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S URGERY, I NCORPORATED

Specialty Update

Whats New in Orthopaedic Research

By Scott A. Rodeo, MD, Demetris Delos, MD, Alex Weber, MD, Xiaodong Ju, MD, Matthew E. Cunningham, MD, PhD, Lisa Fortier, DVM, PhD, and Suzanne Maher, PhD There has been continued innovation in orthopaedic basic science research over the past year. In this review, we highlight notable studies published in the last twelve months. We have reviewed papers from the annual meeting of the Orthopaedic Research Society as well as major orthopaedic journals. These studies demonstrate an exciting multidisciplinary approach to understanding the mechanisms underlying tissue degeneration, injury, repair, and replacement. Inuence of the Mechanical Environment on Tendon and Ligament It is well established that the mechanical environment inuences tendon structure and function. Over the past year, a number of studies have increased our understanding of the effect of mechanical load on tendon and ligament homeostasis, which will provide further insight into the mechanisms underlying tendinopathy and tendon healing. Rumian and colleagues examined the response of the patellar tendon of sheep to stress-shielding in vivo1. Their results suggested that stress-shielding caused a signicant reduction in the structural and material properties of the patellar tendon compared with mechanically loaded controls. They also noted that, on restressing the stress-shielded tendons, there was recovery in terms of the material and structural properties. This in vivo study substantiates previous in vitro work that suggested that mechanical load is necessary for optimal tendon structure and function. Maeda et al. studied gene expression in isolated rat tail tendon fascicles exposed to cyclic tensile strain in vitro2. They investigated the temporal regulation of selected anabolic and catabolic gene expression in tenocytes subjected to tensile strain. Two groups of rat tail tendon fascicles were exposed to cyclic tensile strain with a 3% amplitude superimposed onto a 2% static strain for ten minutes. Following the initial loading, the control group received no additional loading for the remainder of the twenty-four-hour incubation period, whereas the loaded group received continuous cyclic loading over the same time period. Six hours after loading, type-III collagen mRNA expression was signicantly upregulated in the loaded group as compared with the unloaded controls; however, no signicant differences in type-I collagen or biglycan mRNA expression were noted between the two groups. There was signicant downregulation in the expression of the decorin core protein in the loaded group as compared with unloaded controls. Matrix metalloproteinase (MMP-3 and MMP-13) mRNA expression was upregulated by the ten-minute application of cyclic strain in both groups and then showed a downregulation over the course of twenty-four hours in both the presence and absence of load. This study provides useful insight into the balance of anabolic and catabolic gene expression that controls tendon homeostasis. Likewise, this study further substantiates that mechanical load at a physiologic level is necessary to maintain homeostasis. Zhang and Wang also explored the homeostatic balance; however, they did so by mechanically loading isolated tendon stem cells in vitro3. They used a loading system to uniaxially stretch rabbit patellar and Achilles tendon stem cells at either 4% or 8% strain at 0.5 Hz for twelve hours. They then examined the cellular and genetic response to load via quantitative polymerase chain reaction. After 4% uniaxial loading, the tendon stem cells signicantly increased the expression of the genetic marker for type-I collagen but not the genetic markers for adipocytes, chondrocytes, or osteocytes. In contrast, after 8% uniaxial loading, the tendon stem cells signicantly increased expression of the genetic markers for adipocytes, chondrocytes, osteocytes, and tenocytes. This result led the authors to conclude that low levels of mechanical load may have a benecial role in tendon homeostasis whereas higher mechanical loads may be detrimental by promoting tendon stem cells to differentiate into cell types responsible for lipid accumulation, mucoid formation, and tissue calcication, which are all markers of tendinopathy.

Specialty Update has been developed in collaboration with the Board of Specialty Societies (BOS) of the American Academy of Orthopaedic Surgeons.

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benets or a commitment or agreement to provide such benets from a commercial entity.

