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Biology of Wound Healing

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Biology of Wound Healing

  1. 1. Biology of Wound Healing
  2. 2. Stages of Wound Healing  Hemostasis  Inflammation  Proliferation/Granulation  Remodeling/Maturation Wound Healing is a continuous, dynamic process with distinct & overlapping phases
  3. 3. 4 Stages of Wound Healing
  4. 4. Stages of Wound Healing
  5. 5. Inflammation  Normal and essential response to injury  Begins immediately, last 2-7 days  Goal is to provide hemostasis & clear away bacteria, foreign material and dead tissues
  6. 6. Inflammation Visible Changes Cells ECM components Key Mediators Erythema Heat Swelling Pain Platelets Mast Cells Neutrophils Macrophages T Lymphocytes Provisional fibrin matrix PDGF TGF-β TNF-α IL-1 IL-6 IL-8 Interleukin-γ
  7. 7. Inflammation  Hemostasis - platelet function  Vasodilation - meet metabolic demands  Mast cells - histamine response  Neutrophils –  Phagocytic  Fight bacteria  Enhance antibiotic function  Macrophages –  Phagocytic  Stimulates fibroblast activity for proliferative phase
  8. 8. Proliferation  Stimulated by inflammatory phase  Overlaps with inflammatory phase  Time to completion is partly dependent upon amount of tissue lost  Goal is to replace lost dermal tissue with scar tissue
  9. 9. Proliferation Visible Changes Cells ECM Components Key Mediators Eschar sloughing New epidermis Granulation Tissue Fibroblasts Endothelial Cells Keratinocytes Myofibroblasts Macrophages Provisional ECM Collagen Elastin Fibronectin GAG Proteoglycans Integrins PDGF FGF VEGF TGF-β IL-10 EGF IGF
  10. 10. Proliferation  Re-epithelialization  Angiogenesis  Collagen deposition  Growth factor production  Contraction
  11. 11. Proliferation  Fibroplasia - fibroblast synthesis for granulation tissue  Endothelial budding - vessels from surrounding tissue migrate to supply nutrients  Collagen matrix of collagen, hyaluronic acid and fibronectin and elastin formation  Myofibroblasts - wound contraction at margins
  12. 12. Remodeling/Maturation  Remodeling of the Extracellular Matrix (ECM)  Epithelial cell migration  Collagen lysis and collagen synthesis balance  Collagen aligns to applied stress - ROM and positioning  Scar formation and remodeling  Lasts 6 months to 2 years  Tensile strength of wound will not exceed 70-80% of the original skin
  13. 13. Cells Involved in Wound Healing  Endothelial cells  Platelets  Neutrophils  Monocytes  Macrophages  Mast Cells  Lymphocytes  Fibroblasts  Keratinocytes
  14. 14. Cells Involved in Wound Healing
  15. 15. Endothelial Cells  Produce Thromboxane A2 and prostaglandin 2-alpha upon injury  Potent vasoconstrictors  Helps to limit hemorrhage/bleeding  Angiogenesis -physiological process through which new blood vessels form from pre-existing vessels  Apoptosis (programmed cell death)  Scar maturation
  16. 16. Platelets  Major constituent of clot/Fibrin clot formation  release platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-b) from their alpha granules to attract neutrophils and macrophages
  17. 17. Neutrophils  Phagocytic  Fight bacteria  Enhance antibiotic function  Scavenge for bacteria and foreign debris
  18. 18. Monocytes  Important phagocytic cell that plays key role in wound healing  Differentiates into macrophages
  19. 19. Macrophages  Phagocytic  Stimulates fibroblast activity for proliferative phase  Macrophages are the most important mediators of wound healing  Macrophages emit growth factors to attract fibroblasts - chemotaxis  Essential for the initiation and maintenance of fibroblast activity
  20. 20. Mast Cells  Histamine response  Respond to tissue injury by releasing inflammatory mediators  Mast cells are known to participate in three phases of wound healing:  Inflammatory reaction  Angiogenesis  Extracellular-matrix reabsorption.
