Copper Oxide Impregnated Wound Dressing: Biocidal and Safety Studies

Gadi Borkow, PhD; Neta Okon-Levy, PhD; Jeffrey Gabbay

Disclosures

Wounds. 2010;22(12):301-310. 

In This Article

Abstract and Introduction

Abstract

Copper plays a key role in angiogenesis and in the expression and stabilization of extracellular skin proteins. Copper also exhibits broad biocidal properties. The authors hypothesized that introducing copper into a wound dressing would not only reduce the risk of wound and dressing contamination, but would also stimulate wound repair. To test this hypothesis, non-stick dressings composed of a highly absorbent internal mesh fabric and an external non-woven fabric were fabricated, and each was impregnated with ~2.65% (weight/weight) copper oxide particles. The application to wounds inflicted in genetically engineered diabetic mice resulted in increased gene and in-situ upregulation of proangiogenic factors, increased blood vessel formation, and enhanced wound closure. The present study reports both the potent broad spectrum antimicrobial and antifungal properties of these wound dressings and the lack of adverse reactions as determined in rabbits and a porcine wound model. The prolonged efficacy of the wound dressing is demonstrated by its capacity to reduce the microbial challenge by more than 99.9% even when spiked 5 consecutive times with a high bacterial titer. The dressing's antimicrobial efficacy is exerted within minutes. The dressing did not cause any skin irritation or sensitization to closed skin. Furthermore, no histological differences were found between open wounds exposed to copper oxide containing wound dressings or control dressings. Therefore, copper containing wound dressings hold significant promise in wound healing and their clinical use should be explored.

Introduction

Copper ions, either alone or in copper complexes, have been used for centuries to disinfect liquids, solids, and human tissue. Several mechanisms for the potent biocidal activity of copper have been proposed, which include alteration of proteins, and inhibition of their biological assembly and activity; plasma membrane permeabilization; and membrane lipid peroxidation.[1] Sensitivity to copper may vary significantly among different bacteria[2] or among bacteria of the same strains. For example, Enterococci bacteria isolated from the gut of pigs whose diet included high copper concentrations over many months were 7-fold less susceptible to copper than Enterococci bacteria isolated from pigs that were not fed copper.[3] The increased tolerance to copper is achieved by the induction of an efflux pump in the tolerant bacteria. Similarly, reduced sensitivity to copper was found in nitrifying soil microorganisms exposed to copper for nearly 80 years under field conditions.[4] However, copper-tolerant microbes are extremely rare, even though copper has been a part of the earth for millions of years and in use by humans for thousands of years.[5] Furthermore, the microorganisms described above were up to 10-fold less sensitive to copper than the sensitive bacteria. This is a clear distinction from antibiotic resistant microbes that have evolved in less than 50 years of use, which in some cases have up to 2200-fold decreased sensitivity to the antibiotic (eg, erythromycin).[6] This lack of resistance to copper may be explained by the capacity of copper to damage in parallel many key components of microorganisms in a nonspecific mechanism.[1]

Human skin, in contrast to microorganisms, is not sensitive to copper and the risk of adverse reactions due to dermal exposure to copper is extremely low.[7,8] Copper is not only considered safe for humans, as demonstrated by the widespread and prolonged use of copper intrauterine devices (IUDs) by women,[9,10] but it is an essential metal that facilitates normal metabolic processes.[11] The US National Academy of Sciences Committee recommends a daily allowance of 0.9 mg of copper for normal adults. This committee also noted that daily intake of up to 3 mg/d in children and 8 mg–10 mg/d for adults is considered tolerable and nontoxic.[12]

More data are being gathered to support the hypothesis that copper is involved and may be a key player in many of the complicated processes that comprise the wound repair mechanism. Some obvious examples include stimulation of angiogenesis facilitated by the Cu2+ -dependent formation of multiprotein complexes containing the S100A[13] protein;[13] stimulation of angiogenesis facilitated by induction of vascular endothelial growth factor (VEGF);[14–16] expression of integrin;[17] stabilization of fibrinogen and collagen;[18–20] upregulation of copper-dependent enzymes, such as lysyl oxidase, important for matrix remodeling, cell proliferation, and re-epithelization;[21,22] reduction of tissue oxidative damage after injury;[23] and activation of tissue remodeling.[24] The importance of copper in wound healing is further demonstrated by the positive and beneficial effect of its administration in cases of severe burn trauma in children[25] and in the management of phosphorus burns.[26]

Evidence continues to show that bacteria in chronic wounds live within biofilm communities, in which the bacteria are protected from host defenses and develop resistance to antibiotic treatment.[27] Considering the potent biocidal activities of copper,[1] the minimal risk of adverse skin reactions associated with copper,[7,8] and its roles in the wound healing process, the authors hypothesized[28] that the addition or application of copper or copper containing products to wounds, such as copper containing Band-Aids and pads, would not only reduce the risk of wound and dressing contamination, as does silver, but, more importantly, may significantly enhance the wound healing process, especially in cases where the healing process is impaired (eg, diabetic ulcers).

Indeed, application of the wound dressings containing copper oxide to wounds inflicted in genetically engineered diabetic mice (C57BL/KsOlaHsd-Leprdb) resulted in increased gene and in-situ upregulation of proangiogenic factors (eg, placental growth factor, HIF-1a, and VEGF), increased blood vessel formation (P < 0.05) and enhanced wound closure (P < 0.01), as compared to control dressings (without copper) or commercial wound dressings containing silver.[29] The following study presents the biocidal properties of nonstick dressings containing copper oxide particles and their safety in animal models.

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