Modeling the Cardiac Tissue Electrode Interface

Using Fractional Calculus

R. L. MAGIN
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607 USA
(rmagin@uic.edu)

M. OVADIA
Department of Pediatrics, Advocate Lutheran General Childrens Hospital, Park Ridge, Chicago,
IL 60068 USA, Department of Bioengineering, University of Illinois at Chicago, IL 60607 USA
(Received 21 June 20061 accepted 4 October 2006)

Abstract: The tissue electrode interface is common to all forms of biopotential recording (e.g., ECG, EMG,
EEG) and functional electrical stimulation (e.g., pacemaker, cochlear implant, deep brain stimulation). Conventional lumped element circuit models of electrodes can be extended by generalization of the order of
differentiation through modification of the defining current-voltage relationships. Such fractional order models provide an improved description of observed bioelectrode behaviour, but recent experimental studies of
cardiac tissue suggest that additional mathematical tools may be needed to describe this complex system.
Key words: Cardiac tissue, impedance, fractional derivative, bioelectrodes

1. INTRODUCTION
Stimulation and recording of fundamental processes in cardiac tissue rests in large measure
on bridging the tissue-electrode interface1 a transduction process that at each level of biologic
integration (membrane, cell, tissue, and whole organ) remains the fundamental mode of examination. Surprisingly, despite the widespread use of electrical and electro-physiological
techniques for probing biological systems, the basic cell/tissue-electrode interface is not yet
completely understood. Recent advances in materials processing, nanofabrication, and biocompatibility cannot be applied effectively to bioelectrodes without more complete knowledge of the mechanisms operating at the tissue-electrode interface (Ovadia and Brink, 2000).
From microelectrode recording of voltage-gated ion channels, whose conductance and subconductance states can reflect single amino acid substitutions (Cymes et al., 2005), to macroelectrode stimulation for cardiac defibrillation (Reilly, 1998), critical design parameters are
either not known or not being observed. The failures reported recently for the implanted
defibrillating pacemakers manufactured by Guidant Corp., and for the gynecological electrosurgery laparoscopic instruments sold by the Ethicon Corp., illustrate that more accurate
tissue/electrode impedance models are needed to ensure patient safety and effective clinical
intervention.

Journal of Vibration and Control, 14(910): 14311442, 2008

1
12008
SAGE Publications Los Angeles, London, New Delhi, Singapore

DOI: 10.1177/1077546307087439

1432 R. L. MAGIN AND M. OVADIA

2. BACKGROUND
In 1972, L. Geddes of Purdue University published sinusoidal steady state transfer function measurements for bioelectrodes, which are now classic (Geddes, 1972). He showed the
specific frequency dependent variation of interfacial impedance, an impedance functionality
1
1
that may be written 2Z2 = 1V/1i = k33 (22 )4 2 (f )4 2 , where 3 5 22f, V is the potential difference, i the observed current, k33 is a constant, and f is the frequency of the signal. This may
1
be written 2Z2 = k34 2 for systems with a linear interfacial iV relationship. Geddes work
showed a common behavior for impedance functionality across virtually the entire range of
electrode materials used. The implication of this is that as one departs from biological signals
with predominant high frequency content (e.g., the step functions that characterize channel
opening and closing in patch clamp, or at a higher level of integration the action potential
and cardiac electrogram and brain encephalogram, which represent a weighted summation
of action potentials for a volume of tissue) the interfacial impedance increases dramatically
for most common electrode materials. In the limit of low frequency, however, electrode interfacial impedance increases without bound, rendering many cellular processes unobservable.
They are unobservable, despite having an electrical signature, because the frequencies contributing to this signature are filtered out by the interface of existing biophysical recording
electrodes, and are therefore lost in noise.

