U.S. patent application number 14/056315 was filed with the patent office on 2014-02-13 for system and method for increasing a target zone for electrical ablation.
This patent application is currently assigned to AngioDymamics, Inc.. The applicant listed for this patent is AngioDynamics, Inc.. Invention is credited to Peter Callas, Wesley Chung Joe.
Application Number | 20140046322 14/056315 |
Document ID | / |
Family ID | 48982824 |
Filed Date | 2014-02-13 |
United States Patent
Application |
20140046322 |
Kind Code |
A1 |
Callas; Peter ; et
al. |
February 13, 2014 |
System and Method for Increasing a Target Zone for Electrical
Ablation
Abstract
System for increasing a target zone for electrical ablation
includes a treatment control module executable by a processor. The
control module directs a pulse generator to apply pre-conditioning
pulses to subject tissue cells in a pre-conditioning zone to
electroporation, the pre-conditioning zone being smaller than a
target ablation zone. After the pre-conditioning pulses have been
applied, the control module directs the pulse generator to apply
treatment pulses to electrically ablate the tissue cells in the
target ablation zone. The pre-conditioning pulses cause the
pre-conditioning zone to have a much higher conductivity so that
the zone acts as a larger electrode area when the treatment pulses
are applied, which results in a much larger target ablation zone
than otherwise possible.
Inventors: |
Callas; Peter; (Castro
Valley, CA) ; Joe; Wesley Chung; (Fremont,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AngioDynamics, Inc. |
Latham |
NY |
US |
|
|
Assignee: |
AngioDymamics, Inc.
Latham
NY
|
Family ID: |
48982824 |
Appl. No.: |
14/056315 |
Filed: |
October 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13762027 |
Feb 7, 2013 |
|
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14056315 |
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61596436 |
Feb 8, 2012 |
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Current U.S.
Class: |
606/41 |
Current CPC
Class: |
A61B 2018/00613
20130101; A61B 2018/00827 20130101; A61B 2018/143 20130101; A61B
18/14 20130101; A61B 2018/00875 20130101 |
Class at
Publication: |
606/41 |
International
Class: |
A61B 18/14 20060101
A61B018/14 |
Claims
1-32. (canceled)
33. A method for increasing a target zone for electrical ablation
comprising: positioning at least one electrode near a target
ablation zone; and applying a first set and a second set of pulses
through the electrode, each set of pulses sufficient to
irreversibly electroporate tissue cells in the target ablation
zone; wherein a first delay of between 1 and 600 seconds is
introduced between the first and second set of pulses.
34. The method of claim 33, wherein the first delay is between 30
and 480 seconds.
35. The method of claim 33, wherein the first delay is between 120
and 480 seconds.
37. The method of claim 33 further comprising: applying a third set
of pulses through the electrode; wherein a second delay of between
1 and 600 seconds is introduced between the second and third set of
pulses.
38. The method of claim 37, wherein the second delay is between 30
and 480 seconds.
39. The method of claim 37, wherein the second delay is between 120
and 480 seconds.
40. The method of claim 37 further comprising: applying a fourth
set of pulses through the electrode; wherein a third delay of
between 1 and 600 seconds is introduced between the third and
fourth set of pulses.
41. The method of claim 40, wherein the third delay is between 30
and 480 seconds.
42. The method of claim 40, wherein the third delay is between 120
and 480 seconds.
43. The method of claim 40 further comprising: applying a fifth set
of pulses through the electrode; wherein a fourth delay of between
1 and 600 seconds is introduced between the fourth and fifth set of
pulses.
44. The method of claim 43, wherein the fourth delay is between 30
and 480 seconds.
45. The method of claim 43, wherein the fourth delay is between 120
and 480 seconds.
46. The method of claim 43 further comprising: applying a sixth set
of pulses through the electrode; wherein a fifth delay of between 1
and 690 seconds is introduced between the fifth and sixth set of
pulses.
47. The method of claim 46, wherein the fifth delay is between 30
and 480 seconds.
48. The method of claim 46, wherein the fifth delay is between 120
and 480 seconds.
49. The method of claim 33, wherein pulse widths in the first set
of pulses are different than pulse widths in the second set of
pulses.
50. The method of claim 33, wherein voltage settings for the first
set of pulses are different from voltage settings for the second
set of pulses.
51. The method of claim 33, wherein prior to an application of the
second set of pulses and subsequent to a start of the application
of the first set of pulses, a parameter for the second set of
pulses is determined based on an impedance measured from the target
zone.
52. The method of claim 33, wherein each set of pulses comprises a
pulse-train.
53. A method for increasing a target zone for electrical ablation
comprising: positioning a bipolar electrode near a target ablation
zone; and applying a plurality of sets of pulses through the
electrode, each of the sets of pulses being sufficient to
irreversibly electroporate tissue cells in the target ablation
zone; wherein a delay of between 1 and 600 seconds is introduced
between each of the plurality of sets of pulses.
54. The method of claim 53, wherein the delay is between 30 and 480
seconds.
55. The method of claim 53, wherein the delay is between 120 and
480 seconds.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. 119(e) to
U.S. Provisional Application No. 61/596,436, filed Feb. 8, 2012,
which is incorporated by reference herein.
[0002] This application is also related to PCT International
Application Number PCT/US10/29243, filed Mar. 30, 2010 and entitled
"System and Method for Estimating a Treatment Region for a Medical
Treatment Device and for Interactively Planning a Treatment of a
Patient", which is incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The present invention relates to a medical treatment device
for ablating a target tissue zone. More particularly, the present
application relates to a system and method for increasing a target
tissue zone for electrical ablation.
BACKGROUND OF THE INVENTION
[0004] Devices for delivering therapeutic energy such as an
ablation device using irreversible electroporation (IRE) include a
pulse generator and one or more electrodes coupled to the
generator. The pulse generator delivers the therapeutic energy to a
targeted tissue through the electrodes, thereby causing ablation of
the tissue.
[0005] Once a target treatment area/region is located within a
patient, the electrodes of the device are placed in such a way as
to create a treatment zone that surrounds the target treatment
region.
[0006] Prior to treatment, a treatment planning system is used to
generate an estimated treatment region that completely covers the
target treatment region. The estimated region is used by a
physician to plan where to place the electrodes in the patient.
[0007] This can be effective when the target area is relatively
small, e.g., less than 2 cm in length. However, when the target
area is much larger, e.g., larger than 3 cm in length, the
physician may be forced to use a large number of electrodes, e.g.,
4 or more electrodes. This makes accurately placing the electrodes
much more difficult as moving one electrode affects the spacing
from all other electrodes.
[0008] Alternatively, the large target area can be divided into two
or more smaller areas and the treatment procedure for one area can
be repeated to cover the other divided areas. However, this makes
the entire treatment procedure much longer. The longer procedure
makes it riskier for the patient since the patient would have to
stay on an operating table much longer, often with an exposed body
portion to be treated. The longer procedure also makes the
procedure more expensive.
[0009] Therefore, it would be desirable to provide a system and
method for increasing a target tissue zone for electrical ablation
for a given set of electrodes.
SUMMARY OF THE DISCLOSURE
[0010] Disclosed herein is a system and method of pre-conditioning
a target tissue near an electrode to increase a target ablation
zone. The system includes a memory, a processor coupled to the
memory and a treatment control module. The treatment control module
stored in the memory and executable by the processor, the treatment
control module applies through at least one electrode a plurality
of pre-conditioning pulses to subject tissue cells in a
pre-conditioning zone surrounding the electrode to electroporation,
the pre-conditioning zone being smaller than a target ablation
zone. After the pre-conditioning pulses have been applied, the
control module applies a plurality of treatment pulses in an amount
sufficient to electrically ablate the tissue cells in the target
ablation zone. Advantageously, the pre-conditioning pulses cause
the pre-conditioning zone to have a much higher conductivity so
that the zone acts as a larger electrode area when the treatment
pulses are applied, which results in a much larger target ablation
zone than otherwise possible.
[0011] In another aspect, the treatment control module applies the
plurality of treatment pulses in an amount sufficient to subject
the tissue cells in the target ablation zone to irreversible
electroporation or supra-poration.
[0012] In another aspect, the treatment control module applies the
pre-conditioning pulses that have a shorter pulse width than the
treatment pulses.
[0013] In another aspect, the treatment control module applies the
pre-conditioning pulses in an amount sufficient to subject tissue
cells in the pre-conditioning zone to irreversible
electroporation.
