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Wound Healing Orlando Canizares, MD Tulane University Health Science Center Division of Plastic & Reconstructive Surgery.

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Presentation on theme: "Wound Healing Orlando Canizares, MD Tulane University Health Science Center Division of Plastic & Reconstructive Surgery."— Presentation transcript:

1 Wound Healing Orlando Canizares, MD Tulane University Health Science Center Division of Plastic & Reconstructive Surgery

2 Overview Wound Healing Phases Factors Influencing Adjuncts to Wound Healing Fetal wound healing Wound Care Principles Dressings Abnormal Scarring

3 Phases of Wound Healing Tissue Injury and Coagulation Inflammation Remove devitalized tissue and prevent infection Early Late Fibroproliferative Balance between scar formation and tissue regeneration Fibroblast migration Collagen synthesis Angiogenesis Epithelialization Maturation/Remodeling Maximize strength and structural integrity Contraction Collagen Remodeling

4 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 Endothelial cells swell and pull away from each other -> allowing serum to enter 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


6 Early Inflammation Complement Cascade Activation Complement Cascade Activation PMN infiltration PMN infiltration hours hours Stimulated by: Stimulated by: Complement components (C5a) Complement components (C5a) Formyl-methionyl peptide products from bacteria Formyl-methionyl peptide products from bacteria Transforming Growth Factor (TGF)-b Transforming Growth Factor (TGF)-b

7 Early Inflammation PMNS Predominant cell type from hours Predominant cell type from hours Phagocytosis and debridement Phagocytosis and debridement Removal of PMNS does not alter wound healing

8 Late Inflammation Macrophage Most critical cell type Most critical cell type Predominates after hours Predominates after hours Attracted by: Attracted by: Growth factors (PDGF, TGF-b) Growth factors (PDGF, TGF-b) Complement Complement Clotting components Clotting components IgG IgG Collagen and elastin breakdown products Collagen and elastin breakdown products Leukotriene B4 Leukotriene B4 Platelet factor IV Platelet factor IV

9 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

10 Late Inflammation Lymphocyte Appears at 72 hours Attracted by: Interleukins IgG Complement products Role yet to be determined


12 Fibroproliferative Fibroblasts Migrate into the wound via ECM Predominant cell type by day 7 Collagen synthesis Begins on days 5-7 Increases in linear fashion for 2 to 3 weeks Angiogenesis Promoted by macrophages (TNF-alpha, FGF, VEGF) Epithelialization Mitosis of epithelial cells after hours Modulated by growth factors (EGF, FGF, KGF)

13 Fibroproliferative Extracellular Matrix Forms a scaffold for cell migration and growth factor sequestration (fibronectin, proteoglycans, collagen, etc.) Proteoglycans and Glycosaminoglycans chondroitin sulfate heparan sulfate keratan sulfate hyaluronic acid (1 st to appear)

14 Collagen Principle building block of connective tissue 1/3 of total body protein content

15 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

16 Collagen Types Type 3 Skin, arteries, uterus, abdominal wall, fetal tissue Association with Type I collagen in varying ratios (remodeling phase) Type 4 Basement membranes only Type 5 Basement membranes, cornea Skin Type 1 : Type 3 ratio is 4:1 Hypertrophic scars/immature scars ratio maybe as high as 2:1

17 Collagen Metabolism Dynamic equilibrium Synthesis (Fibrosis) vs. Degradation (collagenases) Collagenase activity Stimulated: PTH, Adrenal corticosteroids, colchicine Inhibited: Alpha 2-macroglobulin, cysteine, progesterone Healing wound 3-5 weeks equilibrium is reached between synthesis and degradation (no net change in quantity)

18 Angiogenesis Formation of new blood vessels throughout inflammatory and proliferative phase of wound healing Initiated by platelets TGF-b and PDGF PMN Macrophages TNF-alpha, FGF, VEGF Endothelial Cell Forms new blood vessels Forms new blood vessels

19 Epithelialization Repithelialization begins within hours of injury Repithelialization begins within hours of injury Stimulated by Stimulated by Loss of contact-inhibition Loss of contact-inhibition Growth factors Growth factors EGF (mitogenesis and chemotaxis) EGF (mitogenesis and chemotaxis) KGF, FGF (proliferation) KGF, FGF (proliferation)

20 Epithelialization Epithelium advances across wound with leading edge cells becoming phagocytic Epithelium advances across wound with leading edge cells becoming phagocytic Collagenase (MMP) Collagenase (MMP) Degrades ECM proteins and collagen Degrades ECM proteins and collagen Enables migration between dermis and fibrin eschar Enables migration between dermis and fibrin eschar Mitosis of epithelial cells hours after injury behind leading edge Mitosis of epithelial cells hours after injury behind leading edge


22 Maturation/Remodeling Longest phase: 3 weeks – 1 year Longest phase: 3 weeks – 1 year Least understood phase Least understood phase Wound Contraction and Collagen Remodeling Wound Contraction and Collagen Remodeling Wound Contraction Wound Contraction Myofibroblast Myofibroblast Fibroblasts with intracellular actin microfilaments Fibroblasts with intracellular actin microfilaments

