SUMMARY
Zinc oxide is a common ingredient in bandages for wound management. Experimental studies have demonstrated beneficial effects of topical zinc oxide on the restoration of epithelium during wound repair by as yet unknown mechanisms of action. In this study, zinc oxide was found to up-regulate one growth factor (insulin-like growth factor-1) and matrix metalloproteinase activity several fold in standardised.porcine wounds. These findings indicate that zinc oxide promotes epithelialisation by enhancing endogenous growth factors and enzymes important for epithelial proliferation and migration.
Zinc is an essential trace element for development and growth. More than 300 enzymes are dependent on zinc for activity such as matrix metalloproteinases; (MMPs), and DNA and RNA polyrnerasesl,2. Zinc fingers belong to an even larger group of zinc-containing proteins. 1-3 These zinc protrusions are found predominately in transcription factors that interact with the promoter region of DNA before a segment is transcribed into RNA coding for growth factors.3
The crucial role of zinc in these biological and biochemical systems can explain the retarded wound repair response seen in zinc deficient patients and normalization of the wound healing mechanisms with zinc therapy.4 However, there is limited evidence for using zinc externally unless the patient is truly zinc deficient. Zinc is more commonly used as zinc oxide in various topical preparations to treat skin lesions.5 In contrast to zinc given orally, zinc administered topically appears to be beneficial regardless of zinc status.6 The increased demand for zinc during wound repair is satisfied for prolonged periods by zinc oxide administered to the wound site.6,7 When applied locally, zinc oxide is solubilized slowly and supraphysiological concentrations of ionic zinc (an elevation of about 4-5 times) are achieved at the wound site over an extended period.8 We have demonstrated a stimulatory action of zinc oxide on the healing of leg ulcers compared with placebo in a double-blind, randomized controlled clinical trial.9 Beneficial healing effects of topical zinc oxide have also been confirmed repeatedly in skin wounds of various depths in zinc-sufficient pigs. Specifically, zinc oxide accelerates re-epithelialisation by yet unknown mechanisms.6 The polypeptide growth factor IGF-I is crucial for epidermis homeostasis and the zinc-dependent MMPs are required for optimal epithelial migration. 10-12 Our aims were to examine the effect of zinc oxide on endogenous IGF-I levels and MMP activation in wounds in domestic pigs on zinc-sufficient diets.

In the present experimental study, locally applied zinc oxide promoted epithelialisation of standardized full-thickness skin wounds confirming previous results in a partial-thickness wound model in pigs.6 Apart from zinc's moderate anti-bacterial, anti-inflammatory and cytoprotective activities, 14-17 our biochemical and cellular findings can possibly explain zinc's mechanisms of action on epithelialisation of cutaneous wounds. Zinc oxide activated endogenous zinc-dependent matrix metalloproteinases, which may facilitate keratinocyte migration. Furthermore, zinc oxide augmented endogenous expression of one growth factor insulin-like growth factor-I (IGF-I) in granulation tissue. Recent in vitro work, where zinc enhanced epithelial migration due to up-regulation of IGFI specifically in fibroblasts, supports the hypothesis that zinc promotes wound healing by increasing endogenous growth factors. 18 In addition, other cell culture studies showed synergistic effects of zinc and IGF-I in NIH 3T3 fibroblasts. 19 Baroni et al.20 added zinc oxide to human dermal fibroblasts and observed increased secretion of fibroblast growth factor (FGF) suggesting that zinc in granulating wounds is also possibly capable of up-reg4lating growth factors other than IGF-I. Hansson2l found that zinc ions up to 1 mM mimicked the action of growth factors by enhancing enzyme-dependent intracellular mitogenic signal pathways in Swiss 3T3 fibroblasts. Topical zinc also appeared to promote healing of small and acute skin wounds in humans.22,23 Work in our laboratory is in progress to elucidate the action of topical zinc oxide on acute wounds healing by secondary intention in humans. Our study indicates that apart from being an essential trace element, zinc exerts beneficial pharmacological actions on wound healing when applied locally as zinc oxide. Oral zinc merely corrects a nutritional deficit. Increased endogenous expression of IGF-I and activation of MMPs may explain the stimulatory action of zinc oxide on resurfacing of wounds.