Zinc in wound healing: Theoretical, experimental, and clinical aspects

Wound Repair and Regeneration

Volumn 15, Issue 1, 2007, Pages 2-16

  Lansdown, Alan B G ^a   Mirastschijski, Ursula ^b   Stubbs, Nicky ^c   Scanlon, Elizabeth ^c   Ågren, Magnus S ^d  

^a CHARING CROSS HOSPITAL   (United Kingdom)

^b OTTO VON GUERICKE UNIVERSITY   (Germany)

^c Leeds North West Primary Care Trust ^*  (United Kingdom)

^d BISPEBJERG HOSPITAL   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFECTIVE AGENT; GLUCOCORTICOID; INTEGRIN; METALLOPROTEINASE; PLACEBO; ZINC; ZINC OXIDE; ZINC SULFATE;

ABDOMINAL PAIN; ACRODERMATITIS ENTEROPATHICA; ANTIINFLAMMATORY ACTIVITY; ANTIMICROBIAL ACTIVITY; BANDAGES AND DRESSINGS; CELL METABOLISM; CHRONIC WOUND; CLINICAL TRIAL; DEBRIDEMENT; DIARRHEA; DRUG ABSORPTION; DRUG EFFICACY; DRUG MECHANISM; DYSPEPSIA; EPITHELIZATION; FUNCTIONS OF THE SKIN AND ITS APPENDAGES; GENETIC DISORDER; HOMEOSTASIS; HUMAN; NAUSEA; NONHUMAN; NUTRITION; PRIORITY JOURNAL; REVIEW; SUPPLEMENTATION; VOMITING; WOUND; WOUND CARE; WOUND HEALING; WOUND HEALING IMPAIRMENT; ZINC DEFICIENCY; ZINC METABOLISM;

DEFICIENCY DISEASES; HUMANS; SKIN PHYSIOLOGY; WOUND HEALING; ZINC;

EID: 33846441652     PISSN: 10671927     EISSN: 1524475X     Source Type: Journal    
DOI: 10.1111/j.1524-475X.2006.00179.x     Document Type: Review

References (222)

1. Prasad AS. Zinc: an overview. Nutrition 1995; 11: 93-9.
2. Jones PW, Williams DR. The use and role of zinc and its compounds in wound healing. Met Ions Biol Syst 2004; 41: 139-83.
3. Keilin D, Mann T. Carbonic anhydrase. Purification and nature of the enzyme. Biochem J 1940; 34: 1163-76.
4. O'Dell BL. Zinc plays both structural and catalytic roles in metalloproteins. Nutr Rev 1992; 50: 48-50.
5. Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev 1993; 73: 79-118.
6. O'Dell BL. Role of zinc in plasma membrane function. J Nutr 2000; 130: 1432S-6S.
7. Pasternak CA, Alder GM, Bashford CL, Korchev YE, Pederzolli C, Rostovtseva TK. Membrane damage: common mechanisms of induction and prevention. FEMS Microbiol Immunol 1992; 5: 83-92.
8. Bao B, Prasad AS, Beck FW, Godmere M. Zinc modulates mRNA levels of cytokines. Am J Physiol Endocrinol Metab 2003; 285: E1095-102.
9. Berg JM, Shi Y. The galvanization of biology: a growing appreciation for the roles of zinc. Science 1996; 271: 1081-5.
10. Sum EY, O'Reilly LA, Jonas N, Lindeman GJ, Visvader JE. The LIM domain protein Lmo4 is highly expressed in proliferating mouse epithelial tissues. J Histochem Cytochem 2005; 53: 475-86.
11. Zhu CH, Ying DJ, Mi JH, Zhang W, Dong SW, Sun JS, Zhang JP. The zinc finger protein A20 protects endothelial cells from burns serum injury. Burns 2004; 30: 127-33.
12. Hock H, Orkin SH. Zinc-finger transcription factor Gfi-1: versatile regulator of lymphocytes, neutrophils and hematopoietic stem cells. Curr Opin Hematol 2006; 13: 1-6.
13. Beyersmann D, Haase H. Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 2001; 14: 331-41.
14. Siemes C, Quast T, Klein E, Bieber T, Hooper NM, Herzog V. Normalized proliferation of normal and psoriatic keratinocytes by suppression of sAPPalpha-release. J Invest Dermatol 2004; 123: 556-63.
15. Scrimshaw NS, Young VR. The requirements of human nutrition. Sci Am 1976; 235: 50-64.
16. Prasad AS, Miale A Jr, Farid Z, Sandstead HH, Schulert AR. Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarfism, and hypognadism. J Lab Clin Med 1963; 61: 537-49.
17. Reinhold JG. High phytate content of rural Iranian bread: a possible cause of human zinc deficiency. Am J Clin Nutr 1971; 24: 1204-6.
18. Pories WJ, Henzel JH, Rob CG, Strain WH. Acceleration of wound healing in man with zinc sulphate given by mouth. Lancet 1967; 1: 121-4.
19. Ågren MS, Ostenfeld U, Kallehave F, Gong Y, Raffn K, Crawford ME, Kiss K, Friis-Möller F, Gluud C, Jorgensen LN. A randomized, double-blind, placebo-controlled multicenter trial evaluating topical zinc oxide for acute open wounds following pilonidal disease excision. Wound Repair Regen 2006; 14: 526-35.
20. Patel GK, Harding KG. Wound problems due to zinc deficiency. Int Wound J 2004; 1: 150-1.
21. Chimienti F, Aouffen M, Favier A, Seve M. Zinc homeostasis-regulating proteins: new drug targets for triggering cell fate. Curr Drug Targets 2003; 4: 323-38.
