Patent Grant
10702326
Field of the Invention
The present invention relates to medical devices and methods for treating, reducing, or preventing stenosis using non-thermal irreversible electroporation. Embodiments of the present invention provide balloon catheter devices for treating or preventing stenosis comprising a plurality of electrodes for selectively and irreversibly electroporating a portion of the inner circumference of a tubular structure within the body. Such devices, systems and methods are particularly useful for treating asymmetrical stenosis.
Description of Related Art
Atherosclerosis is the main cause of heart attack, stroke and gangrene of the extremities. See Burt H M, Hunter W L (2006), Drug-eluting stents: a multidisciplinary success story, Adv Drug Deliv Rev 58: 350-357 (“Burt 2006”); and Lusis A J (2000) Atherosclerosis, Nature 407: 233-241 (“Lusis 2000”). Three different processes have been identified in studies of animals with induced hypercholesterolaemia that are thought to participate in the formation of atherosclerotic lesions: 1) proliferation of smooth muscle cells, macrophages and lymphocytes; 2) the formation by smooth muscle cells of a connective tissue matrix comprising elastic fiber proteins, collagen and proteoglycans; and 3) accumulation of lipid and mostly free and esterified cholesterol in the surrounding matrix and the associated cells. See Ross R (1993), The pathogenesis of atherosclerosis: a perspective for the 1990s, Nature 362: 801-809.
The introductions of balloon angioplasty and stent implantation in the coronary arteries have reduced significantly the fatalities associated with this disease, however, coronary artery restenosis and neointimal hyperplasia remain clinical problems. See Lusis 2000; and Al Suwaidi J, Berger P B, Holmes D R, Jr. (2000) Coronary artery stents, Jama 284: 1828-1836. Millions of people are affected by atherosclerosis. One feature of this disease is stenosis, which is defined as an abnormal narrowing or contraction of a tubular body part such as arteries, veins, non-vascular ducts and other tubular structures such as urethra, fallopian tubes, esophageal, bronchial passages, and the like. Stenosis causes decreased blood flow through the vessel. A common treatment for stenosis is bypass surgery with less invasive procedures, such as angioplasty procedures like PTA (percutaneous transluminal angioplasty) also available. Angioplasty involves inserting a balloon catheter into the body to the location of the stenosis, then inflating the balloon against the lesion, and applying pressure to compress the lesion and widen or restore the inside diameter of the blood vessel to restore blood flow. Variations of PTA procedures have been used to treat peripheral arterial stenosis, coronary lesions and other non-vascular tubular structures such as biliary ducts.
Although PTA treatments find success in restoring blood flow, such success may be limited or temporary under certain circumstances. For instance, it has been found that anywhere from three to six months following the angioplasty procedure about half of those treated with PTA develop a re-narrowing or occlusion of the vessel, referred to as restenosis. While the original blockage is formed by plaque deposits on the vessel wall, restenosis is caused by growth of smooth muscle cells of the treated artery after angioplasty. It is the trauma imposed on the vessel wall during angioplasty itself that is the cause of restenosis. More particularly, the body reacts to the angioplasty procedure as an injury and produces scar tissue as cells regenerate on the inner wall of the blood vessel in response to the procedure. It is overgrowth of these cells that causes the restenosis, which is the recurrence of stenosis after the PTA procedure. A second angioplasty procedure or bypass are common treatments for restenosis, but each of these exposes the patient to additional risks. This is because the angioplasty procedure is often a temporary fix as it will retraumatize the vessel wall—resulting in the recurrence of smooth muscle cell proliferation. Adding further complexity to the issue, restenosis often presents itself asymmetrically, characterized by cellular regrowth on only portions of the circumference of the vessel wall. It has been found that eccentric and polypoid narrowings are not amenable to treatment with PTA alone. See Becker G J, Katzen B T, Dake M D, Noncoronary angioplasty, Radiology 1989; 170:921-940.
In attempts to limit the amount of restenosis after angioplasty, efforts have been made to reduce the trauma associated during treatment procedures for stenosis. Such efforts include using balloon catheters equipped for cutting or excising the lesions or in combination with an endomyocardial biopsy device. These efforts, however, have not proven any greater success over conventional angioplasty techniques in preventing restenosis after surgery.
Post-angioplasty approaches for reducing restenosis have also been pursued. One such technique involves implanting drug-eluting stents comprising compositions for suppressing the growth of scar tissue. These techniques have been known to reduce restenosis but are not preferred due to complications, such as localized blood clots after elution of the drug, stent fracture, or other long-term implant issues. Most notable risk factors with stents concern the arterial wall injury that is generated with the implantation of the stent and the pressure applied by the balloon. In-stent restenosis after bare-metal stent (BMS) placement results in an aggressive healing response (neointimal hyperplasia) that causes vascular narrowing. See Burt 2006; Legrand V (2007), Therapy insight: diabetes and drug-eluting stents, Nat Clin Pract Cardiovasc Med 4: 143-150; and Ward M R, Pasterkamp G, Yeung A C, Borst C (2000) Arterial remodeling, Mechanisms and clinical implications, Circulation 102: 1186-1191.
Still others have used angioplasty combined with a technique referred to as non-thermal irreversible electroporation. The IRE approach generally involves treatment of the cells subjected to angioplasty to a therapeutic electric field. The goal is to target the vascular cells to ablate and kill the cells without causing thermal or mechanical damage. This approach selectively kills the target cells while avoiding damage to the structure of the artery and surrounding tissue. Restenosis is thus avoided or reduced because the targeted vascular cells are killed, which then do not have the capability of forming scar tissue (neointimal).
Generally, irreversible electroporation (IRE) is a minimally invasive technique to ablate undesired tissue. See Davalos R V, Mir L M, Rubinsky B (2005), Tissue ablation with irreversible electroporation, Annals of Biomedical Engineering 33: 223-231 (“Davalos 2005”). Maor and colleagues showed that IRE reduces the vascular smooth muscle cells population of major blood vessels without affecting the extracellular matrix, which is crucial in the treatment of coronary artery disease. See Maor E, Ivorra A, Leor J, Rubinsky B (2007), The effect of irreversible electroporation on blood vessels, Technology in Cancer Research and Treatment 6: 307-312. The procedure involves delivering a series of low energy (intense but short) electric pulses to the targeted tissue. These pulses permanently destabilize the cell membranes of the treated tissue and cause cell death. IRE has been shown to be an effective means of tissue ablation that does not require drugs, and creates no secondary thermal effects thereby, preserves extracellular matrix, micro-vasculature and nerves. See Rubinsky B (2007), Irreversible Electroporation in Medicine, Technology in Cancer Research and Treatment 6: 255-260. Furthermore, IRE ablates tissue with sub-millimeter resolution and the treated area can be imaged in real-time using ultrasound, or other imaging techniques such as Magnetic Resonance Imaging, Computed Tomography and/or Intravascular Ultrasound (IVUS).
More particularly, as a result of being exposed to the IRE electric field, the pores of the target cells are opened to a degree beyond which they can recover and the cells die. Concerning restenosis in particular, with fewer cells remaining on the vascular wall after the angioplasty procedure, the cells are unable to grow thus preventing restenosis altogether, or the cells which are limited in number can only experience a limited amount of cellular regrowth thus reducing the amount of restenosis. IRE can be performed before, during, and/or after angioplasty. In some cases, the IRE is preferably performed before restenosis occurs, e.g., before angioplasty to treat tissue that will later be exposed to an angioplasty procedure.
It has been known to use IRE on blood vessels using plate electrodes placed around the carotid artery to apply the electric pulses. See Maor, E., A. Ivorra, J. Leor, and B. Rubinsky, The Effect of Irreversible Electroporation on Blood Vessels, Technol Cancer Res Treat, 2007, 6(4): p. 307-312; Maor, E., A. Ivorra, J. Leor, and B. Rubinsky, Irreversible electroporation attenuates neointimal formation after angioplasty, IEEE Trans Biomed Eng, 2008, 55(9): p. 2268-74; and Maor, E., A. Ivorra, and B. Rubinsky, Non Thermal Irreversible Electroporation: Novel Technology for Vascular Smooth Muscle Cells Ablation, PLoS ONE, 2009, 4(3): p. e4757. Unfortunately, this electrode design is highly invasive and requires the physical exposure of the targeted vessel in order to treat it.
In other existing IRE procedures for treatment of restenosis, the entire circumference of the vessel wall is exposed to the IRE electric field. In such designs it has been known to use an electrode with positive and negative independent conducting surfaces, which are energized in an all-or-nothing system, energizing the entire circumference of the electrode at the same time and with equal energy delivery. Such an approach is not desirable for cases of asymmetrical restenosis, however, where only a portion or less than the entire circumference of the vessel wall is diseased. In treating asymmetric restenosis with circumferential IRE, vascular cells on non-diseased portions of the vessel wall are unnecessarily destroyed.
Thus, it is apparent that there is a need for less invasive, less traumatic treatment procedures for treating, reducing, or preventing restenosis. Especially needed are procedures capable of targeting only the diseased portions of the vascular structure, or capable of targeting only portions of the vascular structure susceptible to restenosis, such as tissue previously subjected to stenosis treatment and/or stenotic tissue prior to treatment.
To this end, embodiments of the present invention provide devices, systems, and methods for treating lesions such as vascular stenosis including restenosis. Especially preferred are such devices, systems, and methods for treating asymmetric lesions, i.e., lesions that extends only partially around the vessel.
Non-thermal irreversible electroporation (NTIRE) treatment methods and devices of the invention include a plurality of electrodes positioned along a balloon of a balloon catheter that are electrically independent from each other so as to be individually selectable in order to more precisely treat an asymmetrical lesion.
According to one aspect of the present invention, a method of treating a stenosis of a tubular body part by non-thermal irreversible electroporation is provided. The method involves: inserting, through the tubular body part, a balloon catheter having at least three electrodes positioned and spaced apart along the balloon, the electrodes being electrically independent from each other; expanding the balloon to bring the electrodes near a stenosis to be treated; determining which electrodes are near the stenosis; and applying electrical pulses to the electrodes according to the determination of which electrodes are near the stenosis, the applied pulses being in an amount which is sufficient to induce irreversible electroporation of cells of the stenosis, but which is insufficient to induce thermal damage to substantially all of the cells of the stenosis such that substantially all stenosis cells are killed by non-thermal irreversible electroporation.
In another aspect of the invention, an entire circumferential area of a vessel can be treated by selectively energizing selected conductive surfaces of an electrode, i.e., delivering the electrical charge asymmetrically with respect to the vessel, however, selection of the conductive surfaces can be rotated for example sequentially to cover a whole circumferential section of a vessel. In such embodiments, since smaller segments of the electrode are being activated at certain times, less power is needed and developing electronics for this would be less complex task.
In another aspect of the invention, the step of applying electrical pulses includes selecting at least one electrode to which the electrical pulses are not to be applied.
In another aspect of the invention, the step of applying electrical pulses includes connecting through a switch a pulse generator output to any pair of the electrodes independent of the other electrodes.
In another aspect of the invention, the step of applying electrical pulses includes control the switch to output the electrical pulses to only those electrodes that have been selected based on a determination of which electrodes are near the stenosis.
In another aspect of the invention, the method further comprises determining at least one individualized electrical parameter for each pair of electrodes based on the determination of which electrodes are near the stenosis.
In another aspect of the invention, the electrical parameter includes Voltage or pulse duration.
In another aspect of the invention, the method further comprises determining at last one individualized electrical parameter for each pair of electrodes based on the depth and proximity of the stenosis in relation to the electrode positions.
In another aspect of the invention, the method includes determining an individualized voltage level to use for each pair of electrodes based on the depth of the restenosis near the each pair.
In another aspect of the invention, which electrodes are near the stenosis is determined by one or more imaging markers disposed near the electrodes.
In another aspect of the invention, the imaging markers include a radiopaque marker capable of rendering an image on any imaging modality, such as CT or IVUS.
In another aspect of the invention, which electrodes are near the stenosis is determined by applying test pulses to different pairs of the electrodes and measuring at least one electrical characteristic of the stenosis cells for the different pairs of electrodes.
In another aspect of the invention, the step of determining includes measuring an electrical resistance as the at least one electrical characteristic of tissue cells.
In another aspect of the invention, the method further comprises displaying a graphical representation and identification of the electrodes in positional relationship to the stenosis. In other words, electrode numbers are shown in relation to the position of the lesion so as to enable a user to determine which electrodes are the closest to the lesion and which electrodes close to the deepest part of the lesion.
In another aspect of the invention, the method further comprises displaying a graphical representation of the stenosis and a graphical representation and identification of the electrodes in positional relationship to the stenosis.
In another aspect of the invention, the method comprises electroplating tissue for the purpose of facilitating electrochemotherapy or electrogenetherapy, wherein cells are reversibly electroporated instead of killed, or the treatment is administered without necessarily killing cells or target tissue. Such methods can include inserting into a vessel an electrode having a plurality of elongated electrically conductive wires disposed lengthwise along the electrode and circumferentially spaced a selected distance from one another; orienting the electrode within the vessel to provide one or more of the electrically conductive wires in position to deliver one or more electrical pulse to target tissue; selecting one or more but less than all of the electrically conductive wires for administering the electrical pulse(s); administering the electrical pulse(s) from the selected electrically conductive wires to deliver the electrical pulse(s) to the target tissue and less than all vessel circumference; and wherein the administering is performed for a time and under circumstances sufficient to deliver drugs or genes to the target tissue or a portion thereof.
Such electrodes can also be used to enable directional targeting for other electroporation based therapies as well. For example, methods of directional targeting for selective macromolecule delivery, such as gene transfer are another application for electrodes of the invention. More particularly, the electrodes can be used for delivering insulin-making genes to pancreatic islets by way of the splenic artery; or can be used in chemotherapy treatments, especially for tumors; or can be used for other improved drug uptakes, such as for non-cancerous drug transports as well. Indeed, devices of the invention can be used as a device for directionally delivering any number of electrically-relevant interventional procedures to be delivered in a radially directed manner through blood vessels. Yet other applications include directional radiofrequency ablation or deep-brain stimulation, to name a couple.
According to another embodiment of the present invention, a medical device for treating a stenosis of a tubular body part by non-thermal irreversible electroporation is provided. The device includes a pulse generator, a balloon catheter, and at least three individually addressable (electrically independent) electrodes. The pulse generator generates electrical pulses in an amount which is sufficient to induce irreversible electroporation of cells of a stenosis to be treated, but which is insufficient to induce thermal damage to substantially all of the cells of the stenosis. The electrodes are positioned and spaced apart along the balloon, and electrically independent from each other. The electrodes are adapted to receive the electrical pulses from the pulse generator such that substantially all of the cells of the stenosis are killed by non-thermal irreversible electroporation. The ability to select which electrodes to energize based on the proximity of the lesion to the electrodes allows more precise targeting of the lesion while minimizing possible damage to surrounding healthy tissue.
In another aspect of the invention, the medical device further comprises a switch connected between a pulse generator and the electrodes, and adapted to connect the pulse generator output to any pair of the electrodes independent of the other electrodes.
In another aspect of the invention, the medical device further comprises a treatment control module adapted to control the switch to output the electrical pulses to those electrodes that have been selected based on a determination of which electrodes are near the stenosis.
In another aspect of the invention, the treatment control module is adapted to determine at least one individualized electrical parameter for each pair of electrodes based on a determination of which electrodes are near the stenosis.
In another aspect of the invention, the electrical parameter of the treatment control module includes Voltage or pulse duration.
In another aspect of the invention, the medical device further comprises one or more imaging markers disposed near the electrodes to determine which electrodes are near the stenosis.
In another aspect of the invention, the medical device comprises imaging markers that include a radiopaque marker.
In another aspect of the invention, the treatment control module is adapted to determine which electrodes are near the stenosis by applying test pulses to different pairs of the electrodes and measuring at least one electrical characteristic of the stenosis cells for the different pairs of electrodes.
In another aspect of the invention, the treatment control module is adapted to measure an electrical resistance as the at least one electrical characteristic of tissue cells.
In another aspect of the invention, the treatment control module is adapted to display a graphical representation and identification of the electrodes in positional relationship to the stenosis.
In another aspect of the invention, the treatment control module is adapted to display a graphical representation of the stenosis and a graphical representation and identification of the electrodes in positional relationship to the stenosis.
In another aspect of the invention, the treatment control module is adapted to determine at last one individualized electrical parameter for each pair of electrodes based on the depth and proximity of the stenosis in relation to the electrode positions.
In another aspect of the invention, the treatment control module is adapted to determine an individualized voltage level to use for each pair of electrodes based on the depth of the restenosis near the each pair.
In another embodiment of the invention, a method for treating a lesion of a tubular body part by non-thermal irreversible electroporation is provided. The method includes: (a) inserting into the tubular body part a plurality of elongated electrodes disposed lengthwise and circumferentially spaced a selected distance from one another; (b) positioning the electrodes within the tubular body part to provide one or more of the electrodes in position to deliver a plurality of electrical pulse to a target lesion; (c) selecting electrodes among the plurality of electrodes for administering the electrical pulses; and (d) administering the electrical pulses through only the selected electrodes to the target lesion in an amount which is sufficient to induce irreversible electroporation of cells of the target lesion, but which is insufficient to induce thermal damage to substantially all of the cells of the target lesion such that substantially all cells of the target lesion are killed by non-thermal irreversible electroporation.
In another aspect of the invention, the electrode comprises a flexible catheter and inflatable balloon and the electrodes are disposed lengthwise along and are circumferentially spaced around a surface of the inflatable balloon.
In another aspect of the invention, the method further comprises determining an orientation of the electrode within the tubular body part by imaging, wherein the electrode comprises at least one imaging marker for determining location of the electrodes.
In another aspect of the invention, the method further comprises measuring a distance between the imaging markers and using the distances to calculate rotational orientation of the electrode.
In another aspect of the invention, the one marker is radio-opaque.
In another aspect of the invention, at least two radio-opaque markers and at least one intravascular ultrasound marker are provided on or near an inflatable balloon.
In another aspect of the invention, the selection step includes: (a) administering one or more test pulses through any one or more of pairs of the electrodes; (b) determining from the test pulses one or more electrical characteristics of tissue subjected to the test pulses and based on the electrical characteristics further determining a depth of the target lesion; and (c) generating a protocol for administering higher voltage electrical pulses between electrode pairs positioned for treating deep restenosis and for administering lower voltage electrical pulses between electrode pairs positioned for treating shallow restenosis.
In another aspect of the invention, the test pulse or signal is a non-electroporating test pulse.
Additionally, in embodiments having an inflatable balloon, the electrically conductive wires (electrodes) can be disposed lengthwise along the electrode and can be circumferentially spaced around the electrode. In preferred embodiments, the electrically conductive wires are disposed circumferentially around the electrode and in contact with a surface of the inflatable balloon.
According to methods of the invention, orientation of the electrode within a body or vessel can be determined. This is particularly helpful for example in situations where it is desired to treat only a portion of the circumferential surface area of a blood vessel. In this situation, it may be desired to know the location of fewer than all of the electrically conductive wires relative to the location of asymmetrical restenosis within a blood vessel. Knowing the relative location of the wires, a practitioner can selectively energize only that portion of the electrode to treat the restenosis site thus leaving intact healthy tissue remaining on other portions of the circumferential surface area of the blood vessel. One such technique can employ an electrode comprising at least one imaging marker and determining the location of the electrically conductive wires by imaging the device in a body or vessel.
Using techniques of the invention and an electrode with at least one imaging marker, methods of the invention can include measuring a distance between the imaging markers and using the distances to calculate rotational orientation of the electrode.
Imaging markers disposed in the electrodes of the invention can be radio-opaque. In embodiments, electrodes can comprise at least one radio-opaque marker. In preferred embodiments, the electrodes can comprise at least two radio-opaque markers and at least one intravascular ultrasound marker. Further, there can be a plurality of radio-opaque markers, each associated with an individual electrically conductive wire of the electrode.
Another method for determining orientation relative to stenotic tissue of electrically conductive wires of an electrode can comprise: (a) inserting into a treatment area, such as a vessel, an electrode having a plurality of electrically conductive wires; (b) administering one or more test signals between two of the electrically conductive wires and subjecting tissue to the test signal(s); (c) determining from the test signal(s) one or more electrical characteristics of the tissue subjected to the test signal(s); and (d) comparing the electrical characteristic(s) to one or more threshold to confirm whether the tissue subjected to the test signal(s) is stenotic and whether the electrically conductive wires are in position to deliver an electrical charge to target stenotic tissue.
The electrical characteristics of the tissue can be determined, e.g., from resistance measurements, impedance measurements, and electrical impedance tomography.