3. FRACTIONAL TISSUE-ELECTRODE INTERFACE MODELS

Ovadia has conducted investigations in this area over 15 years, with the goals of, first, analyzing the electrode living tissue interface and, second, introducing materials that can avoid
the above interfacial impedance functionality. The first goal was addressed (Ovadia and Zavitz, 1998) with the introduction of the finite (spatially-confined) Warburg impedance Z D (as
a generalization of the single-parameter Z W 6 ) as the correct expression of impedance functionality for electrodes in tissues as disparate as the living, beating, heart and nonexcitable
tissue such as cartilage. Ovadia and Zavitz (2004) also observed that the interfacial electrical behavior is neither single-valued nor time-independent1 rather, it is a bistable or tristable
function with stochastic interconversion between states, each corresponding to a particular
surface architecture. Magin (2004a,b,c) has applied these solutions, which he recast in their
most natural form (using the Weyl or Riemann-Liouville fractional integro-differential operators), as a fractional order differential equation, and studied a broad range of related models.
As regards the second goal, this has been achieved by the introduction of a series of
macroscopically processable organic thin films, electrically conductive but nonmetallic in
physicochemical properties, whose interfacial impedance does not conform to the mathematical functionality described above (Ovadia et al., 2006b). One group, based on self-assembled
monolayer 2-dimensional crystals bonded covalently to polycrystalline Au, is characterized
by impedance functionality 2Z2 = k3 /3, i.e., that of an electronic parallel plate capacitor. This
group of materials has been studied in chronic implantation in excitable tissues, and has been
found to have superior properties. A second group of materials (Ovadia and Zavitz, 2004)
consists of semiconducting organic polymers. These are characterized by Ohmicity in the
frequency range relevant to biophysical signal recording, i.e., 2Z2 = K where K is a constant.

MODELING THE CARDIAC TISSUE ELECTRODE INTERFACE 1433

Figure 1. Three element electrical circuit model for electrode-tissue interface with impedance Z (3).

3.1. Bioelectrode Models

The design of recording and stimulating electrodes is an important area of bioengineering

where the basic phenomena can be described by fractional order differential equations. Pacemakers, defibrillators, and neural prosthetics all require electrodes optimized to conduct current across an electrode-tissue interface. The process of design optimization often begins
with the development of an equivalent circuit model for the electrical impedance of the interface (Grahame, 1952). Much effort has been directed toward the development of accurate impedance models for electrophysiological recording and electrical stimulation (Plonsey, 19691
Gulrajani, 19981 Reilly, 1998). In the simplest cases, a three-element resistor-capacitor-Z i
model (Figure 1) can be used to represent the electrode-tissue interface.
In the three element model, R1 represents the intrinsic resistance of the electrolyte, and
C represents the capacitance associated with the interface (ideally a perfectly polarized electrode, e.g., bare Pt wire). Z i (3) represents the impedance at the interface (ideally a perfectly
non-polarized electrode, e.g., Ag/AgCl), needed to represent or model the observed behavior
of Z(3) as a function of angular frequency j3. By making appropriate assumptions about the
R, C, and Z i (3) elements, this circuit can serve as a first order model for both macro and
micro-electrodes, describe the skin-tissue interface for ECG electrodes, and model the behavior of electrodes in contact with single cells, cell suspensions and whole tissues (Schwan,
1957, 19681 Greatbatch and Chardack, 19681 Dymond, 1976). Such models, for the most
part, involve conventional circuit components for the reactive elements. However, in some
applications, the agreement between the theoretical model of Z(3) and the observed experimental data is improved if we assume a form for Z i (3) that varies as a non-integer power of
the angular frequency (the so-called constant phase element impedance Z C P E 7 145 j 367 C 7 ,
for example, where 0 8 7 8 1). In these cases, 7 is usually treated as a fitting parameter for
modeling the impedance data. In this section, we will examine such fractional impedance
models from the perspective of fractional calculus. We should anticipate that the observed
fractional power dependence of Z i (3) implies fractional dynamics in the rate of charge transfer, and that this behavior should be expected, given the distributed space-time nature of the
electrode-tissue interface and the importance of diffusion in many electrochemical processes.
Consider the response to a step input in current I(t) = I 0 u(t) of a three element electrode
model where Z i (3) is a Warburg impedance (Z C P E with 7 7 095), and R1 and C are fixed
values. The overall electrode impedance for this circuit model in the Laplace domain can be
written as

