Biological aspects of segmental bone defects management.

Segmental bone defect management is among the most demanding issues in orthopaedics and there is a great medical need for establishing an appropriate treatment option. Tissue transfer, including bone autografts or free flaps, depending on the size of the bone deficiency, is currently the "gold standard" for treatment of such defects. Osteogenic cells in combination with adequate growth factors and a suitable scaffold, from the aspect of osteoinductivity, osteoconductivity and mechanical stability, are mandatory to successfully restore a bone defect as determined in the "diamond concept". Our current knowledge on this topic is limited and mostly based on retrospective studies, case reports and a few small randomised clinical trials due to the lack of large and accurately designed randomised clinical trials using novel approaches to regenerative orthopaedics. However, preclinical research on different animal models for critical size defects is abundant, showing emerging candidate cells and cytokines for defect rebridgement. In this article we provide an overview on existing clinical studies and promising preclinical experiments that utilised osteogenic cells, growth factors and biomaterials, as well as their combination for repair of segmental bone defects.

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing.

PURPOSE: The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW. METHODS: Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by µCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits. RESULTS: Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number. CONCLUSIONS: Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.