Further embodiments of the invention include a method of mapping depth of stenotic tissue in real-time comprising: (a) inserting into a vessel an electrode having pairs of electrically conductive wires; (b) administering one or more test pulse between any one or more, or all, of the electrically conductive wire pairs; (c) determining from the test pulse(s) one or more electrical characteristics of tissue subjected to the test pulse(s) and based on the electrical characteristics further determining depth of stenosis; and (d) generating a protocol for administering higher voltage electrical pulse(s) between electrically conductive wire pairs positioned for treating deep stenosis and for administering lower voltage electrical pulse(s) between electrically conductive wire pairs positioned for treating shallow stenosis.
Methods disclosed in this specification can be used for treating, preventing, and/or reducing stenosis. Thus, methods according to embodiments of the invention may include identifying stenotic tissue as the target tissue.
An irreversible electroporation medical device is also encompassed within the scope of the present invention and can comprise: (a) an intravascular catheter type electrode having an inflatable balloon and a plurality of electrically conductive wires disposed lengthwise along the electrode/balloon/catheter; and (b) a plurality of imaging markers, each disposed relative to an electrically conductive wire, such that the markers, when subjected to imaging, reveal the identification of each wire and the distance between markers from which rotational orientation of the electrode within a body can be determined. In embodiments, the electrically conductive wires can be elongated and circumferentially spaced around the electrode a selected distance from one another. In other embodiments, the electrically conductive wires can be annular and longitudinally spaced along the length of the electrode a selected distance from one another.
Such methods can employ devices comprising imaging markers that are radio-opaque. Preferably, methods can comprise an electrode with at least two radio-opaque markers and at least one intravascular ultrasound marker to be used in determining orientation of the electrode relative to a treatment site.
Systems are also included within the scope of the invention. Such systems can include an intravascular IRE system comprising: (a) at least one intravascular catheter type electrode having an inflatable balloon and a plurality of electrically conductive wires disposed lengthwise along the electrode and circumferentially spaced a selected distance from one another; (b) an electrical pulse generator in operable communication with and for delivering electrical pulses to the plurality of electrically conductive wires; and (c) a control system in operable communication with the electrical pulse generator comprising a computer program embodied in a computer-readable storage medium, which program when executed, enables a computer to perform a method comprising: (i) determining orientation of the electrically conductive wires relative to target tissue; (ii) selecting one or more but less than all of the electrically conductive wires for administering the electrical pulse(s); and (iii) energizing one or more of the electrically conductive wires to deliver the electrical pulse(s) to the target tissue.
Objects of the invention include computer programs for running the IRE methods, systems, and devices described in this specification. Such computer programs can be embodied in a computer-readable storage medium, which when executed, enables a computer to perform a method comprising: (a) determining orientation relative to target tissue of at least one electrically conductive wire of an electrode; (b) selecting one or more but less than all of the electrically conductive wires for administering electrical pulse(s); and (c) energizing the selected wires to deliver the electrical pulse(s) to the target tissue.
The accompanying drawings illustrate certain aspects of some embodiments of the present invention, and should not be used to limit or define the invention. Together with the written description the drawings serve to explain certain principles of the invention.
Reference will now be made in detail to various exemplary embodiments of the invention. It is to be understood that the following discussion of exemplary embodiments is not intended as a limitation on the invention. Rather, the following discussion is provided to give the reader a more detailed understanding of certain aspects and features of the invention.
Embodiments of the present invention include devices, systems, and methods employing expandable radially targeting electrodes. The electrodes can be designed for endovascular-based electroporation therapies and adapted for implementation with catheter-based guidance. This type of electrode with independently energized surfaces is also adaptable to any number of physical and clinical scenarios where radial targeting is desired.
Preferred electrode designs can be configured to use the combination of electrically conductive wires with an angioplasty balloon to bring the electrodes into direct contact with the targeted region, such as neointimal tissue. More specifically, designs of the present invention can employ for example eight independent conducting surfaces (wires or highly conducting solutions) to administer the electric pulses. The use of multiple conducting surfaces contained within the same electrode presents many advantages over the current state of the art designs. The electrically conductive surfaces of the electrode are not limited to wires. For example, any structure capable of providing a surface for delivering an electric charge can be used, including where the electrically conductive surfaces are bands or strips of material, or are printed on the surface of the balloon, or even further are compartments within an inflatable balloon comprising a highly conductive solution. Energizing the electrically conductive surfaces in sequence rather than collectively promotes an outward distribution of the electric field, reducing thermal effects and requiring lower voltages for treatment. Such techniques provide for an expanded treatment zone by energizing only a few of the electrically conductive wires at a time rather than the entire circumference of the electrode in one shot. In addition, by allowing independent spatial control of which portions of the electrode are energized (i.e., which wires), the electric field distribution may be customized in a manner that most effectively treats a specific lesion, such as an asymmetrical restenosis, while minimizing any damaging effects on healthy tissue. This allows a practitioner to more aggressively treat focally enlarged portions of a lesion while being more conservative on smaller regions of the same stenosis, which is important because it allows for improved accuracy in restenosis-ablation vascular-based surgeries. Further, applications include targeting other volumes located only on one side of a vessel, such as gene transfer targets just outside the vessel or tumor ablation using the tumor vasculature.
Accordingly, embodiments of this invention may be used as a catheter-style electrode to access target restenotic lesions from within the vessel. Embodiments of the present invention may also be used to target tissue disposed outside of the outer circumference of a vessel, such as an area between two or more blood vessels within a body. The use of a catheter electrode allows a practitioner to insert the electrode through a peripheral vessel, as is typical of current percutaneous vascular techniques, such as angioplasty and stenting. This renders treatments minimally invasive and advantageous over previous IRE investigations on blood vessels.
In the context of this specification, it should be noted that the terms “electrode,” “electrode device,” “device,” “balloon catheter electrode,” “catheter electrode,” or “device” are typically used to refer to the IRE medical device as a whole, which may include a catheter, balloon, and electrically conductive wires. The terms “conducting surfaces,” “electrically conductive wires,” “conducting wires,” “wire electrodes,” and “wires” are typically used to refer to a portion of the electrode, such as a pair or pairs of electrodes, which may be selectively energized to deliver electrical pulses. Notwithstanding these typical meanings, in some embodiments in this specification, the terms may be used interchangeably.
Exemplary electrodes according to embodiments of the invention are shown in
Modern micromachining techniques will allow for the construction of even smaller designs that may target smaller vessels, such as the distal portions and branches of the coronary arteries. Indeed, the devices of the present invention may also be scaled up for other applications. Accordingly, the diameter of the outer body of electrodes of the invention can range for example from about 0.1 mm up to about 5 cm. Preferably, electrode embodiments of the invention have an outer diameter ranging from about 0.5 mm to 5 mm, such as from about 1 mm to about 3 mm, such as about 1.5 mm to about 2 mm, or from about 0.75 mm to 3 cm.
In embodiments, the guidewire is the narrowest physical component and is used to direct the surgeon into the appropriate vessel. Although not typical, it can be hollow so that it may be used with a soluble contrast agent used for angiography and fluoroscopy, similar to typical endovascular therapies. See Schwartz, R. S., J. G. Murphy, W. D. Edwards, A. R. Camrud, R. E. Vliestra, and D. R. Holmes, Restenosis after balloon angioplasty, A practical proliferative model in porcine coronary arteries, Circulation, 1990, 82(6): p. 2190-200. The guidewire is usually of a smaller diameter than the diameter of the outer body of the balloon.
The guidewire or catheter forms the support for which all other components of the device are arranged. Over a portion of the catheter between the distal tip and the proximal end of the device is disposed an inflatable balloon. The balloon is secured to the catheter at the distal and proximal ends of the device. An inflation mechanism for providing a fluid into the area between the balloon and catheter is also provided. The balloon can be inflated during use with any inert fluid, such as saline, contrast fluid, air, or even low electrical conductivity sucrose solution. In embodiments where the electrically conductive wires are disposed on the inside of the balloon (between the balloon and the catheter) and where there is present a highly conductive fluid in the lumen (inside the balloon), the flow of the current would be preferentially through the fluid rather than through the wires which may result in a more diffuse electrical field. In preferred embodiments, a low-conductivity buffer is preferred as the fluid to inflate the balloon to more accurately treat target tissue.
The partially insulated conductive wires or electrodes provide for delivering the IRE electrical charge to target tissue from an electrical pulse generator. During use of the device, proximal ends of the wires/electrodes are in operable communication with a pulse generator. The wires can be hardwired directly to the pulse generator, or in preferred embodiments the electrode is equipped with a universal connector (or other connecting structure) for securing the electrically conductive wires/electrodes to the electrical pulse generator in an operably connective manner. For electrodes having a greater number of electrically conductive wires than the number of outputs available on a pulse generator it is desired to be used with, the electrodes and or pulse generator can be retrofitted or adapted accordingly to operably cooperate with one another. In embodiments, when there are more conductive wires on the electrode, e.g., 8 wires, than there are outputs on the pulse generator, e.g., 6 outputs, systems of the invention can comprise an electrode-generator interface that cooperates with the generator to switch which wires are active for a given pulse set in the overall sequence. More specifically, the interface can comprise a switch for switching between wires 4 and 8 for an 8-electrode system, since those wires would be least likely to be energized at the same time at 180° apart. Other examples for operation of an interface for treatments using basic 2-at-a-time pulsing pairs, the system can be connected to all 8 wires on the output, and just have a positive and negative input to take from the generator, where it would automatically switch pairs 1-2 to 2-3 and so on, while the generator's positive and negative outputs (port 1 and 2) would change pulse set 1 at (ex.) 2000 V (wires 1-2), then change to 1500 V (wires 2-3) for the second.
In this embodiment, the electrically conductive wires are elongated and are disposed along the length of the balloon. The wires are spaced a selected distance from one another around the circumference of the electrode. In
The distal tip of the balloon preferably includes a conical distal end to allow easy advancement through the vessel lumen. The conical distal end is preferably formed from or is in operable communication with a portion of the outer body of the device. The outer body of the device is an insulative encasing providing protection for the components of the device and for controlling the amount of exposure of the electrically conductive wires. Another portion of the outer body of the device provides for a proximal encasing disposed at the proximal end of the electrode. In embodiments, there is a gap or separation distance between the distal and proximal encasings or portions of the outer body. This gap or unprotected area of the electrode exposes the electrically conductive wires to the atmosphere.
A connector is disposed proximally of the balloon. The connector is hollow to allow movement with respect to the guidewire, and has an internal chamber that extends all the way back to the proximal ends of the balloon catheter that can carry fluids, such as physiologic saline or air or low electrical conductivity sucrose solution.
The balloon is attached to the connector. Running through the body/connector assembly is an array of 8 conducting 35 gauge wires (0.15 mm). These wires are insulated throughout the electrode apparatus until they reach the highly insulative balloon, after which they are exposed. In embodiments, the conducting wires can be attached to the proximal portion of the connector, but their distal ends are free and enclosed within the casing of the tip. This allows free expansion of the wires with inflation of the balloon. In other embodiments, the wires can be attached to the surface of the balloon and/or the distal ends of the wires attached to the distal tip, or distal outer body, or distal portion of the connector of the electrode. One example of an electrode balloon catheter is disclosed in U.S. patent application Ser. No. 12/413,332 filed Mar. 27, 2009 and entitled “Irreversible Electroporation Device And Method For Attenuating Neointimal”, which is incorporated herein by reference.
During use with the electrode inserted into a blood vessel, when the balloon is inflated with a fluid, the electrodes (electrically conductive wires) are expanded, and placed into contact with the targeted neointimal tissue disposed within the inner circumference of the blood vessel. In the embodiment shown, the length of exposure of each electrode is about 5 mm. However, larger exposure lengths may be used to treat diffuse restenosis lesions. See Rajagopal, V. and S. G. Rockson, Coronary restenosis: a review of mechanisms and management, The American Journal of Medicine, 2003, 115(7): p. 547-553. In specific embodiments, the exposure length of the electrically conductive wires and thus the exposed portion of the electrode can range from about 0.1 mm to about 5 cm, such as from about 0.5 mm to about 3 cm, or from about 0.8 mm to about 2 cm, or from about 1 mm to about 1 cm, or from about 1.5 mm to about 0.5 cm, or from about 2 mm to about 10 mm, or from about 2.5 mm to about 7 mm, or from about 3 mm to about 6 mm, such as from about 3.5 mm to about 4 mm, etc.
The device 700 illustrated here in
The electrically conductive wires can comprise any type of conducting metal, such as platinum/iridium. Different materials will have different radio-opacity and can be selected according to this characteristic to achieve a particular result. For example, silver is much more radio-opaque than titanium and thus some embodiments of electrodes of the invention can have titanium conductive surfaces/wires, while using silver for the markers. To ensure biocompatibility, embodiments of the electrode can be sheathed with an insulating polyurethane jacket 770 to enclose the electrically conductive wires leading to the electrical pulse generator. In embodiments, the electrical conducting wires do not need to be entirely conducting. For example, the electrical conductive surfaces can comprise a portion or portions with an insulating coating (especially near their base). The exposed portions or surfaces of the electrically conductive wires 711, 712 on the distal tip 710 can be any thickness and width. Likewise, the amount of separation distance between the electrically conductive wires at the distal tip 710 can be any amount, and the electrodes can comprise any number of conductive wires. In embodiments, the electrodes can be configured in a manner to provide for an adjustable separation distance between electrically conductive wires, and/or an adjustable amount of exposed conductive surface.
This embodiment is constructed as a thin device, which allows for easy navigation through the cardiovascular system directly into the treatment site. In embodiments where there is no guidance catheter placed first (as in
The device can be customized by varying the diameters and separation distances of the electrically conductive wires, thus unique IRE treated areas can be predicted using mathematical models. As a result, successful treatment for neointimal hyperplasia is ensured due to the ability to match different plaque sizes and shapes.
Further, in some embodiments, the IRE device, or a portion thereof, is flexible. A flexible device is advantageous for use in accessing lesions non-invasively or minimally invasively through natural body cavities. In embodiments where the device or a portion of it is flexible, the shape of the device can change based on contact with body tissues, can be pre-set, or can be altered in real-time through use of wires or other control elements, as known in the art, for example in use with laparoscopic instruments.
Smooth muscle cells are the primary component of the neointimal hyperplasia typical of in-stent restenosis. See Rajagopal, V. and S. G. Rockson, Coronary restenosis: a review of mechanisms and management, The American Journal of Medicine, 2003, 115(7): p. 547-553. In order to kill these cells without damaging the healthy vessel architecture, it is desirable to harness the non-thermal mechanism of IRE to kill cells without inducing thermal damage. Mitigating thermal damage allows the extracellular matrix, nerves, and other sensitive structures to be spared. This allows for healthy regrowth of the tissue.
The primary factor determining the effect of an electroporation procedure is the electric field to which the tissue is exposed. However, IRE protocols have a variety of electrical pulse parameters that may also affect the toxicity of the treatment. In addition to the electric field, these include pulse shape, number of pulses, pulse length, and repetition rate. The thermal effects of an IRE treatment during a pulse are a direct function of the conductivity of the tissue and the voltage to which it is exposed. Therefore, minimizing the thermal effects for a particular tissue type may be done by finding the minimum required electric field, and thus applied voltage, to kill the cells in the tissue.
To this end, pulsing parameters and electrode configurations according to embodiments of the invention can include any combination of any of the following: a pulse length in the range of about 1 μs to 1 ms; a number of pulses ranging from 1 to 10,000; an electric field distribution for each conductive wire pair and/or across a treatment region ranging from about 5-5,000 V/cm; a total electrical charge delivered by way of each conductive wire pair and/or across a treatment region of about 0.1 to about 500 mC; a frequency of pulse application ranging from about 0.001-100 Hz; a frequency of pulse signal ranging from about 0-100 MHz; a pulse shape that is square, exponential decay, sawtooth, sinusoidal, or of alternating polarity although the currently favored pulse shape is a biphasic DC pulse; a positive, negative, and neutral electrical charge pulses (changing polarity within the pulse); a resulting current in the treated tissue ranging from about 0 to about 100 amps; from 1-20 electrodes and/or electrically conductive wires; an electrode and/or electrically conductive wire separation distance ranging from about 0.1 mm to about 5 cm; and multiple sets of pulse/electrode parameters for a single treatment, including changing any of the above parameters within the same treatment, such as removing the electrodes and replacing them in different locations within the tissue or changing the number of electrodes, to specialize/customize outcome.
For example, in embodiments a pulse length in the range of about 1 μs to 1 ms, such as from about 5 μs to about 0.5 ms, or from about 10 μs to about 0.1 ms, or from about 15 μs to about 95 μs. Pulse lengths of 20 μs, 25 μs, 30 μs, 35 μs, 40 μs, 45 μs, 50 μs, 55 μs, 60 μs, 65 μs, 70 μs, 75 μs, 80 μs, 85 μs, 90 μs, 110 μs, 150 μs, or 200 μs, and so on are also acceptable. The number of pulses can range for example from 5 to 5,000, or from about 10 to 2,000, or from about 20 to 1,000, or from about 30 to 500, or from about 50 to 200, or from about 75 to 150, or from about 90 to 120, or from about 95 to 110, or about 100 pulses.
Typically, the electric field distribution for each conductive wire pair and/or across a treatment region for IRE is performed using voltages ranging for example between 1500 V/cm to 4,000 V/cm. Voltages of much lower power can also be used, including using less than about 1500 V/cm. Applied fields of about 500 V/cm to 1000 V/cm can be used, or even of about 10 V/cm to about 750 V/cm, such as from about 50 V/cm to about 200 V/cm, or an electric field distribution of about 75 V/cm to about 100 V/cm. For example, in the treatment of brain tumors, typically, an applied field of less than 1000 V/cm can be used. Electrical pulse generators that can be used include those capable of delivering from 0 to about 5,000 V, such as the NanoKnife® system of AngioDynamics®, which for example can deliver from 0-3,000 V.
In preferred embodiments, a total electrical charge delivered by way of each conductive wire pair and/or across a treatment region of about 0.5 to about 25 mC can be used, such as about 1 mC to about 20 mC, or from about 1.5 mC to about 15 mC, or from about 2 mC to about 10 mC, or from about 5 mC to about 8 mC, and so on. Similarly, in preferred embodiments, the resulting current in the treated tissue can range for example from about 1 A to about 8 A, or from about 2 A to about 6 A, or from about 3 A to about 5 A, such as 4 A. Indeed, for certain applications the total electrical charge delivered can range from about 0.5 to about 500 mC, such as about 10 mC to about 200 mC, or from about 15 mC to about 150 mC, or from about 20 mC to about 100 mC, or from about 50 mC to about 80 mC, and so on. The resulting current in the treated tissue can range for example from about 1 A to about 80 A, or from about 20 A to about 60 A, or from about 30 A to about 50 A, such as 40 A. It is not uncommon for currents for IRE treatments to reach or exceed 40 and 50 amps, and it is further feasible to operate under even higher current with pulse generators capable of operating under such conditions as well. Currents are expected to be high in certain applications, especially when working in an area where the tissue or the medium is highly conductive, such as with blood present in a blood vessel. Pulse width, pulse shape, number of pulses, and the resultant current in the tissue can be adjusted to achieve specific target goals for limiting the total electric charge, and any of the specific values disclosed in this specification can be used to calculate the target expected charge.
Any number of electrically conductive wires or electrodes can also be used. However, in preferred embodiments 3 to about 18 electrodes are used, such as 3 to 16, or from about 3 to 15, or from 4 to 12, or from 5 to 10, or from 6 to 8. Any one or more of the electrodes/wires can be selectively energized to achieve a particular treatment result. Further, the separation distance between electrically conductive surfaces, such as electrically conductive wires and/or electrodes, can range from about 0.2 mm to about 4 mm, such as ranging from about 0.3 mm to about 3 mm, or from about 0.4 mm to about 2 mm, or from about 0.5 mm to about 1 mm, or from about 0.8 mm to about 4 cm, such as from about 0.9 mm to about 3 cm, or from about 1.2 cm to about 2 cm, or from about 1.5 cm to about 1.8 cm, and so on.
The electric field needed for a particular situation may be predicted through numerical modeling, allowing for reliable treatment planning. See Davalos, R. V., L. M. Mir, and B. Rubinsky, Tissue Ablation with Irreversible Electroporation, Ann Biomed Eng, 2005, 33(2): p. 223-231; Robert E. Neal II and R. V. Davalos, The Feasibility of Irreversible Electroporation for the Treatment of Breast Cancer and Other Heterogeneous Systems, Ann Biomed Eng, 2009, 37(12): p. 2615-2625; and Edd, J. F. and R. V. Davalos, Mathematical Modeling of Irreversible Electroporation for Treatment Planning, Technol Cancer Res Treat, 2007, 6(4): p. 275-286. To determine the efficacy of the electrode and understand the effects of the pulses on tissue, a numerical model has been developed capable of simulating treatments. This was done using a finite element software package, COMSOL Multiphysics (COMSOL, Stockholm, Sweden).
