tendon structure 10% of the cellular elements of tendons consists of chondro- cytes at the bone attachment and insertion sites, synovial Tendons vary in form, and can be rounded cords, strap- cells of the tendon sheath, and vascular cells, including cap- 6 like bands or flattened ribbons4. When healthy they appear illary endothelial cells and smooth muscle cells of arterioles . Tenocytes synthesize collagen and all components of the brilliant white, and have a fibroelastic texture. Structurally, 7 tendon is composed of tenoblasts and tenocytes lying within ECM, and are also active in energy generation . The aerobic Krebs cycle, anaerobic glycolysis and the pentose phosphate a network of extracellular matrix (ECM). Tenoblasts are shunt are all present in human tenocytes8. With increasing immature tendon cells. They are spindle-shaped, with age, metabolic pathways shift from aerobic to more anaero- numerous cytoplasmic organelles reflecting their high meta- bic energy production9. bolic activity5. As they age, tenoblasts become elongated and 5 Oxygen consumption by tendons and ligaments is 7.5 transform into tenocytes . These have a lower nucleus-to- times lower than skeletal muscles10. Given their low meta- cytoplasm ratio than tenoblasts, with decreased metabolic bolic rate and well-developed anaerobic energy generation 5 activity . Together, tenoblasts and tenocytes account for 90- capacity, tendons are able to carry loads and maintain ten- 5 95% of the cellular elements of tendons . The remaining 5- sion for long periods, whilst avoiding the risk of ischaemia and subsequent necrosis. However, a low metabolic rate results in slow healing after injury11. The authors have no conflict of interest. Tenocytes and tenoblasts lie between the collagen fibres along the long axis of the tendon11. The dry mass of human Corresponding author: Nicola Maffulli, North Staffordshire Hospital, Thornbur- tendons is approximately 30% of the total tendon mass, with row Drive, Hartshill, Stoke-on-Trent, UK ST4 7QB water accounting for the remaining 70%. Collagen type I E-mail: [email protected] accounts for 65-80%, and elastin accounts for approximate- Accepted 31 January 2006 ly 2% of the dry mass of tendons7.

181 P. Sharma and N. Maffulli: Tendon injury and healing

Figure 1. Schematic structure of a normal tendon.

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

60 STRESS

24 68

MACROSCOPIC FAILURE STRAIN (%)

LINEAR DEFORMATION MICROSCOPIC FAILURE

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.

