Review Article

Tissue Engineering Solutions for

Tendon Repair

Abstract
MaCalus V. Hogan, MD Tendon injuries range from acute traumatic ruptures and
Namory Bagayoko, MD lacerations to chronic overuse injuries, such as tendinosis. Even
with improved nonsurgical, surgical, and rehabilitation techniques,
Roshan James, MS
outcomes following tendon repair are inconsistent. Primary repair
Trevor Starnes, MD, PhD remains the standard of care. However, repaired tendon tissue
Adam Katz, MD rarely achieves functionality equal to that of the preinjured state.
A. Bobby Chhabra, MD Poor results have been linked to alterations in cellular organization
within the tendon that occur at the time of injury and throughout the
early stages of healing. Enhanced understanding of the biology of
tendon healing is needed to improve management and outcomes.
The use of growth factors and mesenchymal stem cells and the
development of biocompatible scaffolds could result in enhanced
tendon healing and regeneration. Recent advances in tendon
bioengineering may lead to improved management following
tendon injury.

L ong-term outcomes are variable

From the Department of
Orthopaedic Surgery (Dr. Hogan,
Dr. Bagayoko, Dr. Starnes, and
Dr. Chhabra), the Department of
Biomedical Engineering (Mr. James),
and the Department of Plastic and
Maxillofacial Surgery (Dr. Katz),
University of Virginia Health System,
Charlottesville, VA.
J Am Acad Orthop Surg 2011;19:
134-142
Copyright 2011 by the American
Academy of Orthopaedic Surgeons.
following surgical repair of ten-
don lacerations and ruptures. Pri-
mary repair remains the standard of
care. However, despite a multitude of
suture techniques and therapy proto-
cols, reproducible satisfactory results
are difficult to achieve. Existing tech-
niques are insufficient to return ten-
don to its normal preinjury condi-
tion. Repair and the healing process
often lead to permanent alteration of
preinjury characteristics such as
strength, tissue structure, organiza-
tion, and composition.
Tissue engineering has been de-
fined as “the application of biologi-
cal, chemical and engineering princi-
ples toward the repair, restoration,
or regeneration of living tissues using
biomaterials, cells, and factors, alone
or in combination.”1 The ability to
regenerate tendon with tissue pos-
sessing properties equal to those of
preinjured tendon could serve as a
turning point in the quest to success-
fully manage tendon injury. Current
research efforts are focused on the
creation of alternative repair meth-
ods using tissue-engineered substi-
tutes to enhance tendon healing, re-
pair, and regeneration.
Normal Tendon
Maintenance and Healing
Extracellular Matrix
Extracellular matrix (ECM) and its
composition are critical to the devel-
opment and maintenance of healthy
tendon.2 Tenocytes are the predomi-
nant cell type in tendon, and they
produce collagen and maintain the
ECM microenvironment.3 The inter-
action of these fibroblast-like cells
with the ECM can affect cell prolifer-
ation, migration, and development.4
The ECM is critical in tendon re-
sponse to mechanical loads and in-

