The effect of copper content in Ti-Cu alloy with bone regeneration ability on the phenotypic transformation of macrophages

Titanium (Ti) alloys are widely used in bone repair due to their excellent biocompatibility and mechanical properties. However, managing post-implantation inflammatory responses in the defect region and accelerating the healing process remain major challenges in the design of such materials. As a bridge between the innate and adaptive immune systems, macrophages play a pivotal role in bone defect healing through their M2 polarization, which facilitates the secretion of tissue repair-promoting cytokines. Research on the role of copper ions (Cu²⁺) in regulating inflammatory responses at injury sites suggests their potential as active ions for incorporation into alloys as a secondary phase to modulate macrophage polarization. However, the effective concentration and mechanisms in this process remain unclear. Here, we synthesized Ti-xCu (x = 3, 5, 7 wt%) alloys and investigated the effects of copper concentration on macrophage M1/M2 polarization and the underlying mechanisms. In an 8-week rat mandibular bone regeneration experiment, Ti-5Cu demonstrated superior performance compared to pure titanium. At the early stage (2 weeks), Ti-5Cu promoted the dominance of M1 macrophages and upregulated inflammatory cytokines, facilitating the initial inflammatory response. Subsequently, a timely M1-to-M2 phenotype transition was observed, accompanied by elevated expression of the repair-related cytokine IL-10, ultimately leading to improved bone healing. This study provides a theoretical foundation for the development of titanium-copper composite materials with anti-inflammatory and pro-healing properties, paving the way for innovative solutions to promote bone defect repair.