An ultrasound-activated PLLA@BaTiO₃&SF Janus membrane enhances fracture healing via synergistic piezoelectricity and bioactivity

Fracture nonunion remains a significant clinical problem, largely due to insufficient mechanistic insight and effective treatments. Piezoelectric materials including polylactic acid (PLA) and barium titanate (BaTiO₃), facilitate bone regeneration through electrical stimulation, but their clinical application is constrained by undefined optimal ratio for achieving maximum electrical energy output and concerns regarding biological toxicity. To overcome these drawbacks, we designed a Janus membrane inspired by asymmetric material architecture, featuring a piezoelectric outer layer of poly (L-lactic acid) (PLLA) doped with BaTiO₃ and an inner silk fibroin (SF) layer. Our findings indicate that PLLA containing 20 wt% BaTiO₃ yields optimal electrical output under ultrasound stimulation, while the SF layer provided a hydrophilic and antioxidant interface for bone marrow-derived mesenchymal stem cells (BMSCs). The results showed that PLLA@BaTiO₃&SF Janus membrane significantly enhanced BMSCs adhesion, proliferation, and osteogenic differentiation, thereby accelerating fracture repair in a mouse femoral fracture model. Mechanistically, ultrasound-activated piezoelectric stimulation triggered PI3K-Akt, MAPK, and TGF-β signaling pathways in an integrin β1 (ITGB1)-dependent manner. Overall, the PLLA@BaTiO₃&SF Janus membrane integrates noninvasive activation, tunable piezoelectricity and excellent biocompatibility to achieve robust bone regeneration, offering a promising therapeutic strategy for reducing fracture nonunion and improving the quality of life for patients.