pathophysiology of soft tissue repair

Bnlisk Midical BulUlm (1992) Vol. 48, No. 3, pp. 698-711© The Bririjh Council 1992

Pathophysiology of softtissue repair

Y BarlowJ WilloughbySmith and Nephew Research Ltd, Giliton Park, Harlow, Essex, UK

Inflammation with subsequent migration of leucocytes andconnective tissue cells to the site of damage, together withthe release of cytokines by these cells are essential forhealing in common sports injuries. Injury to the musculo-tendinous unit resulting from either blunt trauma, tears orlaceration, heal primarily by formation of granulation tissueand scarring. Early diagnosis with appropriate therapy mayminimize any potential loss of function. Ligament repairalso follows a classical healing response, although thequality of healing is site dependent and may be related toexposure to synovial fluid. In contrast, cartilage, which isavascular, lacks the inflammatory response seen in otherconnective tissues and this frequently results in poor tissuerepair with subsequent degeneration of the injuredcartilage. Mechanisms of repair in these tissues aredescribed.

Most types of soft tissue injury involve damage to the structuralelements of the tissue and result in the rupture of capillaries,arterioles and venules which initiates the healing response. Ingeneral, healing, regardless of site of injury, comprises three mainphases of repair—inflammation, nbro-proliferation and theremodelling of connective tissue. Acute inflammation involves awell regulated series of cellular and humoral mechanisms/thatproduce an increase in vascular permeability and the accumulationof leucocytes, mainly neutrophils and macrophages, in theinflammatory focus which begin the process of decontaminationand debridement of the wound.1"4

After 24-72 h, migration of fibroblasts and endothelial cellsoccurs in response to chemotactic factors, such as fibronectin and

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fibrin in the clot and from factors released by other cell types atthe wound site.5"7 Fibroblasts proliferate and synthesi2e abundantextracellular matrix mainly in the form of type III collagen whichis progressively remodelled to type I collagen and cross-linked togive greater tensile strength.8 Wound healing relating to specifictissues and types of injury will be discussed.

Sports injuries can be divided into two categories—acute andoveruse injuries. Acute injuries include lacerations, contusions andpartial or complete rupture of connective tissues. Overuse injuriesresult from repetitive stresses associated with prolonged activities.At least 50% of sporting injuries are due to overuse,9"12 duringwhich repeated microtrauma, as a result of any of several types offorce, exceed the adaptive ability of the tissue, and injury andinitiation of the repair process occurs.13 The tissue most com-monly affected by overuse is the musculo-tendinous unit.

TENDON

Muscle and tendon, although distinct tissues, functionally act asa single unit in which muscle is attached to bone by the tendon.Tendons consist predominantly of type I collagen, approximately5% of type III and type V collagen,14 with smaller amounts ofelastin embedded in proteoglycan.15 Similar to ligament, tendonis composed of dense bundles of collagen fibrils oriented parallelto the long axis of the tendon. Fibroblasts (or tenocytes) arearranged in long parallel rows in the spaces between the collagenbundles. Several tendon bundles form the tendon fascicle, whichis surrounded by the endotenon and a number of fascicles aresurrounded by the epitenon to form the basic tendon unit. Aroundthis a loose connective tissue—the paratenon—functions as anelastic sleeve allowing free movement of the tendon against othertissues. Where the tendon passes over zones of friction, the parat-enon is replaced by a true bi-layered tendon sheath lined withsynovial cells, e.g. digital flexor tendons.

Historically opinion was divided as to the cellular events intendon healing. Early studies showed that cellular repair wasmediated by the tenocytes within the tendon migrating from thecut tendon ends, i.e. intrinsic repair,16 while other studies indi-cated that granulation tissue resulted only from migration of cellsfrom peritendinous tissue.1718 More recently it has been demon-strated using rabbit flexor tendon, which had been repaired andtransplanted 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 studieshave also confirmed that tenocytes will proliferate in cell and organculture.20-21 These two controversial concepts of tendon repairare not mutually exclusive and the type of healing which occursdepends on local factors and on the nature and extent of theinjuries.

