WO2011047387A2 - Planification du traitement pour les thérapies par électroporation - Google Patents

Planification du traitement pour les thérapies par électroporation Download PDF

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WO2011047387A2
WO2011047387A2 PCT/US2010/053077 US2010053077W WO2011047387A2 WO 2011047387 A2 WO2011047387 A2 WO 2011047387A2 US 2010053077 W US2010053077 W US 2010053077W WO 2011047387 A2 WO2011047387 A2 WO 2011047387A2
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pulse
pulses
tissue
treatment
treatment planning
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PCT/US2010/053077
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WO2011047387A3 (fr
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Robert E. Neal
Paulo A. Garcia
Rafael V. Davalos
John H. Rossmeisl
John L. Robertson
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Virginia Tech Intellectual Properties, Inc.
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Priority to EP10824248.8A priority Critical patent/EP2488251A4/fr
Publication of WO2011047387A2 publication Critical patent/WO2011047387A2/fr
Publication of WO2011047387A3 publication Critical patent/WO2011047387A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • the present invention provides systems, methods, and devices for
  • Embodiments provide patient-specific treatment protocols derived by the numerical modeling of 3D reconstructions of target tissue from images taken of the tissue, and optionally accounting for one or more of physical constraints and/or dynamic tissue properties.
  • the present invention further relates to systems, methods, and devices for delivering bipolar electric pulses for irreversible electroporation without damage to tissue typically associated with an EBT-induced excessive charge delivered to the tissue and mitigate electrochemical effects that may distort the treatment region.
  • EBTs electrogenetransfer or electrochemotherapy
  • electrogenetransfer or electrochemotherapy may often be administered in a minimally invasive fashion.
  • changes in the tissue's permeability, and therefore also its electrical conductivity allow one to visualize and monitor affected regions in real-time. These changes are most pronounced in homogeneous and image-dense tissues, such as hyperechoic ultrasound tissues, where increased permeability decreases the electroporated echogenicity.
  • Many tumors and other tissues are far too heterogeneous or exhibit properties that do not allow for simple visualization of the electroporated areas.
  • these changes for real-time imaging typically only designate electroporated regions, not necessarily those killed for IRE therapies.
  • typical electrodes and pulsing parameters (number of pulses, pulse polarity, pulse length, repetition rate, pulse shape, applied voltage, electrode geometry and orientation, etc.) will have a large impact on the affected areas.
  • Typical therapeutic geometries dictated by current electrode setups will be ellipsoidal in general shape. However, many tumors do not distinctly fit the shapes created by a single setup of an electrode.
  • EBTs typically requires a complex array of electrodes and pulse parameters arranged in a specific manner to ensure complete treatment of the targeted area while minimizing effects to healthy tissue and sparing vital structures.
  • Such predictions of superimposing treatment regions for complex protocols can be cumbersome. Therefore, treatment planning techniques that aid or allow a practitioner to develop general treatment protocols for most clinical tumors are typically used to effectively capitalize on the great therapeutic potential for IRE and other EBTs.
  • the interpolation techniques provide the physician with diagrams of 3D numerical model solution predicted treatment areas from very specific settings, including an exact number of pulses, pulse length, voltage, and electrode setup (e.g., separation distance, exposure length, and diameter) with dimensions provided for the treatment areas in 2 planes and the general shape.
  • the predicted treatment dimensions are taken from the experimental results of applying that specific set of conditions in experimental subjects, typically in healthy, homogeneous environments. It is from this diagram of expected region, that the physician would set up their electrodes the same way and use the same pulses and arrange multiple applications to the point where they anticipate they will have treated the entire volume.
  • the targeted volume is smaller than the dimensions in the diagram, the practitioner has no information about how much to change the physical setup (exposure length, separation distance, etc.), or pulse parameters (voltage, number of pulses, etc.) in order to prevent damaging the surrounding tissue.
  • the practitioner will not be able to adjust the protocol to minimize damage beyond the targeted margin while still treating the targeted area.
  • lookup table of treatment dimensions or uses a calibrated analytical solution to mimic the shape of numerical simulations.
  • the lookup table may be taken from a large compilation of simulations run at varying the physical and pulse parameters, where dimensions of interest for predicted treatment regions are taken based on a calibrated electric field threshold found to represent the affected margin of interest observed in experiments on healthy tissue (IRE, reversible electroporation, no electroporation, thermal damage).
  • NanoKnife® embodiment see how the predicted affected margins vary in real-time. This provides the practitioner a much better method to find and place an appropriate electrode array with variable voltages to treat the entire region.
  • the analytical embodiment is a simple cross-sectional view of predicted margins at the center of the electrodes. This means that it cannot account for the fa 11 off of electric field distribution (and therefore affected margins) at the tips of the electrodes. Although use of this approach can mimic the shape and size of these regions in 2D, it is not possible to accurately depict 3D scenario shapes in detail. Further, the lookup table cannot easily provide an accurate 3D shape, nor can the analytical solution be adapted.
  • FIGS. 1A-D A comparison of the electric field distribution (A,C) and conductivity map (B,D) of two identical numerical models without (A,B) and with (C,D) changing conductivity is shown in FIGS. 1A-D. From these figures, one can see how the conductivity increases from 0.1 S/m (the baseline level for the entire tissue domain, constant in part B) up to 0.155 S/m, an increase of 55%, for regions experiencing predicted IRE (deep red in part D), with regions experiencing varying extents of predicted reversible electroporation filling in between this (cyan through bright red).
  • Tumors will often have different electrical and physical properties than their neighboring tissues or even from their native tissues of origin (e.g., cancerous astrocytes which may not behave the same as normal ones).
  • surrounding tissues of different tissue types will also have different properties from each other (bone, muscle, fat, blood).
  • EBTs electric field to which the tissue is exposed
  • these changes will change the shape and size of the affected regions.
  • Numerical simulations are capable of modeling the electric field distribution in such heterogeneous systems.
  • the rigid analytical solutions cannot be adjusted to account for such differences, and therefore could not as accurately predict affected regions for the different environments in clinical cases.
  • the analytical solution e.g., could not predict the differences between a tumor situated adjacent to the skull, the quadriceps muscle, or the heart.
  • lookup tables could theoretically be developed for the dimensions of the affected regions in a number of environments, the great variability between the anatomy of each patient, each specific tumor, and each exact tumor location relative to its environment is impractical and futile.
  • FIGS.2A-J demonstrate the effect of heterogeneous systems on electric field distribution. These figures show the electric field and temperature distribution for a three- dimensional numerical model. More particularly, FIG. 2J shows the model setup, where two needle electrodes (1 mm in diameter) are placed within the outer borders of a targeted region of tissue, surrounded by a peripheral region. The red and black regions on the electrodes represent the energized surfaces, where 4200 V was applied to one electrode and the other was set to ground. The thermal properties were set to represent a targeted region of a tumor within fat.
