Bnlisk Midical BulUlm (1992) Vol. 48, No. 3, pp. 698-711 © The Bririjh Council 1992
Pathophysiology of soft tissue repair Y Barlow J Willoughby Smith and Nephew Research Ltd, Giliton Park, Harlow, Essex, UK
Inflammation with subsequent migration of leucocytes and connective tissue cells to the site of damage, together with the release of cytokines by these cells are essential for healing in common sports injuries. Injury to the musculotendinous unit resulting from either blunt trauma, tears or laceration, heal primarily by formation of granulation tissue and scarring. Early diagnosis with appropriate therapy may minimize any potential loss of function. Ligament repair also follows a classical healing response, although the quality of healing is site dependent and may be related to exposure to synovial fluid. In contrast, cartilage, which is avascular, lacks the inflammatory response seen in other connective tissues and this frequently results in poor tissue repair with subsequent degeneration of the injured cartilage. Mechanisms of repair in these tissues are described.
Most types of soft tissue injury involve damage to the structural elements of the tissue and result in the rupture of capillaries, arterioles and venules which initiates the healing response. In general, healing, regardless of site of injury, comprises three main phases of repair—inflammation, nbro-proliferation and the remodelling of connective tissue. Acute inflammation involves a well regulated series of cellular and humoral mechanisms/that produce an increase in vascular permeability and the accumulation of leucocytes, mainly neutrophils and macrophages, in the inflammatory focus which begin the process of decontamination and debridement of the wound.1"4 After 24-72 h, migration of fibroblasts and endothelial cells occurs in response to chemotactic factors, such asfibronectinand
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fibrin in the clot and from factors released by other cell types at the wound site.5"7 Fibroblasts proliferate and synthesi2e abundant extracellular matrix mainly in the form of type III collagen which is progressively remodelled to type I collagen and cross-linked to give greater tensile strength.8 Wound healing relating to specific tissues and types of injury will be discussed. Sports injuries can be divided into two categories—acute and overuse injuries. Acute injuries include lacerations, contusions and partial or complete rupture of connective tissues. Overuse injuries result from repetitive stresses associated with prolonged activities. At least 50% of sporting injuries are due to overuse,9"12 during which repeated microtrauma, as a result of any of several types of force, exceed the adaptive ability of the tissue, and injury and initiation of the repair process occurs.13 The tissue most commonly affected by overuse is the musculo-tendinous unit. TENDON Muscle and tendon, although distinct tissues, functionally act as a single unit in which muscle is attached to bone by the tendon. Tendons consist predominantly of type I collagen, approximately 5% of type III and type V collagen,14 with smaller amounts of elastin embedded in proteoglycan.15 Similar to ligament, tendon is composed of dense bundles of collagen fibrils oriented parallel to the long axis of the tendon. Fibroblasts (or tenocytes) are arranged in long parallel rows in the spaces between the collagen bundles. Several tendon bundles form the tendon fascicle, which is surrounded by the endotenon and a number of fascicles are surrounded by the epitenon to form the basic tendon unit. Around this a loose connective tissue—the paratenon—functions as an elastic sleeve allowing free movement of the tendon against other tissues. Where the tendon passes over zones of friction, the paratenon is replaced by a true bi-layered tendon sheath lined with synovial cells, e.g. digital flexor tendons. Historically opinion was divided as to the cellular events in tendon healing. Early studies showed that cellular repair was mediated by the tenocytes within the tendon migrating from the cut tendon ends, i.e. intrinsic repair,16 while other studies indicated that granulation tissue resulted only from migration of cells from peritendinous tissue. 1718 More recently it has been demonstrated using rabbit flexor tendon, which had been repaired and transplanted back into the synovium of the knee joint, that tendon
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is capable of healing by intrinsic tenocyte repair.19 In vitro studies have also confirmed that tenocytes will proliferate in cell and organ culture.20-21 These two controversial concepts of tendon repair are not mutually exclusive and the type of healing which occurs depends on local factors and on the nature and extent of the injuries. In acute injury, tendon, like other connective tissue, heals by inflammation, granulation tissue formation and scarring. 1718 ' 22 Inflammatory cells migrate to the site of injury from the peritendinous structures and from the epi- and endotenon. After approximately 3 days, the inflammatory phase gradually resolves and granulation tissue formation begins. All structures surrounding the tendon—synovial sheath, subcutaneous tissue, fascia and periosteum of bone—provide a fibroblastic and vascular component for healing. These cells readily migrate into the defect in the tendon and tenocytes within the tendon also proliferate, although their contribution to the granulation tissue is less than the response from the sheath and the surrounding tissue. Collagen synthesis begins within the first week of injury and increases during the first month post wounding. Capillaries also migrate into the granulation tissue to restore the blood flow and the synovial layer of the sheath is gradually restored. During the remodelling phase (1-2 months post wounding), the strength of the tendon increases as the collagen synthesis changes from predominantly type III to type I collagen and the fibres are stabilized by cross-linking. In clean experimental wounds, functional re-alignment of collagen is usually complete after 2 months. This scar tissue never achieves the strength of the original tendon. However, the remodelling phase can be influenced by load bearing and mechanical stimulation. Complete immobilisation of the tendon results in a reduction in glycosaminoglycan content and in the strength of the tendon.23 Very early weight bearing can result in rupture of the repaired tendon, but judicious use of controlled passive motion appears to enhance tensile strength and improve the quality of repair.24'25 Controlled passive motion is also believed to improve the nutrition of sheathed tendons by forcing synovial fluid into the tendon. Some studies even suggest that the rate of uptake of the nutrients via the synovial route is more rapid than from the vasculature.26'27 These data support the preservation of the sheath where possible and early mobilization. It has been argued that poor nutrition of the tendon may contribute to rupture and poor healing.27 For example, in the Achilles tendon, both proximal muscle and distal
