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, TiCuN_xO_y coating with an immunomodulatory strategy was proposed for the first time, using nanostructured TiCuN_xO_y coating synthesized on Ti-Cu alloy by oxygen and nitrogen plasma-based surface modification. It was found that TiCuN_xO_y 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 TiCuN_xO_y 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, TiCuN_xO_y 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 TiCuN_xO_y coating maintained perfect long-term antibacterial activity (≥99.9%), mainly relying on Cu₂O/CuO contact sterilization. These results indicated that TiCuN_xO_y coating might offer novel insights into the creation of a surface with immunomodulatory effects and long-term bactericidal potential for cardiovascular applications.