Subnanosecond Pulsed-Power Generated Electric Fields for Cancer ...

More details and application forms are available awards subcommittee, can be reached at Medical
on the NPSS awards website: http://www.ewh. Imaging Research Group, Department of Radiol-
In a rut
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ogy, UBC & Vancouver Coastal Health Research
People make such
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and it really isn’t
Anna Celler, Ph.D. FCCPM, Chair, NMISC aceller@phas.ubc.ca.
that important...
You go to bed at
SPECIAL ARTICLE
night and you fall
asleep and it’s all
Subnanosecond Pulsed-Power Generated Electric
over. Then you
Fields for Cancer Treatment
wake up the next
day and you have
Serhat Altunc, Ph.D.
Abstract— This article summarizes ongoing research on the use of pulsed power-generated electric fields
to start all over
as a delicate tool for skin cancer treatment. A prolate-spheroidal impulse radiating antenna is used as
again.
a noninvasive technique for generating an electromagnetic implosion to kill melanoma cells.
Index Terms—Pulsed-power generated electric field, Impulse radiating antennas, Cancer treatment
Andy Warhol
INTRODUCTION
H
mors [1-4]. A prolate-spheroidal IRA (psIRA)
IGH-intensity nanosecond pulsed power- can be used to obtain electromagnetic focusing
generated electric fields have been used in a on the target to reduce the damage to the tissue
variety of biological applications and have layers surrounding the target and skin [5-9].
initiated the establishment of a brand new research
area cal ed bioelectrics. Bioelectrics combines two BACKGROUND AND MOTIVATION
distinct disciplines: pulsed high voltage engineering Intense nanosecond electric pulses (nEPs) pro-
and cell biology [1-4].
vide a new tool for cancer treatment, gene ther-
Millions of people around the world are dy- apy, etc. For example, nEP can induce apoptosis
ing each year because of cancer. Even though in mammalian cells. One promising result is the
considerable progress has been made in treating discovery, by the Frank Reidy Center for Bio-
Serhat Altunc
several forms of this disease, we need to develop electrics at Old Dominion University (http://
safer, cheaper, more effective, and less invasive www.odu.edu/engr/bioelectrics/), that nEPs
treatment methods.
can destroy tumors in mice[1-3].
The effects of intense electrical pulses on
Pulsed electric fields of 10’s kV amplitude de-
biological cells provide a new tool for therapeu- livered in nanoseconds or shorter timescale are
tic applications such as cancer treatments and an exciting new development in the biomedi-
gene therapy. Needle arrays have been used for cal field. nEPs have shown the potential to kill
treating melanoma tumors using pulsed electric skin cancer cells and also allow the insertion of
fields. This, however, is an invasive approach, new genes into living cells with the aim of cor-
resulting in discomfort to the patient. Impulse recting genetic defects. The initial method of
radiating antennas (IRA) are now being investi- applying such electric fields, through implant-
gated as a noninvasive pulsed electric field deliv- able electrodes, is a limiting factor with respect
ery system for skin cancer treatment. IRAs can to practical applications. A psIRA can be used
deliver a subnanosecond pulse into tissue with as a noninvasive cancer treatment tool, opening
a spatial resolution in the centimeter range and up the subnanosecond pulse regime, which is
even in the millimeter range with the use of a thought to offer greater treatment advantages
focusing electromagnetic lens [5]. In addition, [1-2].
IRAs can deliver subnanosecond electric fields
A cell can be modeled as an electrical cir-
to melanoma tissues that are not easily accessible cuit as in Fig. 1 [4]. One can model the vari-
with needles. Most recently it has been shown ous cell membranes by their capacitances. The
that such pulsed electric fields cause shrinkage cytoplasm and organelles can be modeled by
and even complete elimination of melanoma tu- their resistances. The cytoplasm is conductive,
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Licence to err
You can break
every
grammatical and
syntactical rule
consciously
when, and only
when, you have
rendered
Figure 1. (a) Structure of a biological cell (as would be seen with a light microscope). (b)
yourself
Double-shell model of a biological cell and superimposed equivalent circuit of the cell [4].
incapable of
whereas the membranes have low conductiv- of large molecules across the cell membrane.
breaking them
ity. Therefore, one can model the cell as a Electroporation is generally reversible and even
unconsciously.
conductor surrounded by an ideally insulating useful, unless the pulse amplitude is too large
envelope. Embedded proteins in the membrane and/or its duration too long. The electropora-
serve as valves or channels for ions.
