ARTICLE IN PRESS

Journal of Biomechanics 37 (2004) 865–877

Biomechanics of tendon injury and repair

Tony W. Lin, Luis Cardenas, Louis J. Soslowsky*
McKay Orthopaedic Research Laboratory, University of Pennsylvania, 424 Stemmler Hall, 36th and Hamilton Walk, Philadelphia,
PA 19104-6081, USA
Accepted 6 November 2003

Abstract

Many clinical and experimental studies have investigated how tendons repair in response to an injury. This body of work has led
to a greater understanding of tendon healing mechanisms and subsequently to an improvement in their treatment. In this review
paper, characterization of normal and healing tendons is first covered. In addition, the debate between intrinsic and extrinsic healing
is examined, and the cellular and extracellular matrix response following a tendon injury is detailed. Next, clinical and experimental
injury and repair methods utilizing animal models are discussed. Animal models have been utilized to study the effect of various
activity levels, motions, injury methods, and injury locations on tendon injury and repair. Finally, current and future treatment
modalities for improving tendon healing, such as tissue engineering, cell therapy, and gene therapy, are reviewed.
r 2003 Elsevier Ltd. All rights reserved.

Keywords: Tendon; Tendon healing; Soft tissue injury; Soft tissue repair; Animal model

1. Introduction cepts to address this problem, from creating scaffolds

and constructs out of relevant biomaterials and cells to
Tendons are soft connective tissues consisting of applying cytokines exogenously to injured tissue, or
parallel collagen fibers embedded within an extracellular using gene and cell therapy. This paper provides an
matrix. This organized structure allows tendons to overview of these studies, which demonstrate that the
withstand and transmit large forces between muscle functional outcome of injured tendons is dependent
and bone. However, as tendons are subjected to upon many factors.
repeated motion and degeneration over time, they are
prone to both acute and chronic injuries. After injury,
the healing process in tendons results in the formation of
2. Normal tendon
a fibrotic scar. The structural, organizational, and
mechanical properties of this healed tissue are inferior
Tendons connect muscle to bone and form a
to normal tendon (Frank et al., 1992, 1983). Although
musculotendinous unit whose primary function is to
these properties improve over time, they do not return
transmit tensile loads generated by muscles to move and
to normal levels, even after long periods (Frank et al.,
stabilize joints. Under normal loads, it has been shown
1997). In an attempt to better understand tendon
that tendons maintain smooth physiological mechanics
healing mechanisms and to improve these inferior
throughout range of motion. While subjected to higher
properties, researchers have investigated a broad range
loads, tendons prevent joint displacement beyond
of factors believed to affect tendon injury and repair,
anatomical barriers, thus preventing injury and main-
such as activity level, motion after injury, various injury
taining normal function (O’Brien, 1992; Dykyj and
modalities, and different injury locations. In addition,
Jules, 1991). Within the tendon there exists a structural
many researchers have applied tissue engineering con-
hierarchy where tendons can be further subdivided into
fascicles, fibrils, subfibrils, microfibrils, and tropocolla-
*Corresponding author. Tel.: +1-215-898-8653; fax: +1-215-573- gen (Fig. 1). The composition of tendon contains
2133. relatively few cells with the predominant cell type being
E-mail address: soslowsk@mail.med.upenn.edu (L.J. Soslowsky). the rod or spindle-shaped fibroblasts. Tendons contain

0021-9290/$ - see front matter r 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jbiomech.2003.11.005
 ARTICLE IN PRESS
866 T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
Fig. 1. Tendon hierarchical structure. Detail A represents the
macromolecular organization of the extracellular matrix. Fibril
associated proteoglycans may be oriented such that their glycosami-
noglycan side chains extend into the extracellular space, perhaps
linking matrix constituents. (Derwin, K., 1998. A quantitative
investigation of structure-function relationships in a tendon fascicle
model. Ph.D. Thesis, University of Michigan, Ann Arbor; with
permission.)
86% collagen, 1–5% proteoglycan, and 2% elastin as
measured by dry weights, and water is responsible for
60–80% of the total wet weight of the tendon (Woo
et al., 2000a, b; Jozsa and Kannus, 1997). Tendons glide
over bone and often move through canals and sheaths
that help direct their path and limit the amount of
friction they must overcome. Tendon sheaths consist of
two layers, in between which contains synovial fluid that
improves lubrication. Tendons that lack this two layer
sheath are surrounded by a loose areolar connective
tissue called paratenon, which acts to provide a division
from and permit free motion of the tendon in relation to
the surrounding tissue (Jozsa and Kannus, 1997).
3. Tendon healing
When tendons are injured, the body initiates a process
of healing and scar formation that can be divided into
phases, which are briefly described below, are distin-
guishable by specific peaks in a cascade of cellular and
biochemical events. These phases overlap and their
duration can vary greatly due to location of injury or
disease (Gomez, 1995; Montgomery, 1989). Although
the tensile strength of the healing tendon improves over
time, it does not reach the levels of uninjured, normal
tissue (Fig. 2).
