U.S. patent application number 12/510011 was filed with the patent office on 2009-11-26 for methods and systems for treating bph using electroporation.
Invention is credited to Paul Mikus, Gary Onik, Boris Rubinsky.
Application Number | 20090292342 12/510011 |
Document ID | / |
Family ID | 37568577 |
Filed Date | 2009-11-26 |
United States Patent
Application |
20090292342 |
Kind Code |
A1 |
Rubinsky; Boris ; et
al. |
November 26, 2009 |
Methods and Systems for Treating BPH Using Electroporation
Abstract
A system for treating benign prostate hyperplasia (BPH) of a
prostate. At least first and second mono-polar electrodes are
configured to be introduced at or near a BPH tissue site of the
prostate gland of the patient. A voltage pulse generator is coupled
to the first and second mono-polar electrodes. The voltage pulse
generator is configured to apply sufficient electrical pulses
between the first and second mono-polar electrodes to induce
electroporation of cells in the BPH tissue site, to create necrosis
of cells of the BPH tissue site, but insufficient to create a
thermal damaging effect to a majority of the BPH tissue site.
Inventors: |
Rubinsky; Boris; (Albany,
CA) ; Onik; Gary; (Orlando, FL) ; Mikus;
Paul; (Coto de Caza, CA) |
Correspondence
Address: |
AFS / ANGIODYNAMICS
666 THIRD AVENUE, FLOOR 10
NEW YORK
NY
10017
US
|
Family ID: |
37568577 |
Appl. No.: |
12/510011 |
Filed: |
July 27, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11166974 |
Jun 24, 2005 |
|
|
|
12510011 |
|
|
|
|
Current U.S.
Class: |
607/72 |
Current CPC
Class: |
A61N 1/327 20130101;
A61N 1/0412 20130101; A61N 1/0476 20130101; A61B 2018/00613
20130101 |
Class at
Publication: |
607/72 |
International
Class: |
A61N 1/04 20060101
A61N001/04 |
Claims
1. A system for treating benign prostate hyperplasia (BPH) of a
prostate, comprising: at least two electrodes configured to be
introduced near a BPH tissue site of a patient; a voltage pulse
generator coupled to the electrodes and configured to apply a
plurality of electrical pulses through the electrodes in an amount
sufficient to produce irreversible electroporation of cells in the
BPH tissue site to create necrosis of cells of the BPH tissue site
but insufficient to create thermal damage to a majority of the BPH
tissue site; and a switching device coupled to the electrodes and
the voltage pulse generator, and configured to activate the
electrodes in a selected pattern.
2. The system of claim 1, wherein the switching device is capable
of individually controlling each of the electrodes.
3. The system of claim 1, further comprising a monitoring electrode
configured to measure a test voltage delivered to cells in the BPH
tissue site.
4. The system of claim 1, wherein the voltage pulse generator is
adapted to generate a test voltage for application to cells of the
BPH tissue site through at least one of the electrodes.
5. The system of claim 1, wherein the electrodes include at least
one bipolar electrode.
6. The system of claim 1, wherein the electroporation is performed
in a controlled manner with monitoring of electrical impedance.
7. The system of claim 1, wherein the electroporation is performed
in a controlled manner with a proper selection of voltage
magnitude, voltage application time or both.
8. The system of claim 1, wherein the voltage pulse generator is
configured to generate each pulse having a duration of about 5
microseconds to about 110 microseconds.
9. The system of claim 8, wherein the voltage pulse generator is
configured to apply a set of about 1 to 15 pulses.
10. The system of claim 1, wherein the voltage pulse generator is
configured to produce a voltage gradient at the BPH tissue site in
a range of from about 50 volt/cm to about 8000 volt/cm.
11. The system of claim 1, wherein the voltage pulse generator
monitors a temperature of the BPH tissue site and adjusts the
pulses to maintain a temperature of 50 degrees Celsius or less at
the BPH tissue site based on the monitoring.
12. A system for treating benign prostate hyperplasia (BPH) of a
prostate, comprising: at least two electrodes configured to be
introduced near a BPH tissue site of a patient; a voltage pulse
generator coupled to the electrodes and configured to apply a
plurality of electrical pulses through the electrodes in an amount
sufficient to produce irreversible electroporation of cells in the
BPH tissue site to create necrosis of cells of the BPH tissue site
but insufficient to create thermal damage to a majority of the BPH
tissue site; a switching device coupled to the electrodes and the
voltage pulse generator; a controller containing software to
control the switching device, the controller and the switching
device together being configured to activate the electrodes in a
selected pattern; and a user interface coupled to the controller
for inputting the selected pattern.
13. The system of claim 1, wherein the switching device is capable
of individually controlling each of the electrodes.
14. The system of claim 1, further comprising a monitoring
electrode configured to measure a test voltage delivered to cells
in the BPH tissue site.
15. The system of claim 1, wherein the voltage pulse generator is
adapted to generate a test voltage for application to cells of the
BPH tissue site through at least one of the electrodes.
16. The system of claim 1, wherein the electrodes include at least
one bipolar electrode.
