Programmed regulation of microenvironment remodeling and bone regeneration for bone repair by coaxial hydrogel scaffold with ultrasound-activated drug delivery

Inflammation triggered by extensive bone defects impairs osteogenic function and hinders the efficacy of bone tissue repair, making it imperative to improve the early immune microenvironment of bone injuries. Here, this study employed coaxial 3D printing to fabricate hydrogel scaffolds with core-shell structured microfilaments for spatio-temporal delivery of bioactive factors, exploring the potential of improving the immune microenvironment and promoting bone tissue regeneration under ultrasound (US) treatment. With US treatment, the shell layer of hydrogel scaffold enabled controlled release of interleukin-10 (IL-10) through the cleavage of thioketal linker. Simultaneously, sustained release of magnesium ions from core layer was achieved by the trapping of alendronate-modified methacrylated gelatin. <i>In vitro</i> studies confirmed that this hydrogel scaffold possessed excellent biocompatibility, effective promotion for angiogenesis and osteogenesis via magnesium ions stimulation, and immunomodulatory effects by IL-10 stimulation with US treatment. The subcutaneous implantation model demonstrated that the hydrogel scaffold had good in vivo biocompatibility, while significantly improved population of M2 macrophage and reduced levels of pro-inflammatory factors, followed by triggering the neovascularization under US treatment. Furthermore, the cranial defect model revealed that enhanced bone regeneration capacity was realized after implantation of hydrogel scaffold with US treatment through activating the PI3K-Akt signaling pathway to promote bone regeneration. Overall, this study developed an ultrasound-responsive hydrogel scaffold that orchestrated the immune microenvironment and bone regeneration, providing an innovative strategy for effective bone repair.