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Journal of Orthopaedic Research
Wiley InterScience : Journal of Orthopaedic Research

  • Altered lumbar spine structure, biochemistry, and biomechanical properties in a canine model of mucopolysaccharidosis type VII
    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disorder characterized by a deficiency in [beta]-glucuronidase activity, leading to systemic accumulation of poorly degraded glycosaminoglycans (GAG). Along with other morbidities, MPS VII is associated with pediatric spinal deformity. The objective of this study was to examine potential associations between abnormal lumbar spine matrix structure and composition in MPS VII, and spine segment and tissue-level mechanical properties, using a naturally occurring canine model with a similar clinical phenotype to the human form of the disorder. Segments from juvenile MPS VII and unaffected dogs were allocated to: radiography, gross morphology, histology, biochemistry, and mechanical testing. MPS VII spines had radiolucent lesions in the vertebral body epiphyses. Histologically, this corresponded to a GAG-rich cartilaginous region in place of bone and elevated GAG staining was seen in the annulus fibrosus. Biochemically, MPS VII samples had elevated GAG in the outer annulus fibrosus and epiphyses, low calcium in the epiphyses, and high water content in all regions except the nucleus pulposus. MPS VII spine segments had higher range of motion and lower stiffness than controls. Endplate indentation stiffness and failure loads were significantly lower in MPS VII samples, while annulus fibrosus tensile mechanical properties were normal. Vertebral body lesions in MPS VII spines suggest a failure to convert cartilage to bone during development. Low stiffness in these regions likely contributes to mechanical weakness in motion segments and is a potential factor in the progression of spinal deformity. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Repair of large osteochondral defects in rabbits using porous hydroxyapatite/collagen (HAp/Col) and fibroblast growth factor-2 (FGF-2)
    Articular cartilage has a limited capacity for self-renewal. This article reports the development of a porous hydroxyapatite/collagen (HAp/Col) scaffold as a bone void filler and a vehicle for drug administration. The scaffold consists of HAp nanocrystals and type I atelocollagen. The purpose of this study was to investigate the efficacy of porous HAp/Col impregnated with FGF-2 to repair large osteochondral defects in a rabbit model. Ninety-six cylindrical osteochondral defects 5 mm in diameter and 5 mm in depth were created in the femoral trochlear groove of the right knee. Animals were assigned to one of four treatment groups: porous HAp/Col impregnated with 50 µl of FGF-2 at a concentration of 10 or 100 µg/ml (FGF10 or FGF100 group); porous HAp/Col with 50 µl of PBS (HAp/Col group); and no implantation (defect group). The defect areas were examined grossly and histologically. Subchondral bone regeneration was quantified 3, 6, 12, and 24 weeks after surgery. Abundant bone formation was observed in the HAp/Col implanted groups as compared to the defect group. The FGF10 group displayed not only the most abundant bone regeneration but also the most satisfactory cartilage regeneration, with cartilage presenting a hyaline-like appearance. These findings suggest that porous HAp/Col with FGF-2 augments the cartilage repair process. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Comparative study of carpal tunnel compliance in the human, dog, rabbit, and rat
    The purpose of this study was to measure the compliance of the carpal tunnel in candidate animal models of carpal tunnel syndrome (CTS), by measuring the resistance when passing a tapered metal rod through the carpal tunnel. Forepaws from 10 dogs, 10 rabbits, and 10 rats with intact carpal tunnels, and 10 fresh frozen human wrist cadavers were used. The slopes of the linear part of the force-displacement curve (a measure of stiffness), normal force, and increasing area ratio (InAR) were significantly different among the four species (p < 0.05). Post hoc analysis indicated that the mean slopes for the human carpal tunnel were the largest, indicating the least compliance, whereas those of the rat were the least (p < 0.05). The features of the compliance for the dog carpal tunnel were closest to the human. The development of animal models of CTS should consider the compliance of the carpal tunnel, as it will be more difficult to increase pressure in a more compliant tunnel. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Lack of quadriceps dysfunction in women with early knee osteoarthritis
    Quadriceps dysfunction, specifically weakness and central activation failure (CAF), has been implicated in the development and progression of knee osteoarthritis (OA), though few data are available to confirm its presence in early OA. The purpose of this study was to determine the presence and magnitude of quadriceps dysfunction in those with and without early knee OA. Thirty-five female volunteers were classified into two groups, OA (n = 22) and control (n = 13), based on the presence [Kellgren-Lawrence (K-L) grade 2] or absence (K-L grade 0-1) of mild OA, respectively. Isometric quadriceps strength and central activation ratio (CAR) were assessed and compared between groups utilizing a one-way ANOVA. Frequency statistics and Fisher's exact test were used to compare the percentage of women with and without CAF between groups. Quadriceps strength (control: 1.47 ± 0.62 Nm/kg; OA: 1.30 ± 0.62 Nm/kg; p = 0.45) was not significantly different for women with and without mild OA. Further, the CAR (control: 0.91 ± 0.07; OA: 0.87 ± 0.12; p = 0.19) did not differ between groups; however, women in both groups presented with CAF (control: 54%; OA: 73%; p = 0.29). Our results suggest that the women with mild osteoarthritis do not present with quadriceps dysfunction. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Mechanobiological response of tendon stem cells: Implications of tendon homeostasis and pathogenesis of tendinopathy
