Stages of Wound Healing

Figure: The cellular, biochemical, and mechanical phases of wound healing - Schwartz's Principles of Surgery

Phase 1: Hemostasis and Inflammation (Day 0 to ~Day 6)

Hemostasis (minutes to hours)

• Tissue injury disrupts blood vessels, exposing subendothelial collagen to platelets
• Platelets aggregate, degranulate, and activate the coagulation cascade
• Platelet alpha granules release key mediators:
  • PDGF (platelet-derived growth factor)
  • TGF-beta (transforming growth factor-beta)
  • PAF (platelet-activating factor)
  • Fibronectin and serotonin
• The resulting fibrin clot stops bleeding and serves as a scaffold for incoming inflammatory cells

Inflammation

• Enter the wound within hours, peak at 24-48 hours
• Recruited by complement factors, IL-1, TNF-alpha, TGF-beta, and bacterial products
• Primary role: phagocytosis of bacteria and tissue debris
• Release cytokines (especially TNF-alpha) that influence angiogenesis and collagen synthesis
• Release proteases (collagenases) for matrix degradation
• Not required for collagen deposition or wound strength

• Derived from circulating monocytes
• Reach significant numbers at 48-96 hours, persist until healing is complete
• Phagocytose debris, generate reactive oxygen species and nitric oxide
• Release TGF-beta, VEGF, IGF, EGF, and lactate to regulate cell proliferation and migration
• Essential to successful healing - macrophage depletion severely impairs wound repair

• Peak at approximately 1 week post-injury
• Bridge the transition from inflammation to proliferation
• CD8+ suppressor subset: depletion enhances healing
• CD4+ helper subset: depletion has no effect
• Regulate fibroblast collagen synthesis via IFN-gamma, TNF-alpha, and IL-1 through direct cell-cell contact

Phase 2: Proliferation (Days 4-12)

Fibroblast Activity and Matrix Synthesis

• Fibroblasts are recruited primarily by PDGF (the strongest chemotactic factor for them)
• Once in the wound, they first proliferate, then become activated by macrophage-derived cytokines
• Wound fibroblasts synthesize more collagen than normal fibroblasts
• Lactate accumulating in the wound (~10 mmol) is a potent regulator of collagen synthesis via ADP-ribosylation

1. mRNA is translated into protocollagen (~1000 amino acids; glycine at every 3rd position)
2. Proline and lysine are hydroxylated (requires oxygen, iron, alpha-ketoglutarate, and vitamin C as electron donor)
3. Glycosylation occurs in the endoplasmic reticulum
4. Three alpha-helical chains coil into a procollagen triple helix
5. Registration peptides are cleaved extracellularly by procollagen peptidase
6. Collagen monomers polymerize and cross-link

1. Early: fibronectin + collagen type III
2. Mid: glycosaminoglycans and proteoglycans (dermatan/chondroitin sulfate peak ~3 weeks)
3. Late: collagen type I (final, dominant matrix)

Angiogenesis

• Endothelial cells migrate from intact venules near the wound
• Stimulated by TNF-alpha, TGF-beta, and VEGF
• Form new capillary tubules - essential for nutrient and oxygen delivery
• The combination of new capillaries + fibroblasts + connective tissue = granulation tissue

Epithelialization

• Epidermal cells at wound margins begin migrating and proliferating
• Stimulated by EGF, KGF (keratinocyte growth factor), and other mediators

Wound Contraction

• Begins almost immediately after injury
• Mediated largely by myofibroblasts (fibroblasts with alpha-smooth muscle actin stress fibers)
• Alpha-smooth muscle actin is undetectable until day 6, peaks around day 15, then fades by week 4 as cells undergo apoptosis
• Significant in healing by secondary intention

Phase 3: Maturation and Remodeling (Weeks to Months - up to 1-2 years)

• Begins during the proliferative phase and continues for 6-12 months post-injury
• Characterized by reorganization of previously synthesized collagen
• Matrix metalloproteinases (MMPs) break down old collagen; net collagen content reflects the balance between collagenolysis and synthesis
• Collagen type III is progressively replaced by collagen type I
• Fibril cross-linking increases tensile strength and enzymatic degradation resistance
• The wound becomes progressively avascular and acellular
• Tensile strength increases for months after collagen reaches its plateau level, but the scar never fully recovers the strength of uninjured tissue (maximum ~80% of normal)

Summary Table

Key Factors That Impair Healing

• Hypoxia / poor blood supply
• Infection
• Nutritional deficiencies (especially vitamin C, zinc, protein)
• Diabetes mellitus
• Corticosteroids
• Excess wound tension
• Age
• Schwartz's Principles of Surgery, 11th Edition, Chapter 9