J Bone Joint Surg Am. 2010;92:2491-501

doi:10.2106/JBJS.J.01174

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Effect of Mechanical Stimulation on Achilles Tendon Healing It is believed that Achilles tendon ruptures that are treated with an initial period of immobilization heal more slowly, whereas early mobilization improves the functional outcome. Recent studies have conrmed that immobilization impairs healing in a rat Achilles tendon rupture model. Schizas et al.4 reported that daily intermittent pneumatic compression treatment can enhance proliferative tendon repair by counteracting biomechanical and morphological decits caused by immobilization. They also noted that the underlying reparative mechanisms may relate to the enhancement of blood ow, neurovascular ingrowth, broblast proliferation, and sensory neuropeptide supply to the healing tendon. Bring and colleagues5 sought to investigate the exact mechanisms responsible for this mechanobiological transduction. They reported changes in gene expression for substance P (NK1) receptor and calcitonin gene-related peptide (CRLR and RAMP-1) receptors and found that longterm immobilization after Achilles tendon rupture led to an inferior healing process. The detrimental effects appeared to be related to a signicant reduction in sensory neuropeptide receptor expression. The effect of mechanical load on the healing rotator cuff tendon was recently evaluated with use of a clinically relevant rodent model of rotator cuff repair and postoperative injection of botulinum toxin A into the muscle to cause paralysis6. The animals were either treated with casting or allowed cage activity ad libitum. The experiment also included a control group of rodents undergoing rotator cuff repair followed by saline solution injection and casting. Animals were killed at seven, fourteen, twenty-one, and fty-six days for histological analysis and at twenty-one and fty-six days for biomechanical evaluations. The saline solution-injected control group had greater scar volume, cross-sectional area, and structural properties when compared with the paralyzed groups. The group treated with paralysis without casting demonstrated improvements in biomechanical properties as compared with the group treated with paralysis with casting. These results led the authors to conclude that complete removal of mechanical load is detrimental to rotator cuff tendon healing. These studies suggest that there is a range of optimal mechanical load that is benecial to tendon or ligament and that loads above or below that range are detrimental. In a series of studies, Soslowsky (winner of this years Kappa Delta Ann Doner Vaughan Award) and colleagues sought to dene the optimal mechanical load range for tendon-bone healing. To elucidate the effects of passive motion on rotator cuff healing, this group utilized a clinically relevant rodent model of rotator cuff repair7. Following rotator cuff transection and repair, animals were separated into three postoperative groups: continuous immobilization, passive motion protocol 1 (600 cycles per day of internal and external rotation at 1 Hz), or passive motion protocol 2 (300 cycles per day of external rotation only at 0.5 Hz). Passive motion protocols were derived from human and dog exor tendon repair studies in which early mobilization had shown a benecial effect on healing. After the initial two postoperative weeks, all three experimental groups underwent a four-week remobilization protocol consisting of cage activity ad libitum for one week followed by gradually increasing treadmill activity over the next three weeks. Passive shoulder joint mechanics were evaluated for each animal prior to assignment to an experimental group and at two and six weeks postoperatively. All animals were killed at six weeks, and their muscle-tendon-bone segments were analyzed either histologically or biomechanically. Total range of motion for both passive motion groups was less than that of the continuous immobilization group at two weeks and remained signicantly lower following the four-week remobilization program. Joint stiffness was also greater in the passive motion groups as compared with the immobilization group at two weeks. At six weeks, there were no differences between the three groups with regard to collagen organization or mechanical properties. The results of this study suggest that immediate postoperative motion has a detrimental effect on range of motion and joint stiffness but may not affect the mechanical properties of the healing tendon-bone interface in a rat model of rotator cuff injury and repair. The authors speculated that passive motion results in increased scar formation in the subacromial space, thereby resulting in decreased range of motion and increased joint stiffness, and concluded that immediate postoperative passive motion was detrimental to passive shoulder mechanics. In a separate study, Peltz et al.8 examined the effects of delayed mechanical loading in the same rat model of rotator cuff repair. In that study, rats were treated with an initial period of immobilization for two weeks, followed by either cage activity or treadmill exercise for twelve weeks following rotator cuff repair. Treadmill exercise resulted in signicant decreases in motion, tendon stiffness, modulus, percentage relaxation, and other structural parameters compared with cage activity ad libitum. The authors concluded that two weeks of immobilization following rotator cuff repair in the rat was not sufcient to allow resolution of postoperative inammation and that at two weeks the healing tendon-bone interface is still relatively immature. Therefore, they concluded that increased activity only serves to produce more disorganized scar tissue and is detrimental to both the shoulder joint mechanics and tendon mechanical properties. One of the many difculties with any in vivo animal model of mechanical loading is accurately and precisely controlling the mechanical load placed on the healing tendon-bone interface. For example, treadmill running places a greater mechanical load on the healing rotator cuff than cage activity ad libitum does, but the absolute difference is difcult to measure. Likewise, the amount of cage activity ad libitum across specimens may vary greatly, as might the amount of cage activity within each specimen across days. To address this limitation, our group has developed a model to precisely control the magnitude, frequency, and duration of mechanical load transferred to

