Wound Healing

MS Orthopaedics - 20 Marks

Introduction

Classification of Wounds

• Incised wounds - clean edges, heal by primary intention
• Lacerated wounds - ragged edges, higher infection risk
• Crush injuries - devitalized tissue, poor vascularity
• Avulsion injuries - loss of tissue

• Superficial (epidermis only)
• Partial thickness (epidermis + superficial dermis)
• Full thickness (through all skin layers)

Types of Wound Healing

1. Primary Intention (Primary Union / First Intention)

• Wound edges are approximated by sutures, staples, or glue
• Minimal tissue loss, minimal scar
• Rapid epithelialization (<48 hours for incised wounds)
• Minimal granulation tissue formation
• Example: surgical incisions, clean lacerations repaired promptly

2. Secondary Intention (Secondary Union)

• Wound edges are NOT approximated; allowed to heal by granulation
• Occurs in large, infected, or contaminated wounds
• Extensive granulation tissue, wound contraction, and more scarring
• Prolonged healing time
• Example: open fracture wounds, pressure sores, abscess cavities

3. Tertiary Intention (Delayed Primary Closure)

• Wound is initially left open (due to contamination or infection)
• Closed surgically 4-5 days later after control of infection
• Intermediate scar formation
• Example: contaminated traumatic wounds, open fractures

Phases of Wound Healing

Phase 1: Hemostasis (Minutes to Hours)

• Platelet activation: Exposed subendothelial collagen triggers platelet aggregation and degranulation
• Coagulation cascade activation: Formation of fibrin clot
• Release of wound-active substances from platelet alpha granules:
  • Platelet-Derived Growth Factor (PDGF)
  • Transforming Growth Factor-beta (TGF-β)
  • Platelet-Activating Factor (PAF)
  • Fibronectin
  • Serotonin

Phase 2: Inflammation (Days 1-4)

Neutrophils (PMNs) - Days 1 to 2 (peak 24-48 hours)

• First cells to arrive at the wound
• Attracted by: complement factors, IL-1, TNF-α, TGF-β, platelet factor 4, bacterial products
• Primary role: phagocytosis of bacteria and tissue debris
• Release proteases (collagenases) for matrix debridement
• Release TNF-α which influences angiogenesis and collagen synthesis
• Important: neutrophils are NOT essential for collagen deposition or wound strength; their factors may actually delay epithelial closure

Macrophages - Days 2 to 4 (peak 48-96 hours)

• Derived from circulating monocytes - essential to successful healing
• Persist until wound healing is complete
• Functions:
  • Phagocytosis and debridement
  • Oxygen radical and nitric oxide synthesis (microbial stasis)
  • Activation and recruitment of other cells via cytokines/growth factors
  • Release TGF-β, VEGF, IGF, EGF, lactate
  • Regulate cell proliferation, matrix synthesis, angiogenesis
• Macrophage depletion leads to severely impaired wound healing

T Lymphocytes - Days 5 to 7

• Arrive after macrophages
• Modulate fibroblast proliferation
• Regulate matrix synthesis through cytokine release
• Bridge inflammation and proliferation phases

Phase 3: Proliferation (Days 4 to 21)

Fibroplasia (Fibroblast Activity)

• Fibroblasts are recruited from local connective tissue by PDGF, FGF, TGF-β
• Begin arriving at 48-72 hours; peak activity at day 5-7
• Fibroblasts are the principal source of extracellular matrix (ECM) proteins
• Produce collagen (initially Type III, later replaced by Type I), proteoglycans, fibronectin
• Fibroplasia produces granulation tissue: a highly vascularized tissue with loose collagen framework

Collagen Synthesis

• The main structural protein of healed wounds
• Type III collagen predominates initially (fetal type, more flexible)
• Gradually replaced by Type I collagen (stronger, less flexible) during remodeling
• Collagen synthesis requires: adequate oxygen, vitamin C (ascorbic acid for hydroxylation of proline/lysine), zinc, iron

Angiogenesis (Neovascularization)

• Stimulated by VEGF, FGF, low pO2, lactate, macrophage-derived factors
• New capillary buds grow into the wound, providing oxygen and nutrients
• Critical for granulation tissue formation

Granulation Tissue

• Characterized by new capillaries (appear as red granules on wound surface), fibroblasts, and loose collagen matrix
• Fills the wound defect; provides the scaffold for epithelialization

Myofibroblasts and Wound Contraction

• Fibroblasts differentiate into myofibroblasts (express alpha-smooth muscle actin)
• Responsible for wound contraction - reducing wound size
• Contraction is distinct from contracture (permanent shortening leading to deformity)
• Maximum contraction: days 5-15
• Clinically important: excessive contraction over joints causes contractures