1434 R. L. MAGIN AND M. OVADIA

1 9
2
514sC6 14 sC W
z5s6 7 R1 8
1
1
8 9sC
sC
W

(1)

which also corresponds to the impedance transfer function for the fractional order differential
equation
C

dV
dI
d 142 V
d 142 I
8 C W 142 7 I 8 RC
8 RC W 142 9
dt
dt
dt
dt

(2)

Note here that C W must have the units of Farad

(sec)4142 . Since z(s) = v(s)/i(s), we can
solve this equation for v(s), assuming i(s) = I 0 /s, to obtain
I0
s 4342
R1 I0
8 9
9
s
C s 8 C W 4C

(3)

3
1
24
s 4342
L t E 1422 4at 142 7 9
s8a

(4)

5
6
CW 9
I0 t
t 9
E 1422 4
V 5t6 7 I0 R1 8
C
C

(5)

5s6 7
Since (Magin, 2004a)

we can write V(t) as

Using the subscript shift property of the two-parameter Mittag-Leffler function (Magin,
2004a),
E 7 5x6 7 x E 778 5x6 8 14 56

(6)

equation (5) can be expressed as

I0
V 5t6 7 I0 R1 8
CW

5 9
7
86
CW 9
2 t 9
9 4 t E 142342 4
t
2
C

(7)

which can be simplified to

5 9
5
7
866
C 9
I0 2 t
C
9 8
V 5t6 7 I0 R1 8
1 4 E 1421 4
t
C
2
C
C

(8)

and since (Magin, 2004a)

9 9

9 9

2
E 1421 4a t 7 ea t er f c a t

(9)

MODELING THE CARDIAC TISSUE ELECTRODE INTERFACE 1435

Figure 2. Graphs of the normalized transient voltage response for a step in current applied to four
different electrode models: (a) Capacitor, (b) series resistor-Warburg element, (c) series resistor plus
a parallel combination of a second resistor with a Warburg element, and (d) series resistor-capacitor
combination. In all cases, R1 7 R2 7 C 7 C W 7 I0 7 1.

we are then able to write V(t) as

5
V 5t6 7 I0 R1 8 I0

9
7
86
2 t
C C2 t4C 2
CW 9
C
9 4 2 8 2 e
er f c
t
9
CW 2
CW
CW
C

(10)

This result agrees with the Laplace transform analysis of the equivalent circuit reported
by Bottelberghs (1978). Note also that, for C = 0, we obtain the transient response for a step
input to a simple series combination of a resistor and a Warburg element
9
2I0 t
9 9
V 5t6 7 I0 R1 8
CW 2

(11)

2
A graph of
5 6 7 [V 5 6 4 I0 R1 ] 5C W
4I0 C6 is shown in Figure 2, where V( ) is plotted
2
2
against  , with  7 C W t4C , and hence

9
19 2
2 

5 6 7 9 4 1 8 e er f c  9
2

(12)

1436 R. L. MAGIN AND M. OVADIA

Figure 3. Simple electrical circuits involving a fractional order impedance element, a resistor and a
capacitor.

For comparison, the transient responses to the same step input for a capacitor, a conventional series R-C circuit, and a Warburg element in series with a resistor are also plotted
in Figure 2. We can see from this analysis that the conventional linear systems theory for a
circuit is easily extended to include fractional elements (e.g., Z W , Z C P E ) by generalizing the
corresponding differential equations from integer to fractional orders. Thus, once an accurate
impedance model for an electrode-tissue interface is established (from sinusoidal frequency
response data, for example), the result can be used to predict the transient response of the
circuit model. The simple model presented here can be extended to include additional series
and parallel elements, each with an associated ordinary or fractional differential equation. A
few examples are shown in Figure 3, and further examples can be found in the review by
Magin (2004c).

