Wound Healing
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Wound Healing DAVID A. JANSEN, MD, F.A.S.C CHIEF, PROGRAM DIRECTOR DIVISION OF PLASTIC AND RECONSTRUCTIVE TULANE UNIVERSITY HEALTH SCIENCE CENTER DIVISION OF PLASTIC & RECONSTRUCTIVE SURGERY Overview Wound Healing Phases Factors Influencing Adjuncts to Wound Healing Fetal wound healing Wound Care Principles Dressings Abnormal Scarring Phases of Wound Healing Tissue Injury and Coagulation Inflammation Remove devitalized tissue and prevent infection Fibroproliferative Balance between scar formation and tissue regeneration Maturation/Remodeling Maximize strength and structural integrity Tissue Injury and Coagulation Tissue Injury and Coagulation INJURY (Physical, antigen-antibody reaction, or infection) Transient (5-10 minute) vasoconstriction Slows blood flow, aid in hemostasis Histamine mediated vasodilation and permeability changes Vessels become lined with leukocytes, platelets and erythrocytes Leukocyte migration into the wound Hemostatic factors from platelets, kinins, complement, and prostaglandins send signals to initiate the inflammatory phase Fibrin, Fibronectin, and plasma help form a clot and stop bleeding Early Inflammation Complement Cascade Activation PMN infiltration 24-48 hours Phagocytosis and debridement Stimulated by: Complement components (C5a) Formyl-methionyl peptide products from bacteria Transforming Growth Factor (TGF)-b Late Inflammation Macrophage Most critical cell type Predominates after 48-72 hours Attracted by: Growth factors (PDGF, TGF-b) Complement Clotting components IgG Collagen and elastin breakdown products Leukotriene B4 Platelet factor IV Late Inflammation Macrophage Functions Phagocytosis Primary producer of Growth Factors (PDGF, TGF-b) Recruitment of fibroblasts (proliferative phase) Proliferation of extracellular matrix by fibroblasts Proliferation of endothelial cells (angiogenesis) Proliferation of smooth muscle cells This leads to the Fibroproliferative phase Late Inflammation Lymphocyte Appears at 72 hours Attracted by: Interleukins IgG Complement products Role yet to be determined Fibroproliferative Fibroblasts Migrate into the wound via ECM Predominant cell type by day 7 Collagen synthesis Begins on days 5-7 Angiogenesis Increases in linear fashion for 2 to 3 weeks Promoted by macrophages (TNF-alpha, FGF, VEGF) Epithelialization Mitosis of epithelial cells after 48-72 hours Modulated by growth factors (EGF, FGF, KGF) Fibroproliferative Extracellular Matrix Forms a scaffold for cell migration and growth factor sequestration (fibronectin, proteoglycans, collagen, etc.) Collagen Principle building block of connective tissue 1/3 of total body protein content Collagen Types Type 1 Bones, skin, and tendons 90% of total body collagen Found in all connective tissues except hyaline cartilage and basement membranes Type 2 Hyaline cartilage, cartilage-like tissues, and eye tissue Collagen Types Type 3 Skin, arteries, uterus, abdominal wall, fetal tissue Association with Type I collagen in varying ratios (remodeling phase) Type 4 Type 5 Basement membranes only Basement membranes, cornea Skin Type 1 : Type 3 ratio is 4:1 Hypertrophic scars/immature scars ratio maybe as high as 2:1 Angiogenesis Formation of new blood vessels throughout inflammatory and proliferative phase Initiated by platelets TGF-b and PDGF PMN Macrophages TNF-alpha, FGF, VEGF Endothelial Cell Forms new blood vessels Epithelialization Stimulated by Loss of contact-inhibition Growth factors EGF (mitogenesis and chemotaxis) KGF, FGF (proliferation) Mitosis of epithelial cells 48-72 hours after injury behind leading edge Epithelialization Epithelium advances across wound with leading edge cells becoming phagocytic Collagenase (MMP) Degrades ECM proteins and collagen Enables migration between dermis and fibrin eschar Maturation/Remodeling Longest phase: 3 weeks – 1 year Least understood phase Wound Contraction and Collagen Remodeling Wound Contraction Myofibroblast Fibroblasts with intracellular actin microfilaments Maturation/Remodeling Collagen Remodeling Type 3 Collagen degraded and replaced with Type 1 Collagen degradation achieved by Matrix Metalloproteinase (MMP) activity Tensile Strength Collagen is the main contributing factor Rate of tensile strength All wounds begin to gain strength during the first 14-21 days (~20% strength), variable then after Strength PEAKs @ 60 days NEVER reaches pre-injury levels Most optimal conditions may reach up to 80% Predominant Cell Types Fetal Wound Healing Lack of inflammation Absence of FGF and TGF-b Regenerative process with minimal or no scar formation Collagen deposition is more organized and rapid Type 3 Collagen (No Type 1) High in hyaluronic acid Factors That Influence Wound Healing Oxygen Fibroblasts are oxygen-sensitive Collagen synthesis cannot occur unless the PO2 >40mmHg Deficiency is the most common cause for wound infection and breakdown Hematocrit Mild to moderate anemia does not appear to have a negative influence wound healing >50% decrease in HCT some studies report a significant decrease in wound tensile strength Factors That Influence Wound Healing Smoking Multifactorial in limiting wound healing Nicotine CO Decreases the oxygen carrying capacity of Hgb Hydrogen Cyanide Vasoconstrictive -> decreases proliferation of erythrocytes, macrophages, and fibroblasts Inhibits oxidative enzymes Increases blood viscosity, decrease collagen deposition A single cigarette may cause cutaneous vasoconstriction for up to 90 minutes Factors That Influence Wound Healing Mechanical Stress - tension Hydration Affects the quantity, aggregation, and orientation of collagen fibers Well hydrated wounds epithelialize faster Environmental Temperature Healing is accelerated at temperatures of 30 C