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In Vivo Muscle Electroporation Threshold Determination: Realistic Numerical Models and In Vivo Experiments

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Abstract

In vivo electroporation is used as an effective technique for delivery of therapeutic agents such as chemotherapeutic drugs or DNA into target tissue cells for different biomedical purposes. In order to successfully electroporate a target tissue, it is essential to know the local electric field distribution produced by an application of electroporation voltage pulses. In this study three-dimensional finite element models were built in order to analyze local electric field distribution and corresponding tissue conductivity changes in rat muscle electroporated either transcutaneously or directly (i.e., two-plate electrodes were placed either on the skin or directly on the skeletal muscle after removing the skin). Numerical calculations of electroporation thresholds and conductivity changes in skin and muscle were validated with in vivo measurements. Our model of muscle with skin also confirms the in vivo findings of previous studies that electroporation “breaks” the skin barrier when the applied voltage is above 50 V.

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References

  • Breton M, Mir LM (2011) Microsecond and nanosecond electric pulses in cancer treatments. Bioelectromagnetics. doi:10.1002/bem.20692

  • Corovic S, Zupanic A, Miklavcic D (2008) Numerical modeling and optimization of electric field distribution in subcutaneous tumor treated with electrochemotherapy using needle electrodes. IEEE Trans Plasma Sci 36:1665–1672

    Article  Google Scholar 

  • Corovic S, Zupanic A, Kranjc S, Al Sakere B, Leroy-Willig A, Mir LM, Miklavcic D (2010) Influence of skeletal muscle anisotropy on electroporation: in vivo study and numerical modeling. Med Biol Eng Comput 48:637–648

    Article  PubMed  Google Scholar 

  • Cukjati D, Batiuskaite D, André F, Miklavcic D, Mir LM (2007) Real time electroporation control for accurate and safe in vivo non-viral gene therapy. Bioelectrochemistry 70:501–507

    Article  PubMed  CAS  Google Scholar 

  • Davalos R, Rubinsky B, Otten DM (2002) A feasibility study for electrical impedance tomography as a means to monitor tissue electroporation for molecular medicine. IEEE Trans Biomed Eng 49:400–403

    Article  PubMed  Google Scholar 

  • Davalos RV, Otten DM, Mir LM, Rubinsky B (2004) Electrical impedance tomography for imaging tissue electroporation. IEEE Trans Biomed Eng 51:761–767

    Article  PubMed  Google Scholar 

  • Denet AR, Vanbever R, Préat V (2004) Skin electroporation for transdermal and topical delivery. Adv Drug Deliv Rev 56:659–674

    Article  PubMed  CAS  Google Scholar 

  • Edhemovic I, Gadzijev EM, Brecelj E, Miklavcic D, Kos B, Zupanic A, Mali B, Jarm T, Pavliha D, Marcan M, Gasljevic G, Gorjup V, Music M, Pecnik Vavpotic T, Cemažar M, Snoj M, Sersa G (2011) Electrochemotherapy: a new technological approach in treatment of metastases in the liver. Technol Cancer Res Treat 10:475–485

    PubMed  CAS  Google Scholar 

  • Gehl J, Mir LM (1999) Determination of optimal parameters for in vivo gene transfer by electroporation, using a rapid in vivo test for cell permeabilization. Biochem Biophys Res Commun 261:377–380

    Article  PubMed  CAS  Google Scholar 

  • Gehl J, Sorensen TH, Nielsen K, Raskmark P, Nielsen SL, Skovsgaard T, Mir LM (1999) In vivo electroporation of skeletal muscle: threshold, efficacy and relation to electric field distribution. Biochim Biophys Acta 1428:233–240

    Article  PubMed  CAS  Google Scholar 

  • Hojman P, Eriksen J, Gehl J (2009) In vivo imaging of far-red fluorescent proteins after DNA electrotransfer to muscle tissue. Biol Proc Online 11:253–262