22. Lansdown ABG. Metallothioneins: potential therapeutic aids for wound healing in the skin. Wound Repair Regen 2002; 10: 130-2.
23. Vasak M. Advances in metallothionein structure and functions. J Trace Elem Med Biol 2005; 19: 13-7.
24. Zalewski PD, Truong-Tran AQ, Grosser D, Jayaram L, Murgia C, Ruffin RE. Zinc metabolism in airway epithelium and airway inflammation: basic mechanisms and clinical targets. A review. Pharmacol Ther 2005; 105: 127-49.
25. Chao Y, Fu D. Kinetic study of the antiport mechanism of an Escherichia coli zinc transporter, ZitB. J Biol Chem 2004; 279: 12043-50.
26. Gaither LA, Eide DJ. The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J Biol Chem 2001; 276: 22258-64.
27. Lioumi M, Ferguson CA, Sharpe PT, Freeman T, Marenholz I, Mischke D, Heizmann C, Ragoussis J. Isolation and characterization of human and mouse ZIRTL, a member of the IRT1 family of transporters, mapping within the epidermal differentiation complex. Genomics 1999; 62: 272-80.
28. Huang L, Gitschier J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet 1997; 17: 292-7.
29. Andrews GK. Cellular zinc sensors: MTF-1 regulation of gene expression. Biometals 2001; 14: 223-37.
30. McCance RA, Widdowson EM. The absorption and excretion of zinc. Biochem J 1942; 36: 692-6.
31. Fox SMR. The status of zinc in human nutrition. World Rev Nutr Diet 1970; 12: 208-26.
32. Osis D, Kramer L, Wiatrowski E, Spencer H. Dietary zinc intake in man. Am J Clin Nutr 1972; 25: 582-8.
33. The effect of five-year zinc supplementation on serum zinc, serum cholesterol and hematocrit in persons randomly assigned to treatment group in the age-related eye disease study: AREDS Report No. 7. J Nutr 2002; 132: 697-702.
34. King JC, Shames DM, Woodhouse LR. Zinc homeostasis in humans. J Nutr 2000; 130: 1360S-6S.
35. Krebs NE, Hambidge KM. Zinc metabolism and homeostasis: the application of tracer techniques to human zinc physiology. Biometals 2001; 14: 397-412.
36. Liuzzi JP, Bobo JA, Lichten LA, Samuelson DA, Cousins RJ. Responsive transporter genes within the murine intestinal-pancreatic axis form a basis of zinc homeostasis. Proc Natl Acad Sci USA 2004; 101: 14355-60.
37. Richards MP, Cousins RJ. Metallothionein and its relationship to the metabolism of dietary zinc in rats. J Nutr 1976; 106: 1591-9.
38. Sandström B. Bioavailability of zinc. Eur J Clin Nutr 1997; 51 (Suppl. 1): S17-9.
39. Lee HH, Hill GM, Sikha VK, Brewer GJ, Prasad AS, Owyang C. Pancreaticobiliary secretion of zinc and copper in normal persons and patients with Wilson's disease. J Lab Clin Med 1990; 116: 283-8.
40. Wastney ME, Aamodt RL, Rumble WF, Henkin RI. Kinetic analysis of zinc metabolism and its regulation in normal humans. Am J Physiol 1986; 251: R398-408.
41. Myung SJ, Yang SK, Jung HY, Jung SA, Kang GH, Ha HK, Hong WS, Min YI. Zinc deficiency manifested by dermatitis and visual dysfunction in a patient with Crohn's disease. J Gastroenterol 1998; 33: 876-9.
42. Narkewicz MR, Krebs N, Karrer F, Orban-Eller K, Sokol RJ. Correction of hypozincemia following liver transplantation in children is associated with reduced urinary zinc loss. Hepatology 1999; 29: 830-3.
43. Taylor CG. Zinc, the pancreas, and diabetes: insights from rodent studies and future directions. Biometals 2005; 18: 305-12.
44. Dufner-Beattie J, Wang F, Kuo YM, Gitschier J, Eide D, Andrews GK. The acrodermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc transporter in mice. J Biol Chem 2003; 278: 33474-81.
45. Cousins RJ, Leinart AS. Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. FASEB J 1988; 2: 2884-90.
46. Sandstead HH. Assessment of zinc nutriture. J Lab Clin Med 1991; 118: 299-300.
47. Scott BJ, Bradwell AR. Identification of the serum binding proteins for iron, zinc, cadmium, nickel, and calcium. Clin Chem 1983; 29: 629-33.
48. Guillard O, Piriou A, Gombert J, Reiss D. Diurnal variations of zinc, copper and magnesium in the serum of normal fasting adults. Biomedicine 1979; 31: 193-4.
49. Berger A. What does zinc do? BMJ 2002; 325: 1062.
50. Ward NI, Soulsbury KA, Zettel VH, Colquhoun ID, Bunday S, Barnes B. The influence of the chemical additive tartrazine on the zinc status of hyperactive children: a double-blind placebo-controlled study. J Nutr Med 1990; 1: 51-8.
51. Gengenbacher M, Stahelin HB, Scholer A, Seiler WO. Low biochemical nutritional parameters in acutely ill hospitalized elderly patients with and without stage III to IV pressure ulcers. Aging Clin Exp Res 2002; 14: 420-3.
