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Plasma Medicine

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ISSN Print: 1947-5764

ISSN Online: 1947-5772

SJR: 0.216 SNIP: 0.263 CiteScore™:: 1.4 H-Index: 24

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Comparative Study between Direct and Indirect Treatment with Cold Atmospheric Plasma on In Vitro and In Vivo Models of Wound Healing

Volume 8, Issue 4, 2018, pp. 379-401
DOI: 10.1615/PlasmaMed.2019028659
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ABSTRACT

Cold-atmospheric plasma (CAP) produces a mixture of molecular, ionic, and radical species as well as electric field visible and ultraviolet lights. Biological effects of CAP and its therapeutic potential have been studied in disciplines such as dermatology, oncology, and dentistry. This study investigates both in vitro and in vivo effects of direct and indirect plasma treatment and their influences on wound healing. The effect of plasma treatment on cellular viability, migration, and proliferation are studied using keratinocytes, fibroblasts, and endothelial cells. Plasma is generated in a helium jet using an alternating-current 50-Hz power supply at 32 kV and 90 mW. Results show that 1-min direct CAP treatment stimulates skin cell migration; however, cellular proliferation remains unchanged. Treatment > 3 min leads to cell death. Using the same treatment parameters, notably exposure time, indirect treatment using a plasma-activated medium fails to stimulate cellular migration. A murine model of full-thickness excisional wound healing is used to study the effect of CAP on wound closure. In vivo studies demonstrate that both direct and indirect treatment do not affect acute wound closure in mice. Taken together, these results suggest that direct plasma treatment with homemade plasma devices has the potential to positively influence wound healing, but optimum parameters and suitable wound models must be identified and validated.

REFERENCES
  1. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008 May 15;453:314-21.

  2. Vig K, Chaudhari A, Tripathi S, Dixit S, Sahu R, Pillai S, Dennis VA, Singh SR. Advances in skin regeneration using tissue engineering. Int J Mol Sci. 2017 Apr 7;18(4):789.

  3. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007 Oct 25;25:2648-59.

  4. Lieberman MA, Lichetenberg AJ. Principles of plasma discharges and materials processing. 2nd edition. New York: John Wiley & Sons; 2005.

  5. Daeschlein G, Napp M, Lutze S, Arnold A, von Podewils S, Guembel D, Junger M. Skin and wound decontamination of multidrug-resistant bacteria by cold atmospheric plasma coagulation. J Dtsch Dermatol Ges. 2015 Feb;13(2):143-50.

  6. Ermolaeva SA, Varfolomeev AF, Chernukha MY, Yurov DS, Vasiliev MM, Kaminskaya AA, Moisenovich MM, Romanova JM, Murashev AN, Selezneva II, Shimizu T, Sysolyatina EV, Shaginyan IA, Petrov OF, Mayevsky EI, Fortov VE, Morfill GE, Naroditsky BS, Gintsburg AL. Bactericidal effects of non-thermal argon plasma in vitro, in biofilms and in the animal model of infected wounds. J Med Microbiol. 2011 Aug;60(Pt 1):75-83.

  7. Mohd Nasir N, Lee BK, Yap SS, Thong KL, Yap SL. Cold plasma inactivation of chronic wound bacteria. Arch Biochem Biophys. 2016 Sept 1;605:76-85.

  8. Klampfl TG, Isbary G, Shimizu T, Li YF, Zimmermann JL, Stolz W, Schelegel J, Morfill GE, Schmidt HU. Cold atmospheric air plasma sterilization against spores and other microorganisms of clinical interest. Appl Environ Microbiol. 2012 Aug;78(15):5077-82.

  9. Chatraie M, Torkaman G, Khani M, Salehi H, Shokri B. In vivo study of non-invasive effects of non-thermal plasma in pressure ulcer treatment. Sci Rep. 2018 Apr 4;8(1):5621.

  10. Schmidt A, Bekeschus S, Wende K, Vollmar B, von Woedtke T. A cold plasma jet accelerates wound healing in a murine model of full-thickness skin wounds. Exp Dermatol. 2017 Feb;26(2):156-62.

  11. Isbary G, Heinlin J, Shimizu T, Zimmermann JL, Morfill G, Schmidt HU, Monetti R, Steffes B, Bunk W, Li Y, Klaempfl L, Karrer S, Landthaler M, Stolz W. Successful and safe use of 2 min cold atmospheric argon plasma in chronic wounds: Results of a randomized controlled trial. Br J Dermatol. 2012 Aug;167(2):404-10.

