Modern Wound Healing: Background and Significance
The physiologic process of wound healing begin immediately upon tissue injury starting with inflammation. The physiological needs during the INFLAMMATORY PHASE (Days 0-5) are4:
- Moist wound environment
- Optimum pH
- Essential trace elements
Winter5 and Hinman et al.6 documented that increased healing rates are associated with moist wound healing versus dry healing. The natural environment of a cell is a moist one and a dehydrated tissue environment may impair normal cell function and repair. Since a wound is a break in the skin, it will allow the escape of moisture vapor from the underlying moist tissues and the eventual death of superficial cells--called dehydration necrosis. This process contributes to crust formation along with the drying of released blood and sera7. The scab itself presents very little barrier to further moisture loss as compared to normal unbroken skin.
B. Optimum pH
All biochemical reactions, in particular enzyme activities are dependent on a specific pH value. The acidification of the tissue by CO2-constriction (acidosis) represents the optimal biochemical condition for the repair of damaged tissue8,9,10.
C. Essential trace elements
Zinc and iron are required substances for various aspects of wound healing. Specifically zinc plays an important role in the activity of different matrix metalloproteinases (MMPs). MMPs are a family of zinc-dependant endopeptidases that cleave peptide bonds of extracellular matrix proteins, such as collagens, elastin and proteoglycans. Jia et al have shown that collagen-degrading MMPs facilitate the initiation of angiogenesis. Newly formed blood vessels participate in granulation tissue formation which is critical in re-establishing skin integrity. Both inflammatory cells and fibroblasts require the interaction with and transmigration through blood vessels to enter the site of injury. Vascular epithelial growth factor, VEGF, is produced in large quantities by the epidermis during wound healing11. This growth factor has potent pro-angiogenic activity and is a prime regulator in the wound, which is critical during granulation tissue formation12. An additional two crucial zinc-dependent enzymes involved in tissue repair are DNA and RNA polymerase. These enzymes play a critical role in cell proliferation and protein synthesis for proper wound healing. Other studies have demonstrated that zinc promotes epidermal proliferation and migration. Agren et al. demonstrated that local zinc oxide treatment promoted re-epithelization in pigs with normal zinc status compared with control un-treated wounds13.
Iron is an essential nutrient, which is utilized by all eukaryotic cells for survival and growth14. Iron is required for cell multiplication through the activity of ribonucleotide reductase, which is an important enzyme in DNA synthesis. Human fibroblasts require iron for in-vitro growth15 Iron is also essential for hydroxylation of collagen, but information regarding its direct role in wound healing is limited.
5 Winter GD. Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig. Nature 193:293 1962
6 Hinman C, Maibach H. Effect of air exposure and occlusion on experimental human skin wounds. Nature 200:377,1963.
7 Nemeth AJ, Eaglstein WH, Taylor JR, et al. Faster healing and less pain in skin biopsy sites treated with an occlusive dressing. Archives of Dermatology, Vol 127, November 1991, pp1679-1683.
8 Liu, K., Kalen, A., Fibroblast proliferation due to exposure to a platelet concentrate in vitro is pH dependent, Wound Repair Regen, 2002 Sep-Oct; 10 (5): 336-40
9 Rippke, F., Schreiner, V., The acidic milieu of the horny layer: new findings on the physiology and pathophysiology of skin pH, Am J Clin Dermatol 2002; 3 (4): 261-72
10 Lengheden, A. Jansson, L., pH-effects on experimental wound healing of human fibroblasts in vitro, Eur J Oral Sci 1995; 103 (3): 148-55
11 Brown LF, Yeo K-T, Berse B, Yeo T-K, Senger HF, Dvorak HF, Van De Water L.Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes dureing wound healing. J Exp Med 176: 1375-9. 1992.
12 NissenNN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, DiPietro LA. Vascular endothelial growth factor meidates angiogenesis activity during the proliferative phase of wound healing. Am J Pathol 152: 1445-52, 1998.
13 Agren, M S, Studies on zinc in wound healing, Acta Derm Venereol Suppl (Stockh) 1990;154:1-36
14 Oken, Emily, Update on micronutrients: iron and zinc, Curr Opin Pediatr 2002 Jun;14(3):350-3
15 Whittaker, P, Iron and zinc interactions in humans, Am J Clin Nutr 1998 Aug;68(2 Suppl):442S-446S.