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Bone fractures at weight-bearing sites are challenging to treat due to the difficulty in maintaining articular congruency. An ideal biomaterial for fracture repair near articulating joints sets rapidly after implantation, stabilizes the fracture with minimal rigid implants, stimulates new bone formation, and remodels at a rate that maintains osseous integrity. Consequently, the design of biomaterials that mechanically stabilize fractures while remodeling to form new bone is an unmet challenge in bone tissue engineering. In this study, we investigated remodeling of resorbable bone cements in a stringent model of mechanically loaded tibial plateau defects in sheep. Nanocrystalline hydroxyapatite-poly(ester urethane) (nHA-PEUR) hybrid polymers were augmented with either ceramic granules (85% β-tricalcium phosphate/15% hydroxyapatite, CG) or a blend of CG and bioactive glass (BG) particles to form a settable bone cement. The initial compressive strength and fatigue properties of the cements were comparable to those of non-resorbable poly(methyl methacrylate) bone cement. In animals that tolerated the initial few weeks of early weight-bearing, CG/nHA-PEUR cements mechanically stabilized the tibial plateau defects and remodeled to form new bone at 16 weeks. In contrast, cements incorporating BG particles resorbed with fibrous tissue filling the defect. Furthermore, CG/nHA-PEUR cements remodeled significantly faster at the full weight-bearing tibial plateau site compared to the mechanically protected femoral condyle site in the same animal. These findings are the first to report a settable bone cement that remodels to form new bone while providing mechanical stability in a stringent large animal model of weight-bearing bone defects near an articulating joint.
Copyright © 2018 Elsevier Ltd. All rights reserved.
BACKGROUND - Osteosarcomas arising in the proximal femur, humerus, and tibia appear to have poorer outcomes than those arising in distal long bones. However, the strength of this association is uncertain, particularly in light of other prognostic factors. Therefore, this retrospective cohort study was performed to compare patient outcomes between proximal and distal tumor location within extremity long bones.
MATERIAL AND METHODS - A total of 153 patients with conventional high-grade osteosarcoma of the extremity long bones, pelvis, or axial skeleton who had undergone neoadjuvant chemotherapy and surgical resection between 1985 and 2010 were identified in the Surgical Pathology files at Vanderbilt Medical Center. Effect of anatomic location within a proximal long bone was assessed using multivariable Cox proportional hazard regression.
RESULTS - Proximal tumor location was a strong predictor of poor prognosis in univariate survival analysis. Multivariate regression analysis showed that after controlling for American Joint Committee on Cancer (AJCC) stage, histologic response to chemotherapy, surgical resection margin status, and histologic type, location in the proximal femur, tibia, and humerus were independent risk factors for death due to osteosarcoma, but not event-free survival.
CONCLUSION - Osteosarcomas of the proximal extremity long bones are associated with decreased disease-specific survival compared to tumors of the distal long bones, even after accounting for other key prognostic covariates.
The risk of developing post-traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help to improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA; however, the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild-type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following (1)H nuclear magnetic resonance spectroscopy, we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice and the integrin α1-null versus wild-type mouse genotype. Our results show the sex-dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA, and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site-specific factors such as surgery.
BACKGROUND - Anomalies of the meniscus are uncommon. These anomalous formations have been predominately described in the lateral compartment of the knee. Congenital abnormalities of the medial meniscus are rare.
METHODS - Chart and radiographic review of a single patient with a symptomatic congenital abnormality of the medial meniscus.
RESULTS - The patient was a 5-year-old boy with popliteal pterygium who developed painful snapping in the medial knee after anterior hemiepiphyseodesis to improve his knee extension. The patient had achieved full-knee extension from a preoperative 45-degree flexion contracture. The newly developed snapping was attributed to the hemiepiphyseodesis implants. After implant removal, the snapping persisted and was localized at the medial joint line. Through an arthrotomy, a medial meniscus abnormality was identified and excised with resolution of symptoms.
CONCLUSIONS - This report describes a symptomatic congenital abnormality of the medial meniscus in a child with popliteal pterygium. The patient was treated with excision of the anomalous structure with complete resolution of the symptoms. This is the first report of an intra-articular knee anomaly associated with popliteal pterygium syndrome.
Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.
Copyright © 2015, American Association for the Advancement of Science.
BACKGROUND - The prevalence and cost of unnecessary advanced imaging studies (AIS) in the evaluation of long bone cartilaginous lesions have not been studied previously.
METHODS - A total of 105 enchondromas and 19 chondrosarcomas arising in long bones from July 2008 until April 2012 in 121 patients were reviewed. Advanced imaging was defined as MRI, CT, bone scan, skeletal survey, or CT biopsy. Two blinded radiologists independently reviewed the initial imaging study and determined if further imaging was indicated based on that imaging study alone. The cost of imaging was taken from our institution's global charge list. Imaging was deemed unnecessary if it was not recommended by our radiologists after review of the initial imaging study. The difference in cost was calculated by subtracting the cost of imaging recommended by each radiologist from the cost of unnecessary imaging. The sensitivity and specificity for distinguishing enchondromas from chondrosarcomas was calculated. A minimum of 2 years from diagnosis of an enchondroma was required to monitor for malignant transformation.
