Periodontal disease is a multifactorial, bacterially induced inflammatory condition characterized by the progressive destruction of periodontal tissues. The successful nonsurgical treatment of periodontitis requires multifunctional technologies offering antibacterial therapies and promotion of bone regeneration simultaneously. For the first time, in this study, an injectable piezoelectric hydrogel (PiezoGEL) was developed after combining gelatin methacryloyl (GelMA) with biocompatible piezoelectric fillers of barium titanate (BTO) that produce electrical charges when stimulated by biomechanical vibrations (e.g., mastication, movements). We harnessed the benefits of hydrogels (injectable, light curable, conforms to pocket spaces, biocompatible) with the bioactive effects of piezoelectric charges. A thorough biomaterial characterization confirmed piezoelectric fillers' successful integration with the hydrogel, photopolymerizability, injectability for clinical use, and electrical charge generation to enable bioactive effects (antibacterial and bone tissue regeneration). PiezoGEL showed significant reductions in pathogenic biofilm biomass (∼41%), metabolic activity (∼75%), and the number of viable cells (∼2-3 log) compared to hydrogels without BTO fillers in vitro. Molecular analysis related the antibacterial effects to be associated with reduced cell adhesion (downregulation of porP and fimA) and increased oxidative stress (upregulation of oxyR) genes. Moreover, PiezoGEL significantly enhanced bone marrow stem cell (BMSC) viability and osteogenic differentiation by upregulating RUNX2, COL1A1, and ALP. In vivo, PiezoGEL effectively reduced periodontal inflammation and increased bone tissue regeneration compared to control groups in a mice model. Findings from this study suggest PiezoGEL to be a promising and novel therapeutic candidate for the treatment of periodontal disease nonsurgically.

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