Biodegradable Mg2+-releasing piezoelectric scaffold for segmental bone defect repair

Critical-sized bone defects, particularly segmental injuries such as radial defects, remain one of the most formidable challenges in orthopedic regeneration, as spontaneous healing is rarely achieved and existing grafts suffer from donor site morbidity, immune rejection, insufficient mechanical and biological performance. In this study, we present a biodegradable piezoelectric cryogel scaffold (PWH Gel) composed of a gelatin methacryloyl (GelMA) matrix embedded with piezoelectric whitlockite nanoparticles (PWH NP). Under physiological loading, PWH Gel generates localized electrical potentials and releases bioactive ions (Ca²⁺, Mg²⁺), creating a dynamic self-powered microenvironment that actively promotes bone regeneration. <i>In vitro</i>, the scaffold enhanced bone marrow mesenchymal stem cells (BMSCs) proliferation, migration, and osteogenic differentiation, facilitated endothelial tube formation, and triggered Piezo1-mediated Ca²⁺ influx and cytoskeletal remodeling. When implanted into a rat critical-size radial segmental defect, PWH Gel achieved complete bone bridging with markedly improved bone volume, trabecular organization, and vascularization. By coupling mechanical, electrical, and ionic stimulation within a single biodegradable system, this Mg²⁺-releasing piezoelectric cryogel establishes a new paradigm for functional reconstruction of segmental bone defects, representing a significant step toward clinically translatable electroactive biomaterials for large skeletal injuries.