A phagocytosis-centric functional taxonomy of macrophages: Implications for biomaterials-based bone regeneration

The success of bone regeneration is orchestrated by functionally diverse macrophages, yet the field remains constrained by the oversimplified M1/M2 paradigm. To transcend this limitation, we propose a new functional taxonomy, centered on specialized phagocytic programs, that reclassifies bone macrophages into four distinct effector subsets: professional efferocytes, matrix-remodeling phagocytes, immunomodulatory phagocytes, and metabolic regulators. Integrating this taxonomy with cellular ontogeny, we establish a "tissue-resident macrophage (TRM)-core, recruitment-supplement" model, which delineates the stage-specific collaboration between self-renewing TRMs and recruited monocytes throughout the inflammatory, soft callus, and hard callus phases of bone healing. This model clarifies the spatiotemporal coordination of macrophage function during bone healing and offers a rational roadmap for developing precise, phase-specific immunomodulatory therapies to overcome refractory healing. Our framework redefines macrophage biology within osteoimmunology and charts a course for advancing targeted immune modulation in orthopedics.