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COMSOL Multiphysics

I. De la Pava, est Ms.C, V. Gomez est Ms.C, O. Henao Ph.D, J. Sanchez Ph.D

Cell physiology group, electrophysiological models and electroporation, UTP, Pereira, Colombia

Keywords: Diffusion equation, cell electroporation, cardiac increase in membrane permeability enhances the uptake of

myocyte, finite elements method. chemotherapeutic drugs into the cell in a cancer treatment

known as electrochemotherapy, it is used to facilitate non-viral

Abstract delivery of DNA to cells, and for transdermal drug delivery.

IRE is used as a low invasive tissue ablation technique, and

Cell electroporation is a technique based on cellular stimula- also in water purification and inactivation of microorganisms

tion by pulsed electric fields. Cardiac myocytes undergo such present in food [1, 2, 3].

stimulation during processes associated with cardiac defibril-

lation. In this paper we simulated a mathematical model of The study of electroporation of cardiac myocytes is of

cardiac myocytes membrane electroporation for different elec- special interest due to its occurrence during cardiac defibrilla-

trode orientations in COMSOL Multiphysics. The model con- tion processes. Several experimental works have been carried

sists of Laplaces equation for the electric potential, a reduced out to study the effects of high-voltage pulsed electric fields

version of Smoluchowskis equation for the pore distribution, on both the whole heart and individual myocytes [4, 5, 6, 7],

and Nernst-Plancks equation for the changes in the ionic con- but in many cases the direct experimental measurement of

centrations. Our results show an asymmetric pore density dis- the different phenomena associated with membrane electro-

tribution, with larger values present on the membrane regions poration is not possible and the use of numerical simulations

facing the positive electrode, in agreement with previous ex- becomes necessary. In this study we implemented a prelim-

perimental studies. inary simulation methodology for electroporation of cardiac

myocytes based on the finite element method. The induced

1 Introduction transmembrane voltage (ITV), and the pore formation density

Electroporation is an increase of the cell membrane permeabil- for different electrode orientations were obtained and ana-

ity due to the formation of aqueous pores in it when the cell lyzed. The total electroporation current and its different ionic

is under the influence of an intense electric field. The electric components for one electrode orientation were also obtained.

field induces a voltage difference across the membrane that

superimposes to the rest membrane potential. The increase in 2 Mathematical model

the membrane permeability takes place when the total voltage

difference across the membrane exceeds a critical value (Vc ). The process of electroporation consists in the formation of hy-

According to the literature, the value of Vc varies between drophilic pores in the cell membrane when the cell is exposed

200 mV and 1 V [1, 2]. Electroporation also depends on the to an external electric field. The presence of these pores alters

characteristics of the voltage pulses used to create the external the membrane conductivity. As the number of pores increases

electric field, such as their amplitude, shape, frequency and so does the conductivity of the cell membrane. Since the cre-

the number of applied pulses. Increasing the pulses ampli- ated pores act as new current conduction pathways, electropo-

tude leads to a bigger permeabilized area on the membrane, ration can be modeled introducing an additional term to the

whereas increasing their number or duration has effect on the expression that describes the current density (J) through the

number and size of the created pores [1, 3]. Needle or parallel membrane, as shown in Equation (1)[8, 9]

plate electrodes are used to generate the voltage pulses. The

induced transmembrane voltage, responsible of the membrane m m

J= (Vi Vo ) + (Vi Vo ) + Iep (1)

permeability increase, can be measured with electrodes or d d t

using fluorescent potentiometric dyes [1]. Electroporation Where Iep is known as the total electroporation current

is divided in reversible electroporation (RE) and irreversible

electroporation (IRE). The mechanism by which the electric Iep = N iep (2)

field permeabilizes the cell membrane is similar in both cases,

however in RE the formed pores reseal after the procedure and Iep is made of several ionic species that flow through the

the cell can survive, while in IRE the electric field induces pores created on the cell membrane due to the presence of the

cellular death. RE has several clinical applications: the external electric field and concentration gradients. The current

though each pore iep for all the ionic species j is given by Equa- 3 Numerical simulation

tion (3)[9]

To solve the set of coupled equations presented in Equations

(6), (7), (8) and (9) for cardiac myocytes we used the AC/DC,

2

rm F vm X Dj zj2 ([cj ]i ezj vm [cj ]o ) Transport of Diluted Species and General Form Boundary

iep = (3)

d i

Aezj vm B PDE (gb) modules of the finite element method (FEM) based

simulation software COMSOL Multiphysics. The FEM is a

wo zj e[zj (wo zj nvm )] nvm numerical method to solve problems that can be model by

A=

wo zj nvm partial differential equations and a set of boundary conditions.

