Masticatory‐Driven Piezoelectric Hydrogels with Electrical Stimulation‐Triggered NPY Condensate for Mandibular Bone Regeneration

ABSTRACT Mandibular bone defects, especially critical‐sized ones, are a major challenge in oral and maxillofacial surgery. Electrical stimulation (ES) enhances bone repair, but its underlying mechanism remains elusive. This study presents a masticatory‐driven piezoelectric hydrogel that converts chewing motions into endogenous‐like ES, triggering on‐demand NPY condensate release to enhance regeneration, validated in rat critical‐sized defect models. NPY as a key mediator is identified: ES triggers its phase transition to activate osteogenic signaling. The engineered hydrogel generates >20 mV cm −1 (exceeding the ≥2 mV cm −1 threshold for NPY liquid‐liquid phase separation, LLPS) under physiological chewing. ES induces NPY conformational rearrangement (N‐terminus buried) to activate Y2 receptors (Y2R) on periodontal ligand‐derived stromal cells (PDLSCs). Mechanistically, ES plus NPY condensate promotes osteogenic differentiation of PDLSCs through pAKT‐Runx2 signaling. In vitro, the hydrogel boosts PDLSCs osteogenesis by 2‐fold ( p < 0.001 ). In 4‐week and 12‐week rat mandibular bone defects, it yielded greater bone volume and higher density ( p < 0.01 ) vs. controls, with Y2R‐pAKT‐RUNX2 activation confirmed. This self‐powered strategy leverages mastication for targeted ES, offering a mechanism‐driven solution that addresses current limitations and holds clinical promise.