3.1. Hemostasis/inflammation
This phase of tendon healing occurs almost immedi-
ately after tendon injury. First, the injury to the
surrounding vascular vessels causes the formation of a
hematoma. Next, the resultant clot and hemostasis
activates a cascade of vasodilators and platelets, as well
as the release of pro-inflammatory chemicals from mast
cells. Inflammatory cells are attracted to the injury site
Fig. 2. Wound healing response in tendons. (Adapted from Gomez,
M., 1995. The physiology and biochemistry of soft tissue healing. In:
Griffin, L., (Eds.), Rehabilitation of the Injured Knee, 2nd Edition.
Mosby Company, St. Louis, MO, pp. 34-44; with permission.)
and aggressively engage in the phagocytosis of necrotic
tissue and debris and break down the blood clot.
Macrophages aid in the recruitment of new fibroblasts
and release of angiogenesis promoting factors to initiate
growth of capillary networks within the wound (Fen-
wick et al., 2002; Gelberman et al., 1992). During this
phase, there is an increase in DNA, fibronectin,
glycosaminoglycan, water, and collagen type III con-
tent, which collectively stabilizes the newly formed
extracellular matrix (Woo et al., 2000a, b; Jozsa and
Kannus, 1997; Gomez, 1995; Montgomery, 1989;
Grinnell, 1984).
3.2. Proliferation/fibroplasia
During this phase, a disorganized matrix of granula-
tion tissue is present at the injury site. Histologically, the
predominant cell types are fibroblasts along with a
smaller number of macrophages and mast cells. Electron
microscopy studies have shown an increase in the
endoplasmic reticulum of fibroblasts, which is indicative
of active matrix synthesis (Jozsa and Kannus, 1997), and
type III collagen and DNA concentrations reach their
peak amounts during the entire reparative process.
These changes are believed to help with the optimization
of collagen synthesis and the gradual conversion of type
III to type I collagen (Gomez, 1995; Woo and
Buckwalter, 1988).
3.3. Remodeling/maturation
Changes in the healing tissue can be seen with the
naked eye as the previous red scar now becomes pinkish
and translucent, forming a connection between the two
ends. Histologically, fibroblasts have decreased in size
and slowed their matrix synthesis, and collagen fibers
have begun to orient themselves longitudinally along the
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T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
long axis of the tendon. As the scar enters maturation
there is a notable return of type III to type I collagen
ratio, collagen crosslinks, and glycosaminoglycan,
water, and DNA concentrations. However, healed
tendon has been shown in many studies to take upwards
to a year to more closely approach the functional
strength of uninjured tissue (Buckwalter and Hunziker,
1996; Gomez, 1995; Woo and Buckwalter, 1988).
3.4. Intrinsic vs. extrinsic healing
The biology of tendon healing is dominated by two
theories, extrinsic and intrinsic healing. There has been
much debate in the literature and much experimental
evidence to prove or disprove each healing mechanism.
In extrinsic healing, it is believed that the tendon has no
internal ability to heal on its own and thus requires the
formation of adhesions, the infiltration of inflammatory
cells and fibroblasts, and an extratendinous blood
supply to heal properly (Potenza, 1969, 1964, 1963,
1962). In intrinsic healing, it is believed that the tendon
is healed by the proliferation of epitenon and endotenon
cells within the tendon, an intratendinous blood supply,
and the lack of adhesion formation (Mass and Tuel,
1991; Lundborg et al., 1985; Manske et al., 1984).
Although there are credible arguments for both extrinsic
and intrinsic healing, there is no clear evidence as to
which theory is correct. It is plausible that tendon
healing most likely occurs as a combination of both
processes and is dependent on tendon location, the
magnitude of tendon trauma, availability of synovial
fluid and a blood supply, and degree of tendon
mobilization. A better understanding of this balance
between processes may allow surgeons to eventually
tailor their surgical procedures to best reestablish
tendon continuity and function (Jaibaji, 2000; Manske,
1988; Lundborg et al., 1985; Manske et al., 1985).
3.5. Cellular and ECM response
As described earlier, the process of tendon repair is a
complex, orchestrated series of physiological events
involving significant synthesis, migration, and degrada-
tion of extracellular matrix (ECM) components (Liu
et al., 1995; Leadbetter, 1992; Doillon et al., 1985). After
trauma, the ECM degradation products are essential for
tendon healing because they provide chemotactic signals
for fibroblasts, leukocytes, and endothelial cells, and
serve as a reservoir for cytokines (Jaibaji, 2000). Despite
the similarity of having cells and extracellular matrix
proteins becoming more active in response to an injury,
tendons do exhibit a differential capacity to heal. This is
due to the intrinsic properties of the tendon and external
factors such as nutrition, location and environment
(Woo et al., 1999). Despite this differential healing
capacity, there still exists a poor healing environment
867
caused by local factors such as infection, disease, tissue
hypoxia due to vascular deficiencies, and malnutrition,
and external factors such as rigid fixation and prolonged
immobilization (Woo et al., 2000a, b). As a result, it is
often difficult to re-establish the continuity of collagen
fibers and restore the sliding surface of the tendon.
Failure to do either makes tendon healing a ‘‘double-
edged sword’’—while adhesions can contribute to
healing, excessive scarring can restrict tendon gliding,
but deficient scarring may lead to premature rupture at
the injury site. Therefore, a combination of many
factors must be simultaneously balanced in order to
achieve a functionally healed tendon.