  • FIGS. 2A-I show the numerical model outputs for conductivity ratios (a a p ) of 0.1 (A,D,G), 1 (B,E, F), and 10 (C,F,I); showing electric field (A-F) during the pulse and temperature (G-l) distributions 1 second after the first pulse.
  • the higher conductivity ratios show progressively more area treated by IRE with less thermal effects.
  • Targeted tissue boundary may be seen as the solid black line. Observing the electric field distribution at the boundary shows that the shape is also changing (not just size) as a result of the heterogeneous environment.
  • Existing treatment planning systems are not capable of accounting for such dynamic tissue properties in real time.
  • the current embodiment of the treatment planning software still leaves it up to the practitioner to select a desired number of probes, but provides no simple method of showing how the optimized distributions will be shaped if the user wants to directly compare using different numbers of probes for a given lesion.
  • the current system therefore also does not select the optimal number of probes for the user, a question that may be difficult to answer for more complex electrode geometries.
  • Temperature changes associated with Joule-type resistive heating of the tissue will also affect local regions conductivity based on its temperature (typically increases by approximately 3%/°C). This will also change the size and shape of the electric field distribution based on the parameters used; including the number of pulses, pulse length, and repetition rate for an entire protocol (more pulses of longer length with higher repetition rates will all increase the thermally-associated conductivity changes, increasing this variation). Because the current treatment planning tools are based on simulations from the electric field distribution of a single application of a pulse, these dynamic conductivity behaviors also cannot be taken into account. Something that does would have to be able to simulate the changes that occur as a result of thermal effects on conductivity.
  • embodiments of the invention provide treatment planning systems, methods, and devices for determining a patient-specific electroporation-based treatment protocol comprising: a) a module operably configured to receive and process information from medical images of a target structure to prepare a 3-D reconstruction model of the target structure; and b) a module operably configured to perform a numerical model analysis using as inputs in the analysis the 3-D reconstruction and information from one or more of physical constraints, tissue heterogeneities, dynamic effects of electropermeabilization, dynamic thermal effects, or effects resulting from multiple treatments; and c) a module operably configured to construct one or more electrical protocols defining a treatment region and treatment parameters for effectively treating the target structure.
  • treatment planning systems for determining a patient-specific electroporation-based treatment protocol comprising: a) a processing module operably configured for performing the following stages: 1) receiving and processing information from medical images of a target structure and preparing a 3-D reconstruction model of the target structure; 2) performing a numerical model analysis using as inputs in the analysis the 3-D reconstruction and information from one or more of physical constraints, tissue heterogeneities, dynamic effects of
  • electropermeabilization, dynamic thermal effects, or effects resulting from multiple treatments and 3) constructing one or more protocols each providing a treatment region with parameters for electroporating the target structure; and b) a processor for executing the stages of the processing module.
  • Such treatment planning systems can comprise a processing module capable of performing one or more of the stages in real time.
  • Information from medical images to be analyzed in treatment systems according to em bodiments of the invention can be extracted from one or an array of images obtained from pathologic specimens or one or more imaging modalities chosen from radiographs, tomograms, nuclear scintigraphic scans, CT, MRI, PET, or US.
  • the information from one or more of these sources can be compiled to prepare a 3D reconstruction of the target area, which is represented by a surface or a solid volume.
  • the treatment planning systems according to embodiments of the invention can have as a target structure a) a targeted region or mass; or b) a targeted region or mass with neighboring regions; or c) a 3D map of voxels to be treated as independent elements in the finite modeling software.
  • Preferred numerical model analysis for treatment systems of the invention comprise finite element modeling (FEM). Even more preferred as treatment planning systems, wherein the numerical model analysis involves accounting for physical constraints, tissue heterogeneities, dynamic effects of electropermeabilization, dynamic thermal effects, and multiple treatment effects.
  • FEM finite element modeling
  • the treatment planning systems can comprise a self-optimization algorithm which is capable of repeatedly evaluating one or more of physical constraints, placement of electrodes, electric field distribution simulations, and evaluation of outcome success until one or more effective protocol is constructed. It can also generate a predicted treatment time that will aid the physician in determining the optimal protocol.
  • the treatment planning systems can involve automatically, interactively, or automatically and interactively with or without user input determining the treatment region and parameters for electroporating.
  • Such treatment planning systems can also be capable of constructing protocols for an initial patient treatment or retreatment with or without additional medical images.
  • Treatment systems according to embodiments of the invention can also be adapted to instruct an electrical waveform generator to perform the protocol.
  • Such systems can further comprise an electrical waveform generator in operable communication with the processing module and capable of receiving and executing the treatment protocol.
  • Instructions for implementing the treatment protocols can comprise specifying a number of bipolar pulses to be delivered, a length of pulse duration, and a length of any delay between pulses. Additionally, the generators of such treatment systems can be operably configured for delivering a bipolar pulse train.
  • treatment planning methods can comprise: a) receiving and processing information from medical images of a target structure and preparing a 3-D reconstruction model of the target structure; b) performing a numerical model analysis using as inputs in the analysis the 3-D reconstruction and information from one or more of physical constraints, tissue heterogeneities, dynamic effects of electropermeabilization, dynamic thermal effects, or effects resulting from multiple treatments; and c) constructing an electroporation protocol based on results of the analyzing; wherein the receiving, processing, analyzing, and constructing is performed in real time.
  • Other methods may comprise method steps for reducing adverse effects of irreversible electroporation of tissue comprising administering electrical pulses through electrodes to tissue in a manner which causes irreversible electroporation of the tissue but minimizes electrical charge build up on the electrodes, or minimizes charge delivered to the tissue, or both.
  • Adverse effects to be avoided may include, to name a few, one or more of thermal damage of the tissue, deleterious electrochemical effects, or electrolysis.
  • Preferred methods according to the invention may comprise electrical pulses comprising a series of unipolar and bipolar pulses with a net charge of zero. More particularly, the net charge of zero can achieved by a change in potential direction for each pulse, or a change in potential direction within each pulse.
  • electrical pulses generated in the methods can together comprise a pulse protocol comprising a train of unipolar pulses followed by a train of unipolar pulses of opposite polarity, or a train of bipolar pulses, or simultaneous unipolar pulses of opposite polarity which are offset from one another by a desired amount, or a combination of protocols.
  • Electrical pulses used in the methods, systems, and devices of the invention can have a waveform which is square, triangular, trapezoidal, exponential decay, sawtooth, sinusoidal, or of alternating polarity, or comprise a combination of one or more waveforms.
