1. Frederick N. Eko, MD Senior Fellow Division of Plastic Surgery Department of Surgery Tulane University School of Medicine

2. History of Wound Healing 1700 BC Papyrus: Lint/animal grease/honey 100 BC Egypt: Wound closure preserved soul 1000 AD Gun Powder 1500 AD Hot Oil 20 th Century Scientific Method

3. Wounds Customize Shotgun approach not acceptable No two patients OR wounds are identical 58y DM, Neuropathy: unaware of R foot gangrene

5. Wounds

6. Reconstructive Ladder Simple to Complex Formal Debridement, Elevation/ABI’s Appropriate IV ABX, Wound Vac, Skin Graft

7. Review of Wound Healing Three basic types of healing Primary Delayed Primary Secondary

8. Primary Wound surfaces opposed Healing without complications Minimal new tissue Results optimal

9. Delayed Primary Left open initially Edges approximated 4-6 days later

10. Secondary Surfaces not approximated Defect filled by granulation Covered with epithelium Less functional More sensitive to thermal and mechanical injury

11. Secondary Wound Healing

14. Three Phases of Wound Healing Inflammatory Phase Proliferative Phase Remodeling Phase

16. Three Phases of Wound Healing Inflammatory Phase Proliferative Phase Begins when wound is covered by epithelium Production of collagen is hallmark 7 days to 6 weeks Remodeling Phase (Maturation Phase)

17. Inflammatory Phase Hemostasis and Inflammation Days 4 - 6 Exposed collagen activates clotting cascade and inflammatory phase Fibrin clot = scaffolding and concentrate cytokines and growth factors

18. Inflammatory: Granulocytes First 48 hours (Neutrophils) Attracted by inflammatory mediators Oxygen-derived free radicals Non-specific

19. Inflammatory: Macrophages Monocytes attracted to area by complement Activated by: fibrin foreign body material exposure to hypoxic and acidotic environment Reached maximum after 24 hours Remain for weeks

20. Inflammatory: Macrophages Activated Macrophage: Essential for progression onto Proliferative Phase Mediate: Angiogenesis: FGF, PDGF, TGF-ɑ & β and TNF-ɑ Fibroplasia: IL’s, EGF and TNF Synthesize NO Secrete collagenases

23. Inflammatory Phase

26. Three Phases of Wound Healing Inflammatory Phase Proliferative Phase Remodeling Phase

27. Proliferative Phase Epithelization, Angiogenesis and Provisional Matrix Formation Begins when wound is covered by epithelium Day 4 through 14 Production of collagen is hallmark 7 days to 6 weeks

28. Epithelialization Basal epithelial cells at the wound margin flatten (mobilize) and migrate into the open wound Basal cells at margin multiply (mitosis) in horizontal direction ) Basal cells behind margin undergo vertical growth (differentiation )

30. Proliferative: Fibroblast Work horse of wound repair Produce Granulation Tissue: Main signals are PDGF and EGF Collagen type III Glycosaminoglycans Fibronectin Elastin fibers Tissue fibroblasts become myofibroblasts induced by TGF-β1

31. Wound Contraction Actual contraction with pulling of edges toward center making wounds smaller Myofibroblast: contractile properties Surrounding skin stretched, thinned Original dermal thickness maintained No hair follicles, sweat glands

32. Epithelialization/Contraction

33. Epithelialization

35. Collagen Homeostasis After Wounding (Optimal Healing) Days 3 - 7 Collagen production begins Days 7 – 42 Synthesis with a net GAIN of collagen Initial increase in tensile strength due to increased amount of collagen Days 42+ Remodeling with No net collagen gain

36. Collagen Normal Skin collagen ratio 4 : 1 Type I/III Hypertrophic Scar collagen ratio 2 : 1 Type I/III

37. Proliferative Phase

38. Three Phases of Wound Healing Inflammatory Phase Proliferative Phase Remodeling Phase

39. Maturation Phase Random to organized fibrils Day 8 through years Type III replaced by type I Wound may increase in strength for up to 2 years after injury Collagen organization Cross linking of collagen

