U.S. patent application number 16/207609 was filed with the patent office on 2019-04-04 for controlled irreversible electroporation.
The applicant listed for this patent is The Regents of the University of California. Invention is credited to CHARLOTTE DANIELS, BORIS RUBINSKY.
Application Number | 20190099214 16/207609 |
Document ID | / |
Family ID | 44011871 |
Filed Date | 2019-04-04 |
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United States Patent
Application |
20190099214 |
Kind Code |
A1 |
RUBINSKY; BORIS ; et
al. |
April 4, 2019 |
CONTROLLED IRREVERSIBLE ELECTROPORATION
Abstract
Electrical pulses are applied to tissue in a manner which
destroys targeted cells such as cancerous cells while sparing
non-targeted cells such as nerve cells. The electrical pulses are
controlled within ranges for voltage, wattage and duration of
application. Multiple pulses or groups of pulses may be applied to
obtain a desired result while maintaining any temperature increase
below a level which destroys cells.
Inventors: |
RUBINSKY; BORIS; (El
Cerrito, CA) ; DANIELS; CHARLOTTE; (Berkeley,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Regents of the University of California |
Oakland |
CA |
US |
|
|
Family ID: |
44011871 |
Appl. No.: |
16/207609 |
Filed: |
December 3, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14679449 |
Apr 6, 2015 |
10143512 |
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16207609 |
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12899389 |
Oct 6, 2010 |
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14679449 |
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61262850 |
Nov 19, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 2018/00613
20130101; A61B 18/14 20130101; A61N 1/327 20130101; A61N 1/0412
20130101 |
International
Class: |
A61B 18/14 20060101
A61B018/14; A61N 1/04 20060101 A61N001/04; A61N 1/32 20060101
A61N001/32 |
Goverment Interests
GOVERNMENT RIGHTS
[0002] This invention was made with government support under
federal grant nos. 403/06 awarded by The National Science
Foundation (NSF). The United States Government has certain rights
in this invention.
Claims
1.-20. (canceled)
21. A method comprising the steps of: identifying cells to be
ablated in a target area, wherein the target area comprises
heterogenous tissue comprising nerve tissue surrounded by myelin
layers; selecting a size, shape, or relative position of a first
electrode and a second electrode; placing the first electrode and
the second electrode in the target area; and applying electrical
pulses between the first electrode and the second electrode in an
amount which compensates for tissue heterogeneity, and is
sufficient to irreversibly electroporate the cells in the target
area; wherein voltage, wattage and duration of the electrical
pulses are maintained within ranges which avoid thermal damage to
nerve tissue and the cells in the target area.
22. The method of claim 21, wherein the myelin layers insulate the
nerve tissue from thermal damage.
23. The method of claim 21, further comprising: monitoring
temperature of the heterogeneous tissue and adjusting the
electrical pulses to maintain the temperature at 50.degree. C. or
less for a period of time that avoids thermal damage to cells of
the heterogeneous tissue.
24. The method of claim 21, further comprising: infusing a material
into the heterogenous tissue prior to applying the electrical
pulses.
25. The method of claim 24, wherein the material is a
chemotherapeutic agent.
26. The method of claim 24, wherein the material is an imaging
agent.
27. The method of claim 21, wherein the first electrode and the
second electrode are substantially circular in shape; and wherein
the first and second electrodes are positioned within less than 2
cm of each other.
28. A method comprising the steps of: identifying a target ablation
area, wherein the target ablation area is heterogenous tissue
comprising cells and mammary ducts, wherein the mammary ducts are
surrounded by myoepithelial cells; placing a first electrode and a
second electrode in the target ablation area; and applying
electrical pulses between the first electrode and the second
electrode in an amount which compensates for tissue heterogeneity,
and is sufficient to irreversibly electroporate the cells in the
target ablation area; wherein voltage, wattage and duration of the
electrical pulses are maintained within ranges which avoid damage
to the mammary ducts and the cells in the target ablation area.
29. The method of claim 28, wherein the myoepithelial cells
insulate the mammary ducts from thermal damage.
30. The method of claim 28, further comprising: monitoring
temperature of the heterogeneous tissue and adjusting the
electrical pulses to maintain the temperature at 50.degree. C. or
less for a period of time that avoids thermal damage to the cells
of the heterogeneous tissue.
31. The method of claim 28, further comprising: infusing a material
into the heterogenous tissue prior to applying the electrical
pulses.
32. The method of claim 28, wherein the material is a
chemotherapeutic agent.
33. The method of claim 31, wherein the material is an imaging
agent.
34. The method of claim 31, wherein the first electrode and the
second electrode are substantially circular in shape; and wherein
the first and second electrodes are positioned within less than 2
cm of each other.
35. A method comprising the steps of: identifying a target ablation
area, wherein the target ablation area is comprised of heterogenous
tissue comprising cancer cells and nerve tissue, wherein the nerve
tissue is surrounded by myelin layers; placing a first electrode
and a second electrode in the target ablation area; and applying
electrical pulses between the first electrode and the second
electrode in an amount which compensates for tissue heterogeneity,
and is sufficient to irreversibly electroporate the cancer cells in
the target ablation area; wherein voltage, wattage and duration of
the electrical pulses are maintained within ranges which avoid
damage to the nerve tissue.
36. The method of claim 35, wherein the myelin layers insulate the
nerve tissue from thermal damage.
37. The method of claim 35, further comprising: monitoring
temperature of the heterogeneous tissue and adjusting the
electrical pulses to maintain the temperature at 50.degree. C. or
less for a period of time that avoids thermal damage to cells of
the heterogeneous tissue.
38. The method of claim 35, further comprising: infusing a material
into the heterogenous tissue prior to applying the electrical
pulses.
39. The method of claim 38, wherein the material is a
chemotherapeutic agent.
40. The method of claim 38, wherein the material is an imaging
agent.
41. The method of claim 35, wherein the first electrode and second
electrode are substantially circular in shape; and wherein the
first and second electrodes are positioned within less than 2 cm of
each other.
Description
CROSS REFERENCES
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/262,850, filed Nov. 19, 2009, which application
is incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The invention relates generally to devices, systems and
methods for carrying out electroporation of cells and particularly
irreversible electroporation which is carried out in a controlled
manner making it possible to selectively destroy certain types of
cells.
BACKGROUND OF THE INVENTION
[0004] In many medical procedures, such as the treatment of benign
or malignant tumors, it is important to be able to ablate the
undesirable tissue in a controlled and focused way without
affecting the surrounding desirable tissue. Over the years, a large
number of minimally invasive methods have been developed to
selectively destroy specific areas of undesirable tissues as an
alternative to resection surgery. There are a variety of techniques
with specific advantages and disadvantages, which are indicated and
contraindicated for various applications. For example, cryosurgery
is a low temperature minimally invasive technique in which tissue
is frozen on contact with a cryogen cooled probe inserted in the
undesirable tissue (Rubinsky, B., ed. Cryosurgery. Annu. Rev.