In acute injury, tendon, like other connective tissue, heals byinflammation, granulation tissue formation and scarring.1718'22

Inflammatory cells migrate to the site of injury from the peritend-inous structures and from the epi- and endotenon. After approxi-mately 3 days, the inflammatory phase gradually resolves andgranulation tissue formation begins. All structures surroundingthe tendon—synovial sheath, subcutaneous tissue, fascia and peri-osteum of bone—provide a fibroblastic and vascular componentfor healing. These cells readily migrate into the defect in thetendon and tenocytes within the tendon also proliferate, althoughtheir contribution to the granulation tissue is less than the responsefrom the sheath and the surrounding tissue. Collagen synthesisbegins within the first week of injury and increases during thefirst month post wounding. Capillaries also migrate into the granu-lation tissue to restore the blood flow and the synovial layer of thesheath is gradually restored. During the remodelling phase (1-2months post wounding), the strength of the tendon increases asthe collagen synthesis changes from predominantly type III totype I collagen and the fibres are stabilized by cross-linking. Inclean experimental wounds, functional re-alignment of collagen isusually complete after 2 months. This scar tissue never achievesthe strength of the original tendon. However, the remodellingphase can be influenced by load bearing and mechanical stimula-tion. Complete immobilisation of the tendon results in a reductionin glycosaminoglycan content and in the strength of the tendon.23

Very early weight bearing can result in rupture of the repairedtendon, but judicious use of controlled passive motion appears toenhance tensile strength and improve the quality of repair.24'25

Controlled passive motion is also believed to improve the nutritionof sheathed tendons by forcing synovial fluid into the tendon.Some studies even suggest that the rate of uptake of the nutrientsvia the synovial route is more rapid than from the vasculature.26'27

These data support the preservation of the sheath where possibleand early mobilization. It has been argued that poor nutrition ofthe tendon may contribute to rupture and poor healing.27 Forexample, in the Achilles tendon, both proximal muscle and distal

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insertion are well supplied with vasculature but in the area ofdepressed vascularity between these regions, rupture of the tendonhas been reported to occur most frequently.28 Whilst a numberof arguments support the nutritional theory, other aetiologicalfactors may also be of importance in tendon injury and include:impaired proprioceptive/mechano-receptor function, corticos-teroid therapy, age and systemic disease.29

Injuries to tendon as a result of sustained athletic activity arecommon.9"13 There is no uniform procedure for classifying theseinjuries and for simplification these are usually based on anatom-ical site, e.g. medical epicondylitis and bicipital tendinitis. Bothintrinsic factors (such as malalignment and limb length discrep-ancies) and extrinsic factors (such as training errors12) contributeto overuse injuries. In overuse, when the reparative capacity ofthe tissue is exceeded, cellular metabolism is altered, damage atthe cellular level occurs and subsequent injury to the microvascul-ature can further impair metabolic activity of the tissue. n~1 3 Theimpairment of the vascular supply is important in tendinitis, par-ticularly rotator cuff injuries and Achilles tendinitis.30 Overuseleads to oedema and inflammation and tissue repair follows theclassical pattern, however, in sheathed tendons, the inflammatoryprocess may affect the synovium rather than the tendon itself.Treatment modalities for overuse (rest, ice, heat, ultrasound,phonophoresis) and surgical techniques for rupture have beenextensively reviewed.10>12p29'31

MUSCLE

Skeletal muscle is composed of long cylindrical syncitial cellssurrounded by an endomysium, which constitutes the musclefibres.32 Lying in close apposition to the muscle fibres are satellitecells. These are muscle stem cells which can differentiate intomyoblasts, form myotubes and new muscle fibres, although theircapacity for regeneration is limited. Parallel muscle fibres aregrouped into fascicles enclosed in the perimysium and the entiremuscle is surrounded by another connective tissue layer—theepimysium. These connective tissue layers carry the blood supplyto the tissue and ramify to form a rich capillary network aroundthe muscle fibres. The connective tissue is continuous within themuscle and attaches to the tendon of insertion. Within the musclefibres 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 contractionrate and are less resistant to fatigue than the type I fibres whichrely largely on aerobic metabolism and are more fatigue resistant.Human muscle is a mixture of type I and type II fibres andalthough there is variability in the relative percentages of eachtype between individuals, within an individual there is a corre-lation between muscle function and fibre composition—musclesinvolved in rapid activities having a greater percentage of type IIfibres.