[0014] In another aspect, the treatment control module waits at
least 30 seconds after the pre-conditioning pulses have been
applied to allow an electrical conductivity in the pre-conditioning
zone to increase.
[0015] In another aspect, the treatment control module waits at
least two minutes after the pre-conditioning pulses have been
applied to allow an electrical conductivity in the pre-conditioning
zone to increase.
[0016] In another aspect, while the pre-conditioning pulses are
being applied, the treatment control module continuously monitors
current to adjust at least one pulse parameter for the
pre-conditioning pulses.
[0017] In another aspect, after the pre-conditioning pulses have
been applied, the treatment control module continuously monitors
impedance and determines when to apply the treatment pulses.
[0018] In another aspect, the treatment control module applies the
pre-conditioning pulses that have a shorter pulse width than the
treatment pulses, and waits at least 30 seconds after the
pre-conditioning pulses have been applied to allow an electrical
conductivity in the pre-conditioning zone to increase.
[0019] In another aspect, the treatment control module applies a
test pulse through the electrode and determines at least one pulse
parameter for the pre-conditioning pulses based on the applied test
pulse.
[0020] In another aspect, treatment control module applies a test
pulse through the electrode after the pre-conditioning pulses have
been applied, and based on the applied test pulse, determines
whether to repeat the application of the pre-conditioning pulses or
proceed to application of the treatment pulses.
[0021] In another aspect, the treatment control module determines
whether to repeat the application of the pre-conditioning pulses
based on an electrical conductivity derived from the test
pulse.
[0022] According to another aspect of the invention, a method for
increasing a target zone for electrical ablation is provided. The
method includes positioning at least one electrode near a target
ablation zone and applying through the positioned electrode a
plurality of pre-conditioning pulses to subject tissue cells in a
pre-conditioning zone surrounding the electrode to electroporation,
the pre-conditioning zone being smaller than the target ablation
zone. After the pre-conditioning pulses have been applied, the
method further includes applying a plurality of treatment pulses in
an amount sufficient to electrically ablate the tissue cells in the
target ablation zone.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 illustrates several components of a medical treatment
system to treat a patient according to the present invention.
[0024] FIG. 2 is a schematic diagram of a treatment control
computer of the present invention.
[0025] FIG. 3 is a screen shot of an "Information" screen of a
treatment control module showing various input boxes.
[0026] FIG. 4 is a screen shot of a "Probe Selection" screen of the
treatment control module showing a side view and top view of the
four probe array and an example of the general shape of the
treatment zone that can be generated by a four probe array.
[0027] FIG. 5 is a screen shot of a "Probe Placement Process"
screen of the treatment control module.
[0028] FIG. 6 illustrates an example of a three probe array
defining three individual treatment zones, which combine to form a
combined treatment region.
[0029] FIG. 7 illustrates details of the generator shown in FIG.
1.
[0030] FIG. 8 illustrates an image of a sample pre-conditioned
tissue zone surrounded by a sample ablation zone.
[0031] FIG. 9 illustrates another image of a sample pre-conditioned
tissue zone surrounded by a sample ablation zone.
DETAILED DESCRIPTION OF THE INVENTION
[0032] Throughout the present teachings, any and all of the one,
two, or more features and/or components disclosed or suggested
herein, explicitly or implicitly, may be practiced and/or
implemented in any combinations of two, three, or more thereof,
whenever and wherever appropriate as understood by one of ordinary
skill in the art. The various features and/or components disclosed
herein are all illustrative for the underlying concepts, and thus
are non-limiting to their actual descriptions. Any means for
achieving substantially the same functions are considered as
foreseeable alternatives and equivalents, and are thus fully
described in writing and fully enabled. The various examples,
illustrations, and embodiments described herein are by no means, in
any degree or extent, limiting the broadest scopes of the claimed
inventions presented herein or in any future applications claiming
priority to the instant application.
[0033] One embodiment of the present invention is illustrated in
FIG. 1. One or more probes/electrodes 22 deliver therapeutic energy
and are powered by a voltage pulse generator 10 that generates high
voltage pulses as therapeutic energy such as pulses capable of
irreversibly electroporating the tissue cells. In the embodiment
shown, the voltage pulse generator 10 includes six separate
receptacles for receiving up to six individual probes 22 which are
adapted to be plugged into the respective receptacle. The
receptacles are each labeled with a number in consecutive order. In
other embodiments, the voltage pulse generator can have any number
of receptacles for receiving more or less than six probes.
[0034] In the embodiment shown, each probe 22 includes either a
monopolar electrode or bipolar electrodes having two electrodes
separated by an insulating sleeve. In one embodiment, if the probe
includes a monopolar electrode, the amount of exposure of the
active portion of the electrode can be adjusted by retracting or
advancing an insulating sleeve relative to the electrode. See, for
example, U.S. Pat. No. 7,344,533, which is incorporated by
reference herein. The generator 10 is connected to a treatment
control computer 40 having input devices such as keyboard 12 and a
pointing device 14, and an output device such as a display device
11 for viewing an image of a target treatment region such as a
lesion 300 surrounded by a safety margin 301. The pulse generator
10 is used to treat a lesion 300 inside a patient 15. An imaging
device 30 includes a monitor 31 for viewing the lesion 300 inside
the patient 15 in real time. Examples of imaging devices 30 include
ultrasonic, CT, MRI and fluoroscopic devices as are known in the
art.
[0035] The present invention includes computer software (treatment
control module 54) which assists a user to plan for, execute, and
review the results of a medical treatment procedure, as will be
discussed in more detail below. For example, the treatment control
module 54 assists a user to plan for a medical treatment procedure
by enabling a user to more accurately position each of the probes
22 of the pulse generator 10 in relation to the lesion 300 in a way
that will generate the most effective treatment zone. The treatment
control module 54 can display the anticipated treatment zone based
on the position of the probes and the treatment parameters. The
treatment control module 54 can display the progress of the
treatment in real time and can display the results of the treatment
procedure after it is completed. This information can be used to
determine whether the treatment was successful and whether it is
necessary to re-treat the patient.
[0036] For purposes of this application, the terms "code",
"software", "program", "application", "software code", "software
module", "module" and "software program" are used interchangeably
to mean software instructions that are executable by a
processor.
[0037] The "user" can be a physician or other medical professional.
The treatment control module 54 executed by a processor outputs
various data including text and graphical data to the monitor 11
associated with the generator 10.
[0038] Referring now to FIG. 2, the treatment control computer 40
of the present invention manages planning of treatment for a
patient. The computer 40 is connected to the communication link 52
through an I/O interface 42 such as a USB (universal serial bus)
interface, which receives information from and sends information
over the communication link 52 to the voltage generator 10. The
computer 40 includes memory storage 44 such as RAM, processor (CPU)
46, program storage 48 such as ROM or EEPROM, and data storage 50
such as a hard disk, all commonly connected to each other through a
bus 53. The program storage 48 stores, among others, a treatment
control module 54 which includes a user interface module that
interacts with the user in planning for, executing and reviewing
the result of a treatment. Any of the software program modules in
the program storage 48 and data from the data storage 50 can be
transferred to the memory 44 as needed and is executed by the CPU
46.
[0039] In one embodiment, the computer 40 is built into the voltage
generator 10. In another embodiment, the computer 40 is a separate
unit which is connected to the voltage generator through the
communication link 52. In a preferred embodiment, the communication
link 52 is a USB link.
[0040] In one embodiment, the imaging device 30 is a stand alone
device which is not connected to the computer 40. In the embodiment
as shown in FIG. 1, the computer 40 is connected to the imaging
device 30 through a communication link 53. As shown, the
communication link 53 is a USB link. In this embodiment, the
computer can determine the size and orientation of the lesion 300
by analyzing the data such as the image data received from the
imaging device 30, and the computer 40 can display this information
on the monitor 11. In this embodiment, the lesion image generated
by the imaging device 30 can be directly displayed on the grid 200
of the monitor 11 of the computer running the treatment control
module 54. This embodiment would provide an accurate representation
of the lesion image on the grid 200, and may eliminate the step of
manually inputting the dimensions of the lesion in order to create
the lesion image on the grid 200. This embodiment would also be
useful to provide an accurate representation of the lesion image if
the lesion has an irregular shape.
[0041] The basic functionality of the computer software (treatment
control module 54) will now be discussed in relation to the
following example.