134 Journal of the American Academy of Orthopaedic Surgeons

 MaCalus V. Hogan, MD, et al

Table 1 cal delivery of a universal MMP in-

Major Components in Tendon Extracellular Matrix
Component Function
Type I collagen2 Predominant collagen type in native tendon tissue (highly
organized)
Type III collagen5 Present during early healing and in smaller amounts in
native tendon (unorganized)
Decorin3,6 Proteoglycan involved in collagen fibril organization; found
in the tensile segments of tendon
Aggrecan6 Proteoglycan involved in collagen fibril organization; found
in compressed segments of tendon
jury.5 Engineered tendon substitute Recent research has focused on the
must closely mimic the structure of role of matrix-remodeling genes in
ECM. tendon (Table 2). Matrix metallopro-
The major components of normal teinases (MMPs) are involved in the
tendon ECM are essential to its over- degradation of tendon ECM compo-
all function (Table 1). Type I colla- nents during development and reas-
gen predominates within the ECM. sembly following injury.9 MMPs are
This is the primary dry constituent of essential to tendon homeostasis and
normal tendon. Type I collagen is repair through upregulation and
well organized into parallel fibrils downregulation, and they counter-
that contribute to the tensile strength balance tissue inhibitors of metallo-
of tendon. Type III collagen is a less proteinases.11 Loiselle et al12 recently
organized form of collagen within developed a murine model of pri-
the ECM that is abundant during the mary tendon repair based on MMP
earlier stages of healing and remodel- and neotendon gene expression in an
ing.6 Several proteoglycans, including effort to further understand the role
decorin and aggrecan, are present of MMP in the healing process. They
within tendon ECM, and they play reported a biphasic response with
an important role in collagen fibril MMPs. Early expression of MMP-9
organization and matrix assembly. was associated with inflammation
They also contribute to tendon vis- and damaged collagen at the zone of
coelastic response to compressive injury. Late expression of MMP-2
forces.7 Water represents slightly and -14 was seen during tendon re-
more than half of tendon weight, modeling. Markers associated with
mostly within the ECM; water facili- neotendon development were ex-
tates gliding of collagen fibril by re- pressed later during the transition to
ducing friction in response to load- normal tendon, at 21 and 28 days.12
ing.8 A recent study demonstrated that lo-
hibitor led to decreased collagen deg-
radation and decreased histologic
changes at the tendon-bone interface
following rotator cuff repair in
rats.10
Several MMPs and tissue inhibitors
of metalloproteinases have been
identified. Although their precise
role is not known, it is well accepted
that this relationship plays a major
role in the turnover process in both
normal and damaged tendon.13
Tendon Development
Genes implicated in tendon cell de-
velopment and maturation are also
important to tissue engineering (Ta-
ble 3). Scleraxis is a transcription
factor and highly specific marker of
tenocyte precursor populations that
regulates ECM gene expression in
tendon fibroblasts.14 Tenomodulin is
a late marker of tenocyte differentia-
tion and proliferation, and it is up-
regulated by scleraxis.15 Together,
scleraxis and tenomodulin expres-
sion serve as strong indicators of
neotendon formation. Tenascin-C is
an ECM glycoprotein that has been
implicated in tendon development at
both the embryonic and differenti-
ated cell levels.16 Smad8 is a marker
of mesenchymal stem cell (MSC) dif-
ferentiation into tendon progenitor
populations. Hoffmann et al17 dem-
onstrated that with specific manipu-
lations of the Smad8 signaling path-
way, MSCs could differentiate into
tenocytes. The role of Smad8 in ten-
don development was further sup-

Dr. Hogan or an immediate family member has received research or institutional support from the Orthopaedic Research and
Education Foundation and serves as a board member, owner, officer, or committee member of the American Academy of Orthopaedic
Surgeons Candidate, Resident, and Fellow Subcommittee and of the J. Robert Gladden Orthopaedic Society. Dr. Katz or an
immediate family member serves as a board member, owner, officer, or committee member of the International Federation of Adipose
Therapeutics and Science and serves as a paid consultant to or is an employee of MicroAire Surgical Instruments and LifeNet
Health. Dr. Chhabra or an immediate family member has received research or institutional support from the National Institutes of
Health (NIH/NIAMS) grant No. AR052891 and the Orthopaedic Research and Education Foundation, and serves as a board member,
owner, officer, or committee member of the American Society for Surgery of the Hand, the Virginia Orthopaedic Society, and Miller
Review Course. None of the following authors or any immediate family member has received anything of value from or owns stock in
a commercial company or institution related directly or indirectly to the subject of this article: Dr. Bagayoko, Mr. James, and
Dr. Starnes.

March 2011, Vol 19, No 3 135

Tissue Engineering Solutions for Tendon Repair

Table 2 ported by a recent murine model of

tendon repair that found elevated
Tendon Extracellular Matrix-remodeling Genes
Smad8 expression at 4 weeks after
Gene Function repair.12 This was associated with the
MMP (eg, -1, -2, -3, -9, -11, -13)8,9 ECM degradation during development and repair formation of neotendon and a reduc-
TIMP (ie, -1, -2, -3, -4)9,10 Reversible inhibition of MMPs tion in adhesions represented by im-
proved metatarsophalangeal joint
ECM = extracellular matrix, MMP = matrix metalloproteinases, TIMP = tissue inhibitors of range of motion.
metalloproteinases

