Pipes Output http://pipes.yahoo.com/pipes/pipe.info?_id=c7c6fc5ae93329176d7f2a690f70788d Thu, 01 Oct 2015 23:13:45 +0000 http://pipes.yahoo.com/pipes/ http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23060 The current study compared the impact of low radiation CT protocols on the accuracy, repeatability, and inter- and intra-observer variability of implant migration studies in total hip arthroplasty. Two total hip replacements were performed in two human cadavers and 6 tantalum beads were inserted into the femur similar to radiostereometric analysis. 6 different 28 mm heads (-3 mm, 0 mm, 2.5 mm, 5.0 mm, 7.5 mm and 10 mm) were added to simulate five reproducible translations (maximum total point migration) of the center of the head. Three CT scans with varying levels of radiation were performed for each head position. The effective dose (mSv) was 3.8 mSv for Protocol A (standard protocol), 0.7 mSv for Protocol B and 1.6 mSv for Protocol C. Implant migration was measured in a 3-D analysis software (Geomagic Studio 7). The accuracy was 0.16 mm for CT Protocol A, 0.13 mm for Protocol B and 0.14 mm for Protocol C; The repeatability was 0.22 mm for CT Protocol A, 0.18 mm for Protocol B and 0.20 mm for Protocol C; ICC for inter observer reliability was 0.89, intra observer reliability was 0.95. The difference in accuracy between standard protocol A and the two low radiation protocols (B, C) was less 0.05 mm. The accuracy, inter- and intra observer reliability of all three CT protocols is comparable to radiostereometric analysis. Reducing the CT radiation exposure to numbers similar to an AP Pelvis radiograph (0.7 mSv protocol B) does not affect the accuracy of implant migration measurements. This article is protected by copyright. All rights reserved Thu, 01 Oct 2015 11:11:12 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23061 The efficacy of biological therapies on intervertebral disc repair was quantitatively studied using a three-dimensional finite element model based on a cell-activity coupled multiphasic mixture theory. In this model, cell metabolism and matrix synthesis and degradation were considered. Three types of biological therapies-increasing the cell density (Case I), increasing the glycosaminoglycan (GAG) synthesis rate (Case II), and decreasing the GAG degradation rate (Case III)-to the nucleus pulposus (NP) of each of two degenerated discs [one mildly degenerated (e.g., 80% viable cells in the NP) and one severely degenerated (e.g., 30% viable cells in the NP)] were simulated. Degenerated discs without treatment were also simulated as a control. The cell number needed, nutrition level demanded, time required for the repair, and the long-term outcomes of these therapies were analyzed. For Case I, the repair process was predicted to be dependent on the cell density implanted and the nutrition level at disc boundaries. With sufficient nutrition supply, this method was predicted to be effective for treating both mildly and severely degenerated discs. For Case II, the therapy was predicted to be effective for repairing the mildly degenerated disc, but not for the severely degenerated disc. Similar results were predicted for Case III. No change in cell density for Cases II and III were predicted under normal nutrition level. This study provides a quantitative guide for choosing proper strategies of biological therapies for different degenerated discs. This article is protected by copyright. All rights reserved Thu, 01 Oct 2015 11:10:07 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23059 Bioelectrical regulation of bone fracture healing is important for many cellular events such as proliferation, migration and differentiation. The aim of this study was to investigate the osteogenic differentiation potential of human mesenchymal stem cells (hMSCs) cultivated on silk scaffolds in response to different modes of electrostimulation (e.g., exogeneous and/or endogeneous). Endogeneous electrophysiology was altered through the use of monensin (10 nM) and glibenclamide (10 μM), along with external electrostimulation (60 kHz; 100-500 mV). Monensin enhanced the expression of early osteogenic markers such as alkaline phosphatase (ALP) and runt-related transcription factor 2 (RUNX-2). When exogeneous electrostimulation was combined with glibenclamide, more mature osteogenic marker upregulation based on bone sialoprotein expression (BSP) and mineralization was found. These results suggest the potential to exploit both exogeneous and endogeneous biophysical control of cell functions towards tissue-specific goals. This article is protected by copyright. All rights reserved Wed, 30 Sep 2015 05:49:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23058 The addition of platelet-rich plasma (PRP) to rotator cuff repair has not translated into improved outcomes after surgery. However, recent work stimulating ligament healing has demonstrated improved outcomes when PRP or whole blood is combined with an extracellular matrix carrier. The objective of this study was to evaluate the effect of three components of blood (plasma, platelets and macrophages) on the in vitro activity of ovine rotator cuff cells cultured in an extracellular matrix environment. Tenocytes were obtained from six ovine infraspinatus tendons and cultured over 14 days in an extracellular matrix scaffold with the following additives: 1) Plasma (PPP), 2) Plasma and platelets (PAP), 3) Plasma and macrophages (PPPM), 4) Plasma, platelets and macrophages (PAPM), 5) Phosphate buffered saline (PBS), and 6) PBS with macrophages (PBSM). Assays measuring cellular metabolism (AlamarBlue), proliferation (Quantitative DNA assay), synthesis of collagen and cytokines (SIRCOL, TNF-α and IL-10 ELISA, and MMP assay), and collagen gene expression (qPCR) were performed over the duration of the experiment, as well as histology at the conclusion. Plasma was found to stimulate cell attachment and spreading on the scaffold, as well as cellular proliferation. Platelets also stimulated cell proliferation, cellular metabolism, transition of cells to a myofibroblast phenotype and contraction of the scaffolds. The addition of macrophages did not have any significant effect on the sheep rotator cuff cells in vitro. In vivo studies are needed to determine if these changes in cellular function will translate into improved tendon healing. This article is protected by copyright. All rights reserved Wed, 30 Sep 2015 05:44:16 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23057 This study evaluated if inhibiting IL1-β activity with an IL1-receptor antagonist (IL1-RA) will prevent pathologic changes commonly seen in tendinopathy. 36 Sprague-Dawley retired-breeder rats were divided into three groups having weekly bilateral patellar tendon injections: CON (0.1ml Saline), CAR (0.1ml 2% carrageenan), IL1-RA (0.1ml 2% CAR plus 0.94mg of the IL1-RA, 2.5mg/kg). Carrageenan was used to establish tendinopathy in two groups due to its ability to develop tendinopathy in prior studies. Animals were euthanized 3 weeks after initial injection. The CAR group demonstrated significantly (P < 0.05) shorter tendon lengths (8.61 ± 0.38mm) relative to CON (8.94 ± 0.38mm) that was prevented in the IL1-RA (9.02 ± 0.30mm) as well as significantly increased collagenase activity in the CAR (0.061 ± 0.043) compared to CON (0.027 ± 0.015) (p < 0.05). By histological evaluation, the CAR group demonstrated significantly greater inflammation than IL1-RA and CON (p < 0.05). CAR showed a trend for increased cross-sectional area relative to CON that was absent in the IL1-RA. IL1-RA can effectively inhibit the development of mechanical, chemical, and histologic changes seen with carrageenan-induced tendonitis. This article is protected by copyright. All rights reserved Tue, 29 Sep 2015 07:12:10 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23055 There is a clear discrepancy between the growth of cell therapy and tissue engineering research in orthopaedics over the last two decades and the number of approved clinical therapies and products available to patients. At the 2015 annual meeting of the Orthopaedic Research Society, a workshop was held to highlight important considerations from the perspectives of an academic scientist, clinical researcher and industry representative with the aim of helping researchers to successfully translate their ideas into clinical and commercial reality. Survey data acquired from workshop participants indicated an overall positive opinion on the future potential of cell-based therapies to make a significant contribution to orthopaedic medicine. The survey also indicated an agreement on areas requiring improvement in the development of new therapies, specifically; increased support for fundamental research and education and improved transparency of regulatory processes. This perspectives article summarises the content and conclusions of the workshop and puts forward suggestions on how translational success of cell-based therapies in orthopaedics may be achieved. This article is protected by copyright. All rights reserved Fri, 25 Sep 2015 03:30:15 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23056 Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the expression of Receptor activation of nuclear factor (NF)-kB (RANKL) by fibroblasts in periprosthetic membrane played a crucial role in wear particle-induced osteolysis. However, the underlying mechanism of RANKL expression remains largely unknown. In the present study, we investigated the effect of TiAl6V4 particle (TiPs)-induced XBP1s (spliced form of X-box binding protein 1) on RANKL expression and osteoclastogenesis both in vitro and in vivo. The levels of XBP1s in peri-implant membrane, animal models and TiPs-stimulated fibroblasts were determined by western blots. To assess the effect of XBP1s on RANKL expression, fibroblasts were treated with both a small interfering RNA (siRNA) and an inhibitor of XBP1 prior to exposure to TiPs. The effect of XBP1s on osteoclasts formation was determined by tartrate-resistant acid phosphatase (TRAP) staining in vitro osteoclastogenesis assay and in animal models. The resorption of bone was assessed by micro-computed tomography (micro-CT) with three-dimensional reconstruction. Our results demonstrated that XBP1s was activated in periprosthetic membrane, mouse calvaria models and TiPs-stimulated human synovial fibroblasts. Further, inhibition of XBP1s decreased the expression of RANKL and osteoclasts formation in vitro. In mouse calvaria models, both of the osteoclastogenesis and osteolysis were inhibited XBP1s inhibitor. Our results suggested that XBP1s mediated TiPs-induced of RANKL expression in fibroblasts, and down regulating XBP1s may represented a potential therapy for wear particle-induced osteolysis. This article is protected by copyright. All rights reserved Fri, 25 Sep 2015 03:29:37 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23054 Platelet rich plasma (PRP) is used to treat many musculoskeletal disorders. We used a canine model to determine the effects of multiple intra-articular injections of leukoreduced PRP (ACP) on anterior cruciate ligament healing, meniscal healing, and progression of osteoarthritis (OA). With Animal Care and Use Committee (ACUC) approval, 12 dogs underwent partial ACL transection and meniscal release in one knee. At weeks 1, 2, 3, 6, and 8 after insult, dogs were treated with intra-articular injections (2 ml) of either ACP (n = 6) or saline (n = 6). Dogs were assessed over 6 months to determine comfortable range of motion (CROM), lameness, pain, effusion, kinetics, and radiographic and arthroscopic assessments. At 6-month endpoint, dogs were assessed for ACL material properties and histopathology. Saline-treated dogs had significantly (p < 0.04) more CROM loss, significantly (p < 0.01) more pain, significantly (p < 0.05) more severe lameness, significantly (p < 0.05) lower function, and significantly (p < 0.05) lower %Total Pressure Index in affected hindlimbs compared to ACP-treated dogs. Radiographic OA increased significantly (p < 0.01) over time within each group. Arthroscopically, saline-treated knees showed moderate to severe synovitis, further ACL disruption, and medial compartment cartilage loss, and ACP-treated knees showed evidence of ACL repair and less severe synovitis. ACL material properties in ACP-treated knees were closer to normal than in saline-treated knees, however, the differences were not statistically significant. ACL histopathology was significantly (p < 0.05) less severe in ACP-treated knees compared to saline-treated knees. Five intra-articular injections of leukoreduced PRP had beneficial effects for ACL healing, improved range of motion, decreased pain, and improved limb function for up to 6 months in this model. This article is protected by copyright. All rights reserved Fri, 25 Sep 2015 03:28:03 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23052 We recently published a paper entitled “Anterior Border of the Tibia as a Landmark for Extramedullary Alignment Guide in Total Knee Arthroplasty for Varus Knees” in J.O.R. (29:919–924, 2011)1. The key finding was identifying consistent external bony landmarks that can be used for aligning extramedullary total knee arthroplasty (TKA) instruments with varus knees from an image-based anatomic study. A recent clinical study has also demonstrated the efficacy of the anterior border of the tibia as appropriate landmarks for the placement of extramedullary tibial guides2. This article is protected by copyright. All rights reserved Thu, 24 Sep 2015 06:48:25 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23053 An accurate preoperative measurement of glenoid orientation is crucial for evaluating pathologies and successful total shoulder arthroplasty. Existing methods may be labor-intensive, observer-dependent, and sensitive to the misalignment between the scapula plane and CT scanning direction. In this study, we proposed a computation framework and performed an automated analysis of the glenoid orientation based on 3D surface data. Methods Three-dimensional models of 12 scapulae were analyzed. The glenoid cavity and external anatomical features were automatically extracted from these 3D models. Glenoid version was calculated using the scapula plane and the fulcrum axis alternatively. Glenoid inclination was measured both relative to transverse axis of the scapula and the medial pole-inferior tip axis. Results The mean (± SD) of the fulcrum-based glenoid version was -0.55° (± 4.17°), while the scapular-plane-based glenoid version was -5.05° (± 3.50°). The mean (± SD) of glenoid inclinations based on the medial pole and inferior tip was 12.75° (± 5.03°) while the mean (± SD) of the glenoid inclination based on the medial pole and glenoid center was 4.63° (± 4.86°). Conclusions Our computational framework was able to extract the reproducible morphological measures free of inter- and intra- observer variability. For the first time in 3D, we showed that the fulcrum axis was practically perpendicular to the glenoid plane normal (radial line), and thus extended the fulcrum-based glenoid version for quantifying 3D glenoid orientation. This article is protected by copyright. All rights reserved Thu, 24 Sep 2015 06:47:43 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23051 Psychological problems are common in shoulder patients. A validated psychological questionnaire measuring clinically relevant psychological symptoms (including distress, depression, anxiety and somatization) in shoulder patients is lacking. The Four-Dimensional Symptom Questionnaire (4DSQ) is a self-report questionnaire to identify distress, depression, anxiety and somatization which has been validated in primary care populations. The aim of this study was to validate the 4DSQ in orthopedic shoulder patients. We assessed whether the 4DSQ measures these four constructs the same way in an orthopedic population with shoulder problems compared to a general practice population. We also investigated the prevalence of psychological symptoms in shoulder patients. The shoulder group consisted of 200 consecutive patients and the general practice group comprised 368 patients, matched for gender and age. Differential item functioning analysis showed that the 4DSQ measures the different psychological symptoms in orthopedic shoulder patients the same way as in general practice patients. The shoulder patients tended to score higher on the somatization scale, resulting in a new cut-off point for somatization. The prevalence of distress, somatization, anxiety and depression in the shoulder group was 23%, 14%, 10% and 8% respectively. It can be concluded from this study that the 4DSQ in orthopedic shoulder patients measures the same constructs as in general practice patients and can therefore be used in orthopedic practice to measure psychological symptoms in patients with shoulder complaints. This article is protected by copyright. All rights reserved Thu, 17 Sep 2015 07:22:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22995 The main reason for intervertebral disc (IVD) degeneration is the decrease in the quantity and activity of IVD cells with subsequent reduction of the extracellular matrix (ECM). In this study, we investigated a cell-based repair strategy by injecting nucleus pulposus cells (NPCs) transduced with human bone morphogenetic protein (hBMP7) by adeno-associated virus-2 into the canine degenerative IVD to determine whether NPCs expressing hBMP7 could delay the degeneration of the IVD. Fourteen canines received annular punctures to induce disc degeneration. Eight weeks later, saline (group A), allogeneic NPCs (group B), or allogeneic NPCs transduced with hBMP7 (group C) were injected into the degenerative discs. Twelve weeks after the injection, MRI scan showed that the degeneration process of groups C was slower and less severe compared with that of groups B and C. The IVD stability in group C was superior to that in groups A and B in left-right bending and rotation. HE, safranin-O staining, and ELISA indicated that the degenerative degree of the IVD in group C was significantly milder than that in groups A and B. The study demonstrated that the implantation of NPCs-hBMP7 could effectively maintained the structural integrity, ECM, and biomechanical properties of the canine degenerated discs. This article is protected by copyright. All rights reserved Mon, 27 Jul 2015 05:44:47 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22973 The present report demonstrates efficacy of fluorescence-guided surgery (FGS) to