[0042] It should be noted that the software can be used
independently of the generator 10. For example, the user can plan
the treatment in a different computer as will be explained below
and then save the treatment parameters to an external memory
device, such as a USB flash drive (not shown). The data from the
memory device relating to the treatment parameters can then be
downloaded into the computer 40 to be used with the generator 10
for treatment.
[0043] After the treatment control module 54 is initialized, it
displays an "Information" screen with various input boxes as shown
in FIG. 3. A keyboard or other input device 12, together with a
mouse or other pointing device 14 (see FIG. 1) are used to input
the data. Any data that is inputted into the input boxes can be
saved into internal or external memory along with a record of the
treatment as described below for future reference. The basic
patient information can be inputted, such as a patient ID number in
input box 100, the name of the patient in input box 101, and the
age of the patient in input box 102. The user can enter clinical
data, such as the clinical indication of the treatment in input box
114. The date of the procedure is automatically displayed at 111 or
can be inputted by the user in another embodiment. The user can
enter other case information such as the name of the physician in
input box 112 and any specific case notes in input box 113.
[0044] The dimensions of the lesion 300 are determined from viewing
it on the monitor 31 of the imaging device 30 (see FIG. 1) such as
an ultrasonic imaging device and using known methods to calculate
the dimensions from the image generated from the imaging device 31.
The dimensions of the lesion 300 (length at input box 103, width at
input box 104, and depth at input box 105) are inputted into the
program. A safety margin is selected at input box 106 which will
surround the entire lesion 300 in three dimensions. According to
the size of the safety margin that is selected, a target treatment
region is automatically calculated and is displayed in boxes 107,
108, and 109 as shown. In one embodiment, the safety margin value
may be set to zero. For example, when treating a benign tumor, a
safety margin may not be necessary.
[0045] In the embodiment shown in FIG. 3, the user has indicated
that the lesion that will be treated has a length of 2 cm, width of
1 cm and a depth of 1 cm. With a user specified margin of 1 cm
(which is a default margin setting), the target treatment region
has a length of 4 cm, width of 3 cm and a depth of 3 cm.
[0046] The user can select the "ECG synchronization" option by
clicking the circle in the box 110 in order to synchronize the
pulses with an electrocardiogram (ECG) device, if such a device is
being used during the procedure. The other options available for
treatment that are included in box 110 can include an option for
"90 PPM" (pulses per minute) or "240 PPM". The user should select
at least one of the three options provided in box 110. After all of
the necessary data has been inputted, the user clicks on the "Next"
button with a pointing device 14 to proceed to the next screen
described below.
[0047] Further regarding the ECG synchronization option, if this
circle is selected in window 110, the treatment control module 54
will test this functionality to verify that the system is working
properly. The treatment control module 54 can automatically detect
whether an error has occurred during the testing phase of the ECG
feature. The detectable errors include, but are not limited to, "no
signal" (such as no pulses for 3.5 seconds) and "noisy" (such as
pulses occurring at a rate greater than 120 beats per minute for at
least 3.5 seconds).
[0048] The treatment control module 54 can synchronize energy
release with cardiac rhythm by analyzing cardiac output such as
electrocardiogram results (or other cardiac function output) and
sending synchronization signals to a controller of the pulse
generator 10. The control module 54 is also capable of generating
internal flags such as a synchronization problem flag and a
synchronization condition flag to indicate to users on a graphic
user interface a synchronization status, so that energy pulse
delivery can be synchronized with the cardiac rhythm for each beat
(in real-time) or aborted as necessary for patient safety and
treatment efficiency.
[0049] Specifically, the control module 54 synchronizes energy
pulses such as IRE (irreversible electroporation) pulses with a
specific portion of the cardiac rhythm. The module uses the R-wave
of the heartbeat and generates a control signal to the pulse
generator 10 indicating that this portion of the heartbeat is
optimal for release of IRE pulses. For clarity, the S wave would be
an optimal time for delivery of an energy pulse, but due to the
fact that the S wave ends nebulously in some cases, the R wave is
used as an indicator to start timing of energy release.
[0050] More specifically, the synchronization feature of the
control module 54 allows for monitoring of heart signals so as to
ensure that changes, maladies, and other alterations associated
with the heartbeat are coordinated such that pulses from the pulse
generator 10 are released at the proper time, and that if the
heartbeat is out of its normal rhythm, that the release of energy
is either altered or aborted.
[0051] Next, the user can select the number of probes that the user
believes will be necessary to produce a treatment zone which will
adequately cover the lesion 300 and any safety margin 301. The
selection is made by clicking the circle next to each type of
device, as shown in the "Probe Selection" screen, illustrated in
FIG. 4.
[0052] In one embodiment, a "Probes Selection Status" box 199
identifies which of the receptacles, if any, on the generator 10
have been connected to a probe by displaying the phrase "Connected"
or the like next to the corresponding probe number.
[0053] In one embodiment, each receptacle includes an RFID device
and a connector for each probe which connects to the receptacle and
includes a compatible RFID device, so that the treatment control
module 54 can detect whether or not an authorized probe has been
connected to the receptacle on the generator 10 by detecting a
connection of the compatible RFID devices. If an authorized probe
is not connected to a receptacle on the generator, the phrase "Not
Connected" or the like will appear next to the probe number. In
addition, the color of each probe shown in the "Probes Selection
Status" box 199 can be used to indicate whether or not each
receptacle on the generator is connected to a compatible probe.
This feature allows the user to verify that the requisite number of
probes are properly connected to the generator 10 before selecting
a probe type for the treatment procedure. For example, if the
treatment control module 54 detects a problem with the probe
connection status (e.g. selecting a three probe array when only two
probes are connected to the generator), it can notify the user by
displaying an error message.
[0054] The user can select which of the connected probes will be
used to perform the treatment procedure, by clicking on the box
next to the selected probes in the "Probes Selection Status" box
199. By default the treatment control module 54 will automatically
select probes in ascending numerical order, as they are
labeled.
[0055] Referring to FIG. 4, circle 150 is used to select a four
probe array. FIG. 4 illustrates a side view 151 and top view 152 of
the four probe array and an example of the general shape of the
treatment zone that can be generated by a four probe array. In the
illustrated example, the exposed portion of each of the electrodes
as shown is 20 mm in length and each pair of the four probes are
equally spaced from each other by 15 mm, as measured at four places
(PLCS) along the perimeter.
[0056] FIG. 5 illustrates a "Probe Placement Process" screen of one
aspect of the invention. The screen illustrated by FIG. 5 shows a
lesion 300 according to the dimensions which were inputted on the
"Information" screen (see FIG. 3) along with a safety margin 301,
if any, that was previously inputted. In the example depicted in
FIG. 5, the lesion 300 has a length of 2.0 cm and a width of 1.0
cm, and the device selected on the "Probe Selection" screen (see
FIG. 4) is a four probe array. The lesion 300 is displayed near the
center of an x-y grid 200 with the distance between two adjacent
grid lines representing 1 mm. Each of the four probes 201, 202,
203, 204 is displayed in the grid 200 and each probe can be
manually positioned within the grid by clicking and dragging the
probe with the pointing device 14. Two fiducials 208, 209 labeled
"A" and "B", respectively, are also displayed on the grid 200 and
are used as a point of reference or a measure as will be described
below.
[0057] The amount of longitudinal exposure of the active electrode
portion for each probe that has already been manually adjusted by
the user as explained above can be manually inputted in input box
210, which can be selected by the user according to the depth (z)
of the lesion. In this way, the treatment control module 54 can
generate an estimated treatment zone according to the treatment
parameters, and locations and depths of the probes. In one
embodiment, a second x-z grid is displayed on the monitor 11 of the
computer running the treatment control module 54. In one
embodiment, the treatment control module 54 can automatically
calculate preferred values for the amount of longitudinal exposure
of the active electrode portions based on the size and shape of the
lesion. The depth (z) of the electric field image can be calculated
analytically or with interpolation and displayed on the x-z grid.
Because the distribution of the electric field (i.e., expected
treatment region) between two monopolar electrodes may "dip in"
along the boundary line (e.g., a peanut shaped treatment region due
to large spacing between the two electrodes where the width of the
region is smaller in the middle; see for example region 305 in FIG.
9) depending on the electrode location and the applied voltage, it
is beneficial to have an x-z grid included on the monitor. For
example, if this "dip" of the boundary line travels into, rather
than surround/cover, the lesion region, then the targeted region
may not be fully treated. As a default to ensure treatment of the
entire lesion region, the probe depth placement and the exposure
length may be set unnecessarily higher to ensure erring on the safe
side. However, this will potentially treat a much larger volume
than needed, killing healthy surrounding tissue, which can be an
issue when treating sensitive tissues such as the pancreas, brain,
etc. By optimizing the treatment depth (z) together with the width
(x) and height (y), this effect may be reduced, further enhancing
procedural protocol and clinical outcome.