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insertion are well supplied with vasculature but in the area of depressed vascularity between these regions, rupture of the tendon has been reported to occur most frequently.28 Whilst a number of arguments support the nutritional theory, other aetiological factors may also be of importance in tendon injury and include: impaired proprioceptive/mechano-receptor function, corticosteroid therapy, age and systemic disease.29 Injuries to tendon as a result of sustained athletic activity are common.9"13 There is no uniform procedure for classifying these injuries and for simplification these are usually based on anatomical site, e.g. medical epicondylitis and bicipital tendinitis. Both intrinsic factors (such as malalignment and limb length discrepancies) and extrinsic factors (such as training errors12) contribute to overuse injuries. In overuse, when the reparative capacity of the tissue is exceeded, cellular metabolism is altered, damage at the cellular level occurs and subsequent injury to the microvasculature can further impair metabolic activity of the tissue. n ~ 1 3 The impairment of the vascular supply is important in tendinitis, particularly rotator cuff injuries and Achilles tendinitis.30 Overuse leads to oedema and inflammation and tissue repair follows the classical pattern, however, in sheathed tendons, the inflammatory process may affect the synovium rather than the tendon itself. Treatment modalities for overuse (rest, ice, heat, ultrasound, phonophoresis) and surgical techniques for rupture have been extensively reviewed.10>12p29'31 MUSCLE Skeletal muscle is composed of long cylindrical syncitial cells surrounded by an endomysium, which constitutes the muscle fibres.32 Lying in close apposition to the muscle fibres are satellite cells. These are muscle stem cells which can differentiate into myoblasts, form myotubes and new muscle fibres, although their capacity for regeneration is limited. Parallel muscle fibres are grouped into fascicles enclosed in the perimysium and the entire muscle is surrounded by another connective tissue layer—the epimysium. These connective tissue layers carry the blood supply to the tissue and ramify to form a rich capillary network around the muscle fibres. The connective tissue is continuous within the muscle and attaches to the tendon of insertion. Within the muscle fibres are the myofibrils arranged in repeating units or sarcomeres, which are made up of contractile proteins myosin and actin. Not
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all fibres are identical.33 Type II fibres have a faster contraction rate and are less resistant to fatigue than the type I fibres which rely largely on aerobic metabolism and are more fatigue resistant. Human muscle is a mixture of type I and type II fibres and although there is variability in the relative percentages of each type between individuals, within an individual there is a correlation between muscle function and fibre composition—muscles involved in rapid activities having a greater percentage of type II fibres. Muscle injuries fall into a number of categories—muscle strain involving complete or partial tears, lacerations, contusions, exercise induced soreness and compartment syndrome. Muscles with a greater percentage of type II fibres, those which cross two joints and those working eccentrically are much more susceptible to strain injuries and injury occurs most commonly at or near the myotendinous junction.34"36 Histological examination of muscles immediately following strain injuries in animals35"37 indicate haematoma formation and fibre disruption. The presence of large amounts of oedema and the infiltration of the site with mononuclear cells was evident at 24-48 hours after injury with typical fibre necrosis. Interestingly, Stauber and his colleagues37 noted that macrophage infiltration into muscle injured by straining was less than into other types of muscle injury and may be related to the degree of bleeding in the two types of injury. They also demonstrated histologically the presence of myoblasts as early as 12 h after injury, which, between 24 and 72 hours had oriented themselves along the longitudinal axis of the broken ends of the fibres. Occasionally myotubes were seen but these were difficult to identify. By 5-7 days post injury fibroblast proliferation was evident and local fibrosis and scarring resulted. A similar pattern of repair is found in partial and complete rupture of muscle. Dense scar tissue formation is frequently the outcome in such wounds and can result in denervation of the affected area with subsequent reduction in the ability of that muscle to produce tension.38 Again, although repair mechanisms are essentially similar, the extent and duration of inflammation is reportedly longer in experimental contusion injuries compared with strains.39 The authors also noted a delay in tissue repair after muscle contusion, particularly the temporal sequence of the synthesis of extracellular matrix components such as sulphated chondroitin proteoglycans. However, the degree of initial injury may be different in these models and in fact different muscles were compared between studies.
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Other factors can also influence the rate of muscle repair. In experimental models 4041 early mobilization of crush injuries resulted in earlier healing, more rapid vascularisation, better orientation of regenerated muscle fibres and greater tensile strength. Other factors can slow repair; age,38 levels of physical activity41 and the use of steroids.42 Occasionally, recovery can also be compromised by calcification or ossification of repairing muscle tissue, i.e. myositis ossificans.43 Exercise induced soreness is typified by pain 24—48 hours after exercise, particularly if the exercise was of unaccustomed duration or intensity.44 Histologically, disruption of the banding pattern in muscles and dissolution of the myofibrillar structure was observed in exercised rats, but unlike the gross tissue disruption that occurs with muscle rupture and laceration, these injuries occur at the cellular and subcellular levels.45 Clinically elevated levels of plasma enzymes (creatinine kinase, lactate dehydrogenase), hydroxyproline and myoglobin from injured muscles have been observed.44i46>47 Both mechanical and metabolic factors may contribute to the muscle damage. High specific tension created in muscle may mechanically disrupt the sarcolemma, sarcoplasmic reticulum and myofilaments, whilst metabolic damage to the cells may be due to high local temperatures produced in muscle during exercise, lactate production, free oxygen radical production or insufficient respiration in the mitochondria. 444748 It has been postulated that common to all these mechanisms of damage is the disruption of calcium homeostasis.44'49 The events involved in the initial phases of healing, before inflammation and repair (which usually results in the regeneration of the myofibres) are not yet fully elucidated. Compartment syndrome is characterised by increased interstitial pressure that usually results from haemorrhage, oedema or intense muscular activity itself and causes transient rises in intracompartmental pressure. With increasing pressure capillary perfusion is compromised, injury to nerves occurs and ischaemia ensues.50 Damage to the muscle tissue is related to the pressure at which capillary perfusion is prevented and will determine whether surgical intervention is necessary. LIGAMENT Ligaments are short bands of connective tissue binding bones to bones and providing internal support for organs. Most experimen-