Tendon Healing
Table 3 An understanding of the natural
Genes Specific to Tendon Development tendon-healing process is vital to the
Gene Function development of tools for modulating
tendon healing. Following tendon in-
13
Scleraxis Expressed in progenitor population and cells of tendon jury, the body begins a healing and scar
tissue (early marker)
formation response with three overlap-
Tenomodulin14 Late marker of tenocyte differentiation and proliferation;
upregulated by scleraxis
ping phases distinguished by their cel-
lular and biochemical events8 (Figure
Tenascin-C15 ECM glycoprotein present in embryonic and differentiated
tendon 1). This healing process reestablishes
Smad816 Intracellular signaling molecule in MSCs; upregulation the tendon fibers and the gliding
represents tendon morphology mechanism needed for tendon excur-
sion. Tensile strength improves with
ECM = extracellular matrix, MSCs = mesenchymal stem cells
time but never reaches the level of
uninjured tendon. This process oc-
Figure 1 curs over a course of 1 year.8

Inflammatory Stage
Hematoma formation occurs following
damage to blood vessels in the zone of
injury. Chemotactic factors such as
proinflammatory molecules and vaso-
dilators are released in response to the
hematoma and attract inflammatory
cells from surrounding tissues. Mono-
cytes, macrophages, and neutrophils
migrate to the injury site, where they
break down the clot and necrotic tissue
via phagocytosis. Macrophages also
aid in the recruitment of new fibro-
blasts and the release of proangiogenic
factors, resulting in the formation of a
new vascular network within the
wound.18 This phase is marked by an
increase in type III collagen, DNA, fi-
bronectin, glycosaminoglycan, and wa-
ter, which collectively stabilize the
ECM.8
Stages of tendon healing following injury. ECM = extracellular matrix,
GAG = glycosaminoglycans. (Adapted with permission from James R, Proliferative Stage
Kesturu G, Balian G, Chhabra AB: Tendon: Biology, biomechanics, repair, Continued recruitment and rapid
growth factors, and evolving treatment options. J Hand Surg Am
2008;33[1]:102-112.) proliferation of fibroblasts is the
hallmark of the proliferative stage.