Biomed. Eng. Vol. 2. 2000. 157-187.). The area affected by low
temperature therapies, such as cryosurgery, can be easily
controlled through imaging. However, the probes are large and
difficult to use. Non-selective chemical ablation is a technique in
which chemical agents such as ethanol are injected in the
undesirable tissue to cause ablation (Shiina, S., et al.,
Percutaneous ethanol injection therapy for hepatocellular
carcinoma: results in 146 patients. AJR, 1993. 160: p. 1023-8).
Non-selective chemical therapy is easy to apply. However, the
affected area cannot be controlled because of the local blood flow
and transport of the chemical species. Elevated temperatures are
also used to ablate tissue. Focused ultrasound is a high
temperature non-invasive technique in which the tissue is heated to
coagulation using high-intensity ultrasound beams focused on the
undesirable tissue (Lynn, J. G., et al., A new method for the
generation of use of focused ultrasound in experimental biology. J.
Gen Physiol., 1942. 26: p. 179-93; Foster, R. S., et al.,
High-intensity focused ultrasound in the treatment of prostatic
disease. Eur. Urol., 1993. 23: p. 44-7). Electrical currents are
also commonly used to heat tissue. Radiofrequency ablation (RF) is
a high temperature minimally invasive technique in which an active
electrode is introduced in the undesirable tissue and a high
frequency alternating current of up to 500 kHz is used to heat the
tissue to coagulation (Organ, L. W., Electrophysiological
principles of radiofrequency lesion making. Appl. Neurophysiol.,
1976. 39: p. 69-76). In addition to RF heating traditional Joule
heating methods with electrodes inserted in tissue and dc or ac
currents are also common, (Erez, A., Shitzer, A. (Controlled
destruction and temperature distribution in biological tissue
subjected to monoactive electrocoagulation) J. Biomech. Eng.
1980:102(1):42-9). Interstitial laser coagulation is a high
temperature thermal technique in which tumors are slowly heated to
temperatures exceeding the threshold of protein denaturation using
low power lasers delivered to the tumors by optical fibers (Bown,
S. G., Phototherapy of tumors. World. J. Surgery, 1983. 7: p.
700-9). High temperature thermal therapies have the advantage of
ease of application. The disadvantage is the extent of the treated
area is difficult to control because blood circulation has a strong
local effect on the temperature field that develops in the tissue.
The armamentarium of surgery is enhanced by the availability of the
large number of minimally invasive surgical techniques in
existence, each with their own advantages and disadvantages and
particular applications. This document discloses another minimally
invasive surgical technique for tissue ablation, irreversible
electroporation. We will describe the technique, evaluate its
feasibility through mathematical modeling and demonstrate the
feasibility with in vivo experimental studies.
[0005] Electroporation is defined as the phenomenon that makes cell
membranes permeable by exposing them to certain electric pulses
(Weaver, J. C. and Y. A. Chizmadzhev, Theory of electroporation: a
review. Bioelectrochem. Bioenerg., 1996. 41: p. 135-60).
Electroporation pulses are defined as those electrical pulses that
through a specific combination of amplitude, shape, time length and
number of repeats produce no other substantial effect on biological
cells than the permeabilization of the cell membrane. The range of
electrical parameters that produce electroporation is bounded by:
a) parameters that have no substantial effect on the cell and the
cell membrane, b) parameters that cause substantial thermal effects
(Joule heating) and c) parameters that affect the interior of the
cell, e.g. the nucleus, without affecting the cell membrane. Joule
heating, the thermal effect that electrical currents produce when
applied to biological materials is known for centuries. It was
noted in the previous paragraph that electrical thermal effects
which elevate temperatures to values that damage cells are commonly
used to ablate undesirable tissues. The pulse parameters that
produce thermal effects are longer and/or have higher amplitudes
than the electroporation pulses whose only substantial effect is to
permeabilize the cell membrane.
[0006] There are a variety of methods to electrically produce
thermal effects that ablate tissue. These include RF, electrode
heating, and induction heating. Electrical pulses that produce
thermal effects are distinctly different from the pulses which
produce electroporation. The distinction can be recognizing through
their effect on cells and their utility. The effect of the thermal
electrical pulses is primarily on the temperature of the biological
material and their utility is in raising the temperature to induce
tissue ablation through thermal effects.
[0007] The effect of the electroporation parameters is primarily on
the cell membrane and their utility is in permeabilizing the cell
membrane for various applications. Electrical parameters that only
affect the interior of the cell, without affecting the cell
membrane were also identified recently. They are normally referred
to as "nanosecond pulses". It has been shown that high amplitude,
and short (substantially shorter than electroporation
pulses--nanoseconds versus millisecond) length pulses can affect
the interior of the cell and in particular the nucleus without
affecting the membrane. Studies on nanosecond pulses show that they
are "distinctly different than electroporation pulses" (Beebe SJ.
Fox PM. Rec LJ. Somers K. Stark RH. Schoenbach KH. Nanosecond
pulsed electric field (nsPEF) effects on cells and tissues:
apoptosis induction and tumor growth inhibition. PPPS-2001 Pulsed
Power Plasma Science 2001. 28th IEEE International Conference on
Plasma Science and 13th IEEE International Pulsed Power Conference.
Digest of Technical Papers (Cat. No. 01CH37251). IEEE. Part vol. 1,
2001, pp. 211-15 vol. 1. Piscataway, N.J., USA. Several
applications have been identified for nano-second pulses. One of
them is for tissue ablation through an effect on the nucleus
(Schoenbach, K. H., Beebe, S. J., Buescher, K. S. Method and
apparatus for intracellular electro-manipulation U.S. Patent
Application Pub No. US 2002/0010491 A1, Jan. 24, 2002). Another is
to regulate genes in the cell interior, (Gunderson, M. A. et al.
Method for intracellular modification within living cells using
pulsed electrical fields--regulate gene transcription and entering
intracellular US Patent application 2003/0170898 A1, Sep. 11,
2003). Electrical pulses that produce intracellular effects are
distinctly different from the pulses which produce electroporation.
The distinction can be recognizing through their effect on cells
and their utility. The effect of the intracellular electrical
pulses is primarily on the intracellular contents of the cell and
their utility is in manipulating the intracellular contents for
various uses--including ablation. The effect of the electroporation
parameters is primarily on the cell membrane and their utility is
in permeabilizing the cell membrane for various applications, which
will be discussed in greater detail later.