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the healing tendon-bone interface during healing. We use an external xator and a specially designed motorized loading device to apply controlled daily axial strain in a clinically relevant rat model of anterior cruciate ligament reconstruction. Using this model, we recently demonstrated that fty cycles of daily uniaxial cyclic loading (at approximately 2% strain), beginning in a delayed fashion (initiated at either postoperative day 4 or 10), resulted in signicantly greater failure loads at two weeks postoperatively when compared with animals treated with immediate loading or immobilization9. Signicantly increased new-bone formation and tissue mineral content was also observed in the tibial tunnels of the delayed-loading groups as compared with the immediate-loading and immobilization groups at both two and four weeks postoperatively. Increasing the applied axial load to 10% strain resulted in poorer healing across all loading groups. From this work, we have concluded that low levels of controlled mechanical loading may be most favorable to healing after a period of immobilization to allow resolution of postoperative inammation. This suggests that both the timing and the magnitude of mechanical stimulation are important for healing in the perioperative period. The research presented in this section demonstrates the importance of mechanical load for optimum tendon and ligament structure and function. Future research is required to further dene the timing, magnitude, and frequency of postoperative loading (which may vary depending on the tendon, ligament, or joint involved) and the cellular and molecular mechanisms involved in soft-tissue homeostasis and healing. This future research will have clinical implications for guiding postoperative rehabilitation as well as for shaping tissue engineering strategies for tendon and ligament healing and reconstruction. Interface Tissue Engineering for Integrative Soft-Tissue Healing Tissue engineering techniques have been evaluated as a method to accelerate tendon-bone and ligament-bone healing. Current soft-tissue reconstruction and mechanical xation methods fail to restore the native complex enthesis, which may compromise the clinical outcome. With the long-term goal of promoting integrated soft-tissue repair, Lu and colleagues focused on methods to regenerate a functional brocartilage interface on soft-tissue grafts with use of tissue engineering techniques. This group demonstrated that the controlled interaction of interface-relevant cell populations on a stratied scaffold with a biomimetic gradient of structural and functional properties can regenerate tissue with structural properties similar to a soft tissue-bone interface10-12. Recently, Lu et al. reported the design and in vivo evaluation of a triphasic scaffold for the regeneration of the anterior cruciate ligament-to-bone interface11,13. Modeled after the multiple-tissue native insertion site, the scaffold consists of three distinct yet continuous phases: Phase A is designed with a polylactic co-glycolic acid (PLGA) mesh for broblast culture and soft-tissue formation, Phase B consists of PLGA microspheres and is the interface region intended for brocartilage formation, and Phase C is composed of sintered PLGA and 45S5 bioactive glass composite microspheres for osteoblast culture and bone formation. After two months of implantation, the biomimetic stratied scaffold design coupled with spatial control over the distribution of interface-relevant cell populations led to the formation of cell-type and phase-specic matrix heterogeneity, with a brocartilage-like interface formed in triculture. Future development may allow the triphasic scaffold to be used to guide the reestablishment of an anatomic brocartilage interface directly on soft-tissue grafts. The potential of a degradable PLGA nanober-based scaffold system for rotator cuff repair was recently evaluated in vitro12. The authors reported that nanober organization (aligned versus unaligned) was the primary factor guiding human rotator cuff broblast morphology, alignment, and integrin expression. Scaffold mechanical properties were directly related to ber alignment, and although they decreased as the polymer degraded, both the elastic modulus and the ultimate tensile strength remained within range of native supraspinatus tendon. These observations demonstrate the potential of the PLGA nanober-based scaffold system for functional rotator cuff repair. Application of Adult Stem Cells in Tendon-Bone and Ligament-Bone Healing Recent studies have shown success in enhancing ligament healing and tendon-bone osseointegration with use of stem cells. However, there are still inconsistent results. We reported that the addition of bone marrow-derived stem cells to the healing rotator cuff insertion site in a rat model did not improve the structure, composition, or strength of the healing tendon-attachment site despite evidence that the cells are present and metabolically active14. These data suggest that the addition of bone marrow-derived stem cells alone is inadequate to improve healing. However, further study showed that bone marrow-derived stem cells that have undergone adenoviral-mediated gene transfer with mouse scleraxis can improve healing in the same model15. Nourissat et al.16 showed that bone marrow-derived stem cells could promote the production of Achilles tendon enthesis at the bone-tendon junction in a rat model. In addition, transplantation of human anterior cruciate ligament-derived CD341 cells was shown to contribute to tendon-bone healing in a rat model of anterior cruciate ligament reconstruction via enhancement of angiogenesis and osteogenesis17. In summary, adult stem-cell therapy represents a potential strategy for tendon-bone and ligament-bone healing. A Bioactive Scaffold-Collagen Platelet Composite Enhances Anterior Cruciate Ligament Healing Murray and colleagues evaluated a collagen platelet composite as a tissue engineering approach to augment anterior cruciate

