Periodic synopsis This report reflects the best data available at the time the report was prepared, but caution should be exercised in interpreting the data. The results of future studies may require alteration of the conclusions or recommendations set forth in this report.
Wound healing Vincent Falanga, M.D.,* John A. Zitelli, M.D.,** and William H. Eaglstein, M.D.*
MiamL FL, and Pittsburgh, PA
I. General concepts A. Skin wounds may be classified as full thickness or partial thickness. B. In full thickness wounds the defect is deeper than the adnexa. 1. Full thickness wounds heal by contraction in addition to granulation formation and epithelialization. Contraction causes a 40% decrease in the size of the wound. 2. In full thickness wounds epithelialization occurs from the wound edges. 3. Contraction may be inhibited by full thickhess grafts and the skin flaps. C. In partial thickness wounds, parts of the adnexa remain in the wound bed. 1. Partial thickness wounds contract less than full thickness wounds and in indirect proportion to the depth. 2. In partial thickness wounds epidermal resurfacing occurs from both the wound edges and the adnexa within the wound bed. D. Wound contraction begins at 1 week after wounding. E. The cosmetic result of healed wounds on the face is better when wounds are located in concave areas than in convex areas. F. Wound colonization with normal skirt flora does not influence wound healing. Light coloFrom the Universityof Miami School of Medicine, Degartmeat of Dermatology and Cutaneous Surgery,* and the University of Pittsburgh School of Medicine, Department of Dermatology.** Reprint requests to: Dr. Vincent Falanga, University of Miami, Department of Dermatology and Cutaneous Surgery, P.O. Box 016250, Miami, FL 33101.
nization with pathogenic bacteria may not interfere, but infection will inhibit healing. G. Tensile strength in a wound increases progressively up to 1 year after wounding. Tensile strength in a healed wound, however, will always be less than 80% of normal. H. Healing time is related to the logarithm of the area, but the width of the wound is a better predictor of healing time than the area. I. Wounds created by destructive techniques (e.g., cryosurgery, electrosurgery, laser surgery, and chemical cautery) heal more slowly than clean wounds created by scalpel or curet surgery. II. Cellular components A. Platelets play a direct role immediately after wounding, and thrombocytopenia may interfere with healing. 1. By adhering to collagen, platelets aggregate and degranulate. 2. Platelet aggregation causes release of adenosine diphosphate, thromboxane A2, and 5-hydroxytryptamine. These substances cause further platelet aggregation. 3. The formation of a clot, important in hemostasis and cellular movement, results from platelet aggregation and the release of tissue thromboplastin. 4. Platelets release factors that are chemotactic for leukocytes. These factors include 12-hydroxyeicosatetraenoic acid (12HETE), 12-hydroperoxytieosatetraenoic acid (12-HPETE), proteolytic enzymes capable of initiating complement activation and production of C5, and growth factors.
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B. Neutrophils appear in a wound 6 hours after the wounding event, reach their greatest number after 24 to 48 hours, and start disappearing after 72 hours. 1. The role of neutrophils is initial wound debridement. 2. Neutrophils are not erucial cells in wound healing, inasmuch as neutropenia does not interfere with healing. C. Macrophages are the essential and most important cells in wound healing. 1. They are derived from blood monocytes and are most numerous in the wound between 3 and 5 days after wounding. 2. Their function includes wound debridement, the release of angiogenic substances, and fibroblast stimulation. 3. Macrophages also produce interleukin 1, which increases fibroblast stimulation and induces helper T ceils to secrete interleukin 2. D. Lymphocytes play an important role in wound healing but not an essential one, inasmuch as lymphopenia does not interfere with healing. 1. Important lymphokines include those that attract and affect macrophages, such as macrophage migration inhibition factor, and macrophage-activating factor. 2. Other lyrnphokines may stimulate fibroblast growth and protein synthesis directly. E. Fibroblasts populate the wound after 48 to 72 hours. 1. Fibroblasts move in the wound along extracellular matrix material, especially collagen, fibrin, and fibronectin. 2. The lag phase refers to the additional 2 days it takes fibroblasts to start macromolecular synthesis after they appear in the wound. 3. Growth of fibroblasts is enhanced by low oxygen and high lactate levels. 4. Fibroblasts synthesize collagen, proteoglycans, and elastin. 5. Myofibroblasts are modified fibroblasts that resemble smooth muscle cells in morphology and function. They contain large amounts of contractile proteins and are responsible for wound contraction. F. Epidermal healing depends first on epidermal cell migration (first 24 hours) and later, epi-