[0058] The probe dock status is indicated in box 210, by indicating
if the probes are "docked" or "undocked". The "UnDock Probes"
button allows the user to "unplug" the probes from the generator
while the "Probe Placement Process" screen is displayed without
causing error messages. In normal operation, the user plugs the
probes into the generator on the "Probe Selection" screen, and then
the probes are "authorized" as being compatible probes according to
the RFID devices, as discussed above. When the user proceeds to the
"Probe Placement Process" screen, the software requires that all
the selected probes remain plugged into the generator, or else the
software will display an error message (e.g. "Probe #2 unplugged",
etc.), and will also force the user back to the "Probe Selection"
screen. However, sometimes doctors may want to perform another scan
of the lesion or perform some other procedure while leaving the
probes inserted in the patient. But, if the procedure cannot be
performed near the generator, the probes are unplugged from the
generator. If the user selects the "UnDock Probes" button, this
will allow the probes to be unplugged from the generator without
causing an error message. Then, after the user has performed the
other procedure that was required, he can re-attach the probes to
the generator, and then select "Dock Probes" in input box 210. In
this way, the user will not receive any error messages while the
"Probe Placement Process" screen is displayed.
[0059] There is a default electric field density setting (Volts/cm)
which is shown in input box 211. In the example, the default
setting is 1500 Volts/cm. This number represents the electric field
density that the user believes is needed to effectively treat the
cells, e.g., ablate the tissue cells. For example, 1500 Volts/cm is
an electric field density that is needed to irreversibly
electroporate the tissue cells. Based on the number selected in
input box 211, the treatment control module 54 automatically
adjusts the voltage (treatment energy level) applied between the
electrodes, as shown in column 222.
[0060] Box 280 allows a user to select between two different
Volts/cm types, namely "Linear" or "Non-Linear Lookup".
[0061] The default Volts/cm setting is "Linear", in which case the
Voltage that is applied between a given pair of electrodes, as
shown in column 222, is determined by the following formula:
Voltage=xd, (1) [0062] where x=the electric field density setting
(Volts/cm) shown in column 225, which is based on the value from
box 211, and [0063] where d=the distance (cm) between the given
pair of electrodes shown in column 226. Therefore, when "Linear" is
selected, the Voltage that is applied between a given pair of
electrodes is directly proportional to the Distance between the
given electrode pair in a linear relationship.
[0064] If the user selects "Non-Linear Lookup" in box 280, then the
Voltage that is applied between the given pair of electrodes will
be similar to the Voltage values for a "Linear" selection when a
pair of electrodes are closely spaced together (e.g. within about 1
cm). However, as a pair of given electrodes are spaced farther from
one another, a "Non-Linear Lookup" will produce lower Voltages
between the given pair of electrodes as compared to the Voltage
values for a "Linear" selection at any given distance. The
"Non-Linear Lookup" feature is particularly useful for reducing
"popping" during treatment. "Popping" refers to an audible popping
noise that sometimes occurs, which is believed to be caused by a
plasma discharge from high voltage gradients at the tip of the
electrodes. The "Non-Linear Lookup" feature can also minimize any
swelling of the tissue that might occur as a result of a treatment.
The Voltage values used for the "Non-Linear Lookup" selection can
be pre-determined based on animal experiments and other research.
In one embodiment, different tissue types can each have their own
"Non-Linear Lookup" table. In the example shown, the tissue being
treated is prostate tissue.
[0065] The details of the treatment parameters are displayed in
window 270. The firing (switching) sequence between probes is
listed automatically in window 270. In the example, the firing
sequence involves six steps beginning with between probes 1 and 2,
then probes 1 and 3, then probes 2 and 3, then probes 2 and 4, then
probes 3 and 4, and then probes 4 and 1. As shown, the polarity of
each of the probes may switch from negative to positive according
to step of the firing sequence. Column 220 displays which probe is
the positive probe (according to a number assigned to each probe)
for each step. Column 221 displays which probe is the negative
probe (according to a number assigned to each probe) for each step.
Column 222 displays the actual voltage generated between each probe
during each step of the firing sequence. In the example, the
maximum voltage that can be generated between probes is limited by
the capabilities of the generator 10, which in the example is
limited to a maximum of 3000 Volts. Column 223 displays the length
of each pulse that is generated between probes during each
respective step of the firing sequence. In the example, the pulse
length is predetermined and is the same for each respective step,
and is set at 100 microseconds. Column 224 displays the number of
pulses that is generated during each respective step of the firing
sequence. In the example, the number of pulses is predetermined and
is the same for each respective step, and is set at 90 pulses which
are applied in a set of 10 pulses at a time. Column 225 displays
the setting for Volts/cm according to the value selected at input
box 211. Column 226 displays the actual distance between the
electrodes (measured in cm), which is automatically calculated
according to the placement of each probe in the grid 200.
[0066] The treatment control module 54 can be programmed to
calculate and display the area of the combined treatment regions on
the grid 200 by several different methods.
[0067] Each method determines a boundary line surrounding a
treatment zone that is created between a pair of electrodes. By
combining a plurality of treatment zones with each treatment zone
being defined by a pair of electrodes, a combined treatment region
can be displayed on the x-y grid. FIG. 6 illustrates three
electrodes 201 (E1), 202 (E2), 203 (E3) defining three individual
treatment zones 311, 312, 313, which combine to form a combined
treatment region 315 which is shown with hatched lines.
[0068] As discussed above, the monitor can further include an x-z
grid to illustrate the depth of the lesion and the shape of the
treatment region. The shape of the treatment zone in the x-z grid
will vary according to the selected amounts of electrode exposure
for each probe and can be determined by one or more methods.
[0069] In one embodiment, the treatment boundary line that is
created between two points on the x-y grid can be rotated about an
axis joining the two points in order to generate the treatment
region boundary line on the x-z grid. In this embodiment, several
points may be selected along the exposed length of the active
electrode portion for each probe at various depths (z). A
three-dimensional combined treatment region can then be generated
by determining the boundary line on the x-y grid between each
individual pair of points and then rotating the boundary line along
the axis joining each pair of points. The resulting boundary lines
can be combined to create a three dimensional image that is
displayed on the monitor.
[0070] The following is an alternate method for determining a
boundary line on the x-z grid, thereby determining a three
dimensional treatment region. This example describes a two probe
array with the probes being inserted in a parallel relationship and
with the probes having the same amount of exposed portions of the
electrode. In this example, the exposed portions of each probe
start at the same "uppermost" depth (z) and end at the same
"lowermost" depth (z). First, a treatment zone boundary line is
created in the x-y plane at the uppermost depth (z). Next, the
treatment zone boundary line is repeatedly created stepwise for all
subsequently lower depths (z), preferably evenly spaced, until the
lowermost depth (z) is reached. The result is a 3-D volume (stacked
set of treatment zone boundary lines) having a flat top surface and
a flat bottom surface. Next, two new focus points are selected,
with the first focus point positioned midway between the probe
positions in the x-y grid and near the uppermost depth (z) of the
exposed electrode. The second focus point is also positioned midway
between the probe positions in the x-y grid, but near the lowermost
depth (z) of the exposed electrode. Next, a treatment zone boundary
line is created in the x-z grid using one of the methods described
earlier. The actual placement of each focus point may be closer
together, namely, not positioned in the uppermost and lowermost x-y
planes defined by the exposed portions. The placement of each focus
point should be selected so that the treatment zone boundary line
that is created in the x-z grid closely matches the treatment zone
boundary lines that were created in the uppermost and lowermost x-y
grids. Next, the treatment zone boundary line that was created in
the x-z grid according to the two focus points is rotated about the
axis joining the two focus points. This creates the shapes for the
upper and lower 3-D volumes which are added to the flat top surface
and the flat bottom surface described above.
[0071] The above methods can be applied by persons of ordinary
skill in the art to create 3-D treatment zones between exposed
portions of electrodes even when the probes are not parallel to
each other and even when the amount of the exposed portion varies
with each probe.
[0072] Furthermore, there are situations where it is advantageous
to show multiple boundary zones as a result of a therapy. For
example, indicating which regimes undergo no change, reversible
electroporation, irreversible electroporation, and conventional
thermal damage is possible in accordance with the present
invention. In addition, it is possible to output the entire
distribution rather than just delineating boundaries.
