Chapter 7 Wound Healing

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1 Chapter 7 Wound Healing 長庚皮膚科 R2 劉人鳳

2 CHAPTER SUMMARY Wound healing occurs in orderly, overlapping phases: the inflammatory, the proliferative, and the remodeling phases. The depth of the wound determines the degree of contraction and the location and source of keratinocytes that serve as a reservoir for reepithelialization. Acute wounds created by a scalpel heal faster than wounds created by destructive or ablative methods.

3 CHAPTER SUMMARY Platelets are the first cell to appear in the healing process, and macrophages are the most important cell in the healing process; they both mediate their actions through cytokines or growth factors. Wound healing is highly regulated by signals from the serum and surrounding extracellular matrix. Physicians can accelerate wound healing by avoiding placing toxic substances on the wound keeping the wound free of necrotic and potentially infected tissue appropriate use of occlusive dressings to create a moist wound environment

5 TYPES OF WOUNDS

6 Acute versus chronic wounds Healing time Anatomic location, shape, wound cause, patient age, and physical condition Ex: an elliptical wound on the face of a healthy child will likely heal faster than a circular burn wound on an elderly person with multiple comorbidities Patient age is a critical factor

7 Primary versus secondary intention healing Acute wound heals without intervention, primarily by contraction of myofibroblasts Second intention healing A surgeon directs closure of the wound Primary intention healing

8 Methods of creating acute wounds Scalpel (steel), laser (heat), liquid nitrogen (cold), or chemicals (acid) Accidental trauma, thermal, or chemical burns Wounds created by sharp steel (surgical incisions) Heal faster Healing of traumatic wounds may be slowed foreign substances prolongation of the inflammatory phase

9 PHASES OF WOUND HEALING Inflammatory phase

10 Inflammatory phase Local vasodilatation, blood and fluid leakage into the extravascular space, and blocking of lymphatic drainage rubor (redness), tumor (swelling), calor (heat), dolor (pain), and functio laesa (loss of function) Usually lasts h, may persist for up to 2 weeks (chronic inflammation)

11 Inflammatory phase Tissue injury blood vessel disruption and bleeding activates keratinocytes release interleukin1 (IL1) Platelets Homeostasis Release of important mediators: platelet derived growth factor (PDGF), epidermal growth factor (EGF), and TGFβ1. Leukocytes, mast cells, basophils, and eosinophils Monocytes Macrophages: phagocytosis, initiation of formation of granulation tissue

12 hemostasisthrombosis/deck/

13 Inflammatory phase -- Vascular response

14 Initially, vasoconstriction hemostasis Histamine is released into the area from mast cells, basophils, and platelets vasodilatation and increased permeability Hemostasis: development of a fibrin clot coagulation

17 Inflammatory phase -- Cellular response

Leukocytes Neutrophils Within 1 hr of the onset of inflammation endothelium of the venules covered with neutrophils = Margination Inflammation persists, neutrophils (days) macrophages

19 Leukocytes Neutrophils Within 1 hr of the onset of inflammation endothelium of the venules covered with neutrophils = Margination Inflammation persists, neutrophils (days) macrophages (tissue-derived monocytes) Chemotactic factors from Mast cells -- TNF, histamine, proteases, leukotrienes, and cytokines (interleukins) Coagulation cascade (fibrinogen, FDP) -- kallikrein, fibrinopeptides

Leukocytes Monocytes, Macrophages Phagocytosis Chronic inflammation angiogenesis and granulation tissue formation ~ Proliferative phase Fibroblasts; Collagen deposition

20 Leukocytes Monocytes, Macrophages Phagocytosis Chronic inflammation angiogenesis and granulation tissue formation ~ Proliferative phase Fibroblasts; Collagen deposition Produce growth factors: PDGF, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), TGF-β, and TGF-α Cell migration, proliferation, and matrix production

21 Mast cells Trigger inflammation, vasodilatation and increased vascular permeability histamine and TNF Regulate hemostasis platelet-activating factor (PAF), heparin, tryptase, chymase, and t- plasminogen activator (tpa) Recruit leukocytes TNF, histamine, proteases, leukotrienes, and cytokines (interleukins) Angiogenesis, extracellular matrix deposition, and remodeling histamine, heparin, cytokines, and growth factors

22 Inflammatory phase -- Chemical mediators of inflammation

23 Histamine Mast cells (mainly), blood platelets and basophils H1 receptor dilatation of arterioles and increase permeability Heparin: anticoagulation during early phase Serotonin Platelets and mast cells Potent vasoconstrictors Fibroblast proliferation and the cross-linking of collagen molecules Kinins Brdykinin, released from plasma protein Vasodilatation Rapidly destroyed with limited activity