Muscle injuries fall into a number of categories—muscle straininvolving complete or partial tears, lacerations, contusions, exer-cise induced soreness and compartment syndrome. Muscles witha greater percentage of type II fibres, those which cross two jointsand those working eccentrically are much more susceptible tostrain injuries and injury occurs most commonly at or near themyotendinous junction.34"36 Histological examination of musclesimmediately following strain injuries in animals35"37 indicate hae-matoma formation and fibre disruption. The presence of largeamounts of oedema and the infiltration of the site with mononu-clear cells was evident at 24-48 hours after injury with typicalfibre necrosis. Interestingly, Stauber and his colleagues37 notedthat macrophage infiltration into muscle injured by straining wasless than into other types of muscle injury and may be related tothe degree of bleeding in the two types of injury. They alsodemonstrated histologically the presence of myoblasts as early as12 h after injury, which, between 24 and 72 hours had orientedthemselves along the longitudinal axis of the broken ends of thefibres. Occasionally myotubes were seen but these were difficultto identify. By 5-7 days post injury fibroblast proliferation wasevident and local fibrosis and scarring resulted. A similar patternof repair is found in partial and complete rupture of muscle. Densescar tissue formation is frequently the outcome in such woundsand can result in denervation of the affected area with subsequentreduction in the ability of that muscle to produce tension.38

Again, although repair mechanisms are essentially similar, theextent and duration of inflammation is reportedly longer in exper-imental contusion injuries compared with strains.39 The authorsalso noted a delay in tissue repair after muscle contusion, particu-larly the temporal sequence of the synthesis of extracellular matrixcomponents such as sulphated chondroitin proteoglycans. How-ever, the degree of initial injury may be different in these modelsand in fact different muscles were compared between studies.

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Other factors can also influence the rate of muscle repair. Inexperimental models4041 early mobilization of crush injuriesresulted in earlier healing, more rapid vascularisation, better orien-tation 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 becompromised by calcification or ossification of repairing muscletissue, i.e. myositis ossificans.43

Exercise induced soreness is typified by pain 24—48 hours afterexercise, particularly if the exercise was of unaccustomed durationor intensity.44 Histologically, disruption of the banding pattern inmuscles and dissolution of the myofibrillar structure was observedin exercised rats, but unlike the gross tissue disruption that occurswith muscle rupture and laceration, these injuries occur at thecellular and subcellular levels.45 Clinically elevated levels ofplasma enzymes (creatinine kinase, lactate dehydrogenase),hydroxyproline and myoglobin from injured muscles have beenobserved.44i46>47 Both mechanical and metabolic factors may con-tribute to the muscle damage. High specific tension created inmuscle may mechanically disrupt the sarcolemma, sarcoplasmicreticulum and myofilaments, whilst metabolic damage to the cellsmay be due to high local temperatures produced in muscle duringexercise, lactate production, free oxygen radical production orinsufficient respiration in the mitochondria.444748 It has beenpostulated that common to all these mechanisms of damage is thedisruption of calcium homeostasis.44'49 The events involved in theinitial phases of healing, before inflammation and repair (whichusually results in the regeneration of the myofibres) are not yetfully elucidated.

Compartment syndrome is characterised by increased inter-stitial pressure that usually results from haemorrhage, oedema orintense muscular activity itself and causes transient rises in intra-compartmental pressure. With increasing pressure capillary per-fusion is compromised, injury to nerves occurs and ischaemiaensues.50 Damage to the muscle tissue is related to the pressureat which capillary perfusion is prevented and will determinewhether surgical intervention is necessary.

