Ultrasound-activated piezoelectric Silk-PVDF hydrogel reprograms the osteoimmune microenvironment via NRF2 signaling for accelerated bone regeneration

Bone defects pose significant clinical challenges due to the limited regenerative capacity of adult bone and the shortcomings of existing biomaterials, which lack dynamic electromechanical signaling crucial for repair. Here, we present an injectable, ultrasound-responsive piezoelectric hydrogel engineered to synergize silk fibroin's (SF) structural adaptability with polyvinylidene fluoride's (PVDF) bioelectrical activity. Methacrylated silk fibroin (SM) enables rapid UV-triggered crosslinking via a cost-effective photoinitiator system, while electrospun PVDF nanofibers, cryosectioned into microscale units, confer dynamic piezoelectric responsiveness. Under ultrasound stimulation, PVDF generates localized electrical cues that transiently elevate reactive oxygen species (ROS), activating the NRF2 antioxidant pathway to resolve oxidative stress, which polarizes macrophages toward pro-regenerative M2 phenotypes, enhances osteogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) and promotes angiogenesis <i>in vitro</i>. Additionally, it was also confirmed that implantation of critical-sized femoral defects in rats could facilitate bone regeneration by micro-CT and histological analysis in vivo. This platform transcends beyond passive scaffolding by recapitulating bone's electromechanical-immune axis offers a paradigm shift toward smart biomaterials for complex skeletal defects. The integration of PVDF's ultrasound-triggered piezoelectricity with SM's bioactivity establishes a multifunctional system that dynamically regulates redox homeostasis, immune modulation, and tissue remodeling, addressing unmet needs in bone tissue engineering.