See the Skin Health Overview article

Summary

  • While each essential mineral has a role in normal skin development and function, few have been studied in the context of optimal skin health; this article highlights the existing research on zinc and selenium. (More information)
  • Minerals are found in the skin as essential components of various enzymes and inside a special metal-binding protein, metallothionein. (More information)
  • Insoluble mineral oxide formulations remain on the upper layers of the skin and are not systemically absorbed. The organic form of selenium, L-selenomethionine, is absorbed through the skin and reaches the bloodstream. (More information)
  • Mineral oxides absorb and filter UVA and UVB, reducing the amount of UVR that penetrates the layers of the skin. Minerals may also augment antioxidant defense mechanisms in the skin. (More information)
  • Zinc oxide may enhance the wound healing process, potentially by meeting the increased demands of cell proliferation that occur during the early phases of healing. (More information)

Overview

Although each of the fourteen essential minerals have a biological basis in several aspects of skin development and function, only a subset have been studied concerning their application to optimal skin health (1). This article highlights zinc and selenium and briefly discusses Dead Sea minerals and copper.

Content and availability

Zinc

Six percent of total body zinc is located in the skin (2). Zinc is present in both the epidermis and dermis, though at levels five-fold higher in the epidermis (3). In skin physiology, zinc stabilizes cell membranes, serves as an essential cofactor for several metalloenzymes, and participates in basal cell mitosis and differentiation (4).

Metallothionein (MT) is a zinc and copper storage molecule that protects cells from excess levels of zinc while providing a locally accessible pool of these minerals (5, 6). In normal human skin, MT is expressed in basal keratinocytes of the epidermis and in hair follicle cells (7). As in humans, MT is expressed in hair follicles and at low levels in basal cells of the epidermis in mice; moreover, MT is significantly induced in proliferating basal keratinocytes upon chemical stimulation or wounding (8) (see Wound healing). The high levels of MT observed in mitotically active keratinocytes has thus implicated a role for zinc in epidermal proliferation (1, 4). In support of this hypothesis, MT-null mice have significantly less epidermal hyperplasia and skin zinc content compared to normal mice following exposure to various chemical agents and UVB radiation, all of which are known to stimulate cell proliferation (9, 10).

Zinc is also present in a number of zinc-dependent metalloenzymes in the skin, including matrix metalloproteases (MMPs), superoxide dismutase (SOD), alkaline phosphatase, and RNA/DNA polymerases (11).

Selenium

Selenium is present in the cells of the skin as a component of various selenoproteins, including phospholipid hydroperoxide glutathionine peroxidase (PHGPx) and thioredoxin reductase (TDR) (12). PHGPx and TDR are antioxidant enzymes that inactivate peroxides, thereby protecting skin cells from the harmful effects caused by these free radicals (13). TDR is associated with keratinocyte cell membranes (14), and its levels appear to correlate with susceptibility to UVB-induced damage (13).

Topical application

Zinc

Overall, insoluble metal oxides of zinc and titanium, common components of sunscreens, applied topically remain on the upper layers of the stratum corneum (SC) (15). However, the ability of nanoparticle formulations of zinc oxide to penetrate the skin remains a matter of debate; further studies in humans under appropriate environmental conditions (e.g., during UV exposure, on sunburned skin) are necessary.

Commercial sunscreens containing microfine zinc oxide (ZnO) and titanium dioxide (TiO2) were applied to pig skin samples mounted in diffusion chambers (16). The ability of the mineral oxides to permeate and cross the skin layers was analyzed at various time points up to 24 hours after topical application. The total amount of applied zinc and titanium were recovered in the SC of the samples, indicating that neither mineral oxide even penetrated the upper layers of the skin. In a human study, a large dose (100 g) of 40% ZnO applied to a large surface area (chest, upper and lower legs) in healthy male subjects (N=6) did not significantly increase serum zinc concentration after three hours (17). The same was true for three patients receiving total parenteral nutrition (TPN) in whom serum zinc remained constant in spite of daily application of 40% ZnO for ten days to their upper thighs. Thus, topical application of 40% ZnO did not result in significant systemic absorption of zinc.

