Surface-engineered WE43 magnesium implants promote bone repair and reshape the peri-implant immune microenvironment

Although the early inflammatory response to biomaterial implantation has been investigated, less is known about how degradation products shape the immune environment during later stages of regeneration. To address this, we analyzed immune responses to WE43 magnesium alloy implants (Mg-Y-Nd-Zr alloy) with distinct surface states: uncoated WE43 and WE43 implants surface-modified by plasma electrolytic oxidation (PEO) using a phosphate electrolyte. These implants were evaluated in a mouse osteotomy model during bone formation, when degradation-related effects on the peri-implant immune environment become increasingly relevant. Ex vivo immunogenicity tests showed that both implants induced moderate levels of TNFα and IL-8 responses, indicating immunological inertness. In vivo bone formation, implant degradation, and immune cell composition were assessed. Micro-CT analysis revealed enhanced bone regeneration in the WE43 PEO group, indicated by higher bone-to-callus ratio and trabecular bone thickness, and reduced cortical bone lysis. Implant density mapping demonstrated a slower, more homogeneous degradation pattern for PEO-modified implants. Flow cytometry analysis revealed an increased leukocyte accumulation and higher proportion of pro-inflammatory M1 macrophages surrounding WE43 implants, whereas WE43 PEO implants were associated with more balanced macrophage, dendritic, and natural killer cell profile. Spatial histological analyses corroborated these findings, showing closer proximity between macrophages and osteoblasts to PEO-modified implants. By integrating degradation mapping with spatial immune and histological analyses, this study identifies distinct peri-implant immune signatures associated with PEO-modulated magnesium degradation during bone regeneration. In conclusion, PEO is associated with a less pro-inflammatory peri-implant immune profile at day 28, and improved bone healing parameters. STATEMENT OF SIGNIFICANCE: Biodegradable magnesium implants can support bone repair, but how their surface treatments shape the local immune response is still unclear. This study compares unmodified WE43 magnesium implants with plasma electrolytic oxidation (PEO)-modified WE43 implants in a mouse osteotomy model. By combining micro-CT bone analysis, spatial mapping of implant degradation, flow cytometry-based immune profiling, and histology, we link distinct degradation patterns to specific peri-implant immune signatures. PEO-modified implants degraded more slowly and uniformly, reduced cortical bone lysis, and improved bone regeneration. They were associated with a more balanced profile of macrophages, dendritic cells, and natural killer cells, whereas unmodified implants showed increased leukocyte counts and pro-inflammatory M1 macrophages. These findings inform the design of immunomodulatory, degradable implants to improve bone healing.