17. The system of claim 1, wherein the electroporation is performed
in a controlled manner with monitoring of electrical impedance.
18. The system of claim 1, wherein the electroporation is performed
in a controlled manner with a proper selection of voltage
magnitude, voltage application time or both.
19. The system of claim 1, wherein the voltage pulse generator is
configured to generate each pulse having a duration of about 5
microseconds to about 110 microseconds.
20. The system of claim 19, wherein the voltage pulse generator is
configured to apply a set of about 1 to 15 pulses.
21. The system of claim 1, wherein the voltage pulse generator is
configured to produce a voltage gradient at the BPH tissue site in
a range of from about 50 volt/cm to about 8000 volt/cm.
22. The system of claim 1, wherein the voltage pulse generator
monitors a temperature of the BPH tissue site and adjusts the
pulses to maintain a temperature of 50 degrees Celsius or less at
the BPH tissue site based on the monitoring.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 11/166,974, filed Jun. 24, 2005, which is
fully incorporated herein by reference. This application is also
related to U.S. Ser. Nos. 11/165,881, 11/165,908 and 11/165,961 all
of which were filed on Jun. 24, 2005 and all of which applications
are fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to electroporation, and
more particularly to systems and methods for treating BPH tissue
sites of a patient using electroporation.
DESCRIPTION OF THE RELATED ART
[0003] 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). 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. (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).
[0004] 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).
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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).
[0009] 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)).
[0010] 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
M. J. 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, malignant
melanoma, adenocarcinoma and head and neck squamous cell carcinoma
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).
[0011] 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 dugs 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.
[0012] Irreversible electroporation, the application of electrical
pulses which induce irreversible electroporation in cells is also
considered for tissue ablation (Davalos, R. V., Real Time Imaging
for Molecular Medicine through electrical Impedance Tomography of
Electroporation, in Mechanical Engineering. 2002, PhD Thesis,
University of California at Berkeley: Berkeley, Davalos, R., L.
Mir, Rubinsky B., "Tissue ablation with irreversible
electroporation" in print February 2005 Annals of Biomedical Eng,).
Irreversible electroporation has the potential for becoming and
important minimally invasive surgical technique. However, when used
deep in the body, as opposed to the outer surface or in the
vicinity of the outer surface of the body, it has a drawback that
is typical to all minimally invasive surgical techniques that occur
deep in the body, it cannot be closely monitored and controlled. In
order for irreversible electroporation to become a routine
technique in tissue ablation, it needs to be controllable with
immediate feedback. This is necessary to ensure that the targeted
areas have been appropriately treated without affecting the
surrounding tissue. This invention provides a solution to this
problem in the form of medical imaging.
[0013] Medical imaging has become an essential aspect of minimally
and non-invasive surgery since it was introduced in the early 1980s
by the group of Onik and Rubinsky (G. Onik, C. Cooper, H. I.
Goldenberg, A. A. Moss, B. Rubinsky, and M. Christianson,
"Ultrasonic Characteristics of Frozen Liver," Cryobiology, 21, pp.
321-328, 1984, J. C. Gilbert, G. M. Onik, W. Haddick, and B.
Rubinsky, "The Use of Ultrasound Imaging for Monitoring
Cryosurgery," Proceedings 6th Annual Conference, IEEE Engineering
in Medicine and Biology, 107-112, 1984 G. Onik, J. Gilbert, W. K.
Haddick, R. A. Filly, P. W. Collen, B. Rubinsky, and L. Farrel,
"Sonographic Monitoring of Hepatic Cryosurgery, Experimental Animal
Model," American J. of Roentgenology, May 1985, pp. 1043-1047.)
Medical imaging involves the production of a map of various
physical properties of tissue, which the imaging technique uses to
generate a distribution. For example, in using x-rays a map of the
x-ray absorption characteristics of various tissues is produced, in
ultrasound a map of the pressure wave reflection characteristics of
the tissue is produced, in magnetic resonance imaging a map of
proton density is produced, in light imaging a map of either photon
scattering or absorption characteristics of tissue is produced, in
electrical impedance tomography or induction impedance tomography
or microwave tomography a map of electrical impedance is
produced.
[0014] Minimally invasive surgery involves causing desirable
changes in tissue, by minimally invasive means. Often minimally
invasive surgery is used for the ablation of certain undesirable
tissues by various means. For instance in cryosurgery the
undesirable tissue is frozen, in radio-frequency ablation, focused
ultrasound, electrical and micro-waves hyperthermia tissue is
heated, in alcohol ablation proteins are denaturized, in laser
ablation photons are delivered to elevate the energy of electrons.
In order for imaging to detect and monitor the effects of minimally
invasive surgery, these should produce changes in the physical
properties that the imaging technique monitors.
[0015] The formation of nanopores in the cell membrane has the
effect of changing the electrical impedance properties of the cell
(Huang, Y, Rubinsky, B., "Micro-electroporation: improving the
efficiency and understanding of electrical permeabilization of
cells" Biomedical Microdevices, Vo 3, 145-150, 2000. (Discussed in
"Nature Biotechnology" Vol 18. pp 368, April 2000), B. Rubinsky, Y
Huang. "Controlled electroporation and mass transfer across cell
membranes U.S. Pat. No. 6,300,108, Oct. 9, 2001).