40. Maturation Phase

41. Impaired Wound Healing

42. Wound Healing To treat the wound, you have to treat the patient Optimize the patient Circulatory Pulmonary Nutrition Associated diseases or conditions

43. Oxygen Fibroblasts are oxygen-sensitive PO2 < 40 mmHg collagen synthesis cannot take place Decreased PO2: most common cause of wound infection Healing is Energy Dependent Proliferative Phase has greatly increased metabolism and protein synthesis

44. Hypoxia: Endothelium responds with vasodilation Capillary leak Fibrin deposition TNF-a induction and apoptosis

45. Edema Increased tissue pressure Compromise perfusion Cell death and tissue ulceration

46. Infection Decreased tissue PO2 and prolongs the inflammatory phase Impaired angiogenesis and epithelialization Increased collagenase activity

47. Nutrition Low protein levels prolong inflammatory phase Impaired fibroplasia Of the essential amino Methionine is critical Hydration A well hydrated wound will epithelialize faster than a dry one Occlusive wound dressings hasten epithelial repair and control the proliferation of granulation tissue

48. Temperature Wound healing is accelerated at environmental temperatures of 30°C Tensile strength decreases by 20% in a cold (12°C) wound environment Denervation Denervation has no effect on either wound contraction or epithelialization

49. Diabetes Mellitus Larger arteries, rather than the arterioles, are typically affected Sorbitol accumulation Increased dermal vascular permeability and pericapillary albumin deposition Impaired oxygen and nutrient delivery Stiffened red blood cells and increased blood viscosity Affinity of glycosylated hemoglobin for oxygen contributing to low O2 delivery Impaired phagocytosis and bacterial killing Neuropathy

50. Radiation Therapy Acute radiation injury stasis and occlusion of small vessels fibrosis and necrosis of capillaries decrease in wound tensile strength direct, permanent, adverse effect on fibroblast may be progressive fibroblast defects are the central problem in the healing of chronic radiation injury

51. Medications Steroids Stabilize lysosomes and arrest of inflammation response Inhibit both macrophages and neutrophils Interferes with fibrogenesis, angiogenesis, and wound contraction Also direct effect on Fibroblasts Minimal endoplasmic reticulum Vitamin A oral ingestion of 25,000 IU per day pre op and 3d post op (not to pregnant women) Restores inflammatory response and promotes epithelializaton Does not reverse detrimental effects on contraction and infection

52. Nutritional Supplements Vitamin C ( Ascorbic Acid) Essential cofactor in synthesis of collagen Excessive concentrations of ascorbic acid do not promote supranormal healing Vitamin E Therapeutic efficacy and indications remain to be defined Large doses of vitamin E inhibit healing Increase the breaking strength of wounds exposed to preoperative irradiation

53. Nutritional Supplements Glutamine Enhance actions of lymphocytes, macrophages and neutrophils Glycine Inhibitory effect on leukocytes, might reduce inflammation related tissue injury Zinc common constituent of dozens of enzymes Influences B and T cell activity epithelial and fibroblastic proliferation is impaired in patients with low serum zinc levels

54. Factors in Wound Healing Smoking 1ppd = 3x ↑ freq of flap necrosis 2ppd = 6x ↑ freq of flap necrosis Nicotine acts via the sympathetic system Vasoconstriction and limit distal perfusion 1 cigarette = vasoconstriction > 90 min Decrease proliferation of erythrocytes, macrophages and fibroblasts Smoke contains high levels of carbon monoxide shifts the oxygen-hemoglobin curve to the left decreased tissue oxygen delivery

55. Syndromes Associated with Abnormal Wound Healing Cutis Laxa Think defective elastin fibers Congenital AD, recessive or X-linked recessive Acquired Drug, neoplasms or inflammatory skin conditions Ehlers-Danlos Syndrome Think defective collagen metabolism AD and recessive patters 10 phenotypes

