Ultrasound-Responsive Hydrogels Empowered by Two-Dimensional Sonosensitizers Enable Spatiotemporally Controlled Fracture Fixation and Bone Regeneration.

Precise adhesion of bone fragments and robust bone regeneration are both essential for successful fracture healing, yet existing hydrogel adhesives rarely achieve controllable fixation and sustained osteogenesis simultaneously. Herein, we report a polyphenol-engineered ultrasound-responsive injectable hydrogel for fracture fixation and bone regeneration. The hydrogel is composed of dihydrocaffeic acid-modified chitosan, gelatin methacryloyl, a 2D sonosensitizer (PGO-Fe) constructed from polydopamine-mediated ferroferric oxide-decorated reduced graphene oxide, and polydopamine-modified hydroxyapatite (PHA). The hydrogel initially forms reversible, shape-adaptable adhesion to bone via catechol-mediated noncovalent interactions. Upon high-intensity ultrasound (HUS), PGO-Fe enhances sonodynamic activity through Fe(III)/Fe(II) redox conversion, triggering secondary covalent crosslinking and enabling a controllable transition from compliant adhesion to rigid fixation. Polyphenolic components confer reactive oxygen species-scavenging capacity and promote macrophage polarization toward the M2 phenotype, creating a favorable regenerative microenvironment. Under low-intensity ultrasound (LUS), the hydrogel activates Piezo1-mediated calcium influx, thereby enhancing osteogenic differentiation. In vivo, this system achieves nearly complete defect bridging and mechanical performance comparable to wire fixation in rat calvarial and rabbit ulna models. This work provides a minimally invasive strategy that integrates controlled fixation, immunomodulation, and mechanically enhanced osteogenesis for complex fracture treatment.