[0016] Thereafter, electrical impedance tomography was developed,
which is an imaging technique that maps the electrical properties
of tissue. This concept was proven with experimental and analytical
studies (Davalos, R. V., Rubinsky, B., Otten, D. M., "A feasibility
study for electrical impedance tomography as a means to monitor
tissue electroporation in molecular medicine" IEEE Trans of
Biomedical Engineering. Vol. 49, No. 4 pp 400-404, 2002, B.
Rubinsky, Y. Huang. "Electrical Impedance Tomography to control
electroporation" U.S. Pat. No. 6,387,671, May 14, 2002.)
[0017] There is a need for improved systems and methods for
treating BPH tissue sites using electroporation.
SUMMARY OF THE INVENTION
[0018] Accordingly, an object of the present invention is to
provide improved systems and methods for treating BPH tissue sites
using electroporation.
[0019] Another object of the present invention is to provide
systems and method for treating BPH tissue sites using
electroporation using sufficient electrical pulses to induce
electroporation of cells in the BPH tissue site, without creating a
thermal damage effect to a majority of the BPH tissue site.
[0020] Yet another object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation with real time monitoring.
[0021] A further object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation where the electroporation is performed in a
controlled manner with monitoring of electrical impedance.
[0022] Still a further object of the present invention is to
provide systems and methods for treating BPH tissue sites using
electroporation that is performed in a controlled manner, with
controlled intensity and duration of voltage.
[0023] Another object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation that is performed in a controlled manner, with a
proper selection of voltage magnitude.
[0024] Yet another object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation that is performed in a controlled manner, with a
proper selection of voltage application time.
[0025] A further object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation, and a monitoring electrode configured to measure a
test voltage delivered to cells in the BPH tissue site and remote
sites such as the rectum and the urethra.
[0026] Still a further object of the present invention is to
provide systems and methods for treating BPH tissue sites using
electroporation that is performed in a controlled manner to provide
for controlled pore formation in cell membranes.
[0027] Still another object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation that is performed in a controlled manner to create
a tissue effect in the cells at the BPH tissue site while
preserving surrounding tissue.
[0028] Another object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation, and detecting an onset of electroporation of cells
at the BPH tissue site.
[0029] Yet another object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation where the electroporation is performed in a manner
for modification and control of mass transfer across cell
membranes.
[0030] A further object of the present invention is to provide
systems and methods for treating BPH tissue sites using
electroporation, and an array of electrodes that creates a boundary
around the BPH tissue site to produce a volumetric cell necrosis
region.
[0031] These and other objects of the present invention are
achieved in, a system for treating benign prostate hyperplasia
(BPH) of a prostate. At least first and second mono-polar
electrodes are configured to be introduced at or near a BPH tissue
site of the prostate gland of the patient. A voltage pulse
generator is coupled to the first and second mono-polar electrodes.
The voltage pulse generator is configured to apply sufficient
electrical pulses between the first and second mono-polar
electrodes to induce electroporation of cells in the BPH tissue
site, to create necrosis of cells of the BPH tissue site, but
insufficient to create a thermal damaging effect to a majority of
the BPH tissue site.
[0032] In another embodiment of the present invention, a system for
treating BPH of a prostate is provided. A bipolar electrode is
configured to be introduced at or near a BPH tissue site of the
prostate gland of the patient. A voltage pulse generator is coupled
to the bipolar electrode. The voltage pulse generator is configured
to apply sufficient electrical pulses to the bipolar electrode to
induce electroporation of cells in the BPH tissue site, to create
necrosis of cells of the BPH tissue site, but insufficient to
create a thermal damaging effect to a majority of the BPH tissue
site.
[0033] In another embodiment of the present invention, a method is
provided for treating BPH of a prostate. At least first and second
mono-polar electrodes are introduced to a BPH tissue site of a
patient. The at least first and second mono-polar electrodes are
positioned at or near the BPH tissue site. An electric field is
applied in a controlled manner to the BPH tissue site. The electric
field is sufficient to produce electroporation of cells at the BPH
tissue site, and below an amount that causes thermal damage to a
majority of the BPH tissue site.
[0034] In another embodiment of the present invention, a method is
provided for treating BPH of a prostate. A bipolar electrode is
introduced to a BPH tissue site of a patient. The bipolar electrode
is positioned at or near the BPH tissue site. An electric field is
applied in a controlled manner to the BPH tissue site. The electric
field is sufficient to produce electroporation of cells at the BPH
tissue site, and below an amount that causes thermal damage to a
majority of the BPH tissue site.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 illustrates a schematic diagram for one embodiment of
a electroporation system of the present invention.
[0036] FIG. 2(a) illustrates an embodiment of the present invention
with two mono-polar electrodes that can be utilized for
electroporation with the FIG. 1 system.