[0008] Electroporation is known for over half a century. It was
found that as a function of the electrical parameters,
electroporation pulses can have two different effects on the
permeability of the cell membrane. The permeabilization of the
membrane can be reversible or irreversible as a function of the
electrical parameters used. In reversible electroporation the cell
membrane reseals a certain time after the pulses cease and the cell
survives. In irreversible electroporation the cell membrane does
not reseal and the cell lyses. A schematic diagram showing the
effect of electrical parameters on the cell membrane
permeabilization (electroporation) and the separation between: no
effect, reversible electroporation and irreversible electroporation
is shown in FIG. 1 (Dev, S. B., Rabussay, D. P., Widera, G.,
Hofmann, G. A., Medical applications of electroporation, IEEE
Transactions of Plasma Science, Vol 28 No 1, February 2000, pp
206-223) Dielectric breakdown of the cell membrane due to an
induced electric field, irreversible electroporation, was first
observed in the early 1970s (Neumann, E. and K. Rosenheck,
Permeability changes induced by electric impulses in vesicular
membranes. J. Membrane Biol., 1972. 10: p. 279-290; Crowley, J. M.,
Electrical breakdown of biomolecular lipid membranes as an
electromechanical instability. Biophysical Journal, 1973. 13: p.
711-724; Zimmermann, U., J. Vienken, and G. Pilwat, Dielectric
breakdown of cell membranes, Biophysical Journal, 1974. 14(11): p.
881-899). The ability of the membrane to reseal, reversible
electroporation, was discovered separately during the late 1970s
(Kinosita Jr, K. and T. Y. Tsong, Hemolysis of human erythrocytes
by a transient electric field Proc. Natl. Acad. Sci. USA, 1977.
74(5): p. 1923-1927; Baker, P. F. and D. E. Knight,
Calcium-dependent exocytosis in bovine adrenal medullary cells with
leaky plasma membranes. Nature, 1978. 276: p. 620-622; Gauger, B.
and F. W. Bentrup, A Study of Dielectric Membrane Breakdown in the
Fucus Egg, J. Membrane Biol., 1979. 48(3): p. 249-264).
[0009] The mechanism of electroporation is not yet fully
understood. It is thought that the electrical field changes the
electrochemical potential around a cell membrane and induces
instabilities in the polarized cell membrane lipid bilayer. The
unstable membrane then alters its shape forming aqueous pathways
that possibly are nano-scale pores through the membrane, hence the
term "electroporation" (Chang, D. C., et al., Guide to
Electroporation and Electrofusion. 1992, San Diego, Calif.:
Academic Press, Inc.). Mass transfer can now occur through these
channels under electrochemical control. Whatever the mechanism
through which the cell membrane becomes permeabilized,
electroporation has become an important method for enhanced mass
transfer across the cell membrane.
[0010] The first important application of the cell membrane
permeabilizing properties of electroporation is due to Neumann
(Neumann, E., et al., Gene transfer into mouse lyoma cells by
electroporation in high electric fields. J. EMBO, 1982. 1: p.
841-5). He has shown that by applying reversible electroporation to
cells it is possible to sufficiently permeabilize the cell membrane
so that genes, which are macromolecules that normally are too large
to enter cells, can after electroporation enter the cell. Using
reversible electroporation electrical parameters is crucial to the
success of the procedure, since the goal of the procedure is to
have a viable cell that incorporates the gene.
[0011] Following this discovery electroporation became commonly
used to reversible permeabilize the cell membrane for various
applications in medicine and biotechnology to introduce into cells
or to extract from cells chemical species that normally do not
pass, or have difficulty passing across the cell membrane, from
small molecules such as fluorescent dyes, drugs and radioactive
tracers to high molecular weight molecules such as antibodies,
enzymes, nucleic acids, HMW dextrans and DNA. It is important to
emphasize that in all these applications electroporation needs to
be reversible since the outcome of the mass transport requires for
the cells to be alive after the electroporation.
[0012] Following work on cells outside the body, reversible
electroporation began to be used for permeabilization of cells in
tissue. Heller, R., R. Gilbert, and M. J. Jaroszeski, Clinical
applications of electrochemotherapy. Advanced drug delivery
reviews, 1999. 35: p. 119-129. Tissue electroporation is now
becoming an increasingly popular minimally invasive surgical
technique for introducing small drugs and macromolecules into cells
in specific areas of the body. This technique is accomplished by
injecting drugs or macromolecules into the affected area and
placing electrodes into or around the targeted tissue to generate
reversible permeabilizing electric field in the tissue, thereby
introducing the drugs or macromolecules into the cells of the
affected area (Mir, L. M., Therapeutic perspectives of in vivo cell
electropermeabilization. Bioelectrochemistry, 2001. 53: p.
1-10).
[0013] The use of electroporation to ablate undesirable tissue was
introduced by Okino and Mohri in 1987 and Mir et al. in 1991. They
have recognized that there are drugs for treatment of cancer, such
as bleomycin and cys-platinum, which are very effective in ablation
of cancer cells but have difficulties penetrating the cell
membrane. Furthermore, some of these drugs, such as bleomycin, have
the ability to selectively affect cancerous cells which reproduce
without affecting normal cells that do not reproduce. Okino and
Mori and Mir et al. separately discovered that combining the
electric pulses with an impermeant anticancer drug greatly enhanced
the effectiveness of the treatment with that drug (Okino, M. and H.
Mohri, Effects of a high-voltage electrical impulse and an
anticancer drug on in vivo growing tumors. Japanese Journal of
Cancer Research, 1987. 78(12): p. 1319-21; Mir, L. M., et al.,
Electrochemotherapy potentiation of antitumour effect of bleomycin
by local electric pulses. European Journal of Cancer, 1991. 27: p.
68-72). Mir et al. soon followed with clinical trials that have
shown promising results and coined the treatment
electrochemotherapy (Mir, L. M., et al., Electrochemotherapy, a
novel antitumor treatment: first clinical trial. C. R. Acad. Sci.,
1991. Ser. III 313(613-8)).
[0014] Currently, the primary therapeutic in vivo applications of
electroporation are antitumor electrochemotherapy (ECT), which
combines a cytotoxic nonpermeant drug with permeabilizing electric
pulses and electrogenetherapy (EGT) as a form of non-viral gene
therapy, and transdermal drug delivery (Mir, L. M., Therapeutic
perspectives of in vivo cell electropermeabilization.
Bioelectrochemistry, 2001. 53: p. 1-10). The studies on
electrochemotherapy and electrogenetherapy have been recently
summarized in several publications (Jaroszeski, M. J., et al., In
vivo gene delivery by electroporation. Advanced applications of
electrochemistry, 1999. 35: p. 131-137; Heller, R., R. Gilbert, and
MJ. Jaroszeski, Clinical applications of electrochemotherapy.