[0073] It has been shown repeatedly in the literature that tissue
properties are highly variable between tissue types, between
individuals, and even within an individual. These changes may
result from differences in body fat composition, hydration levels,
and hormone cycles. Due to the large dependence of IRE
(irreversible electroporation) treatments on tissue conductivity,
it is imperative to have accurate values. Therefore, to obtain
viable conductivity values prior to treatment, a low amplitude
voltage pulse is used between the electrode conductors and the
resultant impedance/conductance is measured as a way to determine
pertinent tissue property data such as the predicted current. The
value determined may then be implemented when assessing field
strength and treatment protocol in real time. For example, the
resulting impedance or predicted current can be used to set the
default electric field density.
[0074] One method of generating an estimated treatment region
between a pair of treatment electrodes is a numerical model based
method involving finite element analysis (FEA). For example, U.S.
Patent Application Publication No. 2007/0043345, which is hereby
incorporated by reference, discloses using FEA models to generate
treatment zones between a pair of electrodes (the calculations were
performed using MATLAB's finite element solver, Femlab v2.2 (The
MathWorks, Inc. Natick, Mass.)).
[0075] Most engineering problems can be solved by breaking the
system into cells where each corner of the cell or mesh is a node.
FEA is used to relate each node to each of the other nodes by
applying sets of partial differential equations. This type of a
system can be coded by scratch, but most people use one of many
commercial FEA programs that automatically define the mesh and
create the equations given the model geometry and boundary
conditions. Some FEA programs only work in one area of engineering,
for example, heat transfer and others are known as multiphysics.
These systems can convert electricity to heat and can be used for
studying the relationships between different types of energy.
[0076] Typically the FEA mesh is not homogeneous and areas of
transition have increased mesh density. The time and resources
(memory) required to solve the FEA problem are proportional to the
number of nodes, so it is generally unwise to have a uniformly
small mesh over the entire model. If possible, FEA users also try
to limit the analysis to 2D problems and/or use planes of symmetry
to limit the size of the model being considered because even a
modest 2D model often requires 30 minutes to several hours to run.
By comparison, a 3D Model usually takes several hours to several
days to run. A complicated model like a weather system or a crash
simulation may take a super computer several days to complete.
[0077] Depending on the complexity of the FEA models that are
required, the purchase price of the FEA modeling software can cost
several thousand dollars for a low end system to $30 k for a non
linear multiphysics system. The systems that model the weather are
custom made and cost tens of millions of dollars.
[0078] In one example, the steps which are required for generating
a treatment zone between a pair of treatment probes using finite
element analysis include: (1) creating the geometry of interest
(e.g., a plane of tissue with two circular electrodes); (2)
defining the materials involved (e.g., tissue, metal); (3) defining
the boundary conditions (e.g., Initial voltage, Initial
temperature); (4) defining the system load (e.g., change the
voltage of the electrodes to 3,000V); (5) determining the type of
solver that will be used; (6) determining whether to use a time
response or steady state solution; (7) running the model and wait
for the analysis to finish; and (8) displaying the results.
[0079] Using FEA, however, may not be practical for use in
calculating and displaying in real time a treatment zone that is
created between a pair of treatment probes in accordance with the
present invention because of the time required to run these types
of analyses. For the present invention, the system should allow a
user to experiment with probe placement and should calculate a new
treatment zone in less than a few seconds. Accordingly, the FEA
model is not appropriate for such use and it would be desirable to
find an analytic solution (closed form solution), which can
calculate the treatment zones with only simple equations, but which
closely approximate the solutions from a numerical model analysis
such as the finite element analysis. The closed loop solutions
should preferably generate the treatment zone calculation in a
fraction of a second so as to allow a physician/user to experiment
with probe placement in real time.
[0080] There are different closed loop (analytical model analysis)
methods for estimating and displaying a treatment zone between a
pair of treatment probes, which produce similar results to what
would have been derived by a numerical model analysis such as FEA,
but without the expense and time of performing FEA. Analytical
models are mathematical models that have a closed form solution,
i.e., the solution to the equations used to describe changes in a
system can be expressed as a mathematical analytic function. The
following method represents just one of the non-limiting examples
of such alternative closed loop solutions.
[0081] In mathematics, a Cassini oval is a set (or locus) of points
in the plane such that each point p on the oval bears a special
relation to two other fixed points q.sub.1 and q.sub.2: the product
of the distance from p to q.sub.1 and the distance from p to
q.sub.2 is constant. That is, if the function dist(x,y) is defined
to be the distance from a point x to a point y, then all points p
on a Cassini oval satisfy the equation:
dist(q.sub.1,p).times.dist(q.sub.2,p)=b.sup.2 (2)
[0082] where b is a constant.
[0083] The points q.sub.1 and q.sub.2 are called the foci of the
oval.
[0084] Suppose q.sub.1 is the point (a,0), and q.sub.2 is the point
(-a,0). Then the points on the curve satisfy the equation:
((x-a).sup.2+y.sup.2)((x+a).sup.2+y.sup.2)=b.sup.4 (3)
[0085] The equivalent polar equation is:
r.sup.4-2a.sup.2r.sup.2 cos 2.theta.=b.sup.4-a.sup.4 (4)
[0086] The shape of the oval depends on the ratio b/a. When b/a is
greater than 1, the locus is a single, connected loop. When b/a is
less than 1, the locus comprises two disconnected loops. When b/a
is equal to 1, the locus is a lemniscate of Bernoulli.
[0087] The Cassini equation provides a very efficient algorithm for
plotting the boundary line of the treatment zone that was created
between two probes on the grid 200. By taking pairs of probes for
each firing sequence, the first probe is set as q.sub.1 being the
point (a,0) and the second probe is set as q.sub.2 being the point
(-a,0).
[0088] The polar equation for the Cassini curve is preferably used
because it provides a more efficient equation for computation. The
current algorithm can work equally as well by using the Cartesian
equation of the Cassini curve. By solving for r.sup.2 from eq. (4)
above, the following polar equation was developed:
r.sup.2=a.sup.2 cos(2*theta)+/-sqrt(b.sup.4-a.sup.4
sin.sup.2(2*theta)) (5) [0089] where a=the distance from the origin
(0,0) to each probe in cm; and [0090] where b is calculated from
the following equation:
[0090] b 2 = [ V [ ln ( a ) ( 595.28 ) + 2339 ] ( A 650 ) ] 2 ( 6 )
##EQU00001## [0091] where V=the Voltage (V) applied between the
probes; [0092] where a=the same a from eq. (5); and [0093] where
A=the electric field density (V/cm) that is required to ablate the
desired type of tissue according to known scientific values.
[0094] As can be seen from the mathematics involved in the
equation, r can be up to four separate values for each given value
for theta.
Example 1
[0095] If V=2495 Volts; a=0.7 cm; and A=650 V/cm;
[0096] Then b.sup.2=1.376377
[0097] and then a cassini curve can be plotted by using eq. (5)
above by solving for r, for each degree of theta from 0 degrees to
360 degrees.
[0098] A portion of the solutions for eq. (5) are shown in Table 1
below:
[0099] where M=a.sup.2 cos(2*theta); and L=sqrt(b.sup.4-a.sup.4
sin.sup.2(2*theta))
TABLE-US-00001 TABLE 1 Theta r = r = r = r = (degrees) sqrt(M + L)
-sqrt(M + L) sqrt(M - L) -sqrt(M - L) 0 1.366154 -1.36615 0 0 1
1.366006 -1.36601 0 0 2 1.365562 -1.36556 0 0 3 1.364822 -1.36482 0
0 4 1.363788 -1.36379 0 0 5 1.362461 -1.36246 0 0 6 1.360843
-1.36084 0 0 7 1.358936 -1.35894 0 0 8 1.356743 -1.35674 0 0 9
1.354267 -1.35427 0 0 10 1.351512 -1.35151 0 0 11 1.348481 -1.34848
0 0 12 1.34518 -1.34518 0 0 13 1.341611 -1.34161 0 0 14 1.337782
-1.33778 0 0 15 1.333697 -1.3337 0 0
[0100] The above eq. (6) was developed according to the following
analysis.
[0101] The curve from the cassini oval equation was calibrated as
best as possible to the 650 V/cm contour line using two 1-mm
diameter electrodes with an electrode spacing between 0.5-5 cm and
an arbitrary applied voltage.
