Tendon-derived stem cells (TDSCs) promote tendon repair in a rat patellar tendon window defect model

Injured tendons heal slowly and often result in the formation of mechanically and functionally inferior fibrotic scar tissue or fibrous adhesions. This study investigated the use of tendon-derived stem cells (TDSCs) for tendon repair in a rat patellar tendon window defect model. Fibrin glue constructs with or without GFP-TDSCs were transplanted into the window defect. The patellar tendons were harvested for histology, ex vivo fluorescent imaging and biomechanical test at various time points up to week 4. Our results showed that TDSCs significantly enhanced tendon healing as indicated by the increase in collagen production as shown by hematolxylin stain-ability of the tissue, improvement of cell alignment, collagen fiber alignment and collagen birefringence typical of tendon. The labeled cells were observed at weeks 1 and 2 and became almost undetectable at week 4. Both the ultimate stress and Young's modulus were significantly higher in the TDSCs group compared to those in the fibrin glue group at week 4. In conclusion, TDSCs promoted earlier and better repair in a rat patellar tendon window defect model.     

Effect of adipose‐derived stromal cells and BMP12 on intrasynovial tendon repair: A biomechanical,biochemical, and proteomics study

The outcomes of flexor tendon repair are highly variable. As recent efforts to improve healing have demonstrated promise for growth factor‐ and cell‐based therapies, the objective of the current study was to enhance repair via application of autologous adipose derived stromal cells (ASCs) and the tenogenic growth factor bone morphogenetic protein (BMP) 12. Controlled delivery of cells and growth factor was achieved in a clinically relevant canine model using a nanofiber/fibrin‐based scaffold. Control groups consisted of repair‐only (no scaffold) and acellular scaffold. Repairs were evaluated after 28 days of healing using biomechanical, biochemical, and proteomics analyses. Range of motion was reduced in the groups that received scaffolds compared to normal. There was no effect of ASC + BMP12 treatment for range of motion or tensile properties outcomes versus repair‐only. Biochemical assays demonstrated increased DNA, glycosaminoglycans, and crosslink concentration in all repair groups compared to normal, but no effect of ASC + BMP12. Total collagen was significantly decreased in the acellular scaffold group compared to normal and significantly increased in the ASC + BMP12 group compared to the acellular scaffold group. Proteomics analysis comparing healing tendons to uninjured tendons revealed significant increases in proteins associated with inflammation, stress response, and matrix degradation. Treatment with ASC + BMP12 amplified these unfavorable changes. In summary, the treatment approach used in this study induced a negative inflammatory reaction at the repair site leading to poor healing. Future approaches should consider cell and growth factor delivery methods that do not incite negative local reactions. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:630–640, 2016.     

Synergy of tendon stem cells and platelet-rich plasma in tendon healing

Injured rat Achilles tendons were treated with botulism toxin to create a mechanically unloaded condition (unloaded) or left untreated (loaded), and then treated with phosphate‐buffered saline (PBS), platelet‐rich plasma (PRP), tendon stem cells (TSCs), or a combination (TSCs + PRP). mRNA and protein expression of collagen I, collagen III, tenascin C, and Smad 8 were determined by real time PCR and immunostaining, respectively. Loaded tendons treated with PBS, PRP, or TSCs for 3 or 14 days had higher collagen I mRNA expression than unloaded tendons. Loaded tendons treated with PBS for 3 or 14 days or with PRP for 3 days had higher collagen I protein levels than unloaded tendons. Loaded tendons treated for 3 days with PBS, for 14 days with PRP or TSCs or TSCs + PRP for 3 or 14 days had higher collagen III protein levels than unloaded tendons. Collagen I mRNA levels were higher in TSCs + PRP‐treated loaded tendons compared to PBS‐treated loaded tendons on day 3 of treatment. Based on changes in the expression of tendon‐healing genes, our data suggest that the combination of TSCs and PRP has synergistic effects on tendon healing under both loaded and unloaded conditions, and loaded conditions improve tendon healing. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:991–997, 2012     

Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect

Tendon healing is a complex coordinated series of events resulting in protracted recovery, limited regeneration, and scar formation. Mesenchymal stem cell (MSC) therapy has shown promise as a new technology to enhance soft tissue and bone healing. A challenge with MSC therapy involves the ability to consistently control the inflammatory response and subsequent healing. Previous studies suggest that preconditioning MSCs with inflammatory cytokines, such as IFN‐γ, TNF‐α, and IL‐1β may accelerate cutaneous wound closure. The objective of this study was to therefore elucidate these effects in tendon. That is, the in vivo healing effects of TNF‐α primed MSCs were studied using a rat Achilles segmental defect model. Rat Achilles tendons were subjected to a unilateral 3 mm segmental defect and repaired with either a PLG scaffold alone, MSC‐seeded PLG scaffold, or TNF‐α‐primed MSC‐seeded PLG scaffold. Achilles tendons were analyzed at 2 and 4 weeks post‐injury. In vivo, MSCs, regardless of priming, increased IL‐10 production and reduced the inflammatory factor, IL‐1α. Primed MSCs reduced IL‐12 production and the number of M1 macrophages, as well as increased the percent of M2 macrophages, and synthesis of the anti‐inflammatory factor IL‐4. Primed MSC treatment also increased the concentration of type I procollagen in the healing tissue and increased failure stress of the tendon 4 weeks post‐injury. Taken together delivery of TNF‐α primed MSCs via 3D PLG scaffold modulated macrophage polarization and cytokine production to further accentuate the more regenerative MSC‐induced healing response. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:269–280, 2017.

     

Impaired biomechanical properties correlate with neoangiogenesis as well as VEGF and MMP‐3 expression during rat patellar tendon healing

Recent studies reveal an important role of vascular endothelial growth factor (VEGF)‐induced angiogenesis in degenerative tendon diseases. The way how VEGF influences mechanical properties of the tendons is not well understood yet. We here hypothesized that tendinopathy results in a hypoxia‐mediated stimulation of VEGF and that the mechanical stability of the tendon is impaired in an angiogenic process by VEGF‐induced matrix metalloproteinases (MMPs). A modified in situ freezing model of patellar tendon was used to create a tendinopathy. 0, 7, 14, and 28 days post‐surgical animals were sacrificed and patellar tendons were dissected for biomechanical and immunohistochemical analysis. Native tendons were used as controls. Immunohistochemical staining revealed a peak in HIF‐1α stabilization immediately after surgery. Both VEGF and MMP‐3 were increased 7 days after surgery. Angiogenesis was also abundant 7 days after surgery. In contrast, biomechanical stability of the tendon was decreased 7 days after surgery. The current results reveal a time‐dependent correlation of HIF‐1/VEGF‐induced and MMP‐3‐supported angiogenesis with decreased biomechanical properties during tendon healing. The therapeutical modulation of neoangiogenesis by influencing the level of VEGF and MMP‐3 might be a promising target for new approaches in degenerative tendon diseases. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1952–1957, 2012     

The native cell population does not contribute to central‐third graft healing at 6, 12, or 26 weeks in the rabbit patellar tendon

Investigators do not yet understand the role of intrinsic tendon cells in healing at the tendon‐to‐bone enthesis. Therefore, our first objective was to understand how the native cell population influences tendon autograft incorporation in the central‐third patellar tendon (PT) defect site. To do this, we contrasted the histochemical and biomechanical properties of de‐cellularized patellar tendon autograft (dcPTA) and patellar tendon autograft (PTA) repairs in the skeletally mature New Zealand white rabbit. Recognizing that soft tissues in many animal models require up to 26 weeks to incorporate into bone, our second objective was to investigate how recovery time affects enthesis formation and graft tissue biomechanical properties. Thus, we examined graft structure and mechanics at 6, 12, and 26 weeks post‐surgery. Our results showed that maintaining the native cell population produced no histochemical or biomechanical benefit at 6, 12, or 26 weeks. These findings suggest that PTA healing is mediated more by extrinsic rather than intrinsic cellular mechanisms. Moreover, while repair tissue biomechanical properties generally increased from 6 to 12 weeks after surgery, no further improvements were noted up to 26 weeks. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 638–644, 2013     