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tal investigations of ligament healing have been carried out on the collateral and cruciate ligaments of the knee which show substantial differences in their repair processes. Healing of the anterior cruciate ligament is poor and, without surgical repair, it will regress or disappear completely.51 The collateral ligaments however, show the standard healing response. Ligaments are made up of tightly packed collagen bundles interspersed with fibroblasts. The collagen is 90% type I and 10% type III. 52 They also contain a small percentage of glycosaminoglycan which, with water, provides the lubrication and spacing crucial to the gliding function of the ligaments. Ultrastructural differences may be shown between the anterior cruciate ligament and the medial collateral ligament. The cells of the anterior cruciate ligament are arranged in columns and are rounded, resembling cells of fibrocartilage. The medial collateral ligament, by contrast, is populated by spindle shaped cells resting directly on a collagen matrix.52 Further differences between the two ligaments may be seen in their blood supply. The medial collateral ligament derives its blood supply from the inferior medial geniculate artery, in addition synovial fluid has been shown to make a nutritional contribution.53 The blood supply to the anterior cruciate ligament from the median geniculate artery is poor,54 and it has been suggested that it derives its primary nutrition from synovial fluid.53 Most of the studies of ligament repair have been based upon animal models where the ligament has been partially or completely transected. Again healing of the medial collateral ligament progresses by inflammation, repair and remodelling. Following a midsubstance tear of the medial collateral ligament, a haematoma forms and inflammatory cells then proliferate from the surrounding tissue. After 2 weeks, immature collagen fibres are present and fibroblasts dominate the central scar region.55"57 At 6 weeks the fibroblasts begin to regress. The collagen fibres then increase in size and strength and align themselves longitudinally. The resulting scar tissue increases in strength but even after 1 year may not achieve the strength of uninjured tissue. Injuries where the ligament is intact but severely weakened have also been investigated using the sheep medial collateral ligament. Histology revealed healing mainly by fibroblasts with no evidence of an inflammatory response. Several other factors may affect healing of the collateral ligaments including repair versus no repair,38"60 and
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mobilization versus immobility.61"63 These approaches are subject to considerable controversy as to their beneficial effects. The first demonstration of the poor healing capacity of the anterior cruciate ligament was demonstrated in dogs.51 Partial transection resulted in necrosis followed by inflammation and early fibroblast proliferation. Little healing at the base of the lesion was observed at 10 weeks. Complete transection resulted in ligament retraction and absorption. Complete transection plus repair resulted in collagen deposition, but, up to 1 year, the ligament never achieved a normal appearance. This model involved transection of the ligament at the tibial insertion sites involving a certain amount of bone healing. Other models involved partial laceration of the anterio-medial portion where vascular proliferation of the area of injury was noted, but no bridging of the gap.64 Partial laceration of the posterio-lateral portion of the cruciate ligament with and without repair has also been investigated but 6 weeks post injury there was no evidence of healing.65 A more favourable repair response was shown following the partial or complete transection of the anterior cruciate ligament in rabbits.66 As expected, there was no regeneration after complete transection. However, following partial transection, an inflammatory response was observed followed by proliferation of fibroblasts and the formation of collagen fibres. At one year the defect was still visible, and partially filled with tissue that resembled ligament but with a higher density of cells. Why the anterior cruciate ligament and medial collateral ligaments should show such different healing capacities is the subject of considerable speculation. Both ligaments are ultrastructurally distinct, the anterior cruciate ligament receives a poor blood supply and is surrounded by a thin layer of synovial tissue, whereas the medial collateral ligament is sheathed by connective tissue. The physiology of the anterior cruciate ligament results in it being exposed to the so-called 'hostile environment' of synovial fluid which, following injury is known to contain haemorrhagic breakdown products and a variety of proteolytic enzymes.67 Synovial fluid has also been shown to adversely affect anterior cruciate ligament fibroblast proliferation in culture.68 Finally, in the anterior cruciate ligament synovial fluid washes away the clot from the site of injury, and this removal of the clot may deplete growth factors and other clot derived substances necessary for stimulating the healing response.69
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ARTICULAR CARTILAGE Articular cartilage provides a firm elastic surface for the smooth gliding of joints. The mechanical properties which enable it to absorb impact, yet resist wear, result from the structure of the extracellular matrix. Articular cartilage is an avascular tissue mainly composed of chondrocytes embedded in a matrix of type II collagen, proteoglycans and non-collagenous protein. The proteoglycans are huge aggregates with a molecular weight of approximately 200 million Daltons embedded and constrained in a dense network of collagen fibres. The proteoglycans are negatively charged and repel each other, keeping their structure extended. Compression forces the proteoglycans together extruding water. On release of pressure the proteoglycans reabsorb water, regaining their previous arrangement. Mechanical injury to articular cartilage produces different responses depending on the nature of the injury and can be summarized as impactive blunt trauma, superficial lacerations (type I defects) and deep full thickness injuries penetrating the subchondral bone (type II defects).70'71 The effect of blunt non-penetrative injury depends on the intensity of loading. Reports of a surface loss of proteoglycan, cellular degeneration, fibrillation and penetration of the subchondral capillaries into the calcified layer of cartilage have been documented.72'73 These changes are thought to be consistent widi those seen in osteoarthritis. Superficial lacerations (type I) confined to the cartilage alone, do not involve injury to blood vessels. The response therefore lacks the inflammatory and repair components seen normally in the healing response. These have been studied by producing partial thickness defects in rabbit articular cartilage.74'75 Following such injury necrosis occurs at the wound margins together with signs of increased metabolic activity. Other investigations have shown increased glycosaminoglycan and protein synthesis.75"77 These changes are short lived and return to uninjured levels within I to 2 weeks. This response does not result in repair of the defect and the lacerations persist unaltered. Full thickness (type II) injuries penetrate the subchondral bone and its blood vessels which elicits an inflammatory response. Type II injuries have been studied by producing full thickness defects in the articular cartilage of mature rabbits.78 The initial response is the formation of a fibrin clot. Within 1 week fibroblasts and collagen fibres have replaced this clot and within 1 month the