Two representative models were developed, simulating the cross section of a typical artery with a symmetric or an asymmetric restenosis. The model setups for the electrodes of
In the numerical models illustrated, both use a blood vessel outer diameter of about 3.6 mm, with a combined tunica media and adventitia thickness of 200 μm, which are representative values derived from visual inspection of results from Maor, E., A. Ivorra, J. Leor, and B. Rubinsky, The Effect of Irreversible Electroporation on Blood Vessels, Technol Cancer Res Treat, 2007, 6(4): p. 307-312. These vessel layers are considered to be composed of collagen and elastin, as described in Saladin, K. S., The Circulatory System III—Blood Vessels, in Human Anatomy. 2008, Mcgraw-Hill: New York. p. 595-638.
The symmetric restenosis (
See Carrara, N. Dielectric Properties of Body Tissues, Italian National Research Council: Institute for Applied Physics, 2007 (“Carrara 2007”) cited 2010, available from: http://niremf.ifac.cnr.it/tissprop/; see also Properties and Selection: Irons, Steels, and High-Performance Alloys, 10 ed. Metals Handbook, Vol. 1, 1990: ASM International (“Metals 1990”); see also Duck, F. A., Physical Properties of Tissue: A Comprehensive Reference Book, 1990, New York: Academic Press (“Duck 1990”); see also Serway, R. A., Principles of Physics, 2nd ed. Principles of Physics, 1998, Fort Worth, Tex.; London: Saunders College Pub (“Serway 1998”); see also Gabriel, C., A. Peyman, and E. H. Grant, Electrical conductivity of tissue at frequencies below 1 MHz, Physics in Medicine and Biology, 2009, 54(16): p. 4863-4878 (“Gabriel 2009”); see also Werner, J. and M. Buse, Temperature profiles with respect to inhomogeneity and geometry of the human body, J Appl Physiol, 1988, 65(30): p. 1110-1118 (“Werner 1988”); see also Kenner, T., H. Leopold, and H. Hinghoferszalkay, Continuous High-Precision Measurement of Density of Flowing Blood, Pflugers Archiv-European Journal of Physiology, 1977, 370(1): p. 25-29 (“Kenner 1977”); see also Bhattacharya, A. and R. L. Mahajan, Temperature dependence of thermal conductivity of biological tissues, Physiological Measurement, 2003, 24(3): p. 769-783 (“Bhattacharya 2003”).
The representative numerical model was solved for the electric field distribution for a voltage of 400 V/cm. This was done either with all conducting surfaces energized in an alternating (V0-0-V0) fashion around the electrode, or with only two adjacent surfaces energized (one as V0 and one as ground). According to embodiments of the invention, any range of energized wire arrangements are possible (E1 at V0 and E3 at 0; or even E1 at V0, E4 at V0/3, and E7 at 0). Indeed, multiple electrodes can be energized while multiple others are set to ground. There is also no limitation on which electrodes can be energized and which are set to ground, which will depend on a particular treatment protocol being administered.
The representative numerical model output of electric field (
It is important to note that the devices of the invention can comprise any number of electrically conductive wires disposed in any manner on the electrode. In methods of the invention, any number of electrically conductive wires can be energized in any order and in any combination. For example, for an electrode having ten electrically conductive wires disposed around the circumference of the electrode and spaced circumferentially or longitudinally from one another and progressing upwardly in number order from 1 to 10, the wires can be selectively energized using all, or less than all of the wires around the circumference of the electrode or along the length of the electrode. Referring to
Referring back to
Notably, when two adjacent wires were energized, the treatment margins of IRE (presumed at 637 V/cm) extend easily through the local neointimal tissue. This shows that lower voltages may be used if pairs of electrodes are energized in succession rather than simultaneously. Furthermore, treating in this way allows for a practitioner to finely tune the applied voltage for each sequence, locally extending treatment regions at thicker regions of restenosis while decreasing treatment margins at thinner regions. From the determination that a lower voltage is required when only two electrodes are energized at a time, it can clearly be seen how the proposed model may be used to investigate the effects of various treatment parameters in order to optimize treatments to be used in clinical and pre-clinical settings.
The electric potentials used to generate the electric fields used in IRE also cause Joule heating of the tissue. This is a function of the electric potential to which a bulk of tissue is exposed, its electrical conductivity, and the time for which it is exposed. The thermal effects of catheter type IRE are illustrated in
More particularly, the thermal behavior of tissue may be assessed using a modified Pennes Bioheat equation with the addition of a Joule heating term as outlined below:
where k is the thermal conductivity of the tissue, T is the temperature, cb and cp are blood and tissue heat capacity, respectively, wb is blood perfusion, Ta is arterial temperature, ρ is tissue density, σ|∇Φ|2 is the joule heating term, and q″ is metabolic heat creation. The outer vessel boundary was treated as adiabatic. See Davalos, R. V. and B. Rubinsky, Temperature considerations during irreversible electroporation, International Journal of Heat and Mass Transfer, 2008, 51(23-24): p. 5617-5622. Because the time scale of the electroporation pulses (microseconds) is much lower than those involved in metabolic heat generation and blood flow (see Werner, J. and M. Buse, Temperature profiles with respect to inhomogeneity and geometry of the human body, J Appl Physiol, 1988, 65(30): p. 1110-1118; and Gautherie, M., Y. Quenneville, and C. M. Gros, Metabolic heat production, growth rate, and prognosis of early breast carcinomas, Biomedicine, 1975, 22: p. 328-336), one is able to see that the dominant terms affecting change in temperature for a volume of tissue is the contributions of heat conduction from neighboring tissues and electroporation pulse induced Joule heating.
By eliminating the blood perfusion and metabolic heat generation terms and rearranging the terms, the equation becomes:
For a single pulse of infinitely small duration, δt, the change in temperature may be described by:
From the modified Pennes' Bioheat equation above, it becomes evident that the controllable terms affecting electroporation-induced temperature changes are the magnitude of the electric field and the duration of the pulse. Assessment of thermal effects from the model would allow one to adjust the protocols to prevent thermal damage and understand its impact on the electric field distribution. For instance, the pulse length could be shortened, a low-conductivity gel could be injected into the tissue, or an actively-cooled electrode could be used to cool the tissue prior to and during pulsing.
The representative numerical model of
To evaluate potential thermal damage, the maximum temperature could be compared to a typical threshold of protein denaturation and scarring of 50° C. (323 K). See Diller, K. R., Advances in Heat Transfer, in Bioengineering Heat Transfer, Y. I. Choi, Editor, 1992, Academic Press Boston. p. 157-357. Because 316 K falls well below this temperature threshold, it is clear that the treatment protocols used in the first part of this numerically modeled example are able to fully treat the targeted region without inflicting thermal damage. It should be noted that thermal damage may occur at temperatures below 50° C. when carried out over a long period of time (such as hours, for example), and that the combined effects of many pulses may further increase the temperatures. However, for the current example of the numerical model outlined above, it may be assumed that the high perfusion rate of blood in an artery will rapidly dissipate the heat generated. In embodiments, however, where the balloon is inflated blood flow within the blood vessel may be greatly reduced or completely blocked and heat dissipation may occur in some other manner. This, in addition to the relatively long span between pulses (for example, meaning 0.25 seconds as compared to 0.0001 seconds of a 100 μs long pulse); allows one to expect that the temperature will return to physiologic temperatures prior to the next pulse, preventing it from ever exceeding the 50° C. threshold.
A method of selectively ablating asymmetric restenosis is illustrated in
Methods of the invention can also include the capability of being able to synchronize the electrical pulses with the cardiac rhythm of the patient to avoid arrhythmia. This is especially important for treatments administered on coronary arteries, e.g., directly at the heart, where chances of arrhythmia are highest. In addition, treatment of arrhythmogenic regions of the heart from the inside is yet another application for the asymmetric ablation protocols of the present invention. In some situations, it is feasible that such treatments could be used in lieu of open heart surgery.
Preferred methods of embodiments of the invention are directed to electrically ablating tissue, with the method comprising: inserting into a vessel an electrode having a plurality of electrically conductive wires disposed lengthwise along the electrode and circumferentially spaced a selected distance from one another; orienting the electrode within the vessel to provide one or more of the electrically conductive wires in position to deliver one or more electrical pulse to target tissue; selecting one or more but less than all of the electrically conductive wires for administering the electrical pulse(s); administering the electrical pulse(s) from the selected electrically conductive wires to deliver the electrical pulse(s) to the target tissue and less than all vessel circumference; and wherein the administering is performed for a time and under circumstances sufficient to cause irreversible electroporation of the target tissue or a portion thereof.
Methods of the invention can also be used for reversible electroporation of tissue to assist or enable electrochemotherapies and/or electrogenetherapies. Even further, aspects of methods of the invention include inserting the electrode device into any organ or vessel which is not in particular a blood vessel, such as within the lymphatic system for treating undesired tissue such as lymphoma. Even further, the electrodes can be used in arrhythmogenic regions of the heart or tumor nodules in the lungs, which can be accessed through vessels of the respiratory tract such as bronchial tubes or blood vessels.
Methods of the invention can employ an electrode comprising a flexible catheter and inflatable balloon with the electrically conductive wires disposed lengthwise along and circumferentially spaced around the electrode, such as on a surface of the inflatable balloon.
In embodiments, the electrically conductive wires can be selectively energized, especially in a sequential manner across only a portion of the circumference of a blood vessel or other treatment area. For example, in embodiments where an electrode comprises eight electrically conductive wires, the method can comprise orienting only a portion of the wires proximate a target treatment area, such as wires 1, 2, and 3 of the eight-wire system. A selected number of pulses at a selected electrical charge can be administered between wires 1 and 2, then a selected number of pulses at a selected electrical charge (which may be different or the same as that applied between wires 1 and 2) may be delivered between wires 2 and 3. Then this pattern or a different pulsing protocol can be administered selectively and sequentially using selected wire pairs. In preferred embodiments, less than all of the wire pairs are used and less than all of the circumference of the electrode is energized during a treatment. In this manner, less than all of the surface area of a blood vessel can be subjected to the IRE.
More particularly, for example, 10 pulses of 50 μs in length at 500 V/cm can be delivered between a first selected electrically conductive wire pair, then 100 pulses of 100 μs in length at 2500 V/cm can be delivered using a second wire pair, then 50 pulses at 75 μs in length at 1000 V/cm can be administered using a third wire pair. This sequence of pulsing can then be repeated any number of times until a desired treatment outcome is reached. Alternatively, any one or more of the pulsing parameters can be changed during the treatment to modify the effect the pulsing protocol is having on the tissue. For example, a second round of pulsing using the first, second, and third wire pairs can be administered by changing the parameters for the third wire pair, such as by delivering 20 pulses that are 90 μs in length at 1500 V/cm. This round of pulsing protocols, or combinations of the protocols, can then be continuously and sequentially administered until a desired treatment result is achieved. By energizing only a portion of the circumference of the electrode (only the first, second, and third wire pairs), only a portion of a selected region of the body that surrounds the electrode, such as a portion of a blood vessel, is subjected to the IRE thus rendering the non-targeted regions unaffected. Changing parameters impacts the depth of IRE ablation. Accordingly, the treatment can be customized to ensure complete treatment of thicker stenotic segments without over-treating regions with shallower stenotic segments.
As shown in
A representative embodiment is provided in
Although a 6-wire system is provided in
Additionally, or alternatively, proximal and distal imaging markers can be provided at one or both ends of the electrode device. In preferred embodiments, the proximal and distal markers can comprise a radio-opaque material with an overall annular shape for disposing each imaging marker around the circumference of the electrode/catheter (to give a definitive start and finish).
With the electrode device inserted into the body of a patient, the region of the body where the device is disposed can be imaged, for example, using x-ray, ultrasound, MRI, CT, or angiography, for example. Depending on the shapes that show up on angiography/x-ray, the orientation of the electrode within the body can be determined, especially its rotational orientation within a blood vessel and relative to a stenotic region. In embodiments, any number of imaging markers can be used, such as from 1-25 and any number in between. In preferred embodiments, at least two markers are used, such as one marker to denote each electrically conductive wire. By measuring the 2D distance from one imaging marker to the next as revealed on an imaging modality, the rotation of the electrode can be determined.
Further, in embodiments, a differential echogenicity (extra bright/dark in ultrasound) can be placed at the distal tip and proximal portions at one or more specific electrically conductive wires so that the marker could be picked up on intravascular ultrasound (IVUS). Using these approaches, it is relatively easy to see wire orientations relative to any asymmetrical stenoses or other targets.
Another embodiment can comprise a radio-opaque spiral rotating in a certain direction from a specific wire. The direction where it rotates from and ends on would give an exact orientation of the catheter.
In yet other embodiments, it is possible to use the wires themselves to identify which are the closest to the restenosis site for purposes of determining which electrodes to energize to treat a targeted area within the vessel. For example, using an electrical charge, a non-electroporating test signal (AC or DC pulse or pulses) can be injected between a pair of wires. Then, the electrical characteristics of the tissue lying between the electrode pair can be measured. The electrical characteristics measured can include, for example, resistance, impedance (complex impedance which includes real and imaginary parts), electrical impedance tomography, and so forth. The measured characteristics of healthy tissue will be different from that of restenotic tissue. The measured characteristics can thus be compared with threshold electrical characteristics determined by experiment, such as shown in U.S. Pat. No. 7,742,795, issued Jun. 22, 2010 to Minnow Medical Inc., incorporated herein by reference.
As shown, the imaging markers in this embodiment are different sizes to identify each marker and differentiate between the two. Here, wire 1's marker is long and wire 3's marker is short. This configuration allows the markers to overlap in length so the distance between the two can be easily measured to get an exact angle of rotation. A schematic providing a cross-sectional view and a side view of the device as it would appear as an image on an imaging device is shown in
Determining the proximity of each wire to the restenotic region is possible due to the differences in impedance between restenotic tissue (densely packed disorganized cells) and blood vessel walls (endothelial layer surrounded by connective tissue). In embodiments, a sequence of non-electroporating electrical test pulses (AC or DC) between any one or more, or all, conducting wire pairs around the perimeter of the catheter could be used to determine the extent/depth of restenosis between each pair in real-time while the balloon is inside the tubular body part. This data could then be used to generate a “map” of restenosis depth around the electrode. This data can further be used to generate a protocol for how strong the electrical pulses should be between each wire pair to ablate all of the restenosis for that portion of the vessel. In other words, greater restenosis depth between electrode pairs would have a greater change in properties, which would guide the practitioner to use higher voltages for that pair to ensure ablation of the entire depth, while areas without as much depth would warrant electrical pulses of lower voltage(s). Accordingly, a machine/program could be used to automatically customize pulse parameters for each pair based on restenosis geometry.
In one embodiment, the treatment control module 54 has been programmed to display on the display device 11 a graphical representation of the stenosis and a graphical representation and identification of the electrodes (e.g., electrode numbers) in positional relationship to the stenosis. Graphically, the image would be similar to that shown in
For example, the module 54 may control the switch to electrically energize pair 0-1 for 10 times, 3-4 for 10 times, 1-2 for 10 times, 2-3 for 10 times, and then repeat the same pattern for 10 times for a total number of 100 repetition for each electrode pair.
Even in such an embodiment, it is preferred to have 2-3 radio-opaque markers as well as at least one intravascular ultrasound marker included, especially in cases where a catheter style electrode is used for applications beyond restenosis ablation, such as a minimally invasive method for targeting ablation/Electrochemotherapy/gene transfer in a region of tissue between two vessels. In such a protocol, one catheter style electrode can be inserted into a first vessel and a second catheter style electrode is inserted into a second vessel proximal in location to the first vessel. Targeting the tissue between the vessels for ablation, wire(s) facing each other from each catheter can be energized to target the tissue in this region. Preferably, only the wires facing each other are energized so that surrounding tissue is not affected.
In specific embodiments, an intravascular IRE system is provided comprising: one or more intravascular catheter type electrode 22 having an inflatable balloon and a plurality of electrically conductive wires disposed lengthwise along the electrode and circumferentially spaced a selected distance from one another; an electrical pulse generator 10 in operable communication with and for delivering electrical pulses to the plurality of electrically conductive wires of the electrodes 22; and a control system 40, 30 in operable communication with the electrical pulse generator 10 comprising a computer program embodied in a computer-readable storage medium, which program when executed, enables a computer 40 to perform a method comprising: determining orientation of the wires of the electrode relative to target tissue 300; selecting one or more but less than all of the electrically conductive wires for administering the electrical pulse(s); and energizing the selected wires to deliver the electrical pulse(s) to the target tissue 300.
The present invention has been described with reference to particular embodiments having various features. In light of the disclosure provided above, it will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the present invention without departing from the scope or spirit of the invention. One skilled in the art will recognize that the disclosed features may be used singularly, in any combination, or omitted based on the requirements and specifications of a given application or design. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.
For example, the device and method described herein may be used to treat other types of lesions such as aneurysm of a blood vessel.
It is noted in particular that where a range of values is provided in this specification, each value between the upper and lower limits of that range is also specifically disclosed. The upper and lower limits of these smaller ranges may independently be included or excluded in the range as well. The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered as exemplary in nature and that variations that do not depart from the essence of the invention fall within the scope of the invention. Further, all of the references cited in this disclosure are each individually incorporated by reference herein in their entireties and as such are intended to provide an efficient way of supplementing the enabling disclosure of this invention as well as provide background detailing the level of ordinary skill in the art.