[0037] FIG. 2(b) illustrates an embodiment of the present invention
with three mono-polar electrodes that can be utilized for
electroporation with the FIG. 1 system.
[0038] FIG. 2(c) illustrates an embodiment of the present invention
with a single bi-polar electrode that can be utilized for
electroporation with the FIG. 1 system.
[0039] FIG. 2(d) illustrates an embodiment of the present invention
with an array of electrodes coupled to a template that can be
utilized for electroporation with the FIG. 1 system.
[0040] FIG. 3 illustrates one embodiment of the present invention
with an array of electrodes positioned around a BPH tissue site,
creating a boundary around the BPH tissue site to produce a
volumetric cell necrosis region.
DETAILED DESCRIPTION
Definitions
[0041] The term "reversible electroporation" encompasses
permeabilization of a 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 or at least to a level such that the cell is viable.
Thus, the cell survives "reversible electroporation." It may be
used as a means for introducing chemicals, DNA, or other materials
into cells.
[0042] The term "irreversible electroporation" also encompasses the
permeabilization of a 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 and as such cell is not
viable. Thus, 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.
[0043] "Ultrasound" is a method used to image tissue in which
pressure waves are sent into the tissue using a piezoelectric
crystal. The resulting returning waves caused by tissue reflection
are transformed into an image.
[0044] "MRI" is an imaging modality that uses the perturbation of
hydrogen molecules caused by a radio pulse to create an image.
[0045] "CT" is an imaging modality that uses the attenuation of an
x-ray beam to create an image.
[0046] "Light imaging" is an imaging method in which
electromagnetic waves with frequencies in the range of visible to
far infrared are send into tissue and the tissue's reflection
and/or absorption characteristics are reconstructed.
[0047] "Electrical impedance tomography" is an imaging technique in
which a tissue's electrical impedance characteristics are
reconstructed by applying a current across the tissue and measuring
electrical currents and potentials
[0048] In accordance with the present invention specific imaging
technologies used in the field of medicine are used to create
images of tissue affected by electroporation pulses. The images are
created during the process of carrying out irreversible
electroporation and are used to focus the electroporation on tissue
to be ablated and to avoid ablating tissue such as nerves. The
process of the invention may be carried out by placing electrodes,
such as a needle electrode in the imaging path of an imaging
device. When the electrodes are activated the image device creates
an image of tissue being subjected to electroporation. The
effectiveness and extent of the electroporation over a given area
of tissue can be determined in real time using the imaging
technology.
[0049] Reversible electroporation requires electrical parameters in
a precise range of values that induce only reversible
electroporation. To accomplish this precise and relatively narrow
range of values (between the onset of electroporation and the onset
of irreversible electroporation) when reversible electroporation
devices are designed they are designed to generally operate in
pairs or in a precisely controlled configuration that allows
delivery of these precise pulses limited by certain upper and lower
values. In contrast, in irreversible electroporation the limit is
more focused on the lower value of the pulse which should be high
enough to induce irreversible electroporation.
[0050] Higher values can be used provided they do not induce
thermal damage. Therefore the design principles are such that no
matter how many electrodes are use the only constrain is that the
electrical parameters between the most distant ones be at least the
value of irreversible electroporation. If within the electroporated
regions and within electrodes there are higher gradients this does
not diminish the effectiveness of the probe. From these principles
we can use a very effective design in which any irregular region to
be ablated can be treated by surrounding the region with ground
electrodes and providing the electrical pulses from a central
electrode. The use of the ground electrodes around the treated area
has another potential value--it protects the tissue outside the
area that is intended to be treated from electrical currents and is
an important safety measure. In principle, to further protect an
area of tissue from stray currents it would be possible to put two
layers of ground electrodes around the area to be ablated. It
should be emphasized that the electrodes can be infinitely long and
can also be curves to better hug the undesirable area to be
ablated.
[0051] In one embodiment of the present invention, methods are
provided to apply an electrical pulse or pulses to BPH tissue
sites. The pulses are applied between electrodes and are applied in
numbers with currents so as to result in irreversible
electroporation of the cells without damaging surrounding cells.
Energy waves are emitted from an imaging device such that the
energy waves of the imaging device pass through the area positioned
between the electrodes and the irreversible electroporation of the
cells effects the energy waves of the imaging device in a manner so
as to create an image.
[0052] Typical values for pulse length for irreversible
electroporation are in a range of from about 5 microseconds to
about 62,000 milliseconds or about 75 microseconds to about 20,000
milliseconds or about 100 microseconds.+-0.10 microseconds. This is
significantly longer than the pulse length generally used in
intracellular (nano-seconds) electro-manipulation which is 1
microsecond or less--see published U.S. application 2002/0010491
published Jan. 24, 2002. Pulse lengths can be adjusted based on the
real time imaging.
[0053] The pulse is at voltage of about 100 V/cm to 7,000 V/cm or
200 V/cm to 2000 V/cm or 300V/cm to 1000 V/cm about 600
V/cm.+-0.10% for irreversible electroporation. This is
substantially lower than that used for intracellular
electro-manipulation which is about 10,000 V/cm, see U.S.
application 2002/0010491 published Jan. 24, 2002. The voltage can
be adjusted alone or with the pulse length based on real time
imaging information.
