Engineering immuno-smart bone scaffolds: Macrophage-centric strategies in 3D-printed tissue regeneration

Large-scale bone defects resulting from trauma, infection, or tumor resection pose a formidable clinical challenge, with traditional grafting approaches limited by donor availability and potential immune complications. While synthetic biomaterials offer alternatives, their clinical efficacy critically depends on their interactions with the host immune system, particularly macrophages. This review explores the emerging paradigm of "immuno-smart" 3D-printed scaffolds that harness macrophage plasticity to enhance bone regeneration. Analysis is focused on the mechanisms by which macrophages orchestrate the transition from inflammation to healing via dynamic M1-to-M2 polarization, thereby directly influencing osteogenesis, angiogenesis, and tissue remodeling. Current evidence indicates that 3D-printed scaffolds can be engineered to modulate macrophage behavior through multiple strategies: controlled release of bioactive ions (e.g., Mg²⁺, Sr²⁺, and Cu²⁺), incorporation of immunomodulatory molecules, optimization of physical properties such as piezoelectricity, photothermal responsiveness, and precise architectural design. These approaches, which regulate the macrophage-mesenchymal stem cell axis to create pro-regenerative microenvironments, are critically evaluated. Despite promising preclinical outcomes, clinical translation remains challenging due to an incomplete understanding of spatiotemporal immune dynamics, insufficient long-term safety data, and a lack of standardized evaluation protocols. Ultimately, this review provides a comprehensive framework for developing next-generation immunomodulatory bone scaffolds, highlighting the integration of materials science, immunology, and regenerative medicine. We conclude that personalized, closed-loop systems capable of real-time immune modulation represent the future of bone tissue engineering, marking a shift from passive structural support to active biological orchestration.