513 C OPYRIGHT  2014

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T HE J OURNAL

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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

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

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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.

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Orthopaedic basic-science research strategies aiming to augment tendon-to-bone healing include 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.

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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.

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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.

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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.

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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 annual 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.

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Fig. 1-A

Fig. 1-B

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 reconstruction 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 anatomical relocation of a tendon, morphological replication of the unique tendon-to-bone insertion site may help to achieve the desired material properties of the tendon-to-bone attachment site8-10. The native tendinous insertion to bone is a highly specialized and organized tissue that functions to transmit complex 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 insertion 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 meticulously 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).

Osteoinductive Growth Factors The use of osteoinductive growth factors is one of the most intensively 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 interface 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 musculoskeletal injuries. The theoretical benefit of PRP is that it provides a local environment for tissue regeneration that is rich in growth factors and other cytokines, such as TGF, insulinlike 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 migration 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. Several investigators have studied the effects of PRP on the proliferation 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 sufficiently 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 interest) to be inserted into a living cell. The genetically modified 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 improves the integration of semitendinosus grafts at the tendonbone 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 therapeutic 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 formation46,47. 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 suturing a periosteal flap onto the torn end of infraspinatus tendon enhances tendon-to-bone healing biomechanically and histologically. 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 significantly higher tendon pullout strength in the periosteumwrapped 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-tobone healing since they provide an osteoconductive and biocompatible environment that facilitates cell proliferation and growth factor recruitment at the interface. In a rat rotator cuff model, Kovacevic et al.51 demonstrated 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 tendonbone 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 alternatives 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 factors; 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 ultrastructure permit invasion and easy attachment of cells, while

creating an environment suitable for cell proliferation and differentiation60. 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. Biomechanically, 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 regions 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 feasibility 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 relationship 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 frequency 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 beneficial in the acceleration of fracture-healing and chronic nonunion67,68, 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 increases 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 reported 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 vascularity 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 surrounding the healing enthesis. LIPUS treatment promotes osteoblast and fibroblast proliferation73, which contributes to improved collagen formation and bone remodeling. VEGF and IL-1b are increased74, thus enhancing angiogenesis and protein 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 mechanisms 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 require 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 tendonto-bone healing76,77. In a delayed healing model at the rabbit patella-patellar tendon junction, animals that received extracorporeal shockwave treatment had more bone formation, increased bone mineral density, and better collagen alignment compared with controls77. Moreover, biomechanical parameters such as load to failure and tensile strength were increased76. High-pressure shockwaves alter the biochemical environment 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 tendonto-bone interface. Although most studies have shown extracorporeal shockwave 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 represent a promising alternative to the time-intensive ultrasound therapy and may have similar benefits for the acceleration 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 structures, which eventually increases the stress on the recently repaired tendon-to-bone attachment. Thomopoulos et al.79 showed in a canine model that complete removal of load by proximal muscle transection resulted 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 trabecular 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 improved mechanical and biological parameters of tendon-tobone healing compared with those associated with immediate loading or prolonged postoperative immobilization of the knee. On the basis of these animal models, neither strict immobilization 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 rehabilitation protocols. Coated Sutures and Interference Screws Several animal model studies have demonstrated that sutures impregnated with growth factors or MSCs provide a local delivery 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 application of an arginine-glycine-aspartic acid coating to enhance tenocyte proliferation85 and collagen coating of sutures to stimulate adhesion, as well as protein synthesis, which may potentially 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 combination 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 TGF BMP

Inhibitory 22,24

Transforming growth factor

Bone morphogenetic protein

MMPs*

21,25,26

TNF-a

92,93

Tumor necrosis factor-a

27,28

FGF

Fibroblast growth factor

G-CSF

Granulocyte colony-stimulating factor

PDGF

89-91

Matrix metalloproteinases

23

29-42

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 biocomposite screws to enhance tendon-to-bone healing in an ovine model. Although histologic scores of early tendon-tobone 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, challenges remain, including timing, dosages, degree of elution, sustainability of the release, effects of coating on fixative materials, 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 remodeling 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 formation of calcified cartilage and enhancement of tendon-bone interface healing58. Furthermore, matrix metalloproteinase expression may have varying effects on the tendon-bone interface at different stages of healing91. Tumor necrosis factor-a (TNF-a), a potent inflammatory mediator, stimulates osteoclast activity and inhibits osteoblast differentiation92. Due to these effects, it may be involved

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 biomechanical and histological improvements in tendon-to-bone healing93. On the basis of the fact that, rather than the native tendonbone interface, a scar tissue interface forms following the attachment 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 fracturehealing, 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 healing 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 investigating the effects of local use of osteoinductive growth factors to augment tendon-to-bone healing, outcomes from studies comparing patients who underwent arthroscopic rotator cuff repair and received local PRP with those who did not receive PRP, and results from animal model studies investigating 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

Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minamimi-ku, Hiroshima 734-8551, Japan M. Nedim Doral, MD Departments of Orthopaedics and Traumatology, and Sports Medicine, Hacettepe University School of Medicine, 06100 Sihhiye, Ankara, Turkey

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

James H. Lubowitz, MD Taos Orthopaedic Institute, 1219A Gusdorf Road, Taos, NM 87571

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

Scott A. Rodeo, MD Sports Medicine and Shoulder Service, Hospital for Special Surgery, 525 East 71st Street, New York, NY 10021. E-mail address for S. A. Rodeo: [email protected]

Mitsuo Ochi, MD, PhD Department of Orthopaedic Surgery,

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