Journal of the American Academy of Dermatology dermal cell mitosis, which peaks after 48 hours. The final step is epidermal cell maturation. 1. A moist environment is helpful for epidermal cell migration. 2. Fibrin and fibronectin provide the substrate for migration. 3. Epidermal cells secrete epidermal thymocyte activation factor, which is identical to interleukin 1. 4. Epidermal migration and proliferation occur from the epithelial cells at the edge of the wound and from appendageal structures remaining in the wound bed. 5. Epidermal migration may be stimulated by serum growth factors and inhibited by epidermally derived factors (chalones). G. Angiogenesis in the wound occurs at about the same time that fibroblasts appear. 1. Angiogenic factors are produced by macrophages. 2. Angiogenesis is increased with low oxygen tension and lactic acid accumulation. 3. Angiogenesis depends on chemotaxis, mitogenesis, and extracellular matrix. III. Substrate and matrix components A. Fibronectin is a 440,000-dalton glycoprotein that is synthesized by fibroblasts and endothelial cells. 1. Fibronectin is present early in the wound. 2. One of the first events in wound healing is the formation of a fibrin-fibronectin matrix that acts as a structural support for cell migration. B. Collagen is made up of three identical polypeptide chains that are wound together in a left-handed helix. Every third amino acid is glycine, and proline makes up 25% of the structure. 1. Type III collagen is first deposited in the wound after 2 days but is replaced by the more stable type I collagen after several weeks. 2. In the process of wound remodeling, new collagen is laid down as old collagen is removed by collagenases, produced by macrophages, neutrophils, and epidermal cells. C. Laminin and collagen type IV are laid down as components of nonmigrating epidermal ceils. D. Proteoglycans, including hyaluronic acid and
Volume 19 Number 3 September 1988 chondroitin sulfate, are synthesized by fibreblasts. Their synthesis is maximal at 2 weeks after wounding. 1. Proteoglycans may participate in the regulation of collagen synthesis and cellular interactions. 2. Together with elastin, also synthesized by fibroblasts, proteoglycans are important matrix components. IV. Growth factors A. Epidermal growth factor is a heat-stable polypeptide with a molecular weight of 6000. Its tissue source is unclear, but epidermal growth factor is present in the epidermis among other tissues and fluids. 1. Epidermal growth factor increases mitosis in epidermal cell cultures. 2. Epidermal growth factor enhances nutrient transport into cells and increases glycolysis, synthesis of fibronectin, and amounts of deoxyribonucleic acid and ribonucleic acid. 3. Epidermal growth factor increases glycesaminoglycans synthesis by dermal fibreblast cutlures. 4. Epidermal growth factor increases granulation tissue and may enhance reepithelialization. B. Platelet-derived growth factor is chemotactic for fibroblasts, smooth muscle cells, neutroplaits, and mononuclear cells. It exists in at least two forms, with a molecular weight of 31,000. Platelet-derived growth factor may stimulate cell division without the need for progression factors in plasma. C. Transforming growth factor-beta is a polypeptide (molecular weight, 24,000) that is stored in platelets and is released during platelet aggregation. It induces fibrosis and angiogenesis in vivo, and collagen and proteoglycan synthesis in vitro. It increases granulation tissue and tensile strength. D. Fibroblast growth factor exists in a basic and acidic form. The basic form may be more potent than the acidic form. Both fibroblast growth factors are potent mitogens for endothelial cells and induce blood vessel growth in vivo. V. W o u n d dressings A. Occlusion of wounds leads to fasterhealing. I. Occlusive dressings allow moist wound