MODELING THE CARDIAC TISSUE ELECTRODE INTERFACE 1437

Figure 4. Tissue-electrode circuit model for a unit surface area. R B is the bulk tissue resistance, Ra 1
and Ra 2 are electrode access resistances,  is the charge transfer resistance, C is the dipole layer
capacitance, and Z D is a spatially confined Warburg impedance.

3.2. Electrode-Tissue Interface in the Heart

A critical element in all cardiac pacemaker designs is the lead electrode (Latimar and Roth,
1998). The electrode, associated lead conductor, and insulation must all meet stringent
mechanical, electrical, and biocompatibility criteria. State of the art lithium-iodine power
sources provide up to 10 years of operation with greater than thirty million 58 volt stimulus
pulses per year. In addition, the electrode must function as both a stimulating electrode for
cardiac pacing and as a sensing electrode for cardiac monitoring. Early, relatively large, bare
metal electrode designs have evolved into smaller (110 mm2 ) coated alloy and porous electrodes, some of which elute steroids to minimize inflammation at the site of fixation (Forde
and Ridgely, 2000).
The design of an effective pacing electrode is very challenging, since the electrical impedance presented to the pulse generator depends on physical, chemical, and biological factors. Recently Ovadia and Zavitz (1998), using electrical impedance spectroscopy, developed
an electrical equivalent circuit model for the electrode-tissue interface that involves constant
phase and Warburg impedance elements reflecting fractional order transfer functions and
fractional differential equations. The basic tissue-electrode equivalent circuit in Ovadias
model for a unit surface area is shown in Figure 4. The network structure reflects the basic
electrode-tissue interface impedance model discussed in the previous section. The new elements are Ra1 and Ra 2 , the electrode access resistances, and , the electrochemical charge
transfer resistance.
Figure 5 shows an illustration of the possible origin of the access resistances (Ra 1 , Ra 2 )
for an acute tissue-electrode interface. The reader is directed to previous work by Ovadia
and Zavitz (1998) for a complete description of the experimental data used to develop this
model. Here, we will focus only on the representation of Z D in terms of two simple constant
phase circuit elements.
In Ovadia and Zavitzs (1998) in vivo study using electrical impedance spectroscopy,
they observed impedance plane (Cole-Cole) plots reflecting two constant phase elements for
large electrodes (1013 mm2 ). An example of such an impedance plane plot is reproduced in
Figure 6.
Ovadia interprets these data in terms of a finite (spatially confined) Warburg impedance.
The overall behavior of this distributed element model has been presented elsewhere (Magin,
2004b). Here, we propose to illustrate that a lumped-element circuit model could also be

1438 R. L. MAGIN AND M. OVADIA

Figure 5. A representation of the acute tissue-electrode interface between cardiac muscle cells and an
implanted electrode.

Figure 6. Impedance plane plot for a large (1013 mm2 ) implanted cardiac electrode for the frequency
range 6 to 925 kHz (replotted from Ovadia and Zavitz, 1998).

MODELING THE CARDIAC TISSUE ELECTRODE INTERFACE 1439

Figure 7. Impedance plane plot for two constant phase element impedances in series with a resistor.
C 7 7 090071, C  7 091, 7 7 0925, and  7 09875.

used to describe this data. If we assume a simple series combination of two constant phase
elements Z C P E 1 and Z C P E 2 , defined in the Laplace domain by
Z C P E1 7

1
s7C 7

and

Z C P E2 7

1
s C 

(13)

then the total impedance for this circuit model can be written as
z5s6 7 R 8

1
s7C 7

1
s C 

(14)

The corresponding impedance plane plot is shown in Figure 7 for the simple case of
7 = 0.25 and  = 0.875, with C7 and C adjusted to approximate the data shown in Figure 6.
We observe that the overall impedance behavior described in Figure 7 can be represented simply by two constant phase elements, corresponding to the high and low frequency
regimes, respectively, by adjusting 7 and . The voltage response of this circuit to a step in
applied current is described in the Laplace domain by

