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Fixation of metallic implants to bone through osseointegration is important in orthopedics and dentistry. Model systems for studying this phenomenon would benefit from a non-destructive imaging modality so that mechanical and morphological endpoints can more readily be examined in the same specimens. The purpose of this study was to assess the utility of an automated micro computed tomography (μCT) program for predicting bone-implant contact (BIC) and mechanical fixation strength in a rat model. Femurs in which 1.5 mm diameter titanium implants had been in place for four weeks were either embedded in polymethylmethacrylate (PMMA) for preparation of 1 mm thick cross-sectional slabs (16 femurs: 32 slabs) or were used for mechanical implant pull-out testing (n = 18 femurs). All samples were scanned by μCT at 70 kVp with 16 μm voxels and assessed by the manufacturer's software for assessing “osseointegration volume per total volume” (OV/TV). OV/TV measures bone volume per total volume (BV/TV) in a 3-voxel thick ring that by default excludes the 3 voxels immediately adjacent to the implant in order to avoid metal-induced artifacts. The plastic-embedded samples were also analyzed by backscatter scanning electron microscopy (bSEM) to provide a direct comparison of OV/TV with a well-accepted technique for BIC. In μCT images in which the implant was directly embedded within PMMA, there was a zone of elevated attenuation (> 50% of the attenuation value used to segment bone from marrow) which extended 48 μm away from the implant surface. Comparison of the bSEM and μCT images showed high correlations for BV/TV measurements in areas not affected by metal-induced artifacts. In addition for bSEM images, we found that there were high correlations between peri-implant BV/TV within 12 μm of the implant surface and BIC (correlation coefficients ≥ 0.8, p < 0.05). OV/TV as measured on μCT images was not significantly correlated with BIC as measured on the corresponding bSEM images. However, OV/TV was significantly, but weakly, correlated with implant pull-out strength (r=0.401, p=0.049) and energy to failure (r=0.435, p=0.035). Thus, the need for the 48 μm thick exclusion zone in the OV/TV program to avoid metal-induced artifacts with the scanner used in this study means that it is not possible to make bone measurements sufficiently close to the implant surface to obtain an accurate assessment of BIC. Current generation laboratory-based μCT scanners typically have voxel sizes of 6–8 μm or larger which will still not overcome this limitation. Thus, peri-implant bone measurements at these resolutions should only be used as a guide to predict implant fixation and should not be over-interpreted as a measurement of BIC. Newer generation laboratory-based μCT scanners have several improvements including better spatial resolution and x-ray sources and appear to have less severe metal-induced artifacts, but will need appropriate validation as they become available to researchers. Regardless of the μCT scanner being used, we recommend that de...

Objective. To assess the ability of sclerostin antibody therapy to blunt the negative effects of polyethylene particles on implant fixation and peri-implant bone structure in a rat implant fixation model.Methods. Thirty-six adult male rats received intramedullary titanium implants; 12 rats received vehicle injections only (control), and 24 rats received intraarticular injections of lipopolysaccharide-doped polyethylene particles. Twelve of the rats that received particles also received sclerostin antibody treatment. The 3 groups of rats were maintained for 12 weeks in a pathogen-free environment, at which time mechanical, micro-computed tomography, and dynamic and static histomorphometry end points were assessed.Results. Sclerostin antibody treatment completely blocked the negative effect of the lipopolysaccharidedoped polyethylene particles on implant fixation and peri-implant bone volume by increasing the bone formation rate and depressing bone resorption.Conclusion. Anabolic agents targeting the Wnt signaling pathway are a promising new alternative for the prevention of periprosthetic osteolysis and aseptic loosening.

We demonstrate that a biomimetic polymer network is capable of affecting bone regeneration in vivo. Starting with a foundation consisting of an environmentally responsive poly(N-isopropylacrylamide-co-acrylic acid) hydrogel, we incorporated matrix metalloproteinase-13 (MMP-13) degradable crosslinkers and peptides containing integrin-binding domains (i.e., Arg-Gly-Asp) to create a biomimetic matrix designed to encourage osteoblast migration and proliferation. We independently tuned matrix stiffness and peptide concentration to generate a response surface model of osteoblast proliferation on different types of matrices. Osteoblast proliferation was significantly influenced by matrix stiffness (i.e., its complex modulus) and peptide concentration. When implanted in a rat femoral ablation model, these matrices induced bone regeneration only when protease degradable crosslinks were used to create the network. For the matrices with MMP-13 degradable crosslinkers, the bone formed had a trabecular-like structure and was distributed throughout the marrow space. Based on the correlated effects of matrix stiffness and ligand concentration, the response surface model will facilitate improvements in the regenerative capacity of these artificial extracellular matrices.

Systemic administration of anti-sclerostin antibodies might be a useful strategy in total joint replacement when bone mass is deficient.

Sclerostin antibody treatment accelerated and enhanced mechanical fixation of medullary implants in a rat model by increasing both cortical and trabecular bone volume.

Enhanced understanding of differential gene expression and biological pathways associated with distinct phases of intramembranous bone regeneration following femoral marrow ablation surgery will improve future advancements regarding osseointegration of joint replacement implants, biomaterials design, and bone tissue engineering. A rat femoral marrow ablation model was performed and genome-wide microarray data were obtained from samples at 1, 3, 5, 7, 10, 14, 28, and 56 days post-ablation, with intact bones serving as controls at Day 0. Bayesian model-based clustering produced eight distinct groups amongst 9,062 significant gene probe sets based on similar temporal expression profiles, which were further categorized into three major temporal classes of increased, variable, and decreased expression. Osteoblastic- and osteoclastic-associated genes were found to be significantly expressed within the increased expression groups. Chondrogenesis was not detected histologically. Adipogenic marker genes were found within variable/decreased expression groups, emphasizing that adipogenesis was inhibited during osteogenesis. Differential biological processes and pathways associated with each major temporal group were identified, and significantly expressed genes involved were visually represented by heat maps. It was determined that the increased expression group exclusively contains genes involved in pathways for matrix metalloproteinases (MMPs), Wnt signaling, TGF-β signaling, and inflammatory pathways. Only the variable expression group contains genes associated with glycolysis and gluconeogenesis, the notch signaling pathway, natural killer cell mediated cytotoxicity, and the B cell receptor signaling pathway. The decreased group exclusively consists of genes involved in heme biosynthesis, the p53 signaling pathway, and the hematopoietic cell lineage. Significant biological pathways and transcription factors expressed at each time point post-ablation were also identified. These data present the first temporal gene expression profiling analysis of the rat genome during intramembranous bone regeneration induced by femoral marrow ablation.