  12. Heinlin J, Morfill G, Landthaler M, Stolz W, Isbary G, Zimmermann JL, Shimizu L, Karrer S. Plasma medicine: Possible applications in dermatology. J Dtsch Dermatol Ges. 2010 Dec;8(12):968-76.

  13. Duval A, Marinov I, Bousquet G, Gapihan G, Starikovskaia SM, Rousseau A, Janin A. Cell death induced on cell cultures and nude mouse skin by non-thermal, nanosecond-pulsed generated plasma. PLoS One. 2013;8(12):e83001.

  14. Kang SU, Cho JH, Chang JW, Shin YS, Kim KI, Park JK, Yang SS, Lee JS, Moon E, Lee K, Kim CH. Nonthermal plasma induces head and neck cancer cell death: The potential involvement of mitogen-activated protein kinase-dependent mitochondrial reactive oxygen species. Cell Death Dis. 2014 Feb 13;5:1056.

  15. Vandamme M, Robert E, Lerondel S, Sarron V, Ries D, Dozias S, Sobilo J, Gosset D, Kieda C, Legrain B, Pouvesle JM, Pape AL. ROS implication in a new antitumor strategy based on non-thermal plasma. Int J Cancer. 2012 May 1;130(9):2185-94.

  16. Nasruddina YN, Kanae M, Heni S, Rahayu E, Nur M, Ishijima T, Enomotod H, Uesugi Y, Sugama J, Nakatani T. Cold plasma on full-thickness cutaneous wound accelerates healing through promoting inflammation, re-epithelialization and wound contraction. Clin Plas Med. 2014;2:28-35.

  17. O'Connor N, Cahill O, Daniels S, Galvin S, Humphreys H. Cold atmospheric pressure plasma and decontamination. Can it contribute to preventing hospital-acquired infections? J Hosp Infect. 2014 Oct;88(2):59-65.

  18. Cahill OJ, Claro T, O'Connor N, CafollaAA, Stevens NT, Daniels S, Humphreys H. Cold air plasma to decontaminate inanimate surfaces of the hospital environment. Appl Environ Microbiol. 2014 Mar;80(6):2004-10.

  19. Betancourt-Angeles M, Pena-Eguiluz R, Lopez-Callejas R, Dominguez-Cadena NA, Mercado-Cabrera A, Munoz-Infante J, Rodriguez-Mendez BG, Valencia-Alvarado R, Moreno-Tapia JA. Treatment in the healing of burns with a cold plasma source. Int J Burn Trauma. 2017;7(7):142-6.

  20. Daeschlein G, Scholz S, Ahmed R, von Woedtke T, Haase H, Niggemeier M, Kindel E, Brandenburg R, Weltmann KD, Juenger M. Skin decontamination by low-temperature atmospheric pressure plasma jet and dielectric barrier discharge plasma. J Hosp Infect. 2012 Jul;81(3):177-83.

  21. Ulrich C, Kluschke F, Patzelt A, Vandersee S, Czaika VA, Richter H, Bob A, Hutten JV, Painsi C, Huge R, Kramer A, Assadian O, Lademann J, Lange-Asschenfeldt B. Clinical use of cold atmospheric pressure argon plasma in chronic leg ulcers: A pilot study. J Wound Care. 2015 May;24(5):196, 198-200, 202-3.

  22. Emmert SBF, Hanflle H, Helmke A, Mertens N, Ahmed R, Simon D, Wandke D, Maus-Friedrichs W, Daschlein G, Schon MP, Viol W. Atmospheric pressure plasma in dermatology: Ulcus treatment and much more. Clin Plas Med. 2013;1:24-9.

  23. Klebes M, Lademann J, Philipp S, Ulrich C, Patzelt A, Ulmer M, Kluschke F, Kramer A, Weltmann KD, Sterry W, Asschenfeldt B. Effects of tissue-tolerable plasma on psoriasis vulgaris treatment compared to conventional local treatment: A pilot study. Clin Plas Med. 2014; 2(1):22-7.

  24. Daeschlein G, Scholz S, Ahmed R, Majumdar A, von Woedtke T, Haase H, Nigemeier M, Kindel E, Brandenburg R, Weltmann KD, Junger M. Cold plasma is well-tolerated and does not disturb skin barier or reduce skin moisture. J Dtsch Dermatol Ges. 2012 Jul;10(7):509-15.

  25. Heinlin J, Isbary G, Stolz W, Zeman F, Landthaler M, Morfill G, Shimizu T, Zimmermann JL, Karrer S. A randomized two-sided placebo-controlled study on the efficacy and safety of atmospheric non-thermal argon plasma for pruritus. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):324-31.