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ligament healing. Collagen platelet composite is a bioactive collagen-based scaffold inltrated with platelets that has a positive effect on the healing of an anterior cruciate ligament graft, both in terms of improving the strength of the graft and in terms of reducing knee laxity after anterior cruciate ligament reconstruction18. Moreover, in an anterior cruciate ligament suture-repair model, Murray and colleagues reported that anterior cruciate ligament repairs supplemented with collagen platelet composite enhanced the structural properties of the anterior cruciate ligament19. The improvement was associated with increased cellularity within the healing ligament. However, the use of a collagen scaffold alone to enhance suture repair of the anterior cruciate ligament was ineffective20. Effect of MMPs and ADAMTS on Tendon Healing Recent studies demonstrate a potentially critical role of matrix metalloproteinases (MMPs) and their inhibitors in the pathophysiology of rotator cuff tears. Our group reported that doxycycline treatment after supraspinatus tendon repair in a rat model signicantly improved collagen organization at the healing enthesis, reduced MMP-13 activity, and increased load to failure21. The tetracycline family of antibiotics inhibits mammalian matrix metalloproteinase activity by a mechanism that is independent of their antimicrobial activity. Modulation of MMP-13 activity after rotator cuff repair may offer a novel biological pathway to augment tendon-bone healing. Bell et al. reported on the geometric, viscoelastic, and mechanical properties of exor digitorum longus and Achilles tendons of ADAMTS-5-decient, ADAMTS-4-decient, and wild-type mice22. The unique biomechanical changes in the exor digitorum longus as compared with the Achilles tendon in the absence of ADAMTS-4 and ADAMTS-5 indicate important roles of these enzymes in regulating tendon-specic cell biological and matrix structural characteristics. Cytokines and Scaffolds to Accelerate Tendon-Bone and Ligament-Bone Healing Recent studies have continued to evaluate the role of cytokines and scaffolds in soft-tissue healing. Derwin et al. reported that augmentation of acute repair of rotator cuff tendons with a newly designed poly-L-lactide repair device improved functional and biomechanical outcomes in a canine model23. The poly-L-lactide repair device provided a tendon-bone bridge and scaffold for host tissue deposition and ingrowth, resulting in enhanced healing after rotator cuff injury. Kadonishi and colleagues applied enamel matrix derivative with propylene glycol alginate as a carrier to the tendon-bone junction in a rat anterior cruciate ligament reconstruction model and found that enamel matrix derivative could accelerate tendon-bone healing with upregulation of Sharpey ber formation24. At this years annual meeting of the Orthopaedic Research Society, several groups described the positive effects of cytokines on tendon-bone and ligament-bone healing. Fox et al. reported that augmentation with TGFb-3 in a calciumphosphate matrix improved the histological and biomechanical properties of the healing enthesis in a rat rotator cuff repair model25. Hee and colleagues showed that the application of low or intermediate-dose rhPDGF-BB (75 or 150 mg) combined with a type-I bovine collagen matrix as an interpositional graft at the site of rotator cuff repair augmented and improved tendon reattachment as evaluated biomechanically and histologically in an ovine model26. Leonard and colleagues reported that combining the anabolic effects of TGF-b1 and bFGF with the potent anticatabolic properties of alpha-2 macroglobulin enhanced primary repair of a surgically transected anterior cruciate ligament in a New Zealand white rabbit model27. These results further support the potential role of growth factors as a therapeutic treatment for the augmentation of soft-tissue healing. Tendon Stem Cells and Treatment of Tendinitis Stem cells have attracted much interest because of their selfrenewing potential and multipotentiality for possible clinical use. Recent studies have involved the isolation and characterization of tendon stem cells from human, mouse, and rat tendon and ligament. These cells exhibited the universal stem cell properties of clonogenicity, self-renewal capacity, multipotency, and specic marker expression in culture28,29. Furthermore, mouse treadmill running for three weeks (i.e., moderate loading) was found to increase the proliferation of tendon stem cells with increased collagen production30; thus, tendon stem cells may play a vital role in maintaining homeostasis of tendons when mechanically challenged. Tendon injuries and tendinitis are notorious for their slow and functionally inferior healing. Several groups recently have used stem cells and other approaches to treat collagenaseinduced tendinitis in an animal model. Nixon and colleagues reported that mesenchymal stem cell (MSC), IGF-I geneenhanced mesenchymal stem cell (Ad-IGF-MSC), and embryonic stem cell injection into collagenase-induced lesions in horse exor digitorum supercialis tendons resulted in signicantly improved tendon biochemical composition and histological and mechanical characteristics, indicating a benet of stem cells for the treatment of tendinopathy 31,32. Meniscal Tissue Engineering Several recent studies have examined the effect of dynamic tension on tissue-engineered meniscus. At this years annual meeting of the Orthopaedic Research Society, Ballyns and Bonassar examined the effect of mechanical load on bovine meniscal brochondrocytes suspended in 2% (weight per volume) alginate33. These constructs were loaded via a custom bioreactor for an hour twice every other day with an hour of rest for two weeks between loading cycles. The authors found that dynamic compression signicantly enhanced extracellular matrix production and the mechanical properties of anatomically shaped tissue-engineered menisci. Baker et al. also examined the effect of cyclic tensile conditioning on a human