183 P. Sharma and N. Maffulli: Tendon injury and healing

Biomechanics ies, as untrained animals may be compared to trained animals. Also, confined animals are likely to have reduced con- Tendons transmit force generated by muscle to bone, and nective tissue mass and tensile strength, and physical train- act as a buffer by absorbing external forces to limit muscle ing may merely return this to normal38. damage33. Tendons exhibit high mechanical strength, good Prolonged immobilization following musculoskeletal flexibility, and an optimal level of elasticity to perform their injury often results in detrimental effects. Collagen fascicles unique role34. Tendons are viscoelastic tissues, which display from stress shielded rabbit patellar tendons display lower stress relaxation and creep35. tensile strength and strain at failure than control samples50. The mechanical behaviour of collagen is dependent on Immobilization reduces the water and proteoglycan content the number and types of intra- and inter-molecular bonds36. of tendons, and increases the number of reducible collagen A stress-strain curve helps to demonstrate the behaviour of cross-links51. Immobilization results in tendon atrophy the tendon (Figure 2). At rest, collagen fibres and fibrils dis- (Maganaris et al., 2005), but, due to low metabolic rate and play a crimped configuration37. The initial concave portion vascularity, these changes occur slowly48,52. of the curve (toe region), where the tendon is strained up to Tendon properties and function also deteriorate with age- 2%, represents flattening of the crimp pattern38. Beyond this ing. Muscle strength and power decline53. This is thought to point, the tendon deforms in a linear fashion due to be due to a loss of collagen and its cross-linking resulting in intramolecular sliding of collagen triple helices, and the an increase in tendon stiffness54. Resistance training in old fibres become more parallel39. If the strain remains below age can partly reverse the deteriorating effect of ageing on 4%, the tendon behaves in an elastic fashion, and returns to tendon properties and function55,56. its original length when unloaded40. Microscopic failure occurs when the strain exceeds 4%, and, beyond 8-10% Tendon injury strain, macroscopic failure occurs from intrafibril damage by molecular slippage41. X-ray diffraction studies have demon- Tendon injuries can be acute or chronic, and are caused strated that collagen fibril elongation initially occurs due to by intrinsic or extrinsic factors, either alone or in combina- molecular elongation, but, as stress increases, the gap tion. In acute trauma, extrinsic factors predominate, whilst between molecules increases, eventually leading to slippage in chronic cases intrinsic factors also play a role. of lateral adjoining molecules41. After this, complete failure occurs rapidly, and the fibres recoil into a tangled bud at the Tendinopathy ruptured end33. The tensile strength of tendons is related to thickness and In chronic tendon disorders, interaction between intrinsic 2 collagen content, and a tendon with an area of 1 cm is capa- and extrinsic factors is common11. Intrinsic factors such as 42 ble of bearing 500-1,000 kg . During strenuous activities alignment and biomechanical faults are claimed to play a such as jumping and weight lifting, very high loads are placed causative role in two-thirds of athletes with Achilles tendon 43 on tendons . In the human Achilles tendon, forces of 9 kN, disorders57. In particular, hyperpronation of the foot has been corresponding to 12.5 times body weight, have been record- linked with an increased incidence of Achilles tendinopathy58. 44 ed during running . Since these forces exceed the single- Excessive loading of tendons during vigorous physical load ultimate tensile strength of the tendon, the rate of load- training is regarded as the main pathological stimulus for 38 ing may also play an important role in tendon rupture . degeneration59. In the presence of intrinsic risk factors, Using non-invasive means, the mechanical properties of excessive loading may carry a greater risk of inducing superficial tendons based on stress-strain curves can now tendinopathy. Tendons respond to repetitive overload 45 been performed in humans in vivo . beyond physiological threshold by either inflammation of Tendons are at the highest risk for rupture if tension is their sheath, degeneration of their body, or a combination of applied quickly and obliquely, and highest forces are seen both60. Different stresses induce different responses. Active during eccentric muscle contraction36. repair of fatigue damage must occur, or tendons would weaken and eventually rupture61. The repair mechanism is Physiological responses of tendon probably mediated by resident tenocytes, which maintain a fine balance between ECM production and degradation. In animal experiments, training results in improved ten- Tendon damage may even occur from stresses within physi- sile strength, elastic stiffness, weight and cross-sectional area ological limits, as frequent cumulative microtrauma may not of tendons46. These effects can be explained by an increase in allow enough time for repair62. Microtrauma can also result collagen and ECM synthesis by tenocytes46. Little data exist from non-uniform stress within tendons, producing abnor- on the effect of exercise on human tendons, although inten- mal load concentrations and frictional forces between the sively trained athletes are reported to have thicker Achilles fibrils, resulting in localised fibre damage62. tendons than control subjects47,48. Most of the current knowl- The aetiology of tendinopathy remains unclear, and many edge is therefore based on the result of animal studies49. causes have been theorised. Hypoxia, ischaemic damage, However, care must be taken when interpreting animal stud- oxidative stress, hyperthermia, impaired apoptosis, inflam-

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- 78 teinase imbalance have all been implicated as mechanisms of tory prostaglandin PG E2 . 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 performed 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