The effect of muscle loading on flexor tendon‐to‐bone healing in a canine model

Previous tendon and ligament studies have demonstrated a role for mechanical loading in tissue homeostasis and healing. In uninjured musculoskeletal tissues, increased loading leads to an increase in mechanical properties, whereas decreased loading leads to a decrease in mechanical properties. The role of loading on healing tissues is less clear. We studied tendon‐to‐bone healing in a canine flexor tendon‐to‐bone injury and repair model. To examine the effect of muscle loading on tendon‐to‐bone healing, repaired tendons were either cut proximally (unloaded group) to remove all load from the distal phalanx repair site or left intact proximally (loaded group). All paws were casted postoperatively and subjected to daily passive motion rehabilitation. Specimens were tested to determine functional properties, biomechanical properties, repair‐site gapping, and bone mineral density. Loading across the repair site led to improved functional and biomechanical properties (e.g., stiffness for the loaded group was 8.2 ± 3.9 versus 5.1 ± 2.5 N/mm for the unloaded group). Loading did not affect bone mineral density or gapping. The formation of a gap between the healing tendon and bone correlated with failure properties. Using a clinically relevant model of flexor tendon injury and repair, we found that muscle loading was beneficial to healing. Complete removal of load by proximal transection resulted in tendon‐to‐bone repairs with less range of motion and lower biomechanical properties compared to repairs in which the muscle‐tendon‐bone unit was left intact. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res     

Effects of corticosteroids and hyaluronic acid on torn rotator cuff tendons in vitro and in rats

Corticosteroids (CS) or hyaluronic acid (HA) is used in subacromial injection for the conservative treatment of rotator cuff tears (RCT); this study addresses the question of how CS and HA affect the tendon tissue and fibroblasts in vitro and in rats. Cell proliferation assays were performed in human tendon fibroblasts from RCT. Rats underwent surgery to create RCT, and the surgical sites were injected with CS or HA. The rotator cuff tendons were subjected to biomechanical testing, microscopic and immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), and ultrastructural analysis. Cell proliferation was significantly decreased with CS in vitro (p < 0.05). Maximal load of CS‐treated tendons was significantly decreased compared with that of HA‐treated tendons (p < 0.05), as well as PCNA⁺ cells at 2 weeks (p < 0.05). Ultrastructural observations of the CS‐treated rats detected apoptosis of tendon fibroblasts 24 h after surgery. Histological and biomechanical data 4 weeks after surgery were not significant among the three groups. Unlike HA, CS caused cell death, and inhibition of the proliferation of tendon fibroblasts, leading to a delay of tendon healing involved and a subsequent decrease of biomechanical strength at the surgical site. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1523–1530, 2015.     

Eccentric training improves tendon biomechanical properties: A rat model

The treatment of choice for tendinopathies is eccentric reeducation. Although the clinical results appear favorable, the biomechanical changes to the tissue are not yet clear. Even if the mechanotransduction theory is commonly accepted, the physiology of tendons is not clearly understood. We aimed to better define the biomechanical and histological changes that affect healthy tendon after eccentric and concentric training. This study compared the effects of two methods of training (eccentric [E] training and concentric [C] training) with untrained (U) rats. The animals were trained over a period of 5 weeks. The tricipital, patellar, and Achilles tendons were removed, measured and a tensile test until failure was performed. A histological analysis (hematoxylin and eosin and Masson's trichrome stains) was also realized. There was a significant increase in the rupture force of the patellar and tricipital tendons between the U and E groups. The tricipital tendons in the control group presented a significantly smaller cross‐sectional area than the E‐ and C‐trained groups, but none was constated between E and C groups. No significant difference was observed for the mechanical stress between the three groups for all three tendons. Histological studies demonstrated the development of a greater number of blood vessels and a larger quantity of collagen in the E group. The mechanical properties of tendons in rats improve after specific training, especially following eccentric training. Our results partly explained how mechanical loading, especially in eccentric mode, could improve the healing of tendon. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:119–124, 2012     

Low‐level laser therapy in collagenase‐induced Achilles tendinitis in rats: Analyses of biochemical and biomechanical aspects