52. Raffoul W, Far MS, Cayeux MC, Berger MM. Nutritional status and food intake in nine patients with chronic low-limb ulcers and pressure ulcers: importance of oral supplements. Nutrition 2006; 22: 82-8.
53. Rojas AI, Phillips TJ. Patients with chronic leg ulcers show diminished levels of vitamins A and E, carotenes, and zinc. Dermatol Surg 1999; 25: 601-4.
54. Mahajan SK, Prasad AS, Rabbani P, Briggs WA, McDonald FD. Zinc metabolism in uremia. J Lab Clin Med 1979; 94: 693-8.
55. Fung EB, Ritchie LD, Woodhouse LR, Roehl R, King JC. Zinc absorption in women during pregnancy and lactation: a longitudinal study. Am J Clin Nutr 1997; 66: 80-8.
56. Halsted JA, Smith JC Jr. Plasma-zinc in health and disease. Lancet 1970; 1: 322-4.
57. Hawkins T, Marks JM, Plummer VM, Greaves MW. Whole body monitoring and other studies of zinc-65 metabolism in patients with dermatological diseases. Clin Exp Dermatol 1976; 1: 243-52.
58. Moynahan EJ. Letter: acrodermatitis enteropathica: a lethal inherited human zinc-deficiency disorder. Lancet 1974; 2: 399-400.
59. Braun OH, Heilmann K, Pauli W, Rossner JA, Bergmann KE. Acrodermatitis enteropathica: recent findings concerning clinical features, pathogenesis, diagnosis and therapy. Eur J Pediatr 1976; 121: 247-61.
60. Borroni G, Brazzelli V, Vignati G, Zaccone C, Vignoli GP, Rabbiosi G. Bullous lesions in acrodermatitis enteropathica. Histopathologic findings regarding two patients. Am J Dermatopathol 1992; 14: 304-9.
61. Küry S, Dréno B, Bézieau S, Giraudet S, Kharfi M, Kamoun R, Moisan JP. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 2002; 31: 239-40.
62. Jacob KN, Garg A. Laminopathies: multisystem dystrophy syndromes. Mol Genet Metab 2006; 87: 289-302.
63. Ågren MS. Percutaneous absorption of zinc from zinc oxide applied topically to intact skin in man. Dermatologica 1990; 180: 36-9.
64. Henzel JH, DeWeese MS, Lichti EL. Zinc concentrations within healing wounds. Significance of postoperative zincuria on availability and requirements during tissue repair. Arch Surg 1970; 100: 349-57.
65. Michaelsson G, Ljunghall K, Danielson BG. Zinc in epidermis and dermis in healthy subjects. Acta Derm Venereol 1980; 60: 295-9.
66. Molokhia MM, Portnoy B. Neutron activation analysis of trace elements in skin. 3. Zinc in normal skin. Br J Dermatol 1969; 81: 759-62.
67. Hanada K, Sawamura D, Hashimoto I, Kida K, Naganuma A. Epidermal proliferation of the skin in metallothionein-null mice. J Invest Dermatol 1998; 110: 259-62.
68. 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: 283-90.
69. van den Oord JJ, De Ley M. Distribution of metallothionein in normal and pathological human skin. Arch Dermatol Res 1994; 286: 62-8.
70. Lansdown ABG. Calcium: a potential central regulator in wound healing in the skin. Wound Repair Regen 2002; 10: 271-85.
71. Sakamoto M, Tzeng S, Fukuyama K, Epstein WL. Light-scattering studies of cation-stimulated filament assembly of newborn rat epidermal keratin. Biochim Biophys Acta 1980; 624: 205-10.
72. Forslind B, Lindberg M, Roomans GM, Pallon J, Werner-Linde Y. Aspects on the physiology of human skin: studies using particle probe analysis. Microsc Res Tech 1997; 38: 373-86.
73. Lansdown ABG, Sampson B, Rowe A. Sequential changes in trace metal, metallothionein and calmodulin concentrations in healing skin wounds. J Anat 1999; 195 (Part 3): 375-86.
74. Vicanova J, Boelsma E, Mommaas AM, Kempenaar JA, Forslind B, Pallon J, Egelrud T, Koerten HK, Ponec M. Normalization of epidermal calcium distribution profile in reconstructed human epidermis is related to improvement of terminal differentiation and stratum corneum barrier formation. J Invest Dermatol 1998; 111: 97-106.
75. Heng MK, Song MK, Heng MC. Reciprocity between tissue calmodulin and cAMP levels: modulation by excess zinc. Br J Dermatol 1993; 129: 280-5.
76. Lengyel I, Fieuw-Makaroff S, Hall AL, Sim AT, Rostas JA, Dunkley PR. Modulation of the phosphorylation and activity of calcium/calmodulin-dependent protein kinase II by zinc. J Neurochem 2000; 75: 594-605.
77. Lansdown ABG. Morphological variations in keratinising epithelia in the beagle. Vet Rec 1985; 116: 127-30.
78. Henkin RI, Schecter PJ, Friedewald WT, Demets DL, Raff M. A double blind study of the effects of zinc sulfate on taste and smell dysfunction. Am J Med Sci 1976; 272: 285-99.
79. Ravanti L, Kähäri VM. Matrix metalloproteinases in wound repair (review). Int J Mol Med 2000; 6: 391-407.
80. Savlov ED, Strain WH, Huegin F. Radiozinc studies in experimental wound healing. J Surg Res 1962; 2: 209-12.
81. Ågren MS, Franzén L. Influence of zinc deficiency on breaking strength of 3-week-old skin incisions in the rat. Acta Chir Scand 1990; 156: 667-70.