4. Tendon injury and repair
Because tendons heal poorly, tendon injury and repair
mechanisms have been studied extensively in both the
clinical and experimental setting. Clinical examples of
different types of injury and widely used treatment
methods are discussed, followed by a review of both
in vitro and in vivo experimental models. As described
below, although clinical and experimental studies have
their own inherent advantages and disadvantages, they
both provide important information on tendon injury
and repair. The correct choice of study is dependent
upon the specific hypotheses it is intended to address.
4.1. Clinical injury/repair
Tendon injury can be classified by types of injury and
are generally considered to be acute or chronic and
either direct or indirect (Hyman and Rodeo, 2000).
Direct acute tendon injuries occur due to either
contusion, non-penetrating blunt injury from accidents
and sports injuries, or laceration by a sharp object.
Indirect, tendon injuries are often the result of acute
tensile overload and repetitive microtrauma as seen in
overuse injuries. Most commonly, tensile overload and
overuse result in injuries to either the musculotendinous
junction (sprains, strains and rupture), or to the
osteotendinous junction (avulsion fractures or bone
detachment). These types of injuries predominate over
mid-tendon ruptures because healthy tendon can with-
stand higher tensile loads than the muscle or most bone
junctions (Woo et al., 2000a, b; Hyman and Rodeo,
2000; Taylor et al., 1993; Silver et al., 1983).
There are a variety of different suture techniques used
clinically, each with their preferred suture material that
can be employed at the discretion of the surgeon. Some
of these techniques include Lin locking, Savage, Kessler,
Becker, modified Kessler, Tajima, and epitenon suture
method. It has been shown that the repair strength is
directly proportional to the number of strands crossing
a repair site (Fig. 3), ruptures usually occur at the knots
 ARTICLE IN PRESS
868 T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
Fig. 3. Comparison of ultimate force vs. time between eight and four-
strand suture techniques. The asterisks denote a significant difference
(po0:05). (Boyer, M.I., Gelberman, R.H., Burns, M.E., Dinopoulos,
H., Hofem, R., Silva, M.J., 2001. Intrasynovial flexor tendon repair.
An experimental study comparing low and high levels of in vivo force
during rehabilitation in canines. Journal of Bone and Joint Surgery—
American 83-A, 891–899; with permission.)
in the suture, and epitenon sutures increase repair
strength over core sutures alone. Gap strength was not
significantly greater among any of the techniques
examined (Woo et al., 2000a, b; Taras and Lamb,
1999; Wang, 1998; Silfverskiold and Andersson, 1993;
Woo and Buckwalter, 1988).
Timing of the repair can be categorized as primary,
delayed primary, secondary and late secondary. A
primary repair is done within 12 h of injury, while
delayed primary is within 14 days. Secondary is
classified as between 2 and 4 weeks with late secondary
after that period (Wright, 1999). Whenever feasible,
tendon repair should be done as early as possible.
Clinically, ultrasound, electrical stimulation and inject-
able growth factors have been used or postulated to
hasten tendon repair (Woo et al., 2000a, b). Post-
operatively, the surgeon faces the problem of when to
introduce active vs. passive motion and remobilization/
immobilization. The dilemma becomes restoring normal
strength and range of motion while minimizing adhe-
sions and protecting the healing tendon from rupture
and gapping at the tendon repair site.
4.2. Experimental injury/repair—cell culture (in vitro)
Experimental in vitro studies allow researchers to
study the effect of a single isolated factor. In vitro
experiments are inexpensive and often serve as pre-
cursors for more complicated and expensive animal
models, which are simulated in vitro using different cell
culture environments. In the case of tendon injury and
repair, some examples of in vitro models have cultured
flexor tendon cells (Wiig et al., 1997; Mass and Tuel,
1989) and tested the strength of flexor tendon repair
(Noguchi et al., 1993; Savage, 1985). In addition, many
in vitro studies have focused on the effect of applying
cyclic loads to tendons (Archambault et al., 2002;
Ditsios et al., 2002; Schechtman and Bader, 1997;
Almekinders et al., 1993). Flexor tendons cultured
in vitro not only survived, but the tendon cells were
also actively dividing, migrating, and synthesizing new
collagen when cultured in a cell-free environment (Mass
and Tuel, 1989). In vitro culture of rabbit flexor tendons
also demonstrated that these cells exhibit a differential
proliferative and healing capacity when compared to
tendon sheaths (Wiig et al., 1997). In vitro studies of
flexor tendon repair have also compared gliding func-
tion and tensile properties of injured tendons repaired
using different suture methods. These parameters
provide a measure of the range of motion and strength
of the repair, which are both important because they
allow a tendon to withstand early mobilization and to
avoid adhesion formation (Noguchi et al., 1993; Savage,
1985).