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meniscus brochondrocyte-laden nanober material34. The constructs were cyclically loaded to 6% tensile strain at 1 Hz in the bioreactor for three hours each day for two weeks. The authors found that dynamic tensile loading increased the mechanical properties of engineered nanober-based meniscal constructs. A cell-based tissue-engineered construct is another promising approach employed for the treatment of meniscal lesions. Yoo et al.35 developed a dynamic cell-seeding technique and a novel in vivo mouse model with use of a three-layered construct (chondrocyte-seeded scaffold placed between devitalized meniscal discs) to assess the seeding and culture conditions (static and dynamic) for the scaffolds and the healing capacity of the cell-seeded scaffolds in a meniscal repair model. The authors reported a continuous layer of new brous and cartilaginous tissue integrating into the native devitalized meniscus tissue in all of the dynamically cultured samples, raising the possibility that meniscal lesions could be repaired with use of isolated articular chondrocytes seeded onto an appropriate degradable scaffold. Platelet-Rich Plasma Platelet-rich plasma is an autologous blood product that is being increasingly used to treat musculoskeletal conditions. Platelets have a rich store of factors and cytokines within their alpha granules and dense granules, which makes platelet-rich plasma an appealing therapeutic alternative. Some of the important factors found within the alpha granules of the platelet include platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-b), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), among others. The dense granules of the platelet contain neuromodulators and inammatory modulators such as histamine and serotonin. Platelets are stimulated to release these growth factors and cytokines by exposure either to collagen36 or to thrombin and calcium. Research into this therapy has expanded exponentially over the last several years. Platelet-Rich Plasma in Tendon and Muscle Healing Randomized clinical trials involving platelet-rich plasma are limited, but over the last year, several key studies have been published, with both positive and equivocal results. A randomized, double-blind, placebo-controlled trial demonstrated no signicant differences between patients managed with either platelet-rich plasma or saline solution injections for the treatment of chronic Achilles tendinopathy37. In a recent abstract presented at the annual meeting of the American Orthopaedic Society for Sports Medicine, Kauffman and colleagues reported no signicant differences in clinical outcomes between platelet-rich-brin-membrane-augmented rotator cuff repairs and controls38. Zumstein et al. noted in a prospective, randomized trial that platelet-rich-brin-augmented rotator cuff repairs demonstrated greater vascularization compared with controls (as measured with power Doppler ultrasound) at six weeks postoperatively but not at three months39. Recent animal studies evaluating platelet-rich plasma and tendon healing have shown positive results. A placebocontrolled trial in horses that was performed to evaluate the effect of platelet-rich plasma on the quality of supercial digital exor tendon repairs of front limbs (one treated with plateletrich plasma, the other treated with saline solution) demonstrated that, after twenty-four weeks, the repair tissue in the platelet-rich plasma group had higher failure strength and greater elastic modulus. On histological examination, plateletrich plasma-treated tendons showed better collagen organization and signs of increased metabolic activity40. The literature on platelet-rich plasma and muscle healing is limited. However, platelet-rich plasma recently was shown to have a positive effect on muscle strain healing in a rat model, with improvements in mechanical testing outcomes and muscle regeneration41. It is speculated that platelet-rich plasma may stimulate muscle satellite cells, explaining the increased muscle regeneration. Platelet-Rich Plasma and Ligament Healing In their prospective, single-blinded study of fty anterior cruciate ligament reconstructions in fty patients, Radice et al. found that anterior cruciate ligament grafts that were treated with platelet-rich plasma gel achieved complete intra-articular homogeneity on magnetic resonance imaging in an average of 179 days, compared with 369 days for anterior cruciate ligament reconstruction without platelet-rich plasma gel42. A recent animal study demonstrated no positive effect of adding platelet-rich plasma to suture repairs of anterior cruciate ligaments in a pig model43. In that study, platelet-rich plasma failed to improve maximum tensile load or linear stiffness of the anterior cruciate ligament repairs after fourteen weeks in vivo. However, earlier work by Murray et al.44 demonstrated a signicant increase in load at yield, maximum load, and linear stiffness at four weeks after anterior cruciate ligament suture repair augmented with collagen-platelet-rich plasma hydrogel in a pig model, suggesting the importance of an appropriate matrix scaffold to support healing with platelet-rich plasma. Platelet-Rich Plasma and Bone Healing The effects of platelet-rich plasma on bone healing have been mixed in the literature. Bi et al.45 found that an injectable scaffold (tricalcium phosphate/chitosan) with platelet-rich plasma led to complete healing of tibial defects in a goat model, at sixteen weeks, with improved mechanical strength, biocompatibility, and osteoinductive properties as compared with controls. However, platelet-rich plasma also has been shown to interfere with the complete differentiation of human osteoclast precursors, with higher concentrations impairing osteoclast formation at earlier stages of differentiation46. Platelet-rich plasma also was shown to inhibit bone deposition

