Temporal Immunomodulatory Hydrogel Regulating the Immune-Osteogenic Cascade for Infected Bone Defects Regeneration

Early pathogen clearance and immunomodulation are critical for the restoration of infected bone defects. Conventional osteoimmunomodulatory strategies mainly emphasize M2 macrophage-mediated bone regeneration, neglecting the pivotal role of early-stage M1 macrophage-activated immune response in microbial elimination. This oversight ultimately compromises repair efficacy in infected bone defects. Herein, a temporal immunomodulatory hydrogel is developed to regulate the immune-osteogenic microenvironment for the repair of infected bone defects. The hydrogel is rapidly formed by crosslinking of acrylate-modified engineered protein with oxidized sodium alginate, mimicking extracellular matrix architecture to promote cell adhesion, angiogenesis, and osteogenesis. To achieve temporal ion release, zinc-based nanoparticles mineralized with hydroxyapatite are incorporated within the hydrogel matrix. The early-stage release of Ca²⁺ promotes M1 polarization to inhibit infection, while sustained release of Zn²⁺ induces M2 polarization to promote osteogenic differentiation. This system further exhibits antioxidant and antibacterial properties, ensuring comprehensive immunomodulation across the bone healing process. In a rat model of infected cranial defects, the hydrogel effectively remodels the osteoimmune microenvironment, suppresses infection, and facilitates vascularized bone regeneration. This work highlights a temporal immunomodulatory strategy for infected bone repair and offers new insights into the design of advanced osteoimmunomodulatory biomaterials.