185 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- 113 The histopathological process as the basis of the clinical lar release of prostaglandins, histamines and cytokines . 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 114 fine balance between ECM production and degradation. poses a major clinical problem . 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 115 their levels are altered during tendon healing70. In a rat flexor 12 months . 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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18. Lundborg G, Myrhage R. The vascularization and struc- References ture of the human digital tendon sheath as related to flexor tendon function. An angiographic and histological 1. Almekinders LC, Almekinders SV. Outcome in the study. Scand J Plast Reconstr Surg 1977; 11:195-203. treatment of chronic overuse sports injuries: a retro- 19. Doyle JR. Anatomy of the finger flexor tendon sheath spective study. J Orthop Sports Phys Ther 1994; 19:157- and pulley system. J Hand Surg (Am) 1988; 13:473-484. 161. 20. Kvist M, Jozsa L, Kannus P, Isola J, Vieno T, Jarvinen 2. James SL, Bates BT, Osternig LR. Injuries to runners. M, Lehto M. Morphology and histochemistry of the Am J Sports Med 1978; 6:40-50. myotendineal junction of the rat calf muscles. Histo- 3. Gruchow HW, Pelletier D. An epidemiologic study of chemical, immunohistochemical and electron-micro- tennis elbow. Incidence, recurrence, and effectiveness of scopic study. Acta Anat (Basel) 1991; 141:199-205. prevention strategies. Am J Sports Med 1979; 7:234-238. 21. Benjamin M, Ralphs JR. Fibrocartilage in tendons and 4. Benjamin M, Ralphs J. Functional and developmental ligaments – an adaptation to compressive load. J Anat anatomy of tendons and ligaments. In: Gordon SL, 1998; 193(Pt 4):481-494. Blair SJ, Fine LJ (eds) Repetitive Motion Disorders of 22. Evans EJ, Benjamin M, Pemberton DJ. Fibrocartilage the Upper Extremity. American Academy of in the attachment zones of the quadriceps tendon and Orthopaedic Surgeons, Rosemont, USA; 1995:185-203. patellar ligament of man. J Anat 1990; 171:155-162. 5. Kannus P, Jozsa, L, Jarvinnen M. Basic science of ten- 23. Carr AJ, Norris SH. The blood supply of the calcaneal dons. In: Garrett WJ, Speer K, Kirkendall DT (eds) tendon. J Bone Joint Surg (Br) 1989; 71:100-101. Principles and Practice of Orthopaedic Sports 24. Naito M, Ogata K. The blood supply of the tendon with Medicine. Lippincott Williams & Wilkins, Philadelphia, a paratenon. An experimental study using hydrogen USA; 2000:21-37. washout technique. Hand 1983; 15:9-14. 6. Sharma P, Maffulli N. Tendon injury and tendinopathy: 25. Reynolds NL, Worrell TW. Chronic Achilles periten- healing and repair. J Bone Joint Surg Am 2005; 87:187-202. dinitis: etiology, pathophysiology, and treatment. J 7. O'Brien M. Structure and metabolism of tendons. Orthop Sports Phys Ther 1991; 13:171-176. Scand J Med Sci Sports 1997; 7:55-61. 26. Field PL. Tendon fibre arrangement and blood supply. 8. Kvist M, Jozsa L, Jarvinen M, Kvist H. Chronic Achilles Aust N Z J Surg 1971; 40:298-302. paratenonitis in athletes: a histological and histochemi- 27. Astrom M. Laser Doppler flowmetry in the assessment cal study. Pathology 1987; 19:1-11. of tendon blood flow. Scand J Med Sci Sports 2000; 9. Kannus P, Jozsa L. Histopathological changes preced- 10:365-367. ing spontaneous rupture of a tendon. A controlled 28. Leversedge FJ, Ditsios K, Goldfarb CA, Silva MJ, Gel- study of 891 patients. J Bone Joint Surg Am 1991; berman RH, Boyer MI. Vascular anatomy of the human 73:1507-1525. flexor digitorum profundus tendon insertion. J Hand 10. Vailas AC, Tipton CM, Laughlin HL, Tcheng TK, Surg (Am) 2002; 27:806-812. Matthes RD. Physical activity and hypophysectomy on 29. Boushel R, Langberg H, Green S, Skovgaard D, Bulow the aerobic capacity of ligaments and tendons. J Appl J, Kjaer M. Blood flow and oxygenation in peritendi- Physiol 1978; 44:542-546. nous tissue and calf muscle during dynamic exercise in 11. Williams JG. Achilles tendon lesions in sport. Sports humans. J Physiol 2000; 524(Pt 1):305-313. Med 1986; 3:114-135. 30. Lephart SM, Pincivero DM, Giraldo JL, Fu FH. The 12. Jozsa L, Kannus P. Human Tendon: Anatomy, Physiology role of proprioception in the management and rehabil- and Pathology. Human Kinetics, Champaign, USA; 1997. itation of athletic injuries. Am J Sports Med 1997; 13. Jozsa L, Kannus P, Balint JB, Reffy A. Three-dimen- 25:130-137. sional ultrastructure of human tendons. Acta Anat 31. Barr ML, Kiernan JA. The Human Nervous System – (Basel) 1991; 142:306-312. An Anatomical Viewpoint. JB Lippincott Company, 14. Kannus P, Jozsa L, Jarvinen TA, Jarvinen TL, Kvist M, London, UK; 1988. Natri A, Jarvinen M. Location and distribution of non- 32. Ackermann PW, Li J, Finn A, Ahmed M, Kreicbergs A. collagenous matrix proteins in musculoskeletal tissues Autonomic innervation of tendons, ligaments and joint of rat. Histochem J 1998; 30:799-810. capsules. A morphologic and quantitative study in the 15. Mehr D, Pardubsky PD, Martin JA, Buckwalter JA. rat. J Orthop Res 2001; 19:372-378. Tenascin-C in tendon regions subjected to compression. 33. Best TM, Garrett WE. Basic science of soft tissue: mus- J Orthop Res 2000; 18:537-545. cle and tendon. In: DeLee JC, Drez D (eds) 16. Mackie EJ, Ramsey S. Expression of tenascin in joint- Orthopaedic Sports Medicine: Principles and Practice. associated tissues during development and postnatal WB Saunders, Philadelphia, USA; 1994:25-45. growth. J Anat 1996; 188:157-165. 34. O' Brien M. Functional anatomy and physiology of ten- 17. Kastelic J, Galeski A, Baer E. The multicomposite dons. Clin Sports Med 1992; 11:505-520. structure of tendon. Connect Tissue Res 1978; 6:11-23. 35. Viidik A. Tendons and ligaments. In: Comper W (ed)

