Excerpt from the Proceedings of the COMSOL Multiphysics User's Conference 2005 Boston

W. Mitchell and R. Sundararajan

Electric Field Distribution in Biological Tissues for Various Electrode Configurations-A FEMLAB Study
Abstract Electroporation or Electropermeabilization (EP) is a non-viral physical process of inducing and/or increasing permeability of biological membranes by the application of high intensity and short duration electrical pulses. The resulting high field strength in the membrane can lead to the formation of regions of increased permeability, often called pores that allow transmembrane transport of macromolecules, such as DNA and chemo drugs. The efficacy of EP depends on a number of parameters, such as electric field strength, duration, number of pulses, size of target cell, and type of drug or DNA to be fed, to mention a few parameters. While electric field strength, duration and number of pulses are the dominant parameters for electroporation effect, the electric field distribution also depends on the shape, the size and the material of electrodes used. The various electrodes used in practice are the parallel plate electrodes, the needle electrodes, the needle array electrodes, and the caliper electrodes. Both six needle array and parallel plate electrodes were used in the skin cancer trials. The electric field distribution varies with the type of electrode. The choice of electrodes depends upon the type of application. For example, parallel plate electrodes produce good results in human clinical trials and the distance between the electrodes can be easily varied. Needle electrodes are the simplest, but due to their configuration, the field distribution is highly nonlinear; there is higher field strength around the needle tip. That is one of the reasons for using multiple needles or needle arrays to make the field distribution as uniform as possible. It is of practical interest to study the electric field distribution of various electrodes to make a more informed choice of which electrodes to use. This paper presents the results of a study of the electric field distribution in biological tissues for various electrode configurations. The configurations studied were, parallel plate electrodessquare and round cross sections, 2 needle electrodes, 4 needle array electrodes and 6 needle array electrodes. FEMLAB was used in this study. For the same voltage applied, the two needle electrode configuration developed the highest electric field strength. Keywords Electroporation, electrodes, Electric Field distribution, FEMLAB _____________________________________________
Electronics & Computer Engineering Technology Arizona State University, Mesa, AZ-85212 Email: raji@asu.edu

_____________________________________________

1 Introduction
Electroporation is the physical process of inducing transient permeability of biological membranes by short pulses of electric fields [1-3]. The resulting high field strength in the membrane can lead to the formation of areas of increased permeability, often called pores, which allow transmembrane transport of molecules. This effect has been used in the laboratory for more than a decade as a research tool to facilitate cellular uptake of genetic material in vitro. More recently, electroporation has also been found effective for the intracellular delivery of molecules in living tissues, which led to a variety of medical applications. Some of these applications have already proceeded to clinical trials. The effectiveness of this technique is evidenced by the Phase I and II skin cancer clinical trials [3]. The most important parameters for effective electroporation are the electrical field strength and the length of time the field applied (pulse length) [4,5]. A number of other parameters can effect the efficacy of electroporation, such as the shape of the electrical pulse, polarity, number of and interval between pulses, size of target cells, and thermal conditions during and after the pulse, as well as other cellular and environmental factors [4-7]. Electric field in the tissue is generated by a potential difference (voltage) between electrodes surrounding, or adjacent to, the tissue. A wide variety of electrode configurations have been developed, appropriate for each specific therapeutic goal [8, 9]. 1.1 Why do we need different configurations of electrodes? The role of the electrodes is to act as a conduit to transform the voltage pulse from a pulse generator into local electric fields in tissues. The most commonly used electrodes are parallel plate electrodes [3, 8, 9] and needle electrodes-either a six needle array [3,8-10] or two needles [11] are used. (a) Parallel plate electrodes. Its the simplest configuration and it produces good results in human clinical trials with tumors close to the surface due to the uniform electric field it develops [8]. With parallel plate electrodes, it is very easy to adjust the distance between them to obtain the desired field strength (V = E x distance). However, plate electrodes

Excerpt from the Proceedings of the COMSOL Multiphysics User's Conference 2005 Boston

are less efficacious for deeper tumors, where needle electrodes are more useful [8]. (b) Needle Electrodes A pair of needles is also a very simple system [8, 11]. However, due to the needle configuration, the field of single-pair-needle electrodes is highly divergent, with high field strength near the needle tip. That is one
Fat r 15 13

of the reasons why multiple needles or needle arrays are needed to develop a more even electric field distribution [8]. Apparently, different cross section of the electrodes will affect the electric field distribution. In this paper, the electric field distributions due to various electrode configurations are studied using FEMLAB 3.0.