NSAIDs are widely prescribed and used over the years to treat tendon injuries despite its well‐known long‐term side effects. In the last years several animal and human trials have shown that low‐level laser therapy (LLLT) presents modulatory effects on inflammatory markers, however the mechanisms involved are not fully understood. The aim of this study was to evaluate the short‐term effects of LLLT or sodium diclofenac treatments on biochemical markers and biomechanical properties of inflamed Achilles tendons. Wistar rats Achilles tendons (n = 6/group) were injected with saline (control) or collagenase at peritendinous area of Achilles tendons. After 1 h animals were treated with two different doses of LLLT (810 nm, 1 and 3 J) at the sites of the injections, or with intramuscular sodium diclofenac. Regarding biochemical analyses, LLLT significantly decreased (p < 0.05) COX‐2, TNF‐α, MMP‐3, MMP‐9, and MMP‐13 gene expression, as well as prostaglandin E₂ (PGE₂) production when compared to collagenase group. Interestingly, diclofenac treatment only decreased PGE₂ levels. Biomechanical properties were preserved in the laser‐treated groups when compared to collagenase and diclofenac groups. We conclude that LLLT was able to reduce tendon inflammation and to preserve tendon resistance and elasticity. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1945–1951, 2012     

Effects of trypsinization and mineralization on intrasynovial tendon allograft healing to bone

The purpose of the current study was to develop a novel technology to enhance tendon‐to‐bone interface healing by trypsinizing and mineralizing (TM) an intrasynovial tendon allograft in a rabbit bone tunnel model. Eight rabbit flexor digitorum profundus (FDP) tendons were used to optimize the trypsinization process. An additional 24 FDP tendons were stratified into control and TM groups; in each group, 4 tendons were used for in vitro evaluation of TM and 8 were transplanted into proximal tibial bone tunnels in rabbits. The samples were evaluated histologically and with mechanical testing at postoperative week 8. Maximum failure strength and linear stiffness were not significantly different between the control and TM tendons. A thin fibrous band of scar tissue formed at the graft‐to‐bone interface in the control group. However, only the TM group showed obvious new bone formation inside the tendon graft and a visible fibrocartilage layer at the bone tunnel entrance. This study is the first to explore effects of TM on the intrasynovial allograft healing to a bone tunnel. TM showed beneficial effects on chondrogenesis, osteogenesis, and integration of the intrasynovial tendon graft, but mechanical strength was the same as the control tendons in this short‐term in vivo study. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:468–474, 2015.     

Recapitulation of the Achilles tendon mechanical properties during neonatal development: A Study of differential healing during two stages of development in a mouse model

During neonatal development, tendons undergo a well‐orchestrated process whereby extensive structural and compositional changes occur in synchrony to produce a normal tissue. Conversely, during the repair response to injury, structural and compositional changes occur, but a mechanically inferior tendon is produced. As a result, developmental processes have been postulated as a potential paradigm through which improved adult tissue healing may occur. By examining injury at distinctly different stages of development, vital information can be obtained into the structure–function relationships in tendon. The mouse is an intriguing developmental model due to the availability of assays and genetically altered animals. However, it has not previously been used for mechanical analysis of healing tendon due to the small size and fragile nature of neonatal tendons. The objective of this study was to evaluate the differential healing response in tendon at two distinct stages of development through mechanical, compositional, and structural properties. To accomplish this, a new in vivo surgical model and mechanical analysis method for the neonatal mouse Achilles tendons were developed. We demonstrated that injury during early development has an accelerated healing response when compared to injury during late development. This accelerated healing model can be used in future mechanistic studies to elucidate the method for improved adult tendon healing. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:448–456, 2012     

组织工程肌腱修复陈旧性跟腱断裂伴缺损的疗效观察

目的探讨应用组织工程肌腱修复陈旧性跟腱断裂伴缺损的手术方法及临床效果。方法1999年8月～2002年6月,采用同种异体肌腱来源的成纤维细胞,以5×106/ml细胞密度接种在医用碳纤维与聚羟基乙酸纤维制作的编织带上,体外培养5d后,修复跟腱缺损7例,缺损长度为5～7cm。术后踝跖屈外固定4～6周后开始功能锻炼。结果7例均获随访22～56个月,平均46.9个月。除1例术后伤口延迟愈合外,其余6例均期愈合。无全身及局部不良反应,无跟腱粘连再手术患者。按尹庆水疗效评定标准,优5例,良1例,可1例。结论组织工程肌腱修复跟腱缺损可获较好临床效果,是一种可选择的新治疗方法。     

Extracorporeal shock waves promote healing of collagenase-induced Achilles tendinitis and increase TGF-beta1 and IGF-I expression.

