Photocurrent-Directed Immunoregulation Accelerates Osseointegration through Activating Calcium Influx in Macrophages

Early osteoimmune microenvironment disorder at the interface between bone and implant can lead to implant loosening, which prolongs patient convalescence, exacerbates postoperative complications, and potentially results in implant failure. The timely regulation of macrophages primarily orchestrates the entire long-term regeneration process. Here, it is proposed to precisely direct macrophage polarization using localized photoelectrical signals generated by an excitable surface in response to remote stimulation via near-infrared light (NIR). The photocurrent generated from the n–n heterojunction between calcium titanate (CaTiO 3 ) and defective titanium dioxide (TiO 2 -V o ) on the excitable surface can accurately direct macrophage polarization, suppressing acute inflammation at the early stage of post-implantation and establishing a favorable osteoimmune microenvironment that promotes bone-to-implant integration. Mechanistic study reveals that photoelectric signals initiate increased calcium influx via voltage-gated calcium ion channels, subsequently modulating calcium/calmodulin-dependent protein kinase kinase 2 (Camkk2) and calcium/calmodulin-dependent protein kinase I (Camk1) expression to regulate macrophage polarization. This optimization of the osteoimmune microenvironment results in enhanced mesenchymal stem cells (MSCs) recruitment and osteogenesis, ultimately accelerating bone-to-implant integration within 14 days post-implantation. This research presents a novel method for adjusting in vivo spatiotemporal immune responses through the use of noninvasive and externally-controlled targeted stimulations.