Review Article

Tissue Engineering Solutions for

Tendon Repair
Abstract
MaCalus V. Hogan, MD
Namory Bagayoko, MD
Roshan James, MS
Trevor Starnes, MD, PhD
Adam Katz, MD
A. Bobby Chhabra, MD

Tendon injuries range from acute traumatic ruptures and

lacerations to chronic overuse injuries, such as tendinosis. Even
with improved nonsurgical, surgical, and rehabilitation techniques,
outcomes following tendon repair are inconsistent. Primary repair
remains the standard of care. However, repaired tendon tissue
rarely achieves functionality equal to that of the preinjured state.
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.

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.

134

ong-term outcomes are variable

following surgical repair of tendon lacerations and ruptures. Primary repair remains the standard of
care. However, despite a multitude of
suture techniques and therapy protocols, reproducible satisfactory results
are difficult to achieve. Existing techniques are insufficient to return tendon to its normal preinjury condition. Repair and the healing process
often lead to permanent alteration of
preinjury characteristics such as
strength, tissue structure, organization, and composition.
Tissue engineering has been defined as the application of biological, chemical and engineering principles 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 possessing properties equal to those of
preinjured tendon could serve as a

turning point in the quest to successfully manage tendon injury. Current

research efforts are focused on the
creation of alternative repair methods using tissue-engineered substitutes to enhance tendon healing, repair, and regeneration.

Normal Tendon
Maintenance and Healing
Extracellular Matrix
Extracellular matrix (ECM) and its
composition are critical to the development and maintenance of healthy
tendon.2 Tenocytes are the predominant cell type in tendon, and they
produce collagen and maintain the
ECM microenvironment.3 The interaction of these fibroblast-like cells
with the ECM can affect cell proliferation, migration, and development.4
The ECM is critical in tendon response to mechanical loads and in-

Journal of the American Academy of Orthopaedic Surgeons

MaCalus V. Hogan, MD, et al

Table 1
Major Components in Tendon Extracellular Matrix
Component
Type I collagen2
Type III collagen5
Decorin3,6
Aggrecan6

Function
Predominant collagen type in native tendon tissue (highly
organized)
Present during early healing and in smaller amounts in
native tendon (unorganized)
Proteoglycan involved in collagen fibril organization; found
in the tensile segments of tendon
Proteoglycan involved in collagen fibril organization; found
in compressed segments of tendon

jury.5 Engineered tendon substitute

must closely mimic the structure of
ECM.
The major components of normal
tendon ECM are essential to its overall function (Table 1). Type I collagen predominates within the ECM.
This is the primary dry constituent of
normal tendon. Type I collagen is
well organized into parallel fibrils
that contribute to the tensile strength
of tendon. Type III collagen is a less
organized form of collagen within
the ECM that is abundant during the
earlier stages of healing and remodeling.6 Several proteoglycans, including
decorin and aggrecan, are present
within tendon ECM, and they play
an important role in collagen fibril
organization and matrix assembly.
They also contribute to tendon viscoelastic response to compressive
forces.7 Water represents slightly
more than half of tendon weight,
mostly within the ECM; water facilitates gliding of collagen fibril by reducing friction in response to loading.8

Recent research has focused on the

role of matrix-remodeling genes in
tendon (Table 2). Matrix metalloproteinases (MMPs) are involved in the
degradation of tendon ECM components during development and reassembly following injury.9 MMPs are
essential to tendon homeostasis and
repair through upregulation and
downregulation, and they counterbalance tissue inhibitors of metalloproteinases.11 Loiselle et al12 recently
developed a murine model of primary tendon repair based on MMP
and neotendon gene expression in an
effort to further understand the role
of MMP in the healing process. They
reported a biphasic response with
MMPs. Early expression of MMP-9
was associated with inflammation
and damaged collagen at the zone of
injury. Late expression of MMP-2
and -14 was seen during tendon remodeling. Markers associated with
neotendon development were expressed later during the transition to
normal tendon, at 21 and 28 days.12
A recent study demonstrated that lo-

