Sequential polarization of macrophages: an immunomodulatory strategy for novel bone repair materials

Within the biomaterial-constructed bone repair microenvironment, intricate crosstalk among immune, osteogenic and vascular cells is essential for maintaining local osteoimmune homeostasis and driving tissue regeneration. Macrophages act as the central orchestrators within this osteoimmune microenvironment. As the first responders to injury, they exert decisive spatiotemporal control over the initiation, maintenance and resolution of inflammation, while bridging osteogenesis, angiogenesis and matrix remodeling. Critically, their dynamic phenotypic transition, specifically the sequential polarization from M1 to M2 phenotypes, directly mediates immune microenvironment remodeling. This sequential shift bidirectionally regulates osteoprogenitor differentiation and endothelial cell function via the secretion of specific cytokines and extracellular vesicles, thereby achieving a dynamic equilibrium between the immune response and tissue regeneration. Consequently, precisely modulating the sequential polarization of macrophages has emerged as a targeted and highly promising strategy for the development of novel bone repair biomaterials. This review systematically summarizes the regulatory mechanisms of distinct macrophage phenotypes in bone regeneration and highlights recent translational advances in designing osteoimmunomodulatory biomaterials tailored for sequential polarization. By critically examining current challenges and future trajectories, this review aims to provide profound insights into the multidimensional macrophage activation spectrum and accelerate the development and optimization of next-generation immunomodulatory biomaterials for robust bone regeneration.