In a small human trial, the systemic absorption of sunscreens containing isotopically labeled 68Zinc oxide (68ZnO) of different particle sizes was assessed under typical outdoor conditions (18, 19). Twenty healthy adults (11 women, 9 men) applied either 68ZnO-containing nanosunscreen (19 nm 68ZnO particles) or bulk sunscreen (>100 nm 68ZnO particles) to their backs for five consecutive days at the beach (18). Blood and urine samples were collected before, during, and after treatment in order to assess systemic absorption of 68Zn from topically applied nanoparticles of zinc oxide. 68Zn was detected in the urine of women, though not men, exposed to the isotopically labeled nanosunscreen (N=4), suggesting that nanoparticles of ZnO may be absorbed through healthy human skin. Importantly, the authors note that the amount of 68Zn detected in the blood represented <0.001% of the applied dose. The mechanism by which topically applied ZnO nanoparticles may reach the systemic circulation was not investigated in the study; zinc may have been absorbed via hair follicles, sweat glands, or skin folds. While this small study demonstrated the potential for dermal absorption of nanoparticles of zinc oxide, the majority of evidence indicates that metal oxide nanoparticles are confined to the SC (15, 20-23). Such factors as nanoparticulate size (anything <100 nm is considered a nanoparticle), chemical composition of the sunscreen, and skin pH may influence the ability of the nanoparticle to penetrate the SC (24).

In contrast to topical formulations containing insoluble zinc oxide, topical administration of zinc chloride in oil increased plasma zinc concentration in pregnant rats concurrently fed a zinc-deficient diet for 24 hours (25). As is the case with essential fatty acids (see the article on Essential Fatty Acids and Skin Health), topical application of zinc in oil may thus provide an alternative strategy to deliver zinc to patients unable to ingest or absorb dietary sources of essential nutrients.

Finally, the ability of topically applied zinc to reach the systemic circulation varies with barrier properties of the skin. When the barrier was disrupted, for example in burn patients, topical application of 40% zinc oxide resulted in a significant increase in serum zinc concentration (26).

Selenium

In vitro experiments using excised animal skin demonstrated that topical L-selenomethionine (L-SM) is absorbed by skin and reaches the systemic circulation (27). Additionally, the selenium content of mouse skin was increased following both topical and oral administration of L-SM (6 ng per week by either route), though topical application increased skin content to a greater extent (27). The transdermal absorption of this organic form of selenium is attributed to the presence of methionine (28). In contrast to L-SM, skin samples were impermeable to the inorganic selenium compound sodium selenite, commonly used in dandruff shampoos (29).

Deficiency

The skin relies on the circulatory system to supply it with nutrients. Systemic nutritional deficiencies often manifest in skin abnormalities, and meeting the Recommended Dietary Allowance (RDA) for each mineral is important for healthy skin (see Minerals). However, at this time there is insufficient clinical evidence to support intakes beyond the RDA as beneficial to skin health (1, 30).

Zinc

Severe zinc deficiency (low serum zinc concentration) resembles acrodermatitis enteropathica, an inherited disorder of impaired zinc absorption characterized by erosive dermatitis, diarrhea, and alopecia (31, 32). Moderate zinc deficiency causes pigmentation changes, decreased hair and nail growth, and skin lesions on body sites exposed to repeated pressure and friction in particular (31).

Selenium

Selenium deficiency is associated with an increased risk of several types of cancer, including skin cancer (see the article on Selenium) (13). Selenium imbalance, both deficiency and excess, causes skin abnormalities. Mice fed diets with either excessive or deficient selenium for 24 weeks developed alopecia with poliosis (a decrease or absence of color), altered hair follicle cycling, and epidermal atrophy, possibly due to increased apoptosis in keratinocytes (33). Genetically altered mice with keratinocyte-specific depletion of selenoproteins developed skin and hair defects within six days after birth, including malformed hair follicles, hyperplastic epidermis, alopecia, and keratinocytes with adhesion and growth defects that underwent apoptosis (34). It appears that a reduction in selenoprotein levels drive the observed skin abnormalities of selenium deficiency.

Functions in Healthy Skin

Photoprotection

Zinc

Mineral oxides such as zinc oxide (ZnO) and titanium dioxide (TiO2) protect the skin from photodamage by reflecting and absorbing ultraviolet radiation (UVR) across the UV spectrum, thus reducing the level of radiation that penetrates the skin (35). Zinc oxide has been in use for decades as a safe and effective physical sunscreen (1, 15). Sunscreen formulations containing micro- and nanoparticles of mineral oxides have improved cosmetic appearance without reducing efficacy. Microfine zinc oxide preparations appear transparent in films, block UVB and UVA radiation, remain intact upon UV exposure, and do not photoreact with organic compounds in sunscreens (35).

