3D printed flexible composite scaffold with ultrasonic-driven wireless electrical stimulation promotes neuro-vascularization for critical-size bone defects regeneration

Regeneration of critical-size bone defects hinges on the reconstruction of neurovascular networks. The electrophysiological properties of native bone underscore the pivotal role of endogenous bioelectricity in coordinating nerve-vascular-bone regeneration. However, traditional piezoelectric scaffolds impede regenerative efficiency due to their intrinsic limitations. To tackle this, 3D printed flexible polyvinyl alcohol/whitlockite/barium titanate (PVA/WH/BaTiO₃) composite scaffolds endowed with ultrasonic-driven wireless electrical stimulation capacity were engineered. The PVA/WH composite strategy significantly enhanced the printability, flexibility, shear-thinning behavior, mechanical robustness, and bioactivity of the scaffolds, systematically addressing the intrinsic limitations of traditional piezoelectric scaffolds while fulfilling the multifaceted requirements of orthopedic applications. By adding BaTiO₃, when subjected to noninvasive low-intensity pulsed ultrasound as a stimulus, the scaffolds exhibited controllable wireless electrical stimulation properties with tunable duration and intensity to meet specific therapeutic requirements. In vitro experiments illustrating electrical stimulation can significantly promote neuralization, vascularization and osteogenic differentiation. Furthermore, the 3D printed flexible composite scaffolds with ultrasonic-driven wireless electrical stimulation facilitated neuro-vascularization network reconstruction and osteogenic proteins up-regulation in rat calvarial critical-sized defect models of 7 mm, thereby accelerating the regeneration and repair of critical-size bone defects. It held great potential as a promising material for critical-size bone defects treatment.