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fibroblasts have undergone metaplasia to a chondrocytic phenotype and are surrounded by high concentrations of proteoglycan. The synthesis of type I collagen is initially high but then type II collagen predominates. At 6 months, defects are present on the surface of the cartilage and there is a loss of proteoglycan in the repair tissue. Within a year the majority of the defects initially repaired have degenerated into erosive lesions resembling early osteoarthritis. The response to such full thickness defects has been well documented.70-71-79-80 The basis of degeneration of the full thickness injuries has been the subject of speculation. One suggestion is that the tissue undergoing repair is significantly different to articular cartilage with regard to its collagen and proteoglycan content.81 At 6 months, the repair tissue contains 33% type I collagen compared to uninjured tissue where type I comprises 1 %. Connective tissues which synthesize type I collagen usually contain dermatan sulphate proteoglycans, unlike the chondroitin and keratin sulphate proteoglycans of articular cartilage. The dermatan sulphate proteoglycan is much smaller and has feeble elastic properties. It has been suggested that substitution with dermatan sulphate contributes to the decreased capacity of the repairing cartilage to resist wear and ultimately leads to its degeneration. SUMMARY The repair of connective tissue injury takes place, in the majority of instances, through 3 well defined processes; inflammation, granulation and resolution. Failure of any of these processes may result in inadequate or ineffectual repair leading to either chronic pathological changes in the tissue or to repeated structural failure. The conditions which occur at specific anatomical sites may affect these processes and the efficiency with which connective tissue repair is effected (e.g. the rotator cuff) may be moderated by factors such as a reduced or impaired blood supply. Cartilage is, by its nature, avascular and this may be reflected in its limited powers of repair and the tendency towards calcification which it shows following injury. It should be noted, however, that the majority of models involve either a sudden disruption or a clean incision of the tissue followed by immediate repair. In vivo it is much more common to have insult or injury to the tissue occurring over a period of time with other factors contributing to both the injury and to any impairment
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of the repair process. Thus better models may be required to accurately examine the processes involved in connective tissue repair. REFERENCES 1 Ward PA, Marks RM. The acute inflammatory reaction. Curr Opinion Immunol 1989; 2: 5-9 2 Roos D, Dolman KM. Neutrophil involvement in inflammatory tissue damage. Neth J Med 1990; 36: 89-94 3 Keshsavs S, Chung L, Gordon S. Macrophage products in Inflammation. Diag Microbiol Infect Dis 1990; 13: 439^147 4 Prober JS, Cotran RS. The role of endothelial cells in inflammation. Transplantation 1990; 50: 537-554 5 Knighton DR, Fiegel VD. Regulation of cutaneous wound healing by growth factors and the microenvironment. Invest Radiol 1991; 26: 604-611 6 McGrath MH. Peptide growth factors and wound healing. Clin Plast Surg 1990; 17: 421^32 7 Wahl SM, Wong H, McCartney-Francis N. Role of growth factors in inflammation and repair. J Cell Biochem 1989; 40: 193-199 8 Clark RAF. Cutaneous Wound Repair. In: Goldsmith LE (ed) Biochemistry and Physiology of the Skin. Oxford: Oxford University Press, 1990 9 Herring SA, Nilson KL. Introduction to overuse injuries. Clin Sports Med 1987; 6: 225-239 10 O'Neil DB, Micheli LJ. Overuse injuries in the young athlete. Clin Sports Med 1988; 7: 591-610 11 Pitner MA. Hand injuries in sport and the performing arts. Hand Clin 1990; 6: 335-364 12 Renstrom P, Johnson RJ. Overuse injuries in sport—A review. Sports Med 1985; 2: 316-333 13 Hess GP, Cappiello WL, Poole RM, Hunter SC. Prevention and treatment of overuse tendon injuries. Sports Med 1989; 8: 371-384 14 Jiminez SA, Yankowski R, Bashley RI. Identification of two new collagen alpha chains in extracts of lathrytic chick embryo tendons. Biochem Biophys Res Commun 1978; 81: 1298-1306 15 Rowe RWD. The structure of rat tail tendon. Connect Tiss Res 1985; 14: 9-20 16 Lindsay WK, Thomson HG. Digital flexor tendons: an experimental study. Br J Plast Surg 1980; 12: 289-316 17 Peacock EE. Fundamental aspects of wound healing relating to the restoration of gliding function after tendon repair. Surg Gynaecol Obstet 1964; 119: 241-250 18 Potenza AD. Tendon healing within the digital flexor sheath in the dog. J Bone Joint Surg 1962; 44A: 49-64 19 Lunborg G, Rank F. Experimental intrinsic healing of flexor tendons based on synovial fluid nutrition. J Hand Surg 1978; 3: 21-31 20 Manske PR, Lasker PA. Histologic evidence of intrinsic flexor tendon repair in various experimental animals—an in vitro study. Clin Orthop 1984; 182: 297-304 21 Chard M, Wright JK, Hazlcman B. Isolation and growth characteristics of adult human tendon fibroblasts. Ann Rhuem Dis 1987; 46: 385-390 22 Potenza AD. Tendon and ligament healing. In: Owen R Goodfellow J Bullough P (eds) Scientific Foundation of Orthopedics and Traumatology. London: William Heinmann, 1990: pp. 300-305
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D Daniel et al. eds. Knee Ligaments: Structure, Function, Injury and Repair. New York: Raven Press, 1990: pp. 365-377 Lanzo A. Articular cartilage repair: A review. Einstein Q J Biol Med 1989; 7: 131-138 Mankin A. Response of articular cartilage to mechanical injury. J Bone Joint Surg 1982; 64A: 460-465 Radin EL, Ehrlich MG, Chemack IL, et al. Effect of repetitive impulse loading on the knee joints of rabbits. Clin Orthop 1978; 131: 288-293 Dekel S, Weissman SL. Joint changes in overuse and peak overloading of rabbit knees in vivo. Acta Orthop Scand 1978; 49: 519-528 Fuller J, Ghadially FN. Ultrastructural observations on surgically produced partial thickness defects in articular cartilage. Clin Orthop 1972 86: 193-205 Ghadially FN, Thomas I, Oryschak AF, et al. Long term results of superficial defects in articular cartilage. A scanning electron microscope study. J Pathol 19 121: 213-217 DePalma AF, McKeever CD, Subin SK. Process of repair of articular cartilage demonstrated by histology and autoradiography with tritiated thymidine. Clin Orthop 1966; 48: 229-242 Mankin HJ, Boyle CJ. The effects of lacerative injury on DNA and protein synthesis in articular cartilage. In: Bassett CAL, ed. Cartilage Degradation and Repair. Washington DC: National Research Council National Academy of Sciences—National Academy of Engineering, 1967: pp. 185-199 Rosenberg L. Chemical basis for the histological use of safranin O in the study of articular cartilage. J Bone Joint Surg 1971; 53A: 69-82 Furukawa T, Eyre D, Koide, S, ct al. Biochemical studies on repair cartilage resurfacing experimental defects in the rabbit knee. J Bone Joint Surg 1980; 62A: 79-89 Kubo T. Ultrastructural studies of healing process of injured articular cartilage. J Jpn Orthop Assoc 1983; 57: 167-185 Rosenberg L. Biological basis for the imperfect repair of articular cartilage following injury. In: Hunt TK, Heppenstall RB, Pines E, et al. eds. Soft and Hard Tissue Repair. Praeger Scientific 1984; pp. 143-169
Pathophysiology of soft tissue repair Y Barlow J Willoughby Smith and Nephew Research Ltd, Giliton Park, Harlow, Essex, UK
Inflammation with subsequent migration of leucocytes and connective tissue cells to the site of damage, together with the release of cytokines by these cells are essential for healing in common sports injuries. Injury to the musculotendinous unit resulting from either blunt trauma, tears or laceration, heal primarily by formation of granulation tissue and scarring. Early diagnosis with appropriate therapy may minimize any potential loss of function. Ligament repair also follows a classical healing response, although the quality of healing is site dependent and may be related to exposure to synovial fluid. In contrast, cartilage, which is avascular, lacks the inflammatory response seen in other connective tissues and this frequently results in poor tissue repair with subsequent degeneration of the injured cartilage. Mechanisms of repair in these tissues are described.