Soluble forms of zinc (i.e., zinc ions, zinc chloride) may also provide antioxidant protection in the skin. Proposed mechanisms include the displacement of redox active molecules, such as iron and copper with zinc, which does not participate in redox (electron transfer) chemistry, and the induction of metallothionein (MT) (11, 32). In addition to functioning as a metal-storage depot, MT exerts free radical scavenging activity. In vitro experiments using MT purified from animal liver extracts demonstrated that MT scavenges multiple types of reactive oxygen species (ROS), including superoxide and hydroxyl radical (36, 37).

Selenium

Selenium is thought to protect the skin from UVR by increasing the activities of the selenium-dependent antioxidant enzymes glutathione peroxidase (GPx) and thioredoxin reductase (TDR) (13). TDR is present in the plasma membrane of human keratinocytes (38), and in vitro experiments support a role for TDR in the protection of the outer keratinocyte membrane against damage from oxygen radicals (14).

In mice, both supplemental L-selenomethionine (L-SM) and sodium selenite increased skin selenium content and GPx activity but provided no protection from the immunosuppressive effects (i.e., reduction in Langherhans and mast cell numbers) of UVB exposure (39). In a second mouse study, however, both oral and topical L-SM were effective in reducing acute damage induced by UVR, including inflammation ("sunburn"), blistering, and pigmentation ("tanning") (27).

The photoprotective effect of oral supplementation with selenium and copper was assessed in a double-blind, placebo-controlled trial in a small sampling of men and women (N=15, aged 20-47 years) (40). Micronutrients were supplied as components of two different commercially available products. Product 1 consisted of selenium-enriched yeast (50 μg) and copper sulphate (4 mg) per capsule, and Product 2 was a vitamin mixture of dl-α-tocopherol acetate (7 mg), retinol palmitate (4,500 IU), nicotinamide (1.8 mg), pyridoxine (0.2 mg), thiamin (0.06 mg), and riboflavin (0.04 mg). Subjects were divided into four groups of four subjects who received varying combinations of supplements and placebo during meals for three weeks. Punch biopsies from the sun-protected lower back were obtained before and after UVR exposure at both the beginning and end of the supplementation period. Neither supplement influenced erythema formation or the number of sunburn cells formed in response to UVR exposure.

Topical L-SM, on the other hand, protected skin from UVR in a small, vehicle-controlled study in healthy women (N=8) (41). Subjects first applied lotion containing vehicle followed by increasing concentrations of L-SM (0.002%, 0.02%, and 0.05%) to their lower backs once each evening in two-week increments for a total of eight weeks; subjects were exposed to UVB during a morning appointment every two weeks of the dosing schedule. Blood was drawn on day 1 and day 56 (the end of the treatment period) to assess potential systemic absorption of selenium through the skin. Topical L-SM dose-dependently increased the MED compared to vehicle treated skin. Although studies in hairless mice demonstrated that topical SM reaches the systemic circulation and increases skin, plasma and liver selenium (27), the small doses used in this human study did not influence the concentration of plasma selenium after six weeks of daily application.

Dead sea minerals

Dermud™ cream containing Dead Sea minerals and other ingredients (vitamin E, aloe vera, provitamin B5, and zinc oxide) was applied to the exposed epidermis of human skin samples obtained from women (20-69 years) undergoing plastic surgery (42). After 36 hours of Dermud™ exposure, samples were washed and exposed to UVR; oxidative stress, cell viability, and cytokine level (indicative of inflammation) were assessed at 0.5, 24 and 48 h post-irradiation. Topically applied Dermud™ attenuated the negative effects caused by UVB compared to untreated skin samples. Notably, Dermud™ is a multiingredient formulation, with several ingredients known to function in photoprotection (see Photoprotection/Zinc above and the article on Vitamin E and Skin Health); it is unclear the extent to which the ingredients even penetrated the stratum corneum, and the study lacked a vehicle control.

Wound healing

The induction of metallothionein (MT) in cells exhibiting high mitotic activity may provide a source of zinc necessary for metalloenzymes that function in the early phases of wound healing (1, 11, 43). For example, copper/zinc-superoxide dismutase (SOD) and glutathione peroxidase (GPx) are significantly upregulated following cutaneous injury, with particularly high expression at the wound edge (44). During the wound-healing process in mice, MT was induced at the wound edges and gradually decreased as reepithelialization occurred (45). Additionally, reactive oxygen species (ROS) are produced by polymorphonuclear leukocytes and macrophages in the early, inflammatory stage of wound healing. Thus, the increased expression of metal-dependent antioxidant enzymes may serve to protect keratinocytes from ROS generated by nearby inflammatory cells during the wound-healing process (44).