  • Control systems for electroporation devices are also considered embodiments of the present invention.
  • Such systems can be configured to comprise: a) a processor in operable communication with a control module; b) a control module executable by the processor and in operable communication with an electrical circuit, wherein the control module is operably configured for initiating switching of the circuit at a rate of between 10 ms to 1 ns; and c) an electrical circuit operably configured to enable delivery of a voltage to an electrode and switching of the voltage to a second electrode to cause reversing of the polarity of the electric potential between the two electrodes.
  • electroporation system embodiments of the invention can comprise: a) an electroporation device capable of delivering a first unipolar electrical pulse; b) the electroporation device further capable of, or a second electroporation device capable of, delivering a second unipolar electrical pulse which is opposite in polarity to the first unipolar pulse; c) a processor in operable communication with a control module; d) a control module executable by the processor and in operable communication with the electroporation device(s), wherein the control module is operably configured for initiating delivery of the first unipolar electrical pulse at a time 1 and for initiating delivery of the second unipolar electrical pulse at time 2 offset from time 1 by 1 second to 1 nanosecond.
  • Electroporation devices can also be operably configured to enable delivery of an electrical pulse to a first electrode, switching of the pulse to a second electrode to cause reversing of the polarity of the electric potential between the two electrodes, and switching of the pulse back to the first electrode or to zero, wherein a cycle of switching is established which cycle is capable of being performed at a rate of between 10 milliseconds to 1 ns.
  • Such devices, systems, and methods can be configured to provide for switching to occur between or within the electrical pulse.
  • Devices for example, can be configured such that the electrical pulses together comprise a pulse protocol comprising a train of unipolar pulses followed by a train of unipolar pulses of opposite polarity or a train of bipolar pulses.
  • FIGS. 1A-D are schematic diagrams comparing the electric field distribution (A,C) and conductivity map (B,D) of two identical numerical models without (A,B) and with (C,D) changing conductivity.
  • FIGS. 2A-I are schematic diagrams showing the numerical model outputs for conductivity ratios (a a p ) of 0.1 (A,D,G), 1 (B,E,F), and 10 (C,F,I); showing electric field (A-F) during the pulse and temperature (G-l) distributions 1 second after the first pulse.
  • FIG. 2J is a schematic diagram showing placement of the electrodes in the targeted tissue for the set up illustrated in FIGS. 2A-I.
  • FIG. 3 is a series of CT images showing the presence of a tumor in the left thigh of the canine patient of Example I.
  • FIG. 4 is a CT image from FIG. 3, within which the region of interest is traced.
  • FIG. 5 is a drawing of a 3D reconstruction of the target region of Example I, which was reconstructed by compiling a series of axial traces to create a representative shape of the targeted region in three dimensions.
  • FIG. 6 is the drawing of the 3D reconstructed geometry shown in FIG. 5 visualized relative to the rest of the patient.
  • FIG. 7 is a graphic representation of the 3D reconstruction of FIG. 5 as imported into and converted within Comsol Multiphysics.
  • FIG. 8 is a graph from Duck, 1990, showing the relationship between conductivity and %-water, which may also be used to estimate a tissue's electrical properties.
  • FIG. 9 is the drawing of the 3D reconstruction of the target tumor of FIG. 5 visualized in relation to surrounding structures within the body, which is a tool useful for developing treatment constraints.
  • FIG. 10 is a graphic representation of the 3D reconstruction of FIG. 5 as imported into and converted within Comsol Multiphysics and further including a demonstrative electrode placement for an exemplary treatment protocol.
  • FIG. 11A is a schematic representation of an electric field distribution map, showing a top view of the electrodes of FIG. 10 in an energized state.
  • FIGS. 11B-D are schematic diagrams demonstrating falloff of the electric field distribution in the third dimension, showing an exemplary electric field distribution in the xz-plane (FIG. 11B), in the xy-plane at the midpoint of the electrodes, and in the xy-plane at the tips of the electrodes.
  • FIG. 12A is a schematic drawing showing a representative geometry of the treatment area in which compiled ellipsoids (shown in pink) illustrate the electroporation protocol developed to attain the desired treatment objectives.
  • FIG. 12B is a schematic drawing showing a top view of the treatment area geometry shown in FIG. 12A, and further demonstrating the electrode insertion paths.
  • FIGS. 13A-B are respectively schematic diagrams of an electric field distribution and a corresponding conductivity map demonstrating a homogeneous distribution that only changes by 0.1% for visualization purposes when irreversible electroporation is accomplished.
  • FIGS. 14A-B are respectively schematic diagrams of an electric field distribution and a corresponding cumulative conductivity map demonstrating a treatment region where more than two electrode pairs are energized and homogeneous distribution only changes by 0.1% for visualization purposes when irreversible electroporation is accomplished.
  • FIGS. 15A-B are respectively schematic diagrams of an electric field distribution and a corresponding conductivity map demonstrating a heterogeneous distribution that changes from 0.67 S/m to 0.241 due to electropermeabilization caused by electroporation.
  • FIGS. 16A-B are respectively schematic diagrams of an electric field distribution and a corresponding conductivity map demonstrating a heterogeneous distribution that changes from 0.67 S/m to 0.241 S/m due to electropermeabilization.
  • FIGS. 20A-B are two-dimensional (2-D) diagnostic Tl post-contrast M RI scans in which the tumor was traced.
  • FIGS. 21A-H is a graphic representation of a three-dimensional (3-D) solid representing a tumor volume and displaying the voltage configurations that would mainly affect tumor tissue in this particular situation.
  • FIG. 22 is a graph showing a Bipolar IRE pulse (100 ⁇ duration) with alternating polarity in the middle of the pulse.
  • FIG. 23A is a schematic diagram of a representative circuit model for switching polarity between pulses and multipolar pulses.
  • FIG. 23B is a graph showing the shape of a bipolar pulse that can be created using the electrical circuit of FIG. 23A.
  • FIGS. 24A-G are graphs showing various pulsing protocols according to the invention, demonstrating exemplary frequencies, pulse length, and time delay between pulses.
  • FIGS. 25A-B are schematic diagrams showing variations in techniques for generating bipolar electrical pulses in accordance with embodiments of the invention.
  • FIG. 25C is a schematic diagram of a representative circuit model for generating and administering simultaneous, continuous, but offset pulses as shown in FIG. 25A.
  • FIG. 26A is a photograph showing the N-TIRE electrodes with attached fiber optic probes, which were used in this intracranial treatment of white matter to measure temperature during pulse delivery.
  • FIG. 26B is a graph showing temperature [°C] distribution during an N-TIRE treatment in the white matter of a canine subject.
  • Irreversible electroporation is a new focal tissue ablation technique.
