Tissue Repair and Wound Healing

Regeneration & Cell Cycle - Repair Kickstart

• Regeneration: Ideal outcome; restores normal tissue. Requires intact Extracellular Matrix (ECM) & proliferative cells.
• Repair: Connective tissue deposition (scarring/fibrosis). Occurs if ECM is damaged or cells are permanent.
• Cell Types by Proliferative Capacity:
  • Labile: Continuously dividing (e.g., epithelia, hematopoietic cells).
  • Stable: Quiescent (G0), can divide if stimulated (e.g., hepatocytes, fibroblasts).

    ⭐ Liver shows remarkable regeneration; quiescent hepatocytes (stable cells) proliferate post-hepatectomy.

  • Permanent: Terminally differentiated, minimal regeneration (e.g., neurons, cardiac muscle).
• Cell Cycle: G0 (quiescence) → G1 → S (DNA synthesis) → G2 → M (mitosis). Progression driven by cyclins & CDKs. ​

ECM & Growth Factors - Matrix & Movers

• Extracellular Matrix (ECM): Provides scaffold & signals.
  • Collagens: Type III (early granulation), replaced by Type I (tensile strength).
  • Elastin: Elasticity.
  • Proteoglycans & Hyaluronan: Hydration, resilience, cell migration.
  • Adhesion Glycoproteins: Fibronectin (scaffold, chemotaxis), Laminin (basement membrane), Integrins (cell-ECM linkage).
• Key Growth Factors (GFs): Regulate cell proliferation, migration, differentiation.
  • PDGF: Recruits macrophages, fibroblasts, smooth muscle cells.
  • FGFs (esp. FGF-2): Angiogenesis, fibroblast proliferation, ECM protein synthesis.
  • TGF-β: Key fibrogenic agent; stimulates collagen/fibronectin synthesis, inhibits MMPs.
  • VEGF: Angiogenesis, ↑ vascular permeability.
  • EGF/TGF-α: Stimulate keratinocyte & fibroblast proliferation.

⭐ TGF-β is a potent fibrogenic agent, stimulating fibroblast chemotaxis, collagen synthesis, and inhibiting MMPs, but also has anti-inflammatory effects in later stages of repair.

Phases of Wound Healing - The Healing Timeline

• 1. Inflammatory Phase (0-3 days): Initial response.
  • Hemostasis (Immediate): Vasoconstriction, platelet plug, coagulation cascade → fibrin clot. Stops bleeding.
  • Inflammation:
    • Neutrophils (PMNs): Peak 24-48 hrs. Phagocytose debris, bacteria.
    • Macrophages (M1): By 48-96 hrs. Phagocytosis, release growth factors (TGF-β, PDGF, VEGF). Orchestrate repair.
• 2. Proliferative Phase (Day 3 - Weeks): Filling wound defect.
  • Granulation Tissue: Hallmark. Pink, soft. Consists of:
    • Fibroblasts: Synthesize Type III collagen, ECM.
    • Angiogenesis: New capillaries (VEGF, FGF-2).

  ⭐ Granulation tissue, hallmark of the proliferative phase, is characterized by angiogenesis (new blood vessels) and fibroblast proliferation, appearing pink and soft.

  • Re-epithelialization: Keratinocyte migration & proliferation.
  • Wound Contraction: Myofibroblasts reduce defect size.
• 3. Remodeling Phase (Maturation) (Weeks - Months/Years): Scar development.
  • Collagen Remodeling: Type III collagen → Type I. Fibers organize & cross-link.
  • Tensile Strength: ↑ progressively. ~20% at 3 wks, max ~70-80% of original.
  • Scar Maturation: Becomes paler, flatter, avascular.

Healing Intentions & Complications - Smooth or Scarred

• Primary Intention: Clean, sutured wounds; minimal tissue loss. Rapid healing, small scar.
• Secondary Intention: Large defects, infected wounds. More inflammation, granulation, contraction; larger scar. (e.g., ulcers, burns)

Factors Impairing Healing:

• Systemic: ↓Nutrition (Protein, Vit C, Zinc), Diabetes, ↓Circulation, Glucocorticoids.
• Local: Infection (commonest delay), mechanical stress, foreign bodies, ↓perfusion.

Complications:

• Deficient Scar:
  • Wound dehiscence (rupture)
  • Ulceration
• Excessive Scar Formation:
  • Hypertrophic Scar: Raised, within wound borders; may regress. Type III collagen.
  • Keloid: Extends beyond borders; rarely regresses, recurs. Disorganized Type I & III. 📌 African descent.

  ⭐ Keloids are composed predominantly of disorganized Type I and III collagen, extend beyond the original wound borders, do not regress, and often recur after excision.

• Contractures: Exaggerated contraction; causes deformities, limits movement (e.g., severe burns).

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High‑Yield Points - ⚡ Biggest Takeaways

• Wound healing phases: Inflammation, Proliferation (granulation tissue), and Remodeling (collagen maturation, scar formation).
• Macrophages are key, releasing growth factors (TGF-β, PDGF, VEGF) that orchestrate repair processes.
• Granulation tissue is characterized by fibroblasts, new capillaries (angiogenesis), and inflammatory cells.
• Collagen transition: Type III collagen (early, weak) is replaced by Type I collagen (late, strong).
• Secondary intention healing: More granulation, significant wound contraction (myofibroblasts), and larger scars.
• Keloids involve excessive collagen beyond wound borders; Vitamin C is crucial for collagen synthesis.