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C OPYRIGHT  2014 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED

Current Concepts Review

Augmentation of Tendon-to-Bone Healing
Kivanc Atesok, MD, MSc, Freddie H. Fu, MD, DSc, DPs, Megan R. Wolf, BS, Mitsuo Ochi, MD, PhD,
Laith M. Jazrawi, MD, M. Nedim Doral, MD, James H. Lubowitz, MD, and Scott A. Rodeo, MD

Investigation performed at the Sports Medicine and Shoulder Service, Hospital for Special Surgery, New York, NY; Center for Musculoskeletal Care,
NYU Hospital for Joint Diseases, New York, NY; the Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania; the Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University,
Hiroshima, Japan; the Department of Orthopaedics and Traumatology, Hacettepe University School of Medicine, Ankara,
Turkey; and Taos Orthopaedic Institute, Taos, New Mexico

ä Tendon-to-bone healing is vital to the ultimate success of the various surgical procedures performed to repair
injured tendons.

ä Achieving tendon-to-bone healing that is functionally and biologically similar to native anatomy can be challenging
because of the limited regeneration capacity of the tendon-bone interface.

ä Orthopaedic basic-science research strategies aiming to augment tendon-to-bone healing include the use of os-
teoinductive growth factors, platelet-rich plasma, gene therapy, enveloping the grafts with periosteum, osteo-
conductive materials, cell-based therapies, biodegradable scaffolds, and biomimetic patches.

ä Low-intensity pulsed ultrasound and extracorporeal shockwave treatment may affect tendon-to-bone healing by
means of mechanical forces that stimulate biological cascades at the insertion site.

ä Application of various loading methods and immobilization times influence the stress forces acting on the recently
repaired tendon-to-bone attachment, which eventually may change the biological dynamics of the interface.

ä Other approaches, such as the use of coated sutures and interference screws, aim to deliver biological factors
while achieving mechanical stability by means of various fixators.

ä Controlled Level-I human trials are required to confirm the promising results from in vitro or animal research studies
elucidating the mechanisms underlying tendon-to-bone healing and to translate these results into clinical practice.

Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. The Deputy Editor
reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or
more exchanges between the author(s) and copyeditors.

Tendon injuries are common in orthopaedic clinical practice and
cause substantial morbidity in sports and in routine daily activities.
The anterior cruciate ligament (ACL) and rotator cuff are included
among the most commonly injured soft-tissue structures. The an-
nual incidence of ACL injury in the United States is estimated to be
approximately one in 3000, with approximately 100,000 to 200,000
injuries occurring annually1,2. Although the precise prevalence of
symptomatic rotator cuff injuries is unknown, it may range from
5% to 30%3. In cadaver studies of elderly donors, the prevalence of
full-thickness tears has been estimated to be as high as 30%4.

Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any
aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this
work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has
had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this
work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

