Bnlisk Midical BulUlm (1992) Vol. 48, No. 3, pp.

698-711
© The Bririjh Council 1992

Pathophysiology of soft
tissue repair

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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 musculo-
tendinous 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
 PATHOPHYSIOLOGY OF SOFT TISSUE REPAIR 699

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.

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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 com-
monly 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 parat-
enon 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 indi-
cated that granulation tissue resulted only from migration of cells
from peritendinous tissue. 1718 More recently it has been demon-
strated using rabbit flexor tendon, which had been repaired and
transplanted back into the synovium of the knee joint, that tendon
700 SPORTS MEDICINE

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

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inflammation, 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 and
granulation tissue formation begins. All structures surrounding
the tendon—synovial sheath, subcutaneous tissue, fascia and peri-
osteum 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 granu-
lation 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 stimula-
tion. 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
 PATHOPHYSIOLOGY OF SOFT TISSUE REPAIR 701

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, corticos-
teroid therapy, age and systemic disease.29

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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 anatom-
ical site, e.g. medical epicondylitis and bicipital tendinitis. Both
intrinsic factors (such as malalignment and limb length discrep-
ancies) 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 microvascul-
ature can further impair metabolic activity of the tissue. n ~ 1 3 The
impairment of the vascular supply is important in tendinitis, par-
ticularly 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
702 SPORTS MEDICINE

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 corre-
lation between muscle function and fibre composition—muscles

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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, exer-
cise 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 hae-
matoma formation and fibre disruption. The presence of large
amounts of oedema and the infiltration of the site with mononu-
clear 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 exper-
imental contusion injuries compared with strains.39 The authors
also noted a delay in tissue repair after muscle contusion, particu-
larly the temporal sequence of the synthesis of extracellular matrix
components such as sulphated chondroitin proteoglycans. How-
ever, the degree of initial injury may be different in these models
and in fact different muscles were compared between studies.
 PATHOPHYSIOLOGY OF SOFT TISSUE REPAIR 703

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 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 be
compromised by calcification or ossification of repairing muscle

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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 con-
tribute 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 inter-
stitial pressure that usually results from haemorrhage, oedema or
intense muscular activity itself and causes transient rises in intra-
compartmental pressure. With increasing pressure capillary per-
fusion 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-
704 SPORTS MEDICINE

tal investigations of ligament healing have been carried out on the

collateral and cruciate ligaments of the knee which show substan-
tial 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 how-
ever, show the standard healing response.

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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 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 cruci-
ate 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 pro-
gresses by inflammation, repair and remodelling. Following a mid-
substance tear of the medial collateral ligament, a haematoma
forms and inflammatory cells then proliferate from the surround-
ing 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 investi-
gated 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
 PATHOPHYSIOLOGY OF SOFT TISSUE REPAIR 705

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

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was observed at 10 weeks. Complete transection resulted in liga-
ment 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 tran-
section 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 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 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 for-
mation 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 liga-
ments 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 sup-
ply 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 break-
down 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
706 SPORTS MEDICINE

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

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II 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 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 sum-
marized as impactive blunt trauma, superficial lacerations (type I
defects) and deep full thickness injuries penetrating the subchond-
ral 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 pene-
tration 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 par-
tial 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
 PATHOPHYSIOLOGY OF SOFT TISSUE REPAIR 707

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 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

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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 under-
going 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 unin-
jured tissue where type I comprises 1 %. Connective tissues which
synthesize type I collagen usually contain dermatan sulphate pro-
teoglycans, unlike the chondroitin and keratin sulphate proteogly-
cans of articular cartilage. The dermatan sulphate proteoglycan is
much smaller and has feeble elastic properties. It has been sug-
gested 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
708 SPORTS MEDICINE

of the repair process. Thus better models may be required to

accurately examine the processes involved in connective tissue
repair.

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