Manipulation of Heterogeneous Surface Electric Potential Promotes Osteogenesis by Strengthening RGD Peptide Binding and Cellular Mechanosensing

The heterogeneity of extracellular matrix (ECM) topology, stiffness, and architecture is a key factor modulating cellular behavior and osteogenesis. However, the effects of heterogeneous ECM electric potential at the micro‐ and nanoscale on osteogenesis remain to be elucidated. Here, the heterogeneous distribution of surface potential is established by incorporating ferroelectric BaTiO3 nanofibers (BTNF) into poly(vinylidene fluoridetrifluoroethylene) (P(VDF‐TrFE)) matrix based on phase‐field and first‐principles simulation. By optimizing the aspect ratios of BTNF fillers, the anisotropic distribution of surface potential on BTNF/P(VDF‐TrFE) nanocomposite membranes can be achieved by strong spontaneous electric polarization of BTNF fillers. These results indicate that heterogeneous surface potential distribution leads to a meshwork pattern of fibronectin (FN) aggregation, which increased FN‐III7‐10 (FN fragment) focal flexibility and anchor points as predicted by molecular dynamics simulation. Furthermore, integrin clustering, focal adhesion formation, cell spreading, and adhesion are enhanced sequentially. Increased traction of actin fibers amplifies mechanotransduction by promoting nuclear translocation of YAP/Runx2, which enhances osteogenesis in vitro and bone regeneration in vivo. The work thus provides fundamental insights into the biological effects of surface potential heterogeneity at the micro‐ and nanoscale on osteogenesis, and also develops a new strategy to optimize the performance of electroactive biomaterials for tissue regenerative therapies. By turning the dimension and aspect ratios of BaTiO3 (BTO) nanofillers, an anisotropic distribution of surface potential is observed on the BTO nanofibers/P(VDF‐TrFE) (BTNF) nanocomposite membrane after polarization. After covering supercritical‐sized calvarial defects in rats, the BTNF composite membrane facilitates improved bone regeneration that leads to almost complete healing after 12 weeks post‐implantation, which is mediated by the heterogeneous electrical microenvironment.