LIGAMENT

Ligaments are short bands of connective tissue binding bones tobones and providing internal support for organs. Most experimen-

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tal investigations of ligament healing have been carried out on thecollateral and cruciate ligaments of the knee which show substan-tial differences in their repair processes. Healing of the anteriorcruciate ligament is poor and, without surgical repair, it willregress or disappear completely.51 The collateral ligaments how-ever, show the standard healing response.

Ligaments are made up of tightly packed collagen bundles inter-spersed with fibroblasts. The collagen is 90% type I and 10%type III.52 They also contain a small percentage of glycosaminog-lycan which, with water, provides the lubrication and spacingcrucial to the gliding function of the ligaments. Ultrastructuraldifferences may be shown between the anterior cruciate ligamentand the medial collateral ligament. The cells of the anterior cruci-ate ligament are arranged in columns and are rounded, resemblingcells of fibrocartilage. The medial collateral ligament, by contrast,is populated by spindle shaped cells resting directly on a collagenmatrix.52 Further differences between the two ligaments may beseen in their blood supply. The medial collateral ligament derivesits blood supply from the inferior medial geniculate artery, inaddition synovial fluid has been shown to make a nutritionalcontribution.53 The blood supply to the anterior cruciate ligamentfrom the median geniculate artery is poor,54 and it has beensuggested that it derives its primary nutrition from synovialfluid.53

Most of the studies of ligament repair have been based uponanimal models where the ligament has been partially or completelytransected. Again healing of the medial collateral ligament pro-gresses by inflammation, repair and remodelling. Following a mid-substance tear of the medial collateral ligament, a haematomaforms and inflammatory cells then proliferate from the surround-ing tissue. After 2 weeks, immature collagen fibres are present andfibroblasts dominate the central scar region.55"57 At 6 weeks thefibroblasts begin to regress. The collagen fibres then increase insize and strength and align themselves longitudinally. Theresulting scar tissue increases in strength but even after 1 yearmay not achieve the strength of uninjured tissue. Injuries wherethe ligament is intact but severely weakened have also been investi-gated using the sheep medial collateral ligament. Histologyrevealed healing mainly by fibroblasts with no evidence of aninflammatory response. Several other factors may affect healing ofthe collateral ligaments including repair versus no repair,38"60 and

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mobilization versus immobility.61"63 These approaches are subjectto considerable controversy as to their beneficial effects.

The first demonstration of the poor healing capacity of theanterior cruciate ligament was demonstrated in dogs.51 Partialtransection resulted in necrosis followed by inflammation andearly fibroblast proliferation. Little healing at the base of the lesionwas observed at 10 weeks. Complete transection resulted in liga-ment retraction and absorption. Complete transection plus repairresulted in collagen deposition, but, up to 1 year, the ligamentnever achieved a normal appearance. This model involved tran-section of the ligament at the tibial insertion sites involving acertain amount of bone healing. Other models involved partiallaceration of the anterio-medial portion where vascular prolifer-ation of the area of injury was noted, but no bridging of the gap.64

Partial laceration of the posterio-lateral portion of the cruciateligament with and without repair has also been investigated but 6weeks post injury there was no evidence of healing.65 A morefavourable repair response was shown following the partial orcomplete transection of the anterior cruciate ligament in rabbits.66

As expected, there was no regeneration after complete transection.However, following partial transection, an inflammatory responsewas observed followed by proliferation of fibroblasts and the for-mation of collagen fibres. At one year the defect was still visible,and partially filled with tissue that resembled ligament but with ahigher density of cells.