resect and prevent recurrence of experimental skeletal metastasis in a nude mouse model of human prostate cancer. Green fluorescent protein (GFP)-expressing PC-3 human prostate cancer cells were injected into the intramedullary cavity of the tibia in 25 nude mice. One week after the implantation, monoclonal antibodies specific for carcinoembryonic antigen (CEA) labeled with DyLight 650 was injected into tail vein of 13 mice. The thirteen mice underwent FGS and the remaining 12 mice underwent bright-light surgery (BLS). Weekly GFP fluorescence imaging of the mice was performed to observe tumor recurrence. The extent of residual tumor after BLS was 13-fold greater than after FGS (P < 0.001). Time-lapse imaging visualized rapid growth of the residual tumor in the BLS group, whereas FGS group showed only slight tumor growth and significantly improved disease-free survival of the treated mice. Our study demonstrated that FGS significantly reduced residual tumor as well as the recurrence of experimental prostate cancer bone metastasis. The present results suggest that FGS will be effective for resection of skeletal metastases in selected patients with prostate cancer. This article is protected by copyright. All rights reserved Wed, 01 Jul 2015 23:39:05 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22824 Increased tendon stiffness in response to mechanical loading is well established in young animals. Given that tendons stiffen with aging, we aimed to determine the effect of increased loading on tendons of old animals. We subjected 28-month-old mice to ten weeks of uphill treadmill running; sedentary 8- and 28-month-old mice served as controls. Following training, plantaris tendon stiffness and modulus were reduced by approximately half, such that the values were not different from those of tendons from adult sedentary animals. The decrease in plantaris tendon stiffness was accompanied by a similar reduction in the levels of advanced glycation end-product protein adducts in tibialis anterior tendons of trained compared with sedentary old mice. In Achilles tendons, elevated mRNA levels for collagen type 1, matrix-metalloproteinase-8, and lysyl oxidase following training suggest that collagen turnover was likely also increased. The dramatic mechanical and structural changes induced by training occurred independent of changes in cell density or tendon morphology. Finally, Achilles tendon calcification was significantly reduced following exercise. These results demonstrate that, in response to exercise, tendons from old animals are capable of replacing damaged and dysfunctional components of extracellular matrix with tissue that is mechanically and structurally comparable to adult tissue. This article is protected by copyright. All rights reserved Sat, 31 Jan 2015 15:58:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22800 Introduction This study evaluates the ability of a Glass Reinforced Hydroxyapatite Composite (GRHC), in a new microporous pellet formulation with autologous bone marrow concentrate (BMC), to enhance bone regeneration and new bone formation. Material and Methods Ninety non-critical sized bone defects were created in the femurs of 9 Merino breed sheep and randomly left unfilled (group A), filled with GRHC pellets alone (group B) or filled with GRHC pellets combined with BMC (group C). The sheep were sacrificed at 3 weeks (3 sheep), 6 weeks (3 sheep) and 12 weeks (3 sheep) and histological analysis (Light Microscopy-LM), scanning electron microscopy (SEM) and histomorphometric analysis (HM) were performed. Results At 3, 6 and 12 weeks, HM revealed an average percentage of new bone of 48, 72, 83%; 25, 73, 80% and 16, 38, 78% for Groups C, B and A respectively (significantly different only at 3 weeks - p<0.05). LM and SEM evaluation revealed earlier formation of well-organized mature lamellar bone in Group C. Conclusion This study demonstrates that the addition of a bone marrow concentrate to a glass reinforced hydroxyapatite composite in a pellet formulation promotes early bone healing. This article is protected by copyright. All rights reserved Wed, 10 Dec 2014 06:25:53 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23026 When faced with posterolateral corner (PLC) deficiency, surgeons must choose a total knee replacement (TKR) construct that provides the appropriate level of constraint. This should match the internal constraint of the device to the soft tissue host laxity pattern. Little guidance is available peroperatively, with factors influencing final component choice remaining ill defined. This study aimed to quantify the effect of PLC insufficiency on the “envelope of laxity” (EoL) after TKR and the effect of increasingly component constraint upon knee behavior through a functional arc of flexion. Using computer navigation, mixed effect modeling and loaded cadaveric legs—laxity was quantified under separate states: the native knee, after implantation of a posterior stabilized (PS)-TKR, after sectioning the lateral (fibular) collateral ligament and popliteus tendon (PS-TKR-PLC), and after re-implantation with a semi-constrained “total stabilized” knee replacement (TS-TKR). Laxity was quantified from 0 to 110° of flexion for anterior draw, varus–valgus, and internal–external rotation. Implantation of the PS-TKR was consistently associated with increased constraint when compared to the native knee. PLC sectioning led to significantly increased laxity during varus stress from mid to deep flexion. Revision to a TS-TKR construct restored constraint mimicking that of the primary state but only for the arc of motion 0–90°. In a posterolateral deficient state, a fixed bearing semi-constrained TS-TKR restored the knee to near normal kinematics but this was only achieved from an arc of motion 0–90° of flexion. At higher flexion angles, there remained an unfavorable laxity pattern with varus stress opening. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 29 Sep 2015 03:19:33 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23048 Restoration of joint stability during total shoulder arthroplasty can be challenging in the face of severe glenoid retroversion. A novel technique of humeral head component anterior-offsetting has been proposed to address posterior instability. We evaluated the biomechanical benefits of this technique in cadaveric specimens. Total shoulder arthroplasty was performed in 14 cadaveric shoulders from 7 donors. Complementary shoulders were assigned to either 10° or 20° glenoid retroversion, with retroversion created by eccentric reaming. Two humeral head component offset positions were tested in each specimen: The anatomic (posterior) and anterior (reverse). With loads applied to the rotator cuff and deltoid, joint contact pressures and the force and energy required for posterior humeral head translation were measured. The force and energy required to displace the humeral head posteriorly increased significantly with the anterior offset position compared to the anatomic offset position. The joint contact pressures were significantly shifted anteriorly, and the joint contact area significantly increased with the anterior offset position. Anterior offsetting of the humeral head component increased the resistance to posterior humeral head translation, shifted joint contact pressures anteriorly, and increased joint contact area, thus, potentially increasing the joint stability in total shoulder arthroplasty with simulated glenoid retroversion. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 24 Sep 2015 04:52:45 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23044 Significant research exists regarding heat production during single-hole bone drilling. No published data exist regarding repetitive sequential drilling. This study elucidates the phenomenon of heat accumulation for sequential drilling with both Kirschner wires (K wires) and standard two-flute twist drills. It was hypothesized that cumulative heat would result in a higher temperature with each subsequent drill pass. Nine holes in a 3 × 3 array were drilled sequentially on moistened cadaveric tibia bone kept at body temperature (about 37°C). Four thermocouples were placed at the center of four adjacent holes and 2 mm below the surface. A battery-driven hand drill guided by a servo-controlled motion system was used. Six samples were drilled with each tool (2.0 mm K wire and 2.0 and 2.5 mm standard drills). K wire drilling increased temperature from 5°C at the first hole to 20°C at holes 6 through 9. A similar trend was found in standard drills with less significant increments. The maximum temperatures of both tools increased from <0.5°C to nearly 13°C. The difference between drill sizes was found to be insignificant (P > 0.05). In conclusion, heat accumulated during sequential drilling, with size difference being insignificant. K wire produced more heat than its twist-drill counterparts. This study has demonstrated the heat accumulation phenomenon and its significant effect on temperature. Maximizing the drilling field and reducing the number of drill passes may decrease bone injury. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 24 Sep 2015 04:39:03 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23036 Formation of chondrocyte clusters is not only a morphological sign of osteoarthritis but it is also observed in cell culture. Active locomotion of chondrocytes is controlled by integrins in vitro. Integrins bind to Laminin-A4 (LAMA4), a protein that is highly expressed in vivo in clusters of hypertrophic chondrocytes. We tested if LAMA4 is relevant for cluster formation. Human chondrocytes were cultured in a 2D matrigel model and treated with different concentrations of a monoclonal inhibitory anti-LAMA4-antibody. Migration and cluster formation was analysed using live cell imaging technique. Full genome gene expression analysis was performed to assess the effect of LAMA4 inhibition. The data set were screened for genes relevant to cell motility. F-actin staining was performed to document cytoskeletal changes. Anti-LAMA4 treatment significantly reduced the rate of cluster formation in human chondrocytes. Cells changed their surface morphology and exhibited fewer protrusions. Expression of genes associated with cellular motility and migration was affected by anti-LAMA4 treatment. LAMA4-integrin signalling affects chondrocyte morphology and gene expression in vitro, thereby contributing to cluster formation in human osteoarthritic chondrocytes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 24 Sep 2015 04:31:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22998 The treatment of articular cartilage injury and disease has become an increasingly relevant part of orthopaedic care. Articular cartilage transplantation, in the form of osteochondral allografting, is one of the most established techniques for restoration of articular cartilage. Our research efforts over the last two decades have supported the transformation of this procedure from experimental “niche” status to a cornerstone of orthopaedic practice. In this Kappa Delta paper, we describe our translational and clinical science contributions to this transformation: (1) to enhance the ability of tissue banks to process and deliver viable tissue to surgeons and patients, (2) to improve the biological understanding of in vivo cartilage and bone remodeling following osteochondral allograft (OCA) transplantation in an animal model system, (3) to define effective surgical techniques and pitfalls, and (4) to identify and clarify clinical indications and outcomes. The combination of coordinated basic and clinical studies is part of our continuing comprehensive academic OCA transplant program. Taken together, the results have led to the current standards for OCA processing and storage prior to implantation and also novel observations and mechanisms of the biological and clinical behavior of OCA transplants in vivo. Thus, OCA transplantation is now a successful and increasingly available treatment for patients with disabling osteoarticular cartilage pathology. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 24 Sep 2015 04:18:08 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23049 The primary objective of this study was to test the hypothesis that gleno-humeral deformity in children and adolescent with obstetrical brachial plexus palsy is three-dimensional (3D). The study also compared the metrological properties of typical two-dimensional gleno-humeral measures to the newly developed 3D measures. Thirteen individuals (age = 11.8 ± 3.3 years) with obstetrical brachial plexus palsy participated in this IRB-approved study. 3D axial magnetic resonance images were acquired for both shoulders. Glenoid and humeral models were created in order to quantify 3D glenoid version, humeral head migration, and glenoid concavity. Two-dimensional (2D) measures were acquired as recommended in the literature. All measures were completed by two observers in this observer-blind study. Compared to the non-involved side, the glenoid was more retroverted (7.91°, p = 0.003) and inferiorly oriented (7.28°, p = 0.009). The humeral head was migrated more posteriorly (5.54 mm, p = 0.007), inferiorly (−3.96 mm, p = 0.013), and medially (−3.63 mm,p = 0.002). Eleven of the 13 glenoids were concave, based on the 3D glenoid models. The concurrent validity between three- and 2D measures were highly dependent of the parameter measured, the slice level used for the 2D analysis, and the presence/absence of pathology (0.63 < r < 0.91). The standard error of measurement for the 2D anterior–posterior version (>3°) was larger than that for the 3D measure of version (<1°) on the involved side. This study clearly demonstrated that the gleno-humeral deformation in obstetrical brachial plexus palsy is 3D, emphasizing the need for 3D subject specific gleno-humeral shape analysis for follow-up and treatment plans in children with obstetrical brachial plexus palsy. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Wed, 23 Sep 2015 03:31:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22942 Differences in matrix compositions in human nucleus pulposus (NP) clinical samples demand different cell isolation protocols for optimal results but there is no clear guide about this to date. Sub-optimal protocols may result in low cell yield, limited reliability of results or even failure of experiments. Cell yield, viability and attachment of cells isolated from bovine NP tissue with different protocols were estimated by cell counting, Trypan blue staining and cell culturing respectively. RNA was extracted from isolated cells and quantified by Nanodrop spectrometry and RT-qPCR. Higher collagenase concentration, longer digestion duration and pronase pre-treatment increased the cell yield. Cell viability remained high (<5% dead cells) even after 0.2% collagenase treatment for overnight. NP cells remained to have high ACAN, COL2A1, CDH2, KRT18, and KRT19 expression compared to muscle cells for different cell isolation conditions tested. Digestion by collagenase alone without the use of pronase could isolate cells from human degenerated NP tissue but clusters of cells were observed. We suggest the use of the disappearance of tissue as an indirect measure of cells released. This study provides a guide for researchers to decide the parameters involved in NP cell isolation for optimal outcome. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 22 Sep 2015 00:25:01 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23050 Particle-induced osteolysis is driven by multiple factors including bone metabolism, inflammation, and age. The objective of this study was to determine the influence of age on polyethylene (PE) particle-induced osteolysis in a murine calvarial model comparing 2-month-old (young) versus 24-month-old (old) mice. After PE particle implantation, calvaria were assessed at days (D) 3, D7, D14, and D21 via chemoluminescent imaging for inflammation (L-012 probe). In addition micro-computed tomography (micro-CT) and histomorphometry end points addressed the bone reaction. Inflammation peaked at D7 in young mice and D14 in old mice. Using micro-CT, a nadir of mature bone was recorded at D7 for young mice, versus D21 for old mice. Besides, regenerating bone peaked at distinct timepoints: D7 for young mice versus D21 for old mice. In the young mice group, the histomorphometric findings correlated with micro-CT regenerating bone findings at D7, associated with ample osteoïd deposition. No osteoïd could be histologically quantified in the old mice group at D7. This study demonstrated that the biological reaction to polyethylene particles is highly influenced by age. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 22 Sep 2015 00:23:10 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23046 Long non-coding RNAs (lncRNAs) have been reported to play important roles in cellular metabolism and development. Various diseases have been associated with aberrant expression of lncRNAs and the related dysregulation of mRNAs. An lncRNA profiling assay was carried out to identify the key lncRNA in osteoarthritic human synoviocytes; the results revealed that prostate cancer gene expression marker 1 (PCGEM1) was significantly overexpressed in osteoarthritic synoviocytes. Exogenous overexpression of PCGEM1 inhibited apoptosis, induced autophagy, and stimulated the proliferation of human synoviocytes. The increased expression of PCGEM1 in human synoviocytes also suppressed the expression of miR-770. Transfection of the miR-770 precursor resulted in reduced proliferation, and induced apoptosis of human synoviocytes. This effect of miR-770 expression was reversed by co-introduction of PCGEM1. Target validation showed a direct binding between PCGEM1 and miR-770. We demonstrate that PCGEM1 act as sponge lncRNA for miR-770 that regulates proliferation/apoptosis and autophagy, and suggest PCGEM1 as possible target for OA therapy. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Mon, 21 Sep 2015 04:51:20 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23043 Articular chondrocytes maintain cartilage matrix turnover and have the capacity for anabolic and catabolic activities that can be influenced by injury and disease. This study tested the hypothesis that catabolic genes are upregulated with regional osteoarthritis (OA) disease severity within a joint. With IRB approval, specimens of knee cartilage obtained as discarded tissues from subjects undergoing arthroplasty were partitioned for each subject by OA disease severity and evaluated for gene expression by RT-PCR. There was regional OA grade-associated upregulation of expected inflammatory mediators TNF-α, TNF receptors, IFN-γ, and interleukins as well as genes encoding proteolytic enzymes, including Adamts-5 and MMPs. Osteoclast-related genes, cathepsin K, tartrate-resistant acid phosphatase (TRAP), RANKL, RANK, M-CSF, and c-fms, but not osteoprotegerin, were induced in advanced grades. In vitro treatment of normal human chondrocytes with interleukin-1β upregulated similar genes; this provides evidence that chondrocytes per se can be the source of osteoclast-related factors. Immunohistochemical staining showed that RANK- and RANKL-positive cells were abundant in advanced grades, especially in chondrocyte clusters. This suggests a possible autocrine mechanism by which an osteoclast phenotype is induced in articular chondrocytes. In sum, these studies identified gene expression signatures in human OA cartilage based upon regional disease severity within a joint. There was an effect of OA Grade on expression of osteoclastic lytic enzymes and regulatory factors in human articular chondrocytes. Induction of an osteoclast-like phenotype in chondrocytes may be part of OA progression and suggests specific therapeutic approaches. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 18 Sep 2015 03:48:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23045 This study characterizes the strain patterns and safe arcs for passive range of motion (ROM) in the superior and inferior subscapularis tendon in seven cadaveric shoulders, mounted for controlled ROM, after deltopectoral approach to the glenohumeral joint, including tenotomy of the subscapularis tendon 1 cm medial to its insertion on the lesser tuberosity. The tenotomy was repaired with end-to-end suture in neutral rotation. Strain patterns were measured during passive ROM in external rotation (ER), ER with 30° abduction (ER+30), abduction, and forward flexion in the scapular plane (SP) before and after surgery. Percentages were calculated from 35 trials corresponding to five trials of each motion across seven specimens. With ER of 0−30°, 89% of trials of superior subscapularis tendon and 100% of trials of inferior subscapularis tendon achieved strains >3%, with very similar patterns noted in ER+30. In abduction of 0−90°, 5.8% of trials of superior and 85.3% of trials of inferior tendon achieved >3% strain. With passive ROM in SP, 26.5% of trials reached 3% strain in superior tendon compared to 100% in inferior tendon. Strain patterns in abduction and SP differed significantly (p < 0.001). Selective tenotomy and repair of the superior subscapularis tendon with open reparative or reconstructive shoulder procedures, when feasible, may be favorable for protected early passive ROM and rehabilitation postoperatively. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 18 Sep 2015 03:47:38 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23031 Pigmented villonodular synovitis (PVNS) is a benign tissue proliferation characterized by its hyper-vascularity within the lesion. The true etiology and cell source of this disease entity still remain unclear. Mesenchymal stem cells (MSCs) exist in various tissues of human body. However, it has not been clarified whether MSCs could be isolated from tissue of PVNS. Here, we isolated MSCs from PVNS (PVNS-SCs), and by comparing to the MSCs from normal synovium (Syn-SCs) of the same individual, we investigated whether PVNS-SCs differed in the capacity for multi-differentiation and inducing angiogenesis. We first demonstrated that PVNS-SCs existed in the lesion of PVNS of three individuals. Moreover, we showed PVNS-SCs had better osteogenic differentiation potential than Syn-SCs, whereas Syn-SCs had better capacity for adipogenic and chondrogenic differentiation. By genome–wide analysis of gene expression profile using a complementary DNA microarray and comparing to Syn-SCs, we identified in PVNS-SCs a distinct gene expression profile characterized by up-regulation of genes involved in angiogenesis. In vitro and in vivo studies further confirmed that PVNS-SCs had better capacities for promoting angiogenesis. In summary, the identification of PVNS-SCs in PVNS tissue and their distinct angiogenic potential may help elucidate the underlying etiology of this disease. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 18 Sep 2015 03:44:14 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23047 We have recently demonstrated that pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of pain-like behavior in ovariectomized (OVX) mice. In addition, bisphosphonate and the antagonist of transient receptor potential vanilloid type 1 (TRPV1), an acid-sensing nociceptor, improved the threshold value of pain-like behaviors accompanying an improvement in the acidic environment in the bone tissue based on osteoclast inactivation. The aim of this study was to evaluate the effect of (i) an inhibitor of vacuolar H+-ATPase, known as an proton pump, (ii) an antagonist of acid-sensing ion channel (ASIC) 3, as another acid-sensing nociceptor, and (iii) the P2X2/3 receptor, as an ATP-ligand nociceptor, on pain-like behavior in OVX mice. This inhibitor and antagonists were found to improve the threshold value of pain-like behavior in OVX mice. These results indicated that the skeletal pain accompanying osteoporosis is possibly associated with the acidic microenvironment and increased ATP level caused by osteoclast activation under a high bone turnover state. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 18 Sep 2015 03:43:44 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23041 Treatment for an initial incidence of patellar dislocation is usually conservative management; however, almost half of patients experience a subsequent, or multiple, dislocation(s). Patients often undergo multiple procedures which fail to treat the underlying anatomic abnormalities. The objective of this study was to evaluate interactions between key predisposing anatomic factors to patellar dislocation and identify combinations of abnormal factors which increase the risk of recurrent lateral dislocation. Four factors associated with lateral patellar dislocation were identified (sulcus angle, Insall-Salvati ratio, tibial tubercle-trochlear groove distance, and femoral anteversion). A finite element model of the patellofemoral joint was developed and parameterized so that a value for each factor could be applied and the model geometry/alignment would be modified accordingly. 100 combinations of the four factors were generated in separate computational simulations and resulting kinematics and forces of the patellofemoral joint were recorded. Sulcus angle was the most impactful factor on constraint. Multiple abnormal factors were generally required to produce the extremes of patellar alignment observed in this analysis. Understanding the underlying anatomic factors, and their effect on joint mechanics, for patients with recurrent lateral patellar dislocation will aid in determining optimal treatment pathways on a patient-specific basis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 15 Sep 2015 04:34:59 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23042 Arthrodesis is the standard of care for numerous pathologic conditions of the cervical spine and is performed over 150,000 times annually in the United States. The primary long-term concern after this surgery is adjacent segment disease (ASD), defined as new clinical symptoms adjacent to a previous fusion. The incidence of adjacent segment disease is approximately 3% per year, meaning that within 10 years of the initial surgery, approximately 25% of cervical arthrodesis patients require a second procedure to address symptomatic adjacent segment degeneration. Despite the high incidence of ASD, until recently, there was little data available to characterize in vivo adjacent segment mechanics during dynamic motion. This manuscript reviews recent advances in our knowledge of adjacent segment mechanics after cervical arthrodesis that have been facilitated by the use of dynamic biplane radiography. The primary observations from these studies are that current in vitro test paradigms often fail to replicate in vivo spine mechanics before and after arthrodesis, that intervertebral mechanics vary among cervical motion segments, and that joint arthrokinematics (i.e., the interactions between adjacent vertebrae) are superior to traditional kinematics measurements for identifying altered adjacent segment mechanics after arthrodesis. Future research challenges are identified, including improving the biofidelity of in vitro tests, determining the natural history of in vivo spine mechanics, conducting prospective longitudinal studies on adjacent segment kinematics and arthrokinematics after single and multiple-level arthrodesis, and creating subject-specific computational models to accurately estimate muscle forces and tissue loading in the spine during dynamic activities. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 10 Sep 2015 03:01:34 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23037 Purpose: The widespread usage of metal-on-metal (MoM) articulations in total hip arthroplasty (THA) has been tempered by concerns of increased metal ion production. The purpose of the study is to evaluate the influence of metal ion exposure on semen quality in young male patients undergoing THA. Methods: Male patients who were scheduled for unilateral THA and aged between 20 and 45 years were prospectively enrolled. Patients were sorted into MoM and metal-on-polyethylene (MoP) groups with equal case number. Semen and blood metal ion levels were measured and sperm analysis was performed before, 6 months after, and 1 year after surgery. Results: Compared to preoperative baseline, patients (n = 50) in both groups had increased cobalt (Co) and chromium (Cr) concentrations in blood and seminal fluid after surgery. Between-group comparisons at 6 months and 1 year after surgery showed that patients in the MoM group both had a greater Co concentration in blood and semen and a greater Cr concentration in blood and semen. Patients receiving MoM prosthesis had a reduced percentage of morphologically normal sperm, and decreases from the preoperative level (44.7%) were significant at 6 months (36.8%, p = 0.03) and 1 year (33.8%, p = 0.004). Conclusions: Our data shows a significantly greater concentration of metal ion in blood and semen in patients with MoM prosthesis with a reduced percentage of morphologically normal sperm. Despite small effects on sperm quality, some concerns remain. Further studies are necessary to determine sources of metal ion and to investigate effects on male fertility. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 10 Sep 2015 02:59:49 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23027 Tissue-engineered constructs (TECs) seeded with mesenchymal stem cells (MSCs) represent a therapy for large bone defects. However, massive cell death in TECs in the early postimplantation period prompted us to investigate the osteoinductive mechanism of TECs. Previous studies demonstrated that stem cell extracts retained equivalent levels of bioactive proteins and exhibited an osteoinductive nature similar to that of intact cells. These data led us to hypothesize that despite the massive cell death in TECs, devitalized MSC-derived proteins remain on the scaffolds and are released to improve cell function. Here, TECs were prepared using demineralized bone matrix seeded with human umbilical cord Wharton's jelly-derived MSCs (hWJMSCs), and the cells seeded in TECs were devitalized by lyophilizing the TECs. Scanning electron microscopy, BCA protein assays, quantitative cytokine array analysis and immunofluorescent staining indicated that approximately 3 mg/cm3 of total protein and 49 types of cytokines derived from hWJMSCs were preserved in the lyophilized TECs (LTECs). The sustainable release of total protein and cytokines from LTECs lasted for more than 2 weeks. The released protein improved the osteogenic behavior of and gene expression in MSCs. Furthermore, the lyophilized hWJMSC-derived proteins had immunoregulatory properties similar to those of live MSCs in mixed lymphocyte reactions. Collectively, we present a novel perspective on the osteoinductive mechanism of TECs and introduce LTECs as new systems for delivering multiple cytokines to enhance MSC behavior. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 10 Sep 2015 02:58:03 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23038 Several studies have demonstrated the benefits of IGF-I gene therapy in enhancing the histologic and biochemical content of cartilage repaired by chondrocyte transplantation. However, there is little to no data on the mechanical performance of IGF-I augmented cartilage grafts. This study evaluated the compressive properties of full-thickness chondral defects in the equine femur repaired with and without IGF-I gene therapy. Animals were randomly assigned to one of three study cohorts based on chondrocyte treatment provided in each defect: (i) IGF-I gene delivered by recombinant adeno-associated virus (rAAV)-5; (ii) AAV-5 delivering GFP as a reporter; (iii) naïve cells without virus. In each case, the opposite limb was implanted with a fibrin carrier without cells. Samples were prepared for confined compression testing to measure the aggregate modulus and hydraulic permeability. All treatment groups, regardless of cell content or transduction, had mechanical properties inferior to native cartilage. Overexpression of IGF-I increased modulus and lowered permeability relative to other treatments. Investigation of structure–property relationships revealed that Ha and k were linearly correlated with GAG content but logarithmically correlated with collagen content. This provides evidence that IGF-I gene therapy can improve healing of articular cartilage and can greatly increase the mechanical properties of repaired grafts. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:41:57 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22999 Open MRI in functional positions has potential to directly and non-invasively assess cam femoroacetabular impingement (FAI). Our objective was to investigate whether open MRI can depict intrusion of the cam deformity into the intra-articular joint space, and whether intrusion is associated with elevated acetabular contact force. Cadaver hips (9 cam; 3 controls) were positioned in an anterior impingement posture and imaged using open MRI with multi-planar reformatting. The β-angle (describing clearance between the femoral neck and acetabulum) was measured around the entire circumference of the femoral neck. We defined a binary “MRI cam-intrusion sign” (positive if β < 0°). We then instrumented each hip with a piezoresistive sensor and conducted six repeated positioning trials, measuring acetabular contact force (F). We defined a binary “contact-force sign” (positive if F > 20N). Cam hips were more likely than controls to have both a positive MRI cam-intrusion sign (p = 0.0182, Fisher's exact test) and positive contact-force sign (p = 0.0083), which represents direct experimental evidence for cam intrusion. There was also a relationship between the MRI cam-intrusion sign and contact-force sign (p = 0.033), representing a link between imaging and mechanics. Our findings indicate that open MRI has significant potential for in vivo investigation of the cam FAI mechanism. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:34:05 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23001 Post-laminectomy/laminotomy epidural fibrosis (EF) has been implicated as an important cause of failed back syndrome (FBS). The various clinical approaches used to control EF yield mixed outcomes. Cross-linked hyaluronic acid hydrogel (cHA) was synthesized to increase mechanical stability and residence time. We evaluated the therapeutic attenuation of proliferative EF in laminectomy/laminotomy groups treated and not treated with cHA. A bilateral T11-L1 total laminectomy or unilateral T12 laminotomy was done on four groups (n = 10 each) of Sprague-Dawley rats and then histologically examined 2 months post-surgery: (I) laminectomy group treated with and (II) not treated with cHA, (III) laminotomy group treated with and (IV) not treated with cHA. The grade of EF, the diameters within the spinal canal, dura mater thickness, and the area of the epidural space, subarachnoid space, and conus medullaris space were assessed. The cHA-treated subgroups (I, III) had a significantly lower grade of EF, thinner dura mater, and larger epidural and subarachnoid spaces than did the control subgroups (II, IV) (p < 0.05). The cHA formed a solid interpositional membrane barrier that prevented invasive fibrosis, and also helped reduce pathological changes to the adjacent structures. In conclusion, topically applied cHA is effective for reducing EF. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:33:38 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23002 Low serum albumin levels and impaired kidney function have been associated with decreased survival in patients with a variety of cancer types. In a retrospective cohort study, we analyzed 84 patients with liposarcoma treated at from May 1994 to October 2011. Uni- and multivariable Cox proportional hazard models and competing risk analyses were performed to evaluate the association between putative biomarkers with disease-specific and overall survival. The median age of the study population was 51.7 (range 19.6–83.8) years. In multivariable analysis adjusted for AJCC tumor stage, serum creatinine was highly associated with disease-specific survival (Subdistribution Hazard ratio (SHR) per 1 mg/dl increase = 2.94; 95%CI 1.39–6.23; p = 0.005). High albumin was associated with improved overall and disease-specific survival (Hazard Ratio (HR) per 10 units increase = 0.50; 95%CI 0.26–0.95; p = 0.033 and SHR = 0.64; 95%CI 0.42–1.00; p = 0.049). The serum albumin-creatinine-ratio emerged to be associated with both overall and disease-specific survival after adjusting for AJCC tumor stage (HR = 0.95; 95%CI 0.92–0.99; p = 0.011 and SHR = 0.96; 95%CI 0.93–0.99; p = 0.08). Our study provides evidence for a tumor-stage-independent association between higher creatinine and lower albumin with worse disease-specific survival. Low albumin and a high albumin-creatinine-ratio independently predict poor overall survival. Our work identified novel prognostic biomarkers for prognosis of patients with liposarcoma. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:31:28 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23033 During the early stages of articular osteochondrosis, cartilage is retained in subchondral bone, but the pathophysiology of this condition of growing humans and domestic animals is poorly understood. A subtractive hybridization study was undertaken to compare gene expression between the cartilage of early experimentally induced equine osteochondrosis lesions and control cartilage. Of the many putative differentially expressed genes identified, eight were confirmed by quantitative PCR analysis as differentially expressed, in addition to those already known to be associated with early lesions. Genes encoding vacuolar H+-ATPase V0 subunit d2 (ATP6V0D2), cathepsin K, integrin-binding sialoprotein, integrin αV, low density lipoprotein receptor-related protein 4, lumican, osteopontin, and thymosin β4 (TMSB4) were expressed at higher levels in lesions than in control cartilage. These genes included 34 genes not previously identified in cartilage. Some genes identified as associated with early lesions are known chondrocyte hypertrophy-associated genes, and in transmission electron microscopy studies normal hypertrophic chondrocytes were observed in lesions. Differential expression of ATP6V0D2 and TMSB4 in the cartilage of early naturally occurring osteochondrosis lesions was confirmed by immunohistochemistry. These results identify novel osteochondrosis-associated genes and provide evidence that articular osteochondrosis does not necessarily result from failure of chondrocytes to undergo hypertrophy. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:30:09 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23032 Surgical technique is one factor that has been identified as critical to success of total knee arthroplasty. Researchers have shown that computer simulations can aid in determining how decisions in the operating room generally affect post-operative outcomes. However, to use simulations to make clinically relevant predictions about knee forces and motions for a specific total knee patient, patient-specific models are needed. This study introduces a methodology for estimating knee soft-tissue properties of an individual total knee patient. A custom surgical navigation system and stability device were used to measure the force–displacement relationship of the knee. Soft-tissue properties were estimated using a parameter optimization that matched simulated tibiofemoral kinematics with experimental tibiofemoral kinematics. Simulations using optimized ligament properties had an average root mean square error of 3.5° across all tests while simulations using generic ligament properties taken from literature had an average root mean square error of 8.4°. Specimens showed large variability among ligament properties regardless of similarities in prosthetic component alignment and measured knee laxity. These results demonstrate the importance of soft-tissue properties in determining knee stability, and suggest that to make clinically relevant predictions of post-operative knee motions and forces using computer simulations, patient-specific soft-tissue properties are needed. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:29:42 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23034 With limited availability of osteochondral allografts, tissue engineered cartilage grafts may provide an alternative treatment for large cartilage defects. An effective storage protocol will be critical for translating this technology to clinical use. The purpose of this study was to evaluate the efficacy of the Missouri Osteochondral Allograft Preservation System (MOPS) for room temperature storage of mature tissue engineered grafts, focusing on tissue property maintenance during the current allograft storage window (28 days). Additional research compares MOPS to continued culture, investigates temperature influence, and examines longer-term storage. Articular cartilage constructs were cultured to maturity using adult canine chondrocytes, then preserved with MOPS at room temperature, in refrigeration, or kept in culture for an additional 56 days. MOPS storage maintained desired chondrocyte viability for 28 days of room temperature storage, retaining 75% of the maturity point Young's modulus without significant decline in biochemical content. Properties dropped past this time point. Refrigeration maintained properties similar to room temperature at 28 days, but proved better at 56 days. For engineered grafts, MOPS maintained the majority of tissue properties for the 28-day window without clearly extending that period as it had for native grafts. These results are the first evaluating engineered cartilage storage. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:27:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23035 Thermal cycling is a temperature modulation process developed to improve the performance, durability and longevity of materials. This process has been successfully utilized in the automotive, aeronautic and manufacturing industries. Surgical cutting tools undergo cyclical loading and generally fail by dulling, suggesting that thermal cycling may improve their performance and longevity. Ten 2.5 mm orthopaedic drill bits were randomized, with five undergoing thermal cycling within their sterile packaging and five serving as untreated controls. Using a servohydraulic testing machine, 100 drilling cycles were performed with each drill bit into the diaphyseal region of bovine femurs. After every 25 cycles, data was collected by performing identical drilling cycles into simulated human cortical bone material. Maximum force, maximum normalized torque and drilling work were measured, and a scanning electron microscope was used to measure outer corner wear. After 100 drilling cycles, the maximum drilling force, maximum normalized torque, drilling work and microscopic outer corner wear were all significantly lower for the treated drill bits (p < 0.05). Thermal cycling has the potential to decrease operating room costs and thermal necrosis associated with dull cutting tools. Application of this technology may also be relevant to surgical cutting tools such as saw blades, burrs and reamers. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 08 Sep 2015 00:26:16 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23039 The aim of this retrospective cohort study is to investigate the association between different subjective and objective assessments of ankle function in a population of athletes with or without functional ankle instability (FAI). 29 athletes with a history of ankle spraining were divided into two groups according to their ankle status: 16 with FAI (initial ankle sprain with residual functional instability) (age 24.6 ± 3.1 years), and 13 COPERS (initial ankle sprain without residual instability) (age 25.3 ± 4.4 years). The assessment of each individual's ankle function was based on three approaches: The “functional-ankle-ability-measure” (FAAM) assessing subjective ankle functionality, measures of sensorimotor control as objective functional measurements and MRI-based T2-mapping as a quantitative marker of compositional joint status. Pearson's product-moment-correlation coefficient, student's t-test and analysis-of-variance were used for statistical analysis. Significant group differences existed for subjective ankle function (FAAM, p = 0.04) and MRI-data mainly in the medial compartment of the ankle joint (p ≤ 0.05). We found unique associations between T2-mapping results and sensorimotor scores in the COPER (r = −0.756–0.849), and “FAI”-group (r = 0.630–0.657). The location and magnitude differed between groups. No correlations existed between these measures and the FAAM. This exploratory study provides preliminary evidence for potential interrelations between various diagnostic measures of ankle function and structure in individuals with and without FAI. We found associations between MRI-results and selected measures of sensorimotor control, indicating a potential link between loss of ankle function and early joint degeneration. Despite these interrelations, each of the different assessment options appears to contain unique information on ankle functionality important in a clinical assessment. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 04 Sep 2015 04:36:08 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22985 ACE-011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG-Fc. The orthopedic utility of ACE-011 was investigated using a murine analogue, RAP-011. Initially, a rat closed fracture model was tested using bi-weekly (biw) 10 mg/kg RAP-011. RAP-011 significantly increased callus length and callus bone volume (BV, +43% at 6w, p < 0.01). The polar moment of inertia was calculated to be substantively increased (+80%, p < 0.01), however mechanical bending tests showed a more modest increase in maximum load to failure (+24%, p < 0.05). Histology indicated enhanced appositional bone growth, but it was hypothesized that reduced remodeling, evidenced by decreased serum CTX (−16% at 6w, p < 0.01), could be compromising bone quality in the callus. A second closed fracture study was performed to examine lower “pulse” [RAP-011(p)] and “sustained” [RAP-011(s)] regimens of biw 0.6mg/kg × 2, 0.35mg/kg × 3 and 0.18mg/kg × 2, 0.1mg/kg × 7 respectively, compared with PTH(1–34) (25 μg/kg/d) and vehicle controls. RAP-011 treatments gave modest increases in callus length and callus BV at 6w (p < 0.01), but did not achieve an increase in maximum load over vehicle. In summary, RAP-011 is effective in promoting bone formation during repair, but optimizing callus bone quality will require further investigation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 01 Sep 2015 14:57:11 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23030 The purpose of this study was to investigate the role of elastase on tendinopathy, as well as to evaluate the potential for peritendinous injections of elastase into rats to cause tendinopathy. We first investigated the expression of elastase in the tendons of patients with tendinopathy, and then established the effects of elastase injection on the Achilles tendons of rats. Ultrasonographic and incapacitance testing was used to conduct tests for 8 weeks. Tendon tissues were collected for histological observation and protein levels of collagen type I and type III were detected using Western blotting. The percentage of elastase-positive cells increased in human specimens with grades II and III tendinopathy. The rat model demonstrated that the thickness of the tendon increased after elastase injection during Week 2–8. Hypercellularity and focal lesions were detected after Week 2. The expression of elastase was increased and elastin was decreased in Week 8. Collagen type I expression was decreased, but type III was increased in Week 4. These results suggested that elastase may be involved in the development of chronic tendinopathy, and that peritendinous injection of elastase may result in tendinopathy in rats. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 01 Sep 2015 14:56:22 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23029 Intervertebral disc herniation rates are quadrupled in astronauts following spaceflight. While bending motions are main contributors to herniation, the effects of microgravity on the bending properties of spinal discs are unknown. Consequently, the goal of this study was to quantify the bending properties of tail discs from mice with or without microgravity exposure. Caudal motion segments from six mice returned from a 30-day Bion M1 mission and eight vivarium controls were loaded to failure in four-point bending. After testing, specimens were processed using histology to determine the location of failure, and adjacent motion segments were scanned with micro-computed tomography (μCT) to quantify bone properties. We observed that spaceflight significantly shortened the nonlinear toe region of the force-displacement curve by 32% and reduced the bending strength by 17%. Flight mouse spinal segments tended to fail within the growth plate and epiphyseal bone, while controls tended to fail at the disc-vertebra junction. Spaceflight significantly reduced vertebral bone volume fraction, bone mineral density, and trabecular thickness, which may explain the tendency of flight specimens to fail within the epiphyseal bone. Together, these results indicate that vertebral bone loss during spaceflight may degrade spine bending properties and contribute to increased disc herniation risk in astronauts. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Mon, 31 Aug 2015 23:03:38 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23028 With the high prevalence of pediatric obesity there is a need for structured physical activity during childhood. However, altered tibiofemoral loading during physical activity in obese children likely contribute to their increased risk of orthopedic disorders of the knee. The goal of this study was to determine the effects of pediatric obesity and walking duration on medial and lateral tibiofemoral contact forces. We collected experimental biomechanics data during treadmill walking at 1 m•s−1 for 20 min in 10 obese and 10 healthy-weight 8–12 year-olds. We created subject-specific musculoskeletal models using radiographic measures of tibiofemoral alignment and centers-of-pressure, and predicted medial and lateral tibiofemoral contact forces at the beginning and end of each trial. Obesity and walking duration affected tibiofemoral loading. At the beginning of the trail, the average percent of the total load passing through the medial compartment during stance was 85% in the obese children and 63% in the healthy-weight children; at the end of the trial, the medial distribution was 90% in the obese children and 72% in the healthy-weight children. Medial compartment loading rates were 1.78 times greater in the obese participants. The medial compartment loading rate increased 17% in both groups at the end compared to the beginning of the trial (p = 0.001). We found a strong linear relationship between body-fat percentage and the medial-lateral load distribution (r2 = 0.79). Altered tibiofemoral loading during walking in obese children may contribute to their increased risk of knee pain and pathology. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1–9, 2015. Fri, 28 Aug 2015 08:36:37 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23025 This study investigates the correlation between the composition of human meniscus and its absorption spectrum in the visible (VIS) and near infrared (NIR) spectral range. Meniscus samples (n = 24) were obtained from nonarthritic knees of human cadavers with no history of joint diseases. Specimens (n = 72) were obtained from three distinct sections of the meniscus, namely; anterior, center, posterior. Absorption spectra were acquired from each specimen in the VIS and NIR spectral range (400–1,100 nm). Following spectroscopic probing, the specimens were subjected to biochemical analyses to determine the matrix composition, that is water, hydroxyproline, and uronic acid contents. Multivariate analytical techniques, including principal component analysis (PCA) and partial least squares (PLS) regression, were then used to investigate the correlation between the matrix composition and it spectral response. Our results indicate that the optical absorption of meniscus matrix is related to its composition, and this relationship is optimal in the NIR spectral range (750–1,100 nm). High correlations (R2uronic = 86.9%, R2water = 83.8%, R2hydroxyproline = 81.7%, p < 0.0001) were obtained between the spectral predicted and measured meniscus composition, thus suggesting that spectral data in the NIR range can be utilized for estimating the matrix composition of human meniscus. In conclusion, optical spectroscopy, particularly in the NIR spectral range, is a potential method for evaluating the composition of human meniscus. This presents a promising technique for rapid and nondestructive evaluation of meniscus integrity in real-time during arthroscopic surgery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 27 Aug 2015 01:26:40 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23024 The optimal reorientation of the acetabulum for developmental dysplasia of the hip (DDH) is unknown in terms of hip range-of-motion (ROM). The simulated ROMs of 52 DDHs after rotational acetabular osteotomy (RAO) with several patterns of femoral head coverage and those of 73 normal hips were analyzed using computer models reconstructed from CT images. After RAO with a lateral center edge angle (LCEA) of 30° and an anterior center edge angle (ACEA) of 55° producing coverage similar to that of normal hips, the maximal flexion and maximal internal rotation at 110° flexion with 20° adduction were significantly smaller than those of the normal group. To achieve ROMs after RAO similar to those of the normal group, an LCEA of 30° with an ACEA of 45°, an LCEA of 25° with an ACEA of 45° to 50°, and an LCEA of 20° with an ACEA of 50° could be preferred angles to target, even though they provided smaller coverage than that of normal hips. After RAO producing femoral head coverage similar to that of normal hips, the maximal flexion and the maximal internal rotation at 110° flexion with 20° adduction were significantly smaller than those of the normal group. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc., J Orthop Res Thu, 27 Aug 2015 00:32:20 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23010 The study compared the OARSI osteoarthritis cartilage histopathology assessment system with the biomechanical quality of human in vivo cartilage samples. In a prospective cohort study, 84 patients (100 knees) with varus deformity of the knee were included between May, 2010 and January, 2012. Osteochondral samples underwent biomechanical and histologic analysis. The dynamic modulus significantly (p < 0.001) decreased with each advancing grade of degeneration from OARSI Grade 0 (surface intact) to OARSI Grade 4 (erosion). For the aggregate modulus, there were significant (p < 0.001) differences between OARSI Grade 0 and OARSI Grade 1 as well as between OARSI Grade 1 and OARSI Grade 2. From OARSI Grade 2 to OARSI Grade 5, no differences in aggregate modulus occurred. The new OARSI grading system provides useful information about the functional properties of cartilage. There is a significant difference in cartilage stiffness between samples with intact surface and no signs of degeneration (OARSI Grade 0) and samples with intact surface and early signs of arthritis (OARSI Grade 1). Surgeons performing joint preserving procedures have to be aware that in knees with an intact cartilage surface (OARSI Grade 0/1), significant differences in the biomechanical properties may exist. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc., J Orthop Res Thu, 27 Aug 2015 00:22:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23008 We previously reported that a toll-like receptor 4 signaling contributes to the development of osteonecrosis of the femoral head. Also, oxidative stress is suggested to be one of the possible pathogenesis of osteonecrosis of the femoral head. A recent study showed that toll-like receptor 4 signaling leads to oxidative stress. The aim of the present study was to evaluate whether toll-like receptor 4 stimulation and subsequent corticosteroid treatment lead to the development of osteonecrosis of the femoral head in rat, and oxidative stress is associated with it. Male Wistar rats were randomly divided into four treatment groups: Saline + Saline, Saline + Methylprednisolone, Lipopolysaccharide + Saline, Lipopolysaccharide + Methylprednisolone. Osteonecrosis of the femoral head at 14 days after the treatment was observed in 1 of 10 Lipopolysaccharide + Saline, and 5 of 10 Lipopolysaccharide + Methylprednisolone treated rats. However, it was not observed at all in the Saline + Saline and Saline + Methylprednisolone treated groups. Glutathione peroxidase activity in the liver at 1 day after the treatment was significantly increased when treated with lipopolysaccharide. However, methylprednisolone treatment reduced the activity. On the other hand, glutathione peroxidase activity in the femur did not change in any intergroup. In conclusion, the present study showed that toll-like receptor 4 stimulation by lipopolysaccharide administration strengthen incidence of corticosteroid-induced osteonecrosis of the femoral head, however, concomitant oxidative stress via toll-like receptor 4 signaling may not contribute to the development of osteonecrosis of the femoral head in rats. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Wed, 19 Aug 2015 08:48:15 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22993 Supraspinatus tears often result in the setting of chronic tendinopathy. However, the typical repair model utilizes an acute injury. In recognition of that distinction, our laboratory developed an overuse animal model; however it is unclear whether induced overuse is necessary in the repair model. We studied the repair properties of overuse-induced tendons compared to normal tendons. We hypothesized that histological and mechanical properties would not be altered between the overuse-induced and normal tendons 1 and 4 weeks after repair. Thirty-one adult male Sprague-Dawley rats were subjected to either overuse or cage activity for 4 weeks prior to bilateral supraspinatus tendon repair surgery. Rats were sacrificed at 1 and 4 weeks post-surgery and evaluated for histology and mechanics. Results at 1 week showed no clear histologic changes, but increased inflammatory protein expression in overuse tendons. At 4 weeks, percent relaxation was slightly increased in the overuse group. No other alterations in mechanics or histology were observed. Our results suggest that the effects of the surgical injury overshadow the changes evoked by overuse. Because clinically relevant mechanical parameters were not altered in the overuse group, we conclude that when examining tendons 4 weeks after repair in the classic rat supraspinatus model, inducing overuse prior to surgery is likely to be unnecessary. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Wed, 19 Aug 2015 08:46:35 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23007 Post-traumatic joint contracture is a debilitating consequence of trauma or surgical procedures. It is associated with fibrosis that develops regardless of the nature of initial trauma and results from complex biological processes associated with inflammation and cell activation. These processes accelerate production of structural elements of the extracellular matrix, particularly collagen fibrils. Although the increased production of collagenous proteins has been demonstrated in tissues of contracted joints, researchers have not yet determined the complex protein machinery needed for the biosynthesis of collagen molecules and for their assembly into fibrils. Consequently, the purpose of our study was to investigate key enzymes and protein chaperones needed to produce collagen-rich deposits. Using a rabbit model of joint contracture, our biochemical and histological assays indicated changes in the expression patterns of heat shock protein 47 and the α-subunit of prolyl 4-hydroxylase, key proteins in processing nascent collagen chains. Moreover, our study shows that the abnormal organization of collagen fibrils in the posterior capsules of injured knees, rather than excessive formation of fibril-stabilizing cross-links, may be a key reason for observed changes in the mechanical characteristics of injured joints. This result sheds new light on pathomechanisms of joint contraction, and identifies potentially attractive anti-fibrotic targets. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 18 Aug 2015 12:43:28 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22991 Fusionless implants are used to correct pediatric progressive spinal deformities, most of them spanning the intervertebral disc. This study aimed at investigating the effects of in vivo static versus dynamic compression application and removal on discs of growing rats. A microloading device applied compression. 48 immature rats (28 d.o.) were divided into two groups (43d, 53d). Each group included four subgroups: control (no surgery), sham (device installed without loading), static (0.2 MPa) and dynamic compressions (0.2 MPa ± 30% with 0.1 Hz). In 43d subgroups, compression was applied for 15 days. In 53d subgroups, compression was followed by 10 days without loading. Disc heights, nucleus/annulus volumetric proportions and nucleus proteoglycan contents were analyzed using one-way ANOVA and post-hoc Tukey comparisons (p < 0.05). Disc heights of 43d and 53d static and dynamic loading rats were lower than shams (p < 0.05). Volumetric proportions remained similar. At 43d, nucleus proteoglycan contents increased in both static and dynamic loading rats. However, at 53d, static loading rats had lower proteoglycan content than dynamic loading rats (p < 0.05). Disc structure is altered following static compression removal, but nucleus proteoglycan content remaining elevated in dynamic group. Dynamic fusionless implants would better preserve disc integrity. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 14 Aug 2015 14:25:32 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23006 Knee instability following anterior cruciate ligament (ACL) rupture is common, compromising function, and causing cartilage and meniscal damage. In this study, instability at the level of the articular surfaces was characterized with a new measure: articular instability. Articular instability was defined as the change in location of the center of contact stress per unit of applied load. The effect of ACL-deficiency on articular instability was quantified in response to combined abduction and internal rotation moments simulating the clinical pivot shift, which recreates the sensation of instability. Eleven cadaver knees were loaded using a robotic manipulator and tibiofemoral contact stress was measured using a stress transducer. Sectioning the ACL led to pronounced articular instability on the lateral compartment in 4 of 11 knees. In these 4 knees articular instability increased posteriorly up to 403% and increased laterally up to 754%. Factors driving inter-specimen variations in articular instability might include articular morphology, ligamentous laxity, and the applied loads. This novel description of contact mechanics confirms that the ACL prevents sudden changes in the relative position of the lateral articular surfaces. It is applicable to any loading conditions and provides a unique measure to quantify the effects of ACL injury and reconstruction. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 14 Aug 2015 14:24:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23009 Subchondral osteosclerosis, characterized by an increase of hypomineralized bone material, is a pathological hallmark of osteoarthritis. The cellular components in the subchondral marrow compartment that participate in this aberrant bone remodeling process remain to be elucidated. This study assessed the presence of marrow inflammatory cells and their relative abundance between nonsclerotic and sclerotic tissues in knee osteoarthritis. Bone samples from osteoarthritic knee tibial plateaus were stratified for histological analyses using computed tomography osteoabsorptiometry. Immunohistological analysis revealed the presence of CD20 (B-lymphocyte) and CD68 (macrophage), but not CD3 (T-lymphocyte) immunoreactive mononuclear cells in subchondral marrow tissues and their relative abundance was significantly increased in sclerotic compared with nonsclerotic bone samples. Multinucleated osteoclasts that stained positive for CD68 and tartrate-resistant acid phosphatase, predominantly associated with CD34-positive blood vessels and their abundance was strongly increased in sclerotic samples. Bone-specific alkaline phosphatase activity in outgrowth osteoblasts was induced by conditioned medium from nonsclerotic, but not sclerotic, bone pieces. These results suggest that an interaction between bone-resident cells and marrow inflammatory cells might play a role in aberrant bone remodeling leading to subchondral osteosclerosis. Elevated osteoclast activity in sclerotic bone suggests that bone formation and resorption activities are increased, yet uncoupled, in human knee osteoarthritis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 14 Aug 2015 03:37:15 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23005 Few studies have analyzed Cathepsin K (CatK) expression in human osteoarthritic tissues. We investigated CatK expression and activation in human articular cartilage using clinical specimens. Human osteoarthritic cartilage was obtained during surgery of total hip arthroplasty (n = 10), and control cartilage was from that of femoral head replacement for femoral neck fracture (n = 10). CatB, CatK, CatL, CatS, and Cystatin C (CysC) expressions were evaluated immunohistochemically and by real-time PCR. Intracellular CatK protein was quantified by ELISA. Intracellular CatK activity was also investigated. Osteoarthritis (OA) chondrocytes were strongly stained with CatK, particularly in the superficial layer and more damaged areas. CatB, CatL, CatS, and CysC were weakly stained. CatK mRNA expression was significantly higher in OA group compared to that in control group (p = 0.043), whereas those of CatB, CatL, CatS, and CysC did not differ significantly. Mean CatK concentration (4.83 pmol/g protein) in OA chondrocytes was higher than that (3.91 pmol/g protein) in control chondrocytes (p = 0.001). CatK was enzymatically more activated in OA chondrocytes as compared with control chondrocytes. This study, for the first time, revealed increased CatK expression and activation in human OA cartilage, suggesting possible crucial roles for it in the pathogenesis of osteoarthritic change in articular cartilage. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Wed, 12 Aug 2015 13:08:43 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23004 This study assessed the effects of static loading on MRI relaxation times of menisci in individuals with and without radiographic knee OA. High-resolution fast spin-echo (FSE) and T1ρ/T2 relaxation time MR sequences were obtained with and without loading at 50% body weight in 124 subjects. T1ρ/T2 relaxation times were calculated in menisci, and meniscus lesions were assessed through clinical grading. Student's t-test compared OA and control unloaded relaxation times as well as within-group changes with loading, Generalized Linear Models evaluated zonal variation, and ANCOVA compared loading response between groups. Unloaded T1ρ and T2 in the middle and inner zones of the lateral anterior horn and outer zone of the medial posterior horn were significantly higher in OA and suggest that meniscal OA change occurs unevenly. Zonal T1ρ and T2 showed differing patterns between anterior and posterior horns, suggesting differences in macromolecular organization. Significant increases with loading were seen largely in the T2 of controls and less frequently in subjects with OA. In the medial posterior horn, T1ρ and T2 decreased with loading in OA but changed negligibly in controls; these significantly different loading responses between groups may indicate load transmission failure in OA menisci. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Wed, 12 Aug 2015 13:08:17 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22992 Ischemia-reperfusion injury (IRI) occurs when blood returns to tissues following a period of ischemia. Reintroduction of blood flow results in the production of free radicals and reactive oxygen species that damage cells. Skeletal muscle IRI is commonly seen in orthopedic trauma patients. Experimental studies in other organ systems have elucidated the importance of extracellular and intracellular matrix metalloproteinase-2 (MMP-2) isoforms in regulating tissue damage in the setting of oxidant stress resulting from IRI. Although the extracellular full-length isoform of MMP-2 (FL-MMP-2) has been previously studied in the setting of skeletal muscle IRI, studies investigating the role of the N-terminal truncated isoform (NTT-MMP-2) in this setting are lacking. In this study, we first demonstrated significant increases in FL- and NTT-MMP-2 gene expression in C2C12 myoblast cells responding to re-oxygenation following hypoxia in vitro. We then evaluated the expression of FL- and NTT-MMP-2 in modulating skeletal muscle IRI using a previously validated murine model. NTT-MMP-2, but not FL-MMP-2 expression was significantly increased in skeletal muscle following IRI. Moreover, the expression of toll-like receptors (TLRs) -2 and -4, IL-6, OAS-1A, and CXCL1 was also significantly up-regulated following IRI. Treatment with the potent anti-oxidant pyrrolidine dithiocarbamate (PDTC) significantly suppressed NTT-MMP-2, but not FL-MMP-2 expression and improved muscle viability following IRI. This data suggests that NTT-MMP-2, but not FL-MMP-2, is the major isoform of MMP-2 involved in skeletal muscle IRI. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Wed, 12 Aug 2015 13:07:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23003 Osteoporosis and osteoarthritis commonly coexist in the elderly. In patients undergoing prosthetic total knee arthroplasty (TKA), the bone quality around the knee joint may affect the safety of prosthetic implantation and consequently satisfaction with the surgical outcome. We recruited 50 postmenopausal women undergoing TKA for primary osteoarthritis; 43 completed the study protocol. The bone quality parameters of the operated knee, including bone mineral density assessed using dual-energy X-ray absorptiometry and microarchitecture variables assessed using micro-computed tomography, were determined. Surgical outcomes were assessed according to immediate (<1 week) postoperative pain quantified using the visual analog scale and knee function quantified using the Knee Injury and Osteoarthritis Outcome Score (KOOS) at 2 and 6 months postoperatively. The influence of bone quality parameters on surgical outcomes was analyzed using simple and multiple regression analyses. Volumetric bone mineral density (R2 = 0.187–0.234, p < 0.01), the structural model index (R2 = 0.103–0.181, p < 0.05), and trabecular separation (R2 = 0.289–0.424, p < 0.05) were significantly associated with postoperative pain and improvement according to the KOOS. In conclusion, local bone quality, including mineral content and microarchitecture, affects the surgical outcome of TKA. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 11 Aug 2015 12:28:01 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22997 Episodes of care defined by the event of hip fracture surgery are widely used for the assessment of surgical wait times and outcomes. However, this approach does not consider nonoperative deaths, implying that survival time begins at the time of procedure. This approach makes treatment effect implicitly conditional on surviving to treatment. The purpose of this article is to describe a novel conceptual framework for constructing an episode of hip fracture care to fully evaluate the incidence of adverse events related to time after admission for hip fracture. This admission-based approach enables the assessment of the full harm of delay by including deaths while waiting for surgery, not just deaths after surgery. Some patients wait until their conditions are optimized for surgery, whereas others have to wait until surgical service becomes available. We provide definitions, linkage rules, and algorithms to capture all hip fracture patients and events other than surgery. Finally, we discuss data elements for stratifying patients according to administrative factors for delay to allow researchers and policymakers to determine who will benefit most from expedited access to surgery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 11 Aug 2015 12:27:16 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22990 Stair motion in the presence of hip osteoarthritis (OA) has received less attention than level walking. Its more strenuous aspect may shed the light on different locomotor strategies when compared to walking. We, therefore, aimed to define stair motion features associated to hip OA and to evaluate whether these specific features would differ from level walking and better characterize the hip pathological condition. Principal component and linear discriminant analyses were, respectively, used as data reduction and classification techniques. Our study highlighted that most of stair motion features associated to hip OA were similar to the ones of walking. Stair descent presented with the lowest misclassification error rate, ranging from 12% to 19% (estimated by cross-validation). But, features that may be considered as a mechanism to reduce demand on the hip abductors were found to be more important in the stair ascent condition. This was reflected by both, greater importance in the classification rule and variance compared with walking, that is, decreased hip internal rotation moment at mid-stance (72.50% vs. 57.63%) and increased trunk lateroflexion toward affected side (56.43% vs. 29.37%). This study emphasized the importance of investigating stair motion in hip osteoarthritic population by highlighting specific locomotor strategies. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 07 Aug 2015 03:16:58 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22994 Methods are needed for identifying poorer quality cadaver proximal humeri to ensure that they are not disproportionately segregated into experimental groups for fracture studies. We hypothesized that measurements made from radiographs of cadaveric proximal humeri are stronger predictors of fracture strength than chronological age or bone density values derived from dual-energy x-ray absorptiometry (DXA) scans. Thirty-three proximal humeri (range: 39–78 years) were analyzed for: (1) bone mineral density (BMD, g/cm2) using DXA, (2) bulk density (g/cm3) using DXA and volume displacement, (3) regional bone density in millimeters of aluminum (mmAl) using radiographs, and (4) regional mean (medial+lateral) cortical thickness and cortical index (CI) using radiographs. The bones were then fractured simulating a fall. Strongest correlations with ultimate fracture load (UFL) were: mean cortical thickness at two diaphyseal locations (r = 0.71; p < 0.001), and mean mmAl in the humeral head (r = 0.70; p < 0.001). Weaker correlations were found between UFL and DXA-BMD (r = 0.60), bulk density (r = 0.43), CI (r = 0.61), and age (r = −0.65) (p values <0.01). Analyses between UFL and the product of any two characteristics showed six combinations with r-values >0.80, but none included DXA-derived density, CI, or age. Radiographic morphometric and densitometric measurements from radiographs are therefore stronger predictors of UFL than age, CI, or DXA-derived density measurements. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 07 Aug 2015 03:16:22 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22982 The effects of the cathepsin K inhibitor odanacatib (ODN) on fracture healing were monitored for ∼6 and 15 weeks post-fracture in two separate studies using the unilateral transverse mid-ulnar osteotomy model in skeletally mature female rabbits. Rabbits were pre-treated for 3–4 weeks with vehicle (Veh), ODN (2 mg/kg, po, daily), or alendronate (ALN) (0.3 mg/kg, sc, twice-weekly) prior to osteotomy. In Study 1, the animals were maintained on the same respective treatment for ∼6 weeks. In Study 2, the animals were also continued on the same therapy or switched from Veh to ODN or ODN to Veh for 15 weeks. No treatment-related impairment of fracture union was seen by qualitative histological assessments in the first study. Cartilage retention was detected in the calluses of ALN-treated rabbits at week-6, while calluses in the ODN and Veh groups contained bony tissue with significantly less residual cartilage. ODN treatment also markedly increased the number of cathepsin K-(+) osteoclasts in the callus, indicating enhanced callus remodeling. From the second study, ex vivo DXA and pQCT confirmed that ODN treatment pre- and post-osteotomy increased callus bone mineral content and bone mineral density (BMD) versus Veh (p < 0.001) and discontinuation of ODN post-surgery returned callus BMD to Veh. Peak load of ODN- or ALN-treated calluses were comparable to Veh. ODN increased callus yield load (20%, p = 0.056) and stiffness (26%, p < 0.05) versus Veh. These studies demonstrated that ODN increased mineralized callus during the early phase of fracture repair without impairing callus formation or biomechanical integrity at the fracture site. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 07 Aug 2015 03:14:20 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22983 During embryogenesis vertebral segmentation is initiated by sclerotomal cell migration and condensation around the notochord, forming anlagen of vertebral bodies and intervertebral discs. The factors that govern the segmentation are not clear. Previous research demonstrated that mutations in growth differentiation factor 6 resulted in congenital vertebral fusion, suggesting this factor plays a role in development of vertebral column. In this study, we detected expression and localization of growth differentiation factor 6 in human fetal spinal column, especially in the period of early ossification of vertebrae and the developing intervertebral discs. The extracellular matrix proteins were also examined. Results showed that high levels of growth differentiation factor 6 were expressed in the nucleus pulposus of intervertebral discs and the hypertrophic chondrocytes adjacent to the ossification centre in vertebral bodies, where strong expression of proteoglycan and collagens was also detected. As fetal age increased, the expression of growth differentiation factor 6 was decreased correspondingly with the progress of ossification in vertebral bodies and restricted to cartilaginous regions. This expression pattern and the genetic link to vertebral fusion suggest that growth differentiation factor 6 may play an important role in suppression of ossification to ensure proper vertebral segmentation during spinal development. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:XX–XX, 2015. Thu, 06 Aug 2015 13:37:45 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22987 Traditional closed reductions of unstable pelvic fractures are mainly performed by surgeons using manual manipulation and subjective verification based on intra-operative roentgenography. It is difficult to perform an accurate closed reduction because of a lack of adequate knowledge of the displacement patterns and an inability to apply the reduction in correct direction. Using the concept of the remote center of motion mechanism and computer-aided design software, we developed a pelvic reduction frame for use in anatomical closed reductions of unstable pelvic fractures. With three-dimensional reconstruction technique and the matrix algorithm, the spatial orientation of the displaced hemipelvis can be calculated and deconstructed into several rotational and translational movements that can be completed with the frame. To verify the accuracy of this system, the rotations were repeated 10 times in arbitrary degrees and directions. After the matrix is calculated, the displaced hemipelvis can be reduced to the anatomical position using our frame. The maximum residual translational and rotational displacements were less than 5 mm and 4 degrees, which indicated the accuracy of this system. The maximum average residual translation and rotation were 1.87 mm in Z-axis (ranging: 4.63–0.1 mm) and 1.1 degrees around Y-axis (ranging: 3.81–0.13 degrees), respectively. Only the Z-axial translation showed a statistically significant difference (p < 0.05). In conclusion, the proposed pelvic reduction frame could be a useful tool for the anatomical reduction of unstable pelvic fractures. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 06 Aug 2015 11:38:32 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22988 To allow prediction of the risk of loosening prior to surgery, we investigated the relationship between innate immune cytokine response via TLR2 stimulation and early migration of six different knee prostheses using RSA (radiostereometry). This study included 114 patients of a prospective RSA-cohort who received a total knee arthroplasty. Whole blood cytokine responses were obtained by ex vivo stimulation with tripalmitoyl-S-glycerylcysteine (Pam3Cys-SK4) for assessment of the TLR2 immune response. Early migration was calculated using the maximum total point motion (MTPM) 1 year post surgery. Principal component analysis (PCA) was applied to the cytokine data to reduce the correlated data of individual cytokines and identified two components. Subsequently, linear mixed model analyses were applied with adjustments for gender, age, BMI, time-to-blood sampling, and prosthesis type. Component 1, consisting of IFNγ, IL-12p40, IL-10, IL-1β, TNFα, and IL-6, showed a significant inverse association (β = −0.128; p = 0.041) with MTPM. Further analysis showed that IFNγ (β = −0.161, p = 0.008) had the highest contribution to this association and is particularly found in patients receiving another prosthesis than Nexgen (β = −0.239; p < 0.001). In conclusion, patients with high levels of IFNγ upon stimulation of TLR2 are at lower risk of early migration of their knee prosthesis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 06 Aug 2015 11:37:09 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22989 This study was designed to characterize the synovium in the joints of Charcot neuroarthropathy (CNA) and investigate the potential role of fibroblast-like synoviocytes (FLS) in the pathology of CNA. Synovial samples were collected from CNA patients (n = 7) and non-CNA patients (n = 7), for control, during orthopaedic procedures and used for histology and isolation of FLS. Histological characterization of synovium included innervation and FLS localization. The isolated FLS from the CNA and non-CNA synovium were cultured, with or without tumor necrosis factor-α (TNF-α), for evaluation of invasiveness, gene expression, and cartilage degradation. Vasoactive intestinal peptide (VIP), a neuropeptide, was supplemented into the co-cultures of FLS and cartilage explants. Compared with the non-CNA synovium, CNA synovium was highly inflammatory, with reduced innervation and intense expression of cadherin-11. The FLS isolated from CNA synovium, particularly when activated with TNF-α, were more invasive, increased the expression of ADAMTS4, IL-6, and RANKL, and depleted proteoglycans from cartilage explants when they were co-cultured. Addition of VIP into the culture medium neutralized the catabolic effect of the CNA FLS on cartilage explants. In conclusion, FLS plays an important role in the pathology of CNA. Therapies targeting synovium and FLS may prevent or treat the joint destruction in CNA. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 06 Aug 2015 11:36:02 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22996 There are no established benchmarks for gait mechanics after total hip arthroplasty (THA). This study sought to identify minimum clinically important postoperative (MCIP) or minimum clinically important improvement (MCII) values for self-selected walking speed, sagittal plane dynamic hip range of motion (HROM) (peak flexion-peak extension) and peak hip adduction moments measured during quantitative gait analysis. Preoperative and 1-year postoperative data collected during quantitative gait analysis, along with Harris Hip Scores (HHS), for 145 subjects were collected from a motion analysis data repository. The MCIP (or MCII) was defined as the 75th percentile mark on a plot of the cumulative percent of subjects with HHS ≥ 80 versus the postoperative value (or change) in the respective variable. 95% confidence intervals (CI) were calculated. Logistic regression was used to test the association of age, sex, BMI, and preoperative HHS with benchmarks. The MCIP of speed was 1.34 m/s (95%CI 1.30, 1.37); MCII was 0.32 (0.30, 0.35) m/s. The HROM MCIP was 30.0° (29.4°, 30.7°); MCII was 13.3° (12.1°, 14.8°). The adduction moment MCIP was 4.2% Body Weight × Height (4.0, 4.4); MCII was 0.87 (0.57, 1.17) % Body Weight × Height. Women were more likely to achieve MCII for HROM and MCIP for adduction moment (ORs 2.4–11.6, p ≤ 0.031). Lower BMI predicted HROM and adduction moment MCIPs (ORs 0.85–0.88, p ≤ 0.015). Lower preoperative HHS predicted speed, HROM and adduction moment MCIIs (ORs 0.95–0.97, p ≤ 0.012). With further validation, clinically-relevant gait benchmarks can enhance efforts to improve THA outcomes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 06 Aug 2015 11:32:05 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23000 Cellular mechanosensitivity is an important factor during the mechanical stimulation of tissue engineered cartilage. While the application of mechanical stimuli improves tissue growth and properties, chondrocytes also rapidly desensitize under prolonged loading thereby limiting its effectiveness. One potential method to mitigate load-induced desensitization is by superimposing noise on the loading waveforms (“stochastic resonance”). Thus, the purpose of this study was to investigate the effects of stochastic resonance on chondrocyte matrix metabolism. Chondrocyte-seeded agarose gels were subjected to dynamic compressive loading, with or without, superimposed vibrations of different amplitudes and frequency bandwidths. Changes in matrix biosynthesis were determined by radioisotope incorporation and subsequent effects on intracellular calcium signaling were evaluated by confocal microscopy. Although dependent on the duration of loading, superimposed vibrations improved cellular sensitivity to mechanical loading by further increasing matrix synthesis between 20–60%. Stochastic resonance also appeared to limit load-induced desensitization by maintaining sensitivity under desensitized loading conditions. While superimposed vibrations had little effect on the magnitude of intracellular calcium signaling, recovery of mechanosensitivity after stimulation was achieved at a faster rate suggesting that less time may be required between successive loading applications. Thus, stochastic resonance appears to be a valuable tool during the mechanical stimulation of cartilage constructs, even when suboptimal stimulation conditions are used. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Thu, 06 Aug 2015 11:29:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22984 The molecular alterations involved in the capsule deformation presented in shoulder instability patients are poorly understood. Increased TGFβ1 acts as a signal for production of matrix macromolecules by fibrogenic cells at joint injury sites. TGFβ1, through its receptor TGFβR1, regulates genes involved in collagen cross-linking, such as LOX, PLOD1, and PLOD2. We evaluated TGFβ1, TGFβR1, LOX, PLOD1, and PLOD2 gene expression in the antero-inferior (macroscopically injured region), antero-superior and posterior regions of the glenohumeral capsule of 29 shoulder instability patients and eight controls. We observed that PLOD2 expression was increased in the anterior-inferior capsule region of the patients compared to controls. LOX expression tended to be increased in the posterior portion of patients. Patients with recurrent shoulder dislocation presented upregulation of TGFβR1 in the antero-inferior capsule portion and of PLOD2 in the posterior region. Conversely, LOX was increased in the posterior portion of the capsule of patients with a single shoulder dislocation episode. In the antero-inferior, LOX expression was inversely correlated and TGFβR1 was directly correlated with the duration of symptoms. In the posterior region, PLOD2, TGFβ1, and TGFβR1 were directly correlated with the duration of symptoms. In conclusion, PLOD2 expression was increased in the macroscopically injured region of the capsule of patients. Upregulation of TGFβ1, TGFβR1, and PLOD2 seems to be related with the maintenance of disease symptoms, especially in the posterior region. LOX upregulation seems to occur only in the initial phase of the affection. Therefore, TGFβ1, TGFβR1, LOX, and PLOD2 may play a role in shoulder instability. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Tue, 04 Aug 2015 00:56:01 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22981 Post-traumatic joint stiffness (PTJS) of the elbow is a debilitating condition that poses unique treatment challenges. While previous research has implicated capsular tissue in PTJS, much regarding the development and progression of this condition remains unknown. The objective of this study was to develop an animal model of post-traumatic elbow contracture and evaluate its potential for studying the etiology of PTJS. The Long-Evans rat was identified as the most appropriate species/breed for development due to anatomical and functional similarities to the human elbow joint. Two surgical protocols of varying severity were utilized to replicate soft tissue damage seen in elbow subluxation/dislocation injuries, including anterior capsulotomy and lateral collateral ligament transection, followed by 6 weeks of unilateral joint immobilization. Following sacrifice, flexion-extension mechanical joint testing demonstrated decreased range-of-motion and increased stiffness for injured-immobilized limbs compared to control and sham animals, where functional impact correlated with severity of injury. Histological evaluation showed increased cellularity, adhesion, and thickness of capsule tissue in injured limbs, consistent with clinical evidence. To our knowledge, this is the first animal model capable of examining challenges unique to the anatomically and biomechanically complex elbow joint. Future studies will use this animal model to investigate mechanisms responsible for PTJS. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 31 Jul 2015 03:52:09 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22980 The purpose of the study was to test a novel treatment that carbodiimide-derivatized-hyaluronic acid-lubricin (cd-HA-lubricin) combined cell-based therapy in an immobilized flexor tendon repair in a canine model. Seventy-eight flexor tendons from 39 dogs were transected. One tendon was treated with cd-HA-lubricin plus an interpositional graft of 8 × 105 BMSCs and GDF-5. The other tendon was repaired without treatment. After 21 day of immobilization, 19 dogs were sacrificed; the remaining 20 dogs underwent a 21-day rehabilitation protocol before euthanasia. The work of flexion, tendon gliding resistance, and adhesion score in treated tendons were significantly less than the untreated tendons (p < 0.05). The failure strength of the untreated tendons was higher than the treated tendons at 21 and 42 days (p < 0.05). However, there is no significant difference in stiffness between two groups at day 42. Histologic analysis of treated tendons showed a smooth surface and viable transplanted cells 42 days after the repair, whereas untreated tendons showed severe adhesion formation around the repair site. The combination of lubricant and cell treatment resulted in significantly improved digit function, reduced adhesion formation. This novel treatment can address the unmet needs of patients who are unable to commence an early mobilization protocol after flexor tendon repair. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 31 Jul 2015 03:51:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22979 Early secure fixation of total joint replacements is crucial for long-term survival. Antiresorptive agents such as bisphosphonates have been shown to increase implant fixation. We investigated whether local delivery of zoledronate from poly-D, L-lactide (PDLLA)-coated implants could improve implant fixation and osseointegration. Experimental titanium implants were bilaterally inserted press-fit into the proximal tibiae of 10 dogs. On one side the implant was coated with PDLLA containing zoledronate. The contralateral implant was uncoated and used as control. Observation period was 12 weeks. Implant fixation was evaluated with histomorphometry and biomechanical push-out test. We found an approximately twofold increase in all biomechanical parameters when comparing data from the zoledronate group with their respective controls. Histomorphometry showed increased amount of preserved bone and increased bone formation around the zoledronate implants. This study indicates that local delivery of zoledronate from a PDDLA coating has the potential to increase implant fixation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Fri, 31 Jul 2015 03:23:22 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22977 Total joint replacement (TJR) has been widely used as a standard treatment for late-stage arthritis. One challenge for long-term efficacy of TJR is the generation of ultra-high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle-induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle-induced osteolysis and the effects of 7ND treatment were evaluated using micro-CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle-induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle-induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:XX–XX, 2015. Wed, 29 Jul 2015 03:59:18 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22978 Femoral neck fractures in the elderly are a common problem in orthopedics. Augmentation of screw fixation with bone cement can provide better stability of implants and lower the risk of secondary displacement. This study aimed to investigate whether cement augmentation of three cannulated screws in non-displaced femoral neck fractures could increase implant fixation. A femoral neck fracture was simulated in six paired human cadaveric femora and stabilized with three 7.3 mm cannulated screws. Pairs were divided into two groups: conventional instrumentation versus additional cement augmentation of screw tips with 2 ml TraumacemV+ each. Biomechanical testing was performed by applying cyclic axial load until failure. Failure cycles, axial head displacement, screw angle changes, telescoping and screw cut-out were evaluated. Failure (15 mm actuator displacement) occurred in the augmented group at 12,500 cycles (± 2,480) compared to 15,625 cycles (± 4,215) in the non-augmented group (p = 0.041). When comparing 3 mm vertical displacement of the head no significant difference (p = 0.72) was detected between the survival curves of the two groups. At 8,500 load-cycles (early onset failure) the augmented group demonstrated a change in screw angle of 2.85° (± 0.84) compared to 1.15° (± 0.93) in the non-augmented group (p = 0.013). The results showed no biomechanical advantage with respect to secondary displacement following augmentation of three cannulated screws in a non-displaced femoral neck fracture. Consequently, the indication for cement augmentation to enhance implant anchorage in osteoporotic bone has to be considered carefully taking into account fracture type, implant selection and biomechanical surrounding. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:XX–XX, 2015. Wed, 29 Jul 2015 03:57:22 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22970 Taper wear at the head-neck junction is a possible cause of early failure in large head metal-on-metal (LH-MoM) hip replacements. We hypothesized that: (i) taper wear may be more pronounced in certain product designs; and (ii) an increased abductor moment arm may be protective. The tapers of 104 explanted LH-MoM hip replacements revised for adverse reaction to metal debris (ARMD) from a single manufacturer were analyzed for linear and volumetric wear using a co-ordinate measuring machine. The mated stem was a shorter 12/14, threaded trunnion (n = 72) or a longer, smooth 11/13 trunnion (n = 32). The abductor moment arm was calculated from pre-revision radiographs. Independent predictors of linear and volumetric wear included taper angle, stem type, and the horizontal moment arm. Tapers mated with the threaded 12/14 trunnion had significantly higher rates of volumetric wear (0.402 mm3/yr vs. 0.123 mm3/yr [t = −2.145, p = 0.035]). There was a trend to larger abductor moment arms being protective (p = 0.055). Design variation appears to play an important role in taper-trunnion junction failure. We recommend that surgeons bear these findings in mind when considering the use of a short, threaded trunnion with a cobalt-chromium head. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Sat, 25 Jul 2015 00:17:45 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.23062 Thu, 01 Oct 2015 18:09:40 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22930 The hypoxia-inducible factors HIF-1α and HIF-2α are important regulators of the chondrocyte phenotype but little is known about HIF-3α in cartilage. The objective of this study was to characterize HIF-3α (HIF3A) expression during chondrocyte differentiation in vitro and in native cartilage tissues. HIF3A, COL10A1, and MMP13 were quantified in mesenchymal stem cells (MSCs) and articular chondrocytes from healthy and osteoarthritic (OA) tissue in three-dimensional cultures and in human embryonic epiphyses and adult articular cartilage. HIF3A was found to have an inverse association with hypertrophic markers COL10A1 and MMP13 in chondrogenic cells and tissues. In healthy chondrocytes, HIF3A was induced by dexamethasone and increased during redifferentiation. By comparison, HIF3A expression was extremely low in chondrogenically differentiated MSCs expressing high levels of COL10A1 and MMP13. HIF3A was also lower in redifferentiated OA chondrocytes than in healthy chondrocytes. In human embryonic epiphyseal tissue, HIF3A expression was lowest in the hypertrophic zone. Distinct splice patterns were also found in embryonic cartilage when compared with adult articular cartilage and redifferentiated chondrocytes. These in vitro and in vivo findings suggest that HIF3A levels are indicative of the hypertrophic state of chondrogenic cells and one or more splice variants may be important regulators of the chondrocyte phenotype. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1561–1570, 2015. Tue, 14 Jul 2015 14:25:50 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22939 Collagen crosslinking enhances many beneficial properties of articular cartilage, including resistance to chemical degradation and mechanical wear, but many crosslinking agents are cytotoxic. The purpose of this study was to evaluate the effectiveness of genipin, a crosslinking agent with favorable biocompatibility and cytotoxicity, as a potential treatment to prevent the degradation and wear of articular cartilage. First, the impact of genipin concentration and treatment duration on the viscoelastic properties of bovine articular cartilage was quantified. Next, two short-term (15 min) genipin crosslinking treatments were chosen, and the change in collagenase digestion, cartilage wear, and the friction coefficient of the tissue with these treatments was measured. Finally, chondrocyte viability after exposure to these genipin treatments was assessed. Genipin treatment increased the stiffness of healthy, intact cartilage in a dose-dependent manner. The 15-min crosslinking treatments improved cartilage's resistance to both chemical degradation, particularly at the articular surface, and to damage due to mechanical wear. These enhancements were achieved without sacrificing the low coefficient of friction of the tissue and at a genipin dose that preserved chondrocyte viability. The results of this study suggest that collagen crosslinking via genipin may be a promising preventative treatment to slow the degradation of cartilage. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1571–1579, 2015. Mon, 18 May 2015 14:02:06 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22950 This study was carried out to assess the feasibility of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in articular cartilage repair and to further determine a suitable delivering hydrogel in a rat model. Critical sized full thickness cartilage defects were created. The hUCB-MSCs and three different hydrogel composites (hydrogel A; 4% hyaluronic acid/30% pluronic (1:1, v/v), hydrogel B; 4% hyaluronic acid, and hydrogel C; 4% hyaluronic acid/30% pluronic/chitosan (1:1:2, v/v)) were implanted into the experimental knee (right knee) and hydrogels without hUCB-MSCs were implanted into the control knee (left knee). Defects were evaluated after 8 weeks. The hUCB-MSCs with hydrogels composites resulted in a better repair as seen by gross and histological evaluation compared with hydrogels without hUCB-MSCs. Among the three different hydrogels, the 4% hyaluronic acid hydrogel composite (hydorgel B) showed the best result in cartilage repair as seen by the histological evaluation compared with the other hydrogel composites (hydrogel A and C). The results of this study suggest that hUCB-MSCs may be a promising cell source in combination with 4% hyaluronic acid hydrogels in the in vivo repair of cartilage defects. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1580–1586, 2015. Tue, 16 Jun 2015 01:28:00 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22951 The aim of this study was to investigate the effect of compressive modulation parameters (mode, magnitude, duration, as well as frequency and amplitude for cyclic modulation) on the viability of growth plate chondrocytes. Swine ulnar growth plate explants (n = 60) were randomly distributed among 10 groups: baseline (n = 1 × 6); culture control (n = 1 × 6); static (n = 3 × 6); and dynamic (n = 5 × 6). Static and dynamic samples were modulated in vitro using a bioreactor. Different compression magnitudes (0.1 MPa or 0.2 MPa), durations (12 h or 24 h), frequencies (0.1 Hz or 1.0 Hz), and amplitudes (30% or 100%) were investigated. Viability was assessed by automatic quantification of number of live/dead cells from confocal images of Live/Dead labeled tissues. Chondrocyte viability was found to be dependent on compression magnitude, duration, frequency, and amplitude in a way that increasing each parameter decreased viability in certain zones of growth plate. More specifically, proliferative and hypertrophic chondrocytes were found to be more sensitive to the applied compression. This study provides an in vitro protocol for studying the effects of compressive modulation on biomechanical and biological responses of growth plate explants, which will be useful in finding efficient and non-detrimental parameters for mechanical modulation of bone growth exploited in scoliosis fusionless treatments. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1587–1593, 2015. Fri, 12 Jun 2015 17:28:43 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22926 Patient-to-patient differences should be accounted for in both clinical evaluations and computational models of knee laxity. Accordingly, the objectives were to determine how variable the laxities are between knees by determining the range of the internal–external (I-E), varus–valgus (V-V), anterior–posterior (A-P), and compression–distraction (C-D) limits of passive motion, and how related the laxities are within a knee by determining whether these limits are correlated with one another. The limits in I-E (± 3 Nm), V-V (± 5 Nm), A-P (± 45 N), and C-D (± 100 N) were measured in 10 normal human cadaveric knees at 0° to 120° flexion in 15° increments using a six degree-of-freedom load application system. The ranges from 15° to 120° flexion of the I-E limits were greater than 3.6°, of the A-P limits were greater than 1.8 mm, and of the varus limits were greater than 1.4°. The ranges from 30° to 120° flexion of the distraction limits were greater than 2.0 mm. Twenty-four of the 28 pair-wise comparisons between the limits had a correlation coefficient less than 0.65. These results demonstrate that a patient-specific approach, including all degrees of freedom of interest, is necessary during clinical evaluations of laxity and when creating and validating computational models of the tibiofemoral joint. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1594–1602, 2015. Thu, 06 Aug 2015 13:01:01 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22927 The canine knee is morphologically similar to the human knee and thus dogs have been used in experimental models to study human knee pathology. To date, there is limited data of normal canine 3D knee kinematics during daily activities. The objective of this study was to characterize 3D in-vivo femorotibial kinematics in normal dogs during commonly performed daily activities. Using single-plane fluoroscopy, six normal dogs were imaged performing walk, trot, sit, and stair ascent activities. CT-generated bone models were used for kinematic measurement using a 3D-to-2D model registration technique. Increasing knee flexion angle was typically associated with increasing tibial internal rotation, abduction and anterior translation during all four activities. The precise relationship between flexion angle and these movements varied both within and between activities. Significant differences in axial rotation and coronal angulation were found at the same flexion angle during different phases of the walk and trot. This was also found with anterior tibial translation during the trot only. Normal canine knees accommodate motion in all planes; precise kinematics within this envelope of motion are activity dependent. This data establishes the characteristics of normal 3D femorotibial joint kinematics in dogs that can be used as a comparison for future studies. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1603–1610, 2015. Wed, 20 May 2015 09:28:30 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22945 Surgical navigation systems for total knee arthroplasty (TKA) surgery are capable of capturing passive three-dimensional (3D) angular joint movement patterns intraoperatively. Improved understanding of patient-specific knee kinematic changes between pre and post-implant states and their relationship with post-operative function may be important in optimizing TKA outcomes. However, a comprehensive characterization of the variability among patients has yet to be investigated. The objective of this study was to characterize the variability within frontal plane joint movement patterns intraoperatively during a passive knee flexion exercise. Three hundred and forty patients with severe knee osteoarthritis (OA) received a primary TKA using a navigation system. Passive kinematics were captured prior to (pre-implant), and after prosthesis insertion (post-implant). Principal component analysis (PCA) was used to capture characteristic patterns of knee angle kinematics among patients, to identify potential patient subgroups based on these patterns, and to examine the subgroup-specific changes in these patterns between pre- and post-implant states. The first four extracted patterns explained 99.9% of the diversity within the frontal plane angle patterns among the patients. Post-implant, the magnitude of the frontal plane angle shifted toward a neutral mechanical axis in all phenotypes, yet subtle pattern (shape of curvature) features of the pre-implant state persisted. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1611–1619, 2015. Wed, 03 Jun 2015 14:41:33 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22948 The mechanics of the knee are complex and dependent on the shape of the articular surfaces and their relative alignment. Insight into how anatomy relates to kinematics can establish biomechanical norms, support the diagnosis and treatment of various pathologies (e.g., patellar maltracking) and inform implant design. Prior studies have used correlations to identify anatomical measures related to specific motions. The objective of this study was to describe relationships between knee anatomy and tibiofemoral (TF) and patellofemoral (PF) kinematics using a statistical shape and function modeling approach. A principal component (PC) analysis was performed on a 20-specimen dataset consisting of shape of the bone and cartilage for the femur, tibia and patella derived from imaging and six-degree-of-freedom TF and PF kinematics from cadaveric testing during a simulated squat. The PC modes characterized links between anatomy and kinematics; the first mode captured scaling and shape changes in the condylar radii and their influence on TF anterior–posterior translation, internal-external rotation, and the location of the femoral lowest point. Subsequent modes described relations in patella shape and alta/baja alignment impacting PF kinematics. The complex interactions described with the data-driven statistical approach provide insight into knee mechanics that is useful clinically and in implant design. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1620–1630, 2015. Tue, 23 Jun 2015 03:05:27 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22949 Osteoarthritis (OA) is a leading cause of chronic joint pain in the older human population. Diagnosis of OA at an earlier stage may enable the development of new treatments to one day effectively modify the progression and prognosis of the disease. In this work, we explore whether an integrated metabolomics approach could be utilized for the diagnosis of OA. Synovial fluid (SF) samples were collected from symptomatic chronic knee OA patients and normal human cadaveric knee joints. The samples were analyzed using 1H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) followed by multivariate statistical analysis. Based on the metabolic profiles, we were able to distinguish OA patients from the controls and validate the statistical models. Moreover, we have integrated the 1H NMR and GC-MS results and we found that 11 metabolites were statistically important for the separation between OA and normal SF. Additionally, statistical analysis showed an excellent predictive ability of the constructed metabolomics model (area under the receiver operating characteristic curve = 1.0). Our findings indicate that metabolomics might serve as a promising approach for the diagnosis and prognosis of degenerative changes in the knee joint and should be further validated in clinical settings. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1631–1638, 2015. Fri, 12 Jun 2015 17:25:50 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22936 The saddle-shaped trapeziometacarpal (TMC) joint contributes importantly to the function of the human thumb. A balance between mobility and stability is essential in this joint, which experiences high loads and is prone to osteoarthritis (OA). Since instability is considered a risk factor for TMC OA, we assessed TMC joint instability during the execution of three isometric functional tasks (key pinch, jar grasp, and jar twist) in 76 patients with early TMC OA and 44 asymptomatic controls. Computed tomography images were acquired while subjects held their hands relaxed and while they applied 80% of their maximum effort for each task. Six degree-of-freedom rigid body kinematics of the metacarpal with respect to the trapezium from the unloaded to the loaded task positions were computed in terms of a TMC joint coordinate system. Joint instability was expressed as a function of the metacarpal translation and the applied force. We found that the TMC joint was more unstable during a key pinch task than during a jar grasp or a jar twist task. Sex, age, and early OA did not have an effect on TMC joint instability, suggesting that instability during these three tasks is not a predisposing factor in TMC OA. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1639–1645, 2015. Fri, 12 Jun 2015 17:28:17 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22947 Many conservative treatments exist for medial knee osteoarthritis (OA) which aims to reduce the external knee adduction moment (EKAM). The objective of this study was to determine the difference between different shoes and lateral wedge insoles on EKAM, knee adduction angular impulse (KAAI), external knee flexion moment, pain, and comfort when walking in individuals with medial knee OA. Seventy individuals with medial knee OA underwent three-dimensional walking gait analysis in five conditions (barefoot, control shoe, typical wedge, supported wedge, and mobility shoe) with pain and comfort recorded concurrently. The change in EKAM, KAAI, external knee flexion moment, pain, and comfort were assessed using multiple linear regressions and pairwise comparisons. Compared with the control shoe, lateral wedge insoles and barefoot walking significantly reduced early stance EKAM and KAAI. The mobility shoe showed no effect. A significant reduction in latter stance EKAM was seen in the lateral wedge insoles compared to the other conditions, with only the barefoot condition reducing the external knee flexion moment. However, the mobility shoe showed significant immediate knee pain reduction and improved comfort scores. Different lateral wedge insoles show comparable reductions in medial knee loading and in our study, the mobility shoe did not affect medial loading. © 2015 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. J Orthop Res 33:1646–1654, 2015. Wed, 03 Jun 2015 14:40:49 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22937 The study objective was to visualize regions of bone that undergo pathological mineralization and/or remodeling during pathogenesis of osteoarthritis, by employing non-radioactive strontium as a dynamic tracer of bone turnover. Post traumatic osteoarthritis was surgically induced in skeletally mature rats, followed by in vivo micro-CT imaging for 12 weeks to assess bone micro-structural changes. Rats either received strontium ranelate daily for the entire course of study or only last 10 days before euthanization. Distribution of strontium in bone was assessed in two and three dimensions, using electron probe micro-analysis (EPMA) and synchrotron dual energy K-edge subtraction micro-CT (SRμCT), respectively. Considerable early formation of osteophytes around the collateral ligament attachments and margins of articulating surfaces were observed, followed by subchondral sclerosis at the later stages. Accordingly, strontium was heavily incorporated by mineralizing osteophytes at 4, 8, and 12 weeks post-surgery, whereas subchondral bone only incorporated strontium between weeks 8–12.This study showed low dose stable strontium can effectively serve as a dynamic tracer of bone turnover to study pathological bone micro-structural changes, at resolution higher than nuclear medicine. Co-administration of strontium during therapeutic drug intervention may show enormous utility in assessing the efficacy of those compounds upon adaptive bone physiology. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1655–1662, 2015. Wed, 03 Jun 2015 14:43:13 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22932 Cobalt (Co) and chromium (Cr) ions and nanoparticles equivalent to those released through tribo-corrosion of prosthetic metal-on-metal (MOM) bearings and taper junctions are detrimental to osteoblast activity and function in vitro when examined as individual species. Here we examined the effects of Co2+:Cr3+ and Co2+:Cr6+ combinations on osteoblast-like SaOS-2 cellular activity, alkaline phosphatase (ALP) activity and mineralization to better reflect clinical exposure conditions in vivo. We also assessed the effect of Co2+:Cr3+ combinations and Co:Cr nanoparticles on SaOS-2 cell osteogenic responses on grit-blasted, plasma-sprayed titanium-coated, and hydroxyapatite-coated prosthesis surfaces. Cellular activity and ALP activity were reduced to a greater extent with combination treatments compared to individual ions. Co2+ and Cr3+ interacted additively and synergistically to reduce cellular activity and ALP activity, respectively, while the Co2+ with Cr6+ combination was dominated by the effect of Cr6+ alone. Mineralization by osteoblasts was greater on hydroxyapatite-coated surfaces compared to grit-blasted and plasma-sprayed titanium-coated surfaces. Treatments with Co2+:Cr3+ ions and Co:Cr nanoparticles reduced the percentage mineralization on all surfaces, with hydroxyapatite-coated surfaces having the least reduction. In conclusion, our data suggests that previous studies investigating individual metal ions underestimate their potential clinical effects on osteoblast activity. Furthermore, the data suggests that hydroxyapatite-coated surfaces may modulate osteoblast responses to metal debris. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1663–1670, 2015. Mon, 18 May 2015 14:01:20 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22933 Aseptic loosening of cemented joint replacements is a complex biological and mechanical process, and remains a clinical concern especially in patients with poor bone quality. Utilizing high resolution finite element analysis of a series of implanted cadaver glenoids, the objective of this study was to quantify relationships between construct morphology and resulting mechanical stresses in cement and trabeculae. Eight glenoid cadavers were implanted with a cemented central peg implant. Specimens were imaged by micro-CT, and subject-specific finite element models were developed. Bone volume fraction, glenoid width, implant-cortex distance, cement volume, cement–cortex contact, and cement–bone interface area were measured. Axial loading was applied to the implant of each model and stress distributions were characterized. Correlation analysis was completed across all specimens for pairs of morphological and mechanical variables. The amount of trabecular bone with high stress was strongly negatively correlated with both cement volume and contact between the cement and cortex (r = −0.85 and −0.84, p < 0.05). Bone with high stress was also correlated with both glenoid width and implant-cortex distance. Contact between the cement and underlying cortex may dramatically reduce trabecular bone stresses surrounding the cement, and this contact depends on bone shape, cement amount, and implant positioning. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1671–1679, 2015. Thu, 18 Jun 2015 00:23:59 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22934 This study assessed whether mechanically measured trabecular bone strength is an independent predictor of dynamic hip screw (DHS) stability, i.e., DHS migration (DHSM) after the fixation of proximal femoral fractures. One-hundred and seven patients older than 50 years with proximal femoral fractures were included. During fracture fixation, a mechanical probe (DensiProbe™ Hip) was inserted at the site where the DHS tip would ultimately be positioned. Peak torque to breakaway the trabecular bone was measured. Fracture reduction, primary implant position and postoperative DHSM were assessed by radiographs taken postoperatively, at 6 and 12 weeks after surgery. Univariate regression analysis revealed no association between peak torque and DHSM (R2 = 0.025, p = 0.135). DHSM correlated with the primary DHS position, i.e., the distance between the DHS and (i) the central femoral neck axis (CNFAD, R2 = 0.230; p < 0.0001) and (ii) the apex of the femoral head (R2 = 0.110; p = 0.001). DHSM did not correlate with areal BMD of the contralateral proximal femur. Multivariable regression modeling revealed the CFNAD as predictive factor for screw migration. The primary implant position measured by the CFNAD, rather than DensiProbe™ Hip measured bone strength, is an independent predictor of DHSM. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1680–1686, 2015. Mon, 18 May 2015 14:01:35 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22935 The incidence of anterior cruciate ligament injuries is considerably higher in females than in males and the underlying mechanisms are still under debate. Research indicates that the neuromuscular system of females and males might respond differently to the same fatigue protocol due to differences in muscle activation during movement tasks. This study analyzed sex differences in hamstring reflex responses and posterior-anterior tibial translation (TT) before and after fatiguing exercise. We measured the isolated movement of the tibia relative to the femur as a consequence of mechanically induced TT in standing subjects as well as muscle activity of the hamstrings before and after repetitive jumping and sprinting until exhaustion. Muscle fatigue delayed reflex onset latencies in females and males. A reduction in reflex responses associated with an increased TT was observed after fatiguing exercise for both sexes. Data indicate that the used fatigue protocol altered the latency and magnitude of reflex responses as well as TT in females and males. Based on the results of previous research and the outcome of this study, it might be that sex-specific effects of fatigue on reflex activity and mechanical stability of the knee depend on the kind of fatiguing exercise. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1687–1692, 2015. Fri, 29 May 2015 13:44:38 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22928 Musculoskeletal injuries greatly affect the U.S. population and current clinical approaches fail to restore long-term native tissue structure and function. Tissue engineering is a strategy advocated to improve tendon healing; however, the field still needs to establish biological benchmarks for assessing the effectiveness of tissue-engineered structures. Investigating superior healing models, such as the MRL/MpJ, offers the opportunity to first characterize successful healing and then apply experimental findings to tissue-engineered therapies. This study seeks to evaluate the MRL/MpJ's healing response following a central patellar tendon injury compared to wildtype. Gene expression and histology were assessed at 3, 7, and 14 days following injury and mechanical properties were measured at 2, 5, and 8 weeks. Native patellar tendon biological and mechanical properties were not different between strains. Following injury, the MRL/MpJ displayed increased mechanical properties between 5 and 8 weeks; however, early tenogenic expression patterns were not different between the strains. Furthermore, expression of the cyclin-dependent kinase inhibitor, p21, was not different between strains, suggesting an alternative mechanism may be driving the healing response. Future studies will investigate collagen structure and alignment of the repair tissue and characterize the complete healing transcriptome to identify mechanisms driving the MRL/MpJ response. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1693–1703, 2015. Mon, 25 May 2015 23:40:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22955 The manner in which strains are passed down the hierarchical length scales of tendons dictates how cells within the collagen network regulate the tissue response to loading. How tendons deform in different hierarchical levels under shear and compression is unknown. The aims of this study were: (i) to evaluate whether specific regions of bovine deep digital flexor tendons exhibited different strain attenuation from macro to micro length scales, and (ii) to elucidate mechanisms responsible for tendon deformation under shear and compression. Samples from distal and proximal regions of flexor tendons were subjected to three-step incremental stress-relaxation tests. Images of tissue markers, photobleached lines on collagen fibers, and nuclei locations were collected before and after loading. Results showed that strain transfer was attenuated from tissue to local matrix under both shear and compression. Nuclear aspect ratios exhibited smaller changes for distal samples, suggesting that cells are more shielded from deformation in the distal region. Collagen fiber sliding was observed to contribute significantly in response to shear, while uncrimping and fiber reorganization were the predominant mechanisms under compression. This study provides insight into microscale mechanisms responsible for multiscale strain attenuation of tendons under non-tensile macroscale loading. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1704–1712, 2015. Tue, 14 Jul 2015 14:26:12 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22957 The purpose of this research was to compare the efficacy and safety of unilateral versus bilateral PKP for osteoporotic vertebral compression fractures (OVCFs). Six databases (Cochrane, PubMed, MEDLINE, EMBASE, SinoMed, and CNKI) were searched without language restrictions. Twelve randomized controlled trials involving a total of 1,030 patients were identified. The results indicate that unilateral PKP had a better degree of pain relief (visual analog scale) than bilateral PKP (p = 0.04; 95%CI = −0.36 to −0.00) with short-term follow-up (within 4 weeks) after operation. The radiological outcome assessment with short-term follow-up after operation indicates bilateral PKP had a better degree of anterior vertebral height restoration (p = 0.03; 95%CI = −2.58 to −0.14). Operation time and cement dosage were less for unilateral PKP (p < 0.05). There were no differences in complications such as cement leakage and adjacent vertebral fractures between two approaches (p = 0.06 and p = 0.97, respectively). Life quality assessment (SF-36) indicates unilateral PKP had a better result of bodily pain relief (p < 0.05; 95%CI = 3.93 to 7.48) and general health benefit (p < 0.05; 95%CI = 0.02 to 2.93) with short-term follow-up after operation. We suggest that a unilateral PKP is advantageous. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1713–1723, 2015. Tue, 14 Jul 2015 08:27:31 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22946 In intervertebral disc herniation with nucleus pulposus (NP) extrusion, the elicited inflammatory response is considered a key pain mechanism. However, inflammatory cytokines are reported in extruded herniated tissue, even before monocyte infiltration, suggesting that the tissue itself initiates the inflammation. Since herniated tissue swells, we investigated whether this simple mechanobiological stimulus alone could provoke an inflammatory response that could cause pain. Furthermore, we investigated whether sustained-release cyclooxygenase-2 (COX2) inhibitor would be beneficial in such conditions. Healthy bovine NP explants were allowed to swell freely or confined. The swelling explants were treated with Celecoxib, applied either as a bolus or in sustained-release. Swelling explants produced elevated levels of interleukin-6 (IL-6) and prostaglandin E2 (PGE2) for 28 days, while confined explants did not. Both a high concentration bolus and 10 times lower concentration in sustained release completely inhibited PGE2 production, but did not affect IL-6 production. Swelling of NP tissue, without the inflammatory system response, can trigger cytokine production and Celecoxib, even in bolus form, may be useful for pain control in extruded disc herniation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1724–1731, 2015. Fri, 19 Jun 2015 16:58:35 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fjor.22943 Frozen shoulder is a relatively common disorder that leads to severe pain and stiffness in the shoulder joint. Although this disorder is self-limiting in nature, the symptoms often persist for years, resulting in severe disability. Recent studies using human specimens and animal models have shown distinct changes in the gene expression patterns in frozen shoulder tissue, indicating that novel therapeutic intervention could be achieved by controlling the genes that are potentially involved in the development of frozen shoulder. To achieve this goal, it is imperative to develop a reliable animal joint contracture model in which gene expression can be manipulated by gene targeting and transgenic technologies. Here, we describe a novel shoulder contracture mouse model. We found that this model mimics the clinical presentation of human frozen shoulder and recapitulates the changes in the gene expression pattern and the histology of frozen shoulder and joint contracture in humans and other larger animal models. The model is highly reproducible, without any major complications. Therefore, the present model may serve as a useful tool for investigating frozen shoulder etiology and for identifying its potential target genes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1732–1738, 2015. Fri, 29 May 2015 13:47:11 +0000