Hematoma-inspired injectable composite hydrogels incorporating hybrid metal ion microspheres for accelerated bone regeneration

Injectable hydrogels emerge as a particularly attractive candidate in bone tissue engineering, due to their minimally invasive administration and conformal filling for irregular bone defects. However, they still lack sufficient osteoinductive activities for effective bone repair. Herein, we engineer a hematoma-inspired injectable composite hydrogel consisting of polylactide microspheres encapsulated with magnesium oxide and strontium oxide and the alginate hydrogel crosslinked by slow release of Ca²⁺ for promoting bone regeneration in critical-sized bone defects. A complementary release of rapidly released Sr²⁺ and gradually released Mg²⁺ effectively promotes the proliferation, migration and osteogenic differentiation of bone marrow mesenchymal stem cells as well as biomineralization, mimicking the release of various growth factors from hematoma for expediting bone healing. The ionic crosslinking alginate composite hydrogel imitates the fibrin network of hematoma to serve as a temporary scaffold to support bone healing. The excellent injectability, high mechanical strength and good biocompatibility are also gathered. Through a critical-sized bone defect rat model, our hematoma-inspired hydrogel displays strong osteogenic ability to upregulate the expression of osteogenesis-related proteins and accelerate new bone formation, ascribed to the synergistic effect of released Mg²⁺ and Sr²⁺. Overall, the novel composite hydrogel offers a significant application potential for the treatment of bone defects.