This application relies on the disclosure of and claims priority to and the benefit of the filing date of U.S. Provisional Application No. 61/508,251, filed Jul. 15, 2011, the disclosure of which is hereby incorporated by reference herein in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1653819 | Northcott et al. | Dec 1927 | A |
| 3730238 | Butler | May 1973 | A |
| 3746004 | Jankelson | Jul 1973 | A |
| 3871359 | Pacela | Mar 1975 | A |
| 4016886 | Doss et al. | Apr 1977 | A |
| 4037341 | Odle et al. | Jul 1977 | A |
| 4216860 | Heimann | Aug 1980 | A |
| 4226246 | Fragnet | Oct 1980 | A |
| 4262672 | Kief | Apr 1981 | A |
| 4267047 | Henne et al. | May 1981 | A |
| 4278092 | Borsanyi et al. | Jul 1981 | A |
| 4299217 | Sagae et al. | Nov 1981 | A |
| 4311148 | Courtney et al. | Jan 1982 | A |
| 4336881 | Babb et al. | Jun 1982 | A |
| 4344436 | Kubota | Aug 1982 | A |
| 4392855 | Oreopoulos et al. | Jul 1983 | A |
| 4406827 | Carim | Sep 1983 | A |
| 4407943 | Cole et al. | Oct 1983 | A |
| 4416276 | Newton et al. | Nov 1983 | A |
| 4447235 | Clarke | May 1984 | A |
| 4469098 | Davi | Sep 1984 | A |
| 4489535 | Veltman | Dec 1984 | A |
| 4512765 | Muto | Apr 1985 | A |
| 4580572 | Granek et al. | Apr 1986 | A |
| 4636199 | Victor | Jan 1987 | A |
| 4672969 | Dew | Jun 1987 | A |
| 4676258 | Inokuchi et al. | Jun 1987 | A |
| 4676782 | Yamamoto et al. | Jun 1987 | A |
| 4687471 | Twardowski et al. | Aug 1987 | A |
| 4716896 | Ackerman | Jan 1988 | A |
| 4723549 | Wholey et al. | Feb 1988 | A |
| D294519 | Hardy | Mar 1988 | S |
| 4756838 | Veltman | Jul 1988 | A |
| 4772269 | Twardowski et al. | Sep 1988 | A |
| 4798585 | Inoue et al. | Jan 1989 | A |
| 4810963 | Blake-Coleman et al. | Mar 1989 | A |
| 4813929 | Semrad | Mar 1989 | A |
| 4819637 | Dormandy et al. | Apr 1989 | A |
| 4822470 | Chang | Apr 1989 | A |
| 4836204 | Landymore et al. | Jun 1989 | A |
| 4840172 | Augustine et al. | Jun 1989 | A |
| 4863426 | Ferragamo et al. | Sep 1989 | A |
| 4885003 | Hillstead | Dec 1989 | A |
| 4886496 | Conoscenti et al. | Dec 1989 | A |
| 4886502 | Poirier et al. | Dec 1989 | A |
| 4889634 | El-Rashidy | Dec 1989 | A |
| 4907601 | Frick | Mar 1990 | A |
| 4919148 | Muccio | Apr 1990 | A |
| 4920978 | Colvin | May 1990 | A |
| 4921484 | Hillstead | May 1990 | A |
| 4946793 | Marshall, III | Aug 1990 | A |
| 4976709 | Sand | Dec 1990 | A |
| 4981477 | Schon et al. | Jan 1991 | A |
| 4986810 | Semrad | Jan 1991 | A |
| 4987895 | Heimlich | Jan 1991 | A |
| 5019034 | Weaver et al. | May 1991 | A |
| 5031775 | Kane | Jul 1991 | A |
| 5052391 | Silberstone et al. | Oct 1991 | A |
| 5053013 | Ensminger et al. | Oct 1991 | A |
| 5058605 | Slovak | Oct 1991 | A |
| 5071558 | Itoh | Dec 1991 | A |
| 5098843 | Calvin | Mar 1992 | A |
| 5122137 | Lennox | Jun 1992 | A |
| 5134070 | Casnig | Jul 1992 | A |
| 5137517 | Loney et al. | Aug 1992 | A |
| 5141499 | Zappacosta | Aug 1992 | A |
| D329496 | Wotton | Sep 1992 | S |
| 5156597 | Verreet et al. | Oct 1992 | A |
| 5173158 | Schmukler | Dec 1992 | A |
| 5186715 | Phillips et al. | Feb 1993 | A |
| 5186800 | Dower | Feb 1993 | A |
| 5188592 | Hakki | Feb 1993 | A |
| 5190541 | Abele et al. | Mar 1993 | A |
| 5192312 | Orton | Mar 1993 | A |
| 5193537 | Freeman | Mar 1993 | A |
| 5209723 | Twardowski et al. | May 1993 | A |
| 5215530 | Hogan | Jun 1993 | A |
| 5224933 | Bromander | Jul 1993 | A |
| 5227730 | King et al. | Jul 1993 | A |
| 5242415 | Kantrowitz et al. | Sep 1993 | A |
| 5273525 | Hofmann | Dec 1993 | A |
| D343687 | Houghton et al. | Jan 1994 | S |
| 5277201 | Stern | Jan 1994 | A |
| 5279564 | Taylor | Jan 1994 | A |
| 5281213 | Milder | Jan 1994 | A |
| 5283194 | Schmukler | Feb 1994 | A |
| 5290263 | Wigness et al. | Mar 1994 | A |
| 5308325 | Quinn et al. | May 1994 | A |
| 5308338 | Helfrich | May 1994 | A |
| 5318543 | Ross et al. | Jun 1994 | A |
| 5318563 | Malis et al. | Jun 1994 | A |
| 5328451 | Davis et al. | Jul 1994 | A |
| 5334167 | Cocanower | Aug 1994 | A |
| 5348554 | Imran et al. | Sep 1994 | A |
| D351661 | Fischer | Oct 1994 | S |
| 5383917 | Desai et al. | Jan 1995 | A |
| 5389069 | Weaver | Feb 1995 | A |
| 5391158 | Peters | Feb 1995 | A |
| 5403311 | Abele et al. | Apr 1995 | A |
| 5405320 | Twardowski et al. | Apr 1995 | A |
| 5425752 | Nguyen | Jun 1995 | A |
| 5439440 | Hofmann | Aug 1995 | A |
| 5458625 | Kendall | Oct 1995 | A |
| 5484400 | Edwards et al. | Jan 1996 | A |
| 5484401 | Rodriguez et al. | Jan 1996 | A |
| 5533999 | Hood et al. | Jul 1996 | A |
| 5536240 | Edwards et al. | Jul 1996 | A |
| 5536267 | Edwards et al. | Jul 1996 | A |
| 5540737 | Fenn | Jul 1996 | A |
| 5546940 | Panescu et al. | Aug 1996 | A |
| 5562720 | Stern et al. | Oct 1996 | A |
| 5575811 | Reid et al. | Nov 1996 | A |
| D376652 | Hunt et al. | Dec 1996 | S |
| 5582588 | Sakurai et al. | Dec 1996 | A |
| 5586982 | Abela | Dec 1996 | A |
| 5588424 | Insler et al. | Dec 1996 | A |
| 5588960 | Edwards et al. | Dec 1996 | A |
| 5599294 | Edwards et al. | Feb 1997 | A |
| 5599311 | Raulerson | Feb 1997 | A |
| 5616126 | Malekmehr et al. | Apr 1997 | A |
| 5620479 | Diederich | Apr 1997 | A |
| 5626146 | Barber et al. | May 1997 | A |
| D380272 | Partika et al. | Jun 1997 | S |
| 5634899 | Shapland et al. | Jun 1997 | A |
| 5643197 | Brucker et al. | Jul 1997 | A |
| 5645855 | Lorenz | Jul 1997 | A |
| 5672173 | Gough et al. | Sep 1997 | A |
| 5674267 | Mir et al. | Oct 1997 | A |
| 5683384 | Gough et al. | Nov 1997 | A |
| 5687723 | Avitall | Nov 1997 | A |
| 5690620 | Knott | Nov 1997 | A |
| 5697905 | d'Ambrosio | Dec 1997 | A |
| 5700252 | Klingenstein | Dec 1997 | A |
| 5702359 | Hofmann et al. | Dec 1997 | A |
| 5718246 | Vona | Feb 1998 | A |
| 5720921 | Meserol | Feb 1998 | A |
| 5735847 | Gough et al. | Apr 1998 | A |
| 5752939 | Makoto | May 1998 | A |
| 5778894 | Dorogi et al. | Jul 1998 | A |
| 5782882 | Lerman et al. | Jul 1998 | A |
| 5800378 | Edwards et al. | Sep 1998 | A |
| 5800484 | Gough et al. | Sep 1998 | A |
| 5807272 | Kun et al. | Sep 1998 | A |
| 5807306 | Shapland et al. | Sep 1998 | A |
| 5807395 | Mulier et al. | Sep 1998 | A |
| 5810742 | Pearlman | Sep 1998 | A |
| 5810762 | Hofmann | Sep 1998 | A |
| 5830184 | Basta | Nov 1998 | A |
| 5836897 | Sakurai et al. | Nov 1998 | A |
| 5836905 | Lemelson et al. | Nov 1998 | A |
| 5843026 | Edwards et al. | Dec 1998 | A |
| 5843182 | Goldstein | Dec 1998 | A |
| 5865787 | Shapland et al. | Feb 1999 | A |
| 5868708 | Hart et al. | Feb 1999 | A |
| 5873849 | Bernard | Feb 1999 | A |
| 5904648 | Arndt et al. | May 1999 | A |
| 5919142 | Boone et al. | Jul 1999 | A |
| 5919191 | Lennox et al. | Jul 1999 | A |
| 5921982 | Lesh et al. | Jul 1999 | A |
| 5944710 | Dev et al. | Aug 1999 | A |
| 5947284 | Foster | Sep 1999 | A |
| 5947889 | Hehrlein | Sep 1999 | A |
| 5951546 | Lorentzen | Sep 1999 | A |
| 5954745 | Gertler et al. | Sep 1999 | A |
| 5957919 | Laufer | Sep 1999 | A |
| 5957963 | Dobak | Sep 1999 | A |
| 5968006 | Hofmann | Oct 1999 | A |
| 5983131 | Weaver et al. | Nov 1999 | A |
| 5984896 | Boyd | Nov 1999 | A |
| 5991697 | Nelson et al. | Nov 1999 | A |
| 5999847 | Elstrom | Dec 1999 | A |
| 6004339 | Wijay | Dec 1999 | A |
| 6009347 | Hofmann | Dec 1999 | A |
| 6009877 | Edwards | Jan 2000 | A |
| 6010613 | Walters et al. | Jan 2000 | A |
| 6016452 | Kasevich | Jan 2000 | A |
| 6029090 | Herbst | Feb 2000 | A |
| 6041252 | Walker et al. | Mar 2000 | A |
| 6043066 | Mangano et al. | Mar 2000 | A |
| 6050994 | Sherman | Apr 2000 | A |
| 6055453 | Hofmann et al. | Apr 2000 | A |
| 6059780 | Gough et al. | May 2000 | A |
| 6066134 | Eggers et al. | May 2000 | A |
| 6068121 | McGlinch | May 2000 | A |
| 6068650 | Hofmann et al. | May 2000 | A |
| 6071281 | Burnside et al. | Jun 2000 | A |
| 6074374 | Fulton | Jun 2000 | A |
| 6074389 | Levine et al. | Jun 2000 | A |
| 6085115 | Weaver et al. | Jul 2000 | A |
| 6090016 | Kuo | Jul 2000 | A |
| 6090105 | Zepeda et al. | Jul 2000 | A |
| 6090106 | Goble et al. | Jul 2000 | A |
| D430015 | Himbert et al. | Aug 2000 | S |
| 6096035 | Sodhi et al. | Aug 2000 | A |
| 6102885 | Bass | Aug 2000 | A |
| 6106521 | Blewett et al. | Aug 2000 | A |
| 6109270 | Mah et al. | Aug 2000 | A |
| 6110192 | Ravenscroft et al. | Aug 2000 | A |
| 6113593 | Tu et al. | Sep 2000 | A |
| 6116330 | Salyer | Sep 2000 | A |
| 6120493 | Hofmann | Sep 2000 | A |
| 6122599 | Mehta | Sep 2000 | A |
| 6123701 | Nezhat | Sep 2000 | A |
| 6132397 | Davis et al. | Oct 2000 | A |
| 6132419 | Hofmann | Oct 2000 | A |
| 6134460 | Chance | Oct 2000 | A |
| 6139545 | Utley et al. | Oct 2000 | A |
| 6150148 | Nanda et al. | Nov 2000 | A |
| 6159163 | Strauss et al. | Dec 2000 | A |
| 6178354 | Gibson | Jan 2001 | B1 |
| D437941 | Frattini | Feb 2001 | S |
| 6193715 | Wrublewski et al. | Feb 2001 | B1 |
| 6198970 | Freed et al. | Mar 2001 | B1 |
| 6200314 | Sherman | Mar 2001 | B1 |
| 6208893 | Hofmann | Mar 2001 | B1 |
| 6210402 | Olsen et al. | Apr 2001 | B1 |
| 6212433 | Behl | Apr 2001 | B1 |
| 6216034 | Hofmann et al. | Apr 2001 | B1 |
| 6219577 | Brown, III et al. | Apr 2001 | B1 |
| D442697 | Hajianpour | May 2001 | S |
| 6233490 | Kasevich | May 2001 | B1 |
| 6235023 | Lee et al. | May 2001 | B1 |
| D443360 | Haberland | Jun 2001 | S |
| 6241702 | Lundquist et al. | Jun 2001 | B1 |
| 6241725 | Cosman | Jun 2001 | B1 |
| D445198 | Frallini | Jul 2001 | S |
| 6258100 | Alferness et al. | Jul 2001 | B1 |
| 6261831 | Agee | Jul 2001 | B1 |
| 6277114 | Bullivant et al. | Aug 2001 | B1 |
| 6278895 | Bernard | Aug 2001 | B1 |
| 6280441 | Ryan | Aug 2001 | B1 |
| 6283988 | Laufer et al. | Sep 2001 | B1 |
| 6283989 | Laufer et al. | Sep 2001 | B1 |
| 6284140 | Sommermeyer et al. | Sep 2001 | B1 |
| 6287293 | Jones et al. | Sep 2001 | B1 |
| 6287304 | Eggers et al. | Sep 2001 | B1 |
| 6296636 | Cheng et al. | Oct 2001 | B1 |
| 6298726 | Adachi et al. | Oct 2001 | B1 |
| 6299633 | Laufer | Oct 2001 | B1 |
| 6300108 | Rubinsky et al. | Oct 2001 | B1 |
| D450391 | Hunt et al. | Nov 2001 | S |
| 6312428 | Eggers et al. | Nov 2001 | B1 |
| 6326177 | Schoenbach et al. | Dec 2001 | B1 |
| 6327505 | Medhkour et al. | Dec 2001 | B1 |
| 6328689 | Gonzalez et al. | Dec 2001 | B1 |
| 6347247 | Dev et al. | Feb 2002 | B1 |
| 6349233 | Adams | Feb 2002 | B1 |
| 6351674 | Silverstone | Feb 2002 | B2 |
| 6375634 | Carroll | Apr 2002 | B1 |
| 6387671 | Rubinsky et al. | May 2002 | B1 |
| 6398779 | Buysse et al. | Jun 2002 | B1 |
| 6403348 | Rubinsky et al. | Jun 2002 | B1 |
| 6405732 | Edwards et al. | Jun 2002 | B1 |
| 6411852 | Danek et al. | Jun 2002 | B1 |
| 6419674 | Bowser et al. | Jul 2002 | B1 |
| 6428802 | Atala | Aug 2002 | B1 |
| 6443952 | Mulier et al. | Sep 2002 | B1 |
| 6463331 | Edwards | Oct 2002 | B1 |
| 6470211 | Ideker et al. | Oct 2002 | B1 |
| 6482221 | Hebert et al. | Nov 2002 | B1 |
| 6482619 | Rubinsky et al. | Nov 2002 | B1 |
| 6485487 | Sherman | Nov 2002 | B1 |
| 6488673 | Laufer et al. | Dec 2002 | B1 |
| 6488678 | Sherman | Dec 2002 | B2 |
| 6488680 | Francischelli et al. | Dec 2002 | B1 |
| 6491706 | Alferness et al. | Dec 2002 | B1 |
| 6493589 | Medhkour et al. | Dec 2002 | B1 |
| 6493592 | Leonard et al. | Dec 2002 | B1 |
| 6500173 | Underwood et al. | Dec 2002 | B2 |
| 6503248 | Levine | Jan 2003 | B1 |
| 6506189 | Rittman et al. | Jan 2003 | B1 |
| 6514248 | Eggers et al. | Feb 2003 | B1 |
| 6520183 | Amar | Feb 2003 | B2 |
| 6526320 | Mitchell | Feb 2003 | B2 |
| D471640 | McMichael et al. | Mar 2003 | S |
| D471641 | McMichael et al. | Mar 2003 | S |
| 6530922 | Cosman et al. | Mar 2003 | B2 |
| 6533784 | Truckai et al. | Mar 2003 | B2 |
| 6537976 | Gupta | Mar 2003 | B1 |
| 6540695 | Burbank et al. | Apr 2003 | B1 |
| 6558378 | Sherman et al. | May 2003 | B2 |
| 6562604 | Rubinsky et al. | May 2003 | B2 |
| 6569162 | He | May 2003 | B2 |
| 6575969 | Rittman et al. | Jun 2003 | B1 |
| 6589161 | Corcoran | Jul 2003 | B2 |
| 6592594 | Rimbaugh et al. | Jul 2003 | B2 |
| 6607529 | Jones et al. | Aug 2003 | B1 |
| 6610054 | Edwards et al. | Aug 2003 | B1 |
| 6611706 | Avrahami et al. | Aug 2003 | B2 |
| 6613211 | Mccormick et al. | Sep 2003 | B1 |
| 6616657 | Simpson et al. | Sep 2003 | B2 |
| 6627421 | Unger et al. | Sep 2003 | B1 |
| D480816 | McMichael et al. | Oct 2003 | S |
| 6634363 | Danek et al. | Oct 2003 | B1 |
| 6638253 | Breznock | Oct 2003 | B2 |
| 6653091 | Dunn et al. | Nov 2003 | B1 |
| 6666858 | Lafontaine | Dec 2003 | B2 |
| 6669691 | Taimisto | Dec 2003 | B1 |
| 6673070 | Edwards et al. | Jan 2004 | B2 |
| 6678558 | Dimmer et al. | Jan 2004 | B1 |
| 6689096 | Loubens et al. | Feb 2004 | B1 |
| 6692493 | Mcgovern et al. | Feb 2004 | B2 |
| 6694979 | Deem et al. | Feb 2004 | B2 |
| 6694984 | Habib | Feb 2004 | B2 |
| 6695861 | Rosenberg et al. | Feb 2004 | B1 |
| 6697669 | Dev et al. | Feb 2004 | B2 |
| 6697670 | Chomenky et al. | Feb 2004 | B2 |
| 6702808 | Kreindel | Mar 2004 | B1 |
| 6712811 | Underwood et al. | Mar 2004 | B2 |
| D489973 | Root et al. | May 2004 | S |
| 6753171 | Karube et al. | Jun 2004 | B2 |
| 6761716 | Kadhiresan et al. | Jul 2004 | B2 |
| D495807 | Agbodoe et al. | Sep 2004 | S |
| 6795728 | Chornenky et al. | Sep 2004 | B2 |
| 6801804 | Miller et al. | Oct 2004 | B2 |
| 6812204 | McHale et al. | Nov 2004 | B1 |
| 6837886 | Collins et al. | Jan 2005 | B2 |
| 6847848 | Sterzer et al. | Jan 2005 | B2 |
| 6860847 | Alferness et al. | Mar 2005 | B2 |
| 6865416 | Dev et al. | Mar 2005 | B2 |
| 6881213 | Ryan et al. | Apr 2005 | B2 |
| 6892099 | Jaafar et al. | May 2005 | B2 |
| 6895267 | Panescu et al. | May 2005 | B2 |
| 6905480 | McGuckin et al. | Jun 2005 | B2 |
| 6912417 | Bernard et al. | Jun 2005 | B1 |
| 6927049 | Rubinsky et al. | Aug 2005 | B2 |
| 6941950 | Wilson et al. | Sep 2005 | B2 |
| 6942681 | Johnson | Sep 2005 | B2 |
| 6958062 | Gough et al. | Oct 2005 | B1 |
| 6960189 | Bates et al. | Nov 2005 | B2 |
| 6962587 | Johnson et al. | Nov 2005 | B2 |
| 6972013 | Zhang et al. | Dec 2005 | B1 |
| 6972014 | Eum et al. | Dec 2005 | B2 |
| 6989010 | Francischelli et al. | Jan 2006 | B2 |
| 6994689 | Zadno-Azizi et al. | Feb 2006 | B1 |
| 6994706 | Chornenky et al. | Feb 2006 | B2 |
| 7011094 | Rapacki et al. | Mar 2006 | B2 |
| 7012061 | Reiss et al. | Mar 2006 | B1 |
| 7027869 | Danek et al. | Apr 2006 | B2 |
| 7036510 | Zgoda et al. | May 2006 | B2 |
| 7053063 | Rubinsky et al. | May 2006 | B2 |
| 7054685 | Dimmer et al. | May 2006 | B2 |
| 7063698 | Whayne et al. | Jun 2006 | B2 |
| 7087040 | McGuckin et al. | Aug 2006 | B2 |
| 7097612 | Bertolero et al. | Aug 2006 | B2 |
| 7100616 | Springmeyer | Sep 2006 | B2 |
| 7113821 | Sun et al. | Sep 2006 | B1 |
| 7130697 | Chornenky et al. | Oct 2006 | B2 |
| 7211083 | Chornenky et al. | May 2007 | B2 |
| 7232437 | Berman et al. | Jun 2007 | B2 |
| 7250048 | Francischelli et al. | Jul 2007 | B2 |
| D549332 | Matsumoto et al. | Aug 2007 | S |
| 7257450 | Auth | Aug 2007 | B2 |
| 7264002 | Danek et al. | Sep 2007 | B2 |
| 7267676 | Chornenky et al. | Sep 2007 | B2 |
| 7273055 | Danek et al. | Sep 2007 | B2 |
| 7291146 | Steinke et al. | Nov 2007 | B2 |
| 7331940 | Sommerich | Feb 2008 | B2 |
| 7331949 | Marisi | Feb 2008 | B2 |
| 7341558 | Torre et al. | Mar 2008 | B2 |
| 7344533 | Pearson et al. | Mar 2008 | B2 |
| D565743 | Phillips et al. | Apr 2008 | S |
| D571478 | Horacek | Jun 2008 | S |
| 7387626 | Edwards et al. | Jun 2008 | B2 |
| 7399747 | Clair et al. | Jul 2008 | B1 |
| D575399 | Matsumoto et al. | Aug 2008 | S |
| D575402 | Sandor | Aug 2008 | S |
| 7419487 | Johnson et al. | Sep 2008 | B2 |
| 7434578 | Dillard et al. | Oct 2008 | B2 |
| 7449019 | Uchida et al. | Nov 2008 | B2 |
| 7451765 | Adler | Nov 2008 | B2 |
| 7455675 | Schur et al. | Nov 2008 | B2 |
| 7476203 | DeVore et al. | Jan 2009 | B2 |
| 7520877 | Lee et al. | Apr 2009 | B2 |
| 7533671 | Gonzalez et al. | May 2009 | B2 |
| D595422 | Mustapha | Jun 2009 | S |
| 7544301 | Shah et al. | Jun 2009 | B2 |
| 7549984 | Mathis | Jun 2009 | B2 |
| 7565208 | Harris et al. | Jul 2009 | B2 |
| 7571729 | Saadat et al. | Aug 2009 | B2 |
| 7632291 | Stephens et al. | Dec 2009 | B2 |
| 7655004 | Long | Feb 2010 | B2 |
| 7674249 | Ivorra et al. | Mar 2010 | B2 |
| 7680543 | Azure | Mar 2010 | B2 |
| D613418 | Ryan et al. | Apr 2010 | S |
| 7718409 | Rubinsky et al. | May 2010 | B2 |
| 7722606 | Azure | May 2010 | B2 |
| 7742795 | Stone et al. | Jun 2010 | B2 |
| 7765010 | Chornenky et al. | Jul 2010 | B2 |
| 7771401 | Hekmat et al. | Aug 2010 | B2 |
| RE42016 | Chornenky et al. | Dec 2010 | E |
| D630321 | Hamilton | Jan 2011 | S |