In vitro cyclic testing of extensor tendons was
performed to describe its fatigue properties, which
may serve as a stimuli for tendon remodeling. The
effects of cyclic loading are important to characterize
because they can cause microdamage, which accumu-
lates over time and could contribute to potential tendon
rupture (Schechtman and Bader, 1997). An example of
an in vitro model studying the effects of repetitive
motion involves culturing tendon fibroblasts on flexible-
bottomed wells, where the amount and rate of
deformation can be precisely controlled. Using this
model, the application of repetitive strain to tendon
fibroblasts caused an increase in prostaglandin E2
(Almekinders et al., 1993) and the combination of both
cyclic strain and inflammatory cytokines results in
greater extracellular matrix damage in tendon than
either factor acting alone (Archambault et al., 2002).
Repaired canine flexor tendons undergoing a different
cyclic loading protocol showed that repetitive loading
has a conditioning effect that affects repair-site rigidity
and strain in a dose-dependent manner (Ditsios et al.,
2002). It is clear that the results from these in vitro
studies provide a foundation for developing hypotheses
and designing in vivo experiments.
4.3. Experimental injury/repair—animal model (in vivo)
The majority of experimental research on tendon
injury and repair has been performed in animal models,
which possess advantages such as lower cost, fewer
ethical issues, less variability, and greater availability of
numbers when compared to clinical trials. However,
animal models also have their shortcomings as well and
researchers must be cautious in applying their results to
humans, just as care must be taken when extrapolating
in vitro results for in vivo settings. Some disadvantages
 ARTICLE IN PRESS
T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
of animal models include inherent biologic variability,
metabolic and hormonal differences from humans,
anatomical differences, and potential difficulty in work-
ing with animals, such as noncompliance. Despite these
factors, animal models have been an invaluable tool as
investigators have utilized animal models to study
specific aspects of tendon injury and repair, including
the effects of activity level and motion as well as
different types of injury modalities and locations.
Finally, animal models have been used to study how
tissue engineering therapies can be used to improve
tendon repair.
4.4. Activity level
The effects of activity levels on tendons have been
studied extensively in animal models. These activity
levels range from overuse, such as exercising, to disuse,
such as immobilization and stress shielding. As a result
of increased or decreased loads, tendon remodeling
leads to structural, biochemical, and mechanical
changes. Investigators have used animal models to
simulate these activity levels in a controlled manner in
order to study how the tendon responds and character-
ize its resulting properties.
Clinically, most overuse tendon injuries are due to
repetitive motion, which creates ‘‘microtrauma’’ that
accumulates over time (Hess et al., 1989). Therefore,
experimental animal models studying overuse have
incorporated exercise protocols that repetitively load
tendons to simulate the microdamage that leads to an
overuse injury. In addition to this intrinsic accumulated
damage, there are other factors that predispose a tendon
to injury. Additional intrinsic factors include muscular
imbalance and muscular insufficiency while extrinsic
factors include anatomical factors, training errors, and
environmental conditions (Soslowsky et al., 1996; Hess
et al., 1989). Examples of animal exercise protocols have
involved running miniature swine or rats on a motorized
treadmill (Soslowsky et al., 2000; Woo et al., 1982).
Short term exercise (3 months) of swine flexor tendons
had minimal effects on tendon properties, but long-term
(12 months) exercised tendons exhibited an increase in
max stress and mass and a decrease in max strain (Woo
et al., 1982). An anatomically appropriate animal model
for studying rotator cuff injuries has been developed by
our lab (Fig. 4) (Soslowsky et al., 1996). Using this
model, an exercise regimen, which lasted for 4, 8, and 16
weeks, imposed on rat supraspinatus tendons resulted in
significantly larger cross-sectional areas at all three time
points and decreased modulus and maximum stress
values (Soslowsky et al., 2000). It was also shown with
this model that a combination of exercise with either an
intrinsic or extrinsic factor led to a more severe injury
than overuse alone (Carpenter et al., 1998a, b). In
general, the duration of exercise affects tissue home-
869
Fig. 4. Photographs and schematics depicting the rat shoulder to be an
anatomically appropriate model for a human shoulder. (Soslowsky,
L.J., Carpenter, J.E., DeBano, C.M., Banerji, I., Moalli, M.R., 1996.
Development and use of an animal model for investigations on rotator
cuff disease. Journal of Shoulder and Elbow Surgery 5, 383–392; with
permission.)
ostasis; the long-term effect of exercise on tendons
appears to be positive, but periods of weakness can
occur during a training period. Therefore, sufficient rest
is often required to allow the tendon to recover through
an adaptive cellular response necessary to maintain
function. Although these exercise models allow for the
study of tendon overuse in a controlled manner, tendon
loads during exercise are not directly measured, so the
magnitude of the overuse is unknown. If in situ loads
can be monitored, then a better understanding of how
tendons react and adapt to exercise can be used to
prescribe a clinically safe exercise regimen (Archambault
et al., 1995).