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healing. They prevent crust formation and drying of the wound bed. 2. The rate of epithelializafion is faster under occlusive dressings. 3. Wound fluid from under occlusive dressings is favorable to fibroblast proliferation. 4. Adhesive occlusive dressings may remove newly formed epithelium. 5. Hydrocolloid adhesive occlusive dressings prevent entry of bacteria into the wound. 6. The use of occlusive dressings in chronic wounds leads to less pain, better granulation tissue, and painless wound debridement. 7. In acute wounds, occlusive dressings promote bacterial growth but their use results in faster reepithelialization. VI. Topical therapy A. Topical steroids may interfere with healing because of their anti-inflammatory action. B. Topical antimicrobial agents that may enhance reepithelialization include neomycin, polymyxin B, Neosporin ointment, silver sulfadiazine, and 20% benzoyl peroxide lotion. Some chemicals such as hexachlorophene, chlorhexidine, and alcohol, among others, may retard reepithelialization. C. Topical vitamin A may offset the detrimental effects of systemic steroids on wound healing. D. Chlorhexidine may cause corneal opacities on contact and should be used cautiously on the face. VII. Systemic factors A. Malnutrition interferes with healing. A low serum albumin or transferrin level suggests malnutrition. B. Vitamin C and zinc deficiency lead to poor healing. C. Systemic steroids in a dose greater than 10 mg a day interfere with healing. D. Dacfinomycin, bleomycin, or carmustine are more likely to impair healing than methotrexate, 5-fluorouracil, or cyclophosphamide. Clinical experience, however, suggests no impairment of wound healing in patients taking chemotherapeutic drugs for internal malignancy. E. Aging may be associated with in vitro effects suggestive of abnormal healing and may result
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in slower acquisition of tensile strength. In most clinical situations, however, age has little effect on wound healing.
Clark RAF, Winn H J, Dvorak HF, Colvin RB. Fibronectin beneath re~pithializing epidermis in vivo: sources and significance. J Invest Dermatol (suppl) 1983;80:2630. Clore YN, Cohen LK, Diegelmann RF. Quantitation of collagen types I and III during wound healing in rat skin. Proc Soc Exp Biol Med 1979;161:337-40. Silbert JE. Structure and metabolism of proteoglycans and glycosaminoglycans. J Invest Dermatol 1982;79(suppl):31-37. Takashima A, Billingham RE, Grinnell F. Activation of rabbit keratinocyte fibronectin receptor function in vivo during wound healing. J Invest Dermatol 1986;86:58590. Woodley DT, O'Keefe E J, Prunieras M. Cutaneous wound healing: a model for cell-matrix interactions. J AM ACAD DERMATOL1985;12:420-33.
General c~ncepts Eaglstein WH. The genesis of wound repair. In: Thiers B, Dobson R, eds. The pathogenesis of sldn disease. New York: Churchill Livingstone, 1985:617-23. Hunt TK, Heppenstall RB, Pines E, Rovee D, eds. Soft and hard tissue repair. New York: Praeger, 1984:31623. Dineen P, et al., eds. The surgical wound. Philadelphia: Lea & Febiger, 1981:150-70. Zitelli JA. Wound healing by secondary intention: a cosmetic appraisal. J AM ACAO DERMhTOL 1983;9:40715. II. Cellular components Alexander S. Patterns of epidermal cell polarity in healing open wounds. J Surg Res 1981;31:456-62. Bar-Shavit R, Kahn A, Fenton JW, Wilner GD. Chemotactic response of monocytes to thrombin. J Cell Biol 1983;96: 282-5. Clark RAF. Cutaneous tissue repair: Basic biologic considerations. I. J AM ACAD DERMATOL 1985;13:70125. Duel TF, Senior RM, Huang J J, Griffin GL. Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest 1982;69:1046-9. Kanzler MH, Gorsulowsky DC, Swanson NA. Basic mechanisms in the healing of cutaneous wound. J Dermatol Surg Oncol 1986;12:1156-64. Leibovich SJ, Ross R. A macrophage-dependent factor that stimulates the proliferation of fibroblasts in vitro. Am J Patbol 1976;84:501-13. Leibovich S J, Ross R. The role of the macrophage in wound repair: a study with hydrocortisone and antimaerophage serum. Am J Pathol 1975;78:71-7. Rutherford R, Ross R. Platelet factors stimulate fibroblasts and smooth musele cells quiescent in plasmaserum to proliferate. J Cell Biol 1976;69:196-203. Schmidt JA, Mizel SB, Cohen D, Green I. Interleukin 1, a potential regulator of fibroblast proliferation. J Immunol 1982;128:2177-82. Thakral KK, Goodson WH III, Hunt TK. Stimulation of wound blood vessel growth by wound macrophages. J Surg Res 1979;26:430-6. Tsukamoto Y, Helsel WE, Wahl SM. Macrophage production of fibronectin, a chemoattractant for fibroblasts. J Immunol 1981;127:673-8. III. Substrate and matrix components Clark RAF. Fibroneotin in the skin. J Invest Dermatol 1983;81:475-9.
