Moldable Alginate/Hydroxyapatite Hydrogel Loaded with Metformin Enhanced Regeneration of the Rabbit Mandibular Defects.

BACKGROUND: Moldable hydrogel-based techniques loaded with osteoinductive agents such as metformin have become a promising field for reconstructing critical-sized bone defects, particularly in those with irregular shapes. Here, we used metformin incorporated in an alginate/hydroxyapatite hydrogel to accelerate the repair of the rabbit critical-sized mandibular defect. METHODS: Cytotoxicity and osteoinduction of the metformin-loaded alginate/hydroxyapatite hydrogel were evaluated by culturing the osteosarcoma cell line (MG63). Moreover, in vivo bone formation was assessed in a rabbit bone defect model using computed tomography and histomorphometric analysis to compare the effects of alginate/hydroxyapatite hydrogel with or without metformin. RESULTS: The data showed that the scaffolds were not cytotoxic and enhanced osteogenic characteristics of the cells, as manifested by augmented alkaline phosphatase activity and calcium deposition. In vivo studies indicated that all the treated groups exhibited more osteogenesis with a significant increase in bone-specific cell population and less residual scaffold remnant at the defect sites compared with the control group, which was significantly prominent in the group treated with alginate/hydroxyapatite/metformin. Moreover, computed tomography scan analysis also confirmed better bone filling in all the treated groups, especially in the defects treated with alginate/hydroxyapatite/metformin hydrogel. CONCLUSIONS: Both In vitro and in vivo experiments revealed that locally loaded metformin with the easy size- and shape-adapted alginate/hydroxyapatite hydrogel has proper biocompatibility and osteogenesis properties. Moreover, our study highlighted the synergistic effect of metformin and hydroxyapatite on osteogenesis.