82. Bernstein IA, Chakrabarti SG, Kumaroo KK, Sibrack LA. Synthesis of protein in the mammalian epidermis. J Invest Dermatol 1970; 55: 291-302.
83. Alpaslan G, Nakajima T, Takano Y. Extracellular alkaline phosphatase activity as a possible marker for wound healing: a preliminary report. J Oral Maxillofac Surg 1997; 55: 56-62.
84. Lukács I, Braun-Falco O. RNA-synthesis of the skin. DNA-dependent RNA-polymerase activity in guinea pig epidermis. Arch Klin Exp Dermatol 1970; 238: 187-96.
85. Gomis-Rüth FX. Structural aspects of the metzincin clan of metalloendopeptidases. Mol Biotechnol 2003; 24: 157-202.
86. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69: 562-73.
87. Springman EB, Nagase H, Birkedal-Hansen H, Van Wart HE. Zinc content and function in human fibroblast collagenase. Biochemistry 1995; 34: 15713-20.
88. Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 1990; 87: 5578-82.
89. Ågren MS, Eaglstein WH, Ferguson MW, Harding KG, Moore K, Saarialho-Kere UK, Schultz GS. Causes and effects of the chronic inflammation in venous leg ulcers. Acta Derm Venereol 2000; 210 (Suppl. Stockholm): 3-17.
90. Gillard JA, Reed MW, Buttle D, Cross SS, Brown NJ. Matrix metalloproteinase activity and immunohistochemical profile of matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 during human dermal wound healing. Wound Repair Regen 2004; 12: 295-304.
91. Mirastschijski U, Impola U, Jahkola T, Karlsmark T, Ågren MS, Saarialho-Kere U. Ectopic localization of matrix metalloproteinase-9 in chronic cutaneous wounds. Hum Pathol 2002; 33: 355-64.
92. Nwomeh BC, Liang HX, Diegelmann RF, Cohen IK, Yager DR. Dynamics of the matrix metalloproteinases MMP-1 and MMP-8 in acute open human dermal wounds. Wound Repair Regen 1998; 6: 127-34.
93. Krampert M, Bloch W, Sasaki T, Bugnon P, Rulicke T, Wolf E, Aumailley M, Parks WE, Werner S. Activities of the matrix metalloproteinase stromelysin-2 (MMP-10) in matrix degradation and keratinocyte organization in wounded skin. Mol Biol Cell 2004; 15: 5242-54.
94. Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 1997; 137: 1445-57.
95. Soo C, Shaw WW, Zhang X, Longaker MT, Howard EW, Ting K. Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. Plast Reconstr Surg 2000; 105: 638-47.
96. Falanga V. The chronic wound: impaired healing and solutions in the context of wound bed preparation. Blood Cells Mol Dis 2004; 32: 88-94.
97. Ågren MS, Engel MA, Mertz PM. Collagenase during burn wound healing: influence of a hydrogel dressing and pulsed electrical stimulation. Plast Reconstr Surg 1994; 94: 518-24.
98. Mirastschijski U, Haaksma CJ, Tomasek JJ, Ågren MS. Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Exp Cell Res 2004; 299: 465-75.
99. Peled ZM, Phelps ED, Updike DL, Chang J, Krummel TM, Howard EW, Longaker MT. Matrix metalloproteinases and the ontogeny of scarless repair: the other side of the wound healing balance. Plast Reconstr Surg 2002; 110: 801-11.
100. Abe M, Kan C, Zaw KK, Ishikawa O. Induction of matrix metalloproteinase-1 in in vitro experimental wound model using a novel three-dimensional culture system. Eur J Dermatol 2001; 11: 112-6.
101. Chinnathambi S, Bickenbach JR. Human skin and gingival keratinocytes show differential regulation of matrix metalloproteinases when combined with fibroblasts in 3-dimensional cultures. J Periodontol 2005; 76: 1072-83.
102. Beare AH, O'Kane S, Krane SM, Ferguson MW. Severely impaired wound healing in the collagenase-resistant mouse. J Invest Dermatol 2003; 120: 153-63.
103. Hartenstein B, Dittrich BT, Stickens D, Heyer B, Vu TH, Teurich S, Schorpp-Kistner M, Werb Z, Angel P. Epidermal development and wound healing in matrix metalloproteinase 13-deficient mice. J Invest Dermatol 2006; 126: 486-96.
104. Mirastschijski U, Zhou Z, Rollman O, Tryggvason K, Å gren MS. Wound healing in membrane-type-1 matrix metalloproteinase-deficient mice. J Invest Dermatol 2004; 123: 600-2.
105. Limb GA, Matter K, Murphy G, Cambrey AD, Bishop PN, Morris GE, Khaw PT. Matrix metalloproteinase-1 associates with intracellular organelles and confers resistance to lamin A/C degradation during apoptosis. Am J Pathol 2005; 166: 1555-63.
106. Zeigler ME, Chi Y, Schmidt T, Varani J. Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes. J Cell Physiol 1999; 180: 271-84.
107. Watelet JB, Demetter P, Claeys C, Van Cauwenberge P, Cuvelier C, Bachert C. Neutrophil-derived metalloproteinase-9 predicts healing quality after sinus surgery. Laryngoscope 2005; 115: 56-61.
108. Chen C, Schultz GS, Bloch M, Edwards PD, Tebes S, Mast BA. Molecular and mechanistic validation of delayed healing rat wounds as a model for human chronic wounds. Wound Repair Regen 1999; 7: 486-94.