cal delivery of a universal MMP inhibitor led to decreased collagen degradation 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 development and maturation are also
important to tissue engineering (Table 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 differentiation and proliferation, and it is upregulated by scleraxis.15 Together,
scleraxis and tenomodulin expression 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 differentiated cell levels.16 Smad8 is a marker
of mesenchymal stem cell (MSC) differentiation into tendon progenitor
populations. Hoffmann et al17 demonstrated that with specific manipulations of the Smad8 signaling pathway, MSCs could differentiate into
tenocytes. The role of Smad8 in tendon 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

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Tissue Engineering Solutions for Tendon Repair

Table 2
Tendon Extracellular Matrix-remodeling Genes
Gene

Function

MMP (eg, -1, -2, -3, -9, -11, -13)8,9

TIMP (ie, -1, -2, -3, -4)9,10

ECM degradation during development and repair

Reversible inhibition of MMPs

ECM = extracellular matrix, MMP = matrix metalloproteinases, TIMP = tissue inhibitors of

metalloproteinases

ported by a recent murine model of

tendon repair that found elevated
Smad8 expression at 4 weeks after
repair.12 This was associated with the
formation of neotendon and a reduction in adhesions represented by improved metatarsophalangeal joint
range of motion.

Tendon Healing
Table 3
Genes Specific to Tendon Development
Gene
Scleraxis13
Tenomodulin14
Tenascin-C15
Smad816

Function
Expressed in progenitor population and cells of tendon
tissue (early marker)
Late marker of tenocyte differentiation and proliferation;
upregulated by scleraxis
ECM glycoprotein present in embryonic and differentiated
tendon
Intracellular signaling molecule in MSCs; upregulation
represents tendon morphology

ECM = extracellular matrix, MSCs = mesenchymal stem cells

Figure 1

An understanding of the natural

tendon-healing process is vital to the
development of tools for modulating
tendon healing. Following tendon injury, the body begins a healing and scar
formation response with three overlapping phases distinguished by their cellular and biochemical events8 (Figure
1). This healing process reestablishes
the tendon fibers and the gliding
mechanism needed for tendon excursion. Tensile strength improves with
time but never reaches the level of
uninjured tendon. This process occurs 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 vasodilators are released in response to the
hematoma and attract inflammatory
cells from surrounding tissues. Monocytes, 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 fibroblasts 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, fibronectin, glycosaminoglycan, and water, which collectively stabilize the
ECM.8
Stages of tendon healing following injury. ECM = extracellular matrix,
GAG = glycosaminoglycans. (Adapted with permission from James R,
Kesturu G, Balian G, Chhabra AB: Tendon: Biology, biomechanics, repair,
growth factors, and evolving treatment options. J Hand Surg Am
2008;33[1]:102-112.)

136

Proliferative Stage
Continued recruitment and rapid
proliferation of fibroblasts is the
hallmark of the proliferative stage.

Journal of the American Academy of Orthopaedic Surgeons

MaCalus V. Hogan, MD, et al

Type III collagen and DNA concentrations peak, and the wound develops a disorganized, scar-like appearance. 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 approximately 6 weeks after the initial injury. A decrease in type III collagen
and matrix synthesis is seen, as well
as an overall decrease in cellularity.
Concomitantly, type I collagen synthesis increases, and these fibers become organized longitudinally along
the long axis of the tendon, providing mechanical strength to the repair
tissue. As remodeling proceeds, collagen crosslinking further increases
the tensile strength of the regenerate
tendon; however, the regenerate
never achieves the strength of uninjured tendon.2
Intrinsic Versus
Extrinsic Healing
The cells involved in tendon healing
are believed to arise predominantly
through intrinsic and extrinsic healing pathways. In the intrinsic healing
pathway, fibroblasts and inflammatory cells from the endotenon and
epitenon migrate to the site of tendon injury, where they then proliferate and promote tendon healing. In
the extrinsic healing pathway model,
these cells originate from the periphery. Evidence exists for both processes, and in most cases, both pathways contribute to tendon healing.
The extrinsic mechanism is activated
earlier, but it contributes to the formation of adhesions. The intrinsic
pathway results in improved biomechanics and fewer complications because it does not contribute to adhesions and because endotenon and
epitenon cells produce more collagen
and glycosaminoglycans.8 The relative contribution pathway of each is
March 2011, Vol 19, No 3