187 P. Sharma and N. Maffulli: Tendon injury and healing

Extracellular Matrix. Vol. 1. Harwood Academic Pub- 1977; 5:15-19. lishers, Amsterdam, Netherlands; 1996:303-327. 52. Maganaris CN, Reeves ND, Rittweger J, Sargeant AJ, 36. Fyfe I, Stanish WD. The use of eccentric training and Jones DA, Gerrits K, DeHaan A. Adaptive response of stretching in the treatment and prevention of tendon human tendon to paralysis. Muscle Nerve 2006; 33:85-92. injuries. Clin Sports Med 1992; 11:601-624. 53. Macaluso A, De Vito G. Muscle strength, power and 37. Diamant J, Keller A, Baer E, Litt M, Arridge RG. Col- adaptations to resistance training in older people. J lagen; ultrastructure and its relation to mechanical Appl Physiol 2004; 91:450-472. properties as a function of ageing. Proceedings of the 54. Bailey AJ, Robins SP, Balian G. Biological significance Royal Society of London. Series B: Biological Sciences of the intermolecular crosslinks of collagen. Nature 1972; 180:293-315. 1984; 251:105-109. 38. Butler DL, Grood ES, Noyes FR, Zernicke RF. Biome- 55. Reeves ND, Narici MV, Maganaris CN. Strength train- chanics of ligaments and tendons. Exerc Sport Sci Rev ing alters the viscoelastic properties of tendons in eld- 1978; 6:125-181. erly humans. Muscle Nerve 2003; 28:74-81. 39. Mosler E, Folkhard W, Knorzer E, Nemetschek- 56. Maganaris CN, Narici MV, Reeves ND. In vivo human Gansler H, Nemetschek T, Koch MH. Stress-induced tendon mechanical properties: effect of resistance train- molecular rearrangement in tendon collagen. J Mol ing in old age. J Musculoskelet Neuronal Interact 2004; Biol 1985; 182:589-596. 4: 204-208. 40. Curwin SL, Stanish WD. Tendinitis: Its Etiology and 57. Kvist M. Achilles tendon overuse injuries in athletes. Treatment. Collamore Press, Lexington, USA; 1984. Sports Med 1994; 18:173-201. 41. Sasaki N, Shukunami N, Matsushima N, Izumi Y. Time- 58. Nigg BM. The role of impact forces and foot pronation: resolved X-ray diffraction from tendon collagen during a new paradigm. Clin J Sports Med 1994; 11:2-9. creep using synchrotron radiation. J Biomech 1999; 59. Selvanetti A, Cipolla M, Puddu, G. Overuse tendon 32:285-292. injuries: basic science and classification. Oper Tech 42. Shadwick RE. Elastic energy storage in tendons: Sports Med 1997; 5:110-117. mechanical differences related to function and age. J 60. Benazzo F, Maffulli N. An operative approach to Appl Physiol 1990; 68:1033-1040. Achilles tendinopathy. Sports Med Arthroscopy Rev 43. Zernicke RF, Garhammer J, Jobe FW. Human patellar- 2000; 8:96-101. tendon rupture. J Bone Joint Surg Am 1977; 59:179-183. 61. Ker RF. The implications of the adaptable fatigue qual- 44. Komi PV, Fukashiro S, Jarvinen M. Biomechanical ity of tendons for their construction, repair and func- loading of Achilles tendon during normal locomotion. tion. Comp Biochem Physiol A Mol Integr Physiol Clin Sports Med 1992; 11:521-531. 2002; 133:987-1000. 45. Maganaris CN, Paul JP. In vivo human tendon mechan- 62. Arndt AN, Komi PV, Bruggemann GP, Lukkariniemi J. ical properties. J Physiol 1999; 521:307-313. Individual muscle contributions to the in vivo achilles 46. Kannus P, Jozsa L, Natri A, Jarvinen M. Effects of tendon force. Clin Biomech 1998; 13:532-541. training, immobilization and remobilization on ten- 63. Goodship AE, Birch HL, Wilson AM. The pathobiolo- dons. Scand J Med Sci Sports 1997; 7:67-71. gy and repair of tendon and ligament injury. Vet Clin 47. Archambault JM, Wiley JP, Bray RC. Exercise loading North Am Equine Pract 1994; 10:323-349. of tendons and the development of overuse injuries. A 64. Bestwick CS, Maffulli N. Reactive oxygen species and review of current literature. Sports Med 1995; 20:77-89. tendon problems: review and hypothesis. Sports Med 48. Maffulli N, King JB. Effects of physical activity on some Arthroscopy Rev 2000; 8:6-16. components of the skeletal system. Sports Med 1992; 65. Birch HL, Wilson AM, Goodship AE. The effect of 13:393-407. exercise-induced localised hyperthermia on tendon cell 49. Banes AJ, Horesovsky G, Larson C, Tsuzaki M, Judex survival. J Exp Biol 1997; 200(Pt 11):1703-1708. S, Archambault J, Zernicke R, Herzog W, Kelley S, 66. Yuan J, Wang MX, Murrell GA. Cell death and Miller L. Mechanical load stimulates expression of tendinopathy. Clin Sports Med 2003; 22:693-701. novel genes in vivo and in vitro in avian flexor tendon 67. Stone D, Green C, Rao U, Aizawa H, Yamaji T, Niy- cells. Osteoarthritis Cartilage 1999; 7:141-153. ibizi C, Carlin G, Woo SL. Cytokine-induced tendinitis: 50. Yamamoto E, Hayashi K, Yamamoto N. Mechanical a preliminary study in rabbits. J Orthop Res 1999; properties of collagen fascicles from stress-shielded 17:168-177. patellar tendons in the rabbit. Clin Biomech 1999; 68. Sullo A, Maffulli N, Capasso G, Testa V. The effects of 14:418-425. prolonged peritendinous administration of PGE1 to the 51. Akeson WH, Amiel D, Mechanic GL, Woo SL, Har- rat Achilles tendon: a possible animal model of chronic wood FL, Hamer ML. Collagen cross-linking alter- Achilles tendinopathy. J Orthop Sci 2001; 6:349-357. ations in joint contractures: changes in the reducible 69. Corps AN, Harrall RL, Curry VA, Fenwick SA, Hazle- cross-links in periarticular connective tissue collagen man BL, Riley GP. Ciprofloxacin enhances the stimula- after nine weeks of immobilization. Connect Tissue Res tion of matrix metalloproteinase 3 expression by inter-

