Iontophoresis and Electroporation

  • Mayank Singhal
  • Yogeshvar N. KaliaEmail author


Iontophoresis and electroporation are techniques that have successfully found their way into clinical practice. Iontophoresis involves the application of a small potential to control and improve the cutaneous and transdermal delivery kinetics of compounds ranging in size from small molecules to small proteins. The current profile can be modulated to enable continuous, pulsatile, or complex input kinetics—it is effectively a “needle-less” infusion pump. Electroporation involves the use of very short, high voltage pulses to transiently increase passive diffusion across biological membranes. This has found applications in electrochemotherapy and gene delivery. This chapter gives an overview of the principles, mechanisms, and clinical applications of iontophoresis and electroporation. Issues linked to safety and the regulatory aspects of existing commercial systems are also briefly addressed. At present, such systems constitute a very small market but this is merely the “end of the beginning” and it is hoped that if the potential of these techniques can be fully realized, then there will be many more clinical applications and, as a result, far greater commercial opportunities.


Iontophoresis Electroporation Drug delivery Topical Transdermal Electrochemotherapy 


  1. 1.
    Monash S (1957) Location of the superficial epithelial barrier to skin penetration. J Invest Dermatol 29(5):367–376CrossRefPubMedGoogle Scholar
  2. 2.
    Scheuplein RJ, Blank IH (1971) Permeability of the skin. Physiol Rev 51(4):702–747PubMedGoogle Scholar
  3. 3.
    Kalia YN, Guy RH (1995) The electrical characteristics of human skin in vivo. Pharm Res 12(11):1605–1613CrossRefPubMedGoogle Scholar
  4. 4.
    Kalia YN, Nonato LB, Guy RH (1996) The effect of iontophoresis on skin barrier integrity: non-invasive evaluation by impedance spectroscopy and transepidermal water loss. Pharm Res 13(6):957–960CrossRefPubMedGoogle Scholar
  5. 5.
    Marra F, Levy JL, Santi P, Kalia YN (2008) In vitro evaluation of the effect of electrotreatment on skin permeability. J Cosmet Dermatol 7(2):105–111CrossRefPubMedGoogle Scholar
  6. 6.
    Naik A, Kalia YN, Guy RH (2000) Transdermal drug delivery: overcoming the skin’s barrier function. Pharm Sci Technolo Today 3(9):318–326CrossRefPubMedGoogle Scholar
  7. 7.
    Turner NG, Kalia YN, Guy RH (1997) The effect of current on skin barrier function in vivo: recovery kinetics post-iontophoresis. Pharm Res 14(9):1252–1257CrossRefPubMedGoogle Scholar
  8. 8.
    Cazares-Delgadillo J, Aziza IB, Balaguer-Fernandez C, Calatayud-Pascual A, Ganem-Rondero A, Quintanar-Guerrero D, Castellano AC, Merino V, Kalia YN (2010) Comparing metoclopramide electrotransport kinetics in vitro and in vivo. Eur J Pharm Sci 41(2):353–359CrossRefPubMedGoogle Scholar
  9. 9.
    Kalaria DR, Patel P, Merino V, Patravale VB, Kalia YN (2013) Controlled iontophoretic transport of huperzine A across skin in vitro and in vivo: effect of delivery conditions and comparison of pharmacokinetic models. Mol Pharm 10(11):4322–4329CrossRefPubMedGoogle Scholar
  10. 10.
    Kalaria DR, Patel P, Merino V, Patravale VB, Kalia YN (2014) Controlled iontophoretic delivery of pramipexole: electrotransport kinetics in vitro and in vivo. Eur J Pharm Biopharm 88(1):56–63CrossRefPubMedGoogle Scholar
  11. 11.
    Kalia YN, Naik A, Garrison J, Guy RH (2004) Iontophoretic drug delivery. Adv Drug Deliv Rev 56(5):619–658CrossRefPubMedGoogle Scholar
  12. 12.
    Becker S, Zorec B, Miklavčič D, Pavšelj N (2014) Transdermal transport pathway creation: electroporation pulse order. Math Biosci 257:60–68CrossRefPubMedGoogle Scholar
  13. 13.
