Wound Healing (student CO2026).pdf

Physiology of Wound Healing Holly Goode, MPAS, PA-C Pathophysiology – Fall 2024 1. Differentiate regeneration from repair by fibrosis. 2. Describe the 5 stages of the cell cycle and how disruption of the cycle can lead to disease with resultant pathology. 3. Defin...

Physiology of Wound Healing Holly Goode, MPAS, PA-C Pathophysiology – Fall 2024 1. Differentiate regeneration from repair by fibrosis. 2. Describe the 5 stages of the cell cycle and how disruption of the cycle can lead to disease with resultant pathology. 3. Define labile, stable and permanent cells and discuss the relevance of each cell type with respect to turnover, repair and recovery of tissue following injury. Describe the steps in wound healing and scar Learning Objectives 4. tissue formation, including the role of key chemical mediators and cell types. 5. Understand multiple factors and different cell types in the stages of wound healing. 6. Contrast healing by primary, secondary, and tertiary intention. 7. Understand factors that influence outcome of wound healing and repair. 8. Describe potential complications in wound healing.  INTRODUCTION ❑ Injury to a tissue may result in cell death and tissue destruction. ❑ A wound is a disruption of the anatomic structure and function in any part of the body. ❑ Healing, on the other hand, is a cell response to injury in an attempt to restore the normal structure and function.  TISSUE HEALING ❑ Involves 2 distinct processes ▪ Regeneration ▪ Repair (scar formation) ❑ Dynamic balance between these two processes, depending on tissue type Inflammation and Repair Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 3, 71-113 Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved.  REGENERATION ❑ Replacement of lost or damaged cells with cells of the same type ▪ proliferation of residual cells ▪ development of mature cells from stem cells ❑ Complete restoration of the structure and function of the tissue is possible ❑ Limited capacity in mammalian tissue/cells: Salamander ▪ Unique cells within bone marrow, epidermis, intestine, and liver ▪ Hepatocytes ▪ Epithelial stem cells PROLIFERATION/ REGENERATION CAPACITY ❑Determines the ability of cells to heal themselves ❑ 3 groups of tissue ▪ Labile ▪ Stable ▪ Permanent  CELL CYCLE ❑Cell proliferation – controlled by the cell cycle & stimulated by growth factors and interactions of cells with the ECM ▪ Physiologic cell proliferation = repair ▪ Pathologic cell proliferation = cancer ❑Non-dividing cells are either in the cell cycle arrest in G1 or they exit the cycle to enter a phase called G0  LABILE TISSUES ❑ Continuously dividing/ proliferating ▪ Readily regenerate as long as pool of stem cells available ❑ Mitosis (M) – phase of cell cycle ❑ Examples: ▪ Hematopoietic cells in the bone marrow and lymphoid organs ▪ Epithelia of the gut, skin, cornea, respiratory tract, reproductive tract, and urinary tract STABLE TISSUES ❑ Quiescent (dormant) cells ❑ Minimal proliferative activity in their normal state → limited capacity/potential to regenerate following stimulus/ injury ❑ G0 phase of cell cycle ❑ Examples: ▪ Parenchyma of most solid tissues, such as liver, kidney, and pancreas ▪ Endothelial cells, fibroblasts, and smooth muscle cells  PERMANENT TISSUES ❑Terminally differentiated and non-proliferative → repair is dominated by scar formation ❑ Cell cycle is complete ❑ Examples: ▪ Neurons ▪ Myocytes ▪ Cardiac cells ▪ Skeletal  REPAIR/ SCAR FORMATION ❑Replacement of injured cells with connective (fibrous) tissue ❑Forms a patch to immediately re-establish both a physical and physiologic continuity to the injured