    Article  CAS  Google Scholar 

  • Ivorra A, Al-Sakere B, Rubinsky B, Mir LM (2009) In vivo electrical conductivity measurements during and after electroporation of sarcomas: conductivity changes reflect treatment outcome. Phys Med Biol 54:5949–5963

    Article  PubMed  Google Scholar 

  • Kos B, Zupanic A, Kotnik T, Snoj M, Sersa G, Miklavcic D (2010) Robustness of treatment planning for electrochemotherapy of deep-seated tumors. J Membr Biol 236:147–153

    Article  PubMed  CAS  Google Scholar 

  • Kotnik T, Macek-Lebar A, Miklavcic D, Mir LM (2000) Evaluation of cell membrane electropermeabilization by means of non-permeant cytotoxic agent. Biotechniques 28:921–926

    PubMed  CAS  Google Scholar 

  • Mali B, Jarm T, Corovic S, Paulin-Kosir MS, Cemazar M, Sersa G, Miklavcic D (2008) The effect of electroporation pulses on functioning of the heart. Med Biol Eng Comput 46:745–757

    Article  PubMed  Google Scholar 

  • 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. Eur J Cancer Suppl 4:3–13

    Article  CAS  Google Scholar 

  • Mathiesen I (1999) Electropermeabilisation of skeletal muscle enhances gene electrotransfer in vivo. Gene Ther 6:508–514

    Article  PubMed  CAS  Google Scholar 

  • Miklavcic D, Beravs K, Semrov D, Cemazar M, Demsar F, Sersa G (1998) The importance of electric field distribution for effective in vivo electroporation of tissues. Biophys J 74:2152–2158

    Article  PubMed  CAS  Google Scholar 

  • Miklavcic D, Semrov D, Mekid H, Mir LM (2000) A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotransfer for gene therapy. Biochim Biophys Acta 1523:73–83

    Article  PubMed  CAS  Google Scholar 

  • Miklavcic D, Pavselj N, Hart FX (2006) Electric properties of tissues. In: Wiley encyclopedia of biomedical engineering. Wiley, New York

  • Mir LM, Orlowski S, Belehradek J Jr, Teissié J, Rols MP, Sersa G, Miklavcic D, Gilbert R, Heller R (1995) Biomedical applications of electric pulses with special emphasis on antitumor electrochemotherapy. Bioelectrochemistry 38:203–207

    Article  CAS  Google Scholar 

  • Mir LM, Bureau MF, Gehl J, Rangara R, Rouy D, Caillaud JM, Delaere P, Branellec D, Schwartz B, Scherman D (1999) High-efficiency gene transfer into skeletal muscle mediated by electric pulses. Proc Natl Acad Sci U S A 74:4262–4267

    Article  Google Scholar 

  • Ngawhirunpat T, Hatanaka T, Katayama K, Yoshikawa H, Kawakami J, Adachi I (2002) Changes in electrophysiological properties of rat skin with age. Biol Pharm Bull 25:1192–1196

    Article  PubMed  CAS  Google Scholar 

  • Pavlin M, Miklavcic D (2003) Effective conductivity of a suspension of permeabilized cells: a theoretical analysis. Biophys J 85:719–729

    Article  PubMed  CAS  Google Scholar 

  • Pavlin M, Pavselj N, Miklavcic D (2002) Dependence of induced transmembrane potential on cell density, arrangement, and cell position inside a cell system. IEEE Trans Biomed Eng 49:605–612

    Article  PubMed  Google Scholar 

  • Pavselj N, Miklavcic D (2008) Numerical modeling in electroporation-based biomedical applications. Radiol Oncol 42:159–168

    Article  Google Scholar 

  • Pavselj N, Bregar Z, Cukjati D, Batiuskaite D, Mir LM, Miklavcic D (2005) The course of tissue permeabilization studied on a mathematical model of a subcutaneous tumor in small animals. IEEE Trans Biomed Eng 52:1373–1381

    Article  PubMed  Google Scholar 

  • Pliquett U, Langer R, Weaver JC (1995) Changes in the passive electrical properties of human stratum corneum due to electroporation. BBA 1239:111–121

