Magnesium Nanocomposite Hydrogel Reverses the Pathologies to Enhance Mandible Regeneration

Abstract The healing of bone defects after debridement in medication‐related osteonecrosis of the jaw (MRONJ) is a challenging medical condition with impaired angiogenesis, susceptible infection, and pro‐inflammatory responses. Magnesium (Mg) nanocomposite hydrogel is developed to specifically tackle multiple factors involved in MRONJ. Mg‐oxide nanoparticles tune the gelation kinetics in the reaction between N‐hydroxysuccinimide‐functionalized hyperbranched poly (ethylene glycol) and proteins. This reaction allows an enhanced mechanical property after instant solidification and, more importantly, also stable gelation in challenging environments such as wet and hemorrhagic conditions. The synthesized hydrogel guides mandible regeneration in MRONJ rats by triggering the formation of type H vessels, activating Osterix+ osteoprogenitor cells, and generating anti‐inflammatory microenvironments. Additionally, this approach demonstrates its ability to suppress infection by inhibiting specific pathogens while strengthening stress tolerance in the affected alveolar bone. Furthermore, the enhanced osteogenic properties and feasibility of implantation of the hydrogel are validated in mandible defect and iliac crest defect created in minipigs, respectively. Collectively, this study offers an injectable and innovative bone substitute to enhance mandible defect healing by tackling multiple detrimental pathologies.