organ ❑ Key players: ▪ cell types ▪ growth factors ▪ cytokines ▪ matrix proteins CELL TYPES  Growth Factors & Cytokines ❑ Secreted by certain cells of the immune system and have an effect on other cells ❑ Essential in tissue repair ❑ Actions: ▪ Stimulate cell division (mitosis) ▪ Involved in (growth) control – can stimulate or inhibit ▪ Protection from apoptotic death (survival) ▪ Stimulate migration, differentiation, angiogenesis, contractility, and fibrogenesis  Growth Factor/Cytokine Cell of Origin Function Platelet Derived Growth Factor Platelets Cell chemotaxis PDGF Macrophages Mitogenic for fibroblasts Endothelial cells Stimulates angiogenesis Stimulates wound contraction Transforming Growth Factor-alpha Macrophages Mitogenic for keratinocytes and TGF-alpha T lymphocytes Fibroblasts Keratinocytes Stimulates keratinocyte migration Transforming Growth Factor-beta Platelets Monocyte chemotaxis TGF-beta T lymphocytes Fibroblast migration & Macrophages Proliferation Endothelial cells Angiogenesis Keratinocytes Collagen & ECM synthesis Epidermal Growth Factor Platelets Mitogenic for keratinocytes and EGF Macrophages Fibroblasts Stimulates keratinocyte Migration Fibroblast growth factor Macrophages Chemotactic and mitogenic for Mast cells fibroblasts and keratinocytes T lymphocytes Stimulates angiogenesis Endothelial cells Fibroblast growth factor Fibroblasts Stimulates keratinocyte FGF migration, differentiation, and proliferation TNF Macrophages Activates macrophages Mast cells Mitogenic for fibroblasts T lymphocytes Stimulates angiogenesis Interleukin (IL)–1, IL-2, IL-6, and Macrophages IL-1 - Induces fever and IL-8 Mast cells adrenocorticotropic hormone Keratinocytes release, enhances TNF-alpha and Lymphocytes interferon (INF)–gamma, activates granulocytes and endothelial cells, and stimulates hematopoiesis IL-2 - Activates macrophages, T cells, natural killer cells, and lymphokine-activated killer cells; stimulates differentiation of activated B cells; stimulates proliferation of activated B and T cells; and induces fever IL-6 - Induces fever and enhances release Keratinocyte of acute- phase reactants by the liver IL-8 - Enhances neutrophil adherence, chemotaxis, and granule release INFs (IFN-alpha, -beta, and - Lymphocytes Activate macrophages delta) Fibroblasts Inhibit fibroblast proliferation Thromboxane A2 Destroyed wound cells Potent vasoconstrictor Stages of Wound Healing HEMOSTASIS INFLAMMATION Recall from Inflammation lecture  PROLIFERATION ❑ Occurs 3 – 21 days post injury ❑ Fibroblasts predominate ❑ 3 Distinct phases: ▪ Re-epithelialization ▪ Formation of granulation tissue by: Angiogenesis and Fibroplasia ▪ Extracellular Matrix (ECM) formation  RE - EPITHELIALIZATION ❑ Growth factors stimulate regrowth of the epidermis ❑ Epithelial cells divide and migrate across the healthy granulation tissue to form a barrier b/t the wound and the environment ❑ Keratinocytes are responsible for epithelialization  GRANULATION TISSUE ❑ Granulation tissue progressively fills the site of injury ❑ Primarily made up of: ▪ Fibroblasts ▪ Type III collagen ▪ New blood vessels ▪ Immune cells ❑ Essential intermediate tissue ▪ Body’s healing tissue ▪ Resistant to infection (macrophages/ antibodies)  E. ANGIOGENESIS Growth of new blood vessels into the wound which brings in O2 and nutrients  FIBROPLASIA ❑ Fibroblasts ▪ replicate/ proliferate/ migrate into wound ❑ Stimulated by cytokines and growth factors ▪ PDGF, FGF-2 and TGFβ ❑ Deposition of collagen ▪ migration and proliferation of fibroblasts into the site of injury ▪ lay down ground substance (ECM) proteins  EXTRACELLULAR MATRIX ❑ Exists as a scaffold