136 Journal of the American Academy of Orthopaedic Surgeons


Type III collagen and DNA concen-
trations peak, and the wound devel-
ops a disorganized, scar-like appear-
ance. The repair tissue is cellular, and
at the end of this stage, the tissue
contains abundant water and ECM
components.19
Remodeling Stage
Tissue begins to remodel approxi-
mately 6 weeks after the initial in-
jury. A decrease in type III collagen
and matrix synthesis is seen, as well
as an overall decrease in cellularity.
Concomitantly, type I collagen syn-
thesis increases, and these fibers be-
come organized longitudinally along
the long axis of the tendon, provid-
ing mechanical strength to the repair
tissue. As remodeling proceeds, col-
lagen crosslinking further increases
the tensile strength of the regenerate
tendon; however, the regenerate
never achieves the strength of unin-
jured tendon.2
Intrinsic Versus
Extrinsic Healing
The cells involved in tendon healing
are believed to arise predominantly
through intrinsic and extrinsic heal-
ing pathways. In the intrinsic healing
pathway, fibroblasts and inflamma-
tory cells from the endotenon and
epitenon migrate to the site of ten-
don injury, where they then prolifer-
ate and promote tendon healing. In
the extrinsic healing pathway model,
these cells originate from the periph-
ery. Evidence exists for both pro-
cesses, and in most cases, both path-
ways contribute to tendon healing.
The extrinsic mechanism is activated
earlier, but it contributes to the for-
mation of adhesions. The intrinsic
pathway results in improved biome-
chanics and fewer complications be-
cause it does not contribute to adhe-
sions and because endotenon and
epitenon cells produce more collagen
and glycosaminoglycans.8 The rela-
tive contribution pathway of each is
March 2011, Vol 19, No 3
dependent on many factors, includ-
ing the type and extent of trauma,
presence of a synovial sheath, tendon
location, and the amount of postop-
erative stress placed on the repair
during motion.
Growth Factors
Many growth factors are involved in
the tendon healing process. The keys
in optimizing tendon repair are de-
termining which growth factors are
necessary and the ideal timing of ad-
ministration. Localization and me-
chanical stimulation at the site of in-
jury is required to prevent adverse
effects.20 During the inflammatory
phase, chemotactic cytokines attract
fibroblasts, macrophages, and neu-
trophils to the site of injury. Trans-
forming growth factor-β concentra-
tion is increased at the zone of
injury, which leads to cell migration.
This in turn leads to a cascade of
events, resulting in increased synthe-
sis of collagen types I and III, initial
scar formation, and production of
other growth factors.21
Insulin-like growth factor-1
(IGF-1) production is upregulated
during the inflammatory phase, in-
ducing chemotaxis of neutrophils
and fibroblasts to the site of injury.
IGF-1 also plays a role in the remod-
eling phase, inducing collagen and
ECM synthesis.22 IGF-1 has a dose-
dependent effect; overexpression of
IGF-1 can lead to stiffness.
Platelet-derived growth factor acts
as a secondary messenger, inducing
the expression of other cytokines
during the repair process. Platelet-
derived growth factor also works
during the proliferative phase to in-
crease production of collagen and
ECM components. Timing of admin-
istration and duration of action af-
fect the specific composition of scar
and repaired tissue.23
Vascular endothelial growth factor
is essential to angiogenesis and is
necessary for tendon repair and heal-
MaCalus V. Hogan, MD, et al
ing. Basic fibroblast growth factor is
expressed by fibroblasts and neutro-
phils at the site of injury and func-
tions in angiogenesis and stimulation
of cell-matrix interactions. Basic fi-
broblast growth factor is also mito-
genic in that it induces proliferation
of local fibroblasts and bone mar-
row–derived MSCs, leading to in-
creased ECM production.24
Bone morphogenetic proteins, in-
cluding growth differentiation factor
(GDF)-5, -6, and -7, have been
shown to be key factors in tendon re-
pair.25 GDF treatment induces cell
proliferation, increases collagen syn-
thesis, and improves organization of
the ECM. GDFs also have been
shown to increase the transcription
of multiple genes involved in tendon
repair, including scleraxis, type I and
type III collagen, and tenascin-C.8
Biomechanics
of Repaired Tendon
Typically, tendons do not fail or rup-
ture under normal conditions. As in-
dividual tendon fibrils begin to fail,
damage accumulates, stiffness is re-
duced, and failure begins with micro-
scopic tears. The overall behavior of
tendon in response to injury depends
on its crimp structure (ie, the wavy
configuration of collagen fibrils that
contributes to the flexibility and
compressibility of tendon tissue) and
the ultimate failure of its collagen fi-
brils. The complex interactions be-
tween the multiple components of
the ECM result in viscoelasticity.
Thus, the rate of elongation to which
tendon is subjected modulates the