Growth factors Brown GL, Curtsinger L III, BrightweU JR, et al. Enhancement of epidermal regeneration by biosynthetic epidermal growth factor. J Exp Meal 1986;163:131924. Castor WC, Cabral AR. Growth factors in human disease: the realities, pitfalls, and promise. SCm Arthritis Rheum 1985; 15:33-44. Buckley A, Davidson J1V[, Kamerath CD, Wolt TB, Woodward SC. Sustained release of epidermal growth factor accelerates wound repair. Proc Natl Acad Sci USA 1985; 82:7340-4. Duel TF, Senior RM, Huang J J, Griffin GL. Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest 1982;69:1046-9. Grotendorst GR, Chang T, Seppa HE J, et al. Plateletderived growth factor is a chemoattractant for vascular smooth muscle cells. J Cell Physiol 1982;113:261-6. Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Deuel TF. Accelerated healing of incisional wounds in rats induced by transforming growth factorbeta. Science 1987;237:1333-6. Sporn MB, Roberts AB, Shull JH, Smith JM, Ward JM. Polypeptide transforming growth factors isolated from bovine sources and used for wound heailng in vivo. Science 1983; 219:1329-31. Sporn MB, Roberts AB. Peptlde growth factors and inflammation, tissue repair and cancer. J Clin Invest 1986;78:328-32. Thomas KA, Gimenez-Gallego G. Fibroblast growth factors: broad spectrum mitogens with potent angiogenic activity. Trends Biochem Sci 1986;11:1-4. Wound dressings Alper JC, Welch EA, Gimberg M, Bogaars H, Maguire P. Moist wound healing under a vapor permeable membrane. J AM ACADDERMATOL1983;8:347-53. Eaglstein WH, Mertz PM, Falanga V. Occlusive dressings. Am Faro Physician 1987;35:211-6.
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Linsky CB, Rovee DT, Dow T. Effect of dressing on wound inflammation and sear tissue. In: Hildick-Smith G, Dineen P, eds. The surgical wound. Philadelphia: Lea & Febiger, 1981:191-206. Mertz PM, Eaglstein WH. The effect of a semiocclusive dressing on the microbial population in superficial wounds. Arch Surg 1984;119:287-9. Mertz PM, Marshall DA, Eaglestein WH. Occlusive wound dressings to prevent bacterial invasion and wound infection. J AM ACAD DERMATOL1985;12:662-8. Pruitt PA, Levine NS. Characteristics and uses of biologic dressings and skin substitutes. Arch Surg 1984;119:312-2Z VI. Topical therapy Eaglestein WH, Mertz PM, Alvarez OM. Effect of topically applied agents on healing wounds. In: Eaglstein WH, ed. Clinics in Dermatology. Philadelphia: Lippincott, 1984:112-5. Hunt TK, Ehrlich PH, Gareia JA, Englebert Dunphy J. Effect of vitamin A on reversing the inhibitory effect of
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cortisone on healing of open wounds in animals and man. Ann Surg 1969;170:633-41. Reed BR, Clark RAF. Cutaneous tissue repair: practical implications of current knowledge. II. J AM ACAD DERMATOL 1985; 13:919-41. VII. Systemic factors Bland K.I, Palin WE, yon Fraunhofer A J, et al. Experimental and clinical observations of the effects of cytotoxie chemotherapeutic drugs on wound healing. Ann Surg 1984;199:782-90. Falanga V, Eaglstein WH. Management of venous ulcers. Am Faro Physician 1986;33:274-81. Goodson WH, Hunt TK. Wound healing and aging. 3 Invest Derrnatol 1979;73:88-91. Pollack SV. Systemic drugs and nutritional aspects of wound healing. In: Eaglstein WH, ed. Clinics in Dermatology. Philadelphia: B Lippineott, 1984:68-80. Zitelli JA. Wound healing for the clinician. Adv Dermatol 1987;2:243-68.