    Vanbever R, Le Boulengé E, Préat V (1996) Transdermal delivery of fentanyl by electroporation I. influence of electrical factors. Pharm Res 13(4):559–565CrossRefPubMedGoogle Scholar
  14. 14.
    Zorec B, Becker S, Rebersek M, Miklavcic D, Pavselj N (2013) Skin electroporation for transdermal drug delivery: the influence of the order of different square wave electric pulses. Int J Pharm 457(1):214–223CrossRefPubMedGoogle Scholar
  15. 15.
    Gratieri T, Kalia YN (2013) Mathematical models to describe iontophoretic transport in vitro and in vivo and the effect of current application on the skin barrier. Adv Drug Deliv Rev 65(2):315–329CrossRefPubMedGoogle Scholar
  16. 16.
    Burnette RR, Ongpipattanakul B (1987) Characterization of the permselective properties of excised human skin during iontophoresis. J Pharm Sci 76(10):765–773CrossRefPubMedGoogle Scholar
  17. 17.
    Kim A, Green PG, Rao G, Guy RH (1993) Convective solvent flow across the skin during iontophoresis. Pharm Res 10(9):1315–1320CrossRefPubMedGoogle Scholar
  18. 18.
    Cullander C, Rao G, Guy RH (1993) Why silver/silver chloride? Criteria for iontophoresis electrodes. In: Brian KR, James VJ, Walters KA (eds) 3rd International conference on prediction of percutaneous penetration, La Grande Motte, France, 1993. STS Publishing, Cardiff (Wales), pp 381–390Google Scholar
  19. 19.
    Articus K, Hechenbichler K, Bornholdt K (2011) EXPECT (EXelon Patch EffeCtiveness Trial): effectiveness and tolerability of transdermal rivastigmin in daily practice. Alzheimers Dement 7(4, Suppl):S777Google Scholar
  20. 20.
    Steiger M (2008) Constant dopaminergic stimulation by transdermal delivery of dopaminergic drugs: a new treatment paradigm in Parkinson’s disease. Eur J Neurol 15(1):6–15PubMedGoogle Scholar
  21. 21.
    Waters C (2013) The development of the rotigotine transdermal patch: a historical perspective. Neurol Clin 31(3, Suppl):S37–S50Google Scholar
  22. 22.
    Kalaria DR, Patel P, Patravale V, Kalia YN (2012) Comparison of the cutaneous iontophoretic delivery of rasagiline and selegiline across porcine and human skin in vitro. Int J Pharm 438(1–2):202–208CrossRefPubMedGoogle Scholar
  23. 23.
    Jacobi U, Kaiser M, Toll R, Mangelsdorf S, Audring H, Otberg N, Sterry W, Lademann J (2007) Porcine ear skin: an in vitro model for human skin. Skin Res Technol 13(1):19–24CrossRefPubMedGoogle Scholar
  24. 24.
    Dick IP, Scott RC (1992) Pig ear skin as an in-vitro model for human skin permeability. J Pharm Pharmacol 44(8):640–645CrossRefPubMedGoogle Scholar
  25. 25.
    Schmook FP, Meingassner JG, Billich A (2001) Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption. Int J Pharm 215(1–2):51–56CrossRefPubMedGoogle Scholar
  26. 26.
    Cazares-Delgadillo J, Balaguer-Fernandez C, Calatayud-Pascual A, Ganem-Rondero A, Quintanar-Guerrero D, Lopez-Castellano AC, Merino V, Kalia YN (2010) Transdermal iontophoresis of dexamethasone sodium phosphate in vitro and in vivo: effect of experimental parameters and skin type on drug stability and transport kinetics. Eur J Pharm Biopharm 75(2):173–178CrossRefPubMedGoogle Scholar
  27. 27.
    Chelly JE (2005) An iontophoretic, fentanyl HCl patient-controlled transdermal system for acute postoperative pain management. Expert Opin Pharmacother 6(7):1205–1214CrossRefPubMedGoogle Scholar
  28. 28.
    Kasha PC, Anderson CR, Morris RL, Sembrowich WL, Chaturvedula A, Banga AK (2012) Subcutaneous concentrations following topical iontophoretic delivery of diclofenac. Drug Discov Ther 6(5):256–262PubMedGoogle Scholar
  29. 29.