109. Bullard KM, Lund L, Mudgett JS, Mellin TN, Hunt TK, Murphy B, Ronan J, Werb Z, Banda MJ. Impaired wound contraction in stromelysin-1-deficient mice. Ann Surg 1999; 230: 260-5.
110. Rechardt O, Elomaa O, Vaalamo M, Paakkonen K, Jahkola T, Hook-Nikanne J, Hembry RM, Häkkinen L, Kere J, Saarialho-Kere U. Stromelysin-2 is upregulated during normal wound repair and is induced by cytokines. J Invest Dermatol 2000; 115: 778-87.
111. Tenaud I, Leroy S, Chebassier N, Dreno B. Zinc, copper and manganese enhanced keratinocyte migration through a functional modulation of keratinocyte integrins. Exp Dermatol 2000; 9: 407-16.
112. Keefer KA, Iocono JA, Ehrlich HP. Zinc-containing wound dressings encourage autolytic debridement of dermal burns. Wounds 1998; 10: 54-8.
113. Lansdown ABG. Influence of zinc oxide in the closure of open skin wounds. Int J Cosmet Sci 1993; 15: 83-5.
114. Apelqvist J, Larsson J, Stenstrom A. Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc. Br J Dermatol 1990; 123: 787-92.
115. Gang RK. Adhesive zinc tape in burns: results of a clinical trial. Burns 1980; 7: 322-5.
116. Ågren MS. Zinc oxide increases degradation of collagen in necrotic wound tissue. Br J Dermatol 1993; 129: 221.
117. Kietzmann M. Improvement and retardation of wound healing: effects of pharmaological agents in laboratory animals. Vet Dermatol 1999; 10: 83-8.
118. Sandstead HH, Lanier VC Jr, Shephard GH, Gillespie DD. Zinc and wound healing. Effects of zinc deficiency and zinc supplementation. Am J Clin Nutr 1970; 23: 514-9.
119. Nezu R, Takagi Y, Ito T, Matsuda H, Okada A. The importance of total parenteral nutrition-associated tissue zinc distribution in wound healing. Surg Today 1999; 29: 34-41.
120. Bates CJ, Evans PH. Incorporation of [3 H]proline into collagen and other proteins in rats fed diets with various zinc concentrations. J Nutr 1992; 122: 1096-104.
121. Ågren MS. Collagen synthesis in connective tissue of wounded rat mesentery: effect of dietary zinc deficiency. Eur J Surg 1991; 157: 453-5.
122. McClain PE, Wiley ER, Beecher GR, Anthony WL, Hsu JM. Influence of zinc deficiency on synthesis and cross-linking of rat skin collagen. Biochim Biophys Acta 1973; 304: 457-65.
123. Prockop DJ, Sieron AL, Li SW. Procollagen N-proteinase and procollagen C-proteinase. Two unusual metalloproteinases that are essential for procollagen processing probably have important roles in development and cell signaling. Matrix Biol 1998; 16: 399-408.
124. Reid RR, Mogford JE, Butt R, deGiorgio-Miller A, Mustoe TA. Inhibition of procollagen C-proteinase reduces scar hypertrophy in a rabbit model of cutaneous scarring. Wound Repair Regen 2006; 14: 138-41.
125. Hallmans G, Lasek J. The effect of topical zinc absorption from wounds on growth and the wound healing process in zinc-deficient rats. Scand J Plast Reconstr Surg 1985; 19: 119-25.
126. Ågren MS. Zinc in wound repair. Arch Dermatol 1999; 135: 1273-4.
127. Ågren MS, Chvapil M, Franzén L. Enhancement of re-epithelialization with topical zinc oxide in porcine partial-thickness wounds. J Surg Res 1991; 50: 101-5.
128. Tarnow P, Ågren M, Steenfos H, Jansson JO. Topical zinc oxide treatment increases endogenous gene expression of insulin-like growth factor-1 in granulation tissue from porcine wounds. Scand J Plast Reconstr Surg Hand Surg 1994; 28: 255-9.
129. Ågren MS. Studies on zinc in wound healing. Acta Derm Venereol 1990; 154 (Suppl. Stockholm): 1-36.
130. Postmes T, Vandeputte J. Recombinant growth factors or honey? Burns 1999; 25: 676-8.
131. Ågren MS, Krusell M, Franzén L. Release and absorption of zinc from zinc oxide and zinc sulfate in open wounds. Acta Derm Venereol 1991; 71: 330-3.
132. Ågren MS, Mirastschijski U. The release of zinc ions from and cytocompatibility of two zinc oxide dressings. J Wound Care 2004; 13: 367-9.
133. 2+ release from zinc and zinc oxide particles in simulated uterine solution. Colloids Surf B Biointerfaces 2006; 47: 140-5.
134. Richard MJ, Guiraud P, Leccia MT, Beani JC, Favier A. Effect of zinc supplementation on resistance of cultured human skin fibroblasts toward oxidant stress. Biol Trace Elem Res 1993; 37: 187-99.
135. Jin L, Murakami TH, Janjua NA, Hori Y. The effects of zinc oxide and diethyldithiocarbamate on the mitotic index of epidermal basal cells of mouse skin. Acta Med Okayama 1994; 48: 231-6.
136. Hansson A. Extracellular zinc ions induces mitogen-activated protein kinase activity and protein tyrosine phosphorylation in bombesin-sensitive Swiss 3T3 fibroblasts. Arch Biochem Biophys 1996; 328: 233-8.
137. Huang JS, Mukherjee JJ, Chung T, Crilly KS, Kiss Z. Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I in fibroblasts. Eur J Biochem 1999; 266: 943-51.
