Applications of cold atmospheric plasma for transdermal drug delivery: a review


Although transdermal drug delivery would be very useful for the treatment of many diseases, in practice it is difficult to accomplish for the obstruction of the stratum corneum. The application of cold atmospheric plasma (CAP) as a pretreatment to the skin surface helps to enhance the delivery of topically applied drugs into the skin and the systemic circulation. CAP can change the skin properties to improve drug penetration by various different effects based on its multiple components. This review first introduces the skin barrier properties and some traditional transdermal drug delivery strategies. Next what is known about the application of CAP in transdermal drug delivery has been summarized, including the mechanisms and possible side effects. We believe that CAP could be developed as a non-invasive and efficient pretreatment to improve the transdermal permeation of drugs in clinical practice, although more research needs to be done to overcome the challenges.

Graphical Abstract

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Lade S, Kosalge S, Shaikh S. Transdermal drug delivery system: a tool for novel drug delivery system: an overview. World Journal of Pharmaceutical Research. 2014;3(2):1892–908.

    Google Scholar 

  2. 2.

    Singh D, Pradhan M, Nag M, Singh MR. Vesicular system: versatile carrier for transdermal delivery of bioactives. Artificial cells, nanomedicine, and biotechnology. 2015;43(4):282–90.

    CAS  PubMed  Google Scholar 

  3. 3.

    Sobanko JF, Miller CJ, Alster TS. Topical anesthetics for dermatologic procedures: a review. Dermatol Surg. 2012;38(5):709–21.

    CAS  PubMed  Google Scholar 

  4. 4.

    Eyerich S, Eyerich K, Traidl-Hoffmann C, Biedermann T. Cutaneous barriers and skin immunity: differentiating a connected network. Trends Immunol. 2018;39(4):315–27.

    CAS  PubMed  Google Scholar 

  5. 5.

    Zhou X, Hao Y, Yuan L, Pradhan S, Shrestha K, Pradhan O, et al. Nano-formulations for transdermal drug delivery: a review. Chin Chem Lett. 2018;29(12):1713–24.

    CAS  Google Scholar 

  6. 6.

    Trommer H, Neubert RH. Overcoming the stratum corneum: the modulation of skin penetration. A review Skin Pharmacology and Physiology. 2006;19(2):106–21.

    CAS  PubMed  Google Scholar 

  7. 7.

    Marwah H, Garg T, Goyal AK, Rath G. Permeation enhancer strategies in transdermal drug delivery. Drug Delivery. 2014;23(2):564–78.

    PubMed  Google Scholar 

  8. 8.

    Benbow TV, Campbell J. Microemulsions as transdermal drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs): a literature review. Drug Dev Ind Pharm. 2019:1–16.

  9. 9.

    Ita KB. Prodrugs for transdermal drug delivery - trends and challenges. J Drug Target. 2016;24(8):671–8.

    CAS  PubMed  Google Scholar 

  10. 10.

    Schoellhammer CM, Blankschtein D, Langer R. Skin permeabilization for transdermal drug delivery: recent advances and future prospects. Expert opinion on drug delivery. 2014;11(3):393–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Banga AK, Bose S, Ghosh TK. Iontophoresis and electroporation: comparisons and contrasts. Int J Pharm. 1999;179(1):1–19.

    CAS  PubMed  Google Scholar 

  12. 12.

    Waghule T, Singhvi G, Dubey SK, Pandey MM, Gupta G, Singh M, et al. Microneedles: a smart approach and increasing potential for transdermal drug delivery system. Biomed Pharmacother. 2019;109:1249–58.

    CAS  PubMed  Google Scholar 

  13. 13.

    von Woedtke T, Metelmann HR, Weltmann KD. Clinical plasma medicine: state and perspectives of in vivo application of cold atmospheric plasma. Contributions to Plasma Physics. 2014;54(2):104–17.

    Google Scholar 

  14. 14.

    Graves DB. Low temperature plasma biomedicine: a tutorial review. Physics of Plasmas. 2014;21(8):080901.

    Google Scholar 

  15. 15.

    Weltmann KD, Kindel E, Brandenburg R, Meyer C, Bussiahn R, Wilke C, et al. Atmospheric pressure plasma jet for medical therapy: plasma parameters and risk estimation. Contributions to Plasma Physics. 2009;49(9):631–40.

    Google Scholar 

  16. 16.

    Weltmann K, Von Woedtke T. Plasma medicine—current state of research and medical application. Plasma Physics and Controlled Fusion. 2016;59(1):014031.

