A multifunctional composite hydrogel that sequentially modulates the process of bone healing and guides the repair of bone defects

Abstract Calcium carbonate (CaCO 3 ), which exhibits excellent biocompatibility and bioactivity, is a well-established bone filling material for bone defects. Here, we synthesized CaCO 3 microspheres (CMs) to use as an intelligent carrier to load bone morphogenetic protein-2 (BMP-2). Subsequently, drug-loaded CMs and catalase (CAT) were added to methacrylated gelatin (GelMA) hydrogels to prepare a composite hydrogel for differential release of the drugs. CAT inside hydrogels was released with a fast rate to eliminate H 2 O 2 and generate oxygen. Constant BMP-2 release from CMs induced rapid osteogenesis. Results in vitro indicated that the composite hydrogels efficiently reduced the level of intracellular reactive oxygen species, preventing cells from being injured by oxidative stress, promoting cell survival and proliferation, and enhancing osteogenesis. Furthermore, animal experiments demonstrated that the composite hydrogels were able to inhibit the inflammatory response, regulate macrophage polarization, and facilitate the healing of bone defects. These findings indicate that a multi-pronged strategy is greatly expected to promote the bone healing by modulating pathological microenvironments.