    Gratieri T, Pujol-Bello E, Gelfuso GM, de Souza JG, Lopez RF, Kalia YN (2013) Iontophoretic transport kinetics of ketorolac in vitro and in vivo: demonstrating local enhanced topical drug delivery to muscle. Eur J Pharm Biopharm 86(2):219–226CrossRefPubMedGoogle Scholar
  30. 30.
    Pierce M, Marbury T, O’Neill C, Siegel S, Du W, Sebree T (2009) Zelrix: a novel transdermal formulation of sumatriptan. Headache 49(6):817–825CrossRefPubMedGoogle Scholar
  31. 31.
    Rapoport AM, Freitag F, Pearlman SH (2010) Innovative delivery systems for migraine: the clinical utility of a transdermal patch for the acute treatment of migraine. CNS Drugs 24(11):929–940CrossRefPubMedGoogle Scholar
  32. 32.
    Siegel SJ, O’Neill C, Dube LM, Kaldeway P, Morris R, Jackson D, Sebree T (2007) A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharm Res 24(10):1919–1926CrossRefPubMedGoogle Scholar
  33. 33.
    Gratieri T, Kalaria D, Kalia YN (2011) Non-invasive iontophoretic delivery of peptides and proteins across the skin. Expert Opin Drug Deliv 8(5):645–663CrossRefPubMedGoogle Scholar
  34. 34.
    Dubey S, Kalia YN (2010) Non-invasive iontophoretic delivery of enzymatically active ribonuclease A (13.6 kDa) across intact porcine and human skins. J Control Release 145(3):203–209CrossRefPubMedGoogle Scholar
  35. 35.
    Cazares-Delgadillo J, Naik A, Ganem-Rondero A, Quintanar-Guerrero D, Kalia YN (2007) Transdermal delivery of cytochrome C—A 12.4 kDa protein—across intact skin by constant-current iontophoresis. Pharm Res 24(7):1360–1368CrossRefPubMedGoogle Scholar
  36. 36.
    Dubey S, Perozzo R, Scapozza L, Kalia YN (2011) Noninvasive transdermal iontophoretic delivery of biologically active human basic fibroblast growth factor. Mol Pharm 8(4):1322–1331CrossRefPubMedGoogle Scholar
  37. 37.
    Dubey S, Kalia YN (2014) Understanding the poor iontophoretic transport of lysozyme across the skin: when high charge and high electrophoretic mobility are not enough. J Control Release 183:35–42CrossRefPubMedGoogle Scholar
  38. 38.
    Dubey S, Kalia YN (2011) Electrically-assisted delivery of an anionic protein across intact skin: cathodal iontophoresis of biologically active ribonuclease T1. J Control Release 152(3):356–362CrossRefPubMedGoogle Scholar
  39. 39.
    Blagus T, Markelc B, Cemazar M, Kosjek T, Preat V, Miklavcic D, Sersa G (2013) In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery. J Control Release 172(3):862–871CrossRefPubMedGoogle Scholar
  40. 40.
    Wong TW, Chen TY, Huang CC, Tsai JC, Hui SW (2011) Painless skin electroporation as a novel way for insulin delivery. Diabetes Technol Ther 13(9):929–935CrossRefPubMedGoogle Scholar
  41. 41.
    Zhang L, Lerner S, Rustrum WV, Hofmann GA (1999) Electroporation-mediated topical delivery of vitamin C for cosmetic applications. Bioelectrochem Bioenerg 48(2):453–461CrossRefPubMedGoogle Scholar
  42. 42.
    Jadoul A, Bouwstra J, Préat V (1999) Effects of iontophoresis and electroporation on the stratum corneum: review of the biophysical studies. Adv Drug Deliv Rev 35(1):89–105CrossRefPubMedGoogle Scholar
  43. 43.
    Jadoul A, Tanojo H, Preat V, Bouwstra JA, Spies F, Bodde HE (1998) Electroperturbation of human stratum corneum fine structure by high voltage pulses: a freeze-fracture electron microscopy and differential thermal analysis study. J Investig Dermatol Symp Proc 3(2):153–158CrossRefPubMedGoogle Scholar
  44. 44.