24 Prostaglandins Prostaglandin E2 (PGE2): increase vascular permeability, attract leukocytes Sensitize pain receptors (proinflammatory) or as inhibitors Synthesis of mucopolysaccharides Inhibited by steroids or NSAIDs in chronic inflammation Complement system Ag Ab complement cascade of sequential reaction facilitate phagocytosis

25 Growth factors

26 Inflammatory phase Chronic inflammation > 2 weeks, often months or years Granulocytes disappear, mononuclear cells (lymphocytes, monocytes, macrophages) persist Necrotic tissue Contaminated with pathogens Bacterial lipopolysaccharide inhibit Keratinocyte migration Contain foreign material cannot be phagocytized Fibroblasts produce collagen granuloma

27 PHASES OF WOUND HEALING Proliferative phase

Re-epithelialization Migration & Proliferation of epidermal keratinocytes Neoepithelium to stratified epidermis Restoration of an intact basement membrane zone

28 Re-epithelialization Migration & Proliferation of epidermal keratinocytes Neoepithelium to stratified epidermis Restoration of an intact basement membrane zone Repopulation of specialized cells Merkel s cells which direct sensory function Melanocytes that foster pigmentation Langerhans cells that regulate immune functions

29 Keratinocyte migration Within 24 h Also occurs from the remaining skin appendages, including the hair follicle leap frog theory -- epidermal cells migrate two or three cell lengths from their initial position and slide over epidermal cells previously implanted in the wound Migrating keratinocytes produce matrix metalloproteinases (MMPs): disrupts and allows for continued migration

30 Restoration of the basement membrane zone Within 7 9 days The BMZ of the skin consists of many extracellular matrix proteins, with collagens and laminins being the major components

31 Reconstitution of the dermis Granulation tissue begins to form within 3 4 days of injury Provisional extracellular matrix or fibronectin rich fibrin clot -- Providing scaffolding and contact guidance for cells to migrate Angiogenesis Fibroplasia Formation of granulation tissue

32 Mechanism of wound contraction In direct proportion to depth Full-thickness wounds -- peaks at 2 weeks, up to a 40% decrease in wound size Partial-thickness wounds -- parts of the adnexa remain and allow epithelialization, contract less than full-thickness wounds Myofibroblasts By day 7, fibroblasts begin to change into myofibroblasts Contraction resulting in skin tension lines

33 Wound angiogenesis During wound healing, endothelial cells released cytokines, low oxygen tension, lactic acid, and biogenic amines stimulate angiogenesis

34 Angiogenic growth factors

35 PHASES OF WOUND HEALING Remodeling phase

36 Deposition of matrix materials Occurs through the whole process of wound repair Total amount of collagen increases maximum 2 and 3 weeks Tensile strength (functional assessment of collagen) increases to 40%, and continue to increase for up to 1 year Never greater than 80% of its pre injury strength Type III collagen is the major collagen in granulation tissue > 1 yr, the dermis returns to the preinjury phenotype (type I collagen)

37 Extracellular matrix In part comprised of glycosaminoglycans and proteoglycans Dermal compliance, flexibility, and integrity Strength, support, and density to tissue

38 Extracellular matrix Hyaluronic acid is nonsulfated glycosaminoglycan peak within the first 4 5 days Stimulus for fibroblast proliferation and migration, absorb large amounts of water space for the migration of fibroblasts

39 Extracellular matrix Sulfated glycosaminoglycans are proteoglycans Stable and resilient matrix that inhibits cell migration and proliferation Chondroitin-4-sulfate and dermatan sulfate eventually replace hyaluronic acid as the major glycosaminoglycan on days 5 7

40 Extracellular matrix Non-weight-bearing skin Progressive decrease of glycosaminoglycan content from fetal development to maturity Weight-bearing skin, such as the plantar aspect of the foot Minimal change in glycosaminoglycan Chondroitin sulfate, are proportionally altered in pathologic skin states, such as Dupuytren s contracture or hypertrophic scarring

41 Collagen 80% of dry weight of the dermis providing structure, strength, and stiffness to dermal tissue In normal adults type I collagen -- 80% type III collagen -- 10% Type III type I collagen during wound healing process

42 Biosynthesis of collagen

43 Elastic fibers Elastin Provides elasticity and extensibility to the dermis Assists in recovery from deformation Comprising only 2% of the total protein in the dermis With aging, the amount of elastin increases

44 Proteinases and tissue remodeling The most important protein are MMPs Partly controlled by a family of tissue inhibitors of metalloproteinases (TIMP1, TIMP2, TIMP3, TIMP4) The balance between MMPs and TIMPs is critical to the wound repair process and remodeling