    Tendons are constantly subjected to mechanical loading in vivo. Recently, stem cells were identified in human, mouse, and rabbit tendons, but the mechanobiological responses of tendon stem cells (TSCs) are still undefined. Using an in vitro system capable of mimicking in vivo loading conditions, it was determined that mechanical stretching increased TSC proliferation in a stretching magnitude-dependent manner. Moreover, low mechanical stretching at 4% ("clamp-to-clamp" engineering strain) promoted differentiation of TSCs into tenocytes, whereas large stretching at 8% induced differentiation of some TSCs into adipogenic, chondrogenic, and osteogenic lineages, as indicated by upregulated expression of marker genes for adipocytes, chondrocytes, and osteocytes. Thus, low mechanical stretching may be beneficial to tendons by enabling differentiation of TSCs into tenocytes to maintain tendon homeostasis. However, large mechanical loading may be detrimental, as it directs differentiation of TSCs into non-tenocytes in tendons, thus resulting in lipid accumulation, mucoid formation, and tissue calcification, which are typical features of tendinopathy at later stages. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Influence of bone-derived matrices on generation of bone in an ectopic rat model
    Most bone regeneration experimental models that test bone-derived matrices take place in conjunction with the native bone. Here, we compared the relative effectiveness of bone matrix components on bone-marrow-directed osteogenesis in an ectopic model. Cortical bone cylinders consisted of diaphysis of DA rat femurs. They were either demineralized (DBM), deproteinized (HABM), or nontreated (MBM). Fresh bone marrow was placed into cylinders and implanted at subcutaneous thoracic sites of 2-month-old DA rats. At designated times the cylinders were surgically removed from the animals. Microradiographs of DBM and histology of DBM and MBM cylinders demonstrated progressive increase in mineralized bone volume and its trabecular configuration. Bone filled the inner volume of DBM and MBM cylinders within 4 weeks, while in HABM cylinders mostly granulation tissue developed. In the DBM cylinders cartilage deposited within 10 days, while in the MBM cylinders bone was directly deposited. As early as day 3 after marrow transplantation, marrow cells interacting with DBM increased significantly the genes that express the cartilage and the bone phenotype. In conclusion, organic components of bone are needed for marrow-directed osteogenesis. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Recombinant human bone morphogenetic protein-7 enhances fracture healing in an ischemic environment
    Ischemia predisposes orthopedic trauma patients to delayed fracture healing or nonunion. The goal of this study was to test the ability of bone morphogenetic protein 7 (BMP7) to stimulate fracture repair in an ischemic environment. Ischemic fractures were generated in male adult mice by resecting the femoral artery prior to the creation of a nonstabilized tibia fracture. Recombinant human BMP7 (rhBMP7, 50 µg) was injected into the fracture site immediately after surgery. At 7 days after injury, more tissue vascularization was observed in rhBMP7 treated fractures. Histomorphometric analyses revealed that rhBMP7 induced more cartilage at day 7, more callus and bone at days 14 and 28, and more adipose tissue and fibrous tissue at days 7, 14, and 28 compared to controls (n = 5/group/time). At day 28, all fractures treated with rhBMP7 (50 µg, n = 5) healed, whereas only three of five control fractures exhibited slight bony bridging. In addition, we found that rhBMP7 (both 10 and 50 µg) significantly increased the amount of cartilage compared to controls in stabilized fractures, confirming its chondrogenic effect. Lastly, using bone marrow transplantation, we determined that no donor-derived osteocytes or chondrocytes were present in rhBMP7-treated fractures, suggesting rhBMP7 did not recruit mesenchymal stem cells from the bone marrow to the fracture site. In conclusion, our results indicate that rhBMP7 is a promising treatment for fractures with severely disrupted blood supply. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Engineering scaffold-free bone tissue using bone marrow stromal cell sheets
    The use of exogenous scaffolds to engineer bone tissue faces several drawbacks including insufficient biological activity, potential immunogenicity, elevated inflammatory reaction, fluctuating degradation rate, and low cell-attachment efficiency. To circumvent these limitations, we sought to engineer large scaffold-free bone tissue using cell sheets. We harvested intact cell sheets from bone marrow stromal cells using a continuous culture method and a scraping technique. The cell sheets were then rolled and fabricated into large constructs. Finally, the constructs were implanted into the subcutaneous pockets of nude mice. The cells within the sheet maintained in vitro osteogenic potential after osteoblast differentiation. Computed tomography scans and histological examination confirmed new bone formation in vivo. Additionally, the engineered bone exhibited enhanced compressive strength. Our results indicate that the BMSC sheets can facilitate the formation of functional three-dimensional bone tissue without the use of exogenous scaffolds. Hence, the study provides an intriguing alternative strategy for bone repair. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Effect of gradual weight-bearing on regenerated articular cartilage after joint distraction and motion in a rabbit model