The method is based on the discretization of the problem

wo zj e[zj (wo zj +nvm )] + nvm domain to create a series of smaller subdomains or finite

B=

wo zj + nvm elements in a process known as meshing. The numerical

Equation (1) can be rewritten as Equation (4) solution corresponds to the values of the variable of interest on

the nodes or edges of the discretized domain. In the interior

(t) m of each element those values are computed from a series of

J= (Vi Vo ) + (Vi Vo ) (4)

d d t interpolation functions previously defined. The solution is

Where the variable membrane conductivity is given by obtained by solving a linear system of equations built from

Equation (5) the differential equation that governs the problem and its

associated boundary conditions [2, 10].

N iep d

(t) = m + (5)

Vm We built a simplified cellular geometry of a cardiac

From Equation (3) (t) can be expressed as Equation (6) myocyte based on the data given in [11, 12], and discretized it

with an adaptive meshing defined by COMSOL as extra-fine

for the model. The minimum and maximum sizes of the

2 F 2 X Dj zj2 ([cj ]i ezj vm [cj ]o )

(t) = m + N rm (6) tetragonal elements used in the domain discretization were

RT i Aezj vm B

0.417 m and 9.73 m, respectively. The simulation was

executed at t=1 ms for three different parallel-plate electrode

F

vm = Vm orientations: with the myocyte axis at 0, 45 and 90 degrees

RT

with respect to the direction of the electric field. The boundary

The change rate of the intracellular ionic concentration conditions needed to solve the set of differential equations are

[cj ]i , present in Equation (6), is described by Nernst-Plancks the same as in [1, 8, 9]. We assumed a monophasic electro-

equation [Equation (7)] that considers the diffusive movement poration pulse, with a frequency under 1 kHz and amplitude

of the ions due to concentration gradients and their migration of 20 V. We treated the electrical properties of the my-

in the electric field. ocyte as isotropic and ignored its excitable characteristics. The

values of the parameters used in the model are listed in Table 1.

[cj ]i Dj zj F

= Dj [cj ]i + [cj ]i i (7)

t RT The average required time to obtain a solution was 35 min-

utes on a DELL Precision T3600 computer with a four Intel

The differential equations that govern the spatial and tem-

Xeon processor, 32 GB RAM and Nvidia Gforce 4600 2 MB.

poral distribution of the electric potential and the pore density

The version of the software used to solve the coupled differen-

N are given by Laplaces equation [Equation (8)] and a re-

tial equations was COMSOL Multiphysics 4.2.

duced version of Smoluchowskis equation [Equation (9)], re-

spectively.

4 Results and discussion

+ (x, y, z, t) = 0 (8) 4.1 Induced transmembrane voltage

t

Vm 2

2 The distribution of the ITV is a determinant factor in the pro-

dN N q V m

= e Vep 1 e Vep

(9) cess of electroporation. In Figures 1, 2 and 3 we show the in-

dt N0 duced transmembrane voltage for the three simulated electrode

Thus, to simulate this electroporation model, developed in orientations vs. the arc length (geometries with polar symme-

detail in [8, 9], it is necessary to solve simultaneously three try). In every case we obtained membrane hyperpolarization in

highly coupled partial differential equations. The pore density the regions facing the positive electrode, and a potential plateau

depends on the induced transmembrane voltage, and also on the close to the magnitude of Vc in the electroporated areas.

