Theoretical analysis of the thermal effects during in vivo tissue electroporation Rafael V. Davalos a , Boris Rubinsky a , Lluis M. Mir b, * a Biomedical Engineering Laboratory, Department of Mechanical Engineering, 6178 Etcheverry Hall-University of California at Berkeley, Berkeley, CA 94720-1740, USA b Vectorology and Gene Transfer, UMR 8121 CNRS, Institut Gustave-Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, Ce ´dex, France Received 10 October 2002; received in revised form 12 February 2003; accepted 30 July 2003 Abstract Tissue electroporation is a technique that facilitates the introduction of molecules into cells by applying a series of short electric pulses to specific areas of the body. These pulses temporarily increase the permeability of the cell membrane to small drugs and macromolecules. The goal of this paper is to provide information on the thermal effects of these electric pulses for consideration when designing electroporation protocols. The parameters investigated include electrode geometry, blood flow, metabolic heat generation, pulse frequency, and heat dissipation through the electrodes. Basic finite-element models were created in order to gain insight and weigh the importance of each parameter. The results suggest that for plate electrodes, the energy from the pulse may be used to adequately estimate the heating in the tissue. However, for needle electrodes, the geometry, i.e. spacing and diameter, and pulse frequency are critical when determining the thermal distribution in the tissue. D 2003 Elsevier B.V. All rights reserved. Keywords: Bioheat equation; Thermal effects; Joule heating; Electrochemotherapy; Electrogenetherapy; Electropermeabilization 1. Introduction Tissue electroporation, also termed electropermeabilisa- tion, is becoming an increasingly popular method to intro- duce small drugs and macromolecules into cells in specific areas of the body. This technique is accomplished by placing electrodes into or around the targeted tissue to generate a pulsed electric field inside the tissue [1]. These fields induce reversible (or irreversible) structural changes in the cell membrane that enhance the penetration of these substances into the cytosol [2]. The two most prevalent applications of in vivo tissue electroporation are gene therapy, electrogenetherapy (EGT) [3], and cancer therapy, electrochemotherapy (ECT) [1,4]. Research on the practice of tissue electroporation focuses primarily on characterizing the electric pulse parameters that maximize the amount of electroporated tissue in the targeted area while minimizing damage to the surrounding tissue [5]. While the amount of tissue electroporated by the electric pulses is the most important effect, there are secondary effects from the electrical currents that need to be considered when design- ing electroporation protocols. One of the most important secondary effects is that of Joule heating. Biological cells are sensitive to temperature. The dam- aging effect of elevated temperatures on biological materials has been investigated for decades [6]. A review of the effects of elevated temperatures on biological materials can be found in Ref. [7]. With respect to electrical trauma consequences, an extensive review on the thermal effects of electrical currents can be found in Ref. [8]. In addition, the thermal effects of electroporation have been addressed in several publications. When the skin is exposed to an electropermeabilizing electric pulse, researchers estimated that the increase in temperature should be on the order of 1 – 10 jC and considered insignificant. However, due to struc- tural changes that result in the creation of highly localized sites from the electroporation itself, the stratum corneum undergoes substantial localized heating [9]. Gallo et al. [10] found that the threshold for electroporation dropped while the recovery time increased at elevated temperatures for experiments with porcine skin. Recently, Kotnik and 1567-5394/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.bioelechem.2003.07.001 * Corresponding author. Tel.: +33-1-42-11-47-92; fax: +33-1-42-11- 52-45. E-mail address: luismir@igr.fr (L.M. Mir). www.elsevier.com/locate/bioelechem Bioelectrochemistry 61 (2003) 99 – 107