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 Zn 2+ and Ca 2+ 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.