Macrophage Polarization-Mediated Osteogenesis by Cuttlebone-Derived Organic Matrix

Objectives: The immune response to bone repair materials critically determines their success. This study investigates the immunomodulatory function of cuttlebone-derived organic matrix (CDOM) and its role in promoting bone regeneration. Methods: We evaluated macrophage polarization and related cytokine expression following CDOMs treatment. The biological effects of macrophage-conditioned medium on angiogenesis and osteoblastic cells were assessed through migration and osteogenic differentiation assays. A rat cranial defect model was used to validate CDOM’s immunomodulatory capabilities during the osteogenic process in vivo. Results: CDOMs dynamically regulate macrophage polarization, initiating a pro-inflammatory M1 phenotype that transitions to a pro-healing M2 phenotype. This shift creates a regenerative microenvironment characterized by increased expression of TGF-β, HIF-1α, and BMP-2. Conditioned medium from CDOM-educated macrophages enhanced angiogenesis and osteogenesis in vitro. In animal studies, CDOMs promoted early M1 response followed by sustained M2 dominance, leading to enhanced vascularization and bone formation. Conclusions: CDOMs promote bone regeneration by orchestrating a beneficial immune response. By guiding macrophage polarization from M1 to M2 phenotypes, CDOMs create a pro-regenerative microenvironment that supports angiogenesis and osteogenesis, offering a promising immunomodulatory strategy for bone repair.