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

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.