  26. Haertel B, von Woedtke T, Weltmann KD, Lindequist U. Non-thermal atmospheric-pressure plasma possible application in wound healing. Biomol Ther (Seoul). 2014;22(6):477-90.

  27. Graves DB. Low temperature plasma biomedicine: A tutorial review. Phys Plasma. 2014 Nov;21(8): 080901-080901.12.

  28. Arndt S, Landthaler M, Zimmermann JL, Unger P, Wacker E, Shimizu T, Li YF, Morfill GE, Bosserhoff AK, Karrer S. Effects ofcold atmospheric plasma (CAP) on P-defensins, inflammatory cytokines, and apoptosis-related molecules in keratinocytes in vitro and in vivo. PLoS One. 2015;10(3):e0120041.

  29. Fridman G, Gutsol A, Shekhter AB, Vasilets VN, Fridman A. Applied plasma medicine. Plasma Proc Polym. 2008;5(6):503-33.

  30. Arjunan KP, Clyne AM. Non-thermal dielectric barrier discharge plasma induces angiogenesis through reactive oxygen species. J Roy Soc Interface. 2012; 9(66):147-57.

  31. Arndt S, Unger P, Wacker E, Shimizu T, Heinlin J, Li YF, Thomas HM, Morfill GE, Zimmermann JL, BosserhoffAK, Karrer S. Cold atmospheric plasma (CAP) changes gene expression of key molecules of the wound healing machinery and improves wound healing in vitro and in vivo. PLoS One. 2013;8(11):e79325.

  32. Kang SU, Choi JW, Chang JW, Kim KI, Kim YS, Park JK, Kim YE, Lee YS, Yang SS, Kim CH. N2 Non-thermal atmospheric pressure plasma promotes wound healing in vitro and in vivo: Potential modulation of adhesion molecules and matrix metalloproteinase-9. Exp Dermatol. 2017 Feb;26(2):163-70.

  33. Arndt S, Unger P, Berneburg M, BosserhoffAK, Karrer S. Cold atmospheric plasma (CAP) activates angiogenesis-related molecules in skin keratinocytes, fibroblasts and endothelial cells and improves wound angiogenesis in an autocrine and paracrine mode. J Dermatol Sci. 2018 Feb;89(2):181-90.

  34. Violleau F, Hadjeba K, Albet J, Cazalis R, Surel O. Effect of oxidative treatment on corn seed germination kinetics. Ozone-Sci Eng. 2015;30:418-22.

  35. Bailly C. Active oxygen species and antioxidants in seed biology. Seed Sci Res. 2004;14:97-107.

  36. Mone Y, Monnin D, Kremer N. The oxidative environment: A mediator of interspecies communication that drives symbiosis evolution. Proc Biol Sci. 2014 Jun 22;281(1785):20133112.

  37. Stallmeyer B, Kampfer H, Kolb N, Pfeilschifter J, Frank S. The function of nitric oxide in wound repair: Inhibition of inducible nitric oxide-synthase severely impairs wound reepithelialization. J Invest Dermatol. 1999 Dec;113(6):1090-8.

  38. Luo JD, Chen AF. Nitric oxide: A newly discovered function on wound healing. Acta Pharmacol Sin. 2005 Mar;26(3):259-64.

  39. Cui HS, Joo SY, Lee DH, Yu JH, Jeong JH, Kim JB, Seo CH. Low temperature plasma induces angiogenic growth factor via up-regulating hypoxia-inducible factor la in human dermal fibroblasts. Arch Biochem Biophys. 2017 Sep 15;630:9-17.

  40. Maisch T, BosserhoffAK, Unger P, Heider J, Shimizu T, Zimmermann JL, Morfill GE, Landthaler M, Karrer S. Investigation of toxicity and mutagenicity of cold atmospheric argon plasma. Environ Mol Mutagen. 2017 Apr;58(3):172-7.

  41. Lee JH, Kim KN. Effects of a nonthermal atmospheric pressure plasma jet on human gingival fibroblasts for biomedical application. Biomed Res Int. 2016;2876916:1-9.

  42. Kim KC, Piao MJ, Madduma Hewage SR, Han X, Kang KA, Jo JO, Mok YS, Shin JH, Park Y, Yoo SJ, Hyun JW. Non-thermal dielectric-barrier discharge plasma damages human keratinocytes by inducing oxidative stress. Int J Mol Med. 2016 Jan;37(1):29-38.

  43. Wende K, Strassenburg S, Haertel B, Harms M, Holtz S, Barton A, Masur K, von Woedtke T, Lindesquist U. Atmospheric pressure plasma jet treatment evokes transient oxidative stress in HaCaT keratinocytes and influences cell physiology. Cell Biol Int. 2014 Apr;38(4):412-25.