Most types of soft tissue injury involve damage to the structural elements of the tissue and result in the rupture of capillaries, arterioles and venules which initiates the healing response. In general, healing, regardless of site of injury, comprises three main phases of repair—inflammation, nbro-proliferation and the remodelling of connective tissue. Acute inflammation involves a well regulated series of cellular and humoral mechanisms/that produce an increase in vascular permeability and the accumulation of leucocytes, mainly neutrophils and macrophages, in the inflammatory focus which begin the process of decontamination and debridement of the wound.1"4 After 24-72 h, migration of fibroblasts and endothelial cells occurs in response to chemotactic factors, such asfibronectinand
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fibrin in the clot and from factors released by other cell types at the wound site.5"7 Fibroblasts proliferate and synthesi2e abundant extracellular matrix mainly in the form of type III collagen which is progressively remodelled to type I collagen and cross-linked to give greater tensile strength.8 Wound healing relating to specific tissues and types of injury will be discussed. Sports injuries can be divided into two categories—acute and overuse injuries. Acute injuries include lacerations, contusions and partial or complete rupture of connective tissues. Overuse injuries result from repetitive stresses associated with prolonged activities. At least 50% of sporting injuries are due to overuse,9"12 during which repeated microtrauma, as a result of any of several types of force, exceed the adaptive ability of the tissue, and injury and initiation of the repair process occurs.13 The tissue most commonly affected by overuse is the musculo-tendinous unit. TENDON Muscle and tendon, although distinct tissues, functionally act as a single unit in which muscle is attached to bone by the tendon. Tendons consist predominantly of type I collagen, approximately 5% of type III and type V collagen,14 with smaller amounts of elastin embedded in proteoglycan.15 Similar to ligament, tendon is composed of dense bundles of collagen fibrils oriented parallel to the long axis of the tendon. Fibroblasts (or tenocytes) are arranged in long parallel rows in the spaces between the collagen bundles. Several tendon bundles form the tendon fascicle, which is surrounded by the endotenon and a number of fascicles are surrounded by the epitenon to form the basic tendon unit. Around this a loose connective tissue—the paratenon—functions as an elastic sleeve allowing free movement of the tendon against other tissues. Where the tendon passes over zones of friction, the paratenon is replaced by a true bi-layered tendon sheath lined with synovial cells, e.g. digital flexor tendons. Historically opinion was divided as to the cellular events in tendon healing. Early studies showed that cellular repair was mediated by the tenocytes within the tendon migrating from the cut tendon ends, i.e. intrinsic repair,16 while other studies indicated that granulation tissue resulted only from migration of cells from peritendinous tissue. 1718 More recently it has been demonstrated using rabbit flexor tendon, which had been repaired and transplanted back into the synovium of the knee joint, that tendon
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is capable of healing by intrinsic tenocyte repair.19 In vitro studies have also confirmed that tenocytes will proliferate in cell and organ culture.20-21 These two controversial concepts of tendon repair are not mutually exclusive and the type of healing which occurs depends on local factors and on the nature and extent of the injuries. In acute injury, tendon, like other connective tissue, heals by inflammation, granulation tissue formation and scarring. 1718 ' 22 Inflammatory cells migrate to the site of injury from the peritendinous structures and from the epi- and endotenon. After approximately 3 days, the inflammatory phase gradually resolves and granulation tissue formation begins. All structures surrounding the tendon—synovial sheath, subcutaneous tissue, fascia and periosteum of bone—provide a fibroblastic and vascular component for healing. These cells readily migrate into the defect in the tendon and tenocytes within the tendon also proliferate, although their contribution to the granulation tissue is less than the response from the sheath and the surrounding tissue. Collagen synthesis begins within the first week of injury and increases during the first month post wounding. Capillaries also migrate into the granulation tissue to restore the blood flow and the synovial layer of the sheath is gradually restored. During the remodelling phase (1-2 months post wounding), the strength of the tendon increases as the collagen synthesis changes from predominantly type III to type I collagen and the fibres are stabilized by cross-linking. In clean experimental wounds, functional re-alignment of collagen is usually complete after 2 months. This scar tissue never achieves the strength of the original tendon. However, the remodelling phase can be influenced by load bearing and mechanical stimulation. Complete immobilisation of the tendon results in a reduction in glycosaminoglycan content and in the strength of the tendon.23 Very early weight bearing can result in rupture of the repaired tendon, but judicious use of controlled passive motion appears to enhance tensile strength and improve the quality of repair.24'25 Controlled passive motion is also believed to improve the nutrition of sheathed tendons by forcing synovial fluid into the tendon. Some studies even suggest that the rate of uptake of the nutrients via the synovial route is more rapid than from the vasculature.26'27 These data support the preservation of the sheath where possible and early mobilization. It has been argued that poor nutrition of the tendon may contribute to rupture and poor healing.27 For example, in the Achilles tendon, both proximal muscle and distal
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insertion are well supplied with vasculature but in the area of depressed vascularity between these regions, rupture of the tendon has been reported to occur most frequently.28 Whilst a number of arguments support the nutritional theory, other aetiological factors may also be of importance in tendon injury and include: impaired proprioceptive/mechano-receptor function, corticosteroid therapy, age and systemic disease.29 Injuries to tendon as a result of sustained athletic activity are common.9"13 There is no uniform procedure for classifying these injuries and for simplification these are usually based on anatomical site, e.g. medical epicondylitis and bicipital tendinitis. Both intrinsic factors (such as malalignment and limb length discrepancies) and extrinsic factors (such as training errors12) contribute to overuse injuries. In overuse, when the reparative capacity of the tissue is exceeded, cellular metabolism is altered, damage at the cellular level occurs and subsequent injury to the microvasculature can further impair metabolic activity of the tissue. n ~ 1 3 The impairment of the vascular supply is important in tendinitis, particularly rotator cuff injuries and Achilles tendinitis.30 Overuse leads to oedema and inflammation and tissue repair follows the classical pattern, however, in sheathed tendons, the inflammatory process may affect the synovium rather than the tendon itself. Treatment modalities for overuse (rest, ice, heat, ultrasound, phonophoresis) and surgical techniques for rupture have been extensively reviewed.10>12p29'31 MUSCLE Skeletal muscle is composed of long cylindrical syncitial cells surrounded by an endomysium, which constitutes the muscle fibres.32 Lying in close apposition to the muscle fibres are satellite cells. These are muscle stem cells which can differentiate into myoblasts, form myotubes and new muscle fibres, although their capacity for regeneration is limited. Parallel muscle fibres are grouped into fascicles enclosed in the perimysium and the entire muscle is surrounded by another connective tissue layer—the epimysium. These connective tissue layers carry the blood supply to the tissue and ramify to form a rich capillary network around the muscle fibres. The connective tissue is continuous within the muscle and attaches to the tendon of insertion. Within the muscle fibres are the myofibrils arranged in repeating units or sarcomeres, which are made up of contractile proteins myosin and actin. Not