  • the treatments are capable of sparing major blood vessels, extracellular matrix and other sensitive or critical structures.
  • the procedure involves the delivery of low-energy electric pulses through minimally invasive electrodes inserted within the tissue.
  • the target tissue is exposed to external electric field distributions around the electrodes, which alter the resting
  • tissue electroporation i.e., no effect, reversible electroporation and/or irreversible electroporation
  • the degree of tissue electroporation depends on the magnitude of the induced transmembrane potential.
  • Numerical models for electric field optimization are available and typically include the physical properties of the tissue and treatment parameters including electrode geometry and pulse parameters (e.g., duration, number, amplitude, polarity, and repetition rate). These models can also incorporate the dynamic changes in tissue electric conductivity due to electroporation and thermal effects.
  • a numerical model to visualize the IRE treated regions using sequential independent combinations of multiple energized and grounded electrodes are capable of being incorporated into the analysis for developing and constructing more effective treatment protocols.
  • a particular embodiment involves setting the resulting conductivity distribution as the initial condition for the next pulse sequence, then repeating this procedure sequentially until all the pulse sequences are completed. In this manner, electric conductivity dependencies from previous pulses are incorporated and more accurate electric field distributions are presented. It is important to note that it is assumed that once a tissue is irreversibly electroporated, the tissue conductivity would not revert back. Consequently, a comprehensive IRE distribution can be presented in which the conductivity changes due to the previous pulses are considered. Such methods are most useful when using three or more electrodes with electrode-pairs being energized independently.
  • the electric conductivity map in certain circumstances can be crucial in the treatment planning of irreversible electroporation and other pulsed electric field therapeutic applications.
  • the conductivity map is what determines how the current generated by the applied voltages/potentials will flow and the magnitude of the electric field. Several factors affect this distribution before, during and after the treatment including tissue heterogeneities, electropermeabilization, thermal effects and multiple treatments.
  • each tissue has its own "resting/unique" electric conductivity before the application of the electric pulses.
  • any particular organ or system there could be a mixture of conductivities that need to be accounted for in the treatment planning as in the case of white matter, gray matter and tumor tissue in the brain for example.
  • each of the tissue's conductivity will vary with changes in temperature as is the case for brain (3.2 % C “1 ) or liver (2 % C "1 ).
  • Numerical modeling methods such as finite element modeling (FEM) are more accurate and are actually where the previous treatment planning systems derive their solutions (the lookup table and analytical solutions are calibrated to mimic the numerical solutions).
  • FEM finite element modeling
  • a canine patient with a 360 cm 3 tumor in the left thigh was treated according to a treatment planning embodiment of the invention. This treatment plan serves to
  • Images of the target lesion or of a portion of the body to be treated can be acquired by taking an array of medical images using one or more imaging modalities, including CT, M RI, PET, or US to name a few.
  • imaging modalities including CT, M RI, PET, or US to name a few.
  • an imaging modality such as computed tomography CT can be used to determine the presence of a tumor.
  • an imaging modality such as computed tomography CT
  • information about or relating to the region of interest can be collected and used to determine a targeted region, its location, its position, any important or relevant nearby structures that must be accounted for (such as blood vessels, nerves, collecting ducts, etc.), and any relative basic dimensions (such as depth within tissue, basic cross-sectional sizes, distance from other structures, etc.).
  • Regions of Interest (ROI) Tracing The target ROI can be outlined in the images used to identify the tumor, whether manually or by way of a computer program, to identify a potential treatment area.
  • a computer program capable of detecting anomalies such as the OsiriX open-source image analysis software (Geneva, Switzerland), could be used to outline the targeted region (e.g., a tumor, site for electrogenetransfer, etc.).
  • the targeted region e.g., a tumor, site for electrogenetransfer, etc.
  • FIG. 4 one of the CT scans from FIG. 3 is shown with the region of interest traced. Tracing the region of interest in each of a series of CT images compiling the 2D traces of each slice would allow for compilation of 3D geometry for the target region.
  • FIG. 5 shows a series of axial traces having been compiled to create a representative shape of the targeted region in three dimensions. This reconstruction may be maneuvered to assess its general shape and thus allow determination of potentially efficient electrode insertion approaches.
  • the reconstructed geometry can also be visualized relative to the rest of the patient.
  • This allows one to assess (in greater detail than the initial FIG. 3 images) physical constraints such as bones preventing electrode insertion, relative location of sensitive structures, and orientation of the lesion relative to the body, allowing a practitioner to evaluate optimal electrode insertion approaches.
  • physical constraints such as bones preventing electrode insertion, relative location of sensitive structures, and orientation of the lesion relative to the body, allowing a practitioner to evaluate optimal electrode insertion approaches.
  • FIG. 6 the long axis of the tumor is roughly parallel to the length leg and femur, so a user may consider reducing the number of electrodes and insertions used by orienting the electrodes along this axis, or they may go with more electrodes perpendicular to the top of the leg (since the femur prevents access from the bottom of the leg).
  • Geometry Modeling The 3D geometry can then be imported into finite element modeling software (FEM). Indeed, several geometries can be imported using software such as Comsol Multiphysics (Comsol, Swiss, Sweden), including: a) just the targeted region or mass; b) the targeted region and other traced neighboring regions (muscle, fat, bone, etc); or a 3D Map of all the voxels to be treated as independent elements in the FEM software. The coordinate system from the medical images can also be matched
  • FIG. 7 shows a model of the 3D target geometry as imported into numerical modeling software. More particularly, the geometry developed and shown in FIG. 5 may be converted to a surface or a solid and imported into numerical modeling software.
  • the black shape is a converted geometry within Comsol Multiphysics for the targeted region reconstructed above. Its dimensions and volume have been normalized to ensure its size matches that of the reconstructed volume.
  • Assign Model Properties Any physical and/or thermal properties and/or electrical properties can be assigned in numerous ways.
  • the properties can be assigned arbitrarily; deduced by designating which of the target region or the other traced neighboring regions are of what tissue type and using properties of these tissue types from the literature; experimentally measured with a "pre-pulse” (e.g., as described in U.S. Patent Application No. 12/491,151, "Irreversible Electroporation to Treat Aberrant Cell Masses;” or the properties can be derived from an algorithm or coordination scheme based on voxel or pixel value imported from the 3D map.
  • the assignment of properties to the model can be performed within software and manually accounted for in placements. If such properties are either assigned arbitrarily or are deduced as described above, the different shapes depicted in the model (e.g., FIG. 7) may each be assigned a different set of properties to best represent the tissue or material used (such as 0.025 S/m for the fatty tumor, and 0.5 S/m for the surrounding tissue).