tion effect can be used for chemotherapy and
Bernard Levin
While investigating the effect of the electri- gene insertion. Electroporation might allow
cal pulses on the biological tissues, one should delivery of certain drugs or nanoparticles into
consider four important characteristics that de- the cell without strongly affecting the viabil-
termine their precise effects on the cells. These ity of the cells. Retention of the pores in the
characteristics are pulse rise time, pulse dura- membrane wall, however, can lead to cell death
tion, the number of pulses, and the amplitude (apoptosis).
of the electric field pulses. Most pulsed electric
If we have a pulsed electric field rising faster
field effects act on the plasma membrane. The than 10 ns, the ions in the cytoplasm have insuf-
plasma membrane charging time, 100 ns, consti- ficient time to migrate to the plasma membrane
tutes a significant division in addressing pulsed and the applied electric field is able to transit the
electric field effects on biological cells. A sub- plasma membrane and affect the intracellular
nanosecond duration electric pulse (sEP) will structures. Electroporation can now occur at
pass through the membrane into the cytoplasm the subcellular membranes and we can manipu-
because the sEP has a faster rise time than most late intracellular structures. This can be used to
mammalian plasma membrane charging time. kill cancer cells and insert gene-modified DNA
If we apply long duration pulses compared to [1,2].
the charging time of the capacitor formed by
the outer membrane, just the outer membrane A PROlATe-sPheROIDAl IMPUlse RADIATING
will be charged and the electric field between ANTeNNA fOR NONINVAsIVe CANCeR
subcellular membranes will be zero for a fully TReATMeNT
insulating outer membrane. However, in prac- Research on nEPs is yielding promising results
tice, we will also have potential differences be- for cancer treatment and gene insertion [1-3].
tween subcellular membranes. This effect will However, in earlier studies the electric field
be significant if the pulse rise time is shorter. If was invasively delivered to the tumor using im-
the sEP has a sufficiently large amplitude it can planted electrodes and this treatment has some
have significant effects on organelles [1,2].
disadvantages, including discomfort. Current
When the amplitude of the pulsed electric research has been initiated into using psIRAs to
field is increased beyond the threshold required noninvasively delivery the sEP to the melanoma
for voltage-gating effects, but with a pulse du- cells [5-9].
ration that is shorter than the charging time
For sPE applications the dielectric proper-
of the plasma membrane, an effect at the cell ties of the tissue play a key role in determining
membrane called electroporation occurs [3]. the electric field distribution compared with the
It is believed that this effect creates openings resistive characteristics of the media. First, for
in the cell membrane, allowing for the transfer sEPs the conductance of the membranes are as-
n u c l e a r & p l a s m a s c i e n c e s s o c i e t y
March 2009
35

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What counts
Throughout all
written history
the kil ing of
people was
never limited by
the ability to kill
people but
always by the
amount of
intention to kill
people.
Figure 2. Experimental setup of psIRA and focusing lens geometry for cancer treatment
Edward Teller
sumed to be zero and the capacitive components neous plane wave from one focal point and re-
of cytoplasm and nucleoplasm are neglected. flect it toward a second focal point where the
Second, subnanosecond regime is giving prom- melanoma tissue is located. We choose a special
ising results for electric field-cell interactions. case of the psIRA’s geometric parameters (as in
psIRAs may be able to induce apoptosis in tis- [6]) where the geometric parameters are
sue instead of needles [1,6].





(1)
Using electrodes embedded in the tissue lim-
where zp is the z-coordinate of the truncation
its the cancer treatment efficacy of the pulsed plane, a and b are the two radii for the prolate-
electric field since the tumor is close to the skin spheroid, and z0 is the focal distance.
or surface of the body. psIRAs allow one to ap-
The experimental set-up that is being investi-
ply such electric fields to tissues more directly gated and would be suitable for cancer treatment
compared with using needles. The psIRA will uses basically four components: a two feed arm
also reduce the damage to the tissue layers sur- psIRA, a sampling-oscilloscope, a pulse genera-
rounding the target and the skin. The spatial tor, and a focusing lens and target. (It should be
resolution of an electric field generated in tis- noted that only a two feed arm is required in this
sue depends on the pulse duration and the per- proof-of-principle experiment since a conduct-
mittivity of the tissue. Even though IRAs have ing ground plane is used. In future actual experi-
been mainly designed for far-field applications, ments with patients a four feed arm full IRA will
for bioelectric applications one needs to operate be used.) As seen in Fig. 2, we use a Tektronix
in the near-field.
TDS 8000B Digital Sampling-Oscilloscope with
A psIRA is used to launch an inhomoge- a Tektronix 80E04 sampling head to measure
the waveform at the second focal point. In addi-
tion, we use a Picosecond Pulse Labs pulser with
a PSPL 4050 RPH fast pulser head generator for
pulse excitation. The output of the step genera-
tor is a 45-ps rise time with a 10 V amplitude.