138. Li X, Yin J, Li D, Chen X, Zang J, Zhou X. Dietary supplementation with zinc oxide increases IGF-I and IGF-I receptor gene expression in the small intestine of weanling piglets. J Nutr 2006; 136: 1786-91.
139. Mertz PM, Cazzaniga AL, Drosou A, Davis SC. The effect of a zinc/iron solution as compared to a topical growth factor on epithelization of partial thickness wounds. Wound Repair Regen 2002; 10: A38.
140. Parat MO, Richard MJ, Pollet S, Hadjur C, Favier A, Beani JC. Zinc and DNA fragmentation in keratinocyte apoptosis: its inhibitory effect in UVB irradiated cells. J Photochem Photobiol B 1997; 37: 101-6.
141. Record IR, Jannes M, Dreosti IE. Protection by zinc against UVA- and UVB-induced cellular and genomic damage in vivo and in vitro. Biol Trace Elem Res 1996; 53: 19-25.
142. Parat MO, Richard MJ, Meplan C, Favier A, Béani JC. Impairment of cultured cell proliferation and metallothionein expression by metal chelator NNN′N′-tetrakis-(2-pyridylmethyl) ethylene diamine. Biol Trace Elem Res 1999; 70: 51-68.
143. Rostan EF, DeBuys HV, Madey DL, Pinnell SR. Evidence supporting zinc as an important antioxidant for skin. Int J Dermatol 2002; 41: 606-11.
144. Vaxman F, Olender S, Maldonado H, Randriamananjo S, Chalkiadakis G, Lambert A, Wittmann T, Volkmar P, Grenier JF. Variations of magnesium, iron, copper and zinc during the colonic wound healing process: experimental study on rabbits. Eur Surg Res 1992; 24: 283-90.
145. Iriyama K, Mori T, Takenaka T, Teranishi T, Mori H. Effect of serum zinc level on amount of collagen-hydroxyproline in the healing gut during total parenteral nutrition: an experimental study. J Parenter Enteral Nutr 1982; 6: 416-20.
146. Tümer AR, Kama NA, Tümer L, Reis E, Müftüoglu S. Effects of 5-fluorouracil and zinc on healing of colonic anastomoses in rabbits. Eur J Surg 1999; 165: 369-77.
147. Watanabe T, Arakawa T, Fukuda T, Higuchi K, Kobayashi K. Zinc deficiency delays gastric ulcer healing in rats. Dig Dis Sci 1995; 40: 1340-4.
148. Korolkiewicz RP, Fujita A, Seto K, Suzuki K, Takeuchi K. Polaprezinc exerts a salutary effect on impaired healing of acute gastric lesions in diabetic rats. Dig Dis Sci 2000; 45: 1200-9.
149. Navarro C, Escolar G, Bravo ML, Jiménez E, Bulbena O. Effect of zinc acexamate and ranitidine on chronic gastric lesions in the rat. Digestion 1990; 45: 121-9.
150. Gaetke LM, McClain CJ, Talwalkar RT, Shedlofsky SI. Effects of endotoxin on zinc metabolism in human volunteers. Am J Physiol 1997; 272: E952-6.
151. Shenkin A. Trace elements and inflammatory response: implications for nutritional support. Nutrition 1995; 11: 100-5.
152. Philcox JC, Coyle P, Michalska A, Choo KH, Rofe AM. Endotoxin-induced inflammation does not cause hepatic zinc accumulation in mice lacking metallothionein gene expression. Biochem J 1995; 308 (Part 2): 543-6.
153. Zorrilla P, Gomez LA, Salido JA, Silva A, Lopez-Alonso A. Low serum zinc level as a predictive factor of delayed wound healing in total hip replacement. Wound Repair Regen 2006; 14: 119-22.
154. Faure H, Peyrin JC, Richard MJ, Favier A. Parenteral supplementation with zinc in surgical patients corrects postoperative serum-zinc drop. Biol Trace Elem Res 1991; 30: 37-45.
155. Mozzillo N, Ayala F, Formato A, Forestieri P, Mazzeo F. First full blown syndrome of acute zinc deficiency in course of long term total parenteral nutrition: a clinical case. Ital J Surg Sci 1984; 14: 229-31.
156. Okada A, Takagi Y, Nezu R, Lee S. Zinc in clinical surgery - a research review. Jpn J Surg 1990; 20: 635-44.
157. Braunschweig CL, Sowers M, Kovacevich DS, Hill GM, August DA. Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response. J Nutr 1997; 127: 70-4.
158. Wilkinson EA, Hawke CI. Does oral zinc aid the healing of chronic leg ulcers? A systematic literature review. Arch Dermatol 1998; 134: 1556-60.
159. Collins N. Zinc supplementation: yea or nay? Adv Skin Wound Care 2003; 16: 226-30.
160. Oon BB, Khong KY, Greaves MW, Plummer VM. Trophic skin ulceration of leprosy: skin and serum zinc concentrations. BMJ 1974; 2: 531-3.
161. Wissing U, Unosson M, Lennernas MA, Ek AC. Nutritional intake and physical activity in leg ulcer patients. J Adv Nurs 1997; 25: 571-8.
162. Lansdown ABG. Zinc in the healing wound. Lancet 1996; 347: 706-7.
163. Sollemann T. A manual of pharmacology. 6th ed. Philadelphia: Saunders, 1942.
164. Ågren MS, Strömberg HE. Topical treatment of pressure ulcers. A randomized comparative trial of Varidase and zinc oxide. Scand J Plast Reconstr Surg 1985; 19: 97-100.