  • the tissue properties are derived from medical images. Due to the properties of tissue and how the tissues are assessed by modern imaging techniques, it may be possible to derive accurate estimations of a tissue's properties based on its response to the various imaging modalities.
  • pixel values are based on the radiodensity of the tissue at that point in the image (its attenuation). It is common practice to scale these attenuations relative to distilled water according to the equation:
  • ⁇ ⁇ , ⁇ ⁇ and ⁇ 3 ⁇ are the linear attenuation coefficients of that point in the tissue, water, and air, respectively. Essentially, this system normalizes the radiodensity of all tissues relative to water.
  • a tissue's Hounds Unit (HU) value may serve as a representation of its relative water content, with larger absolute value HU's (it can be negative as well) containing less water.
  • FIG. 9 shows a graphic 3D reconstruction of the target tumor in relation to surrounding structures within the body, which is useful for developing treatment constraints.
  • the physical location of the tumor relative to the rest of the body (shown in FIG. 9 by arrows pointing out vasculature and nerves, for example) can be demonstrated using the previously prepared 3D geometric representation of the tumor. This information may be used to constrain or direct where the electrodes should be placed and give priority to regions that should be spared relative to regions that would not cause as significant of problems.
  • FIG. 10 is a graphic 3D representation of the imported tumor geometry with electrodes placed. Here, the geometric representation of the targeted region is depicted in red, while representations of electrodes are shown at two locations in blue. The number, orientation, and location of these electrodes is capable of being manipulated to satisfy the desired treatment objectives.
  • Simulation of the Electric Field Distribution are capable of being correlated with experimental data to superimpose predicted volumes of affected regions (treated, untreated, thermal damage).
  • FIG. 11 shows the electrodes depicted in FIG. 10 in an energized state.
  • a section on the end has been set to a voltage while a section on the rest has been set to ground with a section of insulation between, creating a voltage gradient that surrounds the single needle.
  • the pair of electrodes on the right the entire length of one electrode has been set to a voltage while the other electrode has been set to ground, creating a voltage gradient between them.
  • the color maps are representative electric field isocontour regions that may be used in determining predicted treatment regions, reversible regions, or safety margins based on electric field thresholds. For example, if the protocol anticipates an IRE electric field threshold of 500 V/cm, then the entire volume of the tissue exposed to this electric field or higher (depicted in green) would be the predicted treatment region. In addition, if it were desired to ensure sparing of a sensitive structure such as a nerve, and an exact resolution of the above-predicted 500 V/cm IRE electric threshold was insufficient to guarantee sparing, a different electric field may be used to predict a safety margin which would be used to ensure that this threshold is not crossed by the sensitive structure (such as 250 V/cm depicted in red).
  • the electric field distribution is typically at a maximum at the cross-sectional region midway between the lengths of the electrodes and tapers off toward the ends of the electrodes.
  • the image shown in FIG. 11B shows the electric field distribution between 35000 and 150000 V/m looking at both electrodes simultaneously in the xz-plane.
  • the grey rectangles are the electrodes, running along the z-axis, and separated by 1.5 cm (center-to-center) along the x-axis.
  • the optimization phase of the system was performed qualitatively and was iterated with the previous four steps until settling on the electrode array shown in FIGS. 12A and B.
  • the resultant representative geometry of compiled ellipsoids (shown in pink) illustrates the satisfactory electroporation protocol developed in order to attain the desired treatment objectives.
  • FIG. 12A it can be seen that a highly complex array of electrodes (blue) was selected, where some electrodes are inserted and exposed an amount (such as 1 or 2 cm), to treat an amount of depth with pulsing, before withdrawing them some and repeating the pulsing. This was done to ensure complete treatment along the depth of the treatment.
  • the blue cylinders depict discrete electrode placements for pulsing, and the ones stacked on top of each other represent this aspect.
  • FIG. 12B a top view of the graphic representation of the treatment area of FIG. 12A is provided, in which the electrode insertion paths can be seen. Since the electrodes were all running perpendicular, spacing dimensions have been outlined to aid the placement of the electrodes for the practitioner. The pulses would be administered between each electrode and the electrodes in closest proximity to it. Electric pulse parameters are adjusted between each electrode firing pair based on separation distance and the desired treatment region (based on targeted volume and avoidance of sensitive tissues). The dimensions in red are also used as guidelines for the placement of the outer electrodes relative to the margins of the tumor to prevent excessive treatment of peripheral (untargeted) regions.
  • the generator system for applying the designated pulsing protocol can be set up for implementation of the desired protocol. More particularly, the practitioner could then place the electrodes according to the prescribed protocol and let the generator apply the pulses.
  • the systems, methods, and or devices according to the invention can be operably configured to monitor certain variables.
  • One such variable can include monitoring the temperature of the electrodes and/or surrounding tissue in real time during treatment to ensure limited to no thermal damage to the tissue being treated. If monitored in real time, adjustments could then be made, if necessary, to avoid damage.
  • One, multiple, or all phases of system embodiments according to the invention can be performed manually or be performed (in whole or in any number of parts) by an automated system capable of performing the phases for the practitioner. Many of these steps can be performed without user input, and could be blocked off into distinct automated processes (with/without coupling to human-performed processes) or could be linked together through a comprehensive system. All of this is able to be done for an initial treatment, or redone for any retreatments that may be necessary, with or without new images (depending on case circumstances).
  • Systems according to embodiments of the invention are flexible in that such systems can be operably configured to solve many scenarios numerically and to select the best electrode geometry and pulse parameters for a given situation. Alternatively or additionally, solutions may be obtained analytically, with tables, etc.
  • Embodiments of the systems according to the invention can be operably configured to be run on an independent system well in advance of treatment administration to allow sufficient computation time, review, and possible re-working of the protocol prior to treatment. The appropriate protocol could then be uploaded directly to the pulse generator.
  • Model Creation Preferred embodiments of systems according to the invention include a model creation stage for establishing an initial model of the target area.
  • Treatment geometries (information, such as tumor dimensions, electrodes, and peripheral tissue dimensions, for example) may be input manually, by analyzing medical images that were taken and any reconstructions, from computer analyses of medical images/tomography, or other (2D and 3D) mapping techniques.
  • Conductivity values for the model subdomains may be obtained by measuring them on the subject directly (placing electrodes within tissue then applying a voltage and measuring the current to get ⁇ / ⁇ ), by taking typical values found in the literature for the tissue types, or by noninvasive ⁇ measuring techniques such as functional Magnetic Resonance Imaging (fMRI), Electrical Impedance Tomography, etc; and combining these with the relevant equations (for E-field distributions, it is the ratio between tissues/regions that alters the field, absolute values will only be important when considering thermal effects).