| D631154 | Hamilton | Jan 2011 | S |
| RE42277 | Jaafar et al. | Apr 2011 | E |
| 7918852 | Tullis et al. | Apr 2011 | B2 |
| 7937143 | Demarais et al. | May 2011 | B2 |
| 7938824 | Chornenky et al. | May 2011 | B2 |
| 7951582 | Gazit et al. | May 2011 | B2 |
| 7955827 | Rubinsky et al. | Jun 2011 | B2 |
| RE42835 | Chornenky et al. | Oct 2011 | E |
| D647628 | Helfteren | Oct 2011 | S |
| 8048067 | Davalos et al. | Nov 2011 | B2 |
| RE43009 | Chornenky et al. | Dec 2011 | E |
| 8109926 | Azure | Feb 2012 | B2 |
| 8114070 | Rubinsky et al. | Feb 2012 | B2 |
| 8162918 | Ivorra et al. | Apr 2012 | B2 |
| 8187269 | Shadduck et al. | May 2012 | B2 |
| 8221411 | Francischelli et al. | Jul 2012 | B2 |
| 8231603 | Hobbs et al. | Jul 2012 | B2 |
| 8240468 | Wilkinson et al. | Aug 2012 | B2 |
| 8251986 | Chornenky et al. | Aug 2012 | B2 |
| 8267927 | Dalal et al. | Sep 2012 | B2 |
| 8267936 | Hushka et al. | Sep 2012 | B2 |
| 8282631 | Davalos et al. | Oct 2012 | B2 |
| 8298222 | Rubinsky et al. | Oct 2012 | B2 |
| 8348921 | Ivorra et al. | Jan 2013 | B2 |
| 8361006 | Kraemer | Jan 2013 | B2 |
| D677798 | Hart et al. | Mar 2013 | S |
| 8425455 | Nentwick | Apr 2013 | B2 |
| 8425505 | Long | Apr 2013 | B2 |
| 8465464 | Travis et al. | Jun 2013 | B2 |
| 8465484 | Davalos et al. | Jun 2013 | B2 |
| 8511317 | Thapliyal et al. | Aug 2013 | B2 |
| 8518031 | Boyden et al. | Aug 2013 | B2 |
| 8562588 | Hobbs et al. | Oct 2013 | B2 |
| 8603087 | Rubinsky et al. | Dec 2013 | B2 |
| 8632534 | Pearson et al. | Jan 2014 | B2 |
| 8634929 | Chornenky et al. | Jan 2014 | B2 |
| 8647338 | Chornenky et al. | Feb 2014 | B2 |
| 8715276 | Thompson et al. | May 2014 | B2 |
| 8753335 | Moshe et al. | Jun 2014 | B2 |
| 8814860 | Davalos et al. | Aug 2014 | B2 |
| 8835166 | Phillips et al. | Sep 2014 | B2 |
| 8845635 | Daniel et al. | Sep 2014 | B2 |
| 8880195 | Azure | Nov 2014 | B2 |
| 8903488 | Callas et al. | Dec 2014 | B2 |
| 8906006 | Chornenky et al. | Dec 2014 | B2 |
| 8926606 | Davalos et al. | Jan 2015 | B2 |
| 8958888 | Chornenky et al. | Feb 2015 | B2 |
| 8968542 | Davalos et al. | Mar 2015 | B2 |
| 8992517 | Davalos et al. | Mar 2015 | B2 |
| 9005189 | Davalos et al. | Apr 2015 | B2 |
| 9078665 | Moss et al. | Jul 2015 | B2 |
| 9149331 | Deem et al. | Oct 2015 | B2 |
| 9173704 | Hobbs et al. | Nov 2015 | B2 |
| 9198733 | Neal et al. | Dec 2015 | B2 |
| 9283051 | Garcia et al. | Mar 2016 | B2 |
| 9414881 | Callas et al. | Aug 2016 | B2 |
| 9598691 | Davalos | Mar 2017 | B2 |
| 9867652 | Sano et al. | Jan 2018 | B2 |
| 10117701 | Davalos et al. | Nov 2018 | B2 |
| 10117707 | Garcia et al. | Nov 2018 | B2 |
| 10154874 | Davalos et al. | Dec 2018 | B2 |
| 10238447 | Neal et al. | Mar 2019 | B2 |
| 10245098 | Davalos et al. | Apr 2019 | B2 |
| 10245105 | Davalos et al. | Apr 2019 | B2 |
| 10272178 | Davalos et al. | Apr 2019 | B2 |
| 10286108 | Davalos et al. | May 2019 | B2 |
| 10292755 | Davalos et al. | May 2019 | B2 |
| 10448989 | Arena et al. | Oct 2019 | B2 |
| 10470822 | Garcia et al. | Nov 2019 | B2 |
| 10471254 | Sano et al. | Nov 2019 | B2 |
| 10537379 | Sano et al. | Jan 2020 | B2 |
| 20010039393 | Mori et al. | Nov 2001 | A1 |
| 20010044596 | Jaafar | Nov 2001 | A1 |
| 20010046706 | Rubinsky et al. | Nov 2001 | A1 |
| 20010047167 | Heggeness | Nov 2001 | A1 |
| 20010051366 | Rubinsky et al. | Dec 2001 | A1 |
| 20020002393 | Mitchell | Jan 2002 | A1 |
| 20020010491 | Schoenbach et al. | Jan 2002 | A1 |
| 20020022864 | Mahvi et al. | Feb 2002 | A1 |
| 20020040204 | Dev et al. | Apr 2002 | A1 |
| 20020049370 | Laufer et al. | Apr 2002 | A1 |
| 20020052601 | Goldberg et al. | May 2002 | A1 |
| 20020055731 | Atala et al. | May 2002 | A1 |
| 20020065541 | Fredricks et al. | May 2002 | A1 |
| 20020072742 | Schaefer et al. | Jun 2002 | A1 |
| 20020077314 | Falk et al. | Jun 2002 | A1 |
| 20020077676 | Schroeppel et al. | Jun 2002 | A1 |
| 20020082543 | Park et al. | Jun 2002 | A1 |
| 20020099323 | Dev et al. | Jul 2002 | A1 |
| 20020104318 | Jaafar et al. | Aug 2002 | A1 |
| 20020111615 | Cosman et al. | Aug 2002 | A1 |
| 20020112729 | DeVore et al. | Aug 2002 | A1 |
| 20020115208 | Mitchell et al. | Aug 2002 | A1 |
| 20020119437 | Grooms et al. | Aug 2002 | A1 |
| 20020133324 | Weaver et al. | Sep 2002 | A1 |
| 20020137121 | Rubinsky et al. | Sep 2002 | A1 |
| 20020138075 | Edwards et al. | Sep 2002 | A1 |
| 20020138117 | Son | Sep 2002 | A1 |
| 20020143365 | Herbst | Oct 2002 | A1 |
| 20020147462 | Mair et al. | Oct 2002 | A1 |
| 20020156472 | Lee et al. | Oct 2002 | A1 |
| 20020161361 | Sherman et al. | Oct 2002 | A1 |
| 20020183684 | Dev et al. | Dec 2002 | A1 |
| 20020183735 | Edwards et al. | Dec 2002 | A1 |
| 20020183740 | Edwards et al. | Dec 2002 | A1 |
| 20020188242 | Wu | Dec 2002 | A1 |
| 20020193784 | McHale et al. | Dec 2002 | A1 |
| 20020193831 | Smith | Dec 2002 | A1 |
| 20030009110 | Tu et al. | Jan 2003 | A1 |
| 20030016168 | Jandrell | Jan 2003 | A1 |
| 20030055220 | Legrain | Mar 2003 | A1 |
| 20030055420 | Kadhiresan et al. | Mar 2003 | A1 |
| 20030059945 | Dzekunov et al. | Mar 2003 | A1 |
| 20030060856 | Chornenky et al. | Mar 2003 | A1 |
| 20030078490 | Damasco et al. | Apr 2003 | A1 |
| 20030088189 | Tu et al. | May 2003 | A1 |
| 20030088199 | Kawaji | May 2003 | A1 |
| 20030096407 | Atala et al. | May 2003 | A1 |
| 20030105454 | Cucin | Jun 2003 | A1 |
| 20030109871 | Johnson et al. | Jun 2003 | A1 |
| 20030127090 | Gifford et al. | Jul 2003 | A1 |
| 20030130711 | Pearson et al. | Jul 2003 | A1 |
| 20030135242 | Mongeon et al. | Jul 2003 | A1 |
| 20030149451 | Chomenky et al. | Aug 2003 | A1 |
| 20030153960 | Chornenky et al. | Aug 2003 | A1 |
| 20030154988 | Devore et al. | Aug 2003 | A1 |
| 20030159700 | Laufer et al. | Aug 2003 | A1 |
| 20030166181 | Rubinsky et al. | Sep 2003 | A1 |
| 20030170898 | Gundersen et al. | Sep 2003 | A1 |
| 20030194808 | Rubinsky et al. | Oct 2003 | A1 |
| 20030195385 | DeVore | Oct 2003 | A1 |
| 20030195406 | Jenkins et al. | Oct 2003 | A1 |
| 20030199050 | Mangano et al. | Oct 2003 | A1 |
| 20030208200 | Palanker et al. | Nov 2003 | A1 |
| 20030208236 | Heil et al. | Nov 2003 | A1 |
| 20030212394 | Pearson et al. | Nov 2003 | A1 |
| 20030212412 | Dillard et al. | Nov 2003 | A1 |
| 20030225360 | Eppstein et al. | Dec 2003 | A1 |
| 20030228344 | Fields et al. | Dec 2003 | A1 |
| 20040009459 | Anderson et al. | Jan 2004 | A1 |
| 20040019371 | Jaafar et al. | Jan 2004 | A1 |
| 20040055606 | Hendricksen et al. | Mar 2004 | A1 |
| 20040059328 | Daniel et al. | Mar 2004 | A1 |
| 20040059389 | Chornenky et al. | Mar 2004 | A1 |
| 20040068228 | Cunningham | Apr 2004 | A1 |
| 20040116965 | Falkenberg | Jun 2004 | A1 |
| 20040133194 | Eum et al. | Jul 2004 | A1 |
| 20040138715 | Groeningen et al. | Jul 2004 | A1 |
| 20040146877 | Diss et al. | Jul 2004 | A1 |
| 20040153057 | Davison | Aug 2004 | A1 |
| 20040176855 | Badylak | Sep 2004 | A1 |
| 20040193042 | Scampini et al. | Sep 2004 | A1 |
| 20040193097 | Hofmann et al. | Sep 2004 | A1 |
| 20040199159 | Lee et al. | Oct 2004 | A1 |
| 20040200484 | Springmeyer | Oct 2004 | A1 |
| 20040206349 | Alferness et al. | Oct 2004 | A1 |
| 20040210248 | Gordon et al. | Oct 2004 | A1 |
| 20040230187 | Lee et al. | Nov 2004 | A1 |
| 20040236376 | Miklavcic et al. | Nov 2004 | A1 |
| 20040243107 | Macoviak et al. | Dec 2004 | A1 |
| 20040267189 | Mayor et al. | Dec 2004 | A1 |
| 20040267340 | Cioanta et al. | Dec 2004 | A1 |
| 20050010209 | Lee et al. | Jan 2005 | A1 |
| 20050010259 | Gerber | Jan 2005 | A1 |
| 20050013870 | Freyman et al. | Jan 2005 | A1 |
| 20050020965 | Rioux et al. | Jan 2005 | A1 |
| 20050043726 | Mchale et al. | Feb 2005 | A1 |
| 20050048651 | Ryttsen et al. | Mar 2005 | A1 |
| 20050049541 | Behar et al. | Mar 2005 | A1 |
| 20050061322 | Freitag | Mar 2005 | A1 |
| 20050066974 | Fields et al. | Mar 2005 | A1 |
| 20050143817 | Hunter et al. | Jun 2005 | A1 |
| 20050165393 | Eppstein | Jul 2005 | A1 |
| 20050171522 | Christopherson | Aug 2005 | A1 |
| 20050171523 | Rubinsky et al. | Aug 2005 | A1 |
| 20050171574 | Rubinsky et al. | Aug 2005 | A1 |
| 20050182462 | Chornenky et al. | Aug 2005 | A1 |
| 20050197619 | Rule et al. | Sep 2005 | A1 |
| 20050261672 | Deem et al. | Nov 2005 | A1 |
| 20050267407 | Goldman | Dec 2005 | A1 |
| 20050282284 | Rubinsky et al. | Dec 2005 | A1 |
| 20050283149 | Thorne et al. | Dec 2005 | A1 |
| 20050288684 | Aronson et al. | Dec 2005 | A1 |
| 20050288702 | McGurk et al. | Dec 2005 | A1 |
| 20050288730 | Deem et al. | Dec 2005 | A1 |
| 20060004356 | Bilski et al. | Jan 2006 | A1 |
| 20060004400 | McGurk et al. | Jan 2006 | A1 |
| 20060009748 | Mathis | Jan 2006 | A1 |
| 20060015147 | Persson et al. | Jan 2006 | A1 |
| 20060020347 | Barrett et al. | Jan 2006 | A1 |
| 20060024359 | Walker et al. | Feb 2006 | A1 |
| 20060025760 | Podhajsky | Feb 2006 | A1 |
| 20060074413 | Behzadian | Apr 2006 | A1 |
| 20060079838 | Walker et al. | Apr 2006 | A1 |
| 20060079845 | Howard et al. | Apr 2006 | A1 |
| 20060079883 | Elmouelhi et al. | Apr 2006 | A1 |
| 20060085054 | Zikorus et al. | Apr 2006 | A1 |
| 20060089635 | Young et al. | Apr 2006 | A1 |
| 20060121610 | Rubinsky et al. | Jun 2006 | A1 |
| 20060142801 | Demarais et al. | Jun 2006 | A1 |
| 20060149123 | Vidlund et al. | Jul 2006 | A1 |
| 20060173490 | Lafontaine et al. | Aug 2006 | A1 |
| 20060182684 | Beliveau | Aug 2006 | A1 |
| 20060195146 | Tracey et al. | Aug 2006 | A1 |
| 20060212032 | Daniel et al. | Sep 2006 | A1 |
| 20060212078 | Demarais et al. | Sep 2006 | A1 |
| 20060217703 | Chornenky et al. | Sep 2006 | A1 |
| 20060224188 | Libbus et al. | Oct 2006 | A1 |
| 20060235474 | Demarais | Oct 2006 | A1 |
| 20060247619 | Kaplan et al. | Nov 2006 | A1 |
| 20060264752 | Rubinsky et al. | Nov 2006 | A1 |
| 20060264807 | Westersten et al. | Nov 2006 | A1 |
| 20060269531 | Beebe et al. | Nov 2006 | A1 |
| 20060276710 | Krishnan | Dec 2006 | A1 |
| 20060278241 | Ruano | Dec 2006 | A1 |
| 20060283462 | Fields et al. | Dec 2006 | A1 |
| 20060293713 | Rubinsky et al. | Dec 2006 | A1 |
| 20060293725 | Rubinsky et al. | Dec 2006 | A1 |
| 20060293730 | Rubinsky et al. | Dec 2006 | A1 |
| 20060293731 | Rubinsky et al. | Dec 2006 | A1 |
| 20060293734 | Scott et al. | Dec 2006 | A1 |
| 20070010805 | Fedewa et al. | Jan 2007 | A1 |
| 20070016183 | Lee et al. | Jan 2007 | A1 |
| 20070016185 | Tullis et al. | Jan 2007 | A1 |
| 20070021803 | Deem et al. | Jan 2007 | A1 |
| 20070025919 | Deem et al. | Feb 2007 | A1 |
| 20070043345 | Davalos et al. | Feb 2007 | A1 |
| 20070060989 | Deem et al. | Mar 2007 | A1 |
| 20070078391 | Wortley et al. | Apr 2007 | A1 |
| 20070088347 | Young et al. | Apr 2007 | A1 |
| 20070093789 | Smith | Apr 2007 | A1 |
| 20070096048 | Clerc | May 2007 | A1 |
| 20070118069 | Persson et al. | May 2007 | A1 |
| 20070129711 | Altshuler et al. | Jun 2007 | A1 |
| 20070129760 | Demarais et al. | Jun 2007 | A1 |
| 20070151848 | Novak et al. | Jul 2007 | A1 |
| 20070156135 | Rubinsky et al. | Jul 2007 | A1 |
| 20070191889 | Lang | Aug 2007 | A1 |
| 20070203486 | Young | Aug 2007 | A1 |
| 20070230757 | Trachtenberg et al. | Oct 2007 | A1 |
| 20070239099 | Goldfarb et al. | Oct 2007 | A1 |
| 20070244521 | Bornzin et al. | Oct 2007 | A1 |
| 20070287950 | Kjeken et al. | Dec 2007 | A1 |
| 20070295336 | Nelson et al. | Dec 2007 | A1 |
| 20070295337 | Nelson et al. | Dec 2007 | A1 |
| 20080015571 | Rubinsky et al. | Jan 2008 | A1 |
| 20080021371 | Rubinsky et al. | Jan 2008 | A1 |
| 20080027314 | Miyazaki et al. | Jan 2008 | A1 |
| 20080027343 | Fields et al. | Jan 2008 | A1 |
| 20080033340 | Heller et al. | Feb 2008 | A1 |
| 20080033417 | Nields et al. | Feb 2008 | A1 |
| 20080045880 | Kjeken et al. | Feb 2008 | A1 |
| 20080052786 | Lin et al. | Feb 2008 | A1 |
| 20080065062 | Leung et al. | Mar 2008 | A1 |
| 20080071262 | Azure | Mar 2008 | A1 |
| 20080097139 | Clerc et al. | Apr 2008 | A1 |
| 20080097422 | Edwards et al. | Apr 2008 | A1 |
| 20080103529 | Schoenbach et al. | May 2008 | A1 |
| 20080121375 | Richason et al. | May 2008 | A1 |
| 20080125772 | Stone et al. | May 2008 | A1 |
| 20080132826 | Shadduck et al. | Jun 2008 | A1 |
| 20080132884 | Rubinsky et al. | Jun 2008 | A1 |
| 20080132885 | Rubinsky et al. | Jun 2008 | A1 |
| 20080140064 | Vegesna | Jun 2008 | A1 |
| 20080146934 | Czygan et al. | Jun 2008 | A1 |
| 20080154259 | Gough et al. | Jun 2008 | A1 |
| 20080167649 | Edwards et al. | Jul 2008 | A1 |
| 20080171985 | Karakoca | Jul 2008 | A1 |
| 20080190434 | Wai | Aug 2008 | A1 |
| 20080200911 | Long | Aug 2008 | A1 |
| 20080200912 | Long | Aug 2008 | A1 |
| 20080208052 | LePivert et al. | Aug 2008 | A1 |
| 20080210243 | Clayton et al. | Sep 2008 | A1 |
| 20080214986 | Ivorra et al. | Sep 2008 | A1 |
| 20080236593 | Nelson et al. | Oct 2008 | A1 |
| 20080249503 | Fields et al. | Oct 2008 | A1 |
| 20080262489 | Steinke | Oct 2008 | A1 |
| 20080269586 | Rubinsky et al. | Oct 2008 | A1 |
| 20080269838 | Brighton et al. | Oct 2008 | A1 |
| 20080275465 | Paul et al. | Nov 2008 | A1 |
| 20080281319 | Paul et al. | Nov 2008 | A1 |
| 20080283065 | Chang et al. | Nov 2008 | A1 |
| 20080288038 | Paul et al. | Nov 2008 | A1 |
| 20080300589 | Paul et al. | Dec 2008 | A1 |
| 20080306427 | Bailey | Dec 2008 | A1 |
| 20080312599 | Rosenberg | Dec 2008 | A1 |
| 20090018206 | Barkan et al. | Jan 2009 | A1 |
| 20090024075 | Schroeppel et al. | Jan 2009 | A1 |
| 20090029407 | Gazit et al. | Jan 2009 | A1 |
| 20090038752 | Weng et al. | Feb 2009 | A1 |
| 20090062788 | Long et al. | Mar 2009 | A1 |
| 20090062792 | Vakharia et al. | Mar 2009 | A1 |
| 20090081272 | Clarke et al. | Mar 2009 | A1 |
| 20090105703 | Shadduck | Apr 2009 | A1 |
| 20090114226 | Deem et al. | May 2009 | A1 |
| 20090125009 | Zikorus et al. | May 2009 | A1 |
| 20090138014 | Bonutti | May 2009 | A1 |
| 20090143705 | Danek et al. | Jun 2009 | A1 |
| 20090157166 | Singhal et al. | Jun 2009 | A1 |
| 20090163904 | Miller et al. | Jun 2009 | A1 |
| 20090171280 | Samuel et al. | Jul 2009 | A1 |
| 20090177111 | Miller et al. | Jul 2009 | A1 |
| 20090186850 | Kiribayashi et al. | Jul 2009 | A1 |
| 20090192508 | Laufer et al. | Jul 2009 | A1 |
| 20090198231 | Esser et al. | Aug 2009 | A1 |
| 20090228001 | Pacey | Sep 2009 | A1 |
| 20090247933 | Maor et al. | Oct 2009 | A1 |
| 20090248012 | Maor et al. | Oct 2009 | A1 |
| 20090269317 | Davalos | Oct 2009 | A1 |
| 20090275827 | Aiken et al. | Nov 2009 | A1 |
| 20090281477 | Mikus et al. | Nov 2009 | A1 |
| 20090292342 | Rubinsky et al. | Nov 2009 | A1 |
| 20090301480 | Elsakka et al. | Dec 2009 | A1 |
| 20090306544 | Ng et al. | Dec 2009 | A1 |
| 20090306545 | Elsakka et al. | Dec 2009 | A1 |
| 20090318905 | Bhargav et al. | Dec 2009 | A1 |
| 20090326436 | Rubinsky et al. | Dec 2009 | A1 |
| 20090326570 | Brown | Dec 2009 | A1 |
| 20100004623 | Hamilton et al. | Jan 2010 | A1 |
| 20100006441 | Renaud et al. | Jan 2010 | A1 |
| 20100023004 | Francischelli et al. | Jan 2010 | A1 |
| 20100030211 | Davalos et al. | Feb 2010 | A1 |
| 20100049190 | Long et al. | Feb 2010 | A1 |
| 20100057074 | Roman et al. | Mar 2010 | A1 |
| 20100069921 | Miller et al. | Mar 2010 | A1 |
| 20100087813 | Long | Apr 2010 | A1 |
| 20100130975 | Long | May 2010 | A1 |
| 20100147701 | Field | Jun 2010 | A1 |
| 20100152725 | Pearson et al. | Jun 2010 | A1 |
| 20100160850 | Ivorra et al. | Jun 2010 | A1 |
| 20100168735 | Deno et al. | Jul 2010 | A1 |
| 20100174282 | Demarais et al. | Jul 2010 | A1 |
| 20100179530 | Long et al. | Jul 2010 | A1 |
| 20100196984 | Rubinsky et al. | Aug 2010 | A1 |
| 20100204560 | Salahieh et al. | Aug 2010 | A1 |
| 20100204638 | Hobbs et al. | Aug 2010 | A1 |
| 20100222677 | Placek et al. | Sep 2010 | A1 |
| 20100228234 | Hyde et al. | Sep 2010 | A1 |
| 20100228247 | Paul et al. | Sep 2010 | A1 |
| 20100241117 | Paul et al. | Sep 2010 | A1 |
| 20100249771 | Pearson et al. | Sep 2010 | A1 |
| 20100250209 | Pearson et al. | Sep 2010 | A1 |
| 20100255795 | Rubinsky et al. | Oct 2010 | A1 |
| 20100256628 | Pearson et al. | Oct 2010 | A1 |
| 20100256630 | Hamilton, Jr. et al. | Oct 2010 | A1 |
| 20100261994 | Davalos et al. | Oct 2010 | A1 |
| 20100286690 | Paul et al. | Nov 2010 | A1 |
| 20100298823 | Cao et al. | Nov 2010 | A1 |
| 20100331758 | Davalos et al. | Dec 2010 | A1 |
| 20110017207 | Hendricksen et al. | Jan 2011 | A1 |
| 20110034209 | Rubinsky et al. | Feb 2011 | A1 |
| 20110064671 | Bynoe | Mar 2011 | A1 |
| 20110106221 | Neal, II et al. | May 2011 | A1 |
| 20110112531 | Landis et al. | May 2011 | A1 |
| 20110118727 | Fish et al. | May 2011 | A1 |
