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Wound Healing

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Overview

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Types of Wound Healing

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Phases of Wound Healing

Phase 1 - Hemostasis and Inflammation (Day 0-4)

• Platelet plug formation (primary hemostasis)
• Fibrin clot formation (secondary hemostasis)

1. Neutrophils (arrive first, 0-2 days): Recruited by complement activation and CXC chemokines released by platelets and keratinocytes. They phagocytose bacteria, debris, and foreign material via oxidative burst (reactive oxygen species). They are not essential for healing in clean wounds.
2. Monocytes/Macrophages (peak at 48-96 hours): The most critical cell in wound healing. They:
   • Continue debridement (phagocytosis)
   • Release cytokines: IL-1, IL-6, TNF-α
   • Release growth factors: VEGF, TGF-β, PDGF, FGF
   • Orchestrate the transition to proliferation
   • Wounds depleted of macrophages heal poorly
3. Lymphocytes (later, day 5-7): T-lymphocytes modulate fibroblast activity; their exact role in wound healing is still being clarified.

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Phase 2 - Proliferation (Day 4-21)

• Fibroblasts migrate into the fibrin clot guided by fibronectin and growth factors
• They proliferate and synthesize collagen (initially type III, later replaced by type I)
• Fibroblasts also produce fibronectin, hyaluronic acid, proteoglycans

• New capillaries sprout from existing vessels - driven by VEGF, FGF-2, PDGF, TGF-β
• Macrophages are the major early source of VEGF
• Hypoxia at the wound core drives further VEGF upregulation
• The combination of new vessels + fibroblasts + matrix = granulation tissue (red, friable, bleeds easily)

• Mediated by myofibroblasts - fibroblasts that acquire smooth muscle characteristics (express α-SMA)
• They pull wound edges together, reducing wound area
• Driven by TGF-β1 and mechanical tension
• Can be excessive in body cavities or joints causing contractures

• Keratinocytes at the wound margin begin migrating across the wound surface within hours of injury
• They dissolve the fibrin clot ahead of them (using plasminogen activator and matrix metalloproteinases)
• Epithelialization rate increases 50% in a moist wound environment vs. dry
• Once wound edges meet, keratinocytes stop migrating (contact inhibition) and resume differentiation
• Re-epithelialization restores the epidermal barrier but does not restore full skin appendages (hair follicles, glands)

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Phase 3 - Matrix Synthesis (Day 7 onward)

• Collagen synthesis is maximal during this phase
• Initial collagen is type III (fetal-type, fine, loosely organized)
• Collagen synthesis requires vitamin C (ascorbate) as a cofactor for prolyl and lysyl hydroxylase - deficiency (scurvy) leads to wound dehiscence
• Zinc is required as a cofactor for collagenase
• Collagen cross-linking is mediated by lysyl oxidase (requires copper)

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Phase 4 - Maturation and Remodeling (Day 21 - up to 2 years)

• Type III collagen is progressively replaced by type I collagen (stronger, larger fibers)
• Matrix metalloproteinases (MMPs) degrade old matrix; balance with TIMPs (tissue inhibitors of MMPs)
• Tensile strength increases but never returns to 100% - maximum ~80% of original tensile strength is achieved at ~3 months
• Wound vascularity decreases (granulation tissue regresses)
• Myofibroblasts undergo apoptosis

• Week 1: ~3% of original
• Week 3: ~30%
• Month 3: ~80%
• Final maximum: ~80%

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Growth Factors in Wound Healing

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Factors Affecting Wound Healing

Local Factors

Systemic Factors

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Wound Complications - Abnormal Scarring

Hypertrophic Scars

• Excess collagen deposition within the original wound boundaries
• Raised, red, firm
• More common after burns, wounds crossing skin tension lines
• May regress spontaneously over months/years
• Treatment: topical silicone, intralesional corticosteroids, compression therapy, surgical excision

Keloid Scars

• Collagen overgrowth extending beyond the original wound margins
• More common in darker skin types (Fitzpatrick types IV-VI)
• Common sites: face, earlobes, deltoid, presternal region
• Do not regress spontaneously; may be locally destructive
• More resistant to treatment; often requires excision + adjuvant radiotherapy or intralesional steroids

Chronic Wounds

• Wounds failing to progress through normal healing phases (typically >3 months)
• Common types: diabetic foot ulcers, venous leg ulcers, pressure injuries, arterial ulcers
• Characterized by persistent inflammation, proteolytic imbalance (excess MMPs), senescent fibroblasts, bacterial biofilm
• Management: debridement, infection control, moisture balance, offloading, advanced dressings, growth factors, negative pressure wound therapy

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Healing in Specific Tissues

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Wound Classification

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Treatment Principles

• Debridement: Remove necrotic tissue (surgical, enzymatic, autolytic, biosurgical)
• Infection control: Topical antiseptics, systemic antibiotics when indicated; biofilm disruption
• Moisture balance: Moist environment accelerates epithelialization by 50%; occlusive/semi-occlusive dressings
• Negative pressure wound therapy (NPWT): Removes exudate, reduces edema, promotes granulation
• Skin substitutes/bioengineered products: Acellular dermal matrices, cultured keratinocytes for chronic wounds
• Hyperbaric oxygen: Increases tissue pO2; useful in diabetic foot ulcers, radiation injuries
• Growth factor therapy: Becaplermin (recombinant PDGF) FDA-approved for diabetic neuropathic ulcers

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• Schwartz's Principles of Surgery, 11th ed., Chapter on Wound Healing, pp. 271-297
• Bailey and Love's Short Practice of Surgery, 28th ed., pp. 699-710
• Fitzpatrick's Dermatology, 9th ed., p. 157