Factors That Influence Wound Healing Denervation No direct effect on epithialization or contraction Loss of sensation and high collagenase activities in skin -> prone to ulcerations Foreign Bodies (including necrotic tissue) Nutrition Delays increases in tensile strength Edema Delay healing and prolong the inflammatory phase May compromise tissue perfusion Age Tensile strength and wound closure rates decrease with age Factors That Influence Wound Healing Infection Prolongs inflammatory phase, impairs epithiliazation and angiogenesis Increased collagenolytic activity -> decreased wound strength and contracture Bacterial counts > 105 Chemotherapy Decreases fibroblast production and wound contraction If started 10-14 days after injury, no significant long term problems, but short term decreased tensile strength Radiation Stasis and occlusion of small blood vessels Decreased tensile strength and collagen deposition Systemic Diseases DM Glycosylated RBCs Stiffened RBCs & Increased blood viscosity Glycosylated WBCs impaired immune function Renal Dz Factors That Influence Wound Healing Steroids Inhibit wound macrophages Interfere with fibrogenesis, angiogenesis, and wound contraction Vitamin A and Anabolic steroids can reverse the effects Vitamin A Stimulates collagen deposition and increase wound breaking strength Factors That Influence Wound Healing Vitamin C Essential cofactor in the synthesis of collagen Deficiency is associated with immune dysfunction and failed wound healing (Scurvy) High concentrations do not accelerate healing Factors That Influence Wound Healing Vitamin E Large doses inhibit wound healing Decreased tensile strength Less collagen accumulation HOWEVER Antioxidant that neutralizes lipid peroxidation caused by radiation Decreasing levels of free radicals and peroxidases increases the breaking strength of wounds exposed to preoperative radiation Factors That Influence Wound Healing Zinc Deficiency: Impairs epithelial and fibroblast proliferation Only accelerates healing when there is a preexisting deficiency Factors That Influence Wound Healing NSAIDs Decrease collagen synthesis an average of 45% (ordinary therapeutic doses) Dose-dependent effect mediated through prostaglandins Wound Care General Principles Cleaning and Irrigation Need at least 7psi to flush bacteria out of a wound High pressure can damage wounds and should be reserved only for heavily contaminated wounds Debridement Most critical step to produce a wound that will heal rapidly without infection Non-selective: Dakin solution, Hydrogen Peroxide, etc. Useful in wounds with heavy contamination When starts to granulate, start selective Selective: sharp, enzymatic, autolytic, or biologic Wound Care General Principles Fundamentals of Surgical Wound Closure Incision should follow tension lines and natural folds in the skin Gentle tissue handling Complete hemostasis Eliminate tension Fine sutures and early removal Evert wound edges Allow scars to mature before repeat intervention (2 weeks to 2 months scar appearance is the worst) Scar appearance depends more on type of injury than method of closure Technical factors of suture placement and removal are more critical than type of suture used Immobilization of wounds to prevent disruptions and excessive scarring (Adhesive strips after suture removal) Wound Dressings Over 2,000 commercially available Red-Yellow-Black Classification Created to help choose appropriate dressings in wounds healing by secondary intention Treat worse colors first Black -> Yellow -> Red Abnormal Scarring Hypertrophic Scars Keloids Widespread Scar Comparison of Abnormal Keloid Hypertrophic Scar Widespread Scar Scars Borders Outgrows wound borders Remains within wound borders Wide, flat, depressed Natural History Appears months after injury, rarely regresses Appears soon after injury, regresses with time Appears within 6 months of injury Location Mostly face, earlobes, chest (Never eyelids or mucosa) Flexor surfaces Arms, legs, abdomen Etiologic Factors Possible autoimmune, endocrine (puberty, pregnancy) Tension Tension and mobility of wound edges Treatment Intralesional steroids, compression therapy, silicone gel sheeting, radiation therapy Often worse after surgery alone Same as Keloids but outcome usually more successful Scar excision/layered closure Comparison of Abnormal Scars Keloid Hypertrophic Scar Widespread Scar Genetic Significant s familial predilection Low familial incidence No inheritance pattern Race African > Caucasian Low racial incidence Not related to race Sex Females > Males Equal (Equal) Unknown Age Most commonly 10-30 years Any Age Any age, mostly less than 20 years Hypertrophic Scar Keloids Keloid: Treatments No universally effective treatment, usually a combination of treatment types Case by Case basis Prevention (the best therapy) Avoid non essential surgery, minimal tension, use cuticular monofilament synthetic sutures, avoid wound-lengthening techniques, and avoid incisions across joints Keloids: Treatments Surgery: Alone 50-80% reoccurrence rate Excision with early postoperative radiation (~25% reoccurrence rate) Excision with corticosteroids (50-70% reoccurrence rate) Pressure- increase collagenase activity 24-30mm Hg, 18-24h/day for 4-6 months Silicone gel sheeting- mechanism unclear (decrease movement/tension) 80-100% -improvement in hypertrophic scars 35%- improvement in keloids Corticosteroids- intralesional Decreases collagen synthesis- unclear mechanism Maybe used in conjunction with surgical excision Complications- hypopigmentation, skin atrophy, telangiectasias Keloid Treatment Radiation Most effective when given post operatively No advantage if given preoperatively ~25% reoccurrence rate when combined with excision 15-20 Gy administered over several doses (5-6) Thank You