    The purpose of this study was to clarify the effect of gradual weight bearing (GWB) on regenerating cartilage. We developed a novel external fixation device (EFD) with a controllable weight-bearing system and continuous passive motion (CPM). A full-thickness defect was created by resection of the entire articular surface of the tibial plateau after the EFD was fixed in the rabbit's left knee. In the GWB group (n = 6), GWB was started 6 weeks after surgery. In the CPM group (n = 6), CPM with EFD was applied in the same manner without GWB. The control group (n = 5) received only joint distraction. All rabbits were sacrificed 9 weeks after surgery. The central one-third of the regenerated tissue was assessed and scored blindly using a grading scale modified from the International Cartilage Repair Society visual histological assessment scale. The areas stained by Safranin-O and type II collagen antibody were measured, and the percentage of each area was calculated. There was no significant difference in the histological assessment scale among the groups. The percentage of the type II collagen-positive area was significantly larger in the GWB group than in the CPM group. The present study suggests that optimal mechanical stress, such as GWB, may affect regeneration of cartilage, in vivo. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • The effect of skeletal maturity on the regenerative function of intrinsic ACL cells
    Anterior cruciate ligament (ACL) injuries are an important clinical problem, particularly for adolescent patients. The effect of skeletal maturity on the potential for ACL healing is as yet unknown. In this study, we hypothesized that fibroblastic cells from the ACLs of skeletally immature animals would proliferate and migrate more quickly than cells from adolescent and adult animals. ACL tissue from skeletally immature, adolescent, and adult pigs and sheep were obtained and cells obtained using explant culture. Cell proliferation within a collagen-platelet scaffold was measured at days 2, 7, and 14 of culture using AM MTT assay. Cellular migration was measured at 4 and 24 h using a modified Boyden chamber assay, and cell outgrowth from the explants also measured at 1 week. ACL cells from skeletally immature animals had higher proliferation between 7 and 14 days (p < 0.01 for all comparisons) and higher migration potential at all time points in both species (p < 0.01 for all comparisons). ACL cells from skeletally immature animals have greater cellular proliferation and migration potential than cells from adolescent or adult animals. These experiments suggest that skeletal maturity may influence the biologic repair capacity of intrinsic ACL cells. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • The influence of muscle load on tibiofemoral knee kinematics
    A comparative kinematics study was conducted on six cadaver limbs, comparing tibiofemoral kinematics in five conditions: unloaded, under a constant 130 N ankle load with a variable quadriceps load, with and without a simultaneous constant 50 N medial and lateral hamstrings load. Kinematics were described as translation of the projected centers of the medial (MFT) and lateral femoral condyles (LFT) in the horizontal plane of the tibia, and tibial axial rotation (TR) as a function of flexion angle. In passive conditions, the tibia rotated internally with increasing flexion to an average of -16° (range: -12/-20°, SD = 3.0°). Between 0 and 40° flexion, the medial condyle translated forwards 4 mm (range: 0.8/5.5 mm, SD = 2.5 mm), followed by a gradual posterior translation, totaling -9 mm (range: -5.8/-18.5 mm, SD = 4.9 mm) between 40-140° flexion. The lateral femoral condyle translated posteriorly with increasing flexion completing -25 mm (range: -22.6 to -28.2 mm, SD = 2.5 mm). Dynamic, loaded measurements simulating a deep knee bend were carried out in a knee rig. Under a fixed ankle load of 130 N and variable quadriceps loading, tibial rotation was inverted, mean TR = 4.7° (range: -3.3°/11.8° SD = 5.4°), MFT = -0.5 mm (range: = -4.3/2.4 mm, SD = 2.4 mm), LFT = 3.3 mm (range: = -3.6/10.6 mm, SD = 5.1 mm). Compared to the passive condition, all these excursions were significantly different (p [le] 0.015). Adding medial and lateral hamstrings force of 50 N each reduced TR, MFT, and LFT significantly compared to the passive condition. In general, loading the knee with hamstrings and quadriceps reduces rotation and translation compared to the passive condition. Lateral hamstring action is more influential on knee kinematics than medial hamstrings action. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Microcomputed tomography assessment of glenoid component cementation techniques in total shoulder arthroplasty
    Various strategies have been described to improve glenoid component cementation technique in shoulder arthroplasty, such as the "weephole" technique (WH), which is thought to allow for improved cement mantles by suction venting the glenoid vault through the coracoid. The purpose of this study was to compare the cement mantle created using standard syringe pressurization (SP) to WH or a new, modified weephole technique (MWH), not requiring specific instrumentation of the coracoid medullary canal. Fourteen cadaveric scapulae underwent preparation of the glenoid to allow for implantation of glenoid components. Component fixation was achieved using SP, WH, or MWH. The volumes of cement surrounding each individual peg on the component, of the cement mantle between the back of the glenoid, and of the reamed glenoid face were quantified using micro-CT. Compared to SP, significantly larger cement mantles were observed around all pegs with both the WH (p = 0.023) and MWH (p = 0.007). Similarly, both the WH and MWH techniques demonstrated significantly decreased cement behind the glenoid component (p = 0.003) compared to SP, with no significant difference between the WH and the MWH techniques. Both WH and MWH techniques increase cement mantle volume around individual pegs and decrease the amount of glenoid face cement compared to conventional SP. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Cyclic loading opens hemichannels to release ATP as part of a chondrocyte mechanotransduction pathway