  44. Hasse S, Duong Tran T, Hahn O, Kindler S, Metelmann HR, von Woedtke T, Masur K. Induction of proliferation of basal epidermal keratinocytes by cold atmospheric-pressure plasma. Clin Exp Dermatol. 2016 Mar;41(2):202-9.

  45. Suzuki K, Yoshino D. Proliferation-related activity in endothelial cells is enhanced by micropower plasma. BioMed Res Int. 2016;4651265:1-11.

  46. Graves DB. The emerging role of reactive oxygen and nitrogen species in redox biology and some implications for plasma applications to medicine and biology. J Phys D Appl Phys. 2012;45:263001.

  47. Kalghatgi S, Kelly CM, Cerchar E, Torabi B, Alekseev O, Fridman A, Friedman G, Azizkhan-Clifford J. Effects ofnon-thermalplasmaonmammaliancells. PLoS One. 2011 Jan21;6(l):el6270.

  48. Schmidt A, von Woedtke T, Bekeschus S. Periodic exposure of keratinocytes to cold physical plasma: An in vitro model for redox-related diseases of the skin. Oxid Med Cell Longev. 2016;2016:17.

  49. Girard D, Laverdet B, Buhe V, Trouillas M, Ghazi K, Alexaline MM, Egles C, Misery L, Coulomb B, Lataillade JJ, Berthod F, Ermouliere A. Biotechnological management of skin burn injuries: Challenges and perspectives in wound healing and sensory recovery. Tissue Eng Part B Rev. 2017 Feb;23(1):59-82.

  50. Dunnill C, Patton T, Brennan J, Barrett J, Dryden M, Cooke J, Leaper D, Georgopoulos NT. Reactive oxygen species (ROS) and wound healing: The functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J. 2017 Feb;14(1):89-96.

  51. Loo AE, Wong YT, Ho R, Wasser M, Du T, Ng WT, Halliwell B. Effects of hydrogen peroxide on wound healing in mice in relation to oxidative damage. PLoS One. 2012;7(11):e49215.

  52. Rinnerthaler M, Bischof J, Streubel MK, Trost A, Richter K. Oxidative stress in aging human skin. Biomolecules. 2015 Apr 21;5(2):545-89.

  53. Soneja A, Drews M, Malinski T. Role of nitric oxide, nitroxidative and oxidative stress in wound healing. Pharmacol Rep. 2005;57(Suppl):108-19.

  54. Witte MB, Barbul A. Role of nitric oxide in wound repair. Am J Surg. 2002 Apr;183(4):406-12.

  55. Ngo Thi M, Shao P, Liao J, Lin CK, Yip H. Enhancement of angiogenesis and epithelialization processes in mice with burn wounds through ROS/RNS signals generated by non-thermal N2/Ar micro-plasma. Plasma Proc Polym. 2014;11(11):1076-88.

  56. Heuer K, Hoffmanns MA, Demir E, Baldus S, Volkmar CM, Rohle M, Furchs PC, Awakowicz P, Suschek CV, Oplander C. The topical use of non-thermal dielectric barrier discharge (DBD): Nitric oxide related effects on human skin. Nitric Oxide. 2015 Jan 30;44:52-60.

  57. Kartaschew K, Mischo M, Baldus S, Brundermann E, Awakowicz P, Havenith M. Unraveling the interactions between cold atmospheric plasma and skin-components with vibrational microspectros-copy. Biointerphases. 2015 Jun 6;10(2):029516.

  58. Kubinova S, Zaviskova K, Uherkova L, Zablotskii V, Churpita O, Lunov O, Dejneka A. Non-thermal air plasma promotes the healing of acute skin wounds in rats. Sci Rep. 2017 Mar 24;7:45183.

  59. Hartwig S, Doll C, Voss JO, Hertel M, Preissner S, Raguse JD. Treatment of wound healing disorders of radial forearm free flap donor sites using cold atmospheric plasma: A proof of concept. J Oral Maxillofac Surg. 2017 Feb;75(2):429-35.

  60. Kim HY, Kang SK, Park SM, Jung HY, Choi BH, Sim JY, Lee JK. Characterization and effects of Ar/air microwave plasma on wound healing. Plasma Proc Polym. 2015;12(12):1423.

  61. Xu GM, Shi XM, Cai JF, Chen SL, Li P, Yao CW, Chang ZS, Zhang GJ. Dual effects of atmospheric pressure plasma jet on skin wound healing of mice. Wound Rep Regen. 2015 Nov-Dec;23(6):878-84.

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