Micro-Galvanic Coupling Programs the Therapeutic Zinc Ion Window to Reconfigure Immune Cascades for Pro-Regenerative...

Ion release-driven inflammation and bone loss underlie metallic implant failure. Here, micro-galvanic coupling design of alloys electrochemically programs essential element releasing dose to modulate immune responses and promote regenerative healing. Using model alloys, finely dispersed Mg₂Zn₁₁ particles in Zn-0.8Mg act as sacrificial anodes, suppressing Zn matrix dissolution. In contrast, coarse FeZn₁₃ phases in Zn-0.8Fe establish a "large cathode-small anode" galvanic regime, elevating anodic current densities by two orders of magnitude. Consequently, Zn-0.8Fe implants in bone marrow release excessive Zn²⁺, drive massive neutrophil recruitment and proinflammatory polarization (Day 3), and induce M1-dominant macrophage responses (Day 14), culminating in poor bone formation at Day 90. Conversely, Zn-0.8Mg releases a moderate Zn²⁺ flux, promotes pro-regenerative neutrophil polarization, and guides an M2-dominant macrophage milieu that fosters osteogenesis rich in type I collagen. Findings here provide the composition design rationale for the development and translational application of a biodegradable Zn alloy cranio-maxillofacial internal fixation system.