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Tissue Repair

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Tissue Repair

  • Regeneration
    • Proliferation of residual cells
    • Development of mature cells form stem cells
    • Intact basement membrane, intact immature cells, and connective tissue
  • Healing with scar formation
    • Damaged scaffold
  • Pure repair with scar formation
    • Permanent tissue
    • No regenerative abilities

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Cell Types

  • Labile-continuously dividing
  • Stable-have ability to re-enter cell cycle
  • Permanent-nondividing

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Growth Factors

  • Ligands that bind to specific receptors and signal transcription of genes that control cell cycle entry and progression

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  • PDGF: migration and proliferation of fibroblasts
  • VEGF: angiogenesis
  • FGF-2: re-epithelization of skin wounds
  • TGF-beta: fibroblast chemotaxis; production of collagen, fibronectin, and proteoglycans

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Repair by Connective Tissue Deposition

  • Inflammation
  • Angiogenesis
  • Migration and proliferation of fibroblasts
  • Scar formation
  • Connective tissue remodeling
  • Prototype – skin
  • Most healing is combination of regeneration and repair; depends on ability of tissue cells to proliferate, integrity of ECM, resolution or chronicity of injury or inflammation

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Granulation Tissue

  • Endothelial cells grown extensions to wound site
  • VEGF increases permeability of existing vessel→pericytes separate and basement membrane breaks down→endothelial cells migrate→mature vessel
  • VEGF-A (stimulates survival and proliferation of endothelial cells) and FGF-2 (proliferation of endothelial cells)

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Connective Tissue Deposition

  • Migration and proliferation of fibroblasts
  • Deposition of ECM proteins
  • PDGF, FGF-2, and TFG-beta
  • Macrophages control fibroblasts
    • Chemokines-migration
    • Growth factors-proliferation
  • Fibroblast
    • Type III collagen and fibronectin

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Extracellular Matrix

  • Control cell growth
  • Scaffold for tissue renewal
  • Establishment of tissue microenvironment
  • Interstitial matrix and basement membrane

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  • Structural Glycoproteins
    • Fibronectin-cross linking
    • Osteonectin-tissue remodeling
    • Tenacin-cell adhesion
    • Laminin-basement membrane
    • Cadherins and integrins-link cell surface and cytoskeleton
  • Proteoglycans and GAGs
    • GAGs-connective tissue structure and permeability

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Stages of Wound Healing

  • Phase 1 (Inflammation)
    • Immediate (2-5 days)
    • Blood clot
    • Vasodilation, phagocytosis
    • Neutrophils then macrophages

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  • Phase 2 (Proliferation)
    • 2 days to 3 weeks
    • Fibroblasts-lay down collagen
    • Angiogenesis-supply regeneration process
  • Phase 3 (Maturation)
    • Type III replaced by type I collagen
    • Scar tissue becomes avascular and acellular
    • Wound contraction (myofibroblasts)

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Healing by First/Second Intention

  • Healing by First Intention
    • Wounds with opposed edges
    • Healing of surgical incision
  • Healing by Second Intention
    • Wounds with unopposed/separate edges
    • More extensive loss of cells and tissue
    • Granulation tissue grows at edges to complete the repair

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Connective Tissue Remodeling

  • Granulation tissue replaced by scar
  • Degradation of collagen and other ECM proteins via MMPs

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Deterrents to Wound Healing

  • Local infection
  • Hypoxia
  • Trauma
  • Foreign bodies
  • Diabetes
  • Malnutrition
  • Immunodeficiency
  • Medications
  • Hormones
  • Mechanics
  • Size, location, type of wound

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Complications

  • Wound dehiscence
  • Ulceration
  • Excessive scar formation:
    • Keloid-disorganized collagen formation
    • Hypertrophic scar-raised, parallel collagen formation, confined to borders of original
  • Contractures

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  • Injury activates coagulation pathway and blood clot forms on wound surface
  • VEGF increases vessel permeability and edema
  • Neutrophils appear within 24 hours, clean out debris and bacteria
  • Neutrophils replaced by macrophages by 48 - 96 hours which clear debris, fibrin, foreign material and promote angiogenesis, ECM deposition
  • Fibroblast migration to injury site mediated by cytokines, TNF, PDGF, TGF-beta, and FGF
  • Fibroblast proliferation triggered by growth factors – macrophages main source
  • 24 to 48 hours - epithelial cells move from wound edge along cut margins of dermis, deposit basement membrane components; produce thin, continuous epithelial layer
  • Increase in collagen fibrils to bridge incision
  • Fibroblasts, vascular endothelial cells proliferate to form granulation tissue by 5 to 7 days, fills wound, neovascularization maximal
  • WBCs infiltrate, edema, increased vascularity disappear by second week
  • TGF-beta is most important fibrogenic agent: causes fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased ECM degradation by MMPs
  • Increased collagen accumulation and regression of vascular channels – original granulation tissue scaffold converted to pale, avascular scar made up of fibroblasts, dense collagen, elastic tissue, other ECM components
  • By end of first/second month – scar is composed of acellular connective tissue without inflammation, covered by intact epithelium

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