    The process of chondrocyte mechanotransduction is poorly understood. However, recent studies suggest the involvement of a purinergic calcium signaling pathway although the mechanism of ATP release has not been identified. The present study tests the hypothesis that cyclic compression opens hemichannels thereby triggering the release of ATP into the extracellular milieu activating P2 receptors. The well-established chondrocyte-agarose model was utilized enabling chondrocytes to be subjected to a 40-min period of cyclic compression at 0-15% strain and 1 Hz. The opening of hemichannels was determined using Lucifer yellow (LY) incorporation and fluorescence microscopy, whereas the release of ATP into the surrounding media was quantified using the luciferin-luciferase assay. Results indicated that cyclic compression activated hemichannels such that the percentage of cells showing LY incorporation increased from 50 to 70%. This was associated with a sevenfold increase in the release of ATP. Both LY incorporation and ATP release in response to mechanical loading were blocked by the hemichannel inhibitor, flufenamic acid. Treatment with apyrase or P2 receptor antagonists, suramin or oxidated-ATP, did not prevent the mechanically induced response. In conclusion, mechanical loading triggers release of ATP via hemichannels. Hence, this study provides the first evidence of hemichannel involvement in chondrocyte mechanobiology. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Influence of the ratio of particulate autogenous bone graft/platelet-rich plasma on bone healing in critical-size defects: A histologic and histometric study in rat calvaria
    The purpose of this study was to analyze histomorphometrically the influence of the ratio of particulate autogenous bone (AB) graft/platelet-rich plasma (PRP) on bone healing in surgically created critical-size defects (CSD) in rat calvaria. Fifty rats were divided into five groups: Group C (control), Group AB, Group AB/PRP-50, Group AB/PRP-100, and Group AB/PRP-150. A 5-mm diameter critical-size defect was created in the calvarium of each animal. In Group C, the defect was filled by blood clot only. In Group AB, the defect was filled with 0.01 mL of AB graft. In Groups AB/PRP-50, AB/PRP-100, and AB/PRP-150, the defects were filled with 0.01 mL of AB graft combined with 50, 100, and 150 µL of PRP, respectively. All animals were euthanized at 30 days postoperative. Histomorphometry, using image analysis software, and histology analyses were performed. New Bone Area (NBA) and the remaining bone graft particles area (RPA) were calculated as a percentage of the total area of the original defect. Percentage data were transformed into arccosine for analysis. No defect completely regenerated with bone. Group AB/PRP-50 (41.78 ± 13.48%) had a significantly greater NBA than Groups C (19.29 ± 5.11%), AB (27.43 ± 10.90%) or AB/PRP-150 (19.17 ± 8.45%) (p < 0.05). No significant differences were observed between groups AB/PRP-50 and AB/PRP-100 or among groups AB, AB/PRP-100, and AB/PRP-150 with regard to NBA (p > 0.05). Group AB/PRP-150 (31.59 ± 3.22%) had a significantly greater RPA than Groups AB (19.09 ± 5.21%), AB/PRP-50 (17.33 ± 4.43%), and AB/PRP-100 (19.72 ± 3.62%) (p < 0.001). No significant differences were observed among groups AB, AB/PRP-50, and AB/PRP-100 with regard to RPA (p > 0.05). The ratio AB graft/PRP influences bone healing in surgically created CSD in rat calvaria. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • The roles of TNFR1 in lipopolysaccharide-induced bone loss: Dual effects of TNFR1 on bone metabolism via osteoclastogenesis and osteoblast survival
    LPS (lipopolysaccharide), a major constituent of Gram-negative bacteria, regulates proliferation and differentiation of osteoclasts directly or indirectly. This study sought to investigate the functions of the RANK/RANKL pathway in LPS-induced bone loss in vivo. Wild-type mice or TNFR1-/- mice were injected LPS with or without osteoprotegerin (OPG) and analyzed histologically. Bone volume was reduced by LPS injection in all groups, and OPG administration prevented the LPS-induced bone loss regardless of genotypes. LPS-induced enhancement of osteoclastogenesis in wild-type mice was blocked by OPG administration. LPS or OPG did not affect osteoclastogenesis in TNFR1-/- mice. Interestingly, osteoblast surface was remarkably reduced in LPS-treated TNFR1-/- mice as a result of enhanced osteoblast apoptosis. TRAIL, induced by TNF-[alpha] in BMC, triggered apoptosis of primary osteoblast only when TNFR1 signal was ablated in vitro. In conclusion, RANK signaling plays a prominent role in osteoclastogenesis downstream of LPS. Furthermore, TNFR1 regulates bone metabolism through not only the regulation of osteoclast differentiation but also osteoblast survival. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Hyaluronic acid modulates gene expression of connective tissue growth factor (CTGF), transforming growth factor-[beta]1 (TGF-[beta]1), and vascular endothelial growth factor (VEGF) in human fibroblast-like synovial cells from advanced-stage osteoarthritis in vitro