amount of load transferred.8
Derangement of collagen fibril ori-
entation and ECM composition fol-
lowing injury, in combination with
the development of scar tissue at the
site of injury, leads to inferior biome-
chanical properties.20 Tissue loss,
particularly segmental defects, fur-
137
Tissue Engineering Solutions for Tendon Repair
ther complicates healing. Although
tendon reapproximation and sutur-
ing may facilitate union following in-
jury, failure to restore proper tendon
length following segmental tissue
loss has severe implications on the
overall balance of forces across the
region in which the tendon acts.
Thus, modalities are needed that can
restore original tendon strength and
length.
Tendon repair is a slow and com-
plicated process that requires appro-
priate and timely tension on the re-
pair. Repaired tendons are at risk of
rerupture under high tensile load.
Controlled physiotherapy is crucial
to the healing process. However, in-
adequate limb movement promotes
adhesions with the surrounding tis-
sues, leading to inhibition of the glid-
ing motion of the tendon under load.
Any tendon-tissue engineering strat-
egy must aim to minimize adhesions
and restore normal tendon gliding
motion that will transfer muscular
forces to the bone in a manner simi-
lar to that of native tendon.26,27
Elements of Tendon
Bioengineering
Improving Repair and
Remodeling
Multiple biomechanical studies sug-
gest that the strength of repair is af-
fected by the number of strands
crossing the repair. Recent efforts to
understand the biology of tendon
healing, as well as the addition of
growth factors and the use of tissue
engineering modalities, are focused
on improving tendon repair at the
cellular, molecular, and biomechani-
cal levels.8
MSCs are multipotent cells that
can be induced to differentiate into
tendon cells. This requires the addi-
tion of specific growth factors in-
volved in the multiple stages of
tendon repair. In this extremely com-
138
plicated process, the growth factors
must be localized to the site of injury
and must be added at the appropri-
ate time during tendon healing. Scaf-
folds have been proposed for struc-
tural support during the healing
process and for local delivery of
growth factors and/or stem cells to
the repair site.28 The optimal con-
struct has yet to be developed, but
the ability to combine MSCs under
the influence of tendon-specific sup-
portive cytokine growth factors with
biocompatible scaffolds exposed to
ideal mechanical stresses is para-
mount to successful tendon bioengi-
neering (Figure 2).
Mesenchymal
Progenitor Cells
Successful isolation and selection of
MSCs or mesenchymal progenitor
cells as a source of multipotent cells
is among the most important princi-
ples of tendon engineering. MSCs
can differentiate into phenotypes un-
der the influence of the appropriate
environmental cues. It is generally
accepted that fibroblasts at the ten-
don healing site arise from undiffer-
entiated MSCs. The MSCs are pres-
ent in adjacent connective tissue and
in circulating blood and bone mar-
row. Autograft MSCs are processed
in vitro. A recent study showed that
the use of human embryonic stems
cells to repair the patellar tendon in
rats led to regeneration of tendon tis-
sue in vitro and in vivo.29 Compared
with control subjects, treated rats
demonstrated increased expression
of tendon-specific genes as well as
improved structural and mechanical
properties.
Bone marrow–derived MSCs
(bMSCs) have been transplanted to
various tissue injury sites, including
injured tendon, resulting in enhanced
tissue repair. Chong et al30 reported
improved and accelerated healing
with intratendinous treatment with
Journal of the American Academy of Orthopaedic Surgeons
Figure 2
The elements of successful tendon
bioengineering: scaffolds,
mesenchymal stem cells (MSCs),
cytokine growth factors, and
mechanical stress.
bMSCs in a rabbit Achilles tendon
primary repair model. A different
study indicated that coculture of
bMSCs with tenocytes led to in-
creased expression of tendon- and
ligament-specific genes.31 Hanke-
meier et al32 injected a mixture of hu-
man bMSCs and fibrin glue into rat
patellar tendon defects, resulting in
more mature tissue and more orga-
nized cell structure compared with
controls. Drawbacks to the use of
bMSCs include the painful bone
marrow harvesting procedure re-
quired to isolate them and the some-
times low cellular yield.
The use of adipose-derived MSCs
(aMSCs) has been investigated for
application in regenerative medicine.
Adipose tissue represents an abun-
dant source of adult stem cells with
the potential to differentiate along
multiple lineage pathways, including
tendon.33 Adipose tissue is abundant,
and harvest-related morbidity is min-
imal compared with that of bone
marrow sources. Recent literature
suggests that aMSC differentiation
and regenerative potential is equal to
that of other sources.34 Kryger et al35
showed aMSCs to be comparable to
tendon sheath fibroblast and bMSCs
in their potential for use as engi-
 MaCalus V. Hogan, MD, et al