[0054] The voltage expressed above is the voltage gradient (voltage
per centimeter). The electrodes may be different shapes and sizes
and be positioned at different distances from each other. The shape
may be circular, oval, square, rectangular or irregular etc. The
distance of one electrode to another may be 0.5 to 10 cm., 1 to 5
cm., or 2-3 cm. The electrode may have a surface area of 0.1-5 sq.
cm. or 1-2 sq. cm.
[0055] The size, shape and distances of the electrodes can vary and
such can change the voltage and pulse duration used and can be
adjusted based on imaging information. Those skilled in the art
will adjust the parameters in accordance with this disclosure and
imaging to obtain the desired degree of electroporation and avoid
thermal damage to surrounding cells.
[0056] Thermal effects require electrical pulses that are
substantially longer from those used in irreversible
electroporation (Davalos, R. V., B. Rubinsky, and L. M. Mir,
Theoretical analysis of the thermal effects during in vivo tissue
electroporation. Bioelectrochemistry, 2003. Vol 61(1-2): p.
99-107). When using irreversible electroporation for tissue
ablation, there may be concern that the irreversible
electroporation pulses will be as large as to cause thermal
damaging effects to the surrounding tissue and the extent of the
BPH tissue site ablated by irreversible electroporation will not be
significant relative to that ablated by thermal effects. Under such
circumstances irreversible electroporation could not be considered
as an effective BPH tissue site ablation modality as it will act in
superposition with thermal ablation. To a degree, this problem is
addressed via the present invention using imaging technology.
[0057] In one aspect of the invention the imaging device is any
medical imaging device including ultrasound, X-ray technologies,
magnetic resonance imaging (MRI), light imaging, electrical
impedance tomography, electrical induction impedance tomography and
microwave tomography. It is possible to use combinations of
different imaging technologies at different points in the
process.
[0058] For example, one type of imaging technology can be used to
precisely locate a BPH tissue site, a second type of imaging
technology can be used to confirm the placement of electrodes
relative to the BPH tissue site. And yet another type of imaging
technology could be used to create images of the currents of
irreversible electroporation in real time. Thus, for example, MRI
technology could be used to precisely locate the BPH tissue site.
Electrodes could be placed and identified as being well positioned
using X-ray imaging technologies. Current could be applied to carry
out irreversible electroporation while using ultrasound technology
to determine the extent of BPH tissue site effected by the
electroporation pulses. It has been found that within the
resolution of calculations and imaging the extent of the image
created on ultrasound corresponds to an area calculated to be
irreversibly electroporated. Within the resolution of histology the
image created by the ultrasound image corresponds to the extent of
BPH tissue site ablated as examined histologically.
[0059] Because the effectiveness of the irreversible
electroporation can be immediately verified with the imaging it is
possible to limit the amount of unwanted damage to surrounding
tissues and limit the amount of electroporation that is carried
out. Further, by using the imaging technology it is possible to
reposition the electrodes during the process. The electrode
repositioning may be carried out once, twice or a plurality of
times as needed in order to obtain the desired degree of
irreversible electroporation on the desired BPH tissue site.
[0060] In accordance with one embodiment of the present invention,
a method may be carried out which comprises several steps. In a
first step an area of BPH tissue site to be treated by irreversible
electroporation is imaged. Electrodes are then placed in the BPH
tissue site with the BPH tissue site to be ablated being positioned
between the electrodes. Imaging can also be carried out at this
point to confirm that the electrodes are properly placed. After the
electrodes are properly placed pulses of current are run between
the two electrodes and the pulsing current is designed so as to
minimize damage to surrounding tissue and achieve the desired
irreversible electroporation of the BPH tissue site. While the
irreversible electroporation is being carried out imaging
technology is used and that imaging technology images the
irreversible electroporation occurring in real time. While this is
occurring the amount of current and number of pulses may be
adjusted so as to achieve the desired degree of electroporation.
Further, one or more of the electrodes may be repositioned so as to
make it possible to target the irreversible electroporation and
ablate the desired BPH tissue site.
[0061] Referring to FIG. 1, one embodiment of the present invention
provides a system, generally denoted as 10, for treating a BPH
tissue site of a patient.
[0062] Two or more monopolar electrodes 12, one or more bipolar
electrodes 14 or an array 16 of electrodes can be utilized, as
illustrated in FIGS. 2(a)-2(d). In one embodiment, at least first
and second monopolar electrodes 12 are configured to be introduced
at or near the BPH tissue site of the patient. It will be
appreciated that three or more monopolar electrodes 12 can be
utilized. The array 16 of electrodes is configured to be in a
substantially surrounding relationship to the BPH tissue site. The
array 16 of electrodes can employ a template 17 to position and/or
retain each of the electrodes. Template 17 can maintain a geometry
of the array 16 of electrodes. Electrode placement and depth can be
determined by the physician. The monopolar and bi-polar electrodes
12 and 14, and the array 16 of electrodes can be introduced
through, the rectal wall, the peritoneum, urethra and the like.