  • fMRI Magnetic Resonance Imaging
  • fMRI Magnetic Resonance Imaging
  • Medical images that obtain the conductivity values (fM RI) or coupled to conductivity values may then be used as the geometries for a numerical/analytical model as the various subdomains, to establish the initial model.
  • Electrodes Once the model geometry has been developed, a single or any set of electrode options (type, number, dimensions, etc.) may be selected to be used or allowed to be selected by the program. [00129] Running the Program. After setting up the geometry and electrode options to consider, the practitioner would essentially select a "GO" button to let the program run through the many variations to use and solve each using FEM or advanced analytical methods. The program would solve each scenario for various effects (no effect, reversible
  • Exemplary Optimization Quality Function can employ a variety of algorithms (iterative, genetic, etc.) in order to optimize the treatment parameters for the best possible result for a particular patient scenario.
  • Such systems can also be operably configured to employ a function for evaluating the quality of each solution, where desired results, D, (IRE and/or REB throughout the targeted regions) are added; and the undesired results, U, (thermal damage, IRE beyond targeted region, etc.) are subtracted, with each aspect having its own unique scaling (since IRE to entire targeted region is far more important that avoiding IRE to healthy tissues).
  • One such function can include:
  • ET Electrode Type and geometry (single/dual, diameter, length);
  • EP Electrode Positioning (location and orientation in 3D space);
  • ⁇ Quality, the value of the protocol on the entire domain of the targeted and surrounding volumes.
  • ⁇ ( ⁇ , EP, ⁇ , 7) This is the value function of a given treatment protocol for the modeled domain previously mentioned as a function of electrode type and geometry, electrode positioning, applied voltage, and any other factors. More specifically: 1) ET(style, number, dimensions), with style referring to the style of the pulse, such as single, multi-unipolar, hybrid, proprietary, etc., with number referring to the number of probes used, and dimensions referring to the geometry and dimensions of all exposed and insulated regions in all three directions for each electrode used.
  • EP refers to the position of each or all electrodes in relation to a reference point arbitrarily chosen within the (x, y, z) domain of the model (location and orientation).
  • the center of the tumor could be selected as the reference point and arbitrarily set to (0, 0, 0).
  • the reference point may also be selected ahead of time or afterwards by the practitioner that will be easy for the practitioner to physically use at the time of treatment administration, such as some anatomical landmark that can be used as a reference for where the electrodes are and the electrode orientation. It is also possible to match the coordinate system from the medical images.
  • the ⁇ function may be solved for altered ET and EP, and the ⁇ may then be scaled accordingly for the geometry (since it the model geometry and properties that will affect the shape of the distribution, the absolute value of it may be scaled to the applied voltage after this shape is found for each ET and EP). This would dramatically reduce the number of iterations and thus the computational cost.
  • the system can be operably configured to iteratively adjust ET, EP, etc. and obtain the resulting ⁇ , storing the top ones (or all those meeting some type of baseline threshold criterion).
  • the resulting stored solutions would then be saved for presentation to the practitioner for conducting a review and visually assessing the value of each solution for selecting the protocol that best meets the demands of the therapy (could range on their arbitrary criterion such as the best quality, most simple to administer and apply the EP in the treatment, most robust, etc.)
  • the electrical parameters used can be set as standardized parameters for typical treatments, and optionally these parameters can be flexible in case certain scenarios require different values - such as abdomino-thoracic procedures requiring repetition rate to be synchronized with the patient's heart rate to reduce the risk of pulse-induced arrhythmias. If known or found experimentally, standard electrical parameters can be used to determine the best combination of treatment parameters to use and have been applied to various tissues/tumors to determine the electric field threshold of each for this set of parameters, thus allowing treatment outcome to be reviewed and not just electric field distributions. Table II provides a list of exemplary electric parameters that can be manipulated within the IRE treatments discussed herein.
  • Pulse length ns - ms range
  • Pulse shape square, triangular, trapezoidal, exponential decay, sawtooth, sinusoidal, alternating polarity
  • Pulse type Positive, negative, neutral electrode charge pulses (changing polarity within pulse)
  • Needle diameter 0. 001 mm - 1 cm
  • Electrode length (needle): 0.1 mm to 30 cm
  • Electrode separation 0.1 mm to 5 cm, or even 5 cm to 20 cm, or 20 cm to 100 cm, and larger (for reversible electroporation, gene delivery, or positive electrode with ground patch on patient's exterior, e.g.)
  • FIGS. 13A-B demonstrate a situation in which there would be little to no change in the physical properties of the tissue as a result of electroporation. More specifically, as shown in FIG. 13A, an electric field distribution [V/cm] generated by an applied voltage difference of 3000V over the upper two electrodes is shown.
  • FIG. 13B provides a conductivity map [S/m] displaying a homogeneous distribution that only changes by 0.1% for visualization purposes when irreversible electroporation is accomplished.
  • the white outline represents the region of tissue that is exposed to an electric field magnitude that is sufficient for generating irreversible electroporation.
  • FIGS. 14A-B demonstrate an electric field distribution and conductivity map for a treatment region for a given situation in which more than two electrode pairs are energized.
  • FIG. 14A an electric field distribution [V/cm] generated by an applied voltage difference of 3000V over the right two electrodes is shown.
  • FIG. 14B shows a conductivity map [S/m] displaying a homogeneous distribution that only changes by 0.1% for visualization purposes when irreversible electroporation is accomplished in this set up.
  • a cumulative visualization of the treatment region is shown.
  • FIGS. 15A-B demonstrate a change in the shape and size of the treatment region due to electropermeabilization. More particularly, in FIG. 15A, an electric field distribution [V/cm] generated by an applied voltage difference of 3000V over the upper two electrodes is shown. FIG. 15B provides a conductivity map [S/m] displaying a heterogeneous distribution that changes from 0.67 S/m to 0.241 due to electropermeabilization as a result of
  • the shape and size of the treatment region is consequently adjusted as a result of this change.
  • FIG. 15B the shape and size of the planned treatment region is different than in the above examples (FIGS. 13B and 14B) in which the conductivity was assumed to remain constant throughout the delivery of the pulses.
  • FIG. 16A provides an electric field distribution [V/cm] generated by an applied voltage difference of 3000V over the right two electrodes
  • FIG. 16B shows a conductivity map [S/m] displaying a heterogeneous distribution that changes from 0.67 S/m to 0.241 S/m due to electropermeabilization.
  • the first set of pulses using the top two electrodes increased the conductivity of the tissue which in turn modified the electric field distribution (i.e., treatment region) for the second application of pulses (right two electrodes) adjacent to the permeabilized region.
  • FIGS. 17-19 are provided.
  • FIG. 17B shows a thermal damage assessment by the potential increase in temperature due to the electric pulses which occurs when greater than 0.53.