188 P. Sharma and N. Maffulli: Tendon injury and healing

leukin-1beta in human tendon-derived cells. A poten- and healing. Surgeon 2005; 3:309-316. tial mechanism of fluoroquinolone-induced tendinopa- 86. Murphy PG, Loitz BJ, Frank CB, Hart DA. Influence of thy. Arthritis Rheum 2002; 46:3034-3040. exogenous growth factors on the synthesis and secretion 70. Riley GP, Curry V, DeGroot J, van El B, Verzijl N, of collagen types I and III by explants of normal and Hazleman BL, Bank RA. Matrix metalloproteinase healing rabbit ligaments. Biochem Cell Biol 1994; activities and their relationship with collagen remodel- 72:403-409. ling in tendon pathology. Matrix Biol 2002; 21:185-195. 87. Oakes BW. Tissue healing and repair: tendons and lig- 71. Maffulli N, Barrass V, Ewen SW. Light microscopic his- aments. In: Frontera WR (ed) Rehabilitation of Sports tology of Achilles tendon ruptures. A comparison with Injuries: Scientific Basis. Blackwell Science, Oxford, unruptured tendons. Am J Sports Med 2000; 28:857-863. UK; 2003:56-98. 72. Khan KM, Cook JL, Bonar F, Harcourt P, Astrom M. 88. Tillman LJ, Chasan NP. Properties of dense connective Histopathology of common tendinopathies. Update tissue and wound healing. In: Hertling D, Kessler RM and implications for clinical management. Sports Med (eds) Management of Common Musculoskeletal Disor- 1999; 27:393-408. ders. Lippincott, Philadelphia, USA; 1996:8-21. 73. Soldatis JJ, Goodfellow DB, Wilber JH. End-to-end 89. Hooley CJ, Cohen RE. A model for the creep behav- operative repair of Achilles tendon rupture. Am J iour of tendon. Int J Biol Macromol 1979; 1:123-132. Sports Med 1997; 25:90-95. 90. Abrahamsson SO. Matrix metabolism and healing in 74. Inglis AE, Scott WN, Sculco TP, Patterson AH. Rup- the flexor tendon. Experimental studies on rabbit ten- tures of the tendo achillis. An objective assessment of don. Scand J Plast Reconstr Surg Hand Surg Suppl surgical and non-surgical treatment. J Bone Joint Surg 1991; 23:1-51. Am 1976; 58:990-993. 91. Amiel D, Akeson W, Harwood FL, Frank CB. Stress 75. Arner O, Lindholm A, Orell SR. Histologic changes in deprivation effect on metabolic turnover of medial col- subcutaneous rupture of the Achilles tendon; a study of lateral ligament collagen. Clin Orthop 1987; 172:25-27. 74 cases. Acta Chir Scand 1959; 116:484-490. 92. Gelberman RH, Manske PR, Vande Berg JS, Lesker 76. Tallon C, Maffulli N, Ewen SW. Ruptured Achilles ten- PA, Akeson WH. Flexor tendon repair in vitro: a com- dons are significantly more degenerated than tendino- parative histologic study of the rabbit, chicken, dog, and pathic tendons. Med Sci Sports Exerc 2001; 33:1983-1990. monkey. J Orthop Res 1984; 2:39-48. 