Advanced drug delivery reviews, 1999. 35: p. 119-129; Mir, L. M.,
Therapeutic perspectives of in vivo cell electropermeabilization.
Bioelectrochemistry, 2001. 53: p. 1-10; Davalos, R. V., Real Time
Imaging for Molecular Medicine through electrical Impedance
Tomography of Electroporation, in Mechanical Engineering. 2002,
University of California at Berkeley: Berkeley. p. 237). A recent
article summarized the results from clinical trials performed in
five cancer research centers. Basal cell carcinoma (32), malignant
melanoma (142), adenocarcinoma (30) and head and neck squamous cell
carcinoma (87) were treated for a total of 291 tumors (Mir, L. M.,
et al., Effective treatment of cutaneous and subcutaneous malignant
tumours by electrochemotherapy. British Journal of Cancer, 1998.
77(12): p. 2336-2342).
[0015] Electrochemotherapy is a promising minimally invasive
surgical technique to locally ablate tissue and treat tumors
regardless of their histological type with minimal adverse side
effects and a high response rate (Dev, S. B., et al., Medical
Applications of Electroporation. IEEE Transactions on Plasma
Science, 2000. 28(1): p. 206-223; Heller, R., R. Gilbert, and M. J.
Jaroszeski, Clinical applications of electrochemotherapy. Advanced
drug delivery reviews, 1999. 35: p. 119-129). Electrochemotherapy,
which is performed through the insertion of electrodes into the
undesirable tissue, the injection of cytotoxic drugs in the tissue
and the application of reversible electroporation parameters,
benefits from the ease of application of both high temperature
treatment therapies and non-selective chemical therapies and
results in outcomes comparable of both high temperature therapies
and non-selective chemical therapies.
[0016] In addition, because the cell membrane permeabilization
electrical field is not affected by the local blood flow, the
control over the extent of the affected tissue by this mode of
ablation does not depend on the blood flow as in thermal and
non-selective chemical therapies. In designing electroporation
protocols for ablation of tissue with drugs that are incorporated
in the cell and function in the living cells it was important to
employ reversible electroporation; because the drugs can only
function in a living cell. Therefore, in designing protocols for
electrochemotherapy the emphasis was on avoiding irreversible
electroporation. The focus of the entire field of electroporation
for ablation of tissue was on using reversible pulses, while
avoiding irreversible electroporation pulses, that can cause the
incorporation of selective drugs in undesirable tissue to
selectively destroy malignant cells. Electrochemotherapy which
employs reversible electroporation in combination with drugs, is
beneficial due to its selectivity however, a disadvantage is that
by its nature, it requires the combination of chemical agents with
an electrical field and it depends on the successful incorporation
of the chemical agent inside the cell.
[0017] An important concern in the studies of electrochemotherapy
and electrogenetherapy in living tissue is the effect of
electroporation on blood flow. Martin et al., have found that when
reversible electroporation is used for introducing genes into cells
on the blood vessel wall the blood vessels remain intact and their
response to stimuli where indistinguishable from those of control
vessels (Martin, J. B., Young, J. L, Benoit, J. N., Dean, D. A.,
Gene transfer to intact Mesenteric arteries by electroporation,
Journal of vascular research, 2000, Vol 37:372-380). Ivanusa et al
have found using MRI that with certain electroporation pulses,
which appear to be in the irreversible electroporation range, that
the electroporation transiently but significantly reduced tumor
blood flow (Ivanusa, T., Beravs, K., Cemazar, M., Jevtic, V.,
Demsar, F., Sersa, G. MRI macromolecular contrast agents as
indicators of changed tumor blood flow, Radiol. Oncol. 2001; 35(2):
139-47). These findings are very different from those described
here.
[0018] Sersa et al performed studies whose goal was to determine
the effect of electrochemotherapy, reversible electroporation with
bleomycin or cisplatin, on tumor blood flow (Sersa, G., Sentjurc,
M., Ivanusa, T., Beravs, K., Komik, V., Coer, A., Swartz, H. M.,
Cemazar, M. Reduced blood flow and axygenation in SA-1 tumours
after electrochemotherapy with cisplatin, Br. J. Cancer, 2002:
87(9):1047-54) (Sersa, G., Cemazar, M., Miklavcic, D. Tumor blood
flow modifying effects of electrochemotherapy: a potential targeted
mechanism radiol. Oncol 2003: 37(1): 43-8). In the first of the
papers they report reduced blood flow that persisted for several
days when using reversible electroporation with cisplatin. In the
second paper they report complete shut down of blood flow after 24
hours when using reversible electroporation with bleomycin and 50%
reduction in blood flow when using reversible electroporation with
cisplatin.
SUMMARY OF THE INVENTION
[0019] A plurality of electrodes which may comprise a first
electrode and a second electrode are applied to tissue which tissue
is targeted for destruction. The targeted tissue may include cancer
cells. The electrodes are used to send electrical current through
the tissue in a manner which achieves irreversible electroporation
of targeted cells while avoiding irreversible electroporation of
non-targeted cells. Parameters which include voltage, wattage,
duration of pulses sent through the tissue are controlled and may
be monitored to confirm that they are in specific ranges which
avoid thermal damage to surrounding cells. Other parameters such as
electrode size, shape and position may be adjusted to avoid damage
including thermal damage to non-targeted cells while keeping the
temperature at 100.degree. C. or less, or 50.degree. C. or less for
a period of time that avoids thermal damage. The methodology may
use multiple pulses or multiple groups of pulses in order to obtain
a desired result which is the irreversible electroporation of
targeted cells without the destruction of non-targeted cells such
as nerve cells and with no thermal damage to any cells.
Specifically, the parameters which include the voltage, wattage,
duration and number of electrical pulses are also controlled in a
manner so as to maintain the temperature of the tissue below a
level which would destroy cells it being understood that time and
temperature are related such that higher temperatures can be
maintained over shorter time periods without thermal damage.
[0020] An aspect of the invention is that a particular type of cell
(e.g. identified tumor cells or cancer tumor cells) within an area
of tissue may be targeted and destroyed without destroying
non-targeted cells within the same tissue and without thermal
damage.
[0021] These and other objects, advantages, and features of the
invention will become apparent to those persons skilled in the art
upon reading the details of the device, system and methodology as
more fully described below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The invention is best understood from the following detailed
description when read in conjunction with the accompanying
drawings. It is emphasized that, according to common practice, the
various features of the drawings are not to-scale. On the contrary,
the dimensions of the various features are arbitrarily expanded or
reduced for clarity. Included in the drawings are the following
figures:
[0023] FIGS. 1A and 1B illustrate the mesh used for homogenous (1A)
and heterogenous (1B) models.
