Hydrogel-Based Immunomodulatory Strategies for Infected Bone Defects Regeneration: Remodeling the Osteoimmune Microenvironment and Future Perspectives.

Infected bone defects remain a major challenge in orthopaedic and reconstructive medicine. Conventional strategies often fail to achieve reliable long-term outcomes lack of adequately addressing the hostile osteoimmune microenvironment. In recent years, hydrogel-based biomaterials have emerged as highly promising platforms for infected bone defect regeneration due to their injectability, defect conformity, extracellular matrix-like architecture, and tunable physicochemical properties. Importantly, hydrogels are evolving from passive drug carriers into dynamic immunomodulatory systems capable of releasing bioactive agents in a controlled manner, reprogramming immune metabolism, and coordinating angiogenic and osteogenic repair. This review summarizes recent progress in hydrogel-based immunomodulatory strategies for infected bone defects from the perspective of osteoimmune microenvironment remodeling. Four major design paradigms include programmed transformation of the osteogenic microenvironment, metabolic reprogramming of the infectious niche, spatiotemporally staged immune-osteogenic regulation, and photothermal-immunomodulatory therapy. However, the translation of these systems faces challenges including biosafety concerns, batch-to-batch variability, manufacturing complexity, and regulatory intricacies. Despite these hurdles, hydrogel-based immunomodulatory platforms represent a clinically relevant strategy for integrated infection control and functional bone regeneration. Future perspectives are proposed, emphasizing multicellular osteoimmune network engineering, disease-specific precision hydrogels, and artificial intelligence (AI)-assisted biomaterial design. Overall, hydrogel-based immunomodulatory systems represent a promising direction for achieving integrated infection control and functional bone regeneration in infected bone defects.