Induction of bone tissue requires three elements: osteoprogenitor cells, osteoinductive factors, and a supporting extracellular matrix. In this study, we report on an experimental model in dogs of heterotopic bone tissue production, based on the integration of these osteo-inductive factors into abdominal implants. The implants consist of either a type I collagen sponge wrapped with periosteum and omentum or a type I collagen sponge embedded with demineralized bone powder, platelet-rich plasma, thrombin, and calcium chloride wrapped with omentum, with or without periosteum. Automated histomorphometric analysis showed an efficient production of trabecular bone, which corresponded to 50-70% of the total tissue composition 4 months after implant formation. High expression of the osteoinductive cytokines transforming growth factor-beta and bone morphogenetic proteins-2 and -4 was shown by immunohistochemistry in macrophages, endothelial cells from neoformed capillaries, osteoblasts, osteoclasts, and the mesenchymal tissue around the bone trabeculae. These approaches are novel and efficient surgical procedures to produce mature trabecular bone that could be used as a potential source of bone tissue for autotransplantation.
Progenitor cell transplantation has been considered as a potential angiogenesis therapy for the ischemic hindlimb. In this work we performed an ischemic hindlimb model in dogs. We ligated the middle sacra and the external right iliac arteries. After 7 days, the femoral artery was ligated and removed, and three Silastic tubes were inserted into the gracilis muscle to create fibrocollagenous tunnels. After Silastic implantation, we administered saline or granulocyte colony stimulating factor (G-CSF) subcutaneously daily during 5 days. Fourteen days after device positioning we transplanted bone marrow mononuclear cells (BMMC) into the tunnels previously formed by Silastic tube reaction. Twenty-eight days later, contrasted angiographies were performed and angiographic scores were calculated. Also, vessels and endothelial cells and proliferating cells were identified by immunochemistry of muscle sections. Results demonstrated that BMMC transplantation enriched by G-CSF administration significantly stimulates angiogenesis in the ischemic hindlimb, and more than BMMC transplantation alone. Transplantation of progenitor cells in an appropriate extracellular matrix is a potential therapy for hindlimb ischemia.
We established a comparative model of angiogenic induction in previously formed fibrocollagenous tunnels in rat inner thigh muscles. A unilateral hindlimb chronic ischemia model was performed in male Sprague-Dawley rats. A device was then inserted in the central portion of the inner thigh muscles. Vascularity in the ischemic limb was determined by means of an angiographic score, capillary/fiber ratio, and endothelial proliferation by histochemistry and immunohistochemistry. Autologous transplant of bone marrow, vascular endothelial growth factor (VEGF), or collagen-polyvinylpyrrolidone plus heparin induced significant vascularization of the ischemic hindlimb when compared to saline solution. However, the bone marrow group presented a higher angiographic score than the other two. No differences among groups were observed in capillary/fiber ratio or proliferation, except for the VEGF group, where capillary proliferating cells were significantly higher than in controls. Based on these results, bone marrow-derived progenitor cells may constitute a safe and viable alternative for the induction of therapeutic angiogenesis.
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