changes in ionic concentrations. The induced transmembrane

voltage depends on the membrane conductivity, and the latter 4.2 Pore density distribution

depends on the pore density N . Finally the changes in ionic

concentrations depend on both, the concentration gradients and In Figures 49 we show the pore density distribution obtained

the electric potential. for the three electrode orientations. There is an evident asym-

Parameter Value

l Myocyte length 100 m

r Myocyte radius 11 m

d Cell membrane thickness 10 nm

i Relative permittivity of the 74,3

cytoplasm

e Relative permittivity of the 74,3

extracellular medium

m Relative permittivity of the 2260

cell membrane

i Conductivity of the cyto- 0,612 S/m

plasm

e Conductivity of the extra- 0,643 S/m

cellular medium

m Conductivity of the mem- 1,081010 S/m

brane (before the formation

of the new pores)

Creation rate coefficient 1109 1/(m2 s)

N0 Equilibrium pore density 1,5109 1/m2 Figure 1. ITV around the cross-sectional area of the myocyte

Vep Characteristic volt- 170 mV for the 90 degrees electrode orientation.

age of electroporation

( 0, 25Vc )

q Pore creation rate 2,46

rp Pore radius 0,8 nm

n Relative length of the pore 0,15

entrance

w0 Energy barrier inside the 2,65

pore

T0 Absolute temperature 298 K

F Faraday constant 9,65104 C/mol

R Ideal gas constant 8,314 J/(Kmol)

DN a+ Diffusion coefficient of 1,33105 cm2 /s

sodium

DK + Diffusion coefficient of 1,96105 cm2 /s

potassium

DCa2+ Diffusion coefficient of cal- 0,79105 cm2 /s

cium

DCl Diffusion coefficient of 2,04105 cm2 /s

chlorine

CiN a+ Intracellular sodium con- 12,5 mM Figure 2. ITV around the longitudinal-sectional area of the my-

centration ocyte for the 45 degrees electrode orientation.

CiK + Intracellular potassium 136,9 mM

concentration

CiCa2+ Intracellular calcium con- 7,9105 mM

centration

CiCl intracellular chlorine con- 1,5 mM

centration

CeN a+ Extracellular sodium con- 140 mM

centration

CeK + Extracellular potassium 4.5 mM

concentration

CeCa2+ Extracellular calcium con- 1,8 mM

centration

CeCl Extracellular chlorine con- 105 mM

centration

zN a+ Valence of sodium ions 1

zK + Valence of potassium ions 1

zCa2+ Valence of calcium ions 2

zCl Valence of chlorine ions -1

V applied electric potential 20 V

Figure 3. ITV around the longitudinal-sectional area of the my-

Table 1. Values of the parameters used in the model ocyte for the 0 degrees electrode orientation.

Figure 4. 3D pore density distribution for the 90 degrees elec- Figure 6. 3D pore density distribution for the 45 degrees elec-

trode orientation. trode orientation.

Figure 5. Pore density around the cross-sectional area of the of the myocyte for the 45 degrees electrode orientation.

myocyte for the 90 degrees electrode orientation.

metry in the pore density, with larger values present at the hy-

perpolarized regions of the membrane, in accordance with pre-

viously reported experimental results [5]. This asymmetry can

be explained taking into account the zero net current flow con-

dition for a source free system, such as an isolated cell. After

the electroporation current iep has been stablished it is several

orders of magnitude larger than the ionic currents, and thus the

total current through the membrane is approximately equal to

the current that flows through the pores created by the external

electric field times the pore density on the whole membrane

(J Iep = N iep ). In function of the concentration gradients

direction, the electric field and the sign of the ions charge, the

currents iep will be larger at one end of the cell than at the other.

To keep the equilibrium in J this must be compensated with a Figure 8. 3D pore density distribution for the 0 degrees elec-

smaller value of N at the end of the cell in which iep is larger. trode orientation.

Figure 9. Pore density around the longitudinal-sectional area Figure 11. Calcium current around the cross-sectional area of

of the myocyte for the 0 degrees electrode orientation. the myocyte for the 90 degrees electrode orientation.