165. Brandrup F, Menné T, Ågren MS, Strömberg HE, Holst R, Frisén M. A randomized trial of two occlusive dressings in the treatment of leg ulcers. Acta Derm Venereol 1990; 70: 231-5.
166. Strömberg HE, Ågren MS. Topical zinc oxide treatment improves arterial and venous leg ulcers. Br J Dermatol 1984; 111: 461-8.
167. Moore J. Diabetes watch: can zinc oxide have an impact on wound healing? Podiatry Today 2003; 16: 22-5.
168. Tronnier H. Experimental study on epithelization. Z Hautkr 1975; 50: 925-9.
169. Greenway SE, Filler LE, Greenway FL. Topical insulin in wound healing: a randomised, double-blind, placebo-controlled trial. J Wound Care 1999; 8: 526-8.
170. Weingart D, Stoll P. The epithelialization of split skin graft donor sites - a test model for the efficacy of topical wound therapeutic agents. Eur J Plast Surg 1993; 16: 22-5.
171. Blencowe DK, Morby AP. Zn(II) metabolism in prokaryotes. FEMS Microbiol Rev 2003; 27: 291-311.
172. Silver S, Phung le T. A bacterial view of the periodic table: genes and proteins for toxic inorganic ions. J Ind Microbiol Biotechnol 2005; 32: 587-605.
173. Söderberg T, Ågren M, Tengrup I, Hallmans G, Banck G. The effects of an occlusive zinc medicated dressing on the bacterial flora in excised wounds in the rat. Infection 1989; 17: 81-5.
174. Fox CL Jr, Rao TN, Azmeth R, Gandhi SS, Modak S. Comparative evaluation of zinc sulfadiazine and silver sulfadiazine in burn wound infection. J Burn Care Rehabil 1990; 11: 112-7.
175. Podbielski A, Boeckh C, Haller B. Growth inhibitory activity of gutta-percha points containing root canal medications on common endodontic bacterial pathogens as determined by an optimized quantitative in vitro assay. J Endod 2000; 26: 398-403.
176. Tchaou WS, Turng BF, Minah GE, Coll JA. In vitro inhibition of bacteria from root canals of primary teeth by various dental materials. Pediatr Dent 1995; 17: 351-5.
177. Akiyama H, Yamasaki O, Kanzaki H, Tada J, Arata J. Effects of zinc oxide on the attachment of Staphylococcus aureus strains. J Dermatol Sci 1998; 17: 67-74.
178. Ågren MS, Söderberg TA, Reuterving CO, Hallmans G, Tengrup I. Effect of topical zinc oxide on bacterial growth and inflammation in full-thickness skin wounds in normal and diabetic rats. Eur J Surg 1991; 157: 97-101.
179. Söderberg TA, Sunzel B, Holm S, Elmros T, Hallmans G, Sjöberg S. Antibacterial effect of zinc oxide in vitro. Scand J Plast Reconstr Surg Hand Surg 1990; 24: 193-7.
180. Sunzel B, Lasek J, Söderberg T, Elmros T, Hallmans G, Holm S. The effect of zinc oxide on Staphylococcus aureus and polymorphonuclear cells in a tissue cage model. Scand J Plast Reconstr Surg Hand Surg 1990; 24: 31-5.
181. Hansson C. The effects of cadexomer iodine paste in the treatment of venous leg ulcers compared with hydrocolloid dressing and paraffin gauze dressing. Cadexomer iodine study group. Int J Dermatol 1998; 37: 390-6.
182. Lansdown ABG, Williams A, Chandler S, Benfield S. Silver absorption and antibacterial efficacy of silver dressings. J Wound Care 2005; 14: 155-60.
183. Edwards R, Harding KG. Bacteria and wound healing. Curr Opin Infect Dis 2004; 17: 91-6.
184. Chvapil M. Effect of zinc on cells and biomembranes. Med Clin North Am 1976; 60: 799-812.
185. Hujanen ES, Seppä ST, Virtanen K. Polymorphonuclear leukocyte chemotaxis induced by zinc, copper and nickel in vitro. Biochim Biophys Acta 1995; 1245: 145-52.
186. 2+ inhibits nitric oxide formation in response to lipopolysaccharides: implication in its anti-inflammatory activity. Eur J Pharmacol 1998; 341: 265-72.
187. Lim Y, Levy M, Bray TM. Dietary zinc alters early inflammatory responses during cutaneous wound healing in weanling CD-1 mice. J Nutr 2004; 134: 811-6.
188. Rydengård V, Andersson Nordahl E, Schmidtchen A. Zinc potentiates the antibacterial effects of histidine-rich peptides against Enterococcus faecalis. FEBS J 2006; 273: 2399-406.
189. Hu Z, Hidalgo G, Houston PL, Hay AG, Shuler ML, Abruna HD, Ghiorse WC, Lion LW. Determination of spatial distributions of zinc and active biomass in microbial biofilms by two-photon laser scanning microscopy. Appl Environ Microbiol 2005; 71: 4014-21.
190. Ugur A, Ceylan O. Occurrence of resistance to antibiotics, metals, and plasmids in clinical strains of Staphylococcus spp. Arch Med Res 2003; 34: 130-6.