| 20110118732 | Rubinsky et al. | May 2011 | A1 |
| 20110130834 | Wilson et al. | Jun 2011 | A1 |
| 20110144524 | Fish et al. | Jun 2011 | A1 |
| 20110144635 | Harper et al. | Jun 2011 | A1 |
| 20110144657 | Fish et al. | Jun 2011 | A1 |
| 20110152678 | Aljuri et al. | Jun 2011 | A1 |
| 20110166499 | Demarais et al. | Jul 2011 | A1 |
| 20110176037 | Benkley | Jul 2011 | A1 |
| 20110202053 | Moss et al. | Aug 2011 | A1 |
| 20110217730 | Gazit et al. | Sep 2011 | A1 |
| 20110251607 | Kruecker et al. | Oct 2011 | A1 |
| 20110301587 | Deem | Dec 2011 | A1 |
| 20120034131 | Rubinsky et al. | Feb 2012 | A1 |
| 20120059255 | Paul et al. | Mar 2012 | A1 |
| 20120071872 | Rubinsky et al. | Mar 2012 | A1 |
| 20120071874 | Davalos et al. | Mar 2012 | A1 |
| 20120085649 | Sano et al. | Apr 2012 | A1 |
| 20120089009 | Omary et al. | Apr 2012 | A1 |
| 20120095459 | Callas et al. | Apr 2012 | A1 |
| 20120109122 | Arena et al. | May 2012 | A1 |
| 20120130289 | Demarais et al. | May 2012 | A1 |
| 20120150172 | Ortiz et al. | Jun 2012 | A1 |
| 20120165813 | Lee et al. | Jun 2012 | A1 |
| 20120179091 | Ivorra et al. | Jul 2012 | A1 |
| 20120226218 | Phillips et al. | Sep 2012 | A1 |
| 20120226271 | Callas et al. | Sep 2012 | A1 |
| 20120265186 | Burger et al. | Oct 2012 | A1 |
| 20120277741 | Davalos et al. | Nov 2012 | A1 |
| 20120303020 | Chornenky et al. | Nov 2012 | A1 |
| 20120310236 | Placek et al. | Dec 2012 | A1 |
| 20130030239 | Weyh et al. | Jan 2013 | A1 |
| 20130090646 | Moss et al. | Apr 2013 | A1 |
| 20130108667 | Soikum et al. | May 2013 | A1 |
| 20130110106 | Richardson | May 2013 | A1 |
| 20130196441 | Rubinsky et al. | Aug 2013 | A1 |
| 20130197425 | Golberg et al. | Aug 2013 | A1 |
| 20130202766 | Rubinsky et al. | Aug 2013 | A1 |
| 20130218157 | Callas et al. | Aug 2013 | A1 |
| 20130253415 | Sano et al. | Sep 2013 | A1 |
| 20130281968 | Davalos et al. | Oct 2013 | A1 |
| 20130345697 | Garcia et al. | Dec 2013 | A1 |
| 20130345779 | Maor et al. | Dec 2013 | A1 |
| 20140017218 | Scott et al. | Jan 2014 | A1 |
| 20140039489 | Davalos et al. | Feb 2014 | A1 |
| 20140046322 | Callas et al. | Feb 2014 | A1 |
| 20140066913 | Sherman | Mar 2014 | A1 |
| 20140081255 | Johnson et al. | Mar 2014 | A1 |
| 20140088578 | Rubinsky et al. | Mar 2014 | A1 |
| 20140121663 | Pearson et al. | May 2014 | A1 |
| 20140121728 | Dhillon et al. | May 2014 | A1 |
| 20140163551 | Maor et al. | Jun 2014 | A1 |
| 20140207133 | Model et al. | Jul 2014 | A1 |
| 20140296844 | Kevin et al. | Oct 2014 | A1 |
| 20140309579 | Rubinsky et al. | Oct 2014 | A1 |
| 20140378964 | Pearson | Dec 2014 | A1 |
| 20150088120 | Garcia et al. | Mar 2015 | A1 |
| 20150088220 | Callas et al. | Mar 2015 | A1 |
| 20150112333 | Chorenky et al. | Apr 2015 | A1 |
| 20150126922 | Willis | May 2015 | A1 |
| 20150152504 | Lin | Jun 2015 | A1 |
| 20150164584 | Davalos et al. | Jun 2015 | A1 |
| 20150173824 | Davalos et al. | Jun 2015 | A1 |
| 20150201996 | Rubinsky et al. | Jul 2015 | A1 |
| 20150265349 | Moss et al. | Sep 2015 | A1 |
| 20150289923 | Davalos et al. | Oct 2015 | A1 |
| 20150320488 | Moshe et al. | Nov 2015 | A1 |
| 20150320999 | Nuccitelli et al. | Nov 2015 | A1 |
| 20150327944 | Davalos et al. | Nov 2015 | A1 |
| 20160022957 | Hobbs et al. | Jan 2016 | A1 |
| 20160066977 | Neal et al. | Mar 2016 | A1 |
| 20160074114 | Pearson et al. | Mar 2016 | A1 |
| 20160113708 | Moss et al. | Apr 2016 | A1 |
| 20160143698 | Garcia et al. | May 2016 | A1 |
| 20160235470 | Callas et al. | Aug 2016 | A1 |
| 20160287313 | Rubinsky et al. | Oct 2016 | A1 |
| 20160287314 | Arena et al. | Oct 2016 | A1 |
| 20160338761 | Chornenky et al. | Nov 2016 | A1 |
| 20160354142 | Pearson et al. | Dec 2016 | A1 |
| 20160367310 | Onik et al. | Dec 2016 | A1 |
| 20170035501 | Chornenky et al. | Feb 2017 | A1 |
| 20170189579 | Davalos | Jul 2017 | A1 |
| 20170209620 | Davalos et al. | Jul 2017 | A1 |
| 20170266438 | Sano | Sep 2017 | A1 |
| 20170360326 | Davalos et al. | Dec 2017 | A1 |
| 20180071014 | Neal et al. | Mar 2018 | A1 |
| 20180125565 | Sano et al. | May 2018 | A1 |
| 20180161086 | Davalos et al. | Jun 2018 | A1 |
| 20190029749 | Garcia | Jan 2019 | A1 |
| 20190046255 | Davalos et al. | Feb 2019 | A1 |
| 20190069945 | Davalos et al. | Mar 2019 | A1 |
| 20190083169 | Single et al. | Mar 2019 | A1 |
| 20190133671 | Davalos et al. | May 2019 | A1 |
| 20190175248 | Neal, II | Jun 2019 | A1 |
| 20190175260 | Davalos | Jun 2019 | A1 |
| 20190223938 | Arena et al. | Jul 2019 | A1 |
| 20190232048 | Latouche et al. | Aug 2019 | A1 |
| 20190233809 | Neal et al. | Aug 2019 | A1 |
| 20190256839 | Neal et al. | Aug 2019 | A1 |
| 20190282294 | Davalos et al. | Sep 2019 | A1 |
| 20190328445 | Sano et al. | Oct 2019 | A1 |
| 20190351224 | Sane et al. | Nov 2019 | A1 |
| 20190376055 | Davalos et al. | Dec 2019 | A1 |
| 20200046432 | Garcia et al. | Feb 2020 | A1 |
| 20200046967 | Ivey et al. | Feb 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 7656800 | Apr 2001 | AU |
| 2002315095 | Dec 2002 | AU |
| 2003227960 | Dec 2003 | AU |
| 2005271471 | Feb 2006 | AU |
| 2006321570 | Jun 2007 | AU |
| 2006321574 | Jun 2007 | AU |
| 2006321918 | Jun 2007 | AU |
| 2297846 | Feb 1999 | CA |
| 2378110 | Feb 2001 | CA |
| 2445392 | Nov 2002 | CA |
| 2458676 | Mar 2003 | CA |
| 2487284 | Dec 2003 | CA |
| 2575792 | Feb 2006 | CA |
| 2631940 | Jun 2007 | CA |
| 2631946 | Jun 2007 | CA |
| 2632604 | Jun 2007 | CA |
| 2751462 | Nov 2010 | CA |
| 1525839 | Sep 2004 | CN |
| 101534736 | Sep 2009 | CN |
| 102238921 | Nov 2011 | CN |
| 102421386 | Apr 2012 | CN |
| 863111 | Jan 1953 | DE |
| 4000893 | Jul 1991 | DE |
| 4000893 | Jul 1991 | DE |
| 60038026 | Feb 2009 | DE |
| 0218275 | Apr 1987 | EP |
| 0339501 | Nov 1989 | EP |
| 0378132 | Jul 1990 | EP |
| 0533511 | Mar 1993 | EP |
| 0998235 | May 2000 | EP |
| 0528891 | Jul 2000 | EP |
| 1196550 | Apr 2002 | EP |
| 1439792 | Jul 2004 | EP |
| 1442765 | Aug 2004 | EP |
| 1462065 | Sep 2004 | EP |
| 1061983 | Nov 2004 | EP |
| 1493397 | Jan 2005 | EP |
| 1506039 | Feb 2005 | EP |
| 0935482 | May 2005 | EP |
| 1011495 | Nov 2005 | EP |
| 1796568 | Jun 2007 | EP |
| 1207797 | Feb 2008 | EP |
| 1406685 | Jun 2008 | EP |
| 1424970 | Dec 2008 | EP |
| 2381829 | Nov 2011 | EP |
| 2413833 | Feb 2012 | EP |
| 1791485 | Dec 2014 | EP |
| 2373241 | Jan 2015 | EP |
| 1962710 | Aug 2015 | EP |
| 1962708 | Sep 2015 | EP |
| 1962945 | Apr 2016 | EP |
| 2300272 | Jun 2008 | ES |
| 2315493 | Apr 2009 | ES |
| 2001510702 | Aug 2001 | JP |
| 2003505072 | Feb 2003 | JP |
| 2003506064 | Feb 2003 | JP |
| 2004203224 | Jul 2004 | JP |
| 2004525726 | Aug 2004 | JP |
| 2004303590 | Oct 2004 | JP |
| 2005501596 | Jan 2005 | JP |
| 2005526579 | Sep 2005 | JP |
| 2008508946 | Mar 2008 | JP |
| 4252316 | Apr 2009 | JP |
| 2009518130 | May 2009 | JP |
| 2009518150 | May 2009 | JP |
| 2009518151 | May 2009 | JP |
| 2009532077 | Sep 2009 | JP |
| 2010503496 | Feb 2010 | JP |
| 2011137025 | Jul 2011 | JP |
| 2011137025 | Jul 2011 | JP |
| 2012510332 | May 2012 | JP |
| 2012515018 | Jul 2012 | JP |
| 2012521863 | Sep 2012 | JP |
| 101034682 | May 2011 | KR |
| 9104014 | Apr 1991 | WO |
| 9634571 | Nov 1996 | WO |
| 9639531 | Dec 1996 | WO |
| 9810745 | Mar 1998 | WO |
| 9814238 | Apr 1998 | WO |
| 9901076 | Jan 1999 | WO |
| 9904710 | Feb 1999 | WO |
| 0020554 | Apr 2000 | WO |
| 0107583 | Feb 2001 | WO |
| 0107584 | Feb 2001 | WO |
| 0107585 | Feb 2001 | WO |
| 0110319 | Feb 2001 | WO |
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| Entry |
|---|
| Garcia et al., “Irreversible electroporation (IRE) to treat brain cancer.” ASME Summer Bioengineering Conference, Marco Island, FL, Jun. 25-29, 2008. |
| Gauger, et al., A Study of Dielectric Membrane Breakdown in the Fucus Egg, J. Membrane Biol., vol. 48, No. 3, pp. 249-264, 1979. |
| Gehl, et al., In Vivo Electroporation of Skeletal Muscle: Threshold, Efficacy and Relation to Electric Field Distribution, Biochimica et Biphysica Acta 1428, 1999, pp. 233-240. |
| Gençer, et al., Electrical Impedance Tomography: Induced-Current Imaging Achieved with a Multiple Coil System, IEEE Transactions on Biomedical Engineering, vol. 43, No. 2, Feb. 1996. |
| Gilbert, et al., Novel Electrode Designs for Electrochemotherapy, Biochimica et Biophysica Acta 1334, 1997, pp. 9-14. |
| Gilbert, et al., The Use of Ultrasound Imaging for Monitoring Cryosurgery, Proceedings 6th Annual Conference, IEEE Engineering in Medicine and Biology, 107-111, 1984. |
| Gilbert, T. W., et al., “Decellularization of tissues and organs”, Biomaterials, Elsevier Science Publishers, Barking, GB, vol. 27, No. 19, Jul. 1, 2006, pp. 3675-3683. |
| Glidewell, et al., The Use of Magnetic Resonance Imaging Data and the Inclusion of Anisotropic Regions in Electrical Impedance Tomography, Biomed, Sci. Instrum. 1993; 29: 251-7. |
| Gothelf, et al., Electrochemotherapy: Results of Cancer Treatment Using Enhanced Delivery of Bleomycin by Electroporation, Cancer Treatment Reviews 2003: 29: 371-387. |
| Griffiths, et al., A Dual-Frequency Electrical Impedance Tomography System, Phys. Med. Biol., 1989, vol. 34, No. 10, pp. 1465-1476. |
| Griffiths, The Importance of Phase Measurement in Electrical Impedance Tomography, Phys. Med. Biol., 1987, vol. 32, No. 11, pp. 1435-1444. |
| Griffiths, Tissue Spectroscopy with Electrical Impedance Tomography: Computer Simulations, IEEE Transactions on Biomedical Engineering, vol. 42, No. 9, Sep. 1995. |
| Gumerov, et al., The Dipole Approximation Method and Its Coupling with the Regular Boundary Element Method for Efficient Electrical Impedance Tomography, Boundary Element Technology XIII, 1999. |
| Hapala, Breaking the Barrier: Methods for Reversible Permeabilization of Cellular Membranes, Critical Reviews in Biotechnology, 17(2): 105-122, 1997. |
| Heller, et al., Clinical Applications of Electrochemotherapy, Advanced Drug Delivery Reviews, vol. 35, pp. 119-129, 1999. |
| Ho, et al., Electroporation of Cell Membranes: A Review, Critical Reviews in Biotechnology, 16(4): 349-362, 1996. |
| Holder, et al., Assessment and Calibration of a Low-Frequency System for Electrical Impedance Tomography (EIT), Optimized for Use in Imaging Brain Function in Ambulant Human Subjects, Annals of the New York Academy of Science, vol. 873, Issue 1, Electrical BI, pp. 512-519, 1999. |
| Huang, et al., Micro-Electroporation: Improving the Efficiency and Understanding of Electrical Permeabilization of Cells, Biomedical Microdevices, vol. 2, pp. 145-150, 1999. |
| Hughes, et al., An Analysis of Studies Comparing Electrical Impedance Tomography with X-Ray Videofluoroscopy in the Assessment of Swallowing, Physiol. Meas. 15, 1994, pp. A199-A209. |
| Issa, et al., The TUNA Procedure for BPH: Review of the Technology: The TUNA Procedure for BPH: Basic Procedure and Clinical Results, Reprinted from Infections in Urology, Jul./Aug. 1998 and Sep./Oct. 1998. |
| Ivanu{hacek over (s)}a, et al., MRI Macromolecular Contrast Agents as Indicators of Changed Tumor Blood Flow, Radiol. Oncol. 2001; 35(2): 139-47. |
| Jaroszeski, et al., In Vivo Gene Delivery by Electroporation, Advanced Drug Delivery Review, vol. 35, pp. 131-137, 1999. |
| Kinosita, et al., Hemolysis of Human Erythrocytes by a Transient Electric Field, Proc. Natl. Acad. Sci. USA, vol. 74, No. 5, pp. 1923-1927, 1977. |
| Liu, et al., Measurement of Pharyngeal Transit Time by Electrical Impedance Tomography, Clin. Phys. Physiol. Meas., 1992, vol. 13, Suppl. A, pp. 197-200. |
| Lundqvist, et al., Altering the Biochemical State of Individual Cultured Cells and Organelles with Ultramicroelectrodes, Proc. Natl. Acad. Sci. USA, vol. 95, pp. 10356-10360, Sep. 1998. |
| Lurquin, Gene Transfer by Electroporation, Molecular Biotechnology, vol. 7, 1997. |
| Lynn, et al., A New Method for the Generation and Use of Focused Ultrasound in Experimental Biology, The Journal of General Physiology, vol. 26, 179-193, 1942. |
| Maor et al., The Effect of Irreversible Electroporation on Blood Vessels, Tech. in Cancer Res. and Treatment, vol. 6, No. 4, Aug. 2007, pp. 307-312. |
| Maor, E., A. Ivorra, and B. Rubinsky, Non Thermal Irreversible Electroporation: Novel Technology for Vascular Smooth Muscle Cells Ablation, PLoS One, 2009, 4(3): p. e4757. |
| Maor, E., A. Ivorra, J. Leor, and B. Rubinsky, Irreversible electroporation attenuates neointimal formation after angioplasty, IEEE Trans Biomed Eng, 2008, 55(9): p. 2268-74. |
| Miklav{hacek over (c)}i{hacek over (c)}, et al., A Validated Model of an in Vivo Electric Field Distribution in Tissues for Electrochemotherapy and for DNA Electrotransfer for Gene Therapy, Biochimica et Biophysica Acta 1523 (2000), pp. 73-83. |
| Miklav{hacek over (c)}i{hacek over (c)}, et al., The Importance of Electric Field Distribution for Effective in Vivo Electroporation of Tissues, Biophysical Journal, vol. 74, May 1998, pp. 2152-2158. |
| Miller, L., et al., Cancer cells ablation with irreversible electroporation, Technology in Cancer Research and Treatment 4 (2005) 699-706. |
| Mir et al., “Mechanisms of Electrochemotherapy” Advanced Drug Delivery Reviews 35:107-118 (1999). |
| Mir, et al., Effective Treatment of Cutaneous and Subcutaneous Malignant Tumours by Electrochemotherapy, British Journal of Cancer, vol. 77, No. 12, pp. 2336-2342, 1998. |
| Mir, et al., Electrochemotherapy Potentiation of Antitumour Effect of Bleomycin by Local Electric Pulses, European Journal of Cancer, vol. 27, No. 1, pp. 68-72, 1991. |
| Mir, et al., Electrochemotherapy, a Novel Antitumor Treatment: First Clinical Trial, C.R. Acad. Sci. Paris, Ser. III, vol. 313, pp. 613-618, 1991. |
| Mir, L.M. and Orlowski, S., The basis of electrochemotherapy, in Electrochemotherapy, electrogenetherapy, and transdermal drug delivery: electrically mediated delivery of molecules to cells, M.J. Jaroszeski, R. Heller, R. Gilbert, Editors, 2000, Humana Press, p. 99-118. |
| Mir, L.M., et al., Electric Pulse-Mediated Gene Delivery to Various Animal Tissues, in Advances in Genetics, Academic Press, 2005, p. 83-114. |
| Mir, Therapeutic Perspectives of in Vivo Cell Electropermeabilization, Bioelectrochemistry, vol. 53, pp. 1-10, 2000. |
| Narayan, et al., Establishment and Characterization of a Human Primary Prostatic Adenocarcinoma Cell Line (ND-1), The Journal of Urology, vol. 148, 1600-1604, Nov. 1992. |
| Naslund, Cost-Effectiveness of Minimally Invasive Treatments and Transurethral Resection (TURP) in Benign Prostatic Hyperplasia (BPH), (Abstract), Presented at 2001 AUA National Meeting,, Anaheim, CA, Jun. 5, 2001. |
| Naslund, Michael J., Transurethral Needle Ablation of the Prostate, Urology, vol. 50, No. 2, Aug. 1997. |
| Neal II, Robert E. and R.V. Davalos, The Feasibility of Irreversible Electroporation for the Treatment of Breast Cancer and Other Heterogeneous Systems, Ann Biomed Eng, 2009, 37(12): p. 2615-2625. |
| Neumann, et al., Gene Transfer into Mouse Lyoma Cells by Electroporation in High Electric Fields, J. Embo., vol. 1, No. 7, pp. 841-845, 1982. |
| Neumann, et al., Permeability Changes Induced by Electric Impulses in Vesicular Membranes, J. Membrane Biol., vol. 10, pp. 279-290, 1972. |
| Okino, et al., Effects of High-Voltage Electrical Impulse and an Anticancer Drug on In Vivo Growing Tumors, Japanese Journal of Cancer Research, vol. 78, pp. 1319-1321, 1987. |
| Onik, et al., Sonographic Monitoring of Hepatic Cryosurgery in an Experimental Animal Model, AJR American J. of Roentgenology, vol. 144, pp. 1043-1047, May 1985. |
| Onik, et al., Ultrasonic Characteristics of Frozen Liver, Cryobiology, vol. 21, pp. 321-328, 1984. |
| Organ, L.W., Electrophysiological principles of radiofrequency lesion making, Apply. Neurophysiol., 1976. 39: p. 69-76. |
| Co-Pending Application No. PCT/US11/62067, filed Nov. 23, 2011. |
| Co-Pending U.S. Appl. No. 13/919,640, filed Jun. 17, 2013. |
| Co-Pending U.S. Appl. No. 13/958,152, filed Aug. 2, 2013. |
| Co-Pending U.S. Appl. No. 13/989,175, filed May 23, 2013. |
| Co-Pending U.S. Appl. No. 14/012,832 , filed Aug. 28, 2013. |
| Co-Pending U.S. Appl. No. 14/017,210, filed Sep. 3, 2013. |
| Co-pending European Application No. 10 824 248.8, Invitation Pursuant to rule 62a(1) EPC (Sep. 25, 2013). |
| Ott, H. C., et al., “Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart”, Nature Medicine, Nature Publishing Group, New York, NY, US, vol. 14, No. 2, Feb. 1, 2008, pp. 213-221. |
| PCT International Search Report (dated Aug. 2, 2011), Written Opinion (dated Aug. 2, 2011), and International Preliminary Report on Patentability (dated Apr. 17, 2012) of PCT/US10/53077. |