Figure 3 ber of transfer options are available

for most injuries. Allografts are more
widely available, and they mimic the
native tendon ECM architecture.
However, they carry a significant risk
of disease transmission and immune
rejection. In addition, the steriliza-
tion process alters the mechanical
properties of allograft. Freeze-dried
allografts are nonliving tissues that
are extensively available from cadav-
ers.
Polymers such as poly(a-hydroxy-
A, Tissue-engineered nanofiber tubular 65:35 poly(lactide-co-glycolide) esters) are US FDA-approved syn-
(PLAGA) polymer scaffold. B, Tubular 65:35 PLAGA scaffold with an 18-
gauge needle through the lumen. (Patent pending, University of Virginia.) thetic materials with highly customi-
zable physiochemical properties.
They can be designed for tendon
Figure 4 graft applications (Figure 3). These
polymers degrade by hydrolysis into
nontoxic products that are easily
eliminated from the body.
The ideal scaffold is biocompatible
and does not incite a host inflamma-
tory response. The selected scaffold
in its composition and fabricated
form must be capable of holding and
supporting the cells (Figure 4). In ad-
dition, the scaffold should be biode-
gradable, serving as a temporary
support for the cells and mechani-
cally augmenting the repaired tendon
while allowing for eventual replace-
ment by matrix components synthe-
Confocal microscopy live/dead assay of adipose mesenchymal stem cells
proliferating on electrospun nanofiber poly(lactide-co-glycolide) 65:35 scaffold sized by the implanted cells. The
at 14 days (magnification, ×10). A, Achilles tendon fibroblasts. B, Adipose scaffold should have high porosity
mesenchymal stem cells. Green = live, red = dead. (Patent pending, and a large surface area. It should
University of Virginia.)
mimic the native tendon ECM archi-
tecture to allow cells to be distrib-
uted throughout the scaffold and to
neered tendons through scaffold Scaffolds allow diffusion of nutrients and fac-
seeding and cell proliferation. An- Currently, tendon repair involves the tors that promote cellular prolifera-
other study demonstrated that aMSC use of either autograft or tendon tion as well as the production of
injections used to treat collagenase- transfer. Autograft supply is limited, ECM (Figure 5). Most important,
induced tendinitis in superficial digi- and donor site morbidity is a con- the scaffold must be mechanically
tal flexor tendons in horse forelimbs cern. Furthermore, only rarely can stable and support limited early limb
resulted in improved tendon organi- autograft be matched to the tensile movement, which is critical in pre-
zation.36 The plastic surgery commu- load of the repair tissue. Tendon venting adhesions and in accelerating
nity, based on their experience with transfer involves detachment of the tendon tissue remodeling. The scaf-
lipoplasty, is particularly interested tendon to be transferred and reat- fold should be reproducible, scal-
in the use of adipose tissue as a po- tachment of it to the injured tendon. able, and readily available, with
tential source of stem cells for a vari- This may restore function in the in- properties customized to the tendon
ety of soft-tissue applications.33 jured limb; however, a limited num- graft required.

