Remodel Heterogeneous Electrical Microenvironment at Nano‐Scale Interface Optimizes Osteogenesis by Coupling of Immunomodulation and Angiogenesis

Abstract Immunomodulation is essential for implants to regulate tissue regeneration, while bioelectricity plays a fundamental role in regulating immune activities. Under natural preferences, the bone matrix electrical microenvironment is heterogeneous in the nanoscale, which provides fundamental electrical cues to regulate bone immunity and regenerative repair. However, remodeling bone nanoscale heterogeneous electrical microenvironment remains a challenge, and the underlying immune modulation mechanism remains to be explored. In this research, in situ discretely distributed nano‐heterojunctions are constructed on titanium oxide nanofibers to mimic the heterogeneous electrical microenvironment exhibited by bone collagen fibers. The material is identified to directly regulate calcium ion channeling for anti‐inflammatory polarization of macrophages. Surprisingly, the highly biomimetic heterogeneous electrical microenvironment can induce a pro‐angiogenic phenotypic transformation of macrophages, leading to enhanced neo‐vascularization at the early stage of osteogenesis. Mechanistic exploration identifies that PI3K signaling pathway‐mediated FGF2 secretion may partially explain for strengthened coupling of immunomodulation and angiogenesis, which optimizes subsequent bone regeneration. These findings highlight the significance of biomimetic heterogeneous electrical cues on immune‐modulation and provide a design principle for future electroactive implant materials.