0.2 0.4

Table 1: Dielectric property of biological tissue in this study Cartilage Smooth muscle Skin d r d r d r 10.4 22.5 0.12 21.0 56 1.4 2.8 33.5 10.3 21 0.13 21.0 52 2.2 1.8 33

0.7 1.0

d 4.5 3.1

We assume the biology tissue in this study is smooth muscle to run all the simulation. _____________________________________________

2 FEMLAB Simulation:
2.1 Parallel Plate Configuration We chose the multiphysics model (conductive media DC & electrostatics model) when using FEMLAB. The general model for parallel plate electrodes and biological tissue is shown in Fig. 1 and Table 1 gives the dimensions and other data used in this simulation. The electrodes were of square cross section and three different dimensions of square tissue cross sections were studied.

Relative permittivity Distance of electrodes and tissue Cage dimension Assume air relative permittivity Assume air conductivity

52 1mm 40mm x 40mm x 40mm 1.0 1e-6S/m

Note: We assume air conductivity is very low comparing with conductivity of tissue. The boundary conditions used in the conductive media DC model were: V=0V ground (the bottom of cage and the right side electrode) nD=0 insulation (at the other edges of cage ) V=1000V electric potential (right side electrode) Sub-domain settings were: -( 0r V) = D=0r E 2.2 Needle Electrode Configuration Fig. 2 shows the configuration where a pair of needle electrodes was inserted in the biological tissue. Table 2 gives the parameters used in this case.

air 1000V

Other edges insulated

Square electrode

Ground

1000V Biological tissue Ground Ground

Square electrode

Biology tissue

Fig. 1: Parallel Plate Electrode Configuration used Table 2: Parameters used in the Parallel Plate Electrode Configuration cross section of electrodes 10mm x 10mm Cross section of tissue 5mm x 20mm, Cross section of tissue 10mm x 30mm, Cross section of tissue 20mm x 20mm Conductivity of tissue 2.2S/m

Electric insulation on other 5 boundaries of this cage

ground

1 pair of needle electrodes

Fig. 2: Needle Electrode Configuration used

Excerpt from the Proceedings of the COMSOL Multiphysics User's Conference 2005 Boston

Table 3: Parameters used for Needle Electrode Configuration Needle dimension Conductivity of tissue Relative permittivity Cage dimension 0.20mm 2.2S/m 52 40mm x 40mm 40mm

The actual field strength in the center is 8878.17V/m, the nominal field strength (voltage divided by the distance between the two electrodes) is 142857 V/m. So, we can tell the actual field strength is much lower than the nominal value. 3.2 Needle Electrodes Fig. 5 shows a typical electric field distribution of needle electrodes with distance of 0.010m.

The boundary condition and the sub-domain setting were the same as for the parallel plate electrode configuration.

3 Results and Discussion

3.1 Parallel Plate Electrodes with tissue cross section 5mm x 20 mm Fig. 3 shows the electric field distribution in the cross section of the cage, when the tissues dimension was 5mm x 20mm. From this, we can see that the electric field distribution in the piece of tissue is comparatively even, the high level electric field strength occurs between the tissue and electrode plates. Fig. 4 shows a contour plot illustrating the various electric field contours.

Fig. 5: Electric Field Distribution due to Needle Electrode Configuration

Fig. 6 compares the electric field strengths of parallel plate electrodes, needle electrodes, and round electrodes (data not shown) at the same coordinates. As expected, when we apply the same voltage to a pair of electrodes, needle electrodes generate the highest electric field strength. This occurs at the area closest to the needle where the field is highly nonuniform due to the sharp needle point. The round electrode with
comparison of electric field strength

Fig. 3: Uniform Electric Field Distribution of Parallel Plate Electrode Configuration studied

120000

100000

80000 electric field strength

square electrode tissue5x20 square electrode tissue 10x30 square electrode tissue20x20 round electrode tissue5x20

60000

round electrode tissue10x30 round electrode tissue20x20 needle electrode distance5 needle electrode distance 10 needle electrode distance 20

40000

20000

Fig. 4: Contour Plot of Electric Field Distribution

0 (0, 0) (0, 2.5) (0, 5) (0, 7.5) (0, 10) point in the cross section

Excerpt from the Proceedings of the COMSOL Multiphysics User's Conference 2005 Boston

Fig. 6: Comparison of Electric Field Strengths due to various electrode configurations at the same coordinates

the largest tissue dimension (20mm x 20mm) has the lowest electric field strength. Fig. 7 shows the electric field distribution for the configuration of two pairs of needles. The parameters used were: Potential applied: 845V

Needle diameter: 0.04cm Electrode spacing: 0.65cm Tissues conductivity: 2.2S/m Tissues relative permittivity: 52 The field strength of the outer configuration is165.6V/cm, which correlates with that obtained in a previous research [8].