[0102] For this worksheet, q.sub.1 and q.sub.2 reference points
(taken to be +/-electrodes) could be moved to locations along the
x-axis to points of (.+-.a,0). A voltage could then be selected,
and an arbitrary scaling factor ("gain denominator") would convert
this voltage to the corresponding "b" used in eq. (4). The
worksheet would then plot the resulting Cassini oval, which has a
shape progression with applied voltage beginning as two circles
around the electrodes that grow into irregular ellipses before
converging into a single "peanut" shape that ultimately becomes an
ellipse expanding from the original electrode locations.
[0103] The Cassini oval creates a reasonable visualization that
mimics the shape of numerical results for the field distribution.
In order to understand which values or levels correspond to a
desired electric field of interest, a calibration involving the
b.sup.4 term was necessary to develop the relationship between the
analytical Cassini oval and the numerical results. This was done
through a backwards calibration process defined as follows:
[0104] 1. A reference contour was selected to correlate the
analytical and numerical solutions. This was chosen to be when
b/a=1, forming a lemniscate of Bernoulli (the point where the two
ellipses first connect, forming "00").
[0105] 2. A reference electric field density value was selected to
be 650 V/cm.
[0106] 3. Numerical models were developed to mimic the x-y output
from the Cassini oval for scenarios where a=.+-.0.25, 0.5, 0.75,
1.0, 1.25, 1.5, 1.75, 2.0, 2.25, and 2.5 cm.
[0107] 4. Models were solved using trial and error to determine
which voltage yielded the electric field contour of 650 V/cm in the
shape of a lemniscate of Bernoulli.
[0108] 5. The determined voltage was placed into the Cassini oval
electronic worksheet for the same electrode geometry and the "gain
denominator" was adjusted until the shape from the cassini oval
matched that from the numerical solution.
[0109] 6. The determined gain denominators for all values of "a"
were collected and a calibration plot was made and fitted with a
logarithmic trendline of:
Gain Denominator=595.28ln(a)+2339; R.sup.2=0.993 (7)
[0110] 7. The calibration trendline function shown above was
incorporated back into the Cassini Oval spreadsheet. At this point,
the worksheet was capable of outputting a field contour of 650 V/cm
for any electrode separation distance (.+-.a) and applied voltage
(V).
[0111] 8. The calibration function was then scaled to a desired
electric field contour input. This allowed the analytical solution
to solve for any electric field for any given a separation distance
and voltage. Since the Laplace equation is linear, scaling should
provide a good estimate for how other fields would look.
[0112] Table 1 incorporates all the steps above to yield a single,
calibrated Cassini Oval output that analytically predicts the
electric field distribution; providing a quick and simple solution
for the prediction of IRE (irreversible electroporation) treatment
regions that may be adjusted in real-time. The inputs are the
electrode location (as a given ".+-.a" distance from the origin
along the x-axis), the applied voltage to the energized electrode,
and the desired electric field to visualize. The resulting output
is a contour representing a threshold where the entire area within
it has been subjected to an electric field the one selected; and
thus treated by IRE. It is important to remember that the
analytical solution was calibrated for an electric field contour of
650 V/cm, and thus yields an accurate approximation for this value.
Other field strength contours of interest still yield reasonable
results that mimic the overall shape of the electric field.
Overall, the analytical solution provided yields consistently good
predictions for electric field strengths, and thus, treatment
regions of IRE that may be used during treatment planning or
analysis.
[0113] A similar algorithm for calibration can be used for a
bipolar electrode.
[0114] In one example, the diameter of the probe is 0.065 cm, and
the lengths of the two electrodes are respectively 0.295 cm and
0.276 cm, separated by an insulation sleeve of 0.315 cm in length.
Adapting this scenario to the cassini oval presents some challenges
because the distribution is now resulting from the two exposed
cylinder lengths, rather than two distinct loci of points. This was
solved by calibrating individual electric field contours for the
same applied voltage and developing two equations that adjust the
separation distance (.+-.a) and gain denominator (GD) according to
the equations:
a=7*10.sup.-9*E.sup.3-2*10.sup.-5*E.sup.2+0.015*E+6.1619;
R.sup.2=0.9806 (8)
GD=1.0121*E+1920; R.sup.2=0.9928 (9)
[0115] where E is the electric field magnitude contour desired.
These two equations may then be used to calibrate the cassini ovals
into a satisfactory shape to mimic the electric field distribution,
and thus treatment region accordingly.
[0116] FIG. 6 illustrates an example of how to generate a combined
treatment zone according to the invention. Three electrodes 201,
202, 203 defining three individual treatment zones 311, 312, 313,
combine to form a combined treatment region 315 which is shown with
hatched lines. By combining a plurality of treatment zones with
each treatment zone being defined by a pair of electrodes, a
combined treatment region 315 can be displayed on the x-y grid.
[0117] FIG. 7 illustrates one embodiment of a pulse generator
according to the present invention. A USB connection 52 carries
instructions from the user computer 40 to a controller 71. The
controller can be a computer similar to the computer 40 as shown in
FIG. 2. The controller 71 can include a processor, ASIC
(application-specific integrated circuit), microcontroller or wired
logic. The controller 71 then sends the instructions to a pulse
generation circuit 72. The pulse generation circuit 72 generates
the pulses and sends electrical energy to the probes. In the
embodiment shown, the pulses are applied one pair of electrodes at
a time, and then switched to another pair using a switch 74, which
is under the control of the controller 71. The switch 74 is
preferably an electronic switch that switches the probe pairs based
on the instructions received from the computer 40. A sensor 73 such
as a sensor can sense the current or voltage between each pair of
the probes in real time and communicate such information to the
controller 71, which in turn, communicates the information to the
computer 40. If the sensor 73 detects an abnormal condition during
treatment such as a high current or low current condition, then it
will communicate with the controller 71 and the computer 40 which
may cause the controller to send a signal to the pulse generation
circuit 72 to discontinue the pulses for that particular pair of
probes.
[0118] The treatment control module 54 can further include a
feature that tracks the treatment progress and provides the user
with an option to automatically retreat for low or missing pulses,
or over-current pulses (see discussion below). Also, if the
generator stops prematurely for any reason, the treatment control
module 54 can restart at the same point where it terminated, and
administer the missing treatment pulses as part of the same
treatment.
[0119] In other embodiments, the treatment control module 54 is
able to detect certain errors during treatment, which include, but
are not limited to, "charge failure", "hardware failure", "high
current failure", and "low current failure".
[0120] According to the invention, the treatment control module 54
in the computer 40 directs the pulse generator 10 to apply a
plurality of pre-conditioning pulses (first set of pulses) between
the electrodes 22 so as to create a "virtual electrode" (i.e.,
pre-conditioning zone) A1 as shown in FIG. 8. Once the
pre-conditioning zone has been created, the control module 54
directs the generator to apply a plurality of treatment pulses
(second set of pulses) to the electrodes 22 to ablate substantially
all tissue cells in the target ablation zone.
[0121] If the treatment pulses were applied without the
pre-conditioning pulses, then the expected target ablation zone
would result in zone A2. However, due to the pre-conditioning zone
A1, the resulting ablation zone has been enlarged to zone A3 which
is much larger than zone A2.
[0122] As shown in FIG. 8, the pre-conditioned tissue zone A1 is
substantially surrounded by ablation zones A2 and A3. In one
exemplary embodiment, at least two electrodes 22 can be provided.
The electrodes can be positioned anywhere in or near the target
tissue.
[0123] The pre-conditioning pulses can be 1) IRE pulses that
irreversibly electroporate the cell membranes in zone A1, 2)
reversible electroporation pulses that temporarily electroporate
the cell membranes in zone A1, or 3) pulses that cause irreversible
electroporation to some cells and reversible electroporation in
other cells in the same zone. Alternatively, the pre-conditioning
pulses can even be supraporation type pulses (typically
sub-microsecond pulses with 10-80 kV/cm of field strength) that
causes disturbances within the cells which tend to weaken them such
that when the treatment pulses are applied, the cells in zone A1
are more vulnerable to irreversible electroporation even when the
voltage applied may be sufficient for only reversible
electroporation. The particular pre-conditioning pulse parameters
would depend on many factors such as the type of tissue and the
size of zone A1 to be created.
