Engineering synthetic bone graft substitutes with improved mechanical properties, enhanced bioactivity, and on-demand growth factor delivery

An unmet clinical need exists for synthetic bone graft substitutes which can perform comparably to autograft in the repair of bone defects. Therefore, the overall objective of this dissertation was to investigate the design of hydroxyapatite (HA)-collagen scaffolds to provide chemotactic and mechanical signals which direct angiogenesis and osteogenesis during bone regeneration. Novel methods were developed for the preparation HA-collagen scaffolds with improved architecture and mechanical properties compared to conventional freeze-dried scaffolds. The effect of the HA volume fraction on in vivo angiogenesis and osteogenesis was investigated after subcutaneous ectopic implantation in mice. HA promoted angiogenesis and osteogenesis in collagen scaffolds that did not otherwise exhibit angiogenesis and osteogenesis, and the effect was dose dependent. In a subsequent study using an orthotopic critical-size femoral defect model in rats, collagen scaffolds did not exhibit bone formation, while HA-collagen scaffolds exhibited bone formation but did not result in mechanically competent union, confirming the need to augment scaffolds with exogenous growth factors for functional bone regeneration. Therefore, scaffolds were modified for on-demand (cell-mediated) delivery of an angiogenic (VEGF) and osteogenic (BMP-2) growth factor with tunable, independent control over the dosing and release kinetics of both. Growth factors immobilized to collagen fibrils via the association of biotin and streptavidin exhibited enzymatically regulated release and growth factors simultaneously encapsulated within a collagen hydrogel filling pore spaces exhibited sustained released. The effects of the growth factor delivery mechanism on in vivo angiogenesis and osteogenesis were investigated after subcutaneous ectopic implantation of HA-collagen scaffolds in mice. Immobilized VEGF promoted increased angiogenesis compared to all other experimental groups while immobilized BMP-2 promoted osteoid deposition.