23 Maturation/Remodeling Collagen Remodeling Collagen Remodeling Type 3 Collagen degraded and replaced with Type 1 Type 3 Collagen degraded and replaced with Type 1 Collagen degradation achieved by Matrix Metalloproteinase (MMP) activity (fibroblasts, PMNs, macrophages) Collagen degradation achieved by Matrix Metalloproteinase (MMP) activity (fibroblasts, PMNs, macrophages) Collagen reorientation Collagen reorientation Larger bundles Larger bundles Increased intermolecular crosslinks Increased intermolecular crosslinks

24 Tensile Strength Collagen is the main contributing factor Load capacity per unit area (Breaking capacity- force required to break a wound regardless of its dimensions) Rate of tensile strength increases in wounds vary greatly amongst species, tissues and individuals All wounds begin to gain strength during the first days (~20% strength), variable then after Strength 60 days NEVER reaches pre-injury levels Most optimal conditions  may reach up to 80%

25 Predominant Cell Types

26 Special Characteristics of 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 Area of ongoing research

27 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 (given sufficient oxygenation) >50% decrease in HCT some studies report a significant decrease in wound tensile strength while other studies find no change

28 Factors That Influence Wound Healing Smoking Multifactorial in limiting wound healing Nicotine Vasoconstrictive -> decreases proliferation of erythrocytes, macrophages, and fibroblasts CO Decreases the oxygen carrying capacity of Hgb Hydrogen Cyanide Inhibits oxidative enzymes Increases blood viscosity, decrease collagen deposition and prostacyclin formation A single cigarette may cause cutaneous vasoconstriction for up to 90 minutes

29 Factors That Influence Wound Healing Mechanical Stress Affects the quantity, aggregation, and orientation of collagen fibers Abnormal tension -> blanching, necrosis, dermal rupture, and permanent stretching Hydration Well hydrated wounds epithelialize faster Environmental Temperature Healing is accelerated at temperatures of 30 C Tensile strength decrease by 20% in 12C environment

30 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) Delay healing and prolong the inflammatory phase Nutrition Delays increases in tensile strength Edema May compromise tissue perfusion

31 Factors That Influence Wound Healing Oxygen Derived Free Radicals Degrade Hyaluronic acid and collagen Destroy cell and organelle membranes Interfere with enzymatic functions Age Tensile strength and wound closure rates decrease with age

32 Factors That Influence Wound Healing Infection Prolongs inflammatory phase, impairs epithiliazation and angiogenesis Increased collagenolytic activity -> decreased wound strength and contracture Bacterial counts > 10 5, b-hemolytic strep Chemotherapy Decreases fibroblast production and wound contraction If started 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

33 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 Topical Vitamin A has been found to accelerate wound reepithealization

34 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) Immature fibroblasts and extracellular material High concentrations do not accelerate healing

35 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

36 Factors That Influence Wound Healing Zinc Deficiency: Impairs epithelial and fibroblast proliferation Decreases B and T cell activity Only accelerates healing when there is a preexisting deficiency

37 Factors That Influence Wound Healing NSAIDs Decrease collagen synthesis an average of 45% (ordinary therapeutic doses) Dose-dependent effect mediated through prostaglandins

38 Adjuncts to Wound Healing Fibrin-based tissue adhesives Increase breaking strength, energy absorption, and elasticity in healing wounds

39 Adjuncts to Wound Healing Hydrotherapy Whirlpool Pulsed Lavage Stimulates formation of granulation tissue Clean non draining wounds with healthy granulation tissue should NEVER be subjected to hydrotherapy Water agitation damages fragile cells

40 Adjuncts to Wound Healing Hyperbaric Oxygen Increases levels of O2 and NO to the wound Benefit: Amputations, osteoradionecrosis, surgical flaps, skin grafts None to minimal benefit with necrotizing soft-tissue infections Wounds require adequate perfusion Many off-label uses (Benefit? Financial?) Acne, Migraines, Lupus, Stroke, MS, and many more Medicare Coverage 14 Covered Areas (next slide)

41 Medicare Coverage of HBO (1) Acute carbon monoxide intoxication (2) Decompression illness (3) Gas embolism (4) Gas gangrene (5) Acute traumatic peripheral ischemia (6) Crush injuries (7) Progressive necrotizing infections (8) Acute peripheral arterial insufficiency (9) Preparation and preservation of compromised skin grafts (10) Chronic refractory osteomyelitis (11) Osteoradionecrosis (ORN) (12) Soft tissue radionecrosis (STRN) (13) Cyanide poisoning (14) Actinomycosis

42 Adjuncts to Wound Healing

43 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

44 Selective Debridement Enzymatic Naturally occurring enzymes that selectively digest devitalized tissue Collagenase (Santyl), Papain-Urea (Accuzyme), etc. Autolytic Uses the body’s own enzymes and moisture to breakdown necrotic tissue 7-10 days under semi occlusive and occlusive dressings Ineffective in malnourished patients Biologic Maggots Calcium salts and bactericidal peptides Separate necrotic from living tissue making surgical debridement easier

45 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)