    Intraarticular injection of hyaluronan (hyaluronic acid; HA) is the common way to treat osteoarthritis (OA) of knees. This treatment cannot only maintain the viscoelastic properties of knee but also release the OA pain. However, the exact molecular mechanism is unknown. In this study, after human synovial cells were stimulated with HA and Hylan (Synvisc®) for 24 h, real-time polymerase chain reaction (real-time PCR) was used to detect the alteration of connective tissue growth factor (CTGF), transforming growth factor-[beta]1 (TGF-[beta]1), and vascular endothelial growth factor (VEGF) gene expression, which were specific genes related to pathogenesis of OA knees. Our results illustrated that both HA and Hylan might not cause cytotoxicity or apoptosis of synovial cells in serum deprivation environment. The gene expressions of TGF-[beta]1 and VEGF were significantly increased at the concentration of 0.1 mg/mL HA and 0.1 mg/mL Hylan, respectively ([alpha] < 0.05). The synovial cells with treatment of 0.1 mg/mL Hylan decreased the CTGF gene expression (0.66-fold) and VEGF (0.78-fold) compared to 0.1 mg/mL HA ([alpha] < 0.05). We suggested that the profile of CTGF, TGF-[beta]1, and VEGF gene expressions in our study might provide the rational mechanism for the therapeutic effect of hyaluronan on OA knees. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Replacement of the medial tibial plateau by a metallic implant in a goat model
    The purposes of the present study were to explore the surgical possibilities for replacement of the medial tibial plateau by a metallic implant in a large animal model and to examine the implications for the opposing cartilage. In six goats, the medial tibial plateau of the right knee was replaced by a cobalt-chromium implant, using polymethylmethacrylate bone cement for fixation. The unoperated left knee served as a control. At 26 weeks after surgery, the animals were killed, and the joints evaluated macroscopically. Cartilage quality was analyzed macroscopically and histologically. Glycosaminoglycan content, synthesis, and release were measured in tissue and medium. All animals were able to move and load the knees without any limitations. Macroscopic articular evaluation scores showed worsening 26 weeks after inserting the implant (p < 0.05). Macroscopic and histologic scores showed more cartilage degeneration of the opposing medial femoral condyle in the experimental knee compared to the control knee (p < 0.05). Higher glycosaminoglycan synthesis was measured at the medial femoral condyle cartilage in the experimental knees (p < 0.05). This study shows that the medial tibial plateau can be successfully replaced by a cobalt-chromium implant in a large animal model. However, considerable femoral cartilage degeneration of the medial femoral condyle was induced, suggesting that care must be taken introducing hemiarthroplasty devices in a human clinical setting for the treatment of postmeniscectomy cartilage degeneration of the medial tibial plateau. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Prolonged survival of experimental extremity allografts: A new protocol with total body irradiation, granulocyte-colony stimulation factor, and FK506
    The induction of a high-level of chimerism (macrochimerism) may be the most reliable strategy for achieving donor-specific tolerance. The purpose of this study was to evaluate the efficacy of a new protocol using total-body irradiation (TBI) and granulocyte-colony stimulation factor (G-CSF) to induce high-level chimerism following rat whole-limb allotransplantation. In this study, we investigated whether the timing of TBI influenced the period of graft survival. In total, 50 whole-limb allotransplants from LacZ transgenic rats to LEW rats were performed. TBI was performed at days 0 and 14, and G-CSF was given for 4 days after TBI. FK506 was given for 28 days after transplant. Nontreated limb allografts were rejected after 4.2 days. The survival time was prolonged to 64 days in the FK506 monotherapy group. In the group receiving TBI at day 14, limb allograft survival was significantly prolonged to 81 days. In the group receiving TBI at day 0, 26% of recipients died but in the surviving recipients the grafts survived for longer than 1 year without lethal graft-versus-host disease (GVHD). Polymerase chain reaction (PCR) analysis revealed a high level of intrabone marrow chimerism in the recipient, thus demonstrating successful induction of macrochimerism. A new protocol of pretransplant TBI followed by treatment with G-CSF and FK506 was found to induce a high level of chimerism and to significantly prolong the survival of limb allografts in recipients without lethal GVHD. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Wear mechanisms in metal-on-metal bearings: The importance of tribochemical reaction layers
    Metal-on-metal (MoM) bearings are at the forefront in hip resurfacing arthroplasty. Because of their good wear characteristics and design flexibility, MoM bearings are gaining wider acceptance with market share reaching nearly 10% worldwide. However, concerns remain regarding potential detrimental effects of metal particulates and ion release. Growing evidence is emerging that the local cell response is related to the amount of debris generated by these bearing couples. Thus, an urgent clinical need exists to delineate the mechanisms of debris generation to further reduce wear and its adverse effects. In this study, we investigated the microstructural and chemical composition of the tribochemical reaction layers forming at the contacting surfaces of metallic bearings during sliding motion. Using X-ray photoelectron spectroscopy and transmission electron microscopy with coupled energy dispersive X-ray and electron energy loss spectroscopy, we found that the tribolayers are nanocrystalline in structure, and that they incorporate organic material stemming from the synovial fluid. This process, which has been termed "mechanical mixing," changes the bearing surface of the uppermost 50 to 200 nm from pure metallic to an organic composite material. It hinders direct metal contact (thus preventing adhesion) and limits wear. This novel finding of a mechanically mixed zone of nanocrystalline metal and organic constituents provides the basis for understanding particle release and may help in identifying new strategies to reduce MoM wear. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Acute repair of chondrocytes in the rabbit tibiofemoral joint following blunt impact using P188 surfactant and a preliminary investigation of its long-term efficacy