Epithelialization

• Begins within 24 hours of injury at wound edges
• Marginal basal cells lose dermal attachment, enlarge, and migrate across provisional matrix
• Fixed basal cells undergo rapid mitotic divisions - cells migrate in "leapfrog" fashion
• Stimulated by: EGF, TGF-β, bFGF, PDGF, IGF-1, fibronectin
• Reepithelialization complete in <48 hours for approximated wounds

Phase 4: Maturation and Remodeling (Days 21 to Months-Years)

• Begins at ~day 21 and continues for months to years (up to 2 years)
• Hallmark: replacement of Type III collagen by Type I collagen
• This is mediated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs)
• TGF-β increases new collagen transcription AND decreases collagen breakdown
• Collagen fibers reorient along lines of stress (from random to parallel arrangement)
• Wound tensile strength increases progressively:
  • Day 7: ~10% of original strength
  • Day 21: ~20%
  • 3 months: ~55%
  • Final strength: ~70-80% of original tissue (never reaches 100%)
• Wound vascularity decreases, granulation tissue matures into scar tissue

Growth Factors in Wound Healing

Healing in Specific Tissues (Orthopaedic Relevance)

Bone Healing

1. Hematoma formation (0-3 days): fracture site bleeds, clot forms
2. Inflammatory phase (1-7 days): cytokines attract osteoprogenitor cells
3. Soft callus (1-3 weeks): fibroblasts and chondrocytes produce fibrocartilaginous callus
4. Hard callus (3-12 weeks): osteoblasts replace cartilaginous callus with woven bone
5. Remodeling (months-years): woven bone replaced by lamellar bone along lines of stress (Wolff's law)

Tendon Healing

• Intrinsic healing (from tenocytes within the tendon itself) - produces stronger repair
• Extrinsic healing (from surrounding paratenon/peritenon) - produces adhesions
• Three phases: inflammation (0-5 days), proliferation (5 days to 6 weeks), remodeling (6 weeks+)
• Full tensile strength takes 6-12 months

Cartilage Healing

• Poor intrinsic healing capacity due to avascularity
• Hyaline cartilage does NOT regenerate; replaced by fibrocartilage
• Full thickness defects reaching subchondral bone may partially heal via marrow elements

Nerve Healing

• Wallerian degeneration occurs distal to injury
• Regeneration rate: 1 mm/day (proximal progressing distally)
• Classified by Seddon (neurapraxia, axonotmesis, neurotmesis) and Sunderland

Factors Affecting Wound Healing

Local Factors

Systemic Factors

Abnormal (Pathological) Wound Healing

Hypertrophic Scar

• Excessive collagen deposition WITHIN wound boundaries
• Raised, red, pruritic scar
• Regresses spontaneously over months to years
• Treatment: pressure garments, silicone gel, intralesional steroids

Keloid

• Collagen deposition EXTENDS BEYOND original wound margins ("finger-like" projections)
• Does NOT regress spontaneously
• More common in darker skin types (African descent)
• Common sites: face, earlobes, deltoid, presternal region
• More resistant to treatment
• Treatment: repeated excision + adjuvant radiotherapy, intralesional steroids, compression
• Key difference from hypertrophic scar: extends beyond wound margins, does not regress

Wound Dehiscence

• Separation of wound edges, typically at 5-10 days
• Causes: infection, poor nutritional status, obesity, technical failure, excessive tension
• Management: reclose surgically (if clean) or allow healing by secondary intention

Chronic Non-Healing Wounds

• Failure to proceed through normal healing sequence
• Stuck in prolonged inflammatory phase
• Causes: diabetes, peripheral vascular disease, pressure, infection, biofilm
• Examples: diabetic foot ulcers, venous ulcers, pressure sores

Contracture

• Excessive wound contraction causing functional disability
• Particularly problematic over joints in burns
• Prevention: early skin grafting, splinting, physiotherapy

Summary Table: Key Events and Timeline

Wound Management Principles

1. Control hemorrhage - direct pressure, tourniquet if needed
2. Irrigation - copious saline lavage reduces bacterial load
3. Debridement - remove devitalized tissue (biological, surgical, or chemical)
4. Dead space elimination - layered closure
5. Appropriate dressing:
   • Maintain moist wound environment (increases epithelialization by 50%)
   • Absorb exudate, protect from infection
6. Nutritional optimization - protein, vitamins A & C, zinc supplementation
7. Control infection - antibiotics when indicated, wound cultures
8. Negative Pressure Wound Therapy (NPWT/VAC): promotes granulation, reduces edema
9. Hyperbaric oxygen - for refractory wounds, particularly in diabetics

Conclusion

• Schwartz's Principles of Surgery, 11th ed., Chapter 9 - Wound Healing
• Bailey and Love's Short Practice of Surgery, 28th ed.
• Sabiston Textbook of Surgery - The Biological Basis of Modern Surgical Practice
• Robbins & Cotran Pathologic Basis of Disease