Functionalized GelMA-based hydrogels for osteoimmunomodulation and bone regeneration

Abstract

Complex bone defects caused by trauma, infection, tumor-related bone loss and metabolic disorders remain clinically challenging because an inflammatory imbalance, impaired vascularization and insufficient osteogenesis often coexist. Gelatin methacryloyl (GelMA) hydrogels are attractive matrices for bone regeneration owing to the extracellular matrix-mimicking structure, tunable physicochemical properties and compatibility with injectable, printable and composite systems. However, pristine GelMA lacks the mechanical strength, osteoinductivity and immunoregulatory capacity required for complex bone repair. This review summarizes recent advances in functionalized GelMA-based hydrogels for osteoimmunomodulation and bone regeneration. We first outline the immune-regenerative mechanisms of bone repair and then discuss major functionalization strategies, including matrix-property regulation, inorganic nanocomponents, bioactive molecules, extracellular vesicles, blood-derived products, and microenvironment-responsive systems. Their applications in critical-sized, infected, metabolic disorder-associated, and oral and maxillofacial bone defects are further examined from a pathology-adapted and mechanism-guided perspective. Collectively, these systems are transforming GelMA from a passive scaffold into a programmable platform that coordinates inflammation resolution, vascularized osteogenesis, and remodeling. By linking material design with osteoimmune-regenerative mechanisms and disease-specific applications, this review provides a framework relevant to the development and translation of advanced regenerative biomaterials.