    Gallo SA, Sen A, Hensen ML, Hui SW (2002) Temperature-dependent electrical and ultrastructural characterizations of porcine skin upon electroporation. Biophys J 82(1):109–119CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Pavlin M, Flisar K, Kanduser M (2010) The role of electrophoresis in gene electrotransfer. J Membr Biol 236(1):75–79CrossRefPubMedGoogle Scholar
  46. 46.
    Regnier V, De Morre N, Jadoul A, Préat V (1999) Mechanisms of a phosphorothioate oligonucleotide delivery by skin electroporation. Int J Pharm 184(2):147–156CrossRefPubMedGoogle Scholar
  47. 47.
    Tokumoto S, Mori K, Higo N, Sugibayashi K (2005) Effect of electroporation on the electroosmosis across hairless mouse skin in vitro. J Control Release 105(3):296–304CrossRefPubMedGoogle Scholar
  48. 48.
    Pliquett U, Gusbeth C, Nuccitelli R (2008) A propagating heat wave model of skin electroporation. J Theor Biol 251(2):195–201CrossRefPubMedGoogle Scholar
  49. 49.
    Pliquett U, Weaver JC (1996) Transport of a charged molecule across the human epidermis due to electroporation. J Control Release 38(1):1–10CrossRefGoogle Scholar
  50. 50.
    Pliquett UF, Zewert TE, Chen T, Langer R, Weaver JC (1996) Imaging of fluorescent molecule and small ion transport through human stratum corneum during high voltage pulsing: localized transport regions are involved. Biophys Chem 58(1–2):185–204CrossRefPubMedGoogle Scholar
  51. 51.
    Pliquett UF, Vanbever R, Preat V, Weaver JC (1998) Local transport regions (LTRs) in human stratum corneum due to long and short `high voltage’ pulses. Bioelectrochemistry 47(1):151–161CrossRefGoogle Scholar
  52. 52.
    Denet AR, Vanbever R, Preat V (2004) Skin electroporation for transdermal and topical delivery. Adv Drug Deliv Rev 56(5):659–674CrossRefPubMedGoogle Scholar
  53. 53.
    Smith KC, Son RS, Gowrishankar TR, Weaver JC (2013) Emergence of a large pore subpopulation during electroporating pulses. Bioelectrochemistry 100:3–10CrossRefPubMedGoogle Scholar
  54. 54.
    Pavselj N, Preat V (2005) DNA electrotransfer into the skin using a combination of one high- and one low-voltage pulse. J Control Release 106(3):407–415CrossRefPubMedGoogle Scholar
  55. 55.
    Todorovic V, Kamensek U, Sersa G, Cemazar M (2013) Changing electrode orientation, but not pulse polarity, increases the efficacy of gene electrotransfer to tumors in vivo. Bioelectrochemistry 100:119–127CrossRefPubMedGoogle Scholar
  56. 56.
    Sedlar A, Dolinsek T, Markelc B, Prosen L, Kranjc S, Bosnjak M, Blagus T, Cemazar M, Sersa G (2012) Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicity. Radiol Oncol 46(4):302–311CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Hui SW (2008) Overview of drug delivery and alternative methods to electroporation. Methods Mol Biol 423:91–107CrossRefPubMedGoogle Scholar
  58. 58.
    Banga AK, Prausnitz MR (1998) Assessing the potential of skin electroporation for the delivery of protein- and gene-based drugs. Trends Biotechnol 16(10):408–412CrossRefPubMedGoogle Scholar
  59. 59.
    Broderick KE, Khan AS, Sardesai NY (2014) DNA vaccination in skin enhanced by electroporation. Methods Mol Biol 1143:123–130CrossRefPubMedGoogle Scholar
  60. 60.
    Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK, Munster PN, Sullivan DM, Ugen KE, Messina JL, Heller R (2008) Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol 26(36):5896–5903CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gothelf A, Gehl J (2014) Electroporation-based DNA delivery technology: methods for gene electrotransfer to skin. Methods Mol Biol 1143:115–122CrossRefPubMedGoogle Scholar
  62. 62.