On the other spectrum of activity level is tendon
disuse, which is clinically relevant in patients who are
bedridden or immobilized post-surgery or immobilized
following repair. Patients are generally immobilized to
allow tendons to sufficiently heal before undergoing a
physical therapy regimen. Experimental animal models
simulating immobilization have focused on different
methods to immobilize limbs and its duration. Immo-
bilization protocols can incorporate a wide variety of
techniques and methods, but they generally achieve the
same result of either immobilizing to control range of
motion or also denervating to prevent loading. Im-
mobilization methods used on tendons include both
internal and external fixators, such as splints, casts, and
frames (Palmes et al., 2002; Murrell et al., 1994;
Enwemeka et al., 1988; Carlstedt et al., 1986). Although
immobilization of sutured tendons minimizes gap
 ARTICLE IN PRESS
870 T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
formation and suture pullout during healing (Nystrom
and Holmlund, 1983), tendons that are immobilized
have been shown to exhibit decreased mechanical
properties, deter functional recovery, and promote
adhesion formation (Palmes et al., 2002; Murrell et al.,
1994; Gelberman et al., 1983). The principal advantages
of these models are also its main disadvantages.
Immobilizing a tendon simulates disuse, but there still
may be loads applied across the tendon. Denervation
removes any potential loading, but the tendon cannot be
reloaded if a remobilization protocol is desired.
Another example that animal models have been used
to study tendon disuse is stress shielding. These studies
have mainly investigated how tendons remodel and
adapt in response to stress alteration. A technique
developed to shield rabbit patellar tendons from stress
utilizes internal fixation to prevent gross movement of
the knee joint and to completely release tension from the
patellar tendon (Yamamoto et al., 1993). Using this
model, investigators have found that tensile strength
and modulus up to 6 weeks post-surgery have decreased
rapidly and markedly (Fig. 5), while cross-sectional area
increased initially before decreasing at 6 weeks (Yama-
moto et al., 1993). In separate studies testing the
mechanical properties of stress shielded rabbit patellar
tendons in either the longitudinal or transverse direc-
tions, there were marked decreases in both tangent
modulus and tensile strength (Yamamoto et al., 2000;
Yamamoto et al., 1993). The advantages of these models
is their ability to control the magnitude of stress applied
Fig. 5. Average stress-strain curves for completely stress-shielded and
control rabbit patellar tendons. (Yamamoto, N., Ohno, K., Hayashi,
K., Kuriyama, H., Yasuda, K., Kaneda, K., 1993. Effects of stress
shielding on the mechanical properties of rabbit patellar tendon.
Journal of Biomechanical Engineering 115, 23–28; with permission.)
to the tendon through varying amount of stress
shielding and to potentially remobilize the tendon after
stress alteration. Some disadvantages include the in-
vasive nature of the procedure, lack of denervation to
avoid any loading, and the uncertainty as to how the
loading pattern is changed.
4.5. Motion
Many studies have examined the effect of motion or
lack thereof following tendon repair. In general, it has
been shown that mobilization after repair has resulted in
improved tensile properties of the repair site, and in the
case of tendons, enhanced gliding function (Gelberman
et al., 1983; Woo et al., 1981; Piper and Whiteside,
1980). Two types of mobilization have been studied
extensively, active and passive motion. Active mobiliza-
tion involves motion of the tendon within the sheath and
application of tension to the tendon across the injury
site through muscle contraction. Passive mobilization
only involves motion of the repaired tendon without the
application of musculotendinous forces.
Animal models investigating the effect of active
motion on tendon healing have mainly studied flexor
tendons. Flexor tendons allowed constrained active
mobilization showed gains in strength compared to
tendons that were immobilized (Fig. 6) (Hitchcock et al.,
1987; Gelberman et al., 1986). Because injured tendons
are often repaired with sutures, the application of active
mobilization may be deleterious if it ruptures the suture
repair. Injured canine flexor tendons repaired by three
different repair techniques were allowed immediate
unrestricted active motion without any weight bearing
for up to 21 days. Tendon rupture occurred in two-
strand repairs, but not in the six-strand ones. The
Fig. 6. Comparison of tensile strengths between immobilized and
actively mobilized flexor tendons after injury and repair. (Gelberman,
R.H., Manske, P.R., Akeson, W.H., Woo, S.L., Lundborg, G., Amiel,
D., 1986. Flexor tendon repair. Journal of Orthopaedic Research 4,
119–128; with permission.)
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T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
strength of the repair is important because the tendon
must be able to withstand early active mobilization if it
is applied (Aoki et al., 1997). Finally, it has been shown
that the combined effects of both motion and tension on
the healing response of injured chicken flexor tendons
resulted in significantly greater tendon repair strength
and cellular activity when compared to either motion or
tension applied alone (Kubota et al., 1996). These
animal models support the use of active mobilization as
long as the forces generated do not exceed the breaking
strength of the repair technique.
A number of studies have investigated the effect of
passive motion on tendon healing as well. Injured canine
or chicken flexor tendons were repaired and subjected to
either immobilization or controlled passive motion by
manually flexing and extending the joints of the digits.
Tendons undergoing controlled passive motion showed
superior tensile properties and gliding function when
compared to immobilized tendons (Feehan and Beau-
chene, 1990; Woo et al., 1981). Similarly, injured human
flexor tendons were repaired and managed by either 312
weeks of immobilization followed by gradual increased
motion or passive motion within 5 days of repair for 412
weeks, after which active motion was allowed. A
grading system assessing return of motion revealed that
tendons undergoing passive motion had better overall
results and fewer ruptures (Strickland and Glogovac,
1980). Generally, enhanced tendon function following
passive motion may be due to a combination of factors,
such as the presence of fewer adhesions and improved
tensile strength of the repair. Therefore these increased
levels of load and greater magnitudes of tendon repair
site excursion due to passive mobilization may enhance
the healing response of repaired flexor tendons (Feehan
and Beauchene, 1990; Strickland and Glogovac, 1980).