| PCT International Search Report (dated Aug. 26, 2005), Written Opinion (dated Aug. 26, 2005), and International Preliminary Report on Patentability (dated Jun. 26, 2006) of PCT/US20041043477. |
| PCT International Search Report (dated Jan. 19, 2010), Written Opinion (dated Jan. 19, 2010), and International Preliminary Report on Patentability (dated Jan. 4, 2010) of PCT/US09/62806, 15 pgs. |
| PCT International Search Report (dated Jul. 15, 2010), Written Opinion (dated Jul. 15, 2010), and International Preliminary Report on Patentability (dated Oct. 11, 2011) from PCT/US2010/030629. |
| PCT International Search Report (dated Jul. 9, 2009), Written Opinion (dated Jul. 9, 2009), and International Preliminary Report on Patentability (dated Nov. 2, 2010) of PCT/US20091042100. |
| PCT International Search Report, 4 pgs, (dated Jul. 30, 2010), Written Opinion, 7 pgs, (dated Jul. 30, 2010), and International Preliminary Report on Patentability, 8 pgs, (dated Oct. 4, 2011) from PCT/US2010/029243. |
| Piñ, ero, et al., Apoptotic and Necrotic Cell Death are Both Induced by Electroporation in HL60 Human Promyeloid Leukaemia Cells, Apoptosis, vol, 2, No. 3, 330-336, Aug. 1997. |
| Precision Office TUNA System, When Patient Satisfaction is Your Goal, VidaMed 2001. |
| Rajagopal, V. and S.G. Rockson, Coronary restenosis: a review of mechanisms and management, The American Journal of Medicine, 2003, 115(7): p. 547-553. |
| Rols, M.P., et al., Highly Efficient Transfection of Mammalian Cells by Electric Field Pulses: Application to Large Volume of Cell Culture by Using a Flow System, Eur. J. Biochem. 1992, 206, pp. 115-121. |
| Rubinsky, B., “Irreversible Electroporation in Medicine”, Technology in Cancer Research and Treatment, vol. 6, No. 4, Aug. 1, 2007, pp. 255-259. |
| Rubinsky, B., ed, Cryosurgery. Annu Rev. Biomed. Eng. vol. 2 2000. 157-187. |
| Sano, M. B., et al., “Towards the creation of decellularized organ constructs using irreversible electroporation and active mechanical perfusion”, Biomedical Engineering Online, Biomed Central Ltd, London, GB, vol. 9, No. 1, Dec. 10, 2010, p. 83. |
| Schmukler, Impedance Spectroscopy of Biological Cells, Engineering in Medicine and Biology Society, Engineering Advances: New Opportunities for Biomedical Engineers, Proceedings of the 16th Annual Internal Conference of the IEEE, vol. 1, p. A74, downloaded from IEEE Xplore website, 1994. |
| Sersa, et al., Reduced Blood Flow and Oxygenation in SA-1 Tumours after Electrochemotherapy with Cisplatin, British Journal of Cancer, 87, 1047-1054, 2002. |
| Sersa, et al., Tumour Blood Flow Modifying Effects of Electrochemotherapy: a Potential Vascular Targeted Mechanism, Radiol. Oncol., 37(1): 43-8, 2003. |
| Sharma, et al., Poloxamer 188 Decreases Susceptibility of Artificial Lipid Membranes to Electroporation, Biophysical Journal, vol. 71, No. 6, pp. 3229-3241, Dec. 1996. |
| Shiina, S., et al, Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. AJR, 1993, 160: p. 1023-8. |
| Tekle, Ephrem, R. Dean Astumian, and P. Boon Chock, Electroporation by using bipolar oscillating electric field: An improved method for DNA transfection of NIH 3T3 cells, Proc. Natl. Acad. Sci., vol. 88, pp. 4230-4234, May 1991, Biochemistry. |
| Thompson, et al., To determine whether the temperature of 2% lignocaine gel affects the initial discomfort which may be associated with its instillation into the male urethra, BJU International (1999), 84, 1035-1037. |
| TUNA—Suggested Local Anesthesia Guidelines, no date available. |
| Vidamed, Inc., Transurethral Needle Ablation (TUNA): Highlights from Worldwide Clinical Studies, Vidamed's Office TUNA System, 2001. |
| Weaver, Electroporation: A General Phenomenon for Manipulating Cells and Tissues, Journal of Cellular Biochemistry, 51: 426-435, 1993. |
| Weaver, et al., Theory of Electroporation: A Review, Bioelectrochemistry and Bioenergetics, vol. 41, pp. 136-160, 1996. |
| Weisstein: Cassini Ovals. From MathWorld—A. Wolfram Web Resource; Apr. 30, 2010; http://mathworld.wolfram.com/ (updated May 18, 2011). |
| Zimmermann, et al., Dielectric Breakdown of Cell Membranes, Biophysical Journal, vol. 14, No. 11, pp. 881-899, 1974. |
| Zlotta, et al., Long-Term Evaluation of Transurethral Needle Ablation of the Prostate (TUNA) for Treatment of Benign Prostatic Hyperplasia (BPH): Clinical Outcome After 5 Years. (Abstract) Presented at 2001 AUA National Meeting, Anaheim, CA—Jun. 5, 2001. |
| Zlotta, et al., Possible Mechanisms of Action of Transurethral Needle Ablation of the Prostate on Benign Prostatic Hyperplasia Symptoms: A Neurohistochemical Study, Reprinted from Journal of Urology, vol. 157, No. 3, Mar. 1997, pp. 894-899. |
| Agerholm-Larsen, B., et al., “Preclinical Validation of Electrochennotherapy as an Effective Treatment for Brain Tumors”, Cancer Research 71: 3753-3762 (2011). |
| Appelbaum, L., et al., “US Findings after Irreversible Electroporation Ablation: Radiologic-Pathologic Correlation” Radiology 262(1), 117-125 (2012). |
| Arena, Christopher B., et al., “Towards the development of latent heat storage electrodes for electroporation-based therapies”, Applied Physics Letters, 101, 083902 (2012). |
| Arena, Christopher B., et al.,“Phase Change Electrodes for Reducing Joule Heating During Irreversible Electroporation”. Proceedings of the ASME 2012 Summer Bioengineering Conference, SBC2012, Jun. 20-23, 2012, Fajardo, Puerto Rico. |
| Bagla, S. and Papadouris, D., “Percutaneous Irreversible Electroporation of Surgically Unresectable Pancreatic Cancer: A Case Report” J. Vascular Int. Radiol. 23(1), 142-145 (2012). |
| Bancroft, et al., Design of a Flow Perfusion Bioreactor System for Bone Tissue-Engineering Applications, Tissue Engineering, vol. 9, No. 3, 2003, p. 549-554. |
| Ben-David, E.,et al., “Characterization of Irreversible Electroporation Ablation in In Vivo Procine Liver” Am. J. Roentgenol. 198(1), W62-W68 (2012). |
| Cemazar M, Parkins CS, Holder AL, Chaplin DJ, Tozer GM, et al., “Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy”, Br J Cancer 84: 565-570 (2001). |
| Corovic, S., et al., “Analytical and numerical quantification and comparison of the local electric field in the tissue for different electrode configurations,” Biomed Eng Online, 6, 2007. |
| Daud, A.I., et al., “Phase I Trial of Interleukin-12 Plasmid Electroporation in Patients With Metastatic Melanoma,” Journal of Clinical Oncology, 26, 5896-5903, Dec. 20, 2008. |
| Davalos, R.V., et al., “Electrical impedance tomography for imaging tissue electroporation,” IEEE Transactions on Biomedical Engineering, 51, 761-767, 2004. |
| Demirbas, M. F., “Thermal Energy Storage and Phase Change Materials: An Overview” Energy Sources Part B 1(1), 85-95 (2006). |
| Ellis TL, Garcia PA, Rossmeisl JH, Jr., Henao-Guerrero N, Robertson J, et al., “Nonthermal irreversible electroporation for intracranial surgical applications. Laboratory investigation”, J Neurosurg 114: 681-688 (2011). |
| Faroja, M., et al., “Irreversible Electroporation Ablation: Is the entire Damage Nonthermal?”, Radiology, 266(2), 462-470 (2013). |
| Foster RS, “High-intensity focused ultrasound in the treatment of prostatic disease”, European Urology, 1993, vol. 23 Suppl 1, pp. 29-33. |
| Garcia P.A., et al., “7.0-T Magnetic Resonance Imaging Characterization of Acute Blood-Brain-Barrier Disruption Achieved with Intracranial Irreversible Electroporation”, PLOS One, Nov. 2012, 7:11, e50482. |
| Garcia P.A., et al., “Pilot study of irreversible electroporation for intracranial surgery”, Conf Proc IEEE Eng Med Biol Soc, 2009:6513-6516, 2009. |
| Garcia PA, Rossmeisl JH, Jr., Neal RE, 2nd, Ellis TL, Davalos RV, “A Parametric Study Delineating Irreversible Electroporation from Thermal Damage Based on a Minimally Invasive Intracranial Procedure”, Biomed Eng Online 10: 34 (2011). |
| Garcia, P. A., et al., “Towards a predictive model of electroporation-based therapies using pre-pulse electrical measurements,” Conf Proc IEEE Eng Med Biol Soc, vol. 2012, pp. 2575-2578, 2012. |
| Garcia, P. A., et al., “Non-thermal Irreversible Electroporation (N-TIRE) and Adjuvant Fractioned Radiotherapeutic Multimodal Therapy for Intracranial Malignant Glioma in a Canine Patient” Technol. Cancer Res. Treatment 10(1), 73-83 (2011). |
| Hjouj, M., et al., “Electroporation-Induced BBB Disruption and Tissue Damage Depicted by MRI”, Neuro-Oncology 13: Issue suppl 3, abstract ET-32 (2011). |
| Hjouj, M., et al., “MRI Study on Reversible and Irreversible Electroporation Induced Blood Brain Barrier Disruption”, PLOS One, Aug. 2012, 7:8, e42817. |
| Lee, E.W., et al., “Imaging guided percutaneous irreversible electroporation: ultrasound and immunohistological correlation”, Technol Cancer Res Treat 6: 287-294 (2007). |
| Li, W., et al., “The Effects of Irreversible Electroporation (IRE) on Nerves” PloS One, Apr. 2011, 6(4), e18831. |
| Mahmood, F., et al., “Diffusion-Weighted MRI for Verification of Electroporation-Based Treatments”, Journal of Membrane Biology 240: 131-138 (2011). |
| Mahnic-Kalamiza, S., et al., “Educational application for visualization and analysis of electric field strength in multiple electrode electroporation,” BMC Med Educ, vol. 12, p. 102, 2012. |
| Marty, M., et al., “Electrochemotherapy—An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study,” European Journal of Cancer Supplements, 4, 3-13, 2006. |
| Neal II, R. E., et al., “Experimental characterization and numerical modeling of tissue electrical conductivity during pulsed electric fields for irreversible electroporation treatment planning,” IEEE Trans Biomed Eng., vol. 59:4, pp. 1076-1085. Epub 2012 Jan. 6, 2012. |
| Neal II, R. E., et al., “Successful Treatment of a Large Soft Tissue Sarcoma with Irreversible Electroporation”, Journal of Clinical Oncology, 29:13, e372-e377 (2011). |
| Rubinsky, B., et al., “Irreversible Electroporation: A New Ablation Modality—Clinical Implications” Technol. Cancer Res. Treatment 6(1), 37-48 (2007). |
| Salford, L.G., et al., “A new brain tumour therapy combining bleomycin with in vivo electropermeabilization”, Biochem. Biophys. Res. Commun., 194(2): 938-943 (1993). |
| Sharma, A. , et al., “Review on Thermal Energy Storage with Phase Change Materials and Applications”, Renewable Sustainable Energy Rev. 13(2), 318-345 (2009). |
| Thomson, K. R., et al., “Investigation of the Safety of Irreversible Electroporation in Humans” J. Vascular Int. Radiol. 22 (5), 611-621 (2011). |
| International Preliminary Report on Patentability of Corresponding International Application No. PCT/2011/062067, dated May 28, 2013. |
| Boone, K., Barber, D. & Brown, B. Review—Imaging with electricity: report of the European Concerted Action on Impedance Tomography. J. Med. Eng. Technol. 21, 201-232 (1997). |
| Davalos, R. V. & Rubinsky, B. Temperature considerations during irreversible electroporation. International Journal of Heat and Mass Transfer 51, 5617-5622, doi:10.1016/j.ijheatmasstransfer.2008.04.046 (2008). |
| Garcia, P. et al. Intracranial nonthermal irreversible electroporation: in vivo analysis. J Membr Biol 236, 127-136 (2010). |
| International Preliminary Report on Patentability of Corresponding International Application No. PCT/2011/066239, dated Jun. 25, 2013. |
| Jossinet et al., Electrical Impedance Endo-Tomography: Imaging Tissue From Inside, IEEE Transactions on Medical Imaging, vol. 21, No. 6, Jun. 2002, pp. 560-565. |
| Lee, E. W. et al. Advanced Hepatic Ablation Technique for Creating Complete Cell Death : Irreversible Electroporation. Radiology 255, 426-433, doi:10.1148/radiol.10090337 (2010). |
| Payselj, N. et al. The course of tissue permeabilization studied on a mathematical model of a subcutaneous tumor in small animals. IEEE Trans Biomed Eng 52, 1373-1381 (2005). |
| Phillips, M., Maor, E. & Rubinsky, B. Non-Thermal Irreversible Electroporation for Tissue Decellularization. J. Biomech. Eng, doi:10.1115/1.4001882 (2010). |
| Sel, D. et al. Sequential finite element model of tissue electropermeabilization. IEEE Transactions on Biomedical Engineering 52, 816-827, doi:10.1109/tbme.2005.845212 (2005). |
| Sel, D., Lebar, A. M. & Miklavcic, D. Feasibility of employing model-based optimization of pulse amplitude and electrode distance for effective tumor electropermeabilization. IEEE Trans Biomed Eng 54, 773-781 (2007). |
| Weaver, J. C., Electroporation of biological membranes from multicellular to nano scales, IEEE Trns. Dielectr. Electr. Insul. 10, 754-768 (2003). |
| PCT International Search Report (dated Aug. 22, 2012), and Written Opinion (dated Aug. 22, 2012) of PCT/US11/66239. |
| PCT International Search Report and Written Opinion (dated Jul. 25, 2012) of PCT/US2011/062067. |
| Al-Sakere, B. et al., 2007, “Tumor ablation with irreversible electroporation.” PLoS One 2. |
| Amasha, et al., Quantitative Assessment of Impedance Tomography for Temperature Measurements in Microwave Hyperthermia, Clin. Phys. Physiol. Meas., 1998, Suppl. A, 49-53. |
| Andreason, Electroporation as a Technique for the Transfer of Macromolecules into Mammalian Cell Lines, J. Tiss. Cult. Meth., 15:56-62, 1993. |
| Baker, et al., Calcium-Dependent Exocytosis in Bovine Adrenal Medullary Cells with Leaky Plasma Membranes, Nature, vol. 276, pp. 620-622, 1978. |
| Barber, Electrical Impedance Tomography Applied Potential Tomography, Advances in Biomedical Engineering, Beneken and Thevenin, eds., IOS Press, 1993. |
| Beebe, S.J., et al., Nanosecond pulsed electric field (nsPEF) effects on cells and tissues: apoptosis induction and tumor growth inhibition. PPPS-2001 Pulsed Power Plasma Science 2001, 28th IEEE International Conference on Plasma Science and 13th IEEE International Pulsed Power Conference, Digest of Technical Papers (Cat. No. 01CH37251). IEEE, Part vol. 1, 2001, pp. 211-215, vol. I, Piscataway, NJ, USA. |
| Blad, et al., Impedance Spectra of Tumour Tissue in Comparison with Normal Tissue; a Possible Clinical Application for Electrical Impedance Tomography, Physiol. Meas. 17 (1996) A105-A115. |
| Bolland, F., et al., “Development and characterisation of a full-thickness acellular porcine bladder matrix for tissue engineering”, Biomaterials, Elsevier Science Publishers, Barking, GB, vol. 28, No. 6, 28 Nov. 2006, pp. 1061-1070. |
| BPH Management Strategies: Improving Patient Satisfaction, Urology Times, May 2001, vol. 29, Supplement 1. |
| Brown, et al., Blood Flow Imaging Using Electrical Impedance Tomography, Clin. Phys. Physiol. Meas., 1992, vol. 13, Suppl. A, 175-179. |
| Brown, S.G., Phototherapy of tumors. World J. Surgery, 1983. 7: p. 700-9. |
| Chandrasekar, et al., Transurethral Needle Ablation of the Prostate (TUNA) —a Propsective Study, Six Year Follow Up, (Abstract), Presented at 2001 National Meeting, Anaheim, CA, Jun. 5, 2001. |
| Coates, C.W.,et al., “The Electrical Discharge of the Electric Eel, Electrophorous Electricus,” Zoologica, 1937, 22(1), pp. 1-32. |
| Cook, et al., ACT3: A High-Speed, High-Precision Electrical Impedance Tomograph, IEEE Transactions on Biomedical Engineering, vol. 41, No. 8, Aug. 1994. |
| Co-pending U.S. Appl. No. 10/571,162, filed Oct. 18, 2006 (published as 2007/0043345 on Feb. 22, 2007). |
| Co-Pending U.S. Appl. No. 12/432,295, filed Apr. 29, 2009. |
| Co-Pending U.S. Appl. No. 12/609,779, filed Oct. 30, 2009. |
| Co-pending U.S. Appl. No. 12/751,826, filed Mar. 31, 2010 (published as 2010/0250209 on Sep. 30, 2010). |
| Co-pending U.S. Appl. No. 12/751,854, filed Mar. 31, 2010 (published as 2010/0249771 on Sep. 30, 2010). |
| Co-Pending U.S. Appl. No. 12/757,901, filed Apr. 9, 2010. |
| Co-Pending U.S. Appl. No. 12/906,923, filed Oct. 18, 2010. |
| Co-Pending U.S. Appl. No. PCT/US04/43477, filed Dec. 21, 2004. |
| Co-Pending Application No. PCT/US09/42100, filed Apr. 29, 2009. |
| Co-Pending Application No. PCT/US09/62806, filed Oct. 30, 2009. |
| Co-Pending Application No. PCT/US10/30629, filed Apr. 9, 2010. |
| Co-Pending Application No. PCT/US10/53077, filed Oct. 18, 2010. |
| Co-Pending Application No. PCT/US11/32067, filed Nov. 23, 2011. |
| Co-Pending Application No. PCT/US11/66239, filed Dec. 20, 2011. |
| Co-pending Application No. PCT/US2010/029243, filed Mar. 30, 2010, published as WO 2010/117806 on Oct. 14, 2010. |
| Co-Pending U.S. Appl. No. 12/491,151, filed Jun. 24, 2009. |
| Co-Pending U.S. Appl. No. 13/332,133, filed Dec. 20, 2011. |
| Cowley, Good News for Boomers, Newsweek, Dec. 30, 1996/Jan. 6, 1997. |