[0124] The mechanism of action for the increased conductivity in
the virtual electrode is as follows. There is a range of non
thermal irreversible electroporation (NTIRE). At one end of the
range, there is just enough irreversible cell membrane damage to
cause cell death. At the other end of the range, there is so much
cell membrane damage that the membrane ruptures (similar to a
balloon popping). The virtual electrode (highest conductivity
tissue) works well in the tissue where the cell membranes have
ruptured. Accordingly, the pre-conditioning pulses are preferably
those that are capable of causing NTIRE which also causes cell
rupturing to at least some of the tissue cells in the
pre-conditioning zone. In another aspect, the pre-conditioning
pulses are capable of causing NTIRE which also causes cell
rupturing to substantially all tissue cells in the pre-conditioning
zone.
[0125] After the target tissue is pre-conditioned using
pre-conditioning electrical pulses, the control module 54 directs
the pulse generator 10 to apply a set of treatment pulses, thereby
forming a second zone of ablation A3 that substantially surrounds
pre-conditioning zone A1. As noted above, zone A3 is substantially
larger than zone A2 which would be the result from application of
only the treatment pulses without the pre-conditioning pulses.
[0126] To pre-condition at least a portion of the target tissue, a
first set of electrical pulses can be delivered to the cells of the
target tissue A1 at a predetermined voltage to form a
pre-conditioned zone. In one aspect, the applied current that is
delivered or electrical impedance during the pre-conditioning pulse
application can be measured to adjust the pulse parameters such as
the number of pulses that need to be delivered to create the
pre-conditioned tissue zone A1. Optionally, one or more test pulses
can be delivered to the electrodes before delivering the first set
of electrical pulses. In one aspect, the applied current/impedance
can be measured using the sensor 73 during the delivery of the test
pulses, and any pulse parameter such as the voltage, number of
pulses, and the duration of the pulses can be adjusted to create
the desired pre-conditioned tissue zone A1 based on the measured
current or impedance. In one exemplary embodiment, the first and
second sets of electrical pulses can be delivered to the target
tissue in the range of from about 2,000 V/cm to about 3,000
V/cm.
[0127] After the target tissue is pre-conditioned using a first set
of electrical pulses, optionally, a predetermined time delay can be
commenced before delivering a second set of electrical pulses to
the target tissue to allow intra-cellular fluid to escape thereby
further increasing the conductance of zone A1. In one exemplary
embodiment, the predetermined time delay between the first set of
electrical pulses and the second set of electrical pulses can be
from about 1 second to about 10 minutes to allow for mixing of
intra-cellular and extra-cellular components. Preferably, the
waiting period ranges from 30 seconds to 8 minutes, and more
preferably 2 minutes to 8 minutes, to allow sufficient time for the
intra-cellular fluid to exit the cells.
[0128] Alternatively, the treatment control module applies a test
pulse through the electrode after the pre-conditioning pulses have
been applied. Based on the applied test pulse, the module 54
determines whether to repeat the application of the
pre-conditioning pulses or proceed to application of the treatment
pulses. In one aspect, the treatment control module 54 determines
whether to repeat the application of the pre-conditioning pulses
based on an electrical conductivity derived from the test pulse.
For example, if the electrical conductivity has not been
sufficiently increased, the module may decide to repeat the
application of pre-conditioning pulses with perhaps lower voltage
or shorter pulse width than before.
[0129] Modeling for the increased ablation area due to an increase
in electrode size is known in the art. See, for example, an article
by Edd entitled "Mathematical Modeling of Irreversible
Electroporation for Treatment Planning", published in Technology in
Cancer Research and Treatment, August 2007, Vol. 6, No. 4, pages
275-286, which is incorporated herein by reference. For more
accuracy, experiments could be performed to modify the equations
discussed herein.
[0130] In one aspect, the first set of electrical pulses can
comprise about 10 pulses to about 100 pulses. More preferably, the
first set of electrical pulses can comprise from about 10 pulses to
about 50 pulses. Still more preferably, the first set of electrical
pulses can comprise from about 10 pulses to about 20 pulses. In one
exemplary embodiment, the first set of electrical pulses can be
delivered to the target tissue with each pulse having a pulse
duration in a range of from about 10 .mu.sec to about 50 .mu.sec at
a voltage between the two electrodes of 2000 to 3000 Volts. In
another embodiment, the pre-conditioning electrical pulses can be
delivered to the target tissue with each pulse having a duration in
a range of from about 10 .mu.sec to about 20 .mu.sec. It has been
observed that large ablations using irreversible electroporation
require longer pulse widths or durations than smaller pulse width
ablations. Narrower pulse widths such as those described herein may
be beneficial because such pulses will substantially affect the
tissue close to the electrodes 22, with a reduced risk of
over-current conditions and reduced joule heating. For example,
applying pulses of 20 .mu.sec width will cause irreversible
electroporation of a narrow band of tissue substantially around the
electrodes 22. The delivery of the first set of electrical pulses
can be repeated until a predetermined level of
conductivity/impedance is measured in the target tissue.
Alternatively, the delivery of the first set of electrical pulses
can be repeated until a predetermined number of electrical pulses
is delivered to the target tissue. In one example, the
predetermined number of pulses can be between about 10 pulses and
about 300 pulses. In another example, the predetermined number of
pulses can be about 100 pulses.
[0131] Pre-conditioning the tissue zone A1 around the electrodes 22
causes the tissue surrounding the electrodes 22 to be more
conductive and increases the ability of the tissue to electrically
couple to the electrodes. If the electrical coupling between the
electrodes and the target tissue is enhanced, this allows higher
voltages to be delivered and larger ablations to be created. The
higher conductivity of the tissue also helps to increase the
ablation size of the tissue and to reduce the incidence of arcing
from the electrode tips. As the target tissue is pre-conditioned by
being irreversibly electroporated, an electric field gradient is
established where the target tissue is most conductive near the
electrodes 22. In one aspect, the pre-conditioned tissue allows the
electric field gradient to become steeper compared to
non-pre-conditioned target tissue.
[0132] The second set of electrical pulses (treatment pulses) can
comprise at least 10 pulses and in one embodiment, about 10 pulses
to about 100 pulses. In another embodiment, the second set of
electrical pulses can comprise about 10 pulses to about 50 pulses.
In yet another embodiment, the second set of electrical pulses can
comprise about 10 pulses to about 20 pulses. In one exemplary
embodiment, the second set of electrical pulses can be delivered to
the target tissue with each pulse having a duration in a range of
from about 70 .mu.sec to about 100 .mu.sec at a voltage between the
two electrodes of 2000 to 3000 Volts. Alternatively, the second set
of pulses (treatment pulses) may be supra-poration pulses that have
a pulse with of 1 microsecond or less and a voltage of 10 kV/cm or
more. Still in another alternative embodiment, the second set of
electrical pulses have a pulse width of 0.3 microsecond to 10
microseconds and a pulse application frequency of 50 kHz or higher.
The higher frequency of the pulses may reduce or even eliminate
movement of the patient and may allow treatment of a zone made of
different tissue types.
[0133] The delivery of an additional second set of pulses to the
target tissue and/or the use of predetermined time delays between
sets of pulses helps to further increase the ablation zone of the
irreversibly electroporated tissue to electric field thresholds
that are lower than currently published values. In one embodiment,
the first predetermined voltage of the first set of electrical
pulses can be greater than the second predetermined voltage of the
second set of electrical pulses. In another embodiment, the first
predetermined voltage of the first set of electrical pulses can be
less than the second predetermined voltage. In yet another
embodiment, the first predetermined voltage can be substantially
equal to the second predetermined voltage. Typically, however,
compared to the pre-conditioning pulses, the treatment pulses have
a higher pulse width, higher voltage or both.
[0134] In one aspect, the virtual electrode A1 can comprise target
tissue that has been severely electroporated. Severe
electroporation is the formation of pores in cell membranes by the
action of high-voltage electric fields. When the cells of the
target tissue are severely electroporated, the intracellular
components of the cells of the target tissue are destroyed in a
very short amount of time, i.e., several minutes compared to two
hours to one day in irreversibly electroporated target tissue. The
severe electroporation of the cells of the target tissue results in
a fatal disruption of the normal controlled flow of material across
a membrane of the cells in the target tissue, such that the target
tissue comprises substantially no intracellular components. When
severely electroporated, the cells of the target tissue
catastrophically fail, yet the target tissue cell nuclei are still
intact. When severe electroporation occurs and sufficient
intra-cellular components have been excreted from the cells of the
target tissue, this helps to make the cells of the target tissue
locally and highly conductive. When the tissue around the
electrodes is highly porated, the local tissue resistance is
greatly reduced, and the tissue will couple better to the active
electrode. The severely electroporated tissue thus forms a virtual
electrode to allow a substantial increase in the target ablation
zone.