[0063] As shown in FIG. 3, the array 16 of electrodes creates a
boundary around the BPH tissue site to produce a volumetric cell
necrosis region. Essentially, the array 16 of electrodes makes a
treatment area the extends from the array 16 of electrodes, and
extends in an inward direction. The array 16 of electrodes can have
a pre-determined geometry, and each of the associated electrodes
can be deployed individually or simultaneously at the BPH tissue
site either percutaneously, or planted in-situ in the patient.
[0064] In one embodiment, the monopolar electrodes 12 are separated
by a distance of about 5 mm to 10 cm and they have a circular
cross-sectional geometry. One or more additional probes 18 can be
provided, including monitoring probes, an aspiration probe such as
one used for liposuction, fluid introduction probes, and the like.
Each bipolar electrode 14 can have multiple electrode bands 20. The
spacing and the thickness of the electrode bands 20 is selected to
optimize the shape of the electric field. In one embodiment, the
spacing is about 1 mm to 5 cm typically, and the thickness of the
electrode bands 20 can be from 0.5 mm to 5 cm.
[0065] Referring again to FIG. 1, a voltage pulse generator 22 is
coupled to the electrodes 12, 14 and the array 16. The voltage
pulse generator 22 is configured to apply sufficient electrical
pulses between the first and second monopolar electrodes 12,
bi-polar electrode 14 and array 16 to induce electroporation of
cells in the BPH tissue site, and create necrosis of cells of the
BPH tissue site. However, the applied electrical pulses are
insufficient to create a thermal damaging effect to a majority of
the BPH tissue site.
[0066] The electrodes 12, 14 and array 16 are each connected
through cables to the voltage pulse generator 22. A switching
device 24 can be included. The switching device 24, with software,
provides for simultaneous or individual activation of multiple
electrodes 12, 14 and array 16. The switching device 24 is coupled
to the voltage pulse generator 22. In one embodiment, means are
provided for individually activating the electrodes 12, 14 and
array 16 in order to produce electric fields that are produced
between pre-selected electrodes 12, 14 and array 16 in a selected
pattern relative to the BPH tissue site. The switching of
electrical signals between the individual electrodes 12, 14 and
array 16 can be accomplished by a variety of different means
including but not limited to, manually, mechanically, electrically,
with a circuit controlled by a programmed digital computer, and the
like. In one embodiment, each individual electrode 12, 14 and array
16 is individually controlled.
[0067] The pulses are applied for a duration and magnitude in order
to permanently disrupt the cell membranes of cells at the BPH
tissue site. A ratio of electric current through cells at the BPH
tissue site to voltage across the cells can be detected, and a
magnitude of applied voltage to the BPH tissue site is then
adjusted in accordance with changes in the ratio of current to
voltage.
[0068] In one embodiment, an onset of electroporation of cells at
the BPH tissue site is detected by measuring the current. In
another embodiment, monitoring the effects of electroporation on
cell membranes of cells at the BPH tissue site are monitored. The
monitoring can be preformed by image monitoring using ultrasound,
CT scan, MRI, CT scan, and the like.
[0069] In other embodiments, the monitoring is achieved using a
monitoring electrode 18. In one embodiment, the monitoring
electrode 18 is a high impedance needle that can be utilized to
prevent preferential current flow to a monitoring needle. The high
impedance needle is positioned adjacent to or in the BPH tissue
site, at a critical location. This is similar in concept and
positioning as that of placing a thermocouple as in a thermal
monitoring. Prior to the full electroporation pulse being delivered
a "test pulse" is delivered that is some fraction of the proposed
full electroporation pulse, which can be, by way of illustration
and without limitation, 10%, and the like. This test pulse is
preferably in a range that does not cause irreversible
electroporation.
[0070] The monitoring electrode 18 measures the test voltage at the
location. The voltage measured is then extrapolated back to what
would be seen by the monitoring electrode 18 during the full pulse,
e.g., multiplied by 10 in one embodiment, because the relationship
is linear). If monitoring for a potential complication at the BPH
tissue site, a voltage extrapolation that falls under the known
level of irreversible electroporation indicates that the BPH tissue
site where monitoring is taking place is safe. If monitoring at
that BPH tissue site for adequacy of electroporation, the
extrapolation falls above the known level of voltage adequate for
irreversible tissue electroporation.
[0071] In one embodiment in which the bipolar electrode 14 is
placed transrectally the monitoring electrode 18 is integral to the
bipolar electrode 14 placed either distal or proximal to the active
bipolar electrodes 14. The monitoring electrode 18 is a fixed
distance form the bipolar electrode 14. In another embodiment the
monitoring electrode 18 is mounted on a sheath through which the
bipolar electrode 14 is placed. The distance from the bipolar
electrode 14 can then be varied and positioned based on imaging and
the structure to be monitored, such as the rectal mucosa. In
another embodiment the monitoring electrode 18 is mounted on a
biopsy guide through which the bipolar electrode 14 is placed. The
moniroing electrode 18 is placed at the tip of the guide and rests
against the rectal mucosa as the bipolar electrode 14 is
placed.
