Repair and Wound Healing.pdf

Wound Healing and Repair Dr. Karen Gil Wound Healing • Regeneration and repair of damaged cells and tissues • Starts almost as soon as the inflammatory process begins • Involves two separate processes: 1. Regeneration of the damaged tissue cells of the same type 2. Tissue repair with replacement b...

Wound Healing and Repair Dr. Karen Gil Wound Healing • Regeneration and repair of damaged cells and tissues • Starts almost as soon as the inflammatory process begins • Involves two separate processes: 1. Regeneration of the damaged tissue cells of the same type 2. Tissue repair with replacement by connective tissue (scar) Regeneration • Different tissues have different regenerative capacities A. Labile cells 1. Regenerate throughout life 2. Examples: surface epithelial cells (skin, cornea, mucosal lining cells), hematopoietic cells, stem cells, etc. Regeneration B. Stable cells 1. Replicate at a low level throughout life 2. Have the capacity to divide if stimulated by some initiating event 3. Examples: hepatocytes, proximal tubule cells, endothelum, etc. C. Permanent cells 1. Cannot replicate 2. Examples: neurons and cardiac muscle Regulation of cell population Cell numbers can be altered by: •increased or decreased rates of cell death (apoptosis) •or by changes in the rates of proliferation or differentiation The Cell Cycle • Stages of the cell cycle: – G1 (presynthetic) and S (synthetic) – stages generally constitute the majority of the time of the cell cycle – M (mitotic) – typically brief • Some cell populations continuously cycle and proliferate most cells in the body are quiescent and are in stages G0 Soluble Mediators •Cell growth and differentiation are dependent on extracellular signals derived from soluble mediators and extracellular matrix • Extracellular signaling occur via soluble mediator in four different forms •Autocrine •Paracrine •Synaptic •Endocrine Cell growth and differentiation are central to repair of tissue damage • Migration and proliferation of fibroblasts • Deposition of extracellular matrix • Angiogenesis or neovascularization • Remodeling Extracellular matrix ( two basic forms) 1. Interstitial matrix 2. Basement membrane Function• Mechanical support • Polarity • Control of cell growth • Maintenance of cell differentiation • Microenvironment (barrier) Components of Extracellular Matrix • Basic components: Collagen – 1. • • • • • 2. fibrous structural proteins conferring tensile strength Type I is the most common in skin, bone, tendons and most organs Type II cartilage and vitreous humor Type III granulation tissue, uterus, keloids Type IV basement membranes Elastin fibers– • • • conferred tissues the ability to recoil and return to a baseline structure after physical stress Are aligned on a fibrillin framework Defect in fibrilllin- Marfan Syndrome Components of Extracellular Matrix 3. Adhesion Molecules- (glycoproteins) • • • Fibronectin Laminin Integrins 4. Proteoglycans and glycosaminoglycans • • Heparan sulfate Chondroitin sulfate Tissue Repair • Replacement of a damaged area by a connective tissue scar • Tissue repair is mediated by various growth factors and cytokines 1. 2. 3. 4. 5. 6. Transforming growth factor (TGF-ß) Platelet derived growth factor (PDGF) Fibroblast growth factor (FGF) Vascular endothelial growth factor (VEGF) Epidermal growth factor (EDF) Tumor necrosis factor (TNF- α) Tissue Repair • Begins as early as 24 hrs after injury • Granulation tissue (FIROSIS OR SCAR) – 3 to 5th day – hallmark of healing • Characteristic feature is proliferation of blood vessels (ANGIOGENESIS O NEOVASCULARIZATION) • Wound contraction is mediated by myofiroblasts • Scar formation Granulation tissue A. Numerous blood vessels, edema and a loose ECM containing inflammatory cells B. Trichrome statin of mature scar (dense collagen stains blue) ANGIOGENESIS • Growth factors that induce angiogenesis: – EGF (endothelial growth factor) – FGF (fibroblast growth factor) – VEGF (vascular endothelial growth factor) • Steps in the process of angiogenesis: 1. Proteolytic degradation of basement membrane 2. Migration of endothelial precursor cells toward angiogenic stimuli 3. Endothelial proliferation (mitosis) 4. Maturation and organization into vessels Angiogenesis Endothelial precursor cells Primary union or healing by first intention • Occurs with clean wounds when there has been little tissue damage and the wound edges are closely approximated (e.g. surgical incision) • 24 hours – Neutrophils appear at margins – Epidermal thickening ( increased mitotic activity) • Day 3 – Granulation tissue – Collagen fibers present at margins but vertically oriented • Day 5 – All space filled by granulation tissue – Maximal neovascularization – Bridging collagen fibers (begin) – Normal epidermal thickness • Second week – Accumulation of collagen and proliferation of fibroblasts – Inflammatory infiltrate, edema and vascular leakage have largely disappeared • 1st month – Scar composed of cellular connective tissue – devoid of inflammatory cells covered by intact epidermis – Tensile strength increases Second union or healing by second intention • Occurs in wounds that have large tissue defects and when the two skin edges are not in contact • It requires larger amounts of granulation tissue to fill in the defect (e.g. infarction, extensive ulceration or surface wound with large defect) • Regeneration of parenchymal cells cannot completely reconstitute the original architecture (wound contraction or larger residual scars) Differences from 1st intention • More intense inflammatory reaction • Grater amount of granulation tissue formed • Wound contraction Factors That Retard Wound Healing Local Factors Blood supply Systemic Factors Mechanical stress Denervation Necrotic tissue Local infection Protection (dressings) Foreign body Surgical techniques Hematoma Type of tissue Age Malnutrition Anemia Obesity Drugs (steroids, cytotoxic medications, intensive antibiotic therapy) Systemic infection Temperature Diabetes Malignant diseases Trauma, hypovolemia Hypoxia Uremia Vitamin deficiency Trace metal deficiency Pathologic aspects that may interfere with repair: • Infection Single most important cause of delay in healing through prolongation of the inflammatory phase. • Nutrition Vit. C deficiency essential for collagen synthesis (Scurvy, bleeding gums) • Drug Glucocorticoids,Immunomodulatory agents • Aberrations in ECM production and collagen accumulation Keloid (predominates collagen type III) Fibroplasia keloid (proud flesh)