Download - Biology of Wound Healing
Biology of Wound Healing
Stages of Wound Healing Hemostasis Inflammation Proliferation/Granulation Remodeling/Maturation
Wound Healing is a continuous, dynamic process with distinct & overlapping phases
4 Stages of Wound Healing
Stages of Wound Healing
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
InflammationVisible Changes Cells ECM components Key Mediators
ErythemaHeatSwellingPain
PlateletsMast CellsNeutrophilsMacrophagesT Lymphocytes
Provisional fibrin matrix
PDGFTGF-βTNF-αIL-1IL-6IL-8Interleukin-γ
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
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
ProliferationVisible Changes Cells ECM
ComponentsKey Mediators
Eschar sloughingNew epidermisGranulation Tissue
FibroblastsEndothelial CellsKeratinocytesMyofibroblastsMacrophages
Provisional ECMCollagenElastinFibronectinGAGProteoglycans
IntegrinsPDGFFGFVEGFTGF-βIL-10EGFIGF
Proliferation Re-epithelialization Angiogenesis Collagen deposition Growth factor production Contraction
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
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
Cells Involved in Wound Healing Endothelial cells Platelets Neutrophils Monocytes Macrophages Mast Cells Lymphocytes Fibroblasts Keratinocytes
Cells Involved in Wound Healing
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
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
Neutrophils Phagocytic Fight bacteria Enhance antibiotic function Scavenge for bacteria and foreign debris
Monocytes Important phagocytic cell that plays key role in wound
healing Differentiates into macrophages
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
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.
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
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
Keratinocytes Stimulate fibroblasts to synthesize growth factors Main cells responsible for the epithelialization phase –
reepithelialization Predominant cell type in the epidermis Epidermal maturation
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)
Growth FactorsGrowth 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
Growth FactorsGrowth 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
Growth FactorsGrowth 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
Growth FactorsGrowth 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
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
Abnormal Wound HealingMolecular 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
Correcting Molecular & Cellular AbnormalitiesClinical Observation Abnormalities Clinical Actions
Infection or Inflammation Increased levels of cytokines & proteasesDecreased Growth Factor Activity
Antimicrobials (topical or systemic)Anti-inflammatoriesProtease inhibitors
Moisture Imbalance Decreased keratinocyte cell migrationWound Maceration
Moisture-balancing dressings, other methods to remove fluid
Edge Margin non-achieving Nonresponsive wound cellsAltered protease activity
Corrective advanced therapies