Micro-galvanic effects of silver-containing titanium implants regulate the immune responses via activating voltage-gated calcium channels in macrophages

To explore the physiological mechanism of silver for the clinical application of silver-containing biomaterials and biomedical devices, the plasma immersion ion implantation method was used to prepare silver-doped titanium samples in this work. The findings disclosed that with the increase of the introduced Ag amount, the micro-galvanic effects formed by silver and the titanium matrix became stronger, which could stimulate the opening of voltage-gated calcium channels in macrophages to facilitate Ca2+ influx. The increase of intracellular Ca2+ concentration could induce macrophages to polarize towards the M1 phenotype by activating the Ca2+-dependent PKC-NF-κB signaling pathway, while it was more favorable to the polarization of M2 macrophages by improving the synthesis and secretion of calcium-dependent PGE2. Therefore, with the increase of Ag amount, the micro-galvanic effect was enhanced, and the anti-inflammatory responses of macrophages on samples were improved. Furthermore, the co-cultured bone marrow mesenchymal stem cells could inhibit the Ca2+ influx of the co-cultured macrophages to down-regulate the Ca2+-dependent PKC-NF-κB signaling pathway in macrophages and secrete PGE2 to promote the polarization of M2 macrophages, which weaken the inflammatory response. Our results indicate that the immune response can be regulated by the micro-galvanic effects of silver and titanium matrix, and provide new insights into designing and developing the silver-containing biomaterials with a desirable biological response.