dependent on many factors, including the type and extent of trauma,

presence of a synovial sheath, tendon
location, and the amount of postoperative 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 determining which growth factors are
necessary and the ideal timing of administration. Localization and mechanical stimulation at the site of injury is required to prevent adverse
effects.20 During the inflammatory
phase, chemotactic cytokines attract
fibroblasts, macrophages, and neutrophils to the site of injury. Transforming growth factor- concentration is increased at the zone of
injury, which leads to cell migration.
This in turn leads to a cascade of
events, resulting in increased synthesis 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, inducing chemotaxis of neutrophils
and fibroblasts to the site of injury.
IGF-1 also plays a role in the remodeling phase, inducing collagen and
ECM synthesis.22 IGF-1 has a dosedependent 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. Plateletderived growth factor also works
during the proliferative phase to increase production of collagen and
ECM components. Timing of administration and duration of action affect 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-

ing. Basic fibroblast growth factor is

expressed by fibroblasts and neutrophils at the site of injury and functions in angiogenesis and stimulation
of cell-matrix interactions. Basic fibroblast growth factor is also mitogenic in that it induces proliferation
of local fibroblasts and bone marrowderived MSCs, leading to increased ECM production.24
Bone morphogenetic proteins, including growth differentiation factor
(GDF)-5, -6, and -7, have been
shown to be key factors in tendon repair.25 GDF treatment induces cell
proliferation, increases collagen synthesis, 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 rupture under normal conditions. As individual tendon fibrils begin to fail,
damage accumulates, stiffness is reduced, and failure begins with microscopic 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 fibrils. The complex interactions between 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 orientation and ECM composition following injury, in combination with
the development of scar tissue at the
site of injury, leads to inferior biomechanical properties.20 Tissue loss,
particularly segmental defects, fur-

137

Tissue Engineering Solutions for Tendon Repair

ther complicates healing. Although

tendon reapproximation and suturing may facilitate union following injury, 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 complicated process that requires appropriate and timely tension on the repair. Repaired tendons are at risk of
rerupture under high tensile load.
Controlled physiotherapy is crucial
to the healing process. However, inadequate limb movement promotes
adhesions with the surrounding tissues, leading to inhibition of the gliding motion of the tendon under load.
Any tendon-tissue engineering strategy must aim to minimize adhesions
and restore normal tendon gliding
motion that will transfer muscular
forces to the bone in a manner similar to that of native tendon.26,27

Elements of Tendon
Bioengineering
Improving Repair and
Remodeling
Multiple biomechanical studies suggest that the strength of repair is affected 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 biomechanical levels.8
MSCs are multipotent cells that
can be induced to differentiate into
tendon cells. This requires the addition of specific growth factors involved 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 appropriate time during tendon healing. Scaffolds have been proposed for structural support during the healing
process and for local delivery of
growth factors and/or stem cells to
the repair site.28 The optimal construct has yet to be developed, but
the ability to combine MSCs under
the influence of tendon-specific supportive cytokine growth factors with
biocompatible scaffolds exposed to
ideal mechanical stresses is paramount to successful tendon bioengineering (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 principles of tendon engineering. MSCs
can differentiate into phenotypes under the influence of the appropriate
environmental cues. It is generally
accepted that fibroblasts at the tendon healing site arise from undifferentiated MSCs. The MSCs are present in adjacent connective tissue and
in circulating blood and bone marrow. 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 tissue 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
marrowderived
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

