Macrophage Modulation for Regenerative Skin Repair Beyond Accelerated Wound Closure: An Evidence Hierarchy Analysis of Preclinical Full-Thickness Wound Research

Adult full-thickness skin wounds usually heal by fibrosis rather than complete restoration. Macrophages regulate inflammation, angiogenesis, fibroblast activity, and extracellular-matrix remodeling, making them therapeutic targets. This paper asks whether local macrophage-modulating interventions in preclinical full-thickness excisional wounds can improve the regenerative quality of repair beyond wound closure. A structured evidence-hierarchy analysis independently classified macrophage mechanisms and tissue outcomes in 12 core studies while considering model, comparator, timing, and follow-up. Seven studies provided functional or causal macrophage evidence and six reported at least one positive regenerative-quality outcome. Only Hu et al. provided a positive linkage within the same comparison: human-monocyte delivery reduced gross scar area, but scar depth, collagen quality, and tensile strength did not improve consistently. Other causal studies clustered around closure, re-epithelialization, angiogenesis, and matrix formation; higher-level outcomes usually lacked macrophage-specific causal testing. Negative and discordant findings showed that faster closure or M2-associated polarization did not necessarily predict tissue restoration. Strong regeneration claims therefore require macrophage causality and regenerative-quality endpoints to converge within the same comparison, with appropriate controls and remodeling follow-up.