  • FIG. 18B shows some thermal damage visualized at the electrode-tissue interface 0.11 cm 2 .
  • FIG. 19B shows significant thermal damage at the electrode-tissue interface due to thermal effects 0.43 cm 2 .
  • Open source image analysis software (OsiriX, Geneva, Switzerland) was used to isolate the brain tumor geometry from the normal brain tissue. The tumor was traced in each of the two-dimensional (2-D) diagnostic Tl post-contrast M RI scans as shown in FIGS. 20A-B. Attempts were made to exclude regions of peritumoral edema from the tumor volume by composite modeling of the tumor geometry using all available M RI sequences (Tl pre- and post- contrast, T2, and FLAIR) and image planes.
  • M RI sequences Tl pre- and post- contrast, T2, and FLAIR
  • a three-dimensional (3-D) solid representation of the tumor volume was generated using previously reported reconstruction procedures.
  • the tumor geometry was then imported into a numerical modeling software (Comsol Multiphysics, v.3.5a, Sweden) in order to simulate the physical effects of the electric pulses in the tumor and surrounding healthy brain tissue.
  • the electric field distribution was determined in which the tissue conductivity incorporates the dynamic changes that occur during
  • V GAP
  • CM EXPOSURE RATIO
  • NanoKnife® AngioDynamics, Queensbury, NY USA
  • the NanoKnife® is an electric pulse generator in which the desired IRE pulse parameters (voltage, pulse duration, number of pulses, and pulse frequency) are entered.
  • the NanoKnife° is also designed to monitor the resulting current from the treatment and to automatically suspend the delivery of the pulses if a current threshold is exceeded.
  • the electrodes were inserted into the tumor tissue in preparation for pulse delivery.
  • the blunt tip electrodes were connected by way of a 6-foot insulated wire (cable) to the generator. After foot pedal activation, the pulses were conducted from the generator to the exposed electrodes.
  • the two sets of pulse strengths were delivered in perpendicular directions to ensure uniform coverage of the tumor and were synchronized with the electrocardiogram (ECG) signal to prevent ventricular fibrillation or cardiac arrhythmias (Ivy Cardiac Trigger Monitor 3000, Branford, CT, USA).
  • ECG electrocardiogram
  • the sets of pulses were delivered with alternating polarity between the sets to reduce charge build-up on the surface of the electrodes.
  • shorter pulse durations than those used in previous IRE studies were used in order to reduce the charge delivered to the tissue and decrease resistive heating during the procedure.
  • alternating polarity of adjacent electrodes minimizes charge build up and provides a more uniform treatment zone. More specifically, in IRE treatments there is an energized and grounded electrode as the pulses are delivered. In embodiments, charge build-up on the surface of the electrodes can be minimized by alternating the polarity between sets of pulses. It is believed that there are still electrode surface effects that can be associated with negative outcomes.
  • FIG. 22 is a graph showing a Bipolar IRE pulse (100 ⁇ duration) with alternating polarity in the middle of the pulse in order to minimize charge delivered to the tissue.
  • negative effects can be prevented, reduced, or avoided as part of IRE treatment in the brain, including deleterious electrochemical effects and/or excessive charge delivered to the tissue as in electroconvulsive therapy.
  • a superficial focal ablative IRE lesion was created in the cranial aspect of the temporal lobe (ectosylvian gyrus) using the NanoKnifeB (AngioDynamics, Queensbury, N.Y.) generator, blunt tip bipolar electrode (AngioDynamics, No. 204002XX) by delivering 9 sets of ten 50 ⁇ pulses (voltage-to-distance ratio 2000 V/cm) with alternating polarity between the sets to prevent charge build-up on the stainless steel electrode surfaces.
  • NanoKnifeB AngioDynamics, Queensbury, N.Y.
  • blunt tip bipolar electrode AngioDynamics, No. 204002XX
  • FIG. 23A is a schematic diagram of a representative circuit model for switching polarity between pulses and multipolar pulses.
  • a basic circuit according to em bodiments of the invention may contain a) a generator supply circuit containing a voltage source and capacitor bank to accumulate sufficient charge for pulse delivery; b) a simultaneous switching mechanism; c) electrodes for pulse delivery (here, 2 electrodes are shown); and d) a parallel capacitor-resistor equivalent to represent the behavior of biological tissues.
  • FIG. 23B shows a bipolar pulse that can be created using the circuit of FIG. 23A.
  • the circuit can be operably configured to function in the following
  • the switches are in position 0.
  • the voltage source would be used to charge an array of capacitors to the desired electric potential for a given pulse.
  • the switches move to position 1. This causes rapid initiation of capacitor discharge, generating a high-slope AV between the electrodes placed in the tissue (the first half of a square wave). This gives electrode 1 a "negative” voltage and electrode 2 a “positive” voltage (based on their relative electric potentials).
  • the capacitor(s) continue delivering the electric charge over time, causing a logarithmic decay of the electric potential to which the tissue is exposed.
  • the switches move to position 2.
  • unipolar pulses may have their polarity reversed every pulse or after any number of pulses by moving the switches from position 0 to 1 for pulse delivery, then back to 0 (first pulse); then from position 0 to 2 for delivery, then back to 0 (second pulse of opposite polarity).
  • a unipolar pulse of any polarity can be reversed after one or more pulses up to any number of desired pulses for a particular application.
  • a time delay between the unipolar pulse and the reversed polarity unipolar pulse can be any desired duration as well, including from 5 times the pulse length (FIG. 24A), to 3 times the pulse length (FIG. 24B), to 1 time the pulse length (FIG. 24C), to no delay (or effectively no delay) at the time of switching (FIG. 24D).
  • the pattern of alternating between pulse polarities can be repeated any number of times to accomplish a desired result.
  • the bipolar pulse of FIG. 24D is shown repeated at timing intervals of 3 times the pulse length (FIG. 24E), to 2 times the pulse length (FIG. 24F), to 1 time the pulse length (FIG. 24G).
  • the delay between bipolar pulses can also be zero (or effectively zero) and/or the bipolar pulses can be repeated any number of time to establish a particular desired pulsing protocol or pattern.
  • the pulses could also be made multipolar by switching from position 0 to 1 (first polarity), then to position 2 (reversed polarity), then back to position 1 (returning to initial polarity), and so on, all within the same pulse.
  • the bipolar pulses can be configured in a manner to deliver a charge to the tissue where the net effect of the pulse is something other than zero.