57. Syndromes Associated with Abnormal Wound Healing Ehlers-Danlos Syndrome Connective tissue abnormalities due to defects: Inherent strength Elasticity Integrity Healing properties

58. Syndromes Associated with Abnormal Wound Healing Ehlers-Danlos Syndrome Four major clinical features Skin hyper-extensibility Joint hyper-mobility Tissue fragility Poor wound healing

60. Electrostimulation Electrical current applied to wounds Increases migration of cells 109% increase in collagen 40% increase in tensile strength 1 to 50 mA direct or pulsed based on wound

61. Hyperbaric Oxygen Developed 1662 by Henshaw: Domicillium Atmospheric pressure at sea level = 1 ATA = 1.5ml O2/dL Normal SubQ O2 tension is 30-50 mmHg. SubQ O2 tension < 30 mmHg = chronic wound

62. Excessive Healing Hypertrophic Scars Keloids

63. Hypertropic Scar

64. Keloids Extends beyond original bounds Raised and firm Rarely occur distal to wrist or knee Predilection for sternum, mandible and deltoid Rate of collagen synthesis increased Water content higher Increased glycosaminoglycans

65. Keloid Treatment Triamcinolone (steroid) injections 3-4 weeks Cross linking modulated Injections continued until no excess abnormal collagen Excise Prevention during healing – pressure and injection

66. Keloid

68. Keloid Scar

70. Marjolin’s Ulcer Jean-Nicolas Marjolin (1828) Aggressive ulcerating SCC Occurs in setting of chronic inflammation Burn wounds Venous stasis ulcers Previous radiation therapy Characterized by Slow growth Painless Persistent granulation

72. Questions

73. The proliferative phase of wound healing occurs how long after the injury? A. 1 day B. 2 days C. 7 days D. 14 days

74. The proliferative phase of wound healing occurs how long after the injury? A. 1 day B. 2 days C. 7 days D. 14 days

75. Which type of collagen is most important in wound healing? A. Type III B. Type V C. Type VII D. Type XI

76. Which type of collagen is most important in wound healing? A. Type III B. Type V C. Type VII D. Type XI

77. The tensile strength of a wound reaches normal (pre-injury) levels: A. 10 days after injury B. 3 months after injury C. 1 year after injury D. never

78. The tensile strength of a wound reaches normal (pre-injury) levels: A. 10 days after injury B. 3 months after injury C. 1 year after injury D. never

79. Which of the following is commonly seen in Ehlers- Danlos syndrome? A. Small bowel obstructions B. Spontaneous thrombosis C. Direct hernia in children D. Abnormal scarring of the hands with contractures.

80. Which of the following is commonly seen in Ehlers- Danlos syndrome? A. Small bowel obstructions B. Spontaneous thrombosis C. Direct hernia in children D. Abnormal scarring of the hands with contractures.

81. Steroids impair wound healing by: A. Decreasing angiogenesis and macrophage migration B. Decreasing platelet plug integrity C. Increasing release of lysosomal enzymes D. Increasing fibrinolysis

82. Steroids impair wound healing by: A. Decreasing angiogenesis and macrophage migration B. Decreasing platelet plug integrity C. Increasing release of lysosomal enzymes D. Increasing fibrinolysis

83. Supplementation of which of the following micronutrients improves wound healing in patients without micronutrient deficiency? A. Vitamin C B. Vitamin A C. Selenium D. Zinc

84. Supplementation of which of the following micronutrients improves wound healing in patients without micronutrient deficiency? A. Vitamin C B. Vitamin A C. Selenium D. Zinc

85. Signs of malignant transformation in a chronic wound include: A. Persistent granulation tissue with bleeding B. Overturned wound edges C. Non-healing after 2 weeks of therapy D. Distal edema

86. Signs of malignant transformation in a chronic wound include: A. Persistent granulation tissue with bleeding B. Overturned wound edges C. Non-healing after 2 weeks of therapy D. Distal edema