    Recent studies have indicated that there may be a correlation between acute chondrocyte damage and joint degeneration reminiscent of early-stage osteoarthritis (OA). P188 surfactant has been shown to acutely restore the integrity of damaged chondrocytes; however, its long-term efficacy is unknown. The hypothesis of this study was that a single injection of P188 into a traumatized joint would acutely repair damaged cell membranes and maintain their viability in the long term. Twelve rabbits were divided into two groups, with and without P188, and sacrificed 4 days after tibiofemoral (TF) impact. Another six rabbits were sacrificed after 6 weeks and divided into two groups, with and without P188 treatment immediately posttrauma. Treatment with P188 increased the viable cell density 4 days posttrauma. A higher density of viable cells was also documented 6 weeks posttrauma in the treated versus untreated limb. The results of the current study confirm the acute efficacy of P188 treatment, and may suggest long-term efficacy of treatment, but additional studies are still needed to investigate the chronic implications of the acute repair of cells in the traumatized joint. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Altered expression of sodium channel distribution in the dorsal root ganglion after gradual elongation of rat sciatic nerves
    To elucidate the pathophysiological mechanisms underlying chronic nerve-stretch injury, we gradually lengthened rat femurs by 15 mm at the rate of 0.5 mm/day (group L, n = 13). The control groups comprised sham-operated (group S, n = 10) and naive (group N, n = 8) rats. Immediately after the lengthening, we performed a conduction study on their sciatic nerves and harvested samples. Electrophysiological and histological analyses showed mild conduction slowing and axonal degeneration of unmyelinated fibers in group L rats. Altered mRNA expression of the voltage-gated sodium channels in the dorsal root ganglion was also observed. Tetrodotoxin-resistant (TTX-R) sodium-channel Nav1.8 mRNA expression was significantly decreased and TTX-R sodium-channel Nav1.9 mRNA expression showed a tendency to decrease when compared with the mRNA expressions in the control groups. However, tetrodotoxin-sensitive (TTX-S) sodium-channel Nav1.3 mRNA expression remained unaltered. The immunohistochemical alteration of Nav1.8 protein expression was parallel to the results of the mRNA expression. Previous studies involving neuropathic states have suggested that pain/paresthesia is modulated by a subset of sodium channels, including downregulation and/or upregulation of TTX-R and TTX-S sodium channels, respectively. Our findings indicate that Nav1.8 downregulation may be one of the pathophysiological mechanisms involved in limb lengthening-induced neuropathy. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Effect of fracture gap on stability of compression plate fixation: A finite element study
    In compression plating, anatomical reduction and compression across the fracture site are the basic principles necessary to achieve primary bone healing. However, varying amounts of gap at the fracture site frequently occur due to technical pitfalls, such as overbending of the plate and inaccurate reduction, and due to the fracture configuration itself. Little is known as to how fracture gap affects stability of the bone-plate construct. We analyzed the effects of fracture gap size (1 and 4 mm) and bone defect (25%, 50%, 75%, 100%) on the biomechanical stability of the compression plate-bone construct through validated finite element analysis. The stiffnesses of eight different models were compared with the stiffness of an ideally compressed model (0 mm/0%). Stress concentration in form of peak von Mises stress (PVMS) was also evaluated. The decrease in stiffness depended mainly on the depth of bone defect. The decrease in stiffness was similar in models with the same defect and different gap size. Considerably more stress was concentrated around the central hole of the plate in gap models with the depth of bone defects of 75% and 100% than with smaller defects. We concluded that even a thin fracture gap (1 mm) with no contact between the fracture after plating decreases stiffness exponentially; contact at the fracture surfaces of [ge]50% was necessary to avoid undue stress concentration in the plate. Published by Wiley Periodicals, Inc. J Orthop Res

  • Nanostructure of collagen fibrils in human nucleus pulposus and its correlation with macroscale tissue mechanics
    Collagen fibrils are the main structural components of the nucleus pulposus tissue in the intervertebral discs. The structure-property relationship of the nucleus pulposus (NP) tissues is still unclear. We investigated the structure of individual collagen fibrils of the NP and evaluated its correlation with the bulk mechanical properties of the tissue. Collagen fibrils were extracted from the NP of discs retrieved from adolescents during scoliosis correction surgery, and the extracts were confirmed by SDS-PAGE. The diameters of the individual collagen fibrils were measured through atomic force microscopy, and the compressive mechanical properties of the tissues were evaluated by confined compression. The correlations between the nanoscale morphology of the collagen fibrils and the macroscale mechanical properties of the tissues were evaluated by linear regression. The SDS-PAGE results showed that the fibril extracts were largely composed of type II collagen. The mean diameter of the collagen fibrils was 92.1 ± 26.54 nm; the mean swelling pressure and compressive modulus of the tissues were 6.15 ± 4.3 kPa and 1.23 ± 0.7 MPa, respectively. The mean fibril diameter had no linear correlation (R2 = 0.30) with the swelling pressure of the tissues. However, it had a mild linear correlation with the compressive modulus (p = 0.023, R2 = 0.68). This is the first study, to our knowledge, to evaluate the nanostructure of the individual collagen fibrils of the nucleus pulposus and its relationship with macroscale mechanical properties of the NP tissues. Published by Wiley Periodicals, Inc. J Orthop Res