As deduced from the previous discussion the total electropo-

ration current has the same magnitude and different signs at

opposite ends of the myocyte, in other words, except for its

sign the electroporation current is symmetric around the mem-

brane. In Figure 10 we present the total electroporation current

measured around the cross-sectional area of the myocyte for

the electrode orientation in which the electric field direction

is perpendicular to the myocyte axis. In Figures 1113 the

electroporation current of Figure 10 is separated in several of

its ionic components: calcium, potassium and sodium currents.

the myocyte for the 90 degrees electrode orientation.

sectional area of the myocyte for the 90 degrees electrode ori-

entation.

Despite the fact that the calcium current has a smaller mag-

nitude than the sodium and potassium currents, its increase

with respect to its initial value after the first instants of the ap- Figure 13. Sodium current around the cross-sectional area of

plication of the external electric field is about two orders of the myocyte for the 90 degrees electrode orientation.

magnitude larger than the analogue increases of the sodium transmembrane potential responses to high-intensity elec-

and potassium currents. This finding opens the door to future trical shocks, American Journal of Physiology - Heart and

models that take into account the active electrical behavior of Circulatory Physiology, Vol. 286, pp. H412-H418, (2004).

myocytes and the central role of calcium in it.

[8] K. A DeBruin and W. Krassowska. Modeling electropo-

ration in a single cell. I. Effects of field strength and rest

5 Conclusions potential. Biophysical journal, Vol. 77, pp. 12131224,

We implemented a 3D mathematical model of cardiac myocyte (1999).

electroporation based on the solution of a set of coupled differ-

[9] K. A DeBruin and W. Krassowska. Modeling electropo-

ential equations through the finite element method, disregard-

ration in a single cell. II. Effects of ionic concentrations.

ing its active electric characteristics and assuming its biophys-

Biophysical journal, Vol. 77, pp. 12251233, (1999).

ical properties as isotropic. We studied the induced transmem-

brane voltage, the pore density and the electroporation current [10] A. C. Polycarpou. Introduction to the Finite Element

for three parallel-plate electrode orientations. The most noto- Method in Electromagnetics. Morgan & Claypool. U.S.A.

rious result obtained from the model was an asymmetric pore (2006).

density distribution on the cell membrane, with larger values

present at the hyperpolarized end of the myocyte. [11] T. OHara ,L. Virag, A. Varro and Y. Rudy, Simulation

of the Undiseased Human Cardiac Ventricular Action Po-

Acknowledgements tential Model Formulation and Experimental Validation,

PLoS Coputational Biology, Vol. 7, pp. 1-29, (2011).

The authors would like to thank the financial support of the

Colombian Administrative Department of Science, Technology [12] A. Kramlich, J. Bohnert and O. Dssel. Transmem-

and Innovation (Colciencias) through a research grant to Ivan brane Voltages Caused by Magnetic Fields Numerical

De La Pava as part of the program Jovenes Investigadores e Studof Schematic Cell Models, part of: Magnetic Par-

Innovadores. ticle Imaging: A Novel SPIO Nanoparticle Imaging Tech-

nique, Springer-Verlag Berlin Heidelberg, pp. 337-342,

(2012).

References

[1] D. Miklavcic, G. Pucihar and T. Kotnik. A time- depen-

dent numerical model of transmembrane voltage induce-

ment and electroporation of irregularly shaped cells. IEEE

transactions on biomedical engineering, Vol. 51, pp.1491-

1501, (2009).

lelectropermeabilisation dans des tissus biologiques

exposes a des impulsions electriques de haut voltage.

Faculte de pharmacie de chatenay-malabry, Universite

Paris-sud, (2010).

electroporation. Springer Science+Business Media, New

York, U.S.A, (2011).

poration of Single Cardiac Myocytes in a Focused Electric

Field, Journal of Analytical Chemistry, Vol. 82, pp. 585-

592, (2010).

Excitation by Ultrashort High-Field Pulses, Biophysical

Journal, Vol. 96, pp. 16401648, (2009).

Electroporation in Defibrillation, Journal of the American

heart association, Vol. 87, pp. 797-804, (2000).

R. Emov. Effects of electroporation on optically recorded

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