[0135] FIG. 9 illustrates at least two severe electroporation zones
49 that are positioned such that they substantially surround at
least a portion of the electrodes 22. In these areas of severe
electroporation the electrical fields are very high. These areas of
target tissue having increased electrical field strength can also
have local edema, which is an abnormal accumulation of fluid
beneath the skin or in one or more cavities of the body that
produces swelling. The increased local fluid content in the target
tissue will improve electrical coupling of the target tissue to the
electrodes 22. The higher local fluid content will help keep the
outer surface of the electrode wet. Further, the mixing of
intra-cellular contents that have a high ionic content with
extra-cellular fluid contents that have a lower ionic content can
increase the local conductivity of the target tissue.
[0136] In yet another aspect, an agent can be provided and
delivered to the target tissue before, during, or after an ablation
to improve electrical coupling between the electrode and the target
tissue. The agent can be a surface tension modifier, a wetting
agent, a liquid, a gel, or any combination thereof. The agent can
be delivered through the electrodes to the target tissue. In one
exemplary embodiment, one or more of the electrodes 22 can have
openings positioned along the outer surface of the electrodes 22.
The openings of the electrodes 22 can be in fluid communication
with an inner lumen of the electrodes. An agent can be delivered
through the lumen of one or more of the electrodes 22 along the
outer surface of the electrodes 22. In one exemplary embodiment,
the one or more agents can be diffused along the entire length of
the electrodes 22 before, during, or after a target tissue
ablation. Additional benefits of "wetting" the target tissue either
through the target tissue's increased fluid content, as described
above, or by manually providing a wetting agent, include a reduced
probability of arcing from the electrode to the target tissue. A
larger ablation area can also be created by using a larger virtual
electrode, as illustrated in FIG. 8. Further, reduced Joule heating
occurs around the electrodes 22 as a result of the delivery of
shorter or narrower width pulses or pulse durations to the target
tissue, which also requires less applied energy. In yet another
aspect, a high conductivity fluid can be infused into the target
tissue before, during, or after the ablation to increase the local
conductivity of the target tissue near the electrodes 22. In one
exemplary aspect, the high conductivity fluid can be, e.g.,
hypertonic saline or a similar liquid.
[0137] In one embodiment, the ablation process as described above,
including the progress thereof, can be monitored by detecting the
associated change in impedance (either real, imaginary or complex)
through the sensor 73 in the ablated tissue for both the
pre-conditioning step and treatment pulse application step. In the
pre-conditioning step, once the outer perimeter of the ablated,
liquid-like pre-conditioned tissue is defined, the impedance can
stabilize or level out. Thus, the progress of the pre-conditioning
step can be monitored by measuring changes in impedance, and
pre-conditioning pulse application can be discontinued once a
change in impedance is no longer observed. Alternatively, once the
pre-conditioning pulses have been applied, the treatment control
module 54 continuously monitors the change in impedance of tissue
between the two electrodes. The impedance should decrease as
conductive intra-cellular fluid from the pre-conditioned tissue
cells starts to ooze out. Once a predetermined impedance (or a
predetermined impedance decrease) has been reached, the treatment
control module 54 moves to the step of applying the treatment
pulses between the electrodes.
[0138] In another embodiment, the applied current of the electrical
pulses can be continuously measured during pre-conditioning pulse
application, and the number of pulses, the voltage level, and the
length of the pulses can be adjusted to create a predetermined
virtual electrode.
[0139] Although the present treatment method has been discussed in
relation to irreversible electroporation (IRE), the principles of
this invention can be applied to any other method where therapeutic
energy is applied at more than one point. For example, other
methods can include reversible electroporation, supraporation, RF
ablation, cryo-ablation, microwave ablation, etc. "Supraporation"
uses much higher voltages, in comparison to electroporation, but
with shorter pulse widths.
[0140] In addition to the example parameters described above,
specific electro-medical applications of this technology include
reversible electroporation as well as irreversible electroporation.
This could include reversible or irreversible damage to the
external cell membranes or membranes of the organelles, or damage
to individual cellular structures such as mitochondrion so as to
affect cellular metabolism or homeostasis of voltage or ion levels.
Example embodiments for reversible electroporation can involve 1-8
pulses with a field strength of 1-100 V/cm. Other embodiment
altering cellular structure adversely involve supraporation pulse
generators having a voltage range of 100 kV-300 kV operating with
nano-second (sub-microsecond) pulses with a minimum field strength
of 2,000V/cm to and in excess of 20,000V/cm between electrodes.
Certain embodiments involve between 1-15 pulses between 5
microseconds and 62,000 milliseconds, while others involve pulses
of 75 microseconds to 20,000 milliseconds. In certain embodiments
the electric field density for the treatment is from 100 Volts per
centimeter (V/cm) to 7,000 V/cm, while in other embodiments the
density is 200 to 2000 V/cm as well as from 300 V/cm to 1000 V/cm.
Yet additional embodiments have a maximum field strength density
between electrodes of 250V/cm to 500V/cm. The number of pulses can
vary. In certain embodiments the number of pulses is from 1 to 100
pulses. In one embodiment, as described herein, between about 10
pulses and about 100 pulses can be applied at about 2,000 V/cm to
about 3,000 V/cm with a pulse width of about 10 .mu.sec to about 50
.mu.sec. After applying these pulses, a predetermined time delay of
from about 1 second to about 10 minutes can optionally be commenced
in order that intra-cellular contents and extra-cellular contents
of the target tissue cells can mix. This procedure can be repeated,
as necessary, until a conductivity change is measured in the
tissue. Following this step, about 1 pulse to about 300 pulses of
about 2,000 V/cm to about 3,000 V/cm can be applied with a pulse
width of about 70 .mu.sec to about 100 .mu.sec to widely ablate the
tissue. This last step can be repeated until a desired number of
ablation pulses is delivered to the tissue, for example, in the
range of about 10 pulses to about 300 pulses, more particularly,
about 100 pulses. In other embodiments, groups of 1 to 100 pulses
(here groups of pulses are also called pulse-trains) are applied in
succession following a gap of time. In certain embodiments the gap
of time between groups of pulses is 0.5 second to 10 seconds.
[0141] In summary, a method of increasing the ablation size in a
living mammal such as a human is executed by the system, which
includes the computer 40 storing the treatment control module 54
and the generator 10. The treatment control module executes the
following steps. The size, shape, and position of a lesion are
identified with an imaging device 30. The treatment control module
54 as described above is started by a user. The dimensions of the
lesion, the type of probe device, and other parameters for
treatment are received either automatically or through user inputs.
Based on these inputs, the treatment control module 54 generates a
lesion image placed on a grid. Based on the lesion size and the
number of probes/electrodes to be used, the treatment module
determines whether it is sufficiently large to require
pre-conditioning steps according to the present invention. If so,
the control module 54 automatically sets the probe locations and
generates an estimated target zone superimposed on the lesion image
based on the enlarged ablation target zone expected from adding the
pre-conditioning step.
[0142] The user is allowed to click and drag each of the
probes/electrodes. The user can verify that the image of the lesion
is adequately covered by the ablation region that is estimated by
the treatment control module 54. If necessary, the user can select
a treatment device with additional probes or make other
adjustments. The user can then physically place the probes in the
patient based on the placement which was selected on the grid. The
user can adjust the placement of the probes on the grid if
necessary based on the actual placement in the patient. The user is
now ready to treat the tissue as described above.
[0143] Therapeutic energy deliver devices disclosed herein are
designed for tissue destruction in general, such as resection,
excision, coagulation, disruption, denaturation, and ablation, and
are applicable in a variety of surgical procedures, including but
not limited to open surgeries, minimally invasive surgeries (e.g.,
laparoscopic surgeries, endoscopic surgeries, surgeries through
natural body orifices), thermal ablation surgeries, non-thermal
surgeries, as well as other procedures known to one of ordinary
skill in the art. The devices may be designed as disposables or for
repeated uses.
[0144] The above disclosure is intended to be illustrative and not
exhaustive. This description will suggest many modifications,
variations, and alternatives may be made by ordinary skill in this
art without departing from the scope of the invention. Those
familiar with the art may recognize other equivalents to the
specific embodiments described herein. Accordingly, the scope of
the invention is not limited to the foregoing specification.
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