Bioelectric signals promote diabetic bone regeneration through Piezo1-mediated activation of the efferocytic immune microenvironment.

Abstract

Defective macrophage efferocytosis sustains inflammation and compromises bone repair in diabetic defects, yet strategies that restore efferocytic immune homeostasis remain limited. Here, we engineered an ultrasound-responsive piezoelectric hydrogel (Gel BC@ZnO) by incorporating zinc oxide (ZnO) nanoparticles into a bacterial cellulose (BC)-reinforced gelatin methacryloyl (GelMA) network to provide localized bioelectric cues. Gel BC@ZnO exhibited good cytocompatibility, structural stability, and robust ultrasound-triggered piezoelectric output. Under diabetic-mimicking conditions, ultrasound activation generated bioelectric signals that engaged Piezo1, induced Piezo1-dependent Ca²⁺ influx, and rescued macrophage efferocytosis. This efferocytic reactivation attenuated ROS accumulation, shifted macrophages toward a pro-regenerative phenotype, enhanced osteogenic differentiation, and suppressed osteoclast genesis, thereby restoring bone-remodeling homeostasis. In a diabetic femoral condyle defect model, Gel BC@ZnO combined with ultrasound accelerated bone repair, increased local Piezo1 expression, promoted collagen deposition and osteogenic marker expression, and rebuilt a favorable immune microenvironment. These results define a bioelectric signal-Piezo1-Ca²⁺-efferocytosis axis for diabetic bone regeneration and establish a non-invasive, ultrasound-controllable immunomodulatory strategy for compromised bone repair.