Extracorporeal shock waves (ESW) have recently been used in resolving tendinitis. However, mechanisms by which ESW promote tendon repair is not fully understood. In this study, we reported that an optimal ESW treatment promoted healing of Achilles tendintis by inducing TGF-beta1 and IGF-I. Rats with the collagenease-induced Achilles tendinitis were given a single ESW treatment (0.16 mJ/mm(2) energy flux density) with 0, 200, 500 and 1000 impulses. Achilles tendons were subjected to biomechanical (load to failure and stiffness), biochemical properties (DNA, glycosaminoglycan and hydroxyproline content) and histological assessment. ESW with 200 impulses restored biomechanical and biochemical characteristics of healing tendons 12 weeks after treatment. However, ESW treatments with 500 and 1000 impulses elicited inhibitory effects on tendinitis repair. Histological observation demonstrated that ESW treatment resolved edema, swelling, and inflammatory cell infiltration in injured tendons. Lesion site underwent intensive tenocyte proliferation, neovascularization and progressive tendon tissue regeneration. Tenocytes at the hypertrophied cellular tissue and newly developed tendon tissue expressed strong proliferating cell nuclear antigen (PCNA) after ESW treatment, suggesting that physical ESW could increase the mitogenic responses of tendons. Moreover, the proliferation of tenocytes adjunct to hypertrophied cell aggregate and newly formed tendon tissue coincided with intensive TGF-beta1 and IGF-I expression. Increasing TGF-beta1 expression was noted in the early stage of tendon repair, and elevated IGF-I expression was persisted throughout the healing period. Together, low-energy shock wave effectively promoted tendon healing. TGF-beta1 and IGF-I played important roles in mediating ESW-stimulated cell proliferation and tissue regeneration of tendon.     

Inhibition of Smad3 promotes the healing of rotator cuff injury in a rat model

To investigate the effect of inhibiting transforming growth factor‐β (TGF‐β1)/Smad2/3 signaling on rotator cuff (RC) healing. A bilateral supraspinatus tendon detachment‐repair model of Sprague‐Dawley (SD) rats was utilized. A total of 120 SD rats were randomly assigned to six groups and each group received the subacromial injection of normal saline, empty vectors, or lentiviral vectors containing small interfering RNA against TGF‐β1, Smad2, Smad3 at the bone‐tendon junction. Biomechanical and histological analyses were performed to evaluate bone‐tendon junction healing quality at 8 weeks after repair. Histologically, scar healing was found in all surgical groups. Animals with inhibited Smad3 exhibited better bone‐tendon junction structures with higher density, parallel orientation, and collagen fiber continuity than other surgical group animals. Immunohistochemistry revealed that the protein expression level of collagen I in animals with inhibited Smad3 was more prominent compared with all other surgical groups. Biomechanically, Animals with inhibited Smad3 showed better results in the maximum load at 4, 6, and 8 weeks after surgery compared with other surgical groups. Besides, C3H10T1/2 (Smad3?) cells increased TT‐D6 cell migration and tendon‐associated genes expression (scleraxis, tenascin C, collagen I) in coculture system. We conclude that inhibition of Smad3 promotes RC tendon healing in the rat supraspinatus model.     

Tendon gradient mineralization for tendon to bone interface integration

Tendon‐to‐bone integration is a great challenge for tendon or ligament reconstruction regardless of use of autograft or allograft tendons. We mineralized the tendon, thus transforming the tendon‐to‐bone into a “bone‐to‐bone” interface for healing. Sixty dog flexor digitorum profundus (FDP) tendons were divided randomly into five groups: (1) normal FDP tendon, (2) CaP (non‐extraction and mineralization without fetuin), (3) CaPEXT (Extraction by Na₂HPO₄ and mineralization without fetuin), (4) CaPFetuin (non‐extraction and mineralization with fetuin), and (5) CaPEXTFetuin (extraction and mineralization with fetuin). The calcium and phosphate content significantly increased in tendons treated with combination of extraction and fetuin compared to the other treatments. Histology also revealed a dense mineral deposition throughout the tendon outer layers and penetrated into the tendon to a depth of 200 µm in a graded manner. Compressive moduli were significantly lower in the four mineralized groups compared with normal control group. No significant differences in maximum failure strength or stiffness were found in the suture pull‐out test among all groups. Mineralization of tendon alters the interface from tendon to bone into mineralized tendon to bone, which may facilitate tendon‐to‐bone junction healing following tendon or ligament reconstruction. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1713–1719, 2013     