  • A biodegradable scaffold for the treatment of a diaphyseal bone defect of the tibia
    The aim of this study was to compare angiogenesis and osteogenesis occurring within 8.0 mm diaphyseal defects created in canine tibiae treated using autograft or a biodegradable bone scaffold. All tibiae were reamed to 7.0 mm and fixed with a 6.5-mm statically locked intramedullary nail. Each of the 18 canines as allotted to one of three treatment groups: (1) left empty (N = 5), (2) treated with iliac crest autograft (N = 6), or (3) treated with a PLGA/calcium phosphate biodegradable scaffold (N = 7). Fluorescent markers were given at successive time periods: calcein green at 6 weeks, xylenol orange at 9 weeks, and tetracycline at 11 and 14 weeks. Animals were sacrificed at 15 weeks and their legs were perfused with a radio opaque compound. Samples were analyzed using Micro CT, bright-field microscopy and fluorescent microscopy. Scaffold samples were found to have significantly greater bone formation (p = 0.015) and blood vessel formation (p < 0.001) at their osteotomy sites than autograft samples. Bone formation rate in the periosteum was significantly greater in the autograft samples than the scaffold samples for all time periods. Bone formation at the osteotomy site was found to be significantly greater when associated with greater blood vessel formation (p = 0.026). The PLGA/calcium phosphate biodegradable scaffold we have employed supports angiogenesis within a segmental tibial defect that has adequate soft tissue coverage. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Ibuprofen upregulates expressions of matrix metalloproteinase-1, -8, -9, and -13 without affecting expressions of types I and III collagen in tendon cells
    Nonsteroidal antiinflammatory drugs are widely used to treat sports-related tendon injuries or tendinopathy. This study was designed to investigate the effect of ibuprofen on expressions of types I and III collagen, as well as collagen-degrading enzymes including matrix metalloproteinase (MMP)-1, -2, -8, -9, and -13. Rat Achilles tendon cells were treated with ibuprofen and then underwent MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Reverse transcription-polymerase chain reaction was used to evaluate mRNA expressions of types I and III collagen, MMP-1, -2, -8, -9, and -13. Protein expressions of types I and III collagen, MMP-1, -8, and -13 were determined by Western blot analysis. Gelatin zymography was used to evaluate the enzymatic activities of MMP-2 and MMP-9. The results revealed that ibuprofen upregulated expressions of MMP-1, -8, -9, and -13, both at mRNA and protein levels. There was no effect of ibuprofen on mRNA and protein expressions of types I and III collagen. Gelatin zymography revealed that the enzymatic activity of MMP-9 was upregulated after ibuprofen treatment. In conclusion, ibuprofen upregulates the expressions of collagenases including MMP-1, -8, -9, and -13 without affecting the expressions of types I and III collagen. These findings suggest a molecular mechanism potentially accounting for the inhibition of tendon healing by ibuprofen. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Nanog maintains human chondrocyte phenotype and function in vitro
    Previous work showed that Nanog, a homeobox family transcription factor, maintains embryonic stem cell pluripotency, suggesting that it has a role in stabilizing cell phenotype. Human chondrocytes lose their phenotype and dedifferentiate after relatively few passages in culture, changes that may limit their value in restoring damaged articular cartilage. We hypothesized that Nanog could stabilize the phenotype of cultured human chondrocytes in long-term monolayer cultures. To test this hypothesis, the human Nanog gene was stably transduced into human chondrocytes using a retroviral vector. Chondrocyte-specific gene expression (collagen type II, aggrecan, cartilage link protein, and Sox9) was measured by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR in monolayer cultured chondrocytes transduced with Nanog and in control chondrocytes transduced with empty vector. In vitro cartilage matrix protein formation by Nanog-transduced and control cells was compared using Safranin-O and immunofluorescence stains. We found that after 25 passages, Nanog-transduced chondrocytes maintained significantly higher expression of collagen type II, aggrecan, and cartilage link protein genes than controls. Under chondrogenic conditions, Nanog-transduced cells produced significantly more cartilage-specific matrix than control cells. These findings support the hypothesis that Nanog maintains the human chondrocyte phenotype and function after long-term monolayer culture. Preservation of the chondrocyte phenotype may improve the ability of cultured chondrocytes to repair or restore articular cartilage. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Optical coherence tomography grading correlates with MRI T2 mapping and extracellular matrix content