    Isaka Y, Imai E (2007) Electroporation-mediated gene therapy. Expert Opin Drug Deliv 4(5):561–571CrossRefPubMedGoogle Scholar
  63. 63.
    Potter H, Heller R (2011) Transfection by electroporation. Curr Protoc Cell Biol 52(20.5):1–10Google Scholar
  64. 64.
    Cadossi R, Ronchetti M, Cadossi M (2014) Locally enhanced chemotherapy by electroporation: clinical experiences and perspective of use of electrochemotherapy. Future Oncol 10(5):877–890CrossRefPubMedGoogle Scholar
  65. 65.
    Gargiulo M, Papa A, Capasso P, Moio M, Cubicciotti E, Parascandolo S (2012) Electrochemotherapy for non-melanoma head and neck cancers: clinical outcomes in 25 patients. Ann Surg 255(6):1158–1164CrossRefPubMedGoogle Scholar
  66. 66.
    Larkin JO, Collins CG, Aarons S, Tangney M, Whelan M, O’Reily S, Breathnach O, Soden DM, O’Sullivan GC (2007) Electrochemotherapy: aspects of preclinical development and early clinical experience. Ann Surg 245(3):469–479CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Matthiessen LW, Johannesen HH, Hendel HW, Moss T, Kamby C, Gehl J (2012) Electrochemotherapy for large cutaneous recurrence of breast cancer: a phase II clinical trial. Acta Oncol 51(6):713–721CrossRefPubMedGoogle Scholar
  68. 68.
    Sersa G (2006) The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical uses. EJC Suppl 4(11):52–59CrossRefGoogle Scholar
  69. 69.
    Marty M, Sersa G, Garbay JR, Gehl J, Collins CG, Snoj M, Billard V, Geertsen PF, Larkin JO, Miklavcic D, Pavlovic I, Paulin-Kosir SM, Cemazar M, Morsli N, Soden DM, Rudolf Z, Robert C, O’Sullivan GC, Mir LM (2006) Electrochemotherapy—an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. EJC Suppl 4(11):3–13CrossRefGoogle Scholar
  70. 70.
    Mir LM, Gehl J, Sersa G, Collins CG, Garbay J-R, Billard V, Geertsen PF, Rudolf Z, O’Sullivan GC, Marty M (2006) Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or non-invasive electrodes. EJC Suppl 4(11):14–25CrossRefGoogle Scholar
  71. 71.
    Gerlini G, Di Gennaro P, Borgognoni L (2012) Enhancing anti-melanoma immunity by electrochemotherapy and in vivo dendritic-cell activation. Oncoimmunology 1(9):1655–1657CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Novellino L, Castelli C, Parmiani G (2005) A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother 54(3):187–207CrossRefPubMedGoogle Scholar
  73. 73.
    Gerlini G, Sestini S, Di Gennaro P, Urso C, Pimpinelli N, Borgognoni L (2013) Dendritic cells recruitment in melanoma metastasis treated by electrochemotherapy. Clin Exp Metastasis 30(1):37–45CrossRefPubMedGoogle Scholar
  74. 74.
    Gehl J (2014) Gene electrotransfer in clinical trials. Methods Mol Biol 1121:241–246CrossRefPubMedGoogle Scholar
  75. 75.
    Kalams SA, Parker SD, Elizaga M, Metch B, Edupuganti S, Hural J, De Rosa S, Carter DK, Rybczyk K, Frank I, Fuchs J, Koblin B, Kim DH, Joseph P, Keefer MC, Baden LR, Eldridge J, Boyer J, Sherwat A, Cardinali M, Allen M, Pensiero M, Butler C, Khan AS, Yan J, Sardesai NY, Kublin JG, Weiner DB (2013) Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery. J Infect Dis 208(5):818–829CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Subramony JA, Sharma A, Phipps JB (2006) Microprocessor controlled transdermal drug delivery. Int J Pharm 317(1):1–6CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan KK 2017

Authors and Affiliations

  1. 1.School of Pharmaceutical Sciences, University of Geneva and LausanneGenevaSwitzerland

Personalised recommendations