77. Alfredson H, Bjur D, Thorsen K, Lorentzon R, Sand- 93. Manske PR, Gelberman RH, Lesker PA. Flexor tendon strom P. High intratendinous lactate levels in painful healing. Hand Clin 1985; 1:25-34. chronic Achilles tendinosis. An investigation using 94. Gelberman RH, Manske PR, Akeson WH, Woo SL, microdialysis technique. J Orthop Res 2002; 20:934-938. Lundborg G, Amiel D. Flexor tendon repair. J Orthop 78. Alfredson H, Thorsen K, Lorentzon R. In situ micro- Res 1986; 4:119-128. dialysis in tendon tissue: high levels of glutamate, but 95. Fujita M, Hukuda S, Doida Y. Experimental study of not prostaglandin E2 in chronic Achilles tendon pain. intrinsic healing of the flexor tendon: collagen synthesis Knee Surg Sports Traumatol Arthrosc 1999; 7:378-381. of the cultured flexor tendon cells of the canine. Nippon 79. Zubrzycka M, Janecka A. Substance P: transmitter of Seikeigeka Gakkai Zasshi 1992; 66:326-333. nociception. Endocr Regul 2000; 34:195-201. 96. Ingraham JM, Hauck RM, Ehrlich HP. Is the tendon 80. Ackermann PW, Finn A, Ahmed M. Sensory neuropep- embryogenesis process resurrected during tendon heal- tidergic pattern in tendon, ligament and joint capsule. A ing? Plast Reconstr Surg 2003; 112:844-854. study in the rat. Neuroreport 1999; 13:2055-2060. 97. Koob TJ. Biomimetic approaches to tendon repair. 81. Gotoh M. Increased substance P in subacromial bursa Comp Biochem Physiol A Mol Integr Physiol 2002; and shoulder pain in rotator cuff diseases. J Orthop Res 133:1171-1192. 1998; 16:618-621. 98. Riederer-Henderson MA, Gauger A, Olson L, Robert- 82. Ljung BO, Alfredson H, Forsgren S. Neurokinin 1- son C, Greenlee TK Jr. Attachment and extracellular receptors and sensory neuropeptides in tendon inser- matrix differences between tendon and synovial fibrob- tions at the medial and lateral epicondyles of the lastic cells. In Vitro 1983; 19:127-133. humerus. Studies on tennis elbow and medial epicondy- 99. Koob TJ, Summers AP. Tendon-bridging the gap. lalgia. J Orthop Res 2004; 22:321-327. Comp Biochem Physiol A Mol Integr Physiol 2002; 83. Ackermann PW, Spetea M, Nylander I, Ploj K, Ahmed 133:905-909. M, Kreicbergs A. An opioid system in connective tissue: 100. Strickland JW. Flexor tendons: acute injuries. In: Green a study of Achilles tendon in the rat. J Histochem D, Hotchkiss R, Pedersen W (eds) Green's Operative Cytochem 2001; 49:1387-1395. Hand Surgery. Churchill Livingstone, New York, USA; 84. Brodin E, Gazelius B, Panopoulos P, Olgart L. Morphine 1999:1851-1897. inhibits substance P release from peripheral sensory 101. Uhthoff HK, Sarkar K. Surgical repair of rotator cuff nerve endings. Acta Physiol Scand 1983; 117:567-570. ruptures. The importance of the subacromial bursa. J 85. Sharma P, Maffulli N. Basic biology of tendon injury Bone Joint Surg (Br) 1991; 73:399-401.