  21. 21. Lymphocytes  Contribute to the immunologic response to foreign debris  Possess the capacity to regulate essential steps wound healing process  Exert many of its effects via cytokines  Capable of modulating fibroblast functions to include:  Migration  Replication  Collagen synthesis
  22. 22. Fibroblasts  Initiate  Angiogenesis  Epithelialization  Collagen formation  Fibroblasts differentiate into myofibroblasts, causing tissue contraction during remodeling/maturation phase  Lay fibrin strands to act as a framework for cellular migration
  23. 23. Keratinocytes  Stimulate fibroblasts to synthesize growth factors  Main cells responsible for the epithelialization phase – reepithelialization  Predominant cell type in the epidermis  Epidermal maturation
  24. 24. Growth Factors (aka Cytokines) • Platelet Derived Growth Factor (PDGF) • Transforming Growth Factor (TGF-β, TGF-α, & others) • Epidermal Growth Factor (EGF) • Hepatocyte Growth Factor (HGF)
  25. 25. Growth Factors Growth factor Abbreviation Main origins Effects Epidermal Growth Factor EGF • Activated macrophages • Salivary glands • Keratinocytes • Platelets • Keratinocyte and fibroblast mitogen • Keratinocyte migration • Granulation tissue formation Transforming growth factor-α TGF-α • Activated macrophages • T-lymphocytes • Keratinocytes • Platelets • Hepatocyte and epithelial cell proliferation • Expression of antimicrobial peptides • Expression of chemotactic cytokines
  26. 26. Growth Factors Growth factor Abbreviation Main origins Effects Hepatocyte Growth Factor HGF • Mesenchymal Cells • Epithelial and endothelial cell proliferation • Hepatocyte motility Vascular endothelial growth factor VEGF • Mesenchymal cells • Endothelial cells • Vascular permeability • Endothelial cell proliferation • Promote angiogenesis during tissue hypoxia
  27. 27. Growth Factors Growth factor Abbreviation Main origins Effects Platelet derived growth factor PDGF •Platelets •Macrophages •Endothelial cells •Smooth muscle cells •Keratinocytes • Granulocyte, macrophage, fibroblast and smooth muscle cell chemotaxis • Granulocyte, macrophage and fibroblast activation • Fibroblast, endothelial cell and smooth muscle cell proliferation • Matrix metalloproteinase, fibronectin and hyaluronan production • Angiogenesis • Wound remodeling • Integrin expression regulation
  28. 28. Growth Factors Growth factor Abbreviation Main origins Effects Transforming growth factor-β TGF-β • Platelets • T-lymphocytes • Macrophages • Endothelial cells • Keratinocytes • Smooth muscle cells • Fibroblasts • Granulocyte, macrophage, lymphocyte, fibroblast and smooth muscle cell chemotaxis • TIMP synthesis • Angiogenesis • Fibroplasia • Matrix metalloproteinase production inhibition • Keratinocyte proliferation
  29. 29. Factors influencing wound healing  Oxygenation  Infection  Diseases  Medications  Stress  Obesity  Smoking  Alcohol consumption  Age  Chronic disease  Immunosuppression  Sensory impairment  Presence of foreign body  Tissue perfusion  Malnutrition  Nutrition  Chemotherapy  Radiation Rx  Trauma  Infection or microbial overload
  30. 30. Abnormal Wound Healing Molecular Environment Chronic Wounds Healing Wounds ECM Damaged Functional Inflammatory Cytokines High Low Protease Activity Increased Low Reactive Oxygen Species Increased Low Mitogenic Activity Low High Cell Competence Senescent Mitotically competent
  31. 31. Correcting Molecular & Cellular Abnormalities Clinical Observation Abnormalities Clinical Actions Infection or Inflammation Increased levels of cytokines & proteases Decreased Growth Factor Activity Antimicrobials (topical or systemic) Anti-inflammatories Protease inhibitors Moisture Imbalance Decreased keratinocyte cell migration Wound Maceration Moisture-balancing dressings, other methods to remove fluid Edge Margin non-achieving Nonresponsive wound cells Altered protease activity Corrective advanced therapies

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