[0072] The effects of electroporation on cell membranes of cells at
the BPH tissue site can be detected by measuring the current
flow.
[0073] In various embodiments, the electroporation is performed in
a controlled manner, with real time monitoring, to provide for
controlled pore formation in cell membranes of cells at the BPH
tissue site, to create a tissue effect in the cells at the BPH
tissue site while preserving surrounding tissue, with monitoring of
electrical impedance, and the like.
[0074] The electroporation can be performed in a controlled manner
by controlling the intensity and duration of the applied voltage
and with or without real time control. Additionally, the
electroporation is performed in a manner to provide for
modification and control of mass transfer across cell membranes.
Performance of the electroporation in the controlled manner can be
achieved by selection of a proper selection of voltage magnitude,
proper selection of voltage application time, and the like.
[0075] The system 10 can include a control board 26 that functions
to control temperature of the BPH tissue site. In one embodiment of
the present invention, the control board 26 receives its program
from a controller. Programming can be in computer languages such as
C or BASIC (registered trade mark) if a personnel computer is used
for a controller 28 or assembly language if a microprocessor is
used for the controller 28. A user specified control of temperature
can be programmed in the controller 28.
[0076] The controller 28 can include a computer, a digital or
analog processing apparatus, programmable logic array, a hardwired
logic circuit, an application specific integrated circuit ("ASIC"),
or other suitable device. In one embodiment, the controller 28
includes a microprocessor accompanied by appropriate RAM and ROM
modules, as desired. The controller 28 can be coupled to a user
interface 30 for exchanging data with a user. The user can operate
the user interface 30 to input a desired pulsing pattern and
corresponding temperature profile to be applied to the electrodes
12, 14 and array 16.
[0077] By way of illustration, the user interface 30 can include an
alphanumeric keypad, touch screen, computer mouse, push-buttons
and/or toggle switches, or another suitable component to receive
input from a human user. The user interface 30 can also include a
CRT screen, LED screen, LCD screen, liquid crystal display,
printer, display panel, audio speaker, or another suitable
component to convey data to a human user. The control board 26 can
function to receive controller input and can be driven by the
voltage pulse generator 22.
[0078] In various embodiments, the voltage pulse generator 22 is
configured to provide that each pulse is applied for a duration of
about, 5 microseconds to about 62 seconds, 90 to 110 microseconds,
100 microseconds, and the like. A variety of different number of
pulses can be applied, including but not limited to, from about 1
to 15 pulses, about eight pulses of about 100 microseconds each in
duration, and the like. In one embodiment, the pulses are applied
to produce a voltage gradient at the BPH tissue site in a range of
from about 50 volt/cm to about 8000 volt/cm.
[0079] In various embodiments, the BPH tissue site is monitored and
the pulses are adjusted to maintain a temperature of, 100 degrees
Celsius or less at the BPH tissue site, 75 degrees CELSIUS or less
at the BPH tissue site, 60 degrees Celsius or less at the BPH
tissue site, 50 degrees Celsius or less at the BPH tissue site, and
the like. The temperature is controlled in order to minimize the
occurrence of a thermal effect to the BPH tissue site. These
temperatures can be controlled by adjusting the current-to-voltage
ratio based on temperature.
[0080] In one embodiment of the present invention, the system 10 is
utilized to treat BPH with electroporation of cells at a BPH tissue
site, creating cell necrosis in the BPH tissue site around the
urethra. The system 10 delivers electroporation pulses along the
muscular fibers and nerves at the BPH tissue site and produces a
volume of necrotic cells at the BPH tissue site around the urethra.
Destruction of these nerves, that create an elevation in tension of
the muscle fibers, is also achieved. The resulting necrotic tissue
is removed by macrophages. The use of electroporation with the
present invention results in the removal of cells at the BPH tissue
site, associated nerves, and the total volume of the BPH tissue
site is reduced, causing a reduction in pressure on the urethra and
a relaxation of the prostate. The electroporation is controllably
applied to spare urethral sphincters and other tissues in the
prostate, as well as in adjacent tissues and organs.
[0081] First and second mono-polar electrodes 12, or more, the
bi-polar electrode 14 or the array 16 of electrodes are introduced
through the rectal wall, the peritoneum or the urethra of the
patient. The electroporation is positioned and monitored by image
monitoring with ultrasound, CT scan, MRI, CT scan, and the like, or
with a monitoring electrode 18. Each of the electrodes 12, 14 or
array 16 can have insulated portions and is connected to the
voltage pulse generator 22.