March 2011, Vol 19, No 3 139

Tissue Engineering Solutions for Tendon Repair
Figure 5
In vivo application of tubular
poly(lactide-co-glycolide) polymer
scaffold to bridge an Achilles
tendon defect and foster tendon
regeneration in a rat. (Patent
pending, University of Virginia.)
Current commercially available
scaffold options for soft-tissue repair
are often composed of small intestine
submucosa (SIS) or collagens. Graft-
Jacket (Wright Medical Technology,
Arlington, TN) is derived from hu-
man allograft dermis.37 Scaffolds
from bovine and porcine sources
have recently been developed.38 Ex-
amples of such xenografts include
CuffPatch Soft Tissue Reinforcement
(Biomet, Warsaw, IN) and Restore
Orthobiologic Soft Tissue Implant
(DePuy, Warsaw, IN), which are de-
rived from porcine SIS. TissueMend
Soft Tissue Repair Matrix (Stryker,
Mahwah, NJ) is an ECM scaffold
derived from fetal bovine dermis,
whereas the Zimmer Collagen Re-
pair Patch (Zimmer, Warsaw, IN) is
made of porcine dermis.37
The aforementioned products are
US FDA-approved for certain indica-
tions related to tendon repair and/or
augmentation.37,38 Few published
studies have compared their use,
however. Derwin et al39 performed
an in vitro analysis comparing the
biophysical properties of commer-
cially available ECM scaffolds for
rotator cuff repair with canine in-
fraspinatus tendon. They concluded
140
that the source, species, age of donor,
and manufacturing process contrib-
uted to the unique properties of each
product. The biochemical composi-
tion of the commercial matrices was
found to be similar to that of native
tendon, but the commercial products
were mechanically inferior.
As the use of scaffolds for tendon
repair expands, so will the need for
improved design. There are several
promising designs on the horizon.
Moffat et al40 designed a poly-
(lactide-co-glycolide) nanofiber-
based scaffold for rotator cuff repair.
This aligned scaffold supported fi-
broblasts in culture, with cells at-
taching along the long axis of the
construct. Cell distribution, matrix
deposition, and mechanical proper-
ties were each not only significantly
improved versus controls (P < 0.05),
but were also maintained after scaf-
fold degradation in an in vitro
model. A different study indicated
that use of MSC-seeded collagen
sponge composite in rabbit patellar
tendon defects resulted in improved
histologic and biomechanical proper-
ties compared with normal tendon.41
These studies represent only a sam-
ple of current advancements in scaf-
fold engineering. More research is
needed to aid in the development of
the optimal scaffold for tendon bio-
engineering.
The Future of Tendon
Repair
Delivery of growth factors via gene
therapy techniques and attachment
to scaffolds has led to improved lo-
calization of the growth factor to in-
jured tendon. Alternatively, growth
factors may be used to induce local
stem cells to differentiate into tendon
or fibroblast cells that support ten-
don healing. MSCs also can be deliv-
ered to the site of injury and, in com-
bination with delivered or local
Journal of the American Academy of Orthopaedic Surgeons
growth factors, can improve the biol-
ogy of tendon healing.28 In future, it
is hoped that tissue engineering strat-
egies can be used not only to aug-
ment repair but also to enhance heal-
ing and regeneration. Translation of
tendon bioengineering to the clinical
setting is on the horizon.
Recently, GDF-5 (ie, bone morpho-
genetic protein [BMP]-14) gene ther-
apy was reported to have increased
rat Achilles tendon tensile strength
without inducing bone or cartilage
formation within the healed ten-
don.42 Basile et al43 successfully
transduced freeze-dried flexor digito-
rum longus tendon allografts with
GDF-5 in a murine model. They
demonstrated accelerated healing
and decreased adhesion formation
compared with controls. GDF-5 aug-
mentation in a murine Achilles ten-
don repair model led to decreased
expression of inflammatory genes
and improved collagen organiza-
tion.44 Schnabel et al45 managed
collagenase-induced flexor digitorum
superficialis tendinitis lesions in
horses with either IGF-1 gene-
enhanced MSCs or MSCs alone.
Both groups showed enhanced ten-
don healing properties at the cellular
and histologic levels. Another recent
study showed that transforming
growth factor-β1–transduced bMSCs
led to accelerated and improved
healing, as well to faster recovery
and improved biomechanical proper-
ties, in an Achilles tendon injury
model in rabbits.46 Seeherman et al47
demonstrated that the delivery of re-
combinant hormone BMP-12 (ie,
GDF-7) in collagen or hyaluronan
sponges led to accelerated healing
following full-thickness rotator cuff
repair in sheep.
Growth factors, MSCs, and scaf-
folds are the most researched aspects
of tissue engineering. However, re-
cent studies have highlighted the im-
portance of mechanical stimulation
in the development of engineered

constructs. Tenocyte-seeded SIS con-
structs were shown to have improved
biomechanical properties following
cyclic loading in vitro.48 Butler et al27
combined MSCs, type I collagen
sponges, and bioreactors for me-
chanical stimulation to create a con-
struct that was able to withstand
peak in vivo forces in a patellar ten-
don rabbit repair model. These re-
searchers previously showed that the
use of stem cell–collagen sponge con-
structs treated with mechanical stim-
ulation in vitro led to improved bio-
mechanical and histologic properties
when implanted in vivo.49
Summary
Many knowledge gaps exist in the clin-
ical and basic science aspects of tendon
healing. Faster, more reliable healing is
needed. The ultimate goal is tendon re-
pair that leads to earlier and improved
rehabilitation, minimal complications,
and regeneration of tissue with charac-
teristics that are as good as or better
than those of normal tendon. Growth
factors, MSCs, and biocompatible scaf-
folds could lead to better healing and
regeneration. Future research in tissue
engineering could lead to changes in
our approach to managing tendon in-
jury.
References
Evidence-based Medicine: Levels of
evidence are described in the table of
contents. In this article, no level I, II,
III, or IV studies are cited. References
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V expert opinion. Most of the refer-
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