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

Abstract 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 Ca 2+ promotes M1 polarization to inhibit infection, while sustained release of Zn 2+ 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.