1440 R. L. MAGIN AND M. OVADIA

5

1
1

5s6 7 R 8 7 7 8  
s C
s C

I0
s

(15)

which, upon inversion of the Laplace transform, becomes

V 5t6 7 I0 R 8

I0 t 7
I0 t 
8
9
C 7 51 8 76 C  51 8 6

(16)

Thus, we have demonstrated that the basic expression for the electrode impedance for
this case can be represented by a series combination of fractional lumped circuit elements.
The overall transfer function, if we assume 7   and set all initial conditions to zero,
corresponds to the fractional order differential equation
C7

7
d7 V
C 7 d 74 I
7d I
7
RC
8
I
5t6
8
9
dt 7
dt 7
C  dt 74

(17)

Fractional lumped circuit elements have long been recognized as providing a useful
model for describing the time domain and sinusoidal steady state frequency response of
dielectrics, biological tissues and bioelectrodes for a review see the work of Magin
(2004a,b,c). A recent book (Grimnes and Martinsen, 2000) provides a compendium of R,
C and Z C P E lumped element models. The bioengineering community is recognizing that,
not only can the complexity of the tissue electrode interface be modeled by constant phase
elements fractional order, dynamic models but that the search for underlying mechanisms stimulates new ways of examining the fundamental phenomena. Grimnes and Martinsen (2000), for example, classify three levels of tissue electrode models: Microanalytical,
organ-oriented, and black box. The microanalytical model starts with the cell membrane,
proteins, and ions, and works up, while the organ model starts with histology and gross
anatomy, and works down1 the black box model turns off the microscope light and just fits
the time or frequency domain data with as concise a function as possible. Such approaches
can be useful in specific situations (modeling skin disease, designing a stimulating electrode,
etc.), but even simple three and four element circuit models are not unique and selection of
a parallel or series elements is, more often than not, based on hidden assumptions relating to
the form of excitation (e.g., current or voltage), key anatomical or tissue barriers, or simple
convenience.
The more fundamental question of the underlying origin or mechanism behind observed
fractional order dynamics of order 7 is still unanswered. Again, Grimnes and Martinsen
(2000, chapter 7) provide a good review of the mechanisms from an impedance perspective, while Jonscher (1983) surveys the experimental and theoretical models underlying the
physics of fractional order dynamics in dielectrics. Physicists employ statistical mechanics to describe observed t47 behavior (Dissado and Hill, 1979) and anomalous diffusion via
continuous-time random walk models in solids and liquids (Hilfer, 2000). For living systems,
however, or, more directly, the transduction of current at interfaces between tissue and electrodes, biophysicists have postulated nonlinear, active, and perhaps even chaotic, systems at
the fundamental molecular and nanometer scales. There is even some hope for a simple connection between fractal tissue electrode structure and fractional order dynamics (Nyikos and
Pajkossy, 1985).

MODELING THE CARDIAC TISSUE ELECTRODE INTERFACE 1441

Despite considerable progress in fractional calculus and its application to modeling the
tissue electrode interface, a good deal more work is needed. Recent results from Ovadia et
al. (2006a) describe experimentation in human fetal tissue that suggests nonlinear behavior,
which could not always be fitted to a Havriliak-Negami fractional order dielectric model,
and in some cases exhibited nonlinear behavior with harmonic generation. Such studies need
replication, but these findings also provide an opportunity for mathematicians to consider
extension of the standard fractional order dynamic models to account for such anomalous
behavior, perhaps through the development of integrated space and time domain fractional
order models, or by allowing the fractional order measure 7 to become a function of time or
space. Clearly, while the structure in living systems is often fractal, and the dynamics have
fractional order, it is the transition between states (growth, development, reproduction, etc)
that is essential, but so far unexplained. We look to experts in the fractional calculus community to suggest mechanisms, and to the philosopher Henri Bergson to provide inspiration, for,
as Bergson noted in his 1911 work Creative Evolution, all things are regulated by a simple
law: the present contains nothing more than the past, and what is found in the effect was
already in the cause.

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