J Bone Joint Surg Am. 2014;96:513-21 d http://dx.doi.org/10.2106/JBJS.M.00009

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Fig. 1-A
Figs. 1-A and 1-B The native tendon-bone interface exhibits distinct yet continuous tissue regions, including ligament, fibrocartilage, and bone. Light microscopy
images, with hematoxylin and eosin (Fig. 1-A) and safranin-O (Fig. 1-B) staining, showing the histological findings in a rat rotator cuff tendon-to-bone insertion site (·20).
Depending on the severity of the injury, and the activity
level, functional status, or occupation of the patient, surgical re-
construction has been the treatment of choice for injuries of the
ACL and rotator cuff. Successful tendon-to-bone healing is critical
for functional surgical treatment of these injuries. Tendon-to-bone
healing occurs more slowly and incompletely compared with
bone-to-bone healing5-7. In addition to the importance of ana-
tomical relocation of a tendon, morphological replication of the
unique tendon-to-bone insertion site may help to achieve the de-
sired material properties of the tendon-to-bone attachment site8-10.
The native tendinous insertion to bone is a highly spe-
cialized and organized tissue that functions to transmit com-
plex mechanical loads from soft tissue to bone. In general,
tendon-to-bone insertions can be divided into two categories:
indirect and direct insertions. Indirect insertions, such as the
tibial insertion of the medial collateral ligament, include mainly
dense fibrous tissue connecting the tendon and/or ligament to
the periosteum. In contrast, direct insertions, such as the in-
sertion of the ACL and rotator cuff, are characterized by the
presence of fibrocartilage tissue connecting these soft-tissue
structures to deeper layers of the bone11. The direct insertion
site includes a transition zone that consists of four distinct
tissue types: tendon, unmineralized fibrocartilage, mineralized
fibrocartilage, and bone (Figs. 1-A and 1-B)12,13.
The tendon-to-bone junction is slow to heal because of
the relative avascularity of the fibrocartilage zone and bone loss
at the site of injury14. The structure and composition of the
native direct tendon-bone interface is not reformed during
healing, resulting in a mechanically and structurally inferior
interface12. This deficit in insertion site microstructure raises
concerns regarding compatible integration of tendon to bone
and the subsequent risk for failure of the tendon attachment5.
During the past decade, strategies to biologically accelerate
and improve tendon-to-bone healing have been studied metic-
ulously in orthopaedic basic-science research. These strategies
primarily aim to augment biological healing of tendon-to-bone
interface using growth factors, cell-based therapies, and various
other delivery and inducement methods (Fig. 2).
A U G M E N TAT I O N OF TENDON-TO-BONE HEALING
Fig. 1-B
Osteoinductive Growth Factors
The use of osteoinductive growth factors is one of the most in-
tensively studied strategies of augmentation of tendon-to-bone
healing. These growth factors, including transforming growth
factor (TGF), bone morphogenetic protein (BMP), fibroblast
growth factor (FGF), and granulocyte colony-stimulating factor
(G-CSF), have positive effects on the repair and healing of
tendon and bone tissues in various animal model studies (see
Appendix)15-28. On the basis of the results from these studies,
osteoinductive growth factors may have a potential role as a
treatment modality in reconstruction of tendon-to-bone in-
terface after injury.
Platelet-Rich Plasma
Platelet-rich plasma (PRP), an autologous derivative of whole
blood that contains a supraphysiological concentration of
platelets, has gained increasing scientific and media attention
for its potential applications in the treatment of musculo-
skeletal injuries. The theoretical benefit of PRP is that it pro-
vides a local environment for tissue regeneration that is rich
in growth factors and other cytokines, such as TGF, insulin-
like growth factor-1 (IGF-1), platelet-derived growth factor
(PDGF), FGF, vascular endothelial growth factor (VEGF), and
interleukins29. This benefit has been supported by in vitro and
animal studies, which suggest a positive influence on the mi-
gration and proliferation of various cell types30-32. PDGF, a
major constituent of PRP, is responsible for the chemotactic
and possibly the mitogenic effects of PRP on osteoblasts. Sev-
eral investigators have studied the effects of PRP on the pro-
liferation of osteoblasts and tenocytes in tendon-bone interface
healing33-35.
In an ovine model, Hee et al.35 evaluated the effects of
an interpositional graft consisting of recombinant human
PDGF-BB (rhPDGF-BB) and a type-I collagen matrix implanted
in rotator cuff repair. Their results demonstrated that higher
doses of rhPDGF-BB produced inferior results compared with
middle doses, which indicates a potential negative feedback
with increasing dose of rhPDGF-BB. In a human study, Sundman
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Fig. 2
Schema summarizing the approaches that have been evaluated for augmentation of tendon-to-bone healing, including the use of osteoinductive growth
factors, platelet-rich plasma, gene therapy, enveloping the grafts with periosteum, osteoconductive materials, cell-based therapies, biodegradable
scaffolds, and biomimetic patches. Low-intensity pulsed ultrasound and extracorporeal shockwave treatment may affect tendon-to-bone healing by means
of mechanical forces that stimulate biological cascades at the insertion site. Application of various loading methods and immobilization times influences
the stress forces acting on the recently repaired tendon-to-bone attachment, which eventually may change the biological dynamics of the interface. Other
approaches such as the use of coated sutures and interference screws aim to deliver biological factors while achieving mechanical stability by means of
various fixators.