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in a rabbit calvarial model47. Furthermore, the combination of mineralized collagen and platelet-rich plasma had no signicant osteoinductive effect in a model of sheep cervical discectomy and fusion48. In a clinical study, Hartmann et al. found that platelet-rich plasma added to bone graft in spinal fusions had the same rate of complete fusion on computed tomography as controls49. Further study on the effects of platelet-rich plasma on both mineralized and soft-tissue healing is required. The molecular mechanism by which platelet-rich plasma affects the area of injury is still unknown. Many other clinical questions remain unanswered, particularly with regard to the timing of therapy, the volume and frequency of treatment, and the optimum vehicle for distribution of the platelet-rich plasma formulation that will allow for sustained growth factor and cytokine release. An increased understanding will allow for more educated use of this increasingly popular therapy. Muscle Biology and Molecular Pathways in Rotator Cuff Tendon Tears A common clinical problem is muscle atrophy and progressive fatty inltration following rotator cuff muscle-tendon injury. These abnormalities appear to be largely irreversible and can adversely affect clinical outcome following rotator cuff repair. In their chronic rotator cuff model in sheep, Frey et al. found that both Myf-5 (a myogenic transcription factor) and PPARg (an adipogenic transcription factor) expression were signicantly increased after infraspinatus tenotomy, providing evidence that upregulation of adipogenic transcription factors can occur simultaneously with muscle regeneration50. Continuous traction on the infraspinatus tendon led to increases in Myf-5 and C/EBPb (adipogenic transcription factor) expression; this was followed by decreases in these factors after tendon xation. The authors concluded that both adipogenic and myogenic gene transcription factors play a role in chronic rotator cuff tendon tears in sheep. A recent study provided evidence implicating Wnt signaling in the molecular mechanism of fat accumulation in rotator cuff muscles with ruptured tendons51. In the in vitro portion of the study, the authors noted that reduction of Wnt10b expression was associated with adipogenic differentiation of myoblasts. Mimicking canonical Wnt signaling with lithium chloride led to adipogenesis inhibition in vitro. In the in vivo portion of the study, the authors noted that rat rotator cuff muscles with torn tendons had decreased gene expression of Wnt10b. They concluded that the reduction in Wnt10b may be a possible molecular mechanism for fat accumulation in rotator cuff muscles with torn tendons. Muscle Healing In a rat muscle contusion model, ebselen, an oxygen free radical scavenger (glutathione peroxidase mimic), was shown to have a positive effect on microcirculation after trauma. Ebselen was found to restore muscle perfusion and inammatory cell interaction to levels found in the noninjured muscle tissue of controls at twenty-four hours after injury, suggesting that ebselen may have a positive effect on posttraumatic circulation and may protect skeletal muscle from inammatory tissue damage52. Using a mouse contusion model, Uehara et al. reported that losartan, an angiotensin receptor blocker, could accelerate skeletal muscle strength recovery, possibly through the expression of follistatin, a positive regulator of skeletal muscle growth53. The same group also reported on the use of muscle-derived stem cells to accelerate skeletal muscle healing after contusion injury54. A number of recent studies have investigated the effects of matrix metalloproteinases and their inhibitors on muscle healing. A synthetic MMP-1 inhibitor was found to increase brosis and to reduce the percentage of cells expressing stem cell markers, suggesting that MMP-1 may play a role in muscle healing and regeneration55. In another study, MMP-2 inhibitor was shown to reduce skeletal muscle atrophy in a mouse Achilles tendon transection model56. The same group also found that deletion of the MMP-9 gene helped to preserve muscle force generation following Achilles tendon transection in the same mouse model57. Bearing Surface Materials for Total Joint Arthroplasty Ultra-high molecular weight polyethylene (hereafter called polyethylene) is a semicrystalline polymer consisting of discrete amorphous and crystalline regions that confer distinct mechanical characteristics to the polymer. For example, while cracks can readily move through crystalline areas, the disorganized amorphous areas have the effect of blunting the cracks. Efforts to improve the wear resistance of polyethylene have focused on increasing the degree of molecular crosslinking with use of ionizing radiation. While increased crosslinking has been shown to reduce wear rates, the crosslinking occurs primarily in the amorphous phase, which also has the potentially undesirable consequence of reducing material fracture toughness. In the quest to balance high fracture toughness with good wearresistance properties, Oral et al. recently proposed a novel technique to produce a depth-dependent variation in crosslink density 58. Vitamin E, which blocks crosslinking, is infused into polyethylene liners in a depth-dependent manner. A high level of vitamin E is infused into the bulk material, whereas a low level is infused into the surface; the entire liner is then subjected to irradiation. The method of manufacture resulted in a material with a high level of crosslinking at the surface (conferring improved wear resistance to this region), whereas the bulk of the material had a much lower level of crosslinking (thereby preserving its fatigue characteristics). The process of crosslinking polyethylene also results in trapped residual free radicals, which over time lead to oxidative degradation and embrittlement. Post-irradiation treatments to eliminate the free radicals involve heating the material to a temperature that is either above or below its melting point (remelting and annealing, respectively). The ability of either

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approach to fully eliminate residual free radicals and thereby avoid in vivo oxidative degradation is being explored by a number of investigators. At the recent annual meeting of the Orthopaedic Research Society, Currier et al. reported that the free radical concentration and oxidative index of annealed and remelted highly crosslinked polyethylene liners and tibial trays in knee arthroplasty implants were measured as a function of time59. Pristine, never-implanted annealed and remelted components were assessed immediately after removal from their protective packaging and after shelf-aging in air. Eightyfour retrieved bearings from both annealed and remelted groups that had been implanted for periods of up to ten years were also assessed. The authors found free radicals in the neverimplanted annealed components, whereas free radicals were not found in the remelted group. The free radical content increased in the annealed components as a function of time of shelf-aging, whereas that of the remelted components did not. Finally, oxidation was present in the retrieved annealed and remelted components, both of which increased as a function of time after in vivo implantation. The clinical relevance of these ndings will only become clear as the number of retrieved annealed and remelted implants increases. Nonetheless, the data suggest that careful monitoring of highly crosslinked polyethylene components is warranted. Metal-on-metal is the only bearing combination available for use in surface replacements. However, concerns over the consequences of the release of metal ions into the local and systemic environment have led to a number of studies aimed at gaining a more thorough understanding of the wear mechanisms of this bearing combination. While it has been previously shown that a tribological reactive layer exists between the surfaces of metal-on-metal articulations, the constituents of that layer and its role in wear have only recently been explored. In a seminal paper, Wimmer et al. described the layer as a nanocrystalline composite of synovial uid-derived organic material, ceramic, and metallic constituents60. Moreover, the tribological reactive layer was associated with changes in the bearing surface from that of a purely metallic composition to that of an organic-metal composite. Given the contents of the layer and the associated changes in the bearing surface material, it is likely that the presence of this layer avoids direct metal-on-metal contact, which in turn helps to explain the absence of adhesive wear in these bearing systems61. The authors hypothesized that encouraging the formation and stability of this layer may reduce wear rates and ion release from this bearing combination. Whats New in Spine Basic Research Highlights in spine research include advancements in growthfactor delivery, the emergence of a possible naturally occurring comparative model for idiopathic scoliosis, new markers and physiology description for the intervertebral disc, and renements in tissue engineering toward a biological articial disc. Clinical use of bone morphogenetic protein (BMP) as an autograft substitute for spine fusion has become more and more prevalent, adding to the already burdensome cost of biological and durable spinal implants. Currently, the most widely used BMP in spine surgery is BMP-2 (INFUSE; Medtronic, Minneapolis, Minnesota), which is delivered in milligram doses after soaking and adhesion onto collagen sponges. Preclinical studies demonstrated that the collagen sponge is important for BMP delivery as it allows the growth factor to be localized and easily manipulated while limiting the immediate diffusion of BMP from the site of implantation. To better limit the diffusion of BMPs away from their site of implantation, a synthetic BMP binding protein (BBP) has been developed62. BBP is a cyclic nineteen-amino-acid peptide that potentiates the in vitro and in vivo osteoinductive capacity of BMP-2 and BMP-7 by tightly binding the BMPs and acting as a slow-release reservoir63,64. The afnity of BBP for binding BMP-2 is in the 0.5-nanomolar range, whereas the afnity for binding BMP-7 is in the micromolar range64. This tight binding was shown to produce a much slower elution of BMP-2, with approximately twofold more BMP-2 being retained at serial time points up to one week when codelivered with BBP64. Interestingly, using the most effective ratios for BBP and the BMPs, the investigators were able to obtain 90% fusion rates in a rat posterolateral spine fusion model with use of BMP-2 or BMP-7 dosing that was 10% or 30% of the standard respective dosing used to obtain 100% fusion. These studies suggest that further improvement of the BBP or other similar methods to create slow release of BMPs after implantation may allow the use of smaller BMP doses clinically, providing improved safety from inammatory complications, reduction in the cost of these expensive biological agents, and, possibly, greater availability of BMPs. Adolescent idiopathic scoliosis continues to attract considerable attention from investigators attempting to describe causes for this condition. Separate groups recently have reported adolescent idiopathic scoliosis-associated genes on the long arm of chromosome 18 with use of genetic linkage analysis65, case-control methodology, and polymerase chain reaction sequence analysis demonstrating an association between adolescent idiopathic scoliosis and specic estrogen receptor polymorphisms66. Cellular and molecular biology analyses of tissue samples from patients and controls have suggested that the leucine-rich repeat protein chondroadherin may be useful as a marker for adolescent idiopathic scoliosis67. Collectively, these studies help to better dene the multifactorial causes of adolescent idiopathic scoliosis. Adolescent idiopathic scoliosis has been found to be sevenfold to eightfold more common in girls than boys, to more commonly affect tall and thin children, and to show rapid progression of curves during peak growth velocity in adolescents. Idiopathic scoliosis does not appear to spontaneously occur commonly in other vertebrates, and comparative models of scoliosis have required pinealectomy, vertebral column