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all fibres are identical.33 Type II fibres have a faster contraction rate and are less resistant to fatigue than the type I fibres which rely largely on aerobic metabolism and are more fatigue resistant. Human muscle is a mixture of type I and type II fibres and although there is variability in the relative percentages of each type between individuals, within an individual there is a correlation between muscle function and fibre composition—muscles involved in rapid activities having a greater percentage of type II fibres. Muscle injuries fall into a number of categories—muscle strain involving complete or partial tears, lacerations, contusions, exercise induced soreness and compartment syndrome. Muscles with a greater percentage of type II fibres, those which cross two joints and those working eccentrically are much more susceptible to strain injuries and injury occurs most commonly at or near the myotendinous junction.34"36 Histological examination of muscles immediately following strain injuries in animals35"37 indicate haematoma formation and fibre disruption. The presence of large amounts of oedema and the infiltration of the site with mononuclear cells was evident at 24-48 hours after injury with typical fibre necrosis. Interestingly, Stauber and his colleagues37 noted that macrophage infiltration into muscle injured by straining was less than into other types of muscle injury and may be related to the degree of bleeding in the two types of injury. They also demonstrated histologically the presence of myoblasts as early as 12 h after injury, which, between 24 and 72 hours had oriented themselves along the longitudinal axis of the broken ends of the fibres. Occasionally myotubes were seen but these were difficult to identify. By 5-7 days post injury fibroblast proliferation was evident and local fibrosis and scarring resulted. A similar pattern of repair is found in partial and complete rupture of muscle. Dense scar tissue formation is frequently the outcome in such wounds and can result in denervation of the affected area with subsequent reduction in the ability of that muscle to produce tension.38 Again, although repair mechanisms are essentially similar, the extent and duration of inflammation is reportedly longer in experimental contusion injuries compared with strains.39 The authors also noted a delay in tissue repair after muscle contusion, particularly the temporal sequence of the synthesis of extracellular matrix components such as sulphated chondroitin proteoglycans. However, the degree of initial injury may be different in these models and in fact different muscles were compared between studies.
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Other factors can also influence the rate of muscle repair. In experimental models 4041 early mobilization of crush injuries resulted in earlier healing, more rapid vascularisation, better orientation of regenerated muscle fibres and greater tensile strength. Other factors can slow repair; age,38 levels of physical activity41 and the use of steroids.42 Occasionally, recovery can also be compromised by calcification or ossification of repairing muscle tissue, i.e. myositis ossificans.43 Exercise induced soreness is typified by pain 24—48 hours after exercise, particularly if the exercise was of unaccustomed duration or intensity.44 Histologically, disruption of the banding pattern in muscles and dissolution of the myofibrillar structure was observed in exercised rats, but unlike the gross tissue disruption that occurs with muscle rupture and laceration, these injuries occur at the cellular and subcellular levels.45 Clinically elevated levels of plasma enzymes (creatinine kinase, lactate dehydrogenase), hydroxyproline and myoglobin from injured muscles have been observed.44i46>47 Both mechanical and metabolic factors may contribute to the muscle damage. High specific tension created in muscle may mechanically disrupt the sarcolemma, sarcoplasmic reticulum and myofilaments, whilst metabolic damage to the cells may be due to high local temperatures produced in muscle during exercise, lactate production, free oxygen radical production or insufficient respiration in the mitochondria. 444748 It has been postulated that common to all these mechanisms of damage is the disruption of calcium homeostasis.44'49 The events involved in the initial phases of healing, before inflammation and repair (which usually results in the regeneration of the myofibres) are not yet fully elucidated. Compartment syndrome is characterised by increased interstitial pressure that usually results from haemorrhage, oedema or intense muscular activity itself and causes transient rises in intracompartmental pressure. With increasing pressure capillary perfusion is compromised, injury to nerves occurs and ischaemia ensues.50 Damage to the muscle tissue is related to the pressure at which capillary perfusion is prevented and will determine whether surgical intervention is necessary. LIGAMENT Ligaments are short bands of connective tissue binding bones to bones and providing internal support for organs. Most experimen-
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tal investigations of ligament healing have been carried out on the collateral and cruciate ligaments of the knee which show substantial differences in their repair processes. Healing of the anterior cruciate ligament is poor and, without surgical repair, it will regress or disappear completely.51 The collateral ligaments however, show the standard healing response. Ligaments are made up of tightly packed collagen bundles interspersed with fibroblasts. The collagen is 90% type I and 10% type III. 52 They also contain a small percentage of glycosaminoglycan which, with water, provides the lubrication and spacing crucial to the gliding function of the ligaments. Ultrastructural differences may be shown between the anterior cruciate ligament and the medial collateral ligament. The cells of the anterior cruciate ligament are arranged in columns and are rounded, resembling cells of fibrocartilage. The medial collateral ligament, by contrast, is populated by spindle shaped cells resting directly on a collagen matrix.52 Further differences between the two ligaments may be seen in their blood supply. The medial collateral ligament derives its blood supply from the inferior medial geniculate artery, in addition synovial fluid has been shown to make a nutritional contribution.53 The blood supply to the anterior cruciate ligament from the median geniculate artery is poor,54 and it has