et al.36 evaluated the effects of leukocytes and inflammatory
molecules in PRP by comparing two different commercial PRP
systems. Catabolic cytokines, such as matrix metalloproteinase
(MMP)-9 and interleukin (IL)-1b, were significantly increased in
leukocyte-rich PRP preparations, which may have detrimental
effects on tendon-to-bone healing.
PRP therapy allows for the local delivery of multiple
cytokines and growth factors in a physiological combination.
This may address the limitations of a single factor therapy such
as inducing only one biological aspect of interface healing.
Although basic-science studies demonstrate the positive effects
of PRP therapy on tendon-to-bone healing, to date, clinical
evidence from controlled human trials involving rotator cuff
tendons does not show any superiority of PRP-augmented
repairs over conventional methods. A table in the Appendix
summarizes the results of human studies involving patients
who underwent arthroscopic repair of rotator cuff tears with or
without PRP37-42.
Gene Therapy
The direct use of growth factors to accelerate healing requires
repeated applications or high loading doses to achieve a suffi-
ciently prolonged biological activity due to the short biological
half-life of these proteins. Although not yet clinically available,
gene therapy offers a promising strategy to ensure a sustained
delivery of growth factors at the tendon-to-bone insertion site
throughout the early healing period43. Viral or nonviral delivery
vehicles (vectors) allow the genetic information (usually a
complementary DNA [cDNA] encoding the protein of in-
terest) to be inserted into a living cell. The genetically mod-
ified cell has the potential to express the protein encoded by
the transferred DNA in a sustained manner, making it a valu-
able vehicle for the targeted, long-term delivery of a protein of
interest44.
In a rabbit model, Lattermann et al.43 inserted flexor
digitorum longus tendon into a bone canal in the calcaneus and
applied gene delivery to the healing tendon insertion site. The
authors showed that gene delivery to the tendon-bone interface
is feasible, and they provided a basis for future use of adenoviral
delivery of growth factor genes to the tendon-bone insertion site.
Martinek et al.45 demonstrated that BMP-2 gene transfer im-
proves the integration of semitendinosus grafts at the tendon-
bone interface after ACL reconstruction in rabbits. Their results
revealed that the stiffness and ultimate load to failure were
significantly enhanced in the adenovirus-BMP-2-transduced
grafts compared with the grafts without gene transfer (p < 0.05).
The authors reported that normal femur-ACL-tibia complexes
demonstrated significantly higher biomechanical values than the
experimental specimens (p < 0.05).
Before gene transfer can be introduced as a therapeu-
tic method to improve tendon-to-bone healing in humans,
questions regarding safety and regulatory issues need to be
answered43,45.
Enveloping the Grafts with Periosteum
Periosteum, with its unique population of mesenchymal stem
cells (MSCs) and progenitor cells, has the potential to form
various connective tissue types and to induce new bone for-
mation46,47. Graft augmentation with periosteal flaps may improve
osseous ingrowth and healing at the tendon-bone interface48-50. In
a rabbit rotator cuff model, Chang et al.49 demonstrated that su-
turing a periosteal flap onto the torn end of infraspinatus tendon
enhances tendon-to-bone healing biomechanically and histo-
logically. Kyung et al.50 investigated the effects of enveloping the
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tendon grafts with periosteum on tendon-bone interface
healing in a rabbit model. The autologous long digital extensor
tendon was harvested and transplanted into a proximal tibial
tunnel with or without wrapping of periosteum around the
graft. Histological examination demonstrated more extensive
bone formation around the tendon with closer apposition of
new bone to the tendon in the periosteum-wrapped limbs
compared with controls. Biomechanical results revealed sig-
nificantly higher tendon pullout strength in the periosteum-
wrapped limbs at all time points.
Although enveloping the grafts with periosteum appears
to be a promising approach, clinical evidence supporting its use
in humans to augment tendon-to-bone healing is lacking.
Osteoconductive Materials
Calcium or magnesium phosphate biocements or adhesives