    Optical coherence tomography (OCT) and T2 mapping are emerging clinical imaging technologies with potential to detect subsurface changes in cartilage retaining a macroscopically intact articular surface. This study tests the hypothesis that OCT correlates with magnetic resonance imaging (MRI) T2 values, and that OCT signal is sensitive to cartilage matrix degeneration. Forty-five osteochondral cores were harvested from five human tibial plateau explants after MRI T2 mapping. Cores underwent OCT imaging and were graded as follows: A, obvious birefringence; B, no birefringence; C, subsurface voids and/or irregular surface. Extracellular matrix content was determined and cores underwent histologic and polarized light microscopy (PLM) evaluation. Grade B and C cores had 25% higher superficial T2 values (p = 0.047) and 50% higher deep T2 values (p = 0.012) than grade A cores. Grade B and C cores had 36% higher glycosaminoglycan (GAG) content compared to grade A cores (p = 0.009). Histology and PLM demonstrated increased surface irregularity and structural disorganization with increasing OCT grade. OCT grade and T2 value increased with increasing collagen disorganization, suggesting that MRI T2 mapping and OCT are sensitive to changes in collagen structure. Our results demonstrate the ability of OCT and T2 mapping to detect early cartilage degeneration in clinically normal appearing cartilage. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Lymphocyte proliferation responses in patients with pseudotumors following metal-on-metal hip resurfacing arthroplasty
    Locally destructive soft tissue pseudotumor has been reported in patients following metal-on-metal hip resurfacing arthroplasty (MoMHRA). A delayed hypersensitivity reaction type IV to nickel (Ni), chromium (Cr), or cobalt (Co) has been suggested to play a role in its aetiology. The aim of this study was to investigate the incidence and level of metal-induced systemic hypersensitivity in patients with MoMHRA, both with and without pseudotumor by measuring lymphocyte proliferation responses to metals. A total of 92 patients were investigated: (1) MoMHRA patients with pseudotumors (nine female, one male); (2) MoMHRA patients without pseudotumors (30 female, 30 male); and (3) age-matched control subjects without metal implants (9 female, 13 male). The venous blood samples were collected for serum Ni, Co, and Cr ion level measurements and lymphocyte transformation tests (LTT). A higher incidence and level of enhanced lymphocyte reactivity only to Ni was found in patients with MoMHRA compared to the patients without MoM implants, reflecting exposure and immune reactivity. However, lymphocyte reactivity to Co, Cr, and Ni did not significantly differ in patients with pseudotumors compared to those patients without pseudotumors. This suggests that systemic hypersensitivity type IV reactions, as measured by lymphocyte proliferation response to these metals, may not be the dominant biological reaction involved in the occurrence of the soft tissue pseudotumors. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Low affinity NGF receptor (p75 neurotrophin receptor) inhibitory antibody reduces pain behavior and CGRP expression in DRG in the mouse sciatic nerve crush model
    Nerve growth factor (NGF) and its low-affinity receptor, p75 neurotrophin receptor (p75NTR), are important mediators of pain. To explore further the mechanisms involved, we examined suppression of pain behavior and expression of neuropeptides such as calcitonin gene-related peptide (CGRP) using a p75 NTR inhibitory antibody, in a mouse sciatic nerve crush model. In the nerve-injured model, 150 µg of a p75 NTR inhibitory antibody or 10 µl of saline were applied. The sciatic nerve in the sham-operated group was uninjured. Mechanical allodynia was measured for 2 weeks. CGRP and p75NTR expression in L5 dorsal root ganglions (DRGs) was examined immunohistochemically. Mechanical allodynia was found in the two nerve injured groups, but not in the sham-operated group (p < 0.05). However, the magnitude of the mechanical allodynia was significantly decreased after application of p75 NTR inhibitory antibody (p < 0.05). CGRP and p75NTR immunoreactivity in the L5 DRG neurons was upregulated in the injured nerve groups compared with the sham-operated group; however, p75 NTR inhibitory antibody decreased the CGRP and p75NTR expression (p < 0.01). Application of the p75 NTR inhibitory antibody to the pinched sciatic nerve suppressed CGRP and p75NTR expression and pain behavior. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

  • Promotion of bone formation by naringin in a titanium particle-induced diabetic murine calvarial osteolysis model
    Diabetic patients have an increased risk of prosthesis failure requiring revision surgery. Furthermore, skeletal defects are observed in conjunction with type 1 diabetes. Using a titanium particle-induced calvarial osteolysis model in diabetic mice, we investigated the effect of diabetes on the osteolytic process and the role of naringin in its prevention. Three groups each of nondiabetic or diabetic mice were treated with vehicle only, with particles only, or with particles then naringin for 10 days. Alteration of bone indices near the midline suture were then analyzed by microcomputed tomography scanning and histology. Serum levels of osteocalcin (OCN) and cross-linked N-telopeptide of type I collagen (NTx) were measured by enzyme-linked immunosorbent assay. The decreases in new bone formation (p < 0.05), calvaria thickness (p < 0.05), bone volume (p < 0.05), midline suture area (p < 0.05), and OCN concentration (p < 0.05) found in diabetic mice were normalized with naringin treatment. Diabetic state promoted particle-induced osteolysis. Naringin, an osteoanabolic agent, improved bone indices apparently by stimulating bone formation. Therefore, naringin may be beneficial in preventing and treating debris-mediated periprosthetic osteolysis after total joint replacement, especially in diabetics. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res


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