Adaptive hydrogel platforms for infected bone defect repair: microenvironmental responsiveness, osteoimmunomodulation, and regenerative remodeling

Abstract

Infected bone defects remain a major clinical challenge because persistent bacterial colonization and biofilm formation coexist with chronic inflammation, oxidative stress, osteoimmune imbalance, vascular injury, and impaired bone regeneration. Conventional treatment relies primarily on surgical debridement, antimicrobial therapy, and bone reconstruction, but often fails to simultaneously eradicate biofilms, maintain effective local drug concentrations, restore the inflammatory microenvironment, and support structural bone repair. Hydrogels have emerged as promising local therapeutic platforms owing to their injectability, defect-filling capacity, local retention, controllable degradation, and cargo-loading versatility. Stimuli-responsive hydrogel modules can react to endogenous pathological cues, including acidic pH, elevated reactive oxygen species, abnormal enzyme activity, and hypoxia, whereas near-infrared light and related physical inputs provide externally triggered control. By integrating responsive modules with multi-cue recognition, lesion-state-dependent release, or coordinated functional regulation, adaptive hydrogel platforms may couple antibacterial and antibiofilm activity with immune remodeling, vascularization, and osteogenic regeneration. This review summarizes the pathological microenvironment of infected bone defects and recent advances in responsive and adaptive hydrogel systems. Particular attention is given to macrophage-mediated osteoimmunomodulation and the regulation of macrophage functional states beyond a fixed M1/M2 framework. Antibacterial defense, inflammation resolution, vascular reconstruction, and regenerative repair are interpreted as overlapping functional requirements rather than universally discrete chronological stages, with their relative importance changing according to bacterial burden, biofilm activity, oxidative and inflammatory stress, tissue perfusion, and regenerative capacity. We further evaluate the integration of antibacterial, immunomodulatory, angiogenic, and osteogenic modules, distinguish direct infected-bone-defect evidence from extrapolated findings, and discuss experimental models, operational criteria for adaptive switching, manufacturing complexity, biosafety, and translational challenges. This framework may guide the development of hydrogel platforms that more precisely match therapeutic functions to the evolving state of infected bone defects.