Although motion has been shown to promote cellular
activity and minimize adhesion formation, it should not
be applied at the expense of a potential rupture.
Therefore, a fine balance exists between the progression
of tendon healing and applying mobilization. Even-
tually, this experimental data can be used to create a
clinical rehabilitation protocol, which consists of a
combination of immobilization and activity that allows
for optimal tendon healing (Enwemeka et al., 1988).
4.6. Transection
In order to study tendon healing in an animal model,
a distinct and reproducible injury must be created. The
two most common types of tendon transection models
have been complete and partial transections. Complete
transections are a better simulation of what occurs
clinically, but the effect of sutures, which are necessary
to reduce gap formation, must be taken into account.
Partial transections can be made in the middle half or
along one side of the tissue. Although they are unlikely
871
to occur clinically, injuries only to the middle half leave
the marginal fibers intact, circumventing the need for
suture repair and allows for immediate postoperative
tendon mobilization (Chan et al., 1998; Kubota et al.,
1996).
Complete transections have been shown to be
reproducible in location, pattern, and extent of damage
(Walsh and Frank, 1988). As a result of a complete
transection, there exists a gap between the two free ends.
Sutures are utilized to achieve tendon apposition in
order to minimize scar tissue formation, hasten collage-
nization, and avoid the presence of any non-tendinous
tissue between the two ends (O’Donoghue et al., 1961).
Animal model studies have confirmed the clinical
finding that the highest suture strand technique from
each study provided the highest tensile strength (Dino-
poulos et al., 2000; Winters et al., 1998, 1997; Noguchi
et al., 1993). When using sutures, other factors to
consider include suture knot location, suture material,
and suture size (Barrie and Wolfe, 2001). One dis-
advantage with using sutures is that they may disrupt
the intrinsic blood supply and reduce overall tensile
strength of the repair site (Bishop et al., 1986).
Investigators have also utilized complete transection
models without sutures, allowing tendon healing to
commence by gap formation. The application of force
on the tendon repair can increase gap formation
(Dinopoulos et al., 2000), which can occur immediately
due to inadequate initial repair strength or can develop
slowly due to cyclic loading. Because the presence of a
gap leads to poor healing and is possibly a major factor
in adhesion formation, gap formation should be
minimized to improve tensile strength. It has been
shown that the tensile strength of a gap that is greater
than 3 mm does not improve over time (Silva et al.,
2002; Gelberman et al., 1999).
Animal models have also been used to study partial
transections, which involve injuring a percentage of the
tendon. Some examples include window defects, re-
moval of the central third of the tendon, and transection
of the medial half of the tendon. Because partial
lacerations in tendons may be difficult to create
reproducibly, caliper-based devices have been designed
and tested to be accurate (Erhard et al., 2002). Although
a partial transection injury is not as clinically relevant as
a complete transection injury, it however still allows the
tendon healing response to be studied. In addition,
partial injuries have the advantage of not requiring
sutures to reduce gap formation since the tendon is still
partially attached. It has also been shown that partially
lacerated tendons are better off without suture repair
(Bishop et al., 1986; Reynolds et al., 1976). In the case of
a window injury, a full-thickness transverse partial
transection is created (Carpenter et al., 1998a, b; Chan
et al., 1998; Kubota et al., 1996). The marginal tendons
on either side of the transection provide enough support
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872 T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
to allow for any potential early active motion (Kubota
et al., 1996). Mechanical testing of the healed specimens
are performed after removal of marginal fibers (Car-
penter et al., 1998a, b; Chan et al., 1998). The central
third of the patellar tendon is often used as an autograft
for ACL reconstruction. However, problems with the
remaining patellar tendon include donor site morbidity,
rupture, and a decrease in quadriceps strength (Mar-
umoto et al., 1996; Burks et al., 1990). Studies on these
partially transected patellar tendons in either rabbits or
dogs have shown opposite trends on the tensile proper-
ties of the healing tendon. When compared to normal
contralateral controls up to 6 months post-operatively,
the failure strength of rabbit patellar tendons increased
while they decreased for canine patellar tendons
(Beynnon et al., 1995; Burks et al., 1990). Differences
in these results may be due to testing protocols as one
study gripped the patella while the other removed it.
Finally, some studies have also created a partial
transection in the medial half of patellar tendons
(Natsu-ume et al., 1997; Nakamura et al., 1996),
however, injuries that are only on one side of the tissue
have been shown to be inconsistent with some injuries
leading to complete rupture (Hefti et al., 1991;
O’Donoghue et al., 1966).
