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

BTO NPs-mediated piezoelectric stimulation effectively induced macrophage M2 polarization and metabolic reprogramming, represented by enhanced TCA cycle and one-carbon folate cycle. After that, anti-inflammatory and pro-differentiation M2 promoted osteogenic differentiation of bone marrow mesenchymal stem cells. The osteo-friendly immune microenvironment formed by piezoelectric stimulation effectively promoted the regeneration of alveolar bone defects.


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.

Author list:

Baiyan Sui†, Tingting Ding†, Xingyi Wan†, Yuxiao Chen, Xiaodi Zhang, Yuanbo Cui, Jie Pan*, Linlin Li*, Xin Liu*

How to cite:

B. Sui, T. Ding, X. Wan, Y. Chen, X. Zhang, Y. Cui, J. Pan, L. Li, X. Liu, Exploration 2024, 20230149.