Piezoelectric ZnO-incorporated bioactive glass nanospheres for enhanced odontogenic differentiation and angiogenesis

Regeneration of the pulp-dentin complex requires coordinated odontogenic differentiation and vascularization, which remain difficult to achieve using conventional biomaterials that rely predominantly on biochemical stimulation. Herein, we developed an ultrasound-responsive nanocomposite system composed of ZnO-incorporated mesoporous bioactive glass nanospheres (Z-MBGNs) to introduce an externally controllable electromechanical cue alongside material-derived ionic signals. By incorporating ZnO-containing phases into the mesoporous bioactive glass matrix, the composite enabled sustained release of Zn²⁺ and Ca²⁺ while reducing the cytotoxicity associated with excessive ZnO-derived ion exposure. Under LIPUS stimulation, Z-MBGNs exhibited an ultrasound-associated electromechanical/electrical response and further enhanced odontogenic and angiogenic responses. In vitro, LIPUS-treated 10Z-MBGNs increased hDPSC migration, ALP activity, mineralized matrix formation, and DSPP/DMP-1 expression, while also enhancing HUVEC tube formation and angiogenesis-related factor expression. In a subcutaneous ectopic implantation model, the treatment promoted extracellular matrix deposition and increased odontogenic- and angiogenic-associated marker expression. Collectively, these findings provide proof-of-concept evidence that Z-MBGNs can combine sustained ionic regulation with ultrasound-associated electromechanical responsiveness to enhance coordinated odontogenic and angiogenic behaviors. Further studies incorporating appropriate mechanistic controls and tooth-specific orthotopic models are required to clarify the underlying mechanisms and translational potential of this strategy.