We have investigated a new manifestation of
an IRA in which we use a prolate spheroid as
a reflector instead of a parabolic reflector and
focus in the near-field region instead of the
far-field region. This technique minimizes skin
damage associated with inserting electrodes
near the tumor. Analytical calculations, numer-
Figure 3. Analytical, numerical and experi-
ical simulations, and experimental data is used
mental focal waveforms for two-arm psIRA
to find the focal waveform characteristics and
without focusing lens.
spot sizes. Figure 3 presents analytical, numeri-
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Dilemma
The coexistence
of an insatiable
Table 1. Radii and er values for each layer in an optimized 10-layer graded permittivity
appetite for more
dielectric focusing lens.
knowledge and
cal and experimental focal waveforms for a two age to adjacent healthy tissue. This ongoing
arm psIRA without a focusing lens. This work research project will speed the development
an intense
has been completed and reported.
and use of pulsed electric fields as a new medi-
suspicion of its
For our final experiments, we will be using cal therapy.
further
a focusing lens at the second focal point of the
psIRA. Our motivations for using a lens before
development is a
the second focal point are to eliminate imped- ACKNOWleDGMeNTs
paradox of
ance mismatch between the dielectric constant The author would like to thank Profs. C.E.
Western culture
of air and the dielectric constant of the target, Baum, C.J. Buchenauer, C.G. Christodoulou,
e
today.
rtarget and to obtain better focusing. The lens
and E. Schamiloglu for useful discussions. This

research has been supported by AFOSR. The
provides
times greater field amplitude author also thanks his colleagues at the Frank
Frank Furedi

Reidy Center for Bioelectrics at Old Dominion
and a reduction in the spot size.
University for their collaboration and support.
In order to eliminate the impedance mis-
match between the target (which is typically RefeReNCes
close to the dielectric constant of water, erwater = 1. K.H. Schoenbach, R.P. Joshi, J.F. Kolb, N.
81) we have designed a graded-permittivity di-
Chen, M. Stacey, P.F. Blackmore, E.S.
electric lens. A lens design procedure, with con-
Buescher, and S.J. Beebe, “Ultrashort
stant wavelength-to-cross-section ratio as (di-
Electrical Pulses Open a New Gateway into
electric constant) increases from unity to ertarget
Biological Cells,” Proc. IEEE, vol. 92, no. 7,
, is used to obtain better focusing at the second
pp. 1122–1137, Jul. 2004.
focal point of a psIRA. Our analytical calcula- 2. K.H. Schoenbach, B. Hargrave, R.P. Joshi,
tions and numerical simulations show that the
J.F. Kolb, C. Osgood, R. Nuccitelli, A.
lens should comprise at least 10 layers and have
Pakhomov, R.J. Swanson, M. Stacey, J.A.
a 15 cm radius to achieve the desired focusing
White, S. Xiao, J. Zhang, S.J. Beebe, P.F.
[5]. (able 1 presents the calculated radii and er
Blackmore, and E.S. Buescher, “Bioelectric
values for different adjacent 10 layers.)
Effects of Intense Nanosecond Pulses,”
For our initial experiments, however, in or-
IEEE Trans. Dielectr. Electr. Insul., vol. 14,
der to simplify construction, we have designed
no. 5, pp. 1088–1119, Oct. 2007.
and fabricated a 5-layer lens and the relative di- 3. K.H. Schoenbach, R. Nuccitelli, and S.J.
electric constant of the 5th layer is ertarget = 9.
Beebe, “Zap,” IEEE Spectrum, pp. 20–28,
Aug. 1980.
CONClUsIONs
4. K.H. Schoenbach, S. Xiao, R.P. Joshi, J.T.
Subnanosecond pulsed electric fields are an ex-
Camp, T. Heeren, J.F. Kolb, and S.J. Beebe
citing new development in the biomedical field
“The Effect of Intense Subnanosecond
for cancer treatment and gene therapy. sPEs
Electrical Pulses on Biological Cells,” IEEE
may kill melanoma and allow for the insertion
Trans. Dielectr. Electr. Insul., vol. 36, no. 2,
of new genes into living cells with the aim of
pp. 414-422, Apr. 2008.
correcting genetic defects. The invasive meth- 5. S. Altunc, C.E. Baum, C.G. Christodoulou,
od of delivering these fields, through implant-
and E. Schamiloglu, “Spatially Limited
able electrodes, is a limiting factor with respect
Exponential Lens Design for Better Focusing
to practical applications. The noninvasive deliv-
an Impulse,” Proc. URSI General Assembly,
ery technology using a psIRA that we described
August 2008, Chicago, IL.
in this article may also be developed for applica- 6. S. Altunc, C.E. Baum, C.G. Christodoulou,
tion to target cells deep within the human body.
