Micro‐Galvanic Coupling Programs the Therapeutic Zinc Ion Window to Reconfigure Immune Cascades for Pro‐Regenerative Bone Healing

ABSTRACT 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 Mg 2 Zn 11 particles in Zn‐0.8Mg act as sacrificial anodes, suppressing Zn matrix dissolution. In contrast, coarse FeZn 13 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 Zn 2+ , 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 Zn 2+ 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.