Piezoelectric stimulation enhances bone regeneration in alveolar bone defects through metabolic reprogramming of macrophages

Immunomodulation has emerged as a promising strategy for promoting bone regeneration. However, designing osteoimmunomodulatory biomaterial that can respond to mechanical stress in the unique microenvironment of alveolar bone under continuous occlusal stress remains a significant challenge. Herein, a wireless piezoelectric stimulation system, namely, piezoelectric hydrogel incorporating BaTiO₃ nanoparticles (BTO NPs), is successfully developed to generate piezoelectric potentials for modulating macrophage reprogramming. The piezoelectric stimulation reprograms macrophages towards the M2 phenotype, which subsequently induces osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RNA sequencing analysis reveals that piezoelectricity-modulated macrophage M2 polarization is closely associated with metabolic reprogramming, including increased amino acid biosynthesis and fatty acid oxidation. The composite hydrogel with excellent biocompatibility exhibits immunomodulatory and osteoinductive activities. In a rat model of alveolar bone defects, the piezoelectric hydrogel effectively promotes endogenous bone regeneration at the load-bearing sites. The piezoelectric-driven osteoimmunomodulation proposed in this study not only broadens understanding of the mechanism underlying piezoelectric biomaterials for tissue regeneration but also provides new insights into the design and development of next-generation immunomodulatory biomaterials.