Built‐In Electric Field Accelerates Nanotopography‐Mediated Enhancement of Vascularized Osseointegration via Ca_v1.2/Piezo/Ca²⁺/PI3K Signaling

Increasing studies have emphasized the role of implant surface modifications in enhancing osseointegration through the synergistic regulation of osteogenesis and angiogenesis. While both topography and electrical cues have been shown to promote these processes, the interplay between these biophysical characteristics and their combined effects remain unclear. This study employs polarized BaTiO₃ nanorod arrays (NBTP) on titanium surfaces as model substrates to engineer a mechanobiological and piezoelectric microenvironment. Nanotopography improves hydrophilicity, piezoelectric properties, and surface potential due to sharp reduction in Young's modulus. In vitro experiments reveal that topography-mediated mechanobiological remodeling primarily enhances osteogenesis in mesenchymal stem cells (MSCs) and angiogenesis in endothelial cells (ECs) via Piezo2/Piezo1/Ca²⁺ signaling. The augmented electric field further amplifies this mechanical stress-driven osteogenic/angiogenic response by activating Ca_v1.2 and potentiating Piezo2/Piezo1 signaling. Microarray analysis and blocking experiments identify the PI3K/AKT/mTOR/GSK3β pathway as a key mediator. Together, topography and the built-in electric field activate paracrine crosstalk between MSCs and ECs, indirectly enhancing osteogenesis and angiogenesis. In vivo studies confirm that nanorod topography significantly improves vascularized osseointegration, while the built-in electric field accelerates bone healing by remodeling the peri-implant microenvironment. These findings advance the design of high-performance bone implants by elucidating the mechanobiological-piezoelectric coupling mechanism underlying vascularized osteogenesis.