165.6V/cm

845V

845V

Fig. 7: Electric Field Distribution of Four Needle Array Electrodes __________________________________________________

4 Summary
The electric field distribution for electroporation applications strongly depends on the electrode configurations. Both parallel plate electrodes and needle array and needle electrodes of various dimensions are most commonly used for preclinical and clinical applications [3, 8-10]. Parallel plate electrodes give the most uniform electric field distribution with the simplest configuration as seen in this simulation and this correlates well with the published data [8]. Needle electrodes need to be used for deeply-seated tumors where parallel plate electrodes cannot be used. Due to the sharp needle point, needle electrodes give nonuniform field distribution with the highest field strength near the tip of the needle. This point has to be taken into consideration during electroporation applications since the electric field in the tissue will be different for a given area and hence the efficacy of the technique will vary. Multiple needle electrode (array) configurations, such as the six needle array (1cm [3] and 0.5cm diameter [10] electrodes are used for in vivo in addition to needle and parallel plate electrodes. Caliper electrodes offer the advantage of adjusting the gap between electrodes while performing in vivo electroporation [8]. Fig. 8 shows commercially available caliper and needle electrode configurations. There are many other electrode configurations that are used in various in vivo applications [9].

Fig. 8: Commercially available Caliper Electrodes (left) and Two Needle Electrodes (right) __________________________________________________ References

Excerpt from the Proceedings of the COMSOL Multiphysics User's Conference 2005 Boston

[1] L.M. Mir, et al., Electrochemotherapy, a novel antitumor treatment: first clinical trial. C.R. Acad. Sci. Paris 313, 613-618 (1991) [2] R.H. Heller, Overview of Electroporation, Technology in Cancer Research & Treatment, Vol. 1, No. 5 (2002) [3] R. Heller, R. Gilbert, and M. J. Jaroszeski, Clinical Trials for solid tumors using electrochemotherapy, in Electrochemotherapy, Electrogenetherapy, and Transdermal Delivery, M. Jaroszeski, R. Heller, and R. Gilbert,, Eds. New Jersey: Humana Press, pp. 137-156 (2000) [4]M.P. Rols, et al., In vivo delivery of drugs and other molecules to cell, in Electrochemotherapy, Electrogenetherapy, and Transdermal Delivery, M. Jaroszeski, R. Heller, and R. Gilbert, Eds. New Jersey: Humana Press, p. 83-97 (2000) [5] L.M. Mir and S. Orlowski., The basis of electrochemotherapy, in Electrochemotherapy, Electrogenetherapy, and Transdermal Delivery, M. Jaroszeski, R. Heller, and R. Gilbert, Eds. New Jersey: Humana Press, p. 99-117 (2000) [6] H. Potter, Molecular Genetic Applications of Electroporation, in Electroporation and Electrofusion in Cell Biology, E. Nuemann, A.E. Sowers, and C.A Jordan, Eds. New York: Plenum Press, p. 319-341 (1989) [7] T. Curd, B. Vernon, C. Pauken, and R. Sundararajan, Optimization of Electroporation Parameters for Human Ovarian Cancer Cells, Proceedings of Electrostatics Society of America (ESA) Annual Meet, University of Alberta, Edmonton, Canada (2005) [8] G.A. Hofmann, Instrumentation and Electrodes for in vivo electroporation, in Electrochemotherapy, Electrogenetherapy, and Transdermal Delivery, Mark Jaroszeski, Richard Heller, and Richard Gilbert, Eds. New Jersey: Humana Press, p. 37-61 (2000) [9] R. Gilbert, M. Jaroszeski, and R. Heller, Novel electrode designs for electrochemotherapy. Biochimica et Biophysica Acta 1334 9-14 (1997) [10]T. Goto et al., Combination electro-gene therapy using herpes virus thymidine kinase and interluekin-12 expression plasmids is highly efficient against murine carcinomas in vivo. Mol. Therapy, Vol. 10, No. 5, p. 929-937 (2004)

[11] Y. Yamashita et al., Electroporation-mediated Interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res. 61, 1005-1012 (2001)