Why the anterior cruciate ligament and medial collateral liga-ments should show such different healing capacities is the subjectof considerable speculation. Both ligaments are ultrastructurallydistinct, the anterior cruciate ligament receives a poor blood sup-ply and is surrounded by a thin layer of synovial tissue, whereasthe medial collateral ligament is sheathed by connective tissue.The physiology of the anterior cruciate ligament results in it beingexposed to the so-called 'hostile environment' of synovial fluidwhich, following injury is known to contain haemorrhagic break-down products and a variety of proteolytic enzymes.67 Synovialfluid has also been shown to adversely affect anterior cruciateligament fibroblast proliferation in culture.68 Finally, in theanterior cruciate ligament synovial fluid washes away the clot fromthe site of injury, and this removal of the clot may deplete growthfactors and other clot derived substances necessary for stimulatingthe healing response.69

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ARTICULAR CARTILAGE

Articular cartilage provides a firm elastic surface for the smoothgliding of joints. The mechanical properties which enable it toabsorb impact, yet resist wear, result from the structure of theextracellular matrix. Articular cartilage is an avascular tissuemainly composed of chondrocytes embedded in a matrix of typeII collagen, proteoglycans and non-collagenous protein. The pro-teoglycans are huge aggregates with a molecular weight of approxi-mately 200 million Daltons embedded and constrained in a densenetwork of collagen fibres. The proteoglycans are negativelycharged and repel each other, keeping their structure extended.Compression forces the proteoglycans together extruding water.On release of pressure the proteoglycans reabsorb water, regainingtheir previous arrangement.

Mechanical injury to articular cartilage produces differentresponses depending on the nature of the injury and can be sum-marized as impactive blunt trauma, superficial lacerations (type Idefects) and deep full thickness injuries penetrating the subchond-ral bone (type II defects).70'71 The effect of blunt non-penetrativeinjury depends on the intensity of loading. Reports of a surfaceloss of proteoglycan, cellular degeneration, fibrillation and pene-tration of the subchondral capillaries into the calcified layer ofcartilage have been documented.72'73 These changes are thoughtto 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 thereforelacks the inflammatory and repair components seen normally inthe healing response. These have been studied by producing par-tial thickness defects in rabbit articular cartilage.74'75 Followingsuch injury necrosis occurs at the wound margins together withsigns of increased metabolic activity. Other investigations haveshown increased glycosaminoglycan and protein synthesis.75"77

These changes are short lived and return to uninjured levels withinI to 2 weeks. This response does not result in repair of the defectand the lacerations persist unaltered.

Full thickness (type II) injuries penetrate the subchondral boneand its blood vessels which elicits an inflammatory response. TypeII injuries have been studied by producing full thickness defectsin the articular cartilage of mature rabbits.78 The initial responseis the formation of a fibrin clot. Within 1 week fibroblasts andcollagen fibres have replaced this clot and within 1 month the

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fibroblasts have undergone metaplasia to a chondrocytic pheno-type and are surrounded by high concentrations of proteoglycan.The synthesis of type I collagen is initially high but then type IIcollagen predominates. At 6 months, defects are present on thesurface of the cartilage and there is a loss of proteoglycan in therepair tissue. Within a year the majority of the defects initiallyrepaired have degenerated into erosive lesions resembling earlyosteoarthritis. The response to such full thickness defects has beenwell documented.70-71-79-80

The basis of degeneration of the full thickness injuries has beenthe subject of speculation. One suggestion is that the tissue under-going repair is significantly different to articular cartilage withregard to its collagen and proteoglycan content.81 At 6 months,the repair tissue contains 33% type I collagen compared to unin-jured tissue where type I comprises 1 %. Connective tissues whichsynthesize type I collagen usually contain dermatan sulphate pro-teoglycans, unlike the chondroitin and keratin sulphate proteogly-cans of articular cartilage. The dermatan sulphate proteoglycan ismuch smaller and has feeble elastic properties. It has been sug-gested that substitution with dermatan sulphate contributes to thedecreased capacity of the repairing cartilage to resist wear andultimately leads to its degeneration.

SUMMARY

The repair of connective tissue injury takes place, in the majorityof instances, through 3 well defined processes; inflammation,granulation and resolution. Failure of any of these processes mayresult in inadequate or ineffectual repair leading to either chronicpathological changes in the tissue or to repeated structural failure.The conditions which occur at specific anatomical sites may affectthese processes and the efficiency with which connective tissuerepair is effected (e.g. the rotator cuff) may be moderated byfactors such as a reduced or impaired blood supply. Cartilage is,by its nature, avascular and this may be reflected in its limitedpowers of repair and the tendency towards calcification which itshows following injury.