could be used as alternative strategies to enhance tendon-to-
bone healing since they provide an osteoconductive and bio-
compatible environment that facilitates cell proliferation and
growth factor recruitment at the interface.
In a rat rotator cuff model, Kovacevic et al.51 demon-
strated that applying an injectable calcium-phosphate (Ca-P)
matrix to a healing tendon-bone interface with or without
TGF-b3 improves tendon-to-bone healing. Mutsuzaki et al.52
used Ca-P hybridized tendons in a rabbit model to enhance the
healing process of ACL grafts at the tendon-bone interface. The
authors concluded that Ca-P hybridization results in a tendon-
bone interface that is similar to the native ACL insertion.
Similarly, magnesium-based bone adhesives have been
reported to augment tendon-to-bone healing by enhancing bone
ingrowth into the scar interface in animal model studies5,53.
Calcium or magnesium-based osteoconductive materials
are readily available and relatively inexpensive compared with
other biological treatment modalities. Further research is required
to prove them as biocompatible and effective treatment alterna-
tives to reconstruct the tendon-to-bone interface in humans.
Cell-Based Therapies
Stem cells have the ability to differentiate into specified cell
types under the influence of endogenous and exogenous fac-
tors; therefore, they are currently being studied by researchers
in tendon formation and for stimulating graft incorporation54.
Local application of stem cells improves tendon-to-bone healing
in several animal model studies (see Appendix)55-59.
Cell-based therapies using stem cells offer the potential
to become a popular treatment alternative in tissue engineering
of tendon-bone interface. Nevertheless, our knowledge about
the conditions that are required to choose a certain type of stem
cell, optimum cell amount, and delivery vehicles, is limited.
Furthermore, serious concerns exist regarding their potential
for differentiation into undesirable lineages, which could result
in tumor-like growth.
Biodegradable Scaffolds and Biomimetic Patches
Biocompatible and biodegradable scaffolds with porous ultra-
structure permit invasion and easy attachment of cells, while
A U G M E N TAT I O N OF TENDON-TO-BONE HEALING
creating an environment suitable for cell proliferation and dif-
ferentiation60. In a rabbit model of rotator cuff injury, Yokoya
et al.60 reported that covering a defect in the rotator cuff insertion
using a polyglycolic acid sheet allows for tendon regeneration at
the interface with a fibrocartilage layer.
Sharpey fibers are strong collagenous fibers connecting
periosteum to bone. These fibers also attach muscles to the
periosteum such as the attachment of the rotator cuff muscles
to the scapula. Additionally, Sharpey fibers support teeth by
attachment of periodontal ligament fibers to alveolar bone.
On the basis of these similarities in Sharpey fiber content,
Kadonishi et al.61 examined whether enamel matrix derivative
(EMD), which has been successfully used in the treatment of
periodontal defects in humans62, could improve healing of
the tendon-bone interface following ACL reconstruction
using a hamstring tendon in a rat model. Histological analysis
demonstrated improved interface healing at eight weeks in
the EMD group compared with the control group, although
the difference was not significant at twelve weeks. Biome-
chanically, the mean load to failure in the EMD group was
significantly higher at eight weeks (p = 0.009) and twelve
weeks (p = 0.047). There was a decrease in load to failure in
both groups at twelve weeks compared with eight weeks, which
was explained by weakening of the intra-articular tendon
grafts.
The multitissue transition (ligament, fibrocartilage, and
bone) represents a major challenge in orthopaedic interface
tissue engineering as several distinct yet contiguous tissue re-
gions constitute this complex insertion site. The use of stratified
biomimetic scaffolds can be highly beneficial for recapturing the
aforementioned complexity of the native ligament-to-bone
interface63. In a rat model, Spalazzi et al.64 evaluated a triphasic
scaffold for the regeneration of the ACL-to-bone interface
(phases 1, 2, and 3 are for ligament formation, the interface,
and the bone region, respectively). The authors found that the
triphasic scaffold supported multilineage cellular interactions
as well as tissue infiltration and abundant matrix production