[0024] FIGS. 2A and 2B show the temperature distribution in the
homogeneous (2A) and heterogenous (2B) models for prostate tissue
with two electrodes.
[0025] FIG. 3 includes four graphs which show temperature changes
where graphs 3A and 3C show the changes with respect to homogeneous
tissue and graphs 3B and 3D show temperature changes with
heterogeneous tissue.
[0026] FIGS. 4A and 4B show the temperature distribution in the
homogeneous (4A) and heterogenous (4B) models for prostate tissue
with two electrodes.
[0027] FIG. 5 includes four graphs which show temperature changes
where graphs 5A and 5C show the changes with respect to homogeneous
tissue and graphs 5B and 5D show temperature changes with
heterogeneous tissue.
[0028] FIGS. 6A and 6B show the temperature distribution in the
homogeneous (6A) and heterogenous (6B) models for prostate tissue
with two electrodes.
[0029] FIG. 7 includes four graphs which show temperature changes
where graphs 7A and 7C show the changes with respect to homogeneous
tissue and graphs 7B and 7D show temperature changes with
heterogeneous tissue.
[0030] FIGS. 8A and 8B illustrate the mesh used for homogenous (8A)
and heterogenous (8B) models.
[0031] FIGS. 9A and 9B show the temperature distribution in the
homogeneous (9A) and heterogenous (9B) models for prostate tissue
with two electrodes.
[0032] FIG. 10 includes four graphs which show temperature changes
where graphs 10A and 10C show the changes with respect to
homogeneous tissue and graphs 10B and 10D show temperature changes
with heterogeneous tissue.
[0033] FIGS. 11A and 11B show the temperature distribution in the
homogeneous (11A) and heterogenous (11B) models for prostate tissue
with two electrodes.
[0034] FIG. 12 includes four graphs which show temperature changes
where graphs 12A and 12C show the changes with respect to
homogeneous tissue and graphs 12B and 12D show temperature changes
with heterogeneous tissue.
DETAILED DESCRIPTION OF THE INVENTION
[0035] Before the present devices, systems, and methods of
treatment and use are described, it is to be understood that this
invention is not limited to particular embodiments described, as
such may, of course, vary. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only, and is not intended to be limiting, since the
scope of the present invention will be limited only by the appended
claims.
[0036] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limits of that range is also specifically disclosed. Each
smaller range between any stated value or intervening value in a
stated range and any other stated or intervening value in that
stated range is encompassed within the invention. The upper and
lower limits of these smaller ranges may independently be included
or excluded in the range, and each range where either, neither or
both limits are included in the smaller ranges is also encompassed
within the invention, subject to any specifically excluded limit in
the stated range. Where the stated range includes one or both of
the limits, ranges excluding either or both of those included
limits are also included in the invention.
[0037] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, some potential and preferred methods and materials are
now described. All publications mentioned herein are incorporated
herein by reference to disclose and describe the methods and/or
materials in connection with which the publications are cited. It
is understood that the present disclosure supercedes any disclosure
of an incorporated publication to the extent there is a
contradiction.
[0038] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "an electrode" includes a plurality of such
electrodes and reference to "the pulse" includes reference to one
or more pulses and equivalents thereof known to those skilled in
the art, and so forth.
[0039] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
Definitions
[0040] The term "reversible electroporation" encompasses
permeabilization of the cell membrane through the application of
electrical pulses across the cell. In "reversible electroporation"
the permeabilization of the cell membrane ceases after the
application of the pulse and the cell membrane permeability reverts
to normal. The cell survives "reversible electroporation." It is
used as a means for introducing chemicals, DNA, or other materials
into cells.
[0041] The term "irreversible electroporation" also encompasses the
permeabilization of the cell membrane through the application of
electrical pulses across the cell. However, in "irreversible
electroporation" the permeabilization of the cell membrane does not
cease after the application of the pulse and the cell membrane
permeability does not revert to normal. The cell does not survive
"irreversible electroporation" and the cell death is caused by the
disruption of the cell membrane and not merely by internal
perturbation of cellular components. Openings in the cell membrane
are created and/or expanded in size resulting in a fatal disruption
in the normal controlled flow of material across the cell membrane.
The cell membrane is highly specialized in its ability to regulate
what leaves and enters the cell. Irreversible electroporation
destroys that ability to regulate in a manner such that the cell
can not compensate and as such the cell dies.
Specific Embodiments
[0042] Models described in the Examples below were created and
tested to demonstrate the importance of investigating heterogeneous
models with NTIRE and to show that NTIRE treatment methods need to
consider the heterogeneous nature of the tissue. Both the model of
the prostate and the breast demonstrated the substantial difference
between homogeneous and heterogeneous cases. Furthermore,
unanticipated information about the effects of electroporation was
also discovered. The impact electroporation has on biological
structures such as nerves, ducts and blood vessels was previously
unknown. This investigation has made clear that nerves can be
preserved in treated tissue because of the insulating effect of
surrounding myelin layers. Additionally, the Examples show that
mammary ducts will also be retained because of myoepithelial cells
and their ability to regenerate. Therefore, heterogeneous models
are not only important to consider in order to generate an accurate
simulation, but also to understand the effects of electroporation
on all included biological structures and to improve clinical
applications.
[0043] A method of targeting cancer cells and subjecting those
cells to irreversible electroporation is disclosed. The method
involves identifying cancer cells which are to be ablated, killed
or in the method of the invention subjected to irreversible
electroporation. These cells are identified in a target area
wherein the target area comprises an identified nerve tissue. The
invention is particularly applicable to killing cancer cells in a
target area where the target area comprises nerve tissue which is
not cancerous. A first electrode and a second electrode are
positioned such that the target area is positioned between the
first and second electrodes. Multiple electrodes may be used.
Electrical pulses are then applied between the first and second
electrodes in sufficient amount to obtain irreversible
electroporation of cancer cells in the target area. The voltage,
wattage and duration of the electrical pulses are maintained within
a distinct range or ranges which avoid damage to nerve tissue in
the target area and at the same time avoid thermal damage to cells
in the target area and the surrounding area while making it
possible to carry out irreversible electroporation of the cancer
cells.
[0044] The method used can include calculating a voltage, wattage
and duration of electrical pulses to be applied in a manner so as
to avoid damage to nerve tissue in the target area and avoid
thermal damage to cells in the target area. It is also possible to
determine the size, shape and relative position of the first
electrode and second electrode in a manner so as to avoid damage to
nerve tissue in the target area and avoid thermal damage to cells
in the target area while subjecting the cancer cells to
irreversible electroporation.