RESULTS - Of patients diagnosed with an enchondroma, 85 % presented with AIS. The average enchondroma patient presented with one unnecessary AIS. The radiologists' interpretations agreed 85 % of the time for enchondromas and 100 % for chondrosarcomas. The sensitivity and specificity for distinguishing enchondromas from chondrosarcomas was 95 % for one radiologist and 87 and 95 % for the other. The average unnecessary cost per enchondroma patient was $1,346.18.
CONCLUSIONS - Unnecessary AIS are frequently performed and are a significant source of expense. The imaging algorithms outlined in this study may reduce unnecessary AIS.
BACKGROUND - The purpose of this study was to compare hemiepiphysiodesis implants for late-onset tibia vara and to evaluate patient characteristics that may predict surgical failure.
METHODS - This is a retrospective review of late-onset tibia vara patients treated with temporary hemiepiphysiodesis from 1998 to 2012. Mechanical axis deviation (MAD), mechanical axis angle, mechanical lateral distal femoral angle, and medial proximal tibial angle were measured on standing bone length radiographs. Surgical failure was defined as residual deformity requiring osteotomy, revision surgery, or MAD exceeding 40 mm at the time of final follow-up. Implant failure was recorded. Costs included implants and disposables required for construct placement. Staple constructs included 2 or 3 staples. Plate constructs included the plate, screws, guide wires, and drill bits.
RESULTS - A total of 25 patients with 38 temporary lateral proximal tibia hemiepiphysiodeses met the inclusion criteria. The average body mass index (BMI) was 39.1 kg/m with an average follow-up of 3.0 years (minimum 1 y). Surgical failure occurred in 57.9% of patients. Greater BMI (P=0.05) and more severe deformity (MAD, mechanical axis angle, and medial proximal tibial angle; P<0.01) predicted higher rates of surgical failure. Younger age predicted higher rates of implant failure (P<0.01). There were no differences in surgical or implant failure between staple and plate systems. Hospital costs of plate constructs ($781 to $1244) were 1.5 to 3.5 times greater than the staple constructs ($332 to $498).
CONCLUSIONS - Greater BMI, more severe deformity, and younger age were predictive of surgical or implant failure. There was no difference in success between implant types, whereas the cost of plate constructs was 1.5 to 3.5 times greater than staples. The rate of surgical failure was high (58%) and consideration should be given to reserving hemiepiphysiodesis for patients with lower BMI and less severe deformity. In our population, if hemiepiphysiodesis was not offered to patients with BMI>35 or MAD>80 mm varus, the surgical failure rate would diminish to 28%. The failure rate outside these parameters would be 88%.
LEVEL OF EVIDENCE - Level II—Prognostic.
Radiographic imaging plays a crucial role in the diagnosis of osteosarcoma. Currently, computed-tomography (CT) is used to measure tumor-induced osteolysis as a marker for tumor growth by monitoring the bone fractional volume. As most tumors primarily induce osteolysis, lower bone fractional volume has been found to correlate with tumor aggressiveness. However, osteosarcoma is an exception as it induces osteolysis and produces mineralized osteoid simultaneously. Given that competent bone is highly anisotropic (systematic variance in its architectural order renders its physical properties dependent on direction of load) and that tumor induced osteolysis and osteogenesis are structurally disorganized relative to competent bone, we hypothesized that μCT-derived measures of anisotropy could be used to qualitatively and quantitatively detect osteosarcoma provoked deviations in bone, both osteolysis and osteogenesis, in vivo. We tested this hypothesis in a murine model of osteosarcoma cells orthotopically injected into the tibia. We demonstrate that, in addition to bone fractional volume, μCT-derived measure of anisotropy is a complete and accurate method to monitor osteosarcoma-induced osteolysis. Additionally, we found that unlike bone fractional volume, anisotropy could also detect tumor-induced osteogenesis. These findings suggest that monitoring tumor-induced changes in the structural property isotropy of the invaded bone may represent a novel means of diagnosing primary and metastatic bone tumors.
Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions.
The relationship between BMP2 expression and the recruitment of skeletogenic stem cells was assessed following bone marrow reaming. BMP2 expression was examined using transgenic mice in which β-galactosidase had been inserted into the coding region of BMP2. Stem cell mobilization was analyzed by FACS analysis using CD73, a marker associated with bone marrow stromal stem cells. BMP2 expression was induced in endosteal lining cells, cortical osteocytes and periosteal cells in both the reamed and in contralateral bones. BMP2 mRNA expression in the reamed bone showed an early peak within the first 24 h of reaming followed by a later peak at 7 days, while contralateral bones only showed the 7 days peak of expression. FACS analysis sorting on CD73 positive cells showed a 50% increase of these cells at 3 and 14 days in the marrow of the injured bone and a single peak at 14 days of the marrow cell population of the contralateral bone. A ∼20% increase of CD73 positive cells was seen in the peripheral blood 2 days after reaming. These data showed that traumatic bone injury caused a systemic induction of BMP2 expression and that this increase is correlated with the mobilization of CD73 positive cells.
© 2013 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society.