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).
Organ Systems
integumentary
immune-hematologic
cardiovascular
Pathway Steps
wound + tissue injury → platelet aggregation + fibrin clot — via coagulation cascade + platelet PDGF/TGF-β/VEGF release; hemostasis phase. Healing begins immediately with hemostasis: platelets aggregate at the injury and a fibrin clot forms to stop bleeding. The clot is also a provisional matrix and a reservoir of platelet-released growth factors (PDGF, TGF-β) that recruit cells for the next phases — so hemostasis and inflammation are linked.
DAMPs + chemokines → neutrophil influx (1–3 d) → macrophage influx (3–7 d) — via inflammatory phase; M1 → M2 macrophage polarization signals resolution. The inflammatory phase follows a defined sequence: DAMPs and chemokines draw neutrophils (days 1-3) to kill bacteria and debride, then monocyte-derived macrophages (days 3-7). Macrophages orchestrate the switch from inflammation toward repair; failure here underlies chronic non-healing wounds.
macrophage M2 + growth factors → keratinocyte migration → re-epithelialization — via EGFR + HGF; basal keratinocytes lose polarity + migrate across wound bed. As macrophages adopt a reparative (M2) phenotype and release growth factors, edge keratinocytes proliferate and migrate across the provisional matrix to restore the epidermal barrier (re-epithelialization). Migration halts on contact once the surface is covered.
VEGF + FGF → angiogenesis → new capillary network — via supplies metabolic demand of granulation tissue. VEGF and FGF drive angiogenesis — new capillaries sprout into the wound to supply oxygen and nutrients for the metabolically demanding repair. This neovascularization gives granulation tissue its red, granular look; inadequate angiogenesis (as in diabetes) is a major cause of impaired healing.
fibroblast migration + proliferation → granulation tissue (type III collagen + GAGs) — via red, soft "filling" tissue bridging the defect. Fibroblasts migrate in and proliferate, depositing a provisional matrix of type III collagen and glycosaminoglycans to build granulation tissue. This new connective-tissue scaffold replaces the fibrin clot and provides the substrate on which contraction and remodeling occur.
myofibroblast differentiation (α-SMA+) → wound contraction — via TGF-β-driven; reduces wound area; excess → contracture. Some fibroblasts differentiate into α-SMA-expressing myofibroblasts that generate contractile force, pulling the wound edges together to shrink the defect. Excessive or persistent myofibroblast activity causes pathological scarring — hypertrophic scars, keloids, and organ fibrosis.
type III → type I collagen (weeks-months) → remodeled scar (tensile ~80% of intact) — via MMP-mediated turnover; remodeling can persist >1 year. Remodeling is the longest phase (weeks to months): type III collagen is gradually replaced by stronger, organized type I collagen as the scar matures. Even fully remodeled scar regains only ~80% of intact skin’s tensile strength and lacks appendages — repair, not true regeneration.
Known Modulators
testosterone (activator) — wound healing (anabolic; ↑muscle + ↑collagen; clinical use in chronic wounds + burns)