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 increased expression of tendon- and
ligament-specific genes.31 Hankemeier et al32 injected a mixture of human bMSCs and fibrin glue into rat
patellar tendon defects, resulting in
more mature tissue and more organized cell structure compared with
controls. Drawbacks to the use of
bMSCs include the painful bone
marrow harvesting procedure required to isolate them and the sometimes low cellular yield.
The use of adipose-derived MSCs
(aMSCs) has been investigated for
application in regenerative medicine.
Adipose tissue represents an abundant 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 minimal 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-

Journal of the American Academy of Orthopaedic Surgeons

MaCalus V. Hogan, MD, et al

Figure 3

A, Tissue-engineered nanofiber tubular 65:35 poly(lactide-co-glycolide)

(PLAGA) polymer scaffold. B, Tubular 65:35 PLAGA scaffold with an 18gauge needle through the lumen. (Patent pending, University of Virginia.)

Figure 4

Confocal microscopy live/dead assay of adipose mesenchymal stem cells

proliferating on electrospun nanofiber poly(lactide-co-glycolide) 65:35 scaffold
at 14 days (magnification, 10). A, Achilles tendon fibroblasts. B, Adipose
mesenchymal stem cells. Green = live, red = dead. (Patent pending,
University of Virginia.)

neered tendons through scaffold

seeding and cell proliferation. Another study demonstrated that aMSC
injections used to treat collagenaseinduced tendinitis in superficial digital flexor tendons in horse forelimbs
resulted in improved tendon organization.36 The plastic surgery community, based on their experience with
lipoplasty, is particularly interested
in the use of adipose tissue as a potential source of stem cells for a variety of soft-tissue applications.33
March 2011, Vol 19, No 3

Scaffolds
Currently, tendon repair involves the
use of either autograft or tendon
transfer. Autograft supply is limited,
and donor site morbidity is a concern. Furthermore, only rarely can
autograft be matched to the tensile
load of the repair tissue. Tendon
transfer involves detachment of the
tendon to be transferred and reattachment of it to the injured tendon.
This may restore function in the injured limb; however, a limited num-

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 sterilization process alters the mechanical
properties of allograft. Freeze-dried
allografts are nonliving tissues that
are extensively available from cadavers.
Polymers such as poly(a-hydroxyesters) are US FDA-approved synthetic materials with highly customizable physiochemical properties.
They can be designed for tendon
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 inflammatory response. The selected scaffold
in its composition and fabricated
form must be capable of holding and
supporting the cells (Figure 4). In addition, the scaffold should be biodegradable, serving as a temporary
support for the cells and mechanically augmenting the repaired tendon
while allowing for eventual replacement by matrix components synthesized by the implanted cells. The
scaffold should have high porosity
and a large surface area. It should
mimic the native tendon ECM architecture to allow cells to be distributed throughout the scaffold and to
allow diffusion of nutrients and factors that promote cellular proliferation as well as the production of
ECM (Figure 5). Most important,
the scaffold must be mechanically
stable and support limited early limb
movement, which is critical in preventing adhesions and in accelerating
tendon tissue remodeling. The scaffold should be reproducible, scalable, and readily available, with
properties customized to the tendon
graft required.