in vivo.
These promising animal results demonstrate the feasi-
bility of the use of biomimetic patches and scaffolds in interface
tissue engineering. The success of these approaches will require
a thorough understanding of the structure-function relation-
ship at the native insertion site, as well as the elucidation of the
mechanisms governing interface regeneration63,65.
Low-Intensity Pulsed Ultrasound
Low-intensity pulsed ultrasound (LIPUS) is defined as a fre-
quency of 1.5 MHz administered in bursts of 200 ms, which
delivers 30 mW/cm2 of energy66. Therapy is typically applied
daily for twenty to thirty minutes67. LIPUS is clinically bene-
ficial in the acceleration of fracture-healing and chronic non-
union67,68, as well as in the treatment of cartilage defects69 and
ligament injuries70.
Recent animal studies have shown that ultrasound not
only accelerates tendon-to-bone healing but also creates a
junction that is similar to the native enthesis. In a sheep rotator
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cuff model, Lovric et al.71 demonstrated that ultrasound in-
creases osteoblast activity and vascularization, creating new
bone with a higher bone mineral density, and a more mature
tendon-to-bone junction. In another study, Qin et al.72 re-
ported that collagen alignment and remodeling of the enthesis
was superior to the control in a rabbit partial patellectomy
model. In a sheep model of ACL reconstruction, Walsh et al.66
showed that LIPUS significantly improved the biomechanical
properties such as peak load to failure and stiffness of the
tendon-to-bone junction compared with control animals at
twenty-six weeks (p < 0.05). There was no significant difference
in biomechanical values between the groups at six weeks and
twelve weeks after reconstruction although interface vascular-
ity significantly improved with LIPUS treatment at three, six,
and twelve weeks (p < 0.05).
Possible explanations for these improved results with
LIPUS treatment include the biochemical environment sur-
rounding the healing enthesis. LIPUS treatment promotes os-
teoblast and fibroblast proliferation73, which contributes to
improved collagen formation and bone remodeling. VEGF and
IL-1b are increased74, thus enhancing angiogenesis and pro-
tein synthesis within the previously avascular environment.
Furthermore, the increased expression of BMPs with LIPUS
treatment may augment tendon-to-bone healing75.
Extracorporeal Shockwave Treatment
Although minimally understood, it is thought that the mech-
anisms by which extracorporeal shockwave treatment affect
bone are through exertion of direct pressure or by causing
cavitation76. Extracorporeal shockwave treatment delivers a
higher amount of energy compared with LIPUS and may re-
quire only two to three treatments; therefore, the therapy would
be more desirable for patients. Relatively few studies have looked
into the use of extracorporeal shockwave treatment for tendon-
to-bone healing76,77. In a delayed healing model at the rabbit
patella-patellar tendon junction, animals that received ex-
tracorporeal shockwave treatment had more bone formation,
increased bone mineral density, and better collagen align-
ment compared with controls77. Moreover, biomechanical
parameters such as load to failure and tensile strength were
increased76.
High-pressure shockwaves alter the biochemical envi-
ronment surrounding the healing tendon-to-bone interface,
which results in upregulation of growth factor proteins such as
VEGF, BMP, and TGF-b78. Overall, these factors create an
environment with a better blood supply and increased bone
and collagen formation, which may create a stronger tendon-
to-bone interface.
Although most studies have shown extracorporeal shock-
wave treatment to be beneficial in a variety of musculoskeletal
disorders76-78, much is still unknown about the exact parameters
of use, including the number of pulses or sessions, or the amount
of energy flux. Extracorporeal shockwave treatment may repre-
sent a promising alternative to the time-intensive ultrasound
therapy and may have similar benefits for the acceleration of
tendon-to-bone healing.
A U G M E N TAT I O N OF TENDON-TO-BONE HEALING
Effects of Various Loading Methods and Immobilization
on Interface Healing
Rehabilitation techniques after rotator cuff or ACL surgery are
controversial. Although immobilization allows for healing of
the tendon-to-bone interface, complete joint immobilization