E. Schamiloglu, and C.J. Buchenauer, “Focal
Given the tightly focused wavebeam spot, this
Waveforms for Various Source Waveforms
would also result in significantly reduced dam-
Driving a Prolate-spheroidal Impulse
n u c l e a r & p l a s m a s c i e n c e s s o c i e t y
March 2009
37

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Radiating Antenna (IRA),” Radio Sci., 43, Engineering from the University of New Mexico
p. RS4S13, 2008.
(UNM), Albuquerque, in 2007. He was a
7. C.E. Baum, “Focal Waveform of a Prolate research/teaching assistant at Yildiz Technical
Spheroidal IRA,” Radio Sci., vol. 42, no. 6, University from 2001 to 2003. He worked as a
p. RS6S27, Nov. 2007.
research/teaching assistant at the University of
8. C.E. Baum, S. Altunc, C.G. Christodoulou, New Mexico from 2004 to 2008. He is currenly a
and E. Schamiloglu, “Electromagnetic Postdoctoral Research Fellow at UNM, where
Implosion using an Array,” IEEE Trans. since August 2004 he has been working in the
Plasma Sci., vol. 36, pp. 757-763, 2008.
Transient Antenna Measurement Laboratory.
9. S. Altunc, C.E. Baum, C.G. Christodoulou, His main research interests are in impulse radi-
and E. Schamiloglu, “Analytical and ating antennas, UWB antenna design, and
Numerical Calculation for the Focal their applications. He is also interested in the
Waveform of a Prolate-Spheroidal IRA,” areas of electromagnetic systems, antenna design
IEEE AP-S International Symposium, June and characteristics, RF and microwave engi-
2007, Honolulu, Hawaii.
neering, computational electromagnetics and
Bioelectrics. He has published over 20 papers in
Serhat Altunc received his B.S. degree in journals, conferences and has one book chapter.
Electronics and Communication Engineering
Dr. Serhat Altunc, Postdoctoral Research Fel-
from Istanbul Technical University in 2000, his low, can be reached at the Department of Elec-
M.S. degree in Communication Engineering trical and Computer Engineering, University of
from Yildiz Technical University in Istanbul in New Mexico, Albuquerque, New Mexico 87131-
2003, and his Ph.D. degree in Electrical 0001 USA; E-mail:saltunc@ece.unm.edu.
OBITUARY
Robert N. Beck
1928-2008
Robert N. Beck, pioneer in the develop- the rapid acceptance of Tc-99m for clinical imag-
ment of the mathematical theory of ing—with the first protocols being some designed
radionuclide imaging and in the con- and executed for brain tumor detection (3). This
ceptualization of the field of imaging science, work was conducted by Paul Harper, Katherine
died August 6, 2008, from myelodysplasia, a Lathrop, Don Charleston, and Bob Beck at the
form of leukemia. He was 80.
UC Argonne Cancer Research Hospital (ACRH).
Bob Beck was born in San Angelo, TX, in 1928; In the 1960s and 70s, Beck and colleagues also de-
served in the U.S. Navy from 1946 to 1948; and veloped a theory of optimum col imator design for
entered in 1948, at age 20, the Hutchins College single-photon emission imaging (1,5); introduced
of the University of Chicago. This entrance was Fourier methods designed to characterize the spa-
the beginning of a direct and continuous affilia- tial resolution of radionuclide imaging systems and
Robert N. Beck
tion with the University of Chicago that lasted 60 to account quantitatively for the effects of septal
1928-2008
years.* In 2008, at the time of his death, Robert penetration and scattering on the contrast of emis-
N. Beck was Professor Emeritus, Department of sion images (4,5,8,9,10); and designed and built
Radiology, the University of Chicago (UC).
several imaging systems, including several animal
Throughout his 50-year professional career, imaging systems (2), a brain scanner (6), and the
Beck made significant contributions to the first whole-body scanner utilizing a scintil ation
fields of nuclear medicine, medical imaging, camera rather than a rectilinear scanner.
and imaging science. Some of those contribu-
In 1976, Beck was promoted from Associate
tions follow.
Professor to Professor; and in 1977, Professor Beck
In the 1950s, through adaptation of principles, was appointed Director of the Franklin McLean Me-
concepts, and methods of the physical sciences, morial Research Institute (FMI, formerly ACRH).
Beck and colleagues developed a statistical-criteri- During the 1980s and 90s, Professor Beck and col-
on-based theory for determination of the optimum leagues advanced their theoretical work on analysis
gamma-ray energies for specific imaging applica- of systems, advanced their foundational work on
tions (l,4,8). Application of the theory was pursued col imator design, and pursued development of
in the early 1960s and resulted in the first uses and application-specific imaging systems (14). They also
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