to stabilize the physical structure of tissues ❑ Two forms of extracellular matrix: ▪ Interstitial matrix – present between cells ▪ Basement membrane – found between epithelium and mesenchymal cells  Functions of the ECM ❑ Mechanical support ▪ Anchorage, migration ❑ Control of growth ▪ Signals through cellular receptors – integrins ❑ Maintenance of cell differentiation ▪ Proteins affect degree of differentiation (fibronectin, vitronectin, thrombospondin) ❑ Scaffolding for tissue renewal ▪ Basement membrane needed for renewal of structure (stroma) ▪ Labile and stable cells depend on ECM to reestablish normal structure ❑ Storage of growth factors ▪ Allows for rapid response to injury and healing  COLLAGEN DEPOSITION ❑ Type I Collagen ▪ most common type (80 – 90% in adults – present in all tissues) ▪ primary collagen in a healed wound - secreted into the extracellular space → assemble into collagen fibrils → aggregate into larger, cable-like bundles called collagen fibers ❑ Type III Collagen ▪ predominates in newborns ▪ seen in early stages of wound healing Maturation/ Remodeling Phase ❑ Wound contraction ▪ Myofibroblasts – chains of fibroblasts (look like smooth muscle) ▪ Centripetal movement of wound edge towards center of the wound ❑ Collagen remodeling ▪ 3 weeks to 2+ years ▪ Number of intra- and intermolecular crosslinks b/t collagen fibers increases ▪ Type III decreases, replaced by Type I ▪ Tensile strength increases (70 - 80% of unwounded skin by 3 months)  Wound Closure Classification ❑ Primary ▪ All layers closed. ▪ Minimal scarring. ❑ Secondary Deep layers closed. Superficial layers left open to granulate from inside out. Prolonged healing requiring frequent wound care. Often leaves wide scar. ❑ Tertiary (Delayed Primary Intention) ❑Deep layers closed primarily. ❑Superficial layers left open until day 4. ❑Reinspection of wound: clean → irrigate and close. Infected → leave open to heal by 2° intention. Secondary Closure Tertiary Closure https://library.kissclipart.com/20181003/vqq/kissclipart-table-clipart-wound-healing-scar-9a65e081466f3870.jpg  Systemic Factors Inhibiting Wound Healing ❑ Infection ❑ Malnutrition ❑ Ischemia ❑ Vitamin deficiencies ▪ Circulation ▪ Vitamin C, Vitamin A ▪ Respiration ❑ Mineral deficiencies ▪ Local tension ▪ Zinc, Iron ❑ Immunocompromised ❑ Exogenous drugs ▪ HIV ▪ Doxorubicin (Adriamycin), ❑ Diabetes mellitus Gluco-corticosteroids ❑ Advanced age ❑ Ionizing radiation ❑ Smoking  COMPLICATIONS ❑ Deficient scar formation ❑ Excessive formation of repair components ❑ Exaggerated contraction  Deficient Scar Formation Dehiscence (rupture of wound) Ulceration (defect in the continuity)  Excessive Formation of Repair Components Keloid/ Hypertrophic Scarring Hypertrophic Granulation Tissue ▪ Excessive collagen (Type III vs Type I) ▪ Appears beefy, red ▪ Keloid scar – grows outside the boundaries of ▪ Prevents re-epithelialization the initial wound ▪ Hypertrophic scar – do not grow outside the boundaries of the initial wound  Exaggerated Contraction ❑ Deformation of surrounding tissue ❑ Can compromise the movement of joints ❑ Most common on: ▪ Palms/ soles ▪ Joints  References Gregory C. Sephel Stephen C. Woodward. Repair, Regeneration, and Fibrosis. Accessed online: http://downloads.lww.com/wolterskluwer_vitalstream_com/sample- content/9780781795166_Rubin/samples/91731_ch03.pdf Heather L. Orsted RN BN ET MSc David Keast MSc MD FCFP Louise ForestLalande RN MEd ET Marie Françoise Mégie MD. Basic Principles of Wound Healing. Wound Care Canada / Volume 9, Number 2 Robbins and Cotran Pathologic Basis of Disease. Ninth edition. Philadelphia, PA: Elsevier/Saunders, 2015.