    Google Scholar 

  17. 17.

    Daeschlein G, Napp M, Lutze S, Arnold A, von Podewils S, Guembel D, et al. Skin and wound decontamination of multidrug-resistant bacteria by cold atmospheric plasma coagulation. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2015;13(2):143–9.

    PubMed  Google Scholar 

  18. 18.

    Haertel B, Von Woedtke T, Weltmann K-D, et al. Non-thermal atmospheric-pressure plasma possible application in wound healing. Biomol Ther. 2014;22(6):477–90.

    CAS  Google Scholar 

  19. 19.

    Zhong S, Dong Y, Liu D, et al. Surface air plasma-induced cell death and cytokine release of human keratinocytes in the context of psoriasis. Br J Dermatol. 2016;174(3):542–52.

    CAS  PubMed  Google Scholar 

  20. 20.

    Bekeschus S, Rödder K, Fregin B, et al. Toxicity and immunogenicity in murine melanoma following exposure to physical plasma-derived oxidants. Oxidative Med Cell Longev. 2017;2017:4396467.

    Google Scholar 

  21. 21.

    Kalghatgi S, Tsai C, Gray R, et al. Transdermal drug delivery using cold plasmas. 22nd International Symposium on Plasma Chemistry 2015:5–10.

  22. 22.

    Shimizu K, Hayashida K, Blajan M. Novel method to improve transdermal drug delivery by atmospheric microplasma irradiation. Biointerphases. 2015;10(2):029517.

    PubMed  Google Scholar 

  23. 23.

    Gan L, Zhang S, Poorun D, Liu D, Lu X, He M, et al. Medical applications of nonthermal atmospheric pressure plasma in dermatology. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2018;16(1):7–13.

    PubMed  Google Scholar 

  24. 24.

    Kalghatgi S, Juluri A. Louis JS, et al. Google Patents: Methods and systems for trans-tissue substance delivery using plasmaporation; 2017.

    Google Scholar 

  25. 25.

    Kristof J, Miyamoto H, Tran AN, et al. Feasibility of transdermal delivery of cyclosporine A using plasma discharges. Biointerphases. 2017;12(2):02B402.

  26. 26.

    Shimizu K, Tran AN, Kristof J, et al. Investigation of atmospheric microplasma for improving skin permeability. Proceedings of the 2016 Electrostatics joint conference, Lafayette 2016:13–18.

  27. 27.

    Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9(3):165–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Fluhr JW, Sassning S, Lademann O, Darvin ME, Schanzer S, Kramer A, et al. In vivo skin treatment with tissue-tolerable plasma influences skin physiology and antioxidant profile in human stratum corneum. Exp Dermatol. 2012;21(2):130–4.

    PubMed  Google Scholar 

  29. 29.

    Machado M, Salgado TM, Hadgraft J, Lane ME. The relationship between transepidermal water loss and skin permeability. Int J Pharm. 2010;384(1–2):73–7.

    CAS  PubMed  Google Scholar 

  30. 30.

    Stoffels E, Sakiyama Y, Graves DB. Cold atmospheric plasma: charged species and their interactions with cells and tissues. IEEE Transactions on Plasma Science. 2008;36(4):1441–57.

    CAS  Google Scholar 

  31. 31.

    Tian W, Kushner MJ. Atmospheric pressure dielectric barrier discharges interacting with liquid covered tissue. J Phys D Appl Phys. 2014;47(16):165201.

    Google Scholar 

  32. 32.

    Van der Paal J, Aernouts S, van Duin ACT, et al. Interaction of O and OH radicals with a simple model system for lipids in the skin barrier: a reactive molecular dynamics investigation for plasma medicine. J Phys D Appl Phys. 2013;46(39):395201.

    Google Scholar 

  33. 33.

    Marschewski M, Hirschberg J, Omairi T, Höfft O, Viöl W, Emmert S, et al. Electron spectroscopic analysis of the human lipid skin barrier: cold atmospheric plasma-induced changes in lipid composition. Exp Dermatol. 2012;21(12):921–5.

    CAS  PubMed  Google Scholar 

  34. 34.

    Suda Y, Tero R, Yamashita R, et al. Reduction in lateral lipid mobility of lipid bilayer membrane by atmospheric pressure plasma irradiation. Japanese Journal of Applied Physics. 2016;55(3S2):03DF05.

  35. 35.