EXAMPLE 1
[0082] An area of the BPH tissue site is imaged. Two bi-polar
electrodes 12, with sharpened distal ends, are introduced into in
the BPH tissue site through the rectal wall of the patient. The
area of the BPH tissue site to be ablated is positioned between the
two electrodes. Imaging is used to confirm that the mono-polar
electrodes are properly placed. The two mono-polar electrodes are
separated by a distance of 5 mm to 10 cm at various locations of
the BPH tissue site. Pulses are applied with a duration of 5
microseconds to about 62 seconds each. Monitoring is preformed
using ultrasound. The BPH tissue site is monitored. In response to
the monitoring, pulses are adjusted to maintain a temperature of no
more than 100 degrees Celsius. A voltage gradient at the BPH tissue
site in a range of from about 50 volt/cm to about 1000 volt/cm is
created. A volume of the BPH tissue site of about 1 cm by 0.5 cm
undergoes cell necrosis.
EXAMPLE 2
[0083] An area of the BPH tissue site is imaged. Two mono-polar
electrodes 12, are introduced into in the BPH tissue site through
the urethra of the patient. The area of the BPH tissue site to be
ablated is positioned between the two mono-polar electrodes 12.
Imaging is used to confirm that the electrodes are properly placed.
The two mono-polar electrodes 12 are separated by a distance of 5
mm to 10 cm at various locations of the BPH tissue site. Pulses are
applied with a duration of about 90 to 110 microseconds each.
Monitoring is performed using a CT scan. The BPH tissue site is
monitored. In response to the monitoring, pulses are adjusted to
maintain a temperature of no more than 75 degrees Celsius. A
voltage gradient at the BPH tissue site in a range of from about 50
volt/cm to about 5000 volt/cm is created. The BPH tissue site
undergoes cell necrosis.
EXAMPLE 3
[0084] An area of the BPH tissue site is imaged. The array 16 of
electrodes are introduced into in the BPH tissue site through the
peritoneum of the patient. The array 16 of electrodes is positioned
in a surrounding relationship to the BPH. Imaging is used to
confirm that the electrodes are properly placed. Pulses are applied
with a duration of about 100 microseconds each. A monitoring
electrode 18 is utilized. Prior to the full electroporation pulse
being delivered a test pulse is delivered that is about 10% of the
proposed full electroporation pulse. The test pulse does not cause
irreversible electroporation. The BPH tissue site is monitored. In
response to the monitoring, pulses are adjusted to maintain a
temperature of no more than 60 degrees Celsius. A voltage gradient
at the BPH tissue site in a range of from about 50 volt/cm to about
8000 volt/cm is created. The BPH tissue site undergoes cell
necrosis.
EXAMPLE 4
[0085] An area of the BPH tissue site is imaged. A single bi-polar
electrode 14, with a sharpened distal end, is introduced into the
BPH tissue site through the rectal wall of the patient. A
monitoring electrode 18 is placed at a tip of a biopsy guide and
rests against the rectal mucosa when the bipolar electrode 14 is
placed. Imaging is used to confirm that the bi-polar electrode 14
is properly placed. Pulses are applied with a duration of 5
microseconds to about 62 seconds each. Monitoring is preformed
using ultrasound. The BPH tissue site is monitored. In response to
the monitoring, pulses are adjusted to maintain a temperature of no
more than 100 degrees Celsius. A voltage gradient at the BPH tissue
site in a range of from about 50 volt/cm to about 1000 volt/cm is
created. The BPH tissue site undergoes cell necrosis.
EXAMPLE 5
[0086] An area of the BPH tissue site is imaged. A array 16 of
electrodes is introduced into the BPH tissue site through the
rectal wall of the patient, and are positioned around the BPH
tissue site. Imaging is used to confirm that the array 16 of
electrodes is properly placed. Pulses are applied with a duration
of about 90 to 110 microseconds each. Monitoring is performed using
a CT scan. The BPH tissue site is monitored. In response to the
monitoring, pulses are adjusted to maintain a temperature of no
more than 75 degrees Celsius. A voltage gradient at the BPH tissue
site in a range of from about 50 volt/cm to about 5000 volt/cm is
created. The BPH tissue site undergoes cell necrosis.
EXAMPLE 6
[0087] An area of the BPH tissue site is imaged. The array 16 of
electrodes is introduced into the BPH tissue site through the
peritoneum of the patient, and positioned in a surrounding
relationship to the BPH tissue site. Imaging is used to confirm
that the array 16 of electrodes is properly placed. Pulses are
applied with a duration of about 100 microseconds each. A
monitoring electrode 18 is utilized. Prior to the full
electroporation pulse being delivered a test pulse is delivered
that is about 10% of the proposed full electroporation pulse. The
test pulse does not cause irreversible electroporation. The BPH
tissue site is monitored. In response to the monitoring, pulses are
adjusted to maintain a temperature of no more than 60 degrees
Celsius. A voltage gradient at the BPH tissue site in a range of
from about 50 volt/cm to about 8000 volt/cm is created. The BPH
tissue site undergoes cell necrosis.
[0088] The foregoing description of embodiments of the present
invention has been presented for purposes of illustration and
description. It is not intended to be exhaustive or to limit the
invention to the precise forms disclosed. Obviously, many
modifications and variations will be apparent to practitioners
skilled in this art. It is intended that the scope of the invention
be defined by the following claims and their equivalents.
* * * * *