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Critical-sized bone defects are critical healing conditions that, if left untreated, often lead to non-unions. To reduce the risk, critical-sized bone defects are often treated with recombinant human BMP-2. Although enhanced bone tissue formation is observed when BMP-2 is administered locally to the defect, spatial and temporal distribution of callus tissue often differs from that found during regular bone healing or in defects treated differently. How this altered tissue patterning due to BMP-2 treatment is linked to mechano-biological principles at the cellular scale remains largely unknown. In this study, the mechano-biological regulation of BMP-2-treated critical-sized bone defect healing was investigated using a multiphysics multiscale in silico approach. Finite element and agent-based modeling techniques were combined to simulate healing within a critical-sized bone defect (5 mm) in a rat femur. Computer model predictions were compared to in vivo microCT data outcome of bone tissue patterning at 2, 4, and 6 weeks postoperation. In vivo, BMP-2 treatment led to complete healing through periosteal bone bridging already after 2 weeks postoperation. Computer model simulations showed that the BMP-2 specific tissue patterning can be explained by the migration of mesenchymal stromal cells to regions with a specific concentration of BMP-2 (chemotaxis). This study shows how computational modeling can help us to further understand the mechanisms behind treatment effects on compromised healing conditions as well as to optimize future treatment strategies. ispartof: BIOMECHANICS AND MODELING IN MECHANOBIOLOGY vol:20 issue:4 pages:1627-1644 ispartof: location:Germany status: published

Background Hypoxia in the vicinity of bone defects triggers the osteogenic differentiation of precursor cells and promotes healing. The activation of STAT3 signaling in mesenchymal stem cells (MSCs) has similarly been reported to mediate bone regeneration. However, the interaction between hypoxia and STAT3 signaling in the osteogenic differentiation of precursor cells during bone defect healing is still unknown. Methods In this study, we assessed the impact of different durations of CoCl2-induced cellular hypoxia on the osteogenic differentiation of MSCs. Role of STAT3 signaling on hypoxia induced osteogenic differentiation was analyzed both in vitro and in vivo. The interaction between cellular hypoxia and STAT3 signaling in vivo was investigated in a mouse femoral bone defect model. Results The peak osteogenic differentiation and expression of vascular endothelial growth factor (VEGF) occurred after 3 days of hypoxia. Inhibiting STAT3 reversed this effect. Hypoxia enhanced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and STAT3 phosphorylation in MSCs. Histology and μ-CT results showed that CoCl2 treatment enhanced bone defect healing. Inhibiting STAT3 reduced this effect. Immunohistochemistry results showed that CoCl2 treatment enhanced Hif-1α, ALP and pSTAT3 expression in cells present in the bone defect area and that inhibiting STAT3 reduced this effect. Conclusions The in vitro study revealed that the duration of hypoxia is crucial for osteogenic differentiation of precursor cells. The results from both the in vitro and in vivo studies show the role of STAT3 signaling in hypoxia-induced osteogenic differentiation of precursor cells and bone defect healing.

Bone loss associated with skeletal trauma or metabolic diseases often require bone grafting. The present study aimed to evaluate the performance of bioactive glass-chitosan composite (BG-CH) produced by a freeze-drying process. BG containing 17% wt% CH was implanted in the femoral condyl of an ovariectomised rat. The resected bone was prepared for analysis using several physico-chemical techniques such as fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX). After 2 weeks, the implanted sample gave a spectrum in which two pronounced absorption bands with the maxima at 932 and 1036 cm-1 arising from (Si-O-Si) groups disappeared 15 days after surgery. These bands were replaced 30 days after implantation by 601 and 564 cm-1(P- O) arisen form bone apatite bands. After 4 weeks, peaks at 31.6 and 25.8° (2θ) were registered thus inducing a degradation of BG-CH which occurred simultaneously with the implant replacement by the bone cells. Our data showed that the incorporation of 17% wt% CH with BG matrix promoted a highly significant bioactivity and generated an osteoinductive property. These effects might make BG-CH an effective biomaterials choice for the biomedical field. Key words: Chitosan-glasses, biominiralisation, osteoinductivity, biomedical applications, bone defect healing.