An in-vivo experimental evaluation of He–Ne laser photostimulation in healing Achilles tendons

There is no method of treatment that has been proven to accelerate the rate of tendon healing or to improve the quality of the regenerating tendon. Low level laser photostimulation has gained a considerable attention for enhancing tissue repair in a wide spectrum of applications. However, there is controversy regarding the effectiveness of laser photostimulation for improvement of the healing process of surgically repaired tendons. Accordingly, the present study was conducted to evaluate the role of helium–neon (He–Ne) laser photostimulation on the process of healing of surgically repaired Achilles tendons. Thirty unilateral Achilles tendons of 30 Raex rabbits were transected and immediately repaired. Operated Achilles tendons were randomly divided into two equal groups. Tendons at group A were subjected to He–Ne laser (632.8 nm) photostimulation, while tendons at group B served as a control group. Two weeks later, the repaired Achilles tendons were histopathologically and biomechanically evaluated. The histopathological findings suggest the favorable qualitative pattern of the newly synthesized collagen of the regenerating tendons after He–Ne laser photostimulation. The biomechanical results support the same favorable findings from the functional point of view as denoted by the better biomechanical properties of the regenerating tendons after He–Ne laser photostimulation with statistical significance (p ≤ 0.01) at most of the biomechanical parameters. He–Ne laser photostimulation reported a great value after surgical repair of ruptured and injured tendons for a better functional outcome. It could be applied safely and effectively in humans, especially with respect to the proposed long-term clinical outcome.     

Effects of selective paralysis of the supraspinatus muscle using botulinum neurotoxin a in rotator cuff healing in rats

We hypothesized that a temporary rotator cuff paralysis using botulinum‐neurotoxin A (BoNtA) would lead to an improved tendon‐to‐bone healing after repair of supraspinatus lesions. One hundred sixty Sprague–Dawley rats were randomly assigned to either the BoNtA or the control (saline) group. BoNtA/saline‐solution was injected into the supraspinatus muscle 1 week prior to surgery. A supraspinatus defect was made; we distinguished between a lesion with normal and increased repair load. Furthermore, one subgroup had the operated shoulder immobilized in a cast. Histologic analysis and biomechanical testing followed. Specimens from the BoNtA‐group, which were treated with an increased repair load, showed less cellularity and more organization in the interface tissue compared to the saline control group. In addition, we found that the collagen 1–3 quotient in the BoNtA specimen was significantly (p = 0.0051) higher than in the control group. Ultimate load at failure between the groups was not significantly different (p > 0.05). We did not observe any significant differences between the mobilized and immobilized specimen (p = 0.2079). The study shows that tendon‐to‐bone healing after rotator cuff repair can be altered positively using BoNtA pre‐operatively. Tears with increased repair load seem to benefit the most—at least histologically. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 716–723, 2013     

Effect of bone morphogenetic protein 2 on tendon‐to‐bone healing in a canine flexor tendon model

Tendon‐to‐bone healing is typically poor, with a high rate of repair‐site rupture. Bone loss after tendon‐to‐bone repair may contribute to poor outcomes. Therefore, we hypothesized that the local application of the osteogenic growth factor bone morphogenetic protein 2 (BMP‐2) would promote bone formation, leading to improved repair‐site mechanical properties. Intrasynovial canine flexor tendons were injured in Zone 1 and repaired into bone tunnels in the distal phalanx. BMP‐2 was delivered to the repair site using either a calcium phosphate matrix (CPM) or a collagen sponge (COL) carrier. Each animal also received carrier alone in an adjacent repair to serve as an internal control. Repairs were evaluated at 21 days using biomechanical, radiographic, and histologic assays. Although an increase in osteoid formation was noted histologically, no significant increases in bone mineral density occurred. When excluding functional failures (i.e., ruptured and gapped repairs), mechanical properties were not different when comparing BMP‐2/CPM groups with carrier controls. A significantly higher percentage of BMP‐2 treated specimens had a maximum force <20 N compared to carrier controls. While tendon‐to‐bone healing can be enhanced by addressing the bone loss that typically occurs after surgical repair, the delivery of BMP‐2 using the concentrations and methods of the current study did not improve mechanical properties over carrier alone. The anticipated anabolic effect of BMP‐2 was insufficient in the short time frame of this study to counter the post‐repair loss of bone. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1702–1709, 2012