been suggested that it derives its primary nutrition from synovial fluid.53 Most of the studies of ligament repair have been based upon animal models where the ligament has been partially or completely transected. Again healing of the medial collateral ligament progresses by inflammation, repair and remodelling. Following a midsubstance tear of the medial collateral ligament, a haematoma forms and inflammatory cells then proliferate from the surrounding tissue. After 2 weeks, immature collagen fibres are present and fibroblasts dominate the central scar region.55"57 At 6 weeks the fibroblasts begin to regress. The collagen fibres then increase in size and strength and align themselves longitudinally. The resulting scar tissue increases in strength but even after 1 year may not achieve the strength of uninjured tissue. Injuries where the ligament is intact but severely weakened have also been investigated using the sheep medial collateral ligament. Histology revealed healing mainly by fibroblasts with no evidence of an inflammatory response. Several other factors may affect healing of the collateral ligaments including repair versus no repair,38"60 and
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mobilization versus immobility.61"63 These approaches are subject to considerable controversy as to their beneficial effects. The first demonstration of the poor healing capacity of the anterior cruciate ligament was demonstrated in dogs.51 Partial transection resulted in necrosis followed by inflammation and early fibroblast proliferation. Little healing at the base of the lesion was observed at 10 weeks. Complete transection resulted in ligament retraction and absorption. Complete transection plus repair resulted in collagen deposition, but, up to 1 year, the ligament never achieved a normal appearance. This model involved transection of the ligament at the tibial insertion sites involving a certain amount of bone healing. Other models involved partial laceration of the anterio-medial portion where vascular proliferation of the area of injury was noted, but no bridging of the gap.64 Partial laceration of the posterio-lateral portion of the cruciate ligament with and without repair has also been investigated but 6 weeks post injury there was no evidence of healing.65 A more favourable repair response was shown following the partial or complete transection of the anterior cruciate ligament in rabbits.66 As expected, there was no regeneration after complete transection. However, following partial transection, an inflammatory response was observed followed by proliferation of fibroblasts and the formation of collagen fibres. At one year the defect was still visible, and partially filled with tissue that resembled ligament but with a higher density of cells. Why the anterior cruciate ligament and medial collateral ligaments should show such different healing capacities is the subject of considerable speculation. Both ligaments are ultrastructurally distinct, the anterior cruciate ligament receives a poor blood supply and is surrounded by a thin layer of synovial tissue, whereas the medial collateral ligament is sheathed by connective tissue. The physiology of the anterior cruciate ligament results in it being exposed to the so-called 'hostile environment' of synovial fluid which, following injury is known to contain haemorrhagic breakdown products and a variety of proteolytic enzymes.67 Synovial fluid has also been shown to adversely affect anterior cruciate ligament fibroblast proliferation in culture.68 Finally, in the anterior cruciate ligament synovial fluid washes away the clot from the site of injury, and this removal of the clot may deplete growth factors and other clot derived substances necessary for stimulating the healing response.69
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ARTICULAR CARTILAGE Articular cartilage provides a firm elastic surface for the smooth gliding of joints. The mechanical properties which enable it to absorb impact, yet resist wear, result from the structure of the extracellular matrix. Articular cartilage is an avascular tissue mainly composed of chondrocytes embedded in a matrix of type II collagen, proteoglycans and non-collagenous protein. The proteoglycans are huge aggregates with a molecular weight of approximately 200 million Daltons embedded and constrained in a dense network of collagen fibres. The proteoglycans are negatively charged and repel each other, keeping their structure extended. Compression forces the proteoglycans together extruding water. On release of pressure the proteoglycans reabsorb water, regaining their previous arrangement. Mechanical injury to articular cartilage produces different responses depending on the nature of the injury and can be summarized as impactive blunt trauma, superficial lacerations (type I defects) and deep full thickness injuries penetrating the subchondral bone (type II defects).70'71 The effect of blunt non-penetrative injury depends on the intensity of loading. Reports of a surface loss of proteoglycan, cellular degeneration, fibrillation and penetration of the subchondral capillaries into the calcified layer of cartilage have been documented.72'73 These changes are thought to be consistent widi those seen in osteoarthritis. Superficial lacerations (type I) confined to the cartilage alone, do not involve injury to blood vessels. The response therefore lacks the inflammatory and repair components seen normally in the healing response. These have been studied by producing partial thickness defects in rabbit articular cartilage.74'75 Following such injury necrosis occurs at the wound margins together with signs of increased metabolic activity. Other investigations have shown increased glycosaminoglycan and protein synthesis.75"77 These changes are short lived and return to uninjured levels within I to 2 weeks. This response does not result in repair of the defect and the lacerations persist unaltered. Full thickness (type II) injuries penetrate the subchondral bone and its blood vessels which elicits an inflammatory response. Type II injuries have been studied by producing full thickness defects in the articular cartilage of mature rabbits.78 The initial response is the formation of a fibrin clot. Within 1 week fibroblasts and collagen fibres have replaced this clot and within 1 month the
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fibroblasts have undergone metaplasia to a chondrocytic phenotype and are surrounded by high concentrations of proteoglycan. The synthesis of type I collagen is initially high but then type II collagen predominates. At 6 months, defects are present on the surface of the cartilage and there is a loss of proteoglycan in the repair tissue. Within a year the majority of the defects initially repaired have degenerated into erosive lesions resembling early osteoarthritis. The response to such full thickness defects has been well documented.70-71-79-80 The basis of degeneration of the full thickness injuries has been the subject of speculation. One suggestion is that the tissue undergoing repair is significantly different to articular cartilage with regard to its collagen and proteoglycan content.81 At 6 months, the repair tissue contains 33% type I collagen compared to uninjured tissue where type I comprises 1 %. Connective tissues which synthesize type I collagen usually contain dermatan sulphate proteoglycans, unlike the chondroitin and keratin sulphate proteoglycans of articular cartilage. The dermatan sulphate proteoglycan is much smaller and has feeble