Immunomodulatory effect of Ti-Cu alloy by surface nanostructure synergistic with Cu²⁺ release

The inflammatory response induced by implant/macrophage interaction has been considered to be one of the vital factors in determining the success of implantation. In this study, TiCuNxOy coating with an immunomodulatory strategy was proposed for the first time, using nanostructured TiCuNxOy coating synthesized on Ti-Cu alloy by oxygen and nitrogen plasma-based surface modification. It was found that TiCuNxOy coating inhibited macrophage proliferation but stimulated macrophage preferential activation and presented an elongated morphology due to the surface nanostructure. The most encouraging discovery was that TiCuNxOy coating promoted the initial pro-inflammatory response of macrophages and then accelerated the M1-to-M2 transition of macrophages via a synergistic effect of fast-to-slow Cu2+ release and surface nanostructure, which was considered to contribute to initial infection elimination and tissue healing. As expected, TiCuNxOy coating released desirable Cu2+ and generated a favorable immune response that facilitated HUVEC recruitment to the coating, and accelerated proliferation, VEGF secretion and NO production of HUVECs. On the other hand, it is satisfying that TiCuNxOy coating maintained perfect long-term antibacterial activity (>= 99.9%), mainly relying on Cu2O/CuO contact sterilization. These results indicated that TiCuNxOy coating might offer novel insights into the creation of a surface with immunomodulatory effects and long-term bactericidal potential for cardiovascular applications.