[0045] In one aspect of the invention there is disclosed a method
of treating cancer which comprises identifying nerve tissue in a
grouping of biological cells in a target area of a mammal and
determining cells in the grouping as being cancer cells. Voltage is
applied across the targeted tissue. The method can include
continuously detecting a ratio of electric current through the
targeted tissue to voltage across the targeted tissue as an
indication of degree of electroporation of cells in the targeted
tissue. With this information it is possible to adjust a determined
magnitude of the applied voltage in accordance with changes in
detected magnitude of the current-to-voltage ratio to achieve
irreversible electroporation of the cancer cells. With this
information it is possible to apply the adjusted voltage to a new
target tissue at a point in time significantly after the initial
steps have been carried out. Specifically, one may carry out
initial testing in order to identify cancer cells within the target
area and then continuously detect the ratio of electric current
through the targeted tissue to voltage across the targeted tissue
as an indication of a degree of electroporation of the cancer cells
in the targeted tissue. After this is carried out it is possible to
adjust the magnitude of the applied voltage in accordance with the
changes detecting in the current-to-voltage ratio to achieve
irreversible electroporation of the cancer cells. Once this has
been achieved it may not be necessary to repeat these processes
each time when applying the adjusted voltage to a new target tissue
at a point in time after the other steps have been carried out and
the proper parameters such as voltage, wattage, duration and number
of electrical pulses has been determined.
EXAMPLES
[0046] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the present invention, and are
not intended to limit the scope of what the inventors regard as
their invention nor are they intended to represent that the
experiments below are all or the only experiments performed.
Efforts have been made to ensure accuracy with respect to numbers
used (e.g. amounts, temperature, etc.) but some experimental errors
and deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Centigrade, and
pressure is at or near atmospheric.
Example 1
[0047] Models were generated using numerical analysis executed by a
commercially available program Comsol Multiphysics (version 3.4).
This initial study utilized 2-dimensional models because these were
sufficient to demonstrate the significant difference between
homogeneous and heterogeneous models. Two equations were solved
simultaneously in Comsol. The first of which was the Laplace
equation for potential distribution associated with an electric
pulse.
-.gradient.d(.sigma..gradient.V-J.sup.e)=dQ.sub.i (1)
[0048] Where .sigma. is electrical conductivity, V is voltage,
J.sup.e is external current density, d is thickness and Q.sub.j is
the current source.
[0049] For all boundaries the external current density and the
current source were set to zero, and thickness was set to one. The
electric field was solved in order to illustrate the electrical
effects of the electroporation in the particular tissue as listed
in Tables 1 and 2. The electric field was solved for in the AC/DC
Conductive Media module using a static analysis. Each structure was
designated a different electrical conductivity, which corresponded
to its representative biological entity. The respective values are
shown in Tables I and II.
TABLE-US-00001 TABLE I Values of electrical conductivity for the
prostate cancer Conductive Media model Electrical Conductivity
Structure (.sigma.) [S/m] Reference Prostate tissue 0.42427
Andreuccetii, et al. Myelin 3.45E-6 Villapecellin- Cid, et al. Axon
1.44 B. J. Roth et al.
TABLE-US-00002 TABLE II Values of electrical conductivity for the
breast cancer Conductive Media model Electrical Conductivity
Structure (.sigma.) [S/m] Reference Fatty breast tissue 0.024192
Andreuccetii, et al. Breast myoepithelial cell 10.sup.-7 Hassan N
et al. Breast gland 0.52427 Andreuccetii, et al. Breast tumor 2.309
A. M. Campbell et al. Blood 0.30709 Andreuccetii, et al.
[0050] The thermal effects of electroporation were determined from
the solution of the Pennes bioheat equation, which was solved
simultaneously as the electrical potential equation. The Pennes
bioheat equation took the following form:
.gradient. ( k .gradient. T ) + .rho. b w b c b ( T a - T ) + q '''
= .rho. c p .differential. T .differential. t ( 2 )
##EQU00001##
[0051] Where k is the thermal conductivity, T is the temperature,
wb is the blood perfusion, cb is the heat capacity of blood, Ta is
the arterial temperature, .rho. is the tissue density, cp is the
tissue heat capacity and q'''=Q.sub.met+Q.sub.ext. Where Qmet is
the metabolic heat generation, which is assumed to be negligible
here. Also, Q.sub.ext=.sigma.|.gradient..PHI.|.sup.2, which
accounts for Joule heating, where .0. is electrical potential and
.sigma. is electrical conductivity of the tissue.
[0052] Heat transfer in living organisms is more complex than other
circumstances. Metabolism and blood flow are important in addition
to conduction, convection, radiation and evaporation. For this
reason, the bioheat equation, which includes terms that account for
blood flow and metabolism, was used. In addition, the bioheat
equation solves for the temperature and ascertains the impact of
the Joule effect. The result of the bioheat equation determines if
the tumor was being treated also by resistive heating, or only
irreversible electroporation.
[0053] The values utilized in the bioheat equation for the
corresponding structures in the prostate and the breast are shown
in Tables III, IV and V.
TABLE-US-00003 TABLE III Values for the prostate cancer Bioheat
model Thermal Conductivity Specific Heat Density Structure (k)
[W/mk] (c) [J/kgK] (.rho.) [kg/m.sup.3] Reference Prostate tissue
0.561 3600 1045 Yusheng Feng et al.[21] Nerve 0.503 3600 1043 S.
DeMarco (axon and myelin) et al.
TABLE-US-00004 TABLE IV Values for the breast cancer Bioheat model
Thermal Conductivity Specific Heat Density Structure (k) [W/mK] (c)
[J/kgK] (.rho.) [kg/m.sup.3] Reference Fatty breast 0.25 2522.5 900
Howorka K. et tissue al.; M. P. Robinson et al.; F. Fidanza Breast
gland 0.41 3492 1030 F. O. Dosekun; M. A. Kolka et al.; C. R.
Moreira et al. Breast tumor 0.48 2926 1186 Kwok et al.; P. Prakash
et al.; B. J. Roth et al.
TABLE-US-00005 TABLE V Values for human blood flow in the prostate
and breast cancer Bioheat models Perfusion Thermal Specific Rate
Conductivity Heat (c) Density Structure [1/s] (k) [W/mK] [J/kgK]
(.rho.) [kg/m.sup.3] Reference Blood 0.002 0.391 3640 1000 L. Sun
et al.; J. Valvano et al.; S. Belov; Elad Maor et al.
Models
[0054] Five models were utilized to demonstrate the differences
between heterogeneous and homogeneous tissues treated with
electroporation with an application that is typical to the current
implementation of the method in animal models (B. Al-Sakere et al.,
"Tumor Ablation with Irreversible Electroporation," PLoS ONE, vol.