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. GraftJacket (Wright Medical Technology,
Arlington, TN) is derived from human allograft dermis.37 Scaffolds
from bovine and porcine sources
have recently been developed.38 Examples of such xenografts include
CuffPatch Soft Tissue Reinforcement
(Biomet, Warsaw, IN) and Restore
Orthobiologic Soft Tissue Implant
(DePuy, Warsaw, IN), which are derived from porcine SIS. TissueMend
Soft Tissue Repair Matrix (Stryker,
Mahwah, NJ) is an ECM scaffold
derived from fetal bovine dermis,
whereas the Zimmer Collagen Repair Patch (Zimmer, Warsaw, IN) is
made of porcine dermis.37
The aforementioned products are
US FDA-approved for certain indications 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 commercially available ECM scaffolds for
rotator cuff repair with canine infraspinatus tendon. They concluded

140

that the source, species, age of donor,

and manufacturing process contributed to the unique properties of each
product. The biochemical composition 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)
nanofiberbased scaffold for rotator cuff repair.
This aligned scaffold supported fibroblasts in culture, with cells attaching along the long axis of the
construct. Cell distribution, matrix
deposition, and mechanical properties were each not only significantly
improved versus controls (P < 0.05),
but were also maintained after scaffold 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 properties compared with normal tendon.41
These studies represent only a sample of current advancements in scaffold engineering. More research is
needed to aid in the development of
the optimal scaffold for tendon bioengineering.

The Future of Tendon

Repair
Delivery of growth factors via gene
therapy techniques and attachment
to scaffolds has led to improved localization of the growth factor to injured tendon. Alternatively, growth
factors may be used to induce local
stem cells to differentiate into tendon
or fibroblast cells that support tendon healing. MSCs also can be delivered to the site of injury and, in combination with delivered or local

growth factors, can improve the biology of tendon healing.28 In future, it

is hoped that tissue engineering strategies can be used not only to augment repair but also to enhance healing and regeneration. Translation of
tendon bioengineering to the clinical
setting is on the horizon.
Recently, GDF-5 (ie, bone morphogenetic protein [BMP]-14) gene therapy was reported to have increased
rat Achilles tendon tensile strength
without inducing bone or cartilage
formation within the healed tendon.42 Basile et al43 successfully
transduced freeze-dried flexor digitorum longus tendon allografts with
GDF-5 in a murine model. They
demonstrated accelerated healing
and decreased adhesion formation
compared with controls. GDF-5 augmentation in a murine Achilles tendon repair model led to decreased
expression of inflammatory genes
and improved collagen organization.44 Schnabel et al45 managed
collagenase-induced flexor digitorum
superficialis tendinitis lesions in
horses with either IGF-1 geneenhanced MSCs or MSCs alone.
Both groups showed enhanced tendon healing properties at the cellular
and histologic levels. Another recent
study showed that transforming
growth factor-1transduced bMSCs
led to accelerated and improved
healing, as well to faster recovery
and improved biomechanical properties, in an Achilles tendon injury
model in rabbits.46 Seeherman et al47
demonstrated that the delivery of recombinant 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 scaffolds are the most researched aspects
of tissue engineering. However, recent studies have highlighted the importance of mechanical stimulation
in the development of engineered

Journal of the American Academy of Orthopaedic Surgeons

MaCalus V. Hogan, MD, et al

constructs. Tenocyte-seeded SIS constructs 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 mechanical stimulation to create a construct that was able to withstand
peak in vivo forces in a patellar tendon rabbit repair model. These researchers previously showed that the
use of stem cellcollagen sponge constructs treated with mechanical stimulation in vitro led to improved biomechanical and histologic properties
when implanted in vivo.49

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Butler DL, Juncosa-Melvin N, Boivin

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Huang D, Balian G, Chhabra AB:

Tendon tissue engineering and gene

Summary
Many knowledge gaps exist in the clinical and basic science aspects of tendon
healing. Faster, more reliable healing is
needed. The ultimate goal is tendon repair that leads to earlier and improved
rehabilitation, minimal complications,
and regeneration of tissue with characteristics that are as good as or better
than those of normal tendon. Growth
factors, MSCs, and biocompatible scaffolds could lead to better healing and
regeneration. Future research in tissue
engineering could lead to changes in
our approach to managing tendon injury.

8.

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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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Journal of the American Academy of Orthopaedic Surgeons