189 P. Sharma and N. Maffulli: Tendon injury and healing

102. Leadbetter WB. Cell-matrix response in tendon injury. GA. Temporal expression of nitric oxide synthase iso- Clin Sports Med 1992; 11:533-578. forms in healing Achilles tendon. J Orthop Res 2001; 103. Oshiro W, Lou J, Xing X, Tu Y, Manske PR. Flexor 19:136-142. tendon healing in the rat: a histologic and gene expres- 110. Ackermann PW. Peptidergic Innervation of Periarticu- sion study. J Hand Surg (Am) 2003; 28:814-823. lar Tissue (Thesis). Karolinska Institute, Stockholm, 104. Evans CH. Cytokines and the role they play in the heal- Sweden; 2001. ing of ligaments and tendons. Sports Med 1999; 28:71-76. 111. Nakamura-Craig M, Smith TW. Substance P and periph- 105. Molloy T, Wang Y, Murrell G. The roles of growth fac- eral inflammatory hyperalgesia. Pain 1989; 38:91-98. tors in tendon and ligament healing. Sports Med 2003; 112. Brain SD, Williams TJ, Tippins JR, Morris HR, MacIn- 33:381-394. tyre I. Calcitonin gene-related peptide is a potent 106. Evans TJ, Buttery LD, Carpenter A, Springall DR, vasodilator. Nature 1985; 313:54-56. Polak JM, Cohen J. Cytokine-treated human neu- 113. Vasko MR, Campbell WB, Waite KJ. Prostaglandin E2 trophils contain inducible nitric oxide synthase that pro- enhances bradykinin-stimulated release of neuropep- duces nitration of ingested bacteria. Proc Natl Acad Sci tides from rat sensory neurons in culture. J Neurosci USA 1996; 93:9553-9558. 1994; 14:4987-4997. 107. Ziche M, Morbidelli L, Masini E, Amerini S, Granger 114. Manske PR. Flexor tendon healing. J Hand Surg (Br) HJ, Maggi CA, Geppetti P, Ledda F. Nitric oxide medi- 1988; 13:237-245. ates angiogenesis in vivo and endothelial cell growth 115. Bruns J, Kampen J, Kahrs J, Plitz W. Achilles tendon and migration in vitro promoted by substance P. J Clin rupture: experimental results on spontaneous repair in Invest 1964; 94:2036-2044. a sheep-model. Knee Surg Sports Traumatol Arthrosc 108. Murrell GA, Szabo C, Hannafin JA, Jang D, Dolan MM, 2000; 8:364-369. Deng XH, Murrell DF, Warren RF. Modulation of ten- 116. Sharma P, Maffulli N. The future: rehabilitation, gene don healing by nitric oxide. Inflamm Res 1997; 46:19-27. therapy, optimization of healing. Foot Ankle Clin 2005; 109. Lin JH, Wang MX, Wei A, Zhu W, Diwan AD, Murrell 10:383-397.

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