4.7. Junctions
Clinically, many indirect muscle injuries are localized
at or near the musculotendinous junction, including
delayed onset muscle soreness and muscle strain
(Noonan and Garrett, 1992). Much of the research in
this area has been performed on rabbit, rat, and canine
models and has yielded interesting insights into the
structure of the musculotendinous junction (MTJ) and
localization of tendon tears (Noonan and Garrett, 1992;
Best et al., 1989; Garrett and Tidball, 1988; Eisenberg
and Milton, 1984; Armstrong et al., 1983; Abraham,
1977).The MTJ is morphologically characterized by a
continuous membrane which is extensively folded and
seems to ‘‘interdigitate’’ with the muscle cell and
extracellular connective tissue of the tendon (Andreev
and Wassilev, 1986). At this junction we seem to find the
greatest weakness due to inherent ability of the tendon
to withstand higher tensile and strain loads than muscle.
Further studies done primarily on rabbit models have
shown that immediate and prolonged muscle fiber death
in this region can be attributed to an ongoing calcium-
induced injury process (Reddy et al., 1991). Although it
was originally believed that reduced extensibility of
sarcomeres resulted in rupture at the MTJ, more recent
studies have reported that ‘‘stiffer’’ sarcomeres do not
entirely account for the localization of fiber rupture and
that fibers do not actually tear at the MTJ but rather a
short distance from the junction (LeCroy et al., 1989).
Much of the research done at the osteotendinous
junction (OTJ) has focused primarily on the structure,
nature and healing properties of the OTJ, which,
mechanically, is the weakest area of the early post-
surgery. The OTJ is a complex transitional region
between bone and tendon and it has been demonstrated
that the short transition between tendon and bone
necessitates a variation in properties along the entire
length of the insertion. This is important in order to
functionally optimize the load transfer that must occur
over this small area (Thomopoulos et al., 2003).
Histological and biomechanical analysis of extensor
tendon healing in a bone tunnel have indicated that
healing occurs by progressive ‘‘bone ingrowth and
mineralization’’ into the fibrovascular tissue in the early
stages of healing with subsequent reestablishment of the
collagen fiber continuity that is characteristic of the OTJ
(Rodeo et al., 1993).
4.8. Tissue engineering
In addition to being used to study tendon healing
mechanisms, animal models have been important in
developing and testing tissue engineering methods to
improve the tendon healing process. Many of the studies
have focused on creating and using composites made
from various biomaterials and cells to facilitate healing
or to serve as potential replacement tissue. More
recently, the development of these repairs and replace-
ments have adhered to the approach of functional tissue
engineering, which proposes to measure in vivo forces in
uninjured tissue and to use this information as a
guideline in designing appropriate constructs that can
withstand in vivo loads (Butler et al., 2000). In addition,
much research has been done on the exogenous
application of cytokines to injured tendons to promote
healing.
The main factors to consider when creating a robust
and functional tissue engineered tendon construct
include a scaffold, cells, cytokines, and mechanical
stress. Traditionally, many studies determining the
biocompatibility of a composite have used a scaffold
seeded with or without cells, which was then used as a
replacement for native tissue. Not only should this
scaffold allow any seeded cells to proliferate rapidly, but
the cells must initially survive after the composite is
implanted in order to synthesize new tendinous tissue
(Butler and Awad, 1999). For example, a composite
constructed from polyester fibers around an elastometric
core was used as a replacement for rabbit Achilles
tendons (Goodship et al., 1985). Porcine small intestinal
submucosa (SIS) was used to repair a segmental Achilles
tendon defect or to replace a completely resected
infraspinatus tendon (Dejardin et al., 2001; Badylak
et al., 1995). Although all of these replacement
biomaterials showed promising results to serve as a
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T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
scaffold for cell growth and collagen deposition, they do
not fulfill the biomechanical requirements of the original
in vivo tendon. More recently, there has been more
research done on the effect of mechanical stress and
cytokines.
Functional tissue engineering (FTE) is a new
approach that places an emphasis on the importance
of mechanical stress in determining the success of a
construct. Because one of the main goals of FTE is to
establish design parameters and safety factors for tissue-
engineered implants, more studies that take into account
the in vivo function of the replaced tissues must be done
(Butler et al., 2000). For example, the determination of
in vivo patellar forces in rabbits during inactivity or
hopping on an inclined treadmill showed that peak
forces and stress during vigorous activity never exceeded
10% of their ultimate values. Peak tendon forces and the
rates of rise and fall in these forces were shown to be
positively correlated with activity level (Juncosa et al.,
2003). By taking different design criteria into considera-
tion, more functional and effective composites can be
designed with a greater likelihood for success in vivo.
A large number of studies have looked at the effects of
cytokines on uninjured and injured tendons both in vitro
and in vivo. Although it is relatively easy to experimen-
tally add cytokines, there are many factors to consider,
some of which include how much to add (dosage), when
to add (timing), and which ones to add (combination),
and how to add it (delivery) (Evans, 1999). It has been
shown that in a healing environment, there are changes
in the expression of both cytokines and their receptors
simultaneously, indicating a complex interaction of
influences leading to a healed structure (Sciore et al.,
1998; Panossian et al., 1997; Duffy et al., 1995). The
aforementioned factors and the complex interaction
between cells, ECM proteins, and cytokines often lead
to the reporting of conflicting results between different
studies. For example, the addition of higher doses of
GDF5 and GDF6 to injured Achilles tendons resulting
in an increase in failure load compared to lower doses
(Aspenberg and Forslund, 1999). However, it was
shown that tendon healing in bone tunnels was
accelerated and superior with lower doses of rhBMP-2
(Rodeo et al., 1999). These differences may also be due
to the bell-shaped dose response curve of cytokines, so
the application of additional cytokines may not always
be more effective (Evans, 1999). Finally, because healing
occurs in a progressive, multifunctional way, optimal
healing may require the sequential application of several
cytokines in various combinations (Evans, 1999; Abra-
hamsson, 1997; Spindler et al., 1996).
