Category: signaling
Skin wound healing proceeds through four overlapping phases. Phase 1: hemostasis (minutes-hours) — platelet aggregation → release of PDGF, TGF-β, VEGF; coagulation cascade → fibrin clot → provisional matrix. Phase 2: inflammation (hours-days) — neutrophils (1-3 d, debridement + antimicrobial) → macrophages (3-7 d, M1 pro-inflammatory then M2 pro-resolution). DAMPs (HMGB1, S100, ATP, mtDNA) drive innate response. Cytokines: IL-1, IL-6, TNF-α, MCP-1. Phase 3: proliferation (days-weeks) — re-epithelialization (keratinocyte migration + proliferation, EGFR/HGF-driven); angiogenesis (VEGF + FGF → new capillaries); granulation tissue (fibroblast migration + matrix + myofibroblast contraction); type III collagen + GAGs initially. Phase 4: remodeling (weeks-months-years) — type III → type I collagen replacement; MMP-mediated reorganization; tensile strength recovers to ~80% of intact skin. Dysfunctional healing: (1) chronic wounds (venous stasis, diabetic, pressure) — stalled in inflammation, persistent MMP elevation, biofilm, neuropathy + ischemia. (2) hypertrophic / keloid scarring — excessive collagen + TGF-β + fibroblast proliferation. Therapeutic landscape: standard care (debridement + moisture + offloading + infection control); growth factor topicals (becaplermin = recombinant PDGF for diabetic foot ulcers — boxed warning for cancer with chronic high-volume use); hyperbaric oxygen for refractory wounds; anti-TGF-β for keloid prevention (investigational); botanicals (curcumin, aloe vera, honey — preclinical + small clinical signal). Cross-links: [[coagulation_cascade]] (hemostasis upstream), [[platelet_aggregation]] (initial response), [[fibrinolysis]] (clot turnover), [[tgf_beta_signaling]] (proliferation + remodeling), [[arachidonic_acid_cascade]] (inflammation mediators).