Induction of M2 Macrophages by Fibrin Hydrogels Enhances Bone Regeneration

Bone regeneration remains a significant challenge in regenerative medicine. In this context, fibrin hydrogels have attracted attention as a promising biomaterial that regulates the inflammatory response and promotes tissue repair by influencing macrophages. In this study, we investigated the immunomodulatory effects of fibrin hydrogels on macrophage polarization and their subsequent impact on bone regeneration. It is widely recognized that M1 macrophages produce tumor necrosis factor alpha (TNF-α), while M2 macrophages produce interleukin-10 (IL-10). When undifferentiated mouse bone marrow-derived macrophages were stimulated with lipopolysaccharides (LPS), a marked increase in the proinflammatory cytokine TNF-α was observed. However, coculture with fibrin hydrogels in the presence of LPS significantly suppressed TNF-α production while enhancing the secretion of the anti-inflammatory cytokine IL-10. Furthermore, in a rat calvarial defect model, tissue analysis 1-week postimplantation of fibrin hydrogels revealed an upregulation of M2 macrophage markers (CD163, CD204, and CD206), indicating a shift toward an anti-inflammatory phenotype. Notably, 11 weeks after implantation, the fibrin hydrogel-treated sites exhibited enhanced bone regeneration. These findings highlight the potential of fibrin hydrogels as an immunomodulatory biomaterial that facilitates bone repair by promoting M2 macrophage polarization and modulating the local inflammatory microenvironment.