A novel multifunctional nanocomposite hydrogel orchestrates the macrophage reprogramming-osteogenesis crosstalk to boost bone defect repair.

Repairing bone defects is a complex cascade reaction process, as immune system regulation, vascular growth, and osteogenic differentiation are essential. Thus, developing a tissue-engineered biomaterial that caters to the complex healing process of bone regeneration remains a major clinical challenge. In the study, Ca-TA-rGO (CTAG)/GelMA hydrogels were synthesized by binding Ca using metal chelation to graphene oxide (GO) nanosheets reduced by tannic acid (TA-rGO) and doping them into gelatin methacrylate (GelMA) hydrogels. TA and rGO exhibited biocompatibility and immunomodulatory properties in this composite, while Ca promoted bone formation and angiogenesis. This novel nanocomposite hydrogel demonstrated good mechanical properties, degradability, and conductivity, and it could achieve slow Ca release during bone regeneration. Both in vitro and in vivo experiments revealed that CTAG/GelMA hydrogel modulated macrophage reprogramming and induced a shift from macrophages to healing-promoting M2 macrophages during the inflammatory phase, promoted vascular neovascularization, and facilitated osteoblast differentiation during bone formation. Moreover, CTAG/GelMA hydrogel could downregulate the NF-κB signaling pathway, offering new insights into regulating macrophage reprogramming-osteogenic crosstalk. Conclusively, this novel multifunctional nanocomposite hydrogel provides a multistage treatment for bone and orchestrates macrophage reprogramming-osteogenic crosstalk to boost bone repair.