Osteo-immunomodulatory effects of macrophage-derived extracellular vesicles treated with biphasic calcium phosphate ceramics on bone regeneration

Literature on osteoimmunology has demonstrated that macrophages have a great influence on biomaterial-induced bone formation. However, there are almost no reports clarifying the osteo-immunomodulatory capacity of macrophage-derived extracellular vesicles (EVs). This study comprehensively investigated the effects of EVs derived from macrophages treated with biphasic calcium phosphate (BCP) ceramics (BEVs) on vital events associated with BCP-induced bone formation such as immune response, angiogenesis, and osteogenesis. It was found that compared with EVs derived from macrophages alone (control, CEVs), BEVs preferentially promoted macrophage polarization towards a wound-healing M2 phenotype, enhanced migration, angiogenic differentiation, and tube formation of human umbilical vein endothelial cells, and induced osteogenic differentiation of mesenchymal stem cells. Analysis of 15 differentially expressed microRNAs (DEMs) related to immune, angiogenesis, and osteogenesis suggested that BEVs exhibited good immunomodulatory, pro-angiogenic, and pro-osteogenic abilities, which might be attributed to their specific miRNA cargos. These findings not only deepen our understanding of biomaterial-mediated osteoinduction, but also suggest that EVs derived from biomaterial-treated macrophages hold great promise as therapeutic agents with desired immunomodulatory capacity for bone regeneration.