It should be noted, however, that the majority of models involveeither a sudden disruption or a clean incision of the tissue followedby immediate repair. In vivo it is much more common to haveinsult or injury to the tissue occurring over a period of time withother factors contributing to both the injury and to any impairment

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of the repair process. Thus better models may be required toaccurately examine the processes involved in connective tissuerepair.

REFERENCES

1 Ward PA, Marks RM. The acute inflammatory reaction. Curr Opinion Immu-nol 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. DiagMicrobiol Infect Dis 1990; 13: 439^147

4 Prober JS, Cotran RS. The role of endothelial cells in inflammation. Transplan-tation 1990; 50: 537-554

5 Knighton DR, Fiegel VD. Regulation of cutaneous wound healing by growthfactors and the microenvironment. Invest Radiol 1991; 26: 604-611

6 McGrath MH. Peptide growth factors and wound healing. Clin Plast Surg1990; 17: 421^32

7 Wahl SM, Wong H, McCartney-Francis N. Role of growth factors in inflam-mation and repair. J Cell Biochem 1989; 40: 193-199

8 Clark RAF. Cutaneous Wound Repair. In: Goldsmith LE (ed) Biochemistryand Physiology of the Skin. Oxford: Oxford University Press, 1990

9 Herring SA, Nilson KL. Introduction to overuse injuries. Clin Sports Med1987; 6: 225-239

10 O'Neil DB, Micheli LJ. Overuse injuries in the young athlete. Clin SportsMed 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 Med1985; 2: 316-333

13 Hess GP, Cappiello WL, Poole RM, Hunter SC. Prevention and treatment ofoveruse tendon injuries. Sports Med 1989; 8: 371-384

14 Jiminez SA, Yankowski R, Bashley RI. Identification of two new collagen alphachains in extracts of lathrytic chick embryo tendons. Biochem Biophys ResCommun 1978; 81: 1298-1306

15 Rowe RWD. The structure of rat tail tendon. Connect Tiss Res 1985; 14: 9-2016 Lindsay WK, Thomson HG. Digital flexor tendons: an experimental study.

Br J Plast Surg 1980; 12: 289-31617 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 BoneJoint Surg 1962; 44A: 49-64

19 Lunborg G, Rank F. Experimental intrinsic healing of flexor tendons basedon synovial fluid nutrition. J Hand Surg 1978; 3: 21-31

20 Manske PR, Lasker PA. Histologic evidence of intrinsic flexor tendon repairin various experimental animals—an in vitro study. Clin Orthop 1984; 182:297-304

21 Chard M, Wright JK, Hazlcman B. Isolation and growth characteristics ofadult human tendon fibroblasts. Ann Rhuem Dis 1987; 46: 385-390

22 Potenza AD. Tendon and ligament healing. In: Owen R Goodfellow J BulloughP (eds) Scientific Foundation of Orthopedics and Traumatology. London:William Heinmann, 1990: pp. 300-305

at Manchester M


ctober 11, 2010bm


ownloaded from



23 Woo SL-Y, Gomez MA, Woo Y-K, ct al. Mechanical properties of tendonsand ligaments. Biorheology 1982; 19: 397-408

24 Lister GD, Kleinert HE, Kutz JE. Primary flexor tendon repair followingimmediate controlled mobilisation. J Hand Surg 1977; 14: 99-107

25 Strickland JW, Glogovac SV. Digital function following flexor tendon repairin Zone II: a comparison of immobilisation and controlled passive motiontechniques. J Hand Surg 1980; 5: 537-543

26 Weber ER. Nutritional pathways for flexor tendons in the digital theca. In:Hunter JM, Schneider LH, Maclrin EJ (eds). Tendon Surgery in the Hand.St Louis: CV Mosby, pp 91-99