Although MT and zinc-dependent metalloenzymes are induced during the early phases of the healing process, oral supplementation of zinc does not appear to improve healing of chronic leg ulcers (46). Topical zinc oxide dressings may enhance the rate of wound healing, though more trials are necessary to support this claim (4).

Other functions

Copper metal in contact with skin is purported to exert anti-inflammatory properties. However, the extent to which copper penetrates the layers of the skin is a matter of debate (47). Skin exudates (e.g., sweat, sebum) may facilitate the oxidation of metals and the formation of skin-diffusible compounds (48).

The ability of copper to penetrate the layers of the skin was evaluated in a small sampling of human volunteers (49). Copper powder (3 mm particle size) was applied to the forearm of three volunteers for 24, 48, and 72 hours under occlusive and semi-occlusive conditions. The amount of copper per unit tissue was measured after tape stripping the exposed area of the skin and measuring copper content by mass spectrometry. Prolonged contact (72 h) in the presence of air led to a slight retention of copper in the outer stratum corneum in one volunteer; copper levels were equivalent to baseline in all other instances.

Conclusion

Topical treatment with zinc and selenium can protect the skin from UV radiation (UVR). Mineral oxides of zinc and titanium operate by blocking UV penetration of the skin, providing a safe and effective means to reduce UVR exposure. Topical zinc also induces metallothionein (MT), which provides a locally accessible pool of mineral for zinc-dependent metalloenzymes while serving as a free radical scavenger in its own right. Oral and topical L-selenomethionine may protect the skin from UV damage by increasing the levels of selenium-dependent antioxidant proteins prior to UV exposure, thus bolstering the antioxidant defense of the skin. Meeting the RDA for the other minerals is important for the development and maintenance of healthy skin, though there is little evidence to warrant oral or topical supplementation in the context of skin health.


Authors and Reviewers

Written in January 2013 by:
Giana Angelo, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in January 2013 by:
Thomas Polefka, Ph.D.
Principal at Life Science Solutions, LLC
Somerset, NJ

This article was underwritten, in part, by a grant from Neutrogena Corporation, Los Angeles, California.

Copyright 2013-2024  Linus Pauling Institute


References

1.  Polefka TG, Bianchini RJ, Shapiro S. Interaction of mineral salts with the skin: a literature survey. Int J Cosmet Sci. 2012;34(5):416-423.  (PubMed)

2.  King JC, Shames DM, Woodhouse LR. Zinc homeostasis in humans. J Nutr. 2000;130(5S Suppl):1360S-1366S.  (PubMed)

3.  Michaelsson G, Ljunghall K, Danielson BG. Zinc in epidermis and dermis in healthy subjects. Acta Derm Venereol. 1980;60(4):295-299.  (PubMed)

4.  Lansdown AB, Mirastschijski U, Stubbs N, Scanlon E, Agren MS. Zinc in wound healing: theoretical, experimental, and clinical aspects. Wound Repair Regen. 2007;15(1):2-16.  (PubMed)

5.  Moffatt P, Denizeau F. Metallothionein in physiological and physiopathological processes. Drug Metab Rev. 1997;29(1-2):261-307.  (PubMed)

6.  Udom AO, Brady FO. Reactivation in vitro of zinc-requiring apo-enzymes by rat liver zinc-thionein. The Biochem J. 1980;187(2):329-335.  (PubMed)

7.  van den Oord JJ, De Ley M. Distribution of metallothionein in normal and pathological human skin. Arch Dermatol Res. 1994;286(1):62-68.  (PubMed)

8.  Karasawa M, Nishimura N, Nishimura H, Tohyama C, Hashiba H, Kuroki T. Localization of metallothionein in hair follicles of normal skin and the basal cell layer of hyperplastic epidermis: possible association with cell proliferation. J Invest Dermatol. 1991;97(1):97-100.   (PubMed)

9.  Hanada K, Sawamura D, Hashimoto I, Kida K, Naganuma A. Epidermal proliferation of the skin in metallothionein-null mice. J Invest Dermatol. 1998;110(3):259-262.  (PubMed)

10.  Hanada K, Sawamura D, Tamai K, et al. Novel function of metallothionein in photoprotection: metallothionein-null mouse exhibits reduced tolerance against ultraviolet B injury in the skin. J Invest Dermatol. 1998;111(4):582-585.  (PubMed)

