Macrophage-centered bone regeneration: A review of in vivo efficacy across tailored, hybrid, and 3D-printed biomaterial platforms

Bone tissue engineering has evolved from the passive use of structural fillers to a sophisticated discipline that actively harnesses endogenous regenerative mechanisms. At the core of this paradigm shift lies the immune system, particularly macrophages, as dynamic regulators of repair. Rather than merely suppressing inflammation, contemporary biomaterials are designed to modulate its trajectory, orchestrating the timely transition from a pro-inflammatory (M1) phenotype toward a pro-resolutive (M2) state. This review synthesizes a decade of progress in macrophage-centered bioengineering, focusing on strategies validated in preclinical in vivo models to ensure biological relevance and translational potential. These approaches are categorized across three levels of increasing complexity: (i) tailored biomaterials, where intrinsic physical and chemical properties direct cell fate; (ii) hybrid scaffolds, integrating diverse material classes and advanced delivery systems; and (iii) 3D-printed bioactive constructs, combining structural precision with ions, drugs, or cellular components. Together, these strategies define the emerging field of osteoimmunomodulation, characterized by the design of immuno-instructive materials. By critically evaluating the evolution of these principles, including their translational barriers and potential pitfalls, this review provides key insights into the field’s progression, identifying effective strategies to guide the development of next-generation bone therapies.