27 Amadio PC, Hunter JM, Jaeger S. ct al. The effect of vincular injury on theresults of flexor tendon surgery in Zone 2. J Hand Surg 1985; 10: 626-632

28 Lagergron C, Lindholm A. Vascular distribution in the Achilles tendon. ActaChir Scand 1959; 116: 491-495

29 Hosey G, Kowalchick E, Tesoro D, et al. Comparisons of mechanical andhistologic properties of Achilles tendon in New Zealand White rabbits second-arily repaired with Marlex mesh. J Foot Surg 1991; 30: 214-233

30 Smart GW, Taunton JE, Clement DB. Achilles tendon disorders in runners—a review. Med Sci Sport Exerc 1980; 12: 231-243

31 Hunter SC, Poole RM. The chronically inflamed tendon. Clin Sport Med1987; 6: 371-388

32 Kaplan A, Carlson B, Faulkner J et al. Skeletal Muscle. In: Woo SL-Y,Buckwalter JA (eds). Injury and repair of. the musculo-skeletal soft tissues. AmAcad Orthop Surg 1988: pp 213-291

33 Garrett WE, Califf JC, Bassett FH. Histological correlates of Hamstring injur-ies. Am J Sport Med 1984; 12: 98-103

34 Nikalaou P, MacDonald BL, Glisson RR et al. The effect of architecture onanatomical failure site of skeletal muscle. Trans Orthop Res Soc 1986; 11:228-232

35 Garrett WE. Muscle strain injuries: Clinical and basic concepts. Med Sci SportExerc 1990; 22: 436-̂ 143

36 Almekinders LC, Garrett WE, Seaber AV. Histopathology of muscle tears instretching injuries 30th Ann Orthop Res Soc 1984

37 Stauber WT, Fritz VK, Vogelbach DW et al. Characterisation of musclesinjured by forced lengthening 1. Cellular infiltrates. Med Sci Sport Exerc 1988;20: 345-355

38 Jarvinen M, Aho AL, Lehto M, et al. Age dependent repair of muscle rupture.Acta Orthop Scand 1983; 54: 64-74

39 Stauber WT, Fritz VK, Dahlman B. Extracellular matrix changes followingblunt trauma to rat skeletal muscle. Exp Mol Pathol 1990; 52: 69-80

40 Kvist M, Jarvinen M. Clinical histochemical and biochemical features of repairof muscle and tendon injuries. Int J Sport Med 1982; 3: 12-14

41 Jarvinen M. Healing of crush injuries in rat striated muscle. Acta Path Micro-biol Scand (Section A) 1976; 84: 85-94

42 Sloper JC, Pergram GD. Regeneration of crushed mammalian skeletal muscleand the effect of steroids. J Pathol Bacteriol 1967; 93: 47-63

43 Jackson DW, Feagin JA. Quardriceps contusions in young athletes. J BoneJoint Surg 1973; 55A: 95

44 Armstrong RB. Initial events in exercise induced muscular injury. Med SciSport Exerc 1990; 22: 429-435

45 Armstrong RB, Ogilivie RW, Schwane JA. Eccentric exercise induced injuryto rat skeletal muscle J Appl Physiol 1983; 54: 80-93

46 Friden J, Sjostrom M, Ekblom B. Myofibrillar damage following intense exer-cise in man. Int J Sport Med 1983; 4: 170-176

47 Stauber WT. Eccentric action of muscles: physiology injury and adaptation.Exerc Sport Sci Rev 1989; 17: 157-185

at Manchester M


ctober 11, 2010bm


ownloaded from


710 SPORTS MEDICINE

48 Jenkins RR. Free radical chemistry. Sport Med. 1988; 5: 156-17049 Duan C, Delp D, Hayes DA, et al. Rat skeletal mitochondxial calcium and

injury from downhill walking. J Appl Physiol 1990; 68: 1241-125150 Mubarak S, Hargens AR. Compartment Syndromes and Volkman's Contrac-

ture 1981 Philadelphia: Saunders, 198 If pp. 106-11851 O'Donoghue DH, Rockwood CA, Frank GR, et al. Repair of the anterior

cruciate ligament in dogs. J Bone and Joint Surg. 1966; 48A: 503-51952 Amiel D, Billings E, Akeson WH. Ligament structure, chemistry and physi-

ology. In: D Daniel et al, cds. Knee Ligaments: Structure, Function, Injuryand Repair. New York: Raven Press, 1990; pp. 77-90

