Ultrasound‐Driven Piezoelectric Strategy and Performance: Polyurethane‐Based Functioning Networks in Actuating Bone Repair

Abstract When severe defects bone occur, limited mobility in patients is accompanied by delayed signal transmission and osteogenesis. A sonodynamic therapy based on ultrasound‐driven piezoelectric scaffolds is designed to restore cellular connections for regeneration. A series of 3D‐printed scaffolds are fabricated using different polyurethane‐based composites (hydroxyapatite/BaTiO 3 ) and further polarized to achieve a high piezoelectric constant. Driven by low‐intensity pulsed ultrasound (LIPUS), the electrical signals from polarized scaffolds are optimized, achieving an increased open‐circuit voltage (197 mV) due to the interconnected piezoelectric phase. The ultrasound‐driven piezoelectric cues elevated the cytosolic and mitochondrial calcium levels in bone marrow mesenchymal stem cells (BMSCs), where calcium ions acted as a key second messenger, fortifying mitochondrial energy metabolism and exciting cellular activity. After applying the sonodynamic therapy to rat skull defects, the calcium signaling pathway, oxidative phosphorylation, and citrate cycle are actuated in the energy metabolism through functioning networks, while the HIF‐1 signaling pathway on angiogenesis, and the AMPK and MAPK signaling pathways on osteogenesis collectively improved. The optimized sonodynamic therapy facilitated ≈27.85% osteogenesis (8 W) with early neovascularization (4 W) in the defects. Given the high efficiency of the piezoelectric‐transducing network, the sonodynamic therapy offers a sustained mitochondria‐excited treatment to maintain bone viability.