4.9. Ultrasound
Although the concept of using ultrasound in the
healing of tendon injuries was first proposed over 75
873
years ago and has general clinical acceptance, its specific
physiological mechanisms and therapeutic effects have
been a source of conflict among researchers. Some
earlier studies had concluded no beneficial effect of
ultrasound treatment to tendon and ligament healing
(Williamson et al., 1986; Roberts et al., 1982). However,
more recent investigations have demonstrated that
therapeutic ultrasound may facilitate fibroblast prolif-
eration and protein synthesis, with a significant increase
in tensile strength, rate of collagen synthesis, and energy
absorption capacity of the tendons (Jackson et al., 1991;
Enwemeka, 1989). The widespread use of this modality
by medical and surgical practitioners suggest efficacy
but a clearer understanding of the precise effects of
ultrasound on tendon healing is needed.
5. Future directions
Over the past decade, new developments and our
understanding of molecular biology have progressed
and allowed investigators to apply new therapies to
improve tendon healing. Cell therapies involve the
delivery of mesenchymal stem cells directly to the injury
site, and gene therapies allow for the introduction of
genetic material into the cells participating in healing.
Each of these methodologies has its own advantages,
and both are very promising for treating tendon injuries.
Mesenchymal stem cells (MSC) are progenitor cells
that differentiate into the body’s specialized cells during
embryonic development. Because fibroblasts are be-
lieved to have their lineage traced to mesenchymal cells
(Caplan, 1994), there has been considerable interest in
utilizing MSCs as a potential therapy for tendon
healing. MSCs can be isolated from bone marrow and
then most often seeded onto a collagen gel to create a
tissue engineered composite, which is implanted in an
injured tendon. Although MSC treated injuries only
showed slight improvements in material properties of
rabbit patellar tendons compared to untreated injuries
(Awad et al., 1999), composites that were contracted
onto a pretensioned suture prior to implantation in an
injured rabbit Achilles tendon exhibited much improved
structural properties compared to controls (Fig. 7)
(Young et al., 1998). A study that injected the MSCs
without seeded onto a collagen gel showed no significant
disruption to tendon healing and demonstrated feasi-
bility for use in an equine tendon healing model (Smith
et al., 2003). The main advantage of using MSCs is their
pluripotent ability to differentiate into a desired cell
lineage.
The delivery of genetic material to cells can be
accomplished through both viral and non-viral methods.
Some examples of viruses include retrovirus, adeno-
virus, and adeno-associated virus, while non-viral
examples include liposomes and naked DNA (Mulligan,
 ARTICLE IN PRESS
874 T.W. Lin et al. / Journal of Biomechanics 37 (2004) 865–877
Fig. 7. Comparison of average stress-strain curves between MSC-
treated and untreated rabbit Achilles tendons after injury and repair.
(Young, R.G., Butler, D.L., Weber, W., Caplan, A.I., Gordon, S.L.,
Fink, D.J., 1998. Use of mesenchymal stem cells in a collagen matrix
for Achilles tendon repair. Journal of Orthopaedic Research. 16, 406-
413; with permission.)
1993). Using specific vectors, the genes of interest can be
introduced into the cells inside (in vivo) or outside (ex
vivo) of the host. For example, in vivo gene transfer of
PDGF-B by liposomes into cells from healing rat
patellar tendons resulted in enhanced expression of
PDGF-B, promotion of angiogenesis, and enhancement
of matrix synthesis 4 weeks later (Nakamura et al.,
1998). In vivo gene transfer of pp125FAK, a protein
that may play a role in adhesion formation, by
adenovirus into chicken tendon cells found an over-
expression of FAK protein induces tendon adhesion
formation (Lou et al., 1997). The advantages of using a
viral vector over a non-viral one are that the genetic
material can be amplified easily and increased efficiency,
however, its disadvantages are its immunogenicity and
toxicity (Yao and Eriksson, 2000).
6. Summary
The clinical treatment of tendon injuries has improved
in no small part due to therapies and rehabilitation
protocols developed from both clinical and experimental
research. Experimental animal models, whether in vitro
or in vivo, allow us to focus on and investigate a certain
aspect or a combination of factors affecting tendon
healing. Whether the study design incorporates activity
level and mobilization or looks at different types of
injuries and injury locations, the findings of each study
contribute towards a more thorough understanding of
tendon healing mechanisms. In addition, tissue engi-
neering concepts provide novel and exciting therapies to
improve the healing process. Although our cumulative
knowledge base is vast, it is still incomplete and more
research needs to be done in tendon injury and repair
before we can achieve the ultimate goal of directing the
healing process of an injured tendon to form tissue that
is structurally and functionally comparable to that of a
normal tendon.
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