53 Amiel D, Abel MF, Kleiner JB et al. Synovial fluid nutrient delivery in thediathrial 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 repairedmedial 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 BoneJoint Surg 1988; 70B: 390-396

58 Chimich D, Frank C, Shrive N, et al. The effects of initial end contact onmedial collateral ligament healing: a morphological and biomechanical studyin a rabbit model. J Orthop Res 1991; 9: 37^47

59 Woo SL-Y, Inoue M, McGurk-Burleson E. Treatment of the medial collateralligament injury. 2 Structure and function of canine knees in response todiffering 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 collateralligament repairs: biomechanic and histologic study. Arch Phys Med Rehabil1984; 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 Soc1983; 8: 31

63 Vailas AC, Tipton CM, Matthes RD et al. Physical activity and its influenceon the repair process of the medial collateral ligaments. Connect Tissue Res1981; 9: 25-31

64 Arnoczsky SP, Rubin RM, Marshall JL. Microvasculature of the cruciateligaments and its response to injury. An experimental study in dogs. J BoneJoint 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 cruciateligament in the rabbit. J Bone Joint Surg 1991; 73-A: 373-383

67 Akeson WH. The response of ligaments to stress modulation and overview ofthe 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:

at Manchester M


ctober 11, 2010bm


ownloaded from



D Daniel et al. eds. Knee Ligaments: Structure, Function, Injury and Repair.New York: Raven Press, 1990: pp. 365-377

70 Lanzo A. Articular cartilage repair: A review. Einstein Q J Biol Med 1989; 7:131-138

71 Mankin A. Response of articular cartilage to mechanical injury. J Bone JointSurg 1982; 64A: 460-465

72 Radin EL, Ehrlich MG, Chemack IL, et al. Effect of repetitive impulse loadingon the knee joints of rabbits. Clin Orthop 1978; 131: 288-293

73 Dekel S, Weissman SL. Joint changes in overuse and peak overloading ofrabbit knees in vivo. Acta Orthop Scand 1978; 49: 519-528

74 Fuller J, Ghadially FN. Ultrastructural observations on surgically producedpartial thickness defects in articular cartilage. Clin Orthop 1972 86: 193-205

75 Ghadially FN, Thomas I, Oryschak AF, et al. Long term results of superficialdefects in articular cartilage. A scanning electron microscope study. J Pathol19 121: 213-217

76 DePalma AF, McKeever CD, Subin SK. Process of repair of articular cartilagedemonstrated by histology and autoradiography with tritiated thymidine. ClinOrthop 1966; 48: 229-242

77 Mankin HJ, Boyle CJ. The effects of lacerative injury on DNA and proteinsynthesis in articular cartilage. In: Bassett CAL, ed. Cartilage Degradation andRepair. Washington DC: National Research Council National Academy ofSciences—National Academy of Engineering, 1967: pp. 185-199

78 Rosenberg L. Chemical basis for the histological use of safranin O in the studyof articular cartilage. J Bone Joint Surg 1971; 53A: 69-82

79 Furukawa T, Eyre D, Koide, S, ct al. Biochemical studies on repair cartilageresurfacing experimental defects in the rabbit knee. J Bone Joint Surg 1980;62A: 79-89

80 Kubo T. Ultrastructural studies of healing process of injured articular cartilage.J Jpn Orthop Assoc 1983; 57: 167-185

81 Rosenberg L. Biological basis for the imperfect repair of articular cartilagefollowing injury. In: Hunt TK, Heppenstall RB, Pines E, et al. eds. Soft andHard Tissue Repair. Praeger Scientific 1984; pp. 143-169

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