45 FACTORS AFFECTING WOUND HEALING Systemic factors Malnutrition, protein deprivation, and deficiencies of vitamin A and vitamin C Vitamin C -- cofactor for the collagen crosslinking Vitamin A -- potentiates epithelial repair and collagen synthesis by enhancing inflammatory reactions Zinc deficiency reduces the rate of epithelialization Corticosteroids, penicillamine, nicotine, NSAIDs, and antineoplastic agents penicillin decreases collagen cross-linking Chronic debilitating illness, endocrine disorders, systemic vascular disorders, and connective tissue disease Advancing age

46 Systemic steroids in the first 3 days postwounding blocks initial inflammation prolongation of healing time loss of skin turgor suppress the mitotic activity of fibroblasts Ameliorated with administration of local and systemic vitamin A, and a single injection of TGFβ

47 Local factors Poor surgical techniques (excessive tension or excess devitalized tissue) Vascular disorders (arteriosclerosis or venous insufficiency), tissue ischemia Infectious processes Certain topically applied medications, extravasation of antineoplastic drugs Hemostatic agents such as aluminum chloride or ferric subsulfate Foreign body reactions Adverse wound microenvironment (dry vs occlusive dressings) Pressure, neuropathy, and chronic radiation injury

48 OPTIMIZING OUTCOMES

49 Surgical techniques Aseptic surgical techniques Use of buried deep sutures lessen risk for hematoma and subsequent infection Proper hemostasis and elimination of necrotic tissue Apposition of wound edges, not closed too tightly prevent ischemia and necrosis

Topical skin adhesives Novel, noninvasive alternative Degrade with skin cells Hemostatic, occlusive dressing, antimicrobial barrier Similar rates of infection and scarring

50 Topical skin adhesives Novel, noninvasive alternative Degrade with skin cells Hemostatic, occlusive dressing, antimicrobial barrier Similar rates of infection and scarring Higher rates of wound dehiscence 2 classes: butyl and octylcyanoacrylates Dermabond (Johnson and Johnson, New Brunswick, NJ) advanced has the greatest strength and is the most flexible

51 Occlusive dressings Healed up to 40% faster than those left exposed to air Film dressings: face and other cosmetically important areas Hydrocolloid dressings: exudative wounds Foam dressings: wound associated pain To be left in place until the exudate leaks from the dressing (early removal can strip away newly formed epithelium)

52 Emerging dressings/topicals Honey decreases oxidative stress Increase proinflammatory cytokines TNF-α, IL-1β, IL-6 reduce healing time in superficial and partial thickness burn wounds But NOT for chronic leg ulcers Protein kinase C keratinocyte and fibroblast migration and differentiation, matrix deposition Topical bacteriophage-based preparation Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli

53 Emerging dressings/topicals Human amniotic membrane allograft many growth factors facilitate angiogenesis, dampen inflammation, prevent infection, and promote healing Thymosin beta-4 released by macrophages and platelets interacts with actin and promotes angiogenesis, cell mobilization, migration, and tissue regeneration, decreasing myofibroblasts Connexin 43 downregulates cell migration at wound edges

54 Investigational tissue and cell therapy Activated allogeneic white blood cells, monocytes, macrophages, neutrophils, and lymphocytes from healthy donors (topical or injected) Living, growth-arrested keratinocytes and fibroblasts (spray) release of growth factors Bone marrow derived mesenchymal stem cells heal chronic wounds Human processed lipoaspirate -- contains stem cells and is easily harvested

55 Future growth factors Topical fibroblast growth factor 1 Chemotaxis, proliferation of fibroblasts and keratinocytes, increase the expression of TGF-β 5-amino acid deleted recombinant human hepatocyte growth factor chronic wounds promoting re-epithelialization, angiogenesis, and granulation tissue formation

56 Partial-thickness versus full-thickness wounds

57 Partial-thickness versus full-thickness wounds Early fetal skin wounds regeneration can take place after dermal injury higher concentrations of type III collagen and glycosaminoglycans decreased inflammatory response and amounts of TGF-β1

58 Summary Wound healing is a complex process Understanding of its underlying mechanisms is vital for practitioners Older patients slower healing less tensile strength, secondary to reduced amounts of collagen less scarring

59 Thank You For Your Attention

After this presentation and discussion, the participants should be able to:

Tissue Repair Robert F. Diegelmann, Ph.D. OBJECTIVES After this presentation and discussion, the participants should be able to: 1. Define the biochemical responses to tissue injury 2. Describe the mechanisms