may lead to weakness and atrophy of the surrounding struc-
tures, which eventually increases the stress on the recently re-
paired tendon-to-bone attachment.
Thomopoulos et al.79 showed in a canine model that
complete removal of load by proximal muscle transection re-
sulted in tendon-to-bone repairs with lower biomechanical
properties than repairs without transection. Brophy et al.80
investigated the effect of short-duration low-magnitude cyclic
loading versus immobilization on tendon-bone healing after
ACL reconstruction in a rat model. The authors reported that
low levels of controlled loading for a short duration starting in
the immediate postoperative period resulted in decreased tra-
becular number at the interface but did not significantly impair
tendon-to-bone healing. In a similar ACL reconstruction in a
rat model, Bedi et al.81 evaluated the effect of early and delayed
loading on tendon-to-bone healing. Delayed loading decreased
scar tissue formation, osteoclast activation, and phagocytic
ED1-positive macrophage recruitment, enhancing the success
of graft healing and recovery. In that study, delayed application
of cyclic axial load after ACL reconstruction resulted in im-
proved mechanical and biological parameters of tendon-to-
bone healing compared with those associated with immediate
loading or prolonged postoperative immobilization of the
knee.
On the basis of these animal models, neither strict im-
mobilization nor immediate initiation of rehabilitation and
loading appear to be beneficial after surgical repair, but rather a
balance between the modalities is essential to optimize the
healing enthesis and obtain a stronger interface.
More research, including randomized controlled clinical
trials, is required to characterize the efficacy of these potential
treatments and to identify optimal post-reconstruction reha-
bilitation protocols.
Coated Sutures and Interference Screws
Several animal model studies have demonstrated that sutures
impregnated with growth factors or MSCs provide a local de-
livery vehicle for these factors and cells to incorporate into the
surgical site in procedures, such as rotator cuff or Achilles
tendon repair, to enhance tendon-to-bone healing82-85.
Other biological enhancement options include applica-
tion of an arginine-glycine-aspartic acid coating to enhance
tenocyte proliferation85 and collagen coating of sutures to stimu-
late adhesion, as well as protein synthesis, which may poten-
tially enhance tendon-to-bone healing86.
Besides the suture material, biocomposite screws and
anchors were developed to allow eventual bone formation at
the fixation site without inducing osteolysis or synovitis,
which can be seen with other bioabsorbable implants87. These
biocomposite screws or anchors are composed of a combi-
nation of bioabsorbable polymer (e.g., polyglycolic acid or
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TABLE I Summary of the Biological Factors That Have Effects on Tendon-to-Bone Healing
Biological Factors Effecting Tendon-to-Bone Healing
Stimulatory
22,24
TGF Transforming growth factor
21,25,26
BMP Bone morphogenetic protein
27,28
FGF Fibroblast growth factor
23
G-CSF Granulocyte colony-stimulating factor
29-42
PDGF Platelet-derived growth factor
*Certain subclasses of MMPs, such as membrane type-1 (MT1) MMP, may have stimulatory effects on tendon-to-bone healing.
hydroxyapatite) and an osteoconductive bioceramic such as
b-tricalcium phosphate. As a result of osteoconductivity of
the material used to produce these novel fixators, they can be
degraded completely while the insertion site is filled with
bone tissue.
Lu et al.88 used sustained-release BMP-2-coated bio-
composite screws to enhance tendon-to-bone healing in an
ovine model. Although histologic scores of early tendon-to-
bone healing from the coated group significantly improved
compared with the uncoated group, mechanical testing did not
show any significant differences between the two groups.
Similar to other growth factor delivery vehicles, chal-
lenges remain, including timing, dosages, degree of elution,
sustainability of the release, effects of coating on fixative ma-
terials, and safety.
Delayed Interface Healing
Identification of the molecules and/or conditions that may
delay the healing of the tendon-bone interface is as important
as the definition of factors that promote the healing (Table I).
MMPs are enzymes that are involved in the degradation