11.  Schwartz JR, Marsh RG, Draelos ZD. Zinc and skin health: overview of physiology and pharmacology. Dermatol Surg. 2005;31(7 Pt 2):837-847; discussion 847.  (PubMed)

12.  Rafferty TS, McKenzie RC, Hunter JA, et al. Differential expression of selenoproteins by human skin cells and protection by selenium from UVB-radiation-induced cell death. Biochem J. 1998;332(Pt 1):231-236.  (PubMed)

13.  McKenzie RC. Selenium, ultraviolet radiation and the skin. Clin Exp Dermatol. 2000;25(8):631-636.  (PubMed)

14.  Schallreuter KU, Pittelkow MR, Wood JM. Free radical reduction by thioredoxin reductase at the surface of normal and vitiliginous human keratinocytes. J Invest Dermatol. 1986;87(6):728-732.  (PubMed)

15.  Newman MD, Stotland M, Ellis JI. The safety of nanosized particles in titanium dioxide- and zinc oxide-based sunscreens. J Am Acad Dermatol. 2009;61(4):685-692.  (PubMed)

16.  Gamer AO, Leibold E, van Ravenzwaay B. The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin. Toxicol In Vitro. 2006;20(3):301-307.  (PubMed)

17.  Derry JE, McLean WM, Freeman JB. A study of the percutaneous absorption from topically applied zinc oxide ointment. JPEN J Parenter Enteral Nutr. 1983;7(2):131-135.  (PubMed)

18.  Gulson B, McCall M, Korsch M, et al. Small amounts of zinc from zinc oxide particles in sunscreens applied outdoors are absorbed through human skin. Toxicol Sci. 2010;118(1):140-149.  (PubMed)

19.  Gulson B, Wong H, Korsch M, et al. Comparison of dermal absorption of zinc from different sunscreen formulations and differing UV exposure based on stable isotope tracing. Sci Total Environ. 2012;420:313-318.  (PubMed)

20.  Monteiro-Riviere NA, Wiench K, Landsiedel R, Schulte S, Inman AO, Riviere JE. Safety evaluation of sunscreen formulations containing titanium dioxide and zinc oxide nanoparticles in UVB sunburned skin: an in vitro and in vivo study. Toxicol Sci. 2011;123(1):264-280.  (PubMed)

21.  Nohynek GJ, Dufour EK. Nano-sized cosmetic formulations or solid nanoparticles in sunscreens: a risk to human health? Arch Toxicol. 2012;86(7):1063-1075.  (PubMed)

22.  Darvin ME, Konig K, Kellner-Hoefer M, et al. Safety assessment by multiphoton fluorescence/second harmonic generation/hyper-Rayleigh scattering tomography of ZnO nanoparticles used in cosmetic products. Skin Pharmacol Physiol. 2012;25(4):219-226.  (PubMed)

23.  Lin LL, Grice JE, Butler MK, et al. Time-correlated single photon counting for simultaneous monitoring of zinc oxide nanoparticles and NAD(P)H in intact and barrier-disrupted volunteer skin. Pharm Res. 2011;28(11):2920-2930.  (PubMed)

24.  Baroli B, Ennas MG, Loffredo F, Isola M, Pinna R, Lopez-Quintela MA. Penetration of metallic nanoparticles in human full-thickness skin. J Invest Dermatol. 2007;127(7):1701-1712.  (PubMed)

25.  Keen CL, Hurley LS. Zinc absorption through skin: correction of zinc deficiency in the rat. Am J Clin Nutr. 1977;30(4):528-530.  (PubMed)

26.  Hallmans G. Healing of experimentally induced burn wounds. A comparative study of the healing of exposed burn wounds and burn wounds covered with adhesive zinc-tape and a scanning electron microscopic study of the microvasculature of wound healing in the rabbit ear. Scand J Plast Reconstr Surg. 1978;12(2):105-109.  (PubMed)

27.  Burke KE, Combs GF, Jr., Gross EG, Bhuyan KC, Abu-Libdeh H. The effects of topical and oral L-selenomethionine on pigmentation and skin cancer induced by ultraviolet irradiation. Nutr Cancer. 1992;17(2):123-137.  (PubMed)

28.  Edwards LJ. The absorption of methionine by the skin of the guinea pig. Biochem J. 1954;57(4):542-547.  (PubMed)

29.  Lin CH, Fang CL, Al-Suwayeh SA, Yang SY, Fang JY. In vitro and in vivo percutaneous absorption of seleno-L-methionine, an antioxidant agent, and other selenium species. Acta Pharmacol Sin. 2011;32(9):1181-1190.  (PubMed)