2, 2007, p. el 135; R. V. Davalos, B. Rubinsky, and L. M. Mir,
"Theoretical analysis of the thermal effects during in vivo tissue
electroporation," Bioelectrochemistry, vol. 61, October 2003, pp.
99-107). The electrodes were taken to have a diameter of one mm.
The electrodes were placed at a distance of one cm, center to
center. For boundary conditions, in each case a uniform voltage was
imposed on each electrode and a voltage difference of 2000 V was
imposed between each electrode.
[0055] Case 1a: (2 cm.times.2 cm) Prostate tissue with two
electrodes separated by 1 cm
[0056] Case 1b: A nerve (axon with myelin sheath) in the center of
(2 cm.times.2 cm) prostate tissue with two electrodes separated by
1 cm. The nerve is modeled as a structure of a circular axon
surrounded by a uniform layer of myelin. The axon radius was 0.1 mm
(A. Takenaka et al., "Variation in course of cavernous nerve with
special reference to details of topographic relationships near
prostatic apex: Histologic study using male cadavers," Urology,
vol. 65, January 2005, pp. 136-142) and the thickness of the myelin
surrounding it was 0.02 mm (J. Schroder, "Altered ratio between
axon diameter and myelin sheath thickness in regenerated nerve
fibers," Brain Research, vol. 45, October 1972, pp. 49-65). The
axon and myelin structure was centered within the square section of
prostate tissue.
[0057] Case 1c: A blood vessel in the center of (2 cm.times.2 cm)
prostate tissue with two electrodes separated by 1 cm. The blood
vessel was 5 E-5 m in radius and was placed in the center of a
square section of prostate tissue.
[0058] Case 2: (2 cm.times.2 cm) fatty breast tissue with two
electrodes separated by 1 cm
[0059] Case 2b: A duct in the center of (2 cm.times.2 cm) fatty
breast tissue with two electrodes separated by 1 cm. We used in the
model a gland surrounded by myoepithelial. The breast gland was 0.7
mm in radius (J. Rusby et al., "Breast duct anatomy in the human
nipple: three-dimensional patterns and clinical implications,"
Breast Cancer Research and Treatment, vol. 106, January 2007, pp.
171-9) and the surrounding layer of myoepithelial cells were 0.13
mm in thickness. The gland and myoepithelial cells were centered
within a square section of breast tissue.
[0060] The model includes a rectangular cross section of tissue (4
cm2 for the prostate and the breast), large enough to account for
fringe effects of the electric field. Electrodes conductive only at
the tips are utilized in vivo, so they were represented as points
in the models. All models were evaluated at a voltage potential
difference between the electrodes of 2000V. Each model simulated a
single voltage pulse of length 0.1 ms, and the temperature
evaluated at time steps of 0.1 E-4 s.
[0061] There were two sets of boundary conditions generated; one
set for the Laplace equation and another for the Pennes bioheat
equation. For the Laplace equation, the edges of the tissue sample
were treated as electrically insulating.
.differential. .0. .differential. n = 0 ( 3 ) ##EQU00002##
[0062] Where .0. is potential. The remaining structures were
prescribed continuity boundary conditions.
n(J.sub.1-J.sub.2)=0 (4)
[0063] Where n is the normal vector and J is the current density.
For the bioheat equation, the edges of the tissue were set to body
temperature.
T=310.15K (5)
[0064] The remaining structures were prescribed continuity boundary
conditions.
Results and Discussion
[0065] FIGS. 1A and 1B illustrate the mesh that was used for the
homogeneous and the heterogeneous models. It is important to note
that the mesh becomes more defined around the boundaries of the
electrodes. This ensures accurate results in the vicinity of the
electrodes and captures even the smallest temperature difference on
the micron scale. This is also true of the mesh used for the
heterogeneous model. The mesh is extra fine around the boundaries
of the inhomogeneity as well as the electrodes.
[0066] FIGS. 2A and 2B show the temperature distribution in the
homogeneous and heterogeneous models of prostate tissue with two
electrodes of voltage potential difference 2000V at the end of the
application of a single pulse. The figures plot isothermal lines
and the details of the temperature distribution can be found in
FIGS. 3A, 3B, 3C and 3D. The elevated temperature reaches a maximum
of 313.431K in the homogeneous case. However, this is only within
nanometers of the electrode. Nevertheless, even the tissue near the
electrode doesn't experience thermal damage. In fact, no tissue in
the homogeneous case experiences thermal damage. This is because a
temperature of 360.15K represents the upper limit before thermal
damage occurs. The highest temperature occurs on either sides of
the electrode, as can be seen by FIG. 3A.
[0067] The heterogeneous plot in FIG. 2B includes a nerve (axon and
myelin) within the prostate tissue. The axon radius was 0.1 mm (A.
Takenaka et al., "Variation in course of cavernous nerve with
special reference to details of topographic relationships near
prostatic apex: Histologic study using male cadavers," Urology,
vol. 65, January 2005, pp. 136-142) and the thickness of the myelin
surrounding it was 0.02 mm (J. Schroder, "Altered ratio between
axon diameter and myelin sheath thickness in regenerated nerve
fibers," Brain Research, vol. 45, October 1972, pp. 49-65). The
axon and myelin structure was centered within the square section of
prostate tissue. The difference between the heterogeneous and
homogeneous cases can be seen in the temperature range. The
homogeneous model ranges from nearly body temperature, 310.234K, to
313.431K. However, the heterogeneous model has a slightly lower
temperature throughout, ranging from 310.23K to 313.278K. From the
maximum temperature reached in both the heterogeneous cases, it is
apparent that it does not experience thermal damage either.
Therefore, the prostate tissue in these models only experiences
electroporation. It is interesting to note that the main difference
between the homogeneous and heterogeneous cases is the dip in the
temperature at the center of the plot in the heterogeneous case,
where the nerve is located. This dip does not exist in the
homogeneous graphs (FIGS. 3A and 3C). The difference in the
temperature distribution between these two plots shows the
importance of taking heterogeneous models into account for an
accurate portrayal.
[0068] The plot in FIGS. 4A and 4B displays lines of constant
electrical field in prostate tissue.
[0069] The detailed field distribution can be found in FIGS. 5A,
5B, 5C and 5D.
[0070] The maximum electric field occurs at the electrodes and
takes a value of
6.964 E 5 v m . ##EQU00003##
The remaining tissue in the rectangular sample above and below the
electrodes receives a lessening effect, with the electric field
forced to reach nearly
0 v m ##EQU00004##
at the edge of the tissue sample. However, it is important to note,
in the location between the electrodes, where the nerve would be in
the heterogeneous model, that the electric field does not quite
reach zero, which is the desired effect. This can be seen in the
plot of the electric field along a vertical cross section of the
homogeneous model (FIG. 5A). It only reaches a minimum of
1.15 E 5 v m . ##EQU00005##
[0071] The electric field in the heterogeneous prostate (FIG. 4B)
is exceptionally different than in the homogeneous prostate (FIG.