    Choi JH, Nam SH, Song YS, Lee HW, Lee HJ, Song K, et al. Treatment with low-temperature atmospheric pressure plasma enhances cutaneous delivery of epidermal growth factor by regulating E-cadherin-mediated cell junctions. Arch Dermatol Res. 2014;306(7):635–43.

    CAS  PubMed  Google Scholar 

  36. 36.

    Lee HY, Choi JH, Hong JW, Kim GC, Lee HJ. Comparative study of the Ar and he atmospheric pressure plasmas on E-cadherin protein regulation for plasma-mediated transdermal drug delivery. J Phys D Appl Phys. 2018;51(21):215401.

    Google Scholar 

  37. 37.

    Tunggal JA, Helfrich I, Schmitz A, Schwarz H, Günzel D, Fromm M, et al. E-cadherin is essential for in vivo epidermal barrier function by regulating tight junctions. EMBO J. 2005;24(6):1146–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Daeschlein G, Scholz S, Ahmed R, Majumdar A, von Woedtke T, Haase H, et al. Cold plasma is well-tolerated and does not disturb skin barrier or reduce skin moisture. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2012;10(7):509–15.

    PubMed  Google Scholar 

  39. 39.

    Isbary G, Shimizu T, Zimmermann JL, Heinlin J, al-Zaabi S, Rechfeld M, et al. Randomized placebo-controlled clinical trial showed cold atmospheric argon plasma relieved acute pain and accelerated healing in herpes zoster. Clinical Plasma Medicine. 2014;2(2):50–5.

    Google Scholar 

  40. 40.

    Shimizu K. Biological effects and enhancement of percutaneous absorption on skin by atmospheric microplasma irradiation. Plasma Medicine. 2015;5(2–4).

  41. 41.

    Lademann J, Richter H, Alborova A, et al. Risk assessment of the application of a plasma jet in dermatology. Journal of biomedical optics.14(5):054025.

  42. 42.

    Lademann O, Richter H, Patzelt A, Alborova A, Humme D, Weltmann KD, et al. Application of a plasma-jet for skin antisepsis: analysis of the thermal action of the plasma by laser scanning microscopy. Laser Phys Lett. 2010;7(6):458–62.

    Google Scholar 

  43. 43.

    Roy S. Impact of UV radiation on genome stability and human health. Adv Exp Med Biol. 2017;996:207–19.

    CAS  PubMed  Google Scholar 

  44. 44.

    Ahmad SI, Christensen L, Baron E. History of UV lamps, types, and their applications. Adv Exp Med Biol. 2017;996:3–11.

    CAS  PubMed  Google Scholar 

  45. 45.

    Merle C, Laugel C, Baillet-Guffroy A. Effect of UVA or UVB irradiation on cutaneous lipids in films or in solution. Photochem Photobiol. 2010;86(3):553–62.

    CAS  PubMed  Google Scholar 

Download references


MRH was supported by US NIH Grants R01AI050875 and R21AI121700.

Author information



Corresponding authors

Correspondence to Michael R Hamblin or Xian Jiang.

Ethics declarations

Conflict of interest

MRH declares the following potential conflicts of interest. Scientific Advisory Boards: Transdermal Cap Inc., Cleveland, OH; BeWell Global Inc., Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc., Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, Sao Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc., Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc., Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries, Inc. Ramsey, NJ; UVLRx Therapeutics, Oldsmar, FL; Ultralux UV Inc., Lansing MI; Illumiheal & Petthera, Shoreline, WA; MB Lasertherapy, Houston, TX; ARRC LED, San Clemente, CA; Varuna Biomedical Corp. Incline Village, NV; Niraxx Light Therapeutics, Inc., Boston, MA. Consulting; Lexington Int, Boca Raton, FL; USHIO Corp, Japan; Merck KGaA, Darmstadt, Germany; Philips Electronics Nederland B.V. Eindhoven, Netherlands; Johnson & Johnson Inc., Philadelphia, PA; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Stockholdings: Global Photon Inc., Bee Cave, TX; Mitonix, Newark, DE.

The other authors declare no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiang Wen and Yue Xin are co-first authors

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wen, X., Xin, Y., Hamblin, M.R. et al. Applications of cold atmospheric plasma for transdermal drug delivery: a review. Drug Deliv. and Transl. Res. (2020).

Download citation


  • Cold atmospheric plasma
  • Dielectric barrier discharge
  • Transdermal drug delivery
  • Skin barrier
  • Stratum corneum