46 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


48 Dressing Types Alginates (Aquacel) Wounds with heavy exudates (dry the wound) Converts in a sodium salt -> hydrophilic gel occlusive environment Change when begins to weep exudate Creams (Silvadene cream) Opaque, soft solid or thick liquids with a slight drying effect Wounds with moist weeping lesions Ointments (bacitracin) Semisolids that melt at body temperature Aid in rehydration and topical application of drugs

49 Dressing Types Foams (Mepilex) Hydrophobic polyurethane sheets with a non absorbent adhesive occlusive cover (very absorbent and nonadherent) Absorb environmental water and slow epitheliaztion Films (Tegaderm) Transparent polyurethane membranes with water-resistant adhesives Conform well, semipermeable to moisture and oxygen, impermeable to bacteria Promote autolytic debridement Good for wound monitoring Can lead to maceration in wounds with a heavy exudate and can tear skin

50 Dressing Types Gauze Highly permeable to air and allow rapid moisture evaporation Stick to granulation tissue and damage the wound with removal Painful removal Lint can harbor bacteria Hydrocolloids Completely impermeable Avoid in anaerobic infections Comfortable and adhere well (good for high-friction areas) Good at absorbing exudate Hydrogels Starch and water polymers in gels, sheets, or impregnated gauze Rehydrate wounds (poor for absorbing exudate)

51 Dressing Types VAC Dressing Sub atmospheric pressure dressing to convert an open wound to a controlled closed wound Decreases interstitial fluid/edema Improves tissue oxygenation Removes inflammatory mediators Increase speed of granulation tissue formation Reduces bacterial counts Silver-impregnated (Acticoat, Arglaes, Silveron) Antibacterial (effective against MRSA, VRE, yeast, and fungi) Moist environment Wound Matrix (Alloderm, Oasis, Apligraft, Dermagraft, Integra)

52 Alloderm Acellular dermal matrix derived from donated human skin Epidermis and all dermal cellular components are removed

53 Oasis Thin (0.15mm), translucent layer of porcine small intestinal submucosa (SIS) Primarily made of a collagen-based ECM Biologically important components of the ECM remain active Glycosaminoglycans (hyaluronic acid), proteoglycans, fibronectin, and growth factors such as FGF and TGF Application: Clean wound base Cut to size slightly larger than wound, apply directly, moisten with saline Dress with standard dressings: moist, compressive, etc. Change dressings with standard frequency

54 Apligraf Living bilayered skin substitute (epidermis and dermis) Dermis is devoid of Langerhans cells, melanocytes, macrophages, lymphocytes, hair or blood vessels Includes: PDGF, TNF, VEGF, FGF Has shown improved healing in Diabetic and Venous stasis ulcers

55 Dermagraft Derived from newborn foreskin tissue Cryopreserved human fibroblast-derived dermal substitute Composed of fibroblasts, ECM, and a bioabsorbable scaffold Fibroblast are seeded into the scaffold and secrete collagen, matrix proteins, growth factors and cytokines to create a human dermal substitute containing living cells Multiple studies showing higher percentage of healed diabetic foot ulcers versus controls

56 Integra Outer layer of a semi- permeable silicone membrane Inner layer is a porous matrix of fibers of cross-linked bovine tendon and glycosaminoglycans, that allows dermal ingrowth After dermal ingrowth the silicone film is removed and a STSG is placed (~3 weeks)

57 Abnormal Scarring Hypertrophic Scars Keloids Widespread Scar

58 Comparison of Abnormal Scars KeloidHypertrophic ScarWidespread Scar Borders Outgrows wound borders Remains within wound borders Wide, flat, depressed Natural HistoryAppears months after injury, rarely regresses Appears soon after injury, regresses with time Appears within 6 months of injury LocationMostly face, earlobes, chest (Never eyelids or mucosa) Flexor surfacesArms, legs, abdomen Etiologic Factors Possible autoimmune, endocrine (puberty, pregnancy) TensionTension and mobility of wound edges TreatmentIntralesional 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

59 Comparison of Abnormal Scars KeloidHypertrophic ScarWidespread Scar GeneticsSignificant familial predilection Low familial incidenceNo inheritance pattern RaceAfrican > CaucasianLow racial incidenceNot related to race SexFemales > Males (Equal) EqualUnknown AgeMost commonly years Any age, mostly less than 20 years Any Age

60 Hypertrophic Scar

61 Keloids

62 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

63 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) % -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 Lack of randomized control trials to determine site specific dosages Cryotherapy Found to be helpful in early vascularized lesions

64 Keloid Treatment Radiation Most effective when given post operatively No advantage if given preoperatively ~25% reoccurrence rate when combined with excision Gy administered over several doses (5-6)

65 Keloid Treatments Antitumor/Immunosuppressive Agents 5-FU Reports of effectiveness Uppal et al.: 50% improvement in Keloid Score Haurani et al.: 19% reoccurrence rate after intralesion injection after surgery at 1 year Literature still in debate over appropriate dosage Bleomycin Limited studies to date suggesting effectiveness Interferon Some reports showing effectiveness others showing none Ongoing study needed

66 Thank You

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