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stapling or tethering, or other similar procedures. Recent studies have evaluated curveback guppies as a comparative model of spontaneous adolescent idiopathic scoliosis68,69. Those studies demonstrated that there is a female bias for severe curves69, that sh with more severe curves have longer corrected-length tails68, and that spine curvatures are typically stable by the time the sh reach sexual maturity68, ndings that are all quite similar to those associated with human adolescent idiopathic scoliosis. The spinal deformity in the curveback guppy is in the sagittal plane (kyphosis and lordosis) and therefore does not look identical to the classical coronal deformity associated with adolescent idiopathic scoliosis. This may prove to be an extremely useful model for further genetic studies investigating how specic genetic manipulations affect the sagittal curvature, spine growth, and other structural observations (vertebral size, morphology, and position). Intervertebral degenerative disc disease is another hot topic in basic science spine investigations. Degenerative disc disease has considerable nancial impact in terms of medical resource utilization and days of lost work. The ability to detect degenerative disc disease earlier in the course of the disease may help to initiate appropriate treatment more quickly, and an improved understanding of the normal physiology of the disc and the pathogenesis of degenerative disc disease may help to guide therapies to stop or reverse the process. The intervertebral disc is an avascular structure with large amounts of hydrated proteoglycan and collagens I and II as well as smaller amounts of other structural and regulatory proteins. Sakai et al. identied alpha-2-macroglobulin (A2M) and neural cell adhesion molecule (NCAM) as two additional molecules present in relative abundance in the nucleus pulposus70. A2M is a potent proteinase inhibitor and is thought to act as an aggrecanase inhibitor in the disc, whereas NCAM is a cell surface protein involved in contact-mediated cell interactions and plays an important role in the nervous system and in multiple tissues during development. Each of these proteins is thought to play a role in maintaining the normal physiology of the intervertebral disc. Iida et al., using rat and human disc cells, reported that proteinase-activated receptor-2 (PAR-2) is upregulated in severely degenerated discs71. They reported that PAR-2 activation results in upregulation of mRNA levels of catabolic ADAMTS and matrix metalloproteinases, demonstrating that the degenerative disc tissue itself contributes to the expression of extracellular matrix-destroying enzymes that further damage the disc extracellular matrix in a vicious cycle. Singh et al. and Furukawa et al. reported complementary ndings concerning the small leucine-rich repeat proteoglycan protein biglycan72,73. Small proteoglycans are thought to be important for regulating collagen bril formation and are known to interact with several extracellular matrix molecules; however, the specic function of biglycan is not known. With use of human disc tissue samples from donors ranging in age from thirty-two to eighty years, biglycan levels were shown to increase in disc tissues with age, a nding suggesting that biglycan is upregulated to preserve the disc and to prevent degeneration72. Similarly, biglycan-decient mice demonstrate greatly accelerated disc degeneration at early ages in comparison with control animals, suggesting that biglycan is important for disc homeostasis. Combining the results of these studies for guiding therapeutics suggests that upregulation of A2M or biglycan or downregulation of PAR-2 early in the degenerative disc disease process may help to stop progression of the disease process and may be valuable markers in comparative studies assessing molecular therapies74-76. Tissue engineering a biological alternative for total disc replacement involves the development of a scaffold that resembles the intervertebral disc and reproduces its mechanical properties, the establishment of cell populations capable of becoming native to the anulus brosus and nucleus pulposus, and stable integration of the composite engineered disc into the graft site. Recent advances have been made in the rst two of these steps. Elliott and colleagues reported an update on their work with electrospun nanobrous scaffolds to produce anulus brosus-like tissue77,78. Their earlier work utilized a poly-epsilon-caprolactone scaffold seeded with bovine anulus brosus cells and showed that the tissue had increasing glycosaminoglycan and collagen production over time as well as improvement in mechanical properties. The subsequent study involved the use of agarose to create a nucleus pulposus and a nanobrous scaffold seeded with bovine mesenchymal stem cells showing mechanical properties, matrix production, and cell morphologies similar to the native tissues as the discs matured in long-term in vitro culture. A somewhat different approach for disc tissue engineering was reported by Bowles et al.79. With this approach, a collagen gel is seeded with ovine anulus brosus cells and then is allowed to contract in culture around a polyethylene or alginate central nucleus pulposus. Contraction and collagen orientation were measured, and the authors concluded that, with optimization of the technique, replication of the native collagen alignment observed in the disc should be possible. Regarding cell populations for seeding onto scaffolds, there have been reports that multipotent cells derived from fat make adequate donor cells to repopulate the nucleus pulposus in a canine model80 and that similar multipotent cell populations exist in the nucleus pulposus81 and anulus brosus82 in humans and comparative models83. Successful production of these rst-generation composites of in vitro tissue-engineered discs suggests that biological total disc replacements are feasible. The methods and technology for securing these tissueengineered discs into surgically prepared disc spaces will be an area of future investigation. Articular Cartilage Recently, there have been several important advances in understanding the genetic predisposition to cartilage deterioration, and, as a result, proteomic proling for cartilage and arthritis research is within reach of becoming a clinical tool. Genetic and