| Cox, et al., Surgical Treatment of Atrial Fibrillation: A Review, Europace (2004) 5, S20-S-29. |
| Crowley, Electrical Breakdown of Biomolecular Lipid Membranes as an Electromechanical Instability, Biophysical Journal, vol. 13, pp. 711-724, 1973. |
| Davalos, et al ., Theoretical Analysis of the Thermal Effects During In Vivo Tissue Electroporation, Bioelectrochemistry, vol. 61, pp. 99-107, 2003. |
| Davalos, et al., A Feasibility Study for Electrical Impedance Tomography as a Means to Monitor T issue Electroporation for Molecular Medicine, IEEE Transactions on Biomedical Engineering, vol. 49, No. 4, Apr. 2002. |
| Davalos, et al., Tissue Ablation with Irreversible Electroporation, Annals of Biomedical Engineering, vol. 33, No. 2, p. 223-231, Feb. 2005. |
| Davalos, Real-Time Imaging for Molecular Medicine through Electrical Impedance Tomography of Electroporation, Dissertation for Ph.D. in Engineering-Mechanical Engineering, Graduate Division of University of California, Berkeley, 2002. |
| Dean, Nonviral Gene Transfer to Skeletal, Smooth, and Cardiac Muscle in Living Animals, Am J. Physiol Cell Physiol 289: 233-245, 2005. |
| Dev, et al., Medical Applications of Electroporation, IEEE Transactions of Plasma Science, vol. 28, No. 1, pp. 206-223, Feb. 2000. |
| Dev, et al., Sustained Local Delivery of Heparin to the Rabbit Arterial Wall with an Electroporation Catheter, Catheterization and Cardiovascular Diagnosis, Nov. 1998, vol. 45, No. 3, pp. 337-343. |
| Duraiswami, et al., Boundary Element Techniques for Efficient 2-D and 3-D Electrical Impedance Tomography, Chemical Engineering Science, vol. 52, No. 13, pp. 2185-2196, 1997. |
| Duraiswami, et al., Efficient 2D and 3D Electrical Impedance Tomography Using Dual Reciprocity Boundary Element Techniques, Engineering Analysis with Boundary Elements 22, (1998) 13-31. |
| Duraiswami, et al., Solution of Electrical Impedance Tomography Equations Using Boundary Element Methods, Boundary Element Technology XII, 1997, pp. 226-237. |
| Edd, J. et al., In-Vivo Results of a New Focal Tissue Ablation Technique: Irreversible Electroporaton, IEEE Trans. Biomed. Eng. 53 (2006) p. 1409-1415. |
| Edd, J.F, et al., 2007, “Mathematical modeling of irreversible electroporation for treatment planning”, Technology in Cancer Research and Treatment, 6:275-286. |
| Erez, et al., Controlled Destruction and Temperature Distributions in Biological Tissues Subjected to Monoactive Electrocoagulation, Transactions of the ASME: Journal of Mechanical Design, vol. 102, Feb. 1980. |
| Extended European Search Report. May 11, 2012. PCT/US2009042100. |
| Foster, R.S., et al., High-intensity focused ultrasound in the treatment of prostatic disease. Eur. Urol., 1993. 23: 44-7). |
| Fox, et al., Sampling Conductivity Images via MCMC, Mathematics Department, Auckland University, New Zealand, May 1997. |
| Co-Pending U.S. Appl. No. 14/558,631, filed Dec. 2, 2014. |
| Seidler et al., “A Cre-loxP-based mouse model for conditional somatic gene expression and knockdown in vivo by using avian retroviral vectors.” Proceedings of the National Academy of Sciences, vol. 105, pp. 10137-10142 (2008). |
| Szot et al., “3D in vitro bioengineered tumors based on collagen I hydrogels.” Biomaterials vol. 32, pp. 7905-7912 (2011). |
| Verbridge et al., “Oxygen-Controlled Three-Dimensional Cultures to Analyze Tumor Angiogenesis.” Tissue Engineering, Part A vol. 16, pp. 2133-2141 (2010). |
| Weaver et al., “A brief overview of electroporation pulse strength-duration space: A region where additional intracellular effects are expected.” Bioelectrochemistry vol. 87, pp. 236-243 (2012). |
| Yang et al., “Dielectric properties of human leukocyte subpopulations determined by electrorotation as a cell separation criterion.” Biophysical Journal, vol. 76, pp. 3307-3314 (1999). |
| Zhang, Y., et al., MR imaging to assess immediate response to irreversible electroporation for targeted ablation of liver tissues: preclinical feasibility studies in a rodent model. Radiology, 2010. 256(2): p. 424-32. |
| A.I. Daud et al., “Phase I Trial of Interleukin-12 Plasmid Electroporation in Patients With Metastatic Melanoma,” Journal of Clinical Oncology, 26, pp. 5896-5903, 2008. |
| Arena et al. “High-Frequency Irreversible Electroporation (H-FIRE) for Non-thermal Ablation without Muscle Contraction.” Biomed. Eng. Online, vol. 10, 20 pages (2011). |
| Arena, C.B., et al., “A three-dimensional in vitro tumor platform for modeling therapeutic irreversible electroporation.” Biophysical Journal, 2012.103(9): p. 2033-2042. |
| Ball, C., K.R. Thomson, and H. Kavnoudias, “Irreversible electroporation: a new challenge in “out of-operating theater” anesthesia.” Anesth Analg, 2010. 110(5): p. 1305-9. |
| Cannon et al., “Safety and early efficacy of irreversible electroporation for hepatic tumors in proximity to vital structures.” Journal of Surgical Oncology, 6 pages (2012). |
| Carpenter A.E. et al., “CellProfiler: image analysis software for identifying and quantifying cell phenotypes.” Genome Biol. 2006; 7(10): R100. Published online Oct. 31, 2006, 11 pages. |
| Charpentier, K.P., et al., “Irreversible electroporation of the pancreas in swine: a pilot study.” HPB: the official journal of the International Hepato Pancreato Biliary Association, 2010. 12(5): p. 348-351. |
| Chen et al., “Classification of cell types using a microfluidic device for mechanical and electrical measurement on single cells.” Lab on a Chip, vol. 11, pp. 3174-3181 (2011). |
| Clark et al., “The electrical properties of resting and secreting pancreas.” The Journal of Physiology, vol. 189, pp. 247-260 (1967). |
| Co-Pending U.S. Appl. No. 14/808,679, filed Jul. 24, 2015. |
| Co-Pending Application No. PCT/US15/30429, filed May 12, 2015. |
| Co-Pending U.S. Appl. No. 14/627,046, filed Feb. 20, 2015. |
| Co-Pending U.S. Appl. No. 14/686,380, filed Apr. 14, 2015. |
| Dahl et al., “Nuclear shape, mechanics, and mechanotransduction.” Circulation Research vol. 102, pp. 1307-1318 (2008). |
| Flanagan et al., “Unique dielectric properties distinguish stem cells and their differentiated progeny.” Stem Cells, vol. 26, pp. 656-665 (2008). |
| Fong et al., “Modeling Ewing sarcoma tumors in vitro with 3D scaffolds.” Proceedings of the National Academy of Sciences vol. 110, pp. 6500-6505 (2013). |
| Gascoyne et al., “Membrane changes accompanying the induced differentiation of Friend murine erythroleukemia cells studied by dielectrophoresis.” Biochimica et Biophysica Acta (BBA)—Biomembranes, vol. 1149, pp. 119-126 (1993). |
| Gimsa et al., “Dielectric spectroscopy of single human erythrocytes at physiological ionic strength: dispersion of the cytoplasm.” Biophysical Journal, vol. 71, pp. 495-506 (1996). |
| Golberg, A. and Rubinsky, B., “A statistical model for multidimensional irreversible electroporation cell death in tissue.” Biomed Eng Online, 9, 13 pages, 2010. |
| Helczynska et al., “Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ.” Cancer Research, vol. 63, pp. 1441-1444 (2003). |
| Ibey et al., “Selective cytotoxicity of intense nanosecond-duration electric pulses in mammalian cells.” Biochimica Et Biophysica Acta—General Subjects, vol. 1800, pp. 1210-1219 (2010). |
| Jarm et al., “Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases.” Expert Rev Anticancer Ther. vol. 10, pp. 729-746 (2010). |
| Jensen et al., “Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18FFDG-microPET or external caliper.” BMC medical Imaging vol. 8:16, 9 Pages (2008). |
| Kinosita et al., “Electroporation of cell membrane visualized under a pulsed-laser fluorescence microscope.” Biophysical Journal, vol. 53, pp. 1015-1019 (1988). |
| Kirson et al., “Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.” Proceedings of the National Academy of Sciences vol. 104, pp. 10152-10157 (2007). |
| Kotnik and Miklavcic, “Theoretical evaluation of voltage inducement on internal membranes of biological cells exposed to electric fields.” Biophysical Journal, vol. 90(2), pp. 480-491 (2006). |
| Labeed et al., “Differences in the biophysical properties of membrane and cytoplasm of apoptotic cells revealed using dielectrophoresis.” Biochimica et Biophysica Acta (BBA)—General Subjects, vol. 1760, pp. 922-929 (2006). |
| Ma{hacek over (c)}ek Lebar and Miklav{hacek over (c)}i{hacek over (c)}, “Cell electropermeabilization to small molecules in vitro: control by pulse parameters.” Radiology and Oncology, vol. 35(3), pp. 193-202 (2001). |
| Malpica et al., “Grading ovarian serous carcinoma using a two-tier system.” The American Journal of Surgical Pathology, vol. 28, pp. 496-504 (2004). |
| Marszalek et al., “Schwan equation and transmembrane potential induced by alternating electric field.” Biophysical Journal, vol. 58, pp. 1053-1058 (1990). |
| Martin, n.R.C.G., et al., “Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma.” Journal of the American College of Surgeons, 2012. 215(3): p. 361-369. |
| Mulhall et al., “Cancer, pre-cancer and normal oral cells distinguished by dielectrophoresis.” Analytical and Bioanalytical Chemistry, vol. 401, pp. 2455-2463 (2011). |
| Neal II et al., “A Case Report on the Successful Treatment of a Large Soft-Tissue Sarcoma with Irreversible Electroporation,” Journal of Clinical Oncology, 29, pp. 1-6, 2011. |
| Neal II, R.E., et al., “Treatment of breast cancer through the application of irreversible electroporation using a novel minimally invasive single needle electrode.” Breast Cancer Research and Treatment, 2010. 123(1): p. 295-301. |
| Nesin et al., “Manipulation of cell volume and membrane pore comparison following single cell permeabilization with 60- and 600-ns electric pulses.” Biochimica et Biophysica Acta (BBA)—Biomembranes, vol. 1808, pp. 792-801 (2011). |
| O'Brien et al., “Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity.” European Journal of Biochemistry, vol. 267, pp. 5421-5426 (2000). |
| Onik, G. and B. Rubinsky, eds. “Irreversible Electroporation: First Patient Experience Focal Therapy of Prostate Cancer. Irreversible Electroporation”, ed. B. Rubinsky 2010, Springer Berlin Heidelberg, pp. 235-247. |
| Onik, G., P. Mikus, and B. Rubinsky, “Irreversible electroporation: implications for prostate ablation.” Technol Cancer Res Treat, 2007. 6(4): p. 295-300. |
| Paszek et al., “Tensional homeostasis and the malignant phenotype.” Cancer Cell, vol. 8, pp. 241-254 (2005). |
| Polak et al., “On the Electroporation Thresholds of Lipid Bilayers: Molecular Dynamics Simulation Investigations.” The Journal of Membrane Biology, vol. 246, pp. 843-850 (2013). |
| Pucihar et al., “Numerical determination of transmembrane voltage induced on irregularly shaped cells.” Annals of Biomedical Engineering, vol. 34, pp. 642-652 (2006). |
| Rossmeisl et al., “Pathology of non-thermal irreversible electroporation (N-TIRE)-induced ablation of the canine brain.” Journal of Veterinary Science vol. 14, pp. 433-440 (2013). |
| Sabuncu et al., “Dielectrophoretic separation of mouse melanoma clones.” Biomicrofluidics, vol. 4, 7 pages (2010). |
| Salmanzadeh et al., “Investigating dielectric properties of different stages of syngeneic murine ovarian cancer cells” Biomicrofiuidics 7, 011809 (2013), 12 pages. |
| Salmanzadeh et al., “Dielectrophoretic differentiation of mouse ovarian surface epithelial cells, macrophages, and fibroblasts using contactless dielectrophoresis.” Biomicrofluidics, vol. 6, 13 Pages (2012). |
| Salmanzadeh et al., “Sphingolipid Metabolites Modulate Dielectric Characteristics of Cells in a Mouse Ovarian Cancer Progression Model.” Integr. Biol., 5(6), pp. 843-852 (2013). |
| Sano et al., “In-vitro bipolar nano- and microsecond electro-pulse bursts for irreversible electroporation therapies.” Bioelectrochemistry vol. 100, pp. 69-79 (2014). |
| Sano et al., “Modeling and Development of a Low Frequency Contactless Dielectrophoresis (cDEP) Platform to Sort Cancer Cells from Dilute Whole Blood Samples.” Biosensors & Bioelectronics, 8 pages (2011). |
| Saur et al., “CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer.” Gastroenterology, vol. 129, pp. 1237-1250 (2005). |
| Seibert et al., “Clonal variation of MCF-7 breast cancer cells in vitro and in athymic nude mice.” Cancer Research, vol. 43, pp. 2223-2239 (1983). |
| Alberts et al., “Molecular Biology of the Cell,” 3rd edition, Garland Science, New York, 1994, 1 page. |
| Asami et al., “Dielectric properties of mouse lymphocytes and erythrocytes.” Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1010 (1989) pp. 49-55. |
| Bower et al., “Irreversible electroporation of the pancreas: definitive local therapy without systemic effects.” Journal of surgical oncology, 2011. 104(1): p. 22-28. |
| Eppich et al., “Pulsed electric fields for selection of hematopoietic cells and depletion of tumor cell contaminants.” Nature Biotechnology 18, pp. 882-887 (2000). |
| Ermolina et al., “Study of normal and malignant white blood cells by time domain dielectric spectroscopy.” IEEE Transactions on Dielectrics and Electrical Insulation, 8 (2001) pp. 253-261. |
| Fischbach et al., “Engineering tumors with 3D scaffolds.” Nat Meth 4, pp. 855-860 (2007). |
| Kingham et al., “Ablation of perivascular hepatic malignant tumors with irreversible electroporation.” Journal of the American College of Surgeons, 2012. 215(3), p. 379-387. |
| Kinosita and Tsong, “Formation and resealing of pores of controlled sizes in human erythrocyte membrane.” Nature, vol. 268 (1977) pp. 438-441. |
| Kinosita and Tsong, “Voltage-induced pore formation and hemolysis of human erythrocytes.” Biochimica et Biophysica Acta (BBA)—Biomembranes, 471 (1977) pp. 227-242. |
| Lebar et al., “Inter-pulse interval between rectangular voltage pulses affects electroporation threshold of artificial lipid bilayers.” IEEE Transactions on NanoBioscience, vol. 1 (2002) pp. 116-120. |
| Ron et al., “Cell-based screening for membranal and cytoplasmatic markers using dielectric spectroscopy.” Biophysical chemistry, 135 (2008) pp. 59-68. |
| Rossmeisl, “New Treatment Modalities for Brain Tumors in Dogs and Cats.” Veterinary Clinics of North America: Small Animal Practice 44, pp. 1013-1038 (2014). |
| Rubinsky et al., “Optimal Parameters for the Destruction of Prostate Cancer Using Irreversible Electroporation.” The Journal of Urology, 180 (2008) pp. 2668-2674. |
| Sano et al., “Contactless Dielectrophoretic Spectroscopy: Examination of the Dielectric Properties of Cells Found in Blood.” Electrophoresis, 32, pp. 3164-3171, 2011. |
| Schoenbach et al., “Intracellular effect of ultrashort electrical pulses.” Bioelectromagnetics, 22 (2001) pp. 440-448. |
| Yao et al., “Study of transmembrane potentials of inner and outer membranes induced by pulsed-electric-field model and simulation.” IEEE Trans Plasma Sci, 2007. 35(5): p. 1541-1549. |
| Co-pending U.S. Appl. No. 14/017,210, Response dated Sep. 8, 2015 Non-Final Office Action, dated Mar. 8, 2016, 57 pages. |
| Co-Pending U.S. Appl. No. US 14/940,863, filed Nov. 13, 2015 and Published as US 2016/0066977 on Mar. 10, 2016. |
| Co-Pending U.S. Appl. No. 15/011,752, filed Feb. 1, 2016. |
| Ivorra et al., “In vivo electric impedance measurements during and after electroporation of rat live.” Bioelectrochemistry, vol. 70, pp. 287-295 (2007). |
| Ivorra et al., “In vivo electrical conductivity measurements during and after tumor electroporation: conductivity changes reflect the treatment outcome.” Physics in Medicine and Biology, vol. 54, pp. 5949-5963 (2009). |
| Ivorra, “Bioimpedance monitoring for physicians: an overview.” Biomedical Applications Group, 35 pages (2002). |
| Laufer et al., “Electrical impedance characterization of normal and cancerous human hepatic tissue.” Physiological Measurement, vol. 31, pp. 995-1009 (2010). |
| Baptista et al., “The Use of Whole Organ Decellularization for the Generation of a Vascularized Liver Organoid,” Heptatology, vol. 53, No. 2, pp. 604-617 (2011). |
| Co-Pending U.S. Appl. No. 14/686,380, filed Apr. 14, 2015 and Published as US 2015/0289923 on Oct. 15, 2015. |
| Co-Pending Application No. PCT/US15/30429, International Search Report and Written Opinion dated Oct. 16, 2015, 19 pages. |
| Co-Pending Application No. PCT/US2015/030429, Published on Nov. 19, 2015 as WO 2015/175570. |
| Co-Pending U.S. Appl. No. 14/017,210, Non-Final Office Action, dated Sep. 8, 2015, 8 pages. |
| Hjouj, Mohammad et al., “Electroporation-Induced BBB Disruption and Tissue Damage Depicted by MRI,” Abstracts from 16th Annual Scientific Meeting of the Society for Neuro-Oncology in