Dual-Strategy Design of Heterojunction-Enhanced Piezoelectric Hydrogels for Periodontitis Treatment.

Abstract

Periodontitis is a widespread chronic inflammatory disease that threatens oral and systemic health by sustaining inflammation and accelerating alveolar bone loss. Although bioelectrical modulation can promote bone repair under inflammatory conditions, the coordinated regulation of electrical signaling, immunoregulation, and osteogenesis within an inflamed microenvironment remains a central challenge. Here, we report a multifunctional piezoelectric hydrogel system that combines heterojunction enhancement with dual-salt synergy. In situ construction of ZnO/ZnS heterojunctions with oxygen vacancies amplifies the piezoelectric output of ZnO, while a polyvinyl alcohol (PVA) multinetwork integrated with magnesium chloride (MgCl) and trisodium citrate (NaCt) provides high ionic conductivity, mechanical robustness, and bioactivity, conferring excellent injectability and environmental adaptability. The composite hydrogel exhibited low impedance and high ionic conductivity (≈3.82 mS·cm), generated a stable voltage of ≈150 mV under ultrasound activation, and maintained sensitive strain response under moist conditions. In vitro, the hydrogel markedly enhanced osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs), with upregulation of Runx2, Col-1, OPN, and OCN, and simultaneously drove macrophage polarization toward the M2 phenotype. A conditioned medium model further confirmed immune remodeling that alleviated the inflammatory burden of hPDLSCs. In a rat periodontitis model, the hydrogel restored alveolar bone architecture, reduced osteoclast activity, and rebalanced the M1/M2 ratio. Collectively, this piezoelectric hydrogel enhanced by heterojunctions provides a versatile platform for immunologically instructive regeneration of inflamed bone defects.