87. The treatment of choice for keloids is: A. Excision alone B. Excision with adjuvant therapy (e.g. radiation) C. Pressure treatment D. Intralesional injection of steroids

88. The treatment of choice for keloids is: A. Excision alone B. Excision with adjuvant therapy (e.g. radiation) C. Pressure treatment D. Intralesional injection of steroids

89. The major cause of impaired wound healing is: A. Anemia B. Diabetes mellitus C. Local tissue infection D. Malnutrition

90. The major cause of impaired wound healing is: A. Anemia B. Diabetes mellitus C. Local tissue infection D. Malnutrition

91. Bradykinin, serotonin, and histamine in wounds are released from: A. Lymphocytes B. Mast cells C. Polymorphonuclear leukocytes D. Platelets

92. Bradykinin, serotonin, and histamine in wounds are released from: A. Lymphocytes B. Mast cells C. Polymorphonuclear leukocytes D. Platelets

93. Platelets in the wound form a hemostatic clot and release clotting factors to produce: A. Fibrin B. Fibrinogen C. Thrombin D. Thromboplastin

94. Platelets in the wound form a hemostatic clot and release clotting factors to produce: A. Fibrin B. Fibrinogen C. Thrombin D. Thromboplastin

95. In a healing wound, metalloproteinases are responsible for: A. Establishing collagen cross-link B. Glycosylation of collagen molecules C. Incorporation of hydroxyproline into the collagen chain D. Initiating collagen degradation

96. In a healing wound, metalloproteinases are responsible for: A. Establishing collagen cross-link B. Glycosylation of collagen molecules C. Incorporation of hydroxyproline into the collagen chain D. Initiating collagen degradation

97. Severe cases of hidradenitis suppurativa in the groin area are best managed by excision of the involved area and? A. Closure by secondary intension B. Delayed primary closure C. Primary closure D. Split thickness skin grafting

98. Severe cases of hidradenitis suppurativa in the groin area are best managed by excision of the involved area and? A. Closure by secondary intension B. Delayed primary closure C. Primary closure D. Split thickness skin grafting

99. All of the following statements about keloids are true except? A. Keloids do not regress spontaneously B. Keloids extend beyond the boundaries of the original wound C. Keloids or hypertrophic scars are best managed by excision and careful reapproximation of the wound D. Keloid tissue contains an abnormally large amount of collagen.

100. All of the following statements about keloids are true except? A. Keloids do not regress spontaneously B. Keloids extend beyond the boundaries of the original wound C. Keloids or hypertrophic scars are best managed by excision and careful reapproximation of the wound D. Keloid tissue contains an abnormally large amount of collagen.

101. The following photograph most accurately demonstrates: A. Hypertropic Scar B. Auricular Lymphedema C. Keloid Scar D. “Cauliflower” ear

102. The following photograph most accurately demonstrates: A. Hypertropic Scar B. Auricular Lymphedema C. Keloid Scar D. “Cauliflower” ear

103. The Proliferative Phase of wound healing is classically described as beginning: A. Immediately after injury B. When the wound is covered with epithelium C. When the collagen content has reached equilibrium D. When the macrophage enters the wound

104. The Proliferate Phase of wound healing is classically described as beginning: A. Immediately after injury B. When the wound is covered with epithelium C. When the collagen content has reached equilibrium D. When the macrophage enters the wound

105. Under ideal circumstances the tensile strength of the wounded area reaches what % of strength compared to normal skin? A. 10-20% B. 20-40% C. 60-70% D. 70-90%

106. Under ideal circumstances the tensile strength of the wounded area reaches what % of strength compared to normal skin? A. 10-20% B. 20-40% C. 60-70% D. 70-90%

107. Which of the following does NOT affect wound healing A. Infection B. Hydration C. Nutrition D. Denervation

108. Which of the following does NOT affect wound healing A. Infection B. Hydration C. Nutrition D. Denervation

109. Acknowledgements Edward R. Newsome, MD

110. Thank You