of the extracellular matrix that forms the connective material
between cells and adjacent tissues. Previously, it was shown that
local inhibition of MMP activity can improve tendon-to-bone
healing after rotator cuff repair in rats89. In a rabbit ACL model,
Demirag et al.90 demonstrated that blocking MMPs enhances
tendon-to-bone healing histologically and biomechanically at
two weeks and five weeks after reconstruction. Although the
majority of the studies to date have focused on the inhibitory
effects of MMPs on tendon-to-bone healing, matrix remodel-
ing is a highly complex process and numerous MMPs exist with
diverse functions. While collagenases such as MMP-1, 8, 9, and
13 may impair healing by disrupting collagen and other matrix
proteins89-91, membrane type-1 MMP has a role in the forma-
tion of calcified cartilage and enhancement of tendon-bone
interface healing58. Furthermore, matrix metalloproteinase ex-
pression may have varying effects on the tendon-bone interface
at different stages of healing91.
Tumor necrosis factor-a (TNF-a), a potent inflamma-
tory mediator, stimulates osteoclast activity and inhibits oste-
oblast differentiation92. Due to these effects, it may be involved
A U G M E N TAT I O N OF TENDON-TO-BONE HEALING
Inhibitory
89-91
MMPs* Matrix metalloproteinases
92,93
TNF-a Tumor necrosis factor-a
in scar tissue formation and may limit bone ingrowth at the
tendon-bone interface. A study of rotator cuff repair in a rat
model demonstrated that TNF-a blockade provides biome-
chanical and histological improvements in tendon-to-bone
healing93.
On the basis of the fact that, rather than the native tendon-
bone interface, a scar tissue interface forms following the at-
tachment of a tendon graft to bone, investigators assessed the
effects of depletion of macrophage infiltration at the healing
interface94,95. Those investigators determined that macrophage
depletion in animal models enhances tendon-to-bone healing
with less fibrous scar-tissue formation95.
Evidence from animal model studies has also shown that
conditions that negatively impact bone formation and fracture-
healing, such as uncontrolled diabetes mellitus, nicotine, and
nonsteroidal anti-inflammatory drugs, also negatively affect
tendon-to-bone healing96-98.
Development of strategies to augment tendon-to-bone
healing will require a thorough understanding of the biological,
physical, and chemical factors that may interfere with the
process of healing to achieve successful outcomes.
In conclusion, the tendon-bone interface has a vital
function in the efficacious transmission of forces between soft
tissue and bone. Therefore, the healing of this interface after
reconstruction directly influences clinical outcomes. Recent
studies have focused on augmentation of tendon-to-bone heal-
ing by modulating either the biological or the biomechanical
environment, or both. Our knowledge about the complexity of
tendon-to-bone healing is still limited and mainly based on
animal studies. Rigorous clinical trials must be conducted to
translate current research from bench to bedside to develop
effective treatment modalities.
Appendix
Tables showing a summary of animal model studies in-
vestigating the effects of local use of osteoinductive growth
factors to augment tendon-to-bone healing, outcomes from
studies comparing patients who underwent arthroscopic ro-
tator cuff repair and received local PRP with those who did not
receive PRP, and results from animal model studies investi-
gating the effects of local MSC therapy on tendon-to-bone
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healing are available with the online version of this article as a
data supplement at jbjs.org. n
Kivanc Atesok, MD, MSc
Laith M. Jazrawi, MD
Center for Musculoskeletal Care,
NYU Hospital for Joint Diseases,
333 East 38th Street,
New York, NY 10016
Freddie H. Fu, MD, DSc, DPs
Megan R. Wolf, BS
Department of Orthopaedic Surgery,
University of Pittsburgh School of Medicine,
3471 Fifth Avenue, Suite 1011,
Pittsburgh, PA 15213
Mitsuo Ochi, MD, PhD
Department of Orthopaedic Surgery,
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Graduate School of Biomedical Sciences,
Hiroshima University,
1-2-3 Kasumi, Minamimi-ku,
Hiroshima 734-8551, Japan
M. Nedim Doral, MD
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Hacettepe University School of Medicine,
06100 Sihhiye,
Ankara, Turkey
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