4A).
[0072] The maximum electric field is
1.853 E 6 v m , ##EQU00006##
which is more than in the homogeneous model. In the heterogeneous
model, the myelin receives the absolute highest levels of electric
field in the entire sample. The electrodes themselves have
substantially different readings. At
1.7 E 6 v m , ##EQU00007##
the electric field in the myelin is almost a magnitude more than
the maximum in the homogeneous model. The electric field elsewhere
is low, beyond the immediate vicinity of the electrodes. The plots
(FIGS. 5B and 5D) also show that the axon receives the lowest
levels of electric field, reaching zero. This implies that the
myelin insulates the axon from the effect of the electric field.
Because axons are able to remyelinate themselves (W. F. Blakemore,
"Remyelination by Schwann cells of axons demyelinated by
intraspinal injection of 6-aminonicotinamide in the rat," Journal
of Neurocytology, vol. 4, December 1975, pp. 745-757), these
results suggest that the nerve structure should be able to fully
recover even if the myelin is damaged. This plot demonstrates the
importance of heterogeneous models to understand the effect of
irreversible electroporation on the nervous system.
[0073] These results explain the outcome in the trials utilizing
NTIRE to treat prostate cancer (G. Onik, P. Mikus, and B. Rubinsky,
"Irreversible electroporation: implications for prostate ablation,"
Technology in cancer research & treatment, vol. 6, August 2007,
pp. 295-300). Nerves surrounding the prostate remained unharmed by
the effects of electroporation. It is now understood why the nerves
near the prostate survived. The myelin insulates the axons from the
electric field. Even if damaged, the axons remyelinate via Schwann
cells and all neurological functionality is retained.
Example 2
[0074] The methodology described above in Example 1 was used to
analyze the prostate with a blood vessel which had a relatively
small radius (e.g. less than 5 mm) which was placed in the center
of a square section of prostate tissue. FIGS. 6A, 6B, 7A, 7B, 7C
and 7D show the temperature distributions in the same manner as
FIGS. 2A, 2B, 3A, 3B, 3C and 3D. The maximum temperature reached
was 313.584K, while it was 313.431K for the homogeneous case. The
blood vessel model has a temperature distribution between 310.238
and 313.584K. Because the maximum temperature reached is below
360.15K, the entire samples stays well below any temperature
necessary for thermal damage. This means that absolutely none of
the tissue receives any thermal damage. However, it is important to
note that an elevated temperature does exist, but only in the
immediate vicinity of the electrodes (FIG. 7A).
[0075] The electrical fields in this case are depicted in FIGS. 7
and 8 in the same manner as FIGS. 4 and 5.
[0076] The maximum electric field of the blood vessel in the
prostate (FIG. 7) is lower than the homogeneous case. The
homogeneous prostate reached
6.964 E 5 v m , ##EQU00008##
while the prostate with a blood vessel reached
6.87 E 5 v m . ##EQU00009##
Additionally, there is a slight rise in the electric field in the
vicinity of the blood vessel. This occurs because the electrical
conductivity of the blood vessel is slightly lower than that of
prostate tissue. Nevertheless it receives a low level of electric
field, indicating that during clinical trials, blood vessels in the
vicinity of a tumor would be unharmed by the effects of the
electroporation.
Example 3
[0077] The methodology of Example 1 above was used to investigate
the effects of electroporation on breast tissue. The model included
a section of fatty breast tissue in the homogeneous model. In the
heterogeneous model a gland surrounded by myoepithelial cells was
included in the breast tissue (FIGS. 8A and 8B). The breast gland
was 0.7 mm in radius (J. Rusby et al., "Breast duct anatomy in the
human nipple: three-dimensional patterns and clinical
implications," Breast Cancer Research and Treatment, vol. 106,
January 2007, pp. 171-9.) and the surrounding layer of
myoepithelial cells were 0.13 mm in thickness. The gland and
myoepithelial cells were centered within a square section of breast
tissue.
[0078] FIGS. 9 and 10 are presented in the same manner as FIGS. 2
and 3 and FIGS. 11 and 12 in the same manner as FIGS. 4 and 5. FIG.
10 shows that in the vertical plane the highest temperature reached
in the homogeneous model is 310.687K, only 0.537 degrees higher
than body temperature. In the heterogeneous case, however, the
maximum temperature, 310.466K, is even lower. There is no portion
of tissue in the entire sample that reaches temperature levels
required for thermal damage. The horizontal cross section yields a
vast difference between the temperature distribution in the
homogeneous and heterogeneous cases (FIG. 10). The homogeneous
model reaches a maximum at the location between the electrodes, but
the heterogeneous model dips to a minimum.
[0079] In the homogeneous model the maximum electric field
reaches
9.307 E 5 v m . ##EQU00010##
The maximum electric field in the heterogeneous model,
1.935 E 6 v m , ##EQU00011##
is slightly higher. However, the electric field between the
electrodes is very different.
[0080] In the heterogeneous model the electric field reaches zero
at the center of the gland (FIG. 12). However, in the homogeneous
model, the electric field only goes as low as
2.9 E 5 v m . ##EQU00012##
Additionally, the homogeneous model, the highest electric field
occurs at the electrodes. But in the heterogeneous model, the
highest electric field is within the myoepithelial cells and is
followed distantly by the electric field near the electrodes. This,
however, does not pose a threat to the physiological function of
the ducts because myoepithelial cells are known to regenerate (S.
TAKAHASHI et al., "Regeneration of myoepithelial cells in rat
submandibular glands after yttrium aluminium garnett laser
irradiation," International Journal of Experimental Pathology, vol.
78, 1997, pp. 91-99).
[0081] The preceding merely illustrates the principles of the
invention. It will be appreciated that those skilled in the art
will be able to devise various arrangements which, although not
explicitly described or shown herein, embody the principles of the
invention and are included within its spirit and scope.
Furthermore, all examples and conditional language recited herein
are principally intended to aid the reader in understanding the
principles of the invention and the concepts contributed by the
inventors to furthering the art, and are to be construed as being
without limitation to such specifically recited examples and
conditions. Moreover, all statements herein reciting principles,
aspects, and embodiments of the invention as well as specific
examples thereof, are intended to encompass both structural and
functional equivalents thereof. Additionally, it is intended that
such equivalents include both currently known equivalents and
equivalents developed in the future, i.e., any elements developed
that perform the same function, regardless of structure. The scope
of the present invention, therefore, is not intended to be limited
to the exemplary embodiments shown and described herein. Rather,
the scope and spirit of present invention is embodied by the
appended claims.
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References