A defined copper ion window coordinates multicellular responses for predictive vascular implant design

Copper ions have demonstrated significant potential in vascular applications due to their pro-regenerative and antimicrobial properties. Yet, the current research remains fragmented, with a conspicuous absence of a holistic, systems-level understanding of how copper ions concurrently orchestrate the responses of all key cellular players in the vascular niche. This study systematically mapped the dose-response relationships of copper ions across five key vascular cell types (endothelial cells, smooth muscle cells, macrophages, mesenchymal stem cells, and fibroblasts), identifying a core therapeutic window (5-20 μM). This window uniquely promotes endothelial and stem cell activity while maintaining smooth muscle cell quiescence and modulating macrophage viability. Beyond concentration, the timing of copper delivery (post-attachment addition being superior to co-culture seeding) and the presence of cell-cell interactions (e.g., endothelial-stem cell crosstalk) were also identified as critical determinants of the pro-regenerative outcome. Guided by the therapeutic window, a copper-modified implant was engineered and evaluated in vivo. This implant significantly reduced neointimal thickness, enhanced endothelial coverage, and mitigated inflammation. These in vivo results validated the in vitro mechanisms, and the systems-level understanding of multicellular responses will provide a guideline for the rational design of implants that orchestrate harmonious tissue repair.