Dual therapeutic cobalt-incorporated bioceramics accelerate bone tissue regeneration

Bone grafting on defects caused by trauma or tumor stimulates bone regeneration, a complex process requiring highly orchestrated cell-signal interactions. Bone vascular growth is coupled with osteogenesis, but less is known about the interplay between angiogenesis and osteogenesis. Understanding this relationship is relevant to improved bone regeneration. Here, tricalcium phosphate (TCP) scaffolds doped with varying concentration of cobalt (Co-TCP) were designed to investigate the dosage effect of vascularization on bone formation. The surface structure, phase composition, mechanical features, and chemical composition were investigated. Co doping improved the mechanical properties of TCP. Co-TCP, particularly 2% and 5% Co-TCP, boosted cell viability of bone marrow stromal cells (BMSCs). The 2% Co-TCP promoted alkaline phosphatase activity, matrix mineralization, and expression of osteogenic genes in BMSCs in vitro. However, excessive Co doping decreased TCP-induced osteogenesis. Meanwhile, Co-TCP dose-dependently favored the growth and migration of human umbilical vein endothelial cells (HUVECs), and the expression of vascular endothelial growth factor (VEGF). The 2% Co-TCP significantly shrank the defect area in rat alveolar bone compared with TCP. Smaller bone volume and more abundant blood vessels were observed for 5% Co-TCP compared with 2% Co-TCP. The CD31 immunostaining in the 5% Co-TCP group was more intense than the other two groups, indicating of the increment of endothelium cells. Besides, 5% Co-TCP led to mild inflammatory response in bone defect area. Overall, TCP doped appropriately with Co has positive effect on osteogenesis, while excessive Co suppressed osteoblast differentiation and bone formation. These data indicate that vascularization within a proper range promotes osteogenesis, which may be a design consideration for bone grafts.