    Article  PubMed  CAS  Google Scholar 

  • Prausnitz MR, Bose VG, Langer R, Weaver JC (1993) Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc Natl Acad Sci U S A 90:10504–10508

    Article  PubMed  CAS  Google Scholar 

  • Prud’homme GJ, Glinka Y, Khan AS, Draghia-Akli R (2006) Electroporation enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene Ther 6:243–273

    Article  PubMed  Google Scholar 

  • Puc M, Kotnik T, Mir LM, Miklavcic D (2003) Quantitative model of small molecules uptake after in vitro cell electropermeabilization. Bioelectrochemistry 60:1–10

    Article  PubMed  CAS  Google Scholar 

  • Pucihar G, Kotnik T, Miklavčič D, Teissié J (2008) Kinetics of transmembrane transport of small molecules into electropermeabilized cells. Biophys J 95:2837–2848

    Article  PubMed  CAS  Google Scholar 

  • Sel D, Cukjati D, Batiuskaite D, Slivnik T, Mir LM, Miklavcic D (2005) Sequential finite element model of tissue electropermeabilization. IEEE Trans Biomed Eng 52:816–827

    Article  PubMed  Google Scholar 

  • Tevz G, Pavlin D, Kamensek U, Kranjc S, Mesojednik S, Coer A, Sersa G, Cemazar M (2008) Gene electrotransfer into murine skeletal muscle: a systematic analysis of parameters for long-term gene expression. Technol Cancer Res Treat 7(2):91–154

    PubMed  CAS  Google Scholar 

  • UKCCCR (1998) UKCCR guidelines for welfare of animals in experimental neoplasia (second edition). Br J Cancer 77:1–10

    Google Scholar 

  • Valic B, Golzio M, Pavlin M, Schatz A, Faurie C, Gabriel B, Teissie J, Rols MP, Miklavcic D (2003) Effect of electric field induced transmembrane potential on spheroidal cells: theory and experiments. Eur Biophys J 32:519–528

    Article  PubMed  Google Scholar 

  • Zupanic A, Ribaric S, Miklavcic D (2007) Increasing the repetition frequency of electric pulse delivery reduces unpleasant sensations that occur in electrochemotherapy. Neoplasma 54:246–250

    PubMed  CAS  Google Scholar 

  • Zupanic A, Corovic S, Miklavcic D (2008) Optimization of electrode position and electric pulse amplitude in electrochemotherapy. Radiol Oncol 42:93–101

    Article  Google Scholar 

Download references

Acknowledgments

This research was supported in part by the European Commission under the fifth framework (Grant Cliniporator QLK3-1999-00484), Slovenian Research Agency, CNRS (Centre National de la Recherche Scientifique), Institute Gustave-Roussy and Ad-Futura. This research was conducted in the scope of LEA EBAM. The authors thank Dr. David Cukjati and Dr. Danute Batiuskaite for the results of in vivo experiments performed in the lab of L. M. M. (Institut Gustave-Roussy, Villejuif, France) as well as Derek Snyder for help in proofreading and editing the text.

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Authors and Affiliations

  1. Faculty of Electrical Engineering, University of Ljubljana, Trzaska 25, 1000, Ljubljana, Slovenia

    Selma Čorović & Damijan Miklavčič

  2. UMR 8203 CNRS, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Institute Gustave-Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France

    Selma Čorović & Lluis M. Mir

  3. UMR 8203, University of Paris-Sud XI, Paris, France

    Selma Čorović & Lluis M. Mir

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  1. Selma Čorović
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  2. Lluis M. Mir
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  3. Damijan Miklavčič
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Correspondence to Damijan Miklavčič.

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Čorović, S., Mir, L.M. & Miklavčič, D. In Vivo Muscle Electroporation Threshold Determination: Realistic Numerical Models and In Vivo Experiments. J Membrane Biol 245, 509–520 (2012). https://doi.org/10.1007/s00232-012-9432-8

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  • DOI: https://doi.org/10.1007/s00232-012-9432-8

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