30.  Richelle M, Sabatier M, Steiling H, Williamson G. Skin bioavailability of dietary vitamin E, carotenoids, polyphenols, vitamin C, zinc and selenium. Br J Nutr. 2006;96(2):227-238.  (PubMed)

31.  Kumar P, Lal NR, Mondal AK, Mondal A, Gharami RC, Maiti A. Zinc and skin: a brief summary. Dermatol Online J. 2012;18(3):1.  (PubMed)

32.  Rostan EF, DeBuys HV, Madey DL, Pinnell SR. Evidence supporting zinc as an important antioxidant for skin. Int J Dermatol. 2002;41(9):606-611.  (PubMed)

33.  Hwang SW, Lee HJ, Suh KS, et al. Changes in murine hair with dietary selenium excess or deficiency. Exp Dermatol. 2011;20(4):367-369.  (PubMed)

34.  Sengupta A, Lichti UF, Carlson BA, et al. Selenoproteins are essential for proper keratinocyte function and skin development. PLoS One. 2010;5(8):e12249.  (PubMed)

35.  Mitchnick MA, Fairhurst D, Pinnell SR. Microfine zinc oxide (Z-cote) as a photostable UVA/UVB sunblock agent. J Am Acad Dermatol. 1999;40(1):85-90.  (PubMed)

36.  Kumari MV, Hiramatsu M, Ebadi M. Free radical scavenging actions of metallothionein isoforms I and II. Free Radic Res. 1998;29(2):93-101.  (PubMed)

37.  Thornalley PJ, Vasak M. Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta. 1985;827(1):36-44.  (PubMed)

38.  Schallreuter KU, Wood JM. The role of thioredoxin reductase in the reduction of free radicals at the surface of the epidermis. Biochem Biophys Res Commun. 1986;136(2):630-637.  (PubMed)

39.  McKenzie RC, Beckett GJ, McLean S, et al. Differential effects of doses and forms of dietary selenium on immune cell numbers in the skin of ultraviolet-irradiated and unirradiated mice. Biol Trace Elem Res. 2008;125(3):255-267.  (PubMed)

40.  la Ruche G, Cesarini JP. Protective effect of oral selenium plus copper associated with vitamin complex on sunburn cell formation in human skin. Photodermatol Photoimmunol Photomed. 1991;8(6):232-235.  (PubMed)

41.  Burke KE, Burford RG, Combs GF, Jr., French IW, Skeffington DR. The effect of topical L-selenomethionine on minimal erythema dose of ultraviolet irradiation in humans. Photodermatol Photoimmunol Photomed. 1992;9(2):52-57.  (PubMed)

42.  Portugal-Cohen M, Soroka Y, Ma'or Z, et al. Protective effects of a cream containing Dead Sea minerals against UVB-induced stress in human skin. Exp Dermatol. 2009;18(9):781-788.  (PubMed)

43.  Lansdown AB. Metallothioneins: potential therapeutic aids for wound healing in the skin. Wound Repair Regen. 2002;10(3):130-132.  (PubMed)

44.  Steiling H, Munz B, Werner S, Brauchle M. Different types of ROS-scavenging enzymes are expressed during cutaneous wound repair. Exp Cell Res. 1999;247(2):484-494.  (PubMed)

45.  Iwata M, Takebayashi T, Ohta H, Alcalde RE, Itano Y, Matsumura T. Zinc accumulation and metallothionein gene expression in the proliferating epidermis during wound healing in mouse skin. Histochem Cell Biol. 1999;112(4):283-290.  (PubMed)

46.  Wilkinson EA. Oral zinc for arterial and venous leg ulcers. Cochrane Database Syst Rev. 2012;8:CD001273.  (PubMed)

47.  Hostynek JJ, Maibach HI. Copper hypersensitivity: dermatologic aspects--an overview. Rev Environ Health. 2003;18(3):153-183.  (PubMed)

48.  Hostynek JJ, Maibach HI. Skin irritation potential of copper compounds. Toxicol Mech Methods. 2004;14(4):205-213.  (PubMed)

49.  Hostynek JJ, Dreher F, Maibach HI. Human stratum corneum penetration by copper: in vivo study after occlusive and semi-occlusive application of the metal as powder. Food Chem Toxicol. 2006;44(9):1539-1543.  (PubMed)