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proteomic tools can be used to identify a genetic predisposition to a disorder, and the resulting information can be leveraged to identify therapeutic targets to address the pathology that results from the genetic variation. As an example, in one study, a variant on chromosome 7 (the C allele of re3815148 on chromosome 7q22) was found that inuences susceptibility to the prevalence and progression of osteoarthritis84. The gene at this site encodes for GPR22, a G protein-coupled receptor that might serve as a therapeutic target. Another study demonstrated that osteoarthritis-related biomarkers exhibit heritability85. In a large multigenerational extended family, osteoarthritis-related biomarkers including hyaluronan, cartilage oligomeric matrix protein, N-propeptide of type-IIA collagen, and type-II collagen neoepitope were found to have substantial heritable components. With use of a gene-comparison approach, another report showed clear differences in gene-expression proles between patients with Kashin-Beck disease, which is endemic in children three to twelve years of age in northwestern China, and those with primary osteoarthritis from non-Kashin-Beck-endemic areas in northwestern China86. These results challenge the paradigm that Kashin-Beck is caused by environmental pressures (such as mycotoxin producing fungi in cereal, humic acid in drinking water, or selenium deciency) and rather suggest that there is an underlying genetic basis for the disorder. Collectively, genetic approaches will provide a quantiable basis to further our understanding of the multifactorial nature of osteoarthritis regardless of race or ethnicity and to identify potential therapeutic targets. Proteomic proling of osteoarthritis will provide a clearer picture of the biological activity present during any stage of cartilage degeneration or repair. Genomics identies possible candidate genes involved in cartilage degeneration, but genomic studies do not tell the whole story. They do not take into account post-translational modication of proteins or proteinprotein interactions, nor do they account for the effects of drugs such as corticosteroids on protein function. Blood, plasma, serum, urine, cartilage, synovial membrane, or synovial uid have all been subjected to proteomic analysis and have identied novel protein biomarkers of osteoarthritis87. These same technologies have been employed in basic-science investigations to identify novel proteins involved in cartilage development and the early response to mechanical stress in chondrocytes88. A clinical vision for proteomic and genomic applications in cartilage research is to provide a test to determine a patient and stage-specic biological and biochemical prole. This information could then be used to generate a personally unique diagnosis and targeted treatment plan to address that specic individuals disease characteristics and symptoms. Conclusions The pace of orthopaedic basic research continues to quicken and expand. The development of new laboratory tools and techniques have resulted in continued advances in basic orthopaedic research. The challenge for orthopaedic clinicians is to develop ways to test these basic ndings in rigorous clinical trials. Ultimately, clinician-scientists need to help dene the agenda for translational research studies.

Scott A. Rodeo, MD Demetris Delos, MD Alex Weber, MD Xiaodong Ju, MD Matthew E. Cunningham, MD, PhD Lisa Fortier, DVM, PhD Suzanne Maher, PhD The Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for S.A. Rodeo: rodeos@hss.edu

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