  • the magnitude of the positive portion of the pulse can be different than the magnitude of the negative portion of the pulse. More specifically, the pulse can be 90% positive and 10% negative or 90% negative and 10% positive. Indeed, any ratio of
  • positivemegative charge can be used, including from 0:100 (mono-polar and positive) to 100:0 (mono-polar and negative). Specifically, 50:50 (net charge of zero) is preferred, but 90:10, 80:20, 75:25, 60:40 and the reverse can be used depending on the desired effect.
  • any switch could be used to alter the length of any pulse or change the pulse repetition rate. And, if varying combinations of different capacitor banks were used in the system, then depending on which ones were connected, it would be possible to change the applied voltage to the electrodes between pulses or within a pulse (of any polarity).
  • the shape and type of pulse can also be varied for particular applications.
  • the individual electric pulses can be unipolar while in other
  • the individual electric pulses can be bipolar.
  • a train of unipolar pulses is delivered in one direction, followed by a subsequent pulse train of opposite polarity.
  • the waveforms of the electric pulses are triangular, square, sinusoidal, exponential, or trapezoidal. Other geometric shapes are contemplated as well.
  • an electrode is connected to a system for employing electrical impedance tomography (EIT), computed tomography (CT), Magnetic Resonance Imaging (MRI), or ultrasound to image the tissue prior to treatment by applying small alternating currents that themselves do not damage the tissue.
  • EIT electrical impedance tomography
  • CT computed tomography
  • MRI Magnetic Resonance Imaging
  • a large variety of other parameters can influence the efficiency of membrane poration, such as the shape of the electrical pulses, polarity, size of target cells, and thermal conditions during and after the pulses.
  • Another method for avoiding excessive charge build up in tissues being treated by electroporation is to deliver counteracting pulses simultaneously from one or more pulse generator.
  • the pulses delivered by the generators can overlap in time for some portion of the pulse and be offset from one another.
  • FIG. 25A illustrates the concept of overlapping the equal but opposite charges delivered from separate pulse generators.
  • a first pulse generator administers a first positive pulse for a desired amount of time.
  • the pulse has a duration in the 10 ns to 10 ms range.
  • a second pulse from a second pulse generator is administered.
  • the second pulse is of the same magnitude as the first pulse yet opposite in polarity.
  • FIG. 25B illustrates one example of administering opposing polarity pulses from two pulse generators simultaneously, but offset and with no overlap.
  • a first positive electrical pulse is initiated by a first pulse generator.
  • a second pulse equal in magnitude to the first pulse but opposite in charge is initiated using a second pulse generator.
  • pulse duration a delay
  • electrical pulses are delivered in a series of two pulses of alternating polarity (from millisecond to nanosecond range).
  • Use of alternating polarities reduces or eliminates charge buildup on the electrode(s).
  • two NanoKnifeTM (AngioDynamics, Queensbury, NY) devices can be linked to the same electrode array, and programmed to deliver synched or slightly offset pulses to the electrodes.
  • the first pulse can generate a 2500 V/cm electric field of 500 ns duration.
  • This pulse is followed immediately (yet slightly offset) by the onset of a second pulse, which generates a -2500 V/cm electric field for 500 ns.
  • the net effect of the pulses in the tissue is a net charge of zero and an additional benefit is avoiding the need for complex circuitry as the need for abrupt switching of the polarity is obviated.
  • the systems, methods, and or devices according to the invention can be operably configured to monitor certain variables, such as temperature of the electrodes and/or surrounding tissue. If monitored during the procedure and in real time, adjustments to the protocol, including adjustments to the type, length, number, and duration of the pulses, could then be made, if necessary, to avoid damage of the tissue being treated.
  • bipolar pulses are only effective for electroporation if each pulse within the train is long enough in duration to charge the plasma membrane to a permeabilizing level. If this is not the case, the pulses offset each other from fully charging the plasma, and supra-poration effects dominate when the pulse amplitude is increased.
  • a delay can be included between pulses within the train, or the total number of pulses within the train can be controlled, to limit the Joule heating in the tissue while still delivering a lethal dose of energy.
  • Embodiments of the invention are equally applicable to any electroporation-based therapy (EBT), including therapies employing reversible electroporation, such as gene delivery therapy and electrochemotherapy, to name a few.
  • EBT electroporation-based therapy
  • One of skill in the art is equipped with the skills to modify the protocols described herein to apply to certain uses.
  • the repetition rate of pulse trains can also be controlled to minimize interference with, and allow treatment of vital organs that respond to electrical signals, such as the heart.
  • the concept of alternating polarity of pulses can be extended to the use of multiple electrodes.
  • this concept can be applied using any numbers of electrodes and pulse times to achieve highly directed cell killing.
  • N-TIRE N-TIRE over other focal ablation techniques
  • the pulses do not generate thermal damage due to resistive heating, thus major blood vessels, extracellular matrix and other tissue structures are spared.
  • B. Al-Sakere, F. Andre, C. Bernat, E. Connault, P. Opolon, R. V. Davalos, B. Rubinsky, and L. M. Mir "Tumor ablation with irreversible electroporation," PLoS ONE, vol. 2, p. ell35, 2007; and J. F. Edd, L. Horowitz, R. V. Davalos, L. M. Mir, and B.
  • temperature in-vivo during the pulse delivery is to use fiber optic probes.
  • FIG. 26A is a photograph showing the N-TIRE electrodes with attached fiber optic probes, which were used in this intracranial treatment of white matter to measure temperature during pulse delivery.
  • FIG. 26B is a graph showing temperature [°C] distribution during an N-TIRE treatment in the white matter of a canine subject. More particularly, what is shown is the temperature distribution measured by the probe located at the electrode-tissue interface and 7.5 mm above the insulation. It is important to note that the starting temperature was approximately 33 °C due to the anesthesia effects and this is neuro-protective during brain procedures in general and that the total pulse delivery took around 300 seconds. For the probe at the interface, four sets of mild increase in temperatures are seen. The probe in the insulation also shows some very mild increase in temperature that is probably due to heat conduction from the treatment region.

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Abstract

Cette invention concerne des systèmes, des procédés, et des dispositifs pour les thérapies par électroporation (EBT). Les modes de réalisation comprennent des protocoles de traitement spécifiques du patient dérivés par modélisation numérique de reconstructions 3D du tissu cible à partir d'images dudit tissu, prenant éventuellement en compte une ou plusieurs contraintes physiques ou propriétés dynamiques du tissu. Cette invention concerne, en outre, des systèmes, des procédés et des dispositifs permettant de délivrer des impulsions électriques bipolaires dans le cadre d'une électroporation irréversible induisant peu, voire aucun des dommages tissulaires typiquement associés à la charge excessive délivrée au tissu et induite par l'EBT.
PCT/US2010/053077 2009-10-16 2010-10-18 Planification du traitement pour les thérapies par électroporation WO2011047387A2 (fr)

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