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