191. Ye J, Kandegedara A, Martin P, Rosen BP. Crystal structure of the
192. Williams C. Examining the range of medicated and paste-impregnated bandages. Br J Nurs 1999; 8: 1019-20.
193. Hardie RA, Benton EC, Hunter JA. Adverse reactions to paste bandages. Clin Exp Dermatol 1982; 7: 135-42.
194. Lindsay E. Innovations in bandage technology: SSL's non-fray Steripaste. Br J Nurs 1999; 8: 8-9.
195. Stacey MC, Jopp-Mckay AG, Rashid P, Hoskin SE, Thompson PJ. The influence of dressings on venous ulcer healing - a randomised trial. Eur J Vasc Endovasc Surg 1997; 13: 174-9.
196. Eriksson G. Comparison of two occlusive bandages in the treatment of venous leg ulcers. Br J Dermatol 1986; 114: 227-30.
197. Villasin JV. Effectiveness of dermagran dual therapeutic system in the treatment of chronic skin ulcers. Ostomy Wound Manage 1989; 22: 44-8.
198. Ziegler UE, Schmidt K, Keller HP, Thiede A. Treatment of chronic wounds with an alginate dressing containing calcium zinc and manganese. Fortschr Med Orig 2003; 121: 19-26.
199. Cameron J, Hoffman D, Wilson J, Cherry G. Comparison of two peri-wound skin protectants in venous leg ulcers: a randomised controlled trial. J Wound Care 2005; 14: 233-6.
200. Baldwin S, Odio MR, Haines SL, O'Connor RJ, Englehart JS, Lane AT. Skin benefits from continuous topical administration of a zinc oxide/petrolatum formulation by a novel disposable diaper. J Eur Acad Dermatol Venereol 2001; 15 (Suppl. 1): 5-11.
201. Söderberg TA, Elmros T, Gref R, Hallmans G. Inhibitory effect of zinc oxide on contact allergy due to colophony. Contact Dermatitis 1990; 23: 346-51.
202. Schwartz JR, Marsh RG, Draelos ZD. Zinc and skin health: overview of physiology and pharmacology. Dermatol Surg 2005; 31: 837-47.
203. Hostynek JJ. Factors determining percutaneous metal absorption. Food Chem Toxicol 2003; 41: 327-45.
204. Morgan CJ, Renwick AG, Friedmann PS. The role of stratum corneum and dermal microvascular perfusion in penetration and tissue levels of water-soluble drugs investigated by microdialysis. Br J Dermatol 2003; 148: 434-43.
205. Frings MM, Kind PP, Goerz G, Abel J. The effect of topically applied corticosteroids and zinc on the metallothionein content of skin in an experimental model. Clin Exp Dermatol 1989; 14: 434-6.
206. Morgan AJ, Lewis G, Van den Hoven WE, Akkerboom PJ. The effect of zinc in the form of erythromycin-zinc complex (Zineryt lotion) and zinc acetate on metallothionein expression and distribution in hamster skin. Br J Dermatol 1993; 129: 563-70.
207. Wormser U, BenZakine S. Increased levels of hepatic and renal metallothionein in the rat and guinea pig after percutaneous application of zinc chloride. Bull Environ Contam Toxicol 1991; 46: 249-54.
208. Lansdown ABG. Interspecies variations in response to topical application of selected zinc compounds. Food Chem Toxicol 1991; 29: 57-64.
209. Lansdown ABG, Grasso P. Physico-chemical factors influencing epidermal damage by surface active agents. Br J Dermatol 1972; 86: 361-73.
210. Pirot F, Millet J, Kalia YN, Humbert P. In vitro study of percutaneous absorption, cutaneous bioavailability and bioequivalence of zinc and copper from five topical formulations. Skin Pharmacol 1996; 9: 259-69.
211. Hostýnek JJ, Hinz RS, Lorence CR, Price M, Guy RH. Metals and the skin. Crit Rev Toxicol 1993; 23: 171-235.
212. Gorodetsky R, Andriessen A, Polyansky I, Vexler A. Measurement of breast skin viscoelasticity and a pilot study on the potential radioprotective effect of a zinc-based cream. J Wound Care 1999; 8: 514-8.
213. Ågren MS. Influence of two vehicles for zinc oxide on zinc absorption through intact skin and wounds. Acta Derm Venereol 1991; 71: 153-6.
214. 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: 301-7.
215. Scott A. The behaviour of radioactive mercury and zinc after application to normal and abnormal skin. Br J Dermatol 1959; 71: 181-9.
216. Grasso P, Lansdown ABG. Methods of measuring and factors affecting percutaneous absorption. Int J Cosmet Sci 1972; 23: 481-521.
217. Hallmans G. Absorption of topically applied zinc and changes in zinc metabolism during wound healing. An experimental and clinical investigation. Acta Derm Venereol Suppl (Stockh) 1978; 58: 1-36.
218. Keen CL, Hurley LS. Zinc absorption through skin: correction of zinc deficiency in the rat. Am J Clin Nutr 1977; 30: 528-30.
219. Whitehouse MW, Rainsford KD, Taylor RM, Vernon-Roberts B. Zinc monoglycerolate: a slow-release source of zinc with anti-arthritic activity in rats. Agents Actions 1990; 31: 47-58.
220. Derry JE, McLean WM, Freeman JB. A study of the percutaneous absorption from topically applied zinc oxide ointment. J Parenter Enteral Nutr 1983; 7: 131-5.
221. Morgan ME, Hughes MA, McMillan EM, King I, Mackie RM. Plasma zinc in psoriatic in-patients treated with local zinc applications. Br J Dermatol 1980; 102: 579-83.
222. Golden MH, Golden BE, Jackson AA. Skin breakdown in kwashiorkor responds to zinc. Lancet 1980; 1: 1256.