elastic properties. It has been suggested that substitution with dermatan sulphate contributes to the decreased capacity of the repairing cartilage to resist wear and ultimately leads to its degeneration. SUMMARY The repair of connective tissue injury takes place, in the majority of instances, through 3 well defined processes; inflammation, granulation and resolution. Failure of any of these processes may result in inadequate or ineffectual repair leading to either chronic pathological changes in the tissue or to repeated structural failure. The conditions which occur at specific anatomical sites may affect these processes and the efficiency with which connective tissue repair is effected (e.g. the rotator cuff) may be moderated by factors such as a reduced or impaired blood supply. Cartilage is, by its nature, avascular and this may be reflected in its limited powers of repair and the tendency towards calcification which it shows following injury. It should be noted, however, that the majority of models involve either a sudden disruption or a clean incision of the tissue followed by immediate repair. In vivo it is much more common to have insult or injury to the tissue occurring over a period of time with other factors contributing to both the injury and to any impairment
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of the repair process. Thus better models may be required to accurately examine the processes involved in connective tissue repair. REFERENCES 1 Ward PA, Marks RM. The acute inflammatory reaction. Curr Opinion Immunol 1989; 2: 5-9 2 Roos D, Dolman KM. Neutrophil involvement in inflammatory tissue damage. Neth J Med 1990; 36: 89-94 3 Keshsavs S, Chung L, Gordon S. Macrophage products in Inflammation. Diag Microbiol Infect Dis 1990; 13: 439^147 4 Prober JS, Cotran RS. The role of endothelial cells in inflammation. Transplantation 1990; 50: 537-554 5 Knighton DR, Fiegel VD. Regulation of cutaneous wound healing by growth factors and the microenvironment. Invest Radiol 1991; 26: 604-611 6 McGrath MH. Peptide growth factors and wound healing. Clin Plast Surg 1990; 17: 421^32 7 Wahl SM, Wong H, McCartney-Francis N. Role of growth factors in inflammation and repair. J Cell Biochem 1989; 40: 193-199 8 Clark RAF. Cutaneous Wound Repair. In: Goldsmith LE (ed) Biochemistry and Physiology of the Skin. Oxford: Oxford University Press, 1990 9 Herring SA, Nilson KL. Introduction to overuse injuries. Clin Sports Med 1987; 6: 225-239 10 O'Neil DB, Micheli LJ. Overuse injuries in the young athlete. Clin Sports Med 1988; 7: 591-610 11 Pitner MA. Hand injuries in sport and the performing arts. Hand Clin 1990; 6: 335-364 12 Renstrom P, Johnson RJ. Overuse injuries in sport—A review. Sports Med 1985; 2: 316-333 13 Hess GP, Cappiello WL, Poole RM, Hunter SC. Prevention and treatment of overuse tendon injuries. Sports Med 1989; 8: 371-384 14 Jiminez SA, Yankowski R, Bashley RI. Identification of two new collagen alpha chains in extracts of lathrytic chick embryo tendons. Biochem Biophys Res Commun 1978; 81: 1298-1306 15 Rowe RWD. The structure of rat tail tendon. Connect Tiss Res 1985; 14: 9-20 16 Lindsay WK, Thomson HG. Digital flexor tendons: an experimental study. Br J Plast Surg 1980; 12: 289-316 17 Peacock EE. Fundamental aspects of wound healing relating to the restoration of gliding function after tendon repair. Surg Gynaecol Obstet 1964; 119: 241-250 18 Potenza AD. Tendon healing within the digital flexor sheath in the dog. J Bone Joint Surg 1962; 44A: 49-64 19 Lunborg G, Rank F. Experimental intrinsic healing of flexor tendons based on synovial fluid nutrition. J Hand Surg 1978; 3: 21-31 20 Manske PR, Lasker PA. Histologic evidence of intrinsic flexor tendon repair in various experimental animals—an in vitro study. Clin Orthop 1984; 182: 297-304 21 Chard M, Wright JK, Hazlcman B. Isolation and growth characteristics of adult human tendon fibroblasts. Ann Rhuem Dis 1987; 46: 385-390 22 Potenza AD. Tendon and ligament healing. In: Owen R Goodfellow J Bullough P (eds) Scientific Foundation of Orthopedics and Traumatology. London: William Heinmann, 1990: pp. 300-305
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48 Jenkins RR. Free radical chemistry. Sport Med. 1988; 5: 156-170 49 Duan C, Delp D, Hayes DA, et al. Rat skeletal mitochondxial calcium and injury from downhill walking. J Appl Physiol 1990; 68: 1241-1251 50 Mubarak S, Hargens AR. Compartment Syndromes and Volkman's Contracture 1981 Philadelphia: Saunders, 198 Ifpp. 106-118 51 O'Donoghue DH, Rockwood CA, Frank GR, et al. Repair of the anterior cruciate ligament in dogs. J Bone and Joint Surg. 1966; 48A: 503-519 52 Amiel D, Billings E, Akeson WH. Ligament structure, chemistry and physiology. In: D Daniel et al, cds. Knee Ligaments: Structure, Function, Injury and Repair. New York: Raven Press, 1990; pp. 77-90 53 Amiel D, Abel MF, Kleiner JB et al. Synovial fluid nutrient delivery in the diathrial joint: An analysis of rabbit knee ligaments. J Orthop Res 1986; 4: 90-95 54 Aim A, Stromberg B. Vascular anatomy of the patellar and cruciate ligaments. Acta Chir Scand [Suppl] 1974; 445: 25 55 Frank C, Schachar N, Dittrich D. Natural history of healing in the repaired medial collateral ligament. J Orthop Res 1983: 1: 179-188 56 Jack EA. Experimental rupture of the medial collateral ligament of the knee. J Bone Joint Surg 1950; 32A: 396-402 57 Laws G, Walton M. Fibroblastic healing of grade II ligament injuries. J Bone Joint Surg 1988; 70B: 390-396 58 Chimich D, Frank C, Shrive N, et al. The effects of initial end contact on medial collateral ligament healing: a morphological and biomechanical study in a rabbit model. J Orthop Res 1991; 9: 37^47 59 Woo SL-Y, Inoue M, McGurk-Burleson E. Treatment of the medial collateral ligament injury. 2 Structure and function of canine knees in response to differing treatment regimens. Sports Med 1987; 15: 22-29 60 Woo SL-Y, Horibe S, Ohland KJ, et al. The response of ligaments to injury. Healing of the collateral ligaments. In: D Daniel, et al. cds. Knee Ligaments: Structure, Function, Injury and Repair. New York: Raven Press, 1990; pp.351-364 61 Goldstein WM, Barmada R. Early mobilization of rabbit medial collateral ligament repairs: biomechanic and histologic study. Arch Phys Med Rehabil 1984; 65: 239-242 62 Fronek J, Frank C, Amiel D, ct al. The effect of intermittent passive motion (IPM) in the healing of the medial collateral ligament. Trans Orthop Res Soc 1983; 8: 31 63 Vailas AC, Tipton CM, Matthes RD et al. Physical activity and its influence on the repair process of the medial collateral ligaments. Connect Tissue Res 1981; 9: 25-31 64 Arnoczsky SP, Rubin RM, Marshall JL. Microvasculature of the cruciate ligaments and its response to injury. An experimental study in dogs. J Bone Joint Surg 1979; 61 A: 1221-1229 65 Amiel D, Kleiner JB. Biochemistry of tendon and ligament. In: Nimni M, Olson B, eds. Collagen vol III Biotechnology. Cleveland: CRC Press, 1988: pp.223-251 66 Hefti FL, Kress A, Fasel J, et al. Healing of the transected anterior cruciate ligament in the rabbit. J Bone Joint Surg 1991; 73-A: 373-383 67 Akeson WH. The response of ligaments to stress modulation and overview of the ligament healing response. In: D Daniel et al. eds. Knee Ligaments: Structure, Function, Injury and Repair. New York: Raven Press, 1990: pp. 315-327 68 Andrish J, Holmes R. Effects of synovial fluid on fibroblasts in tissue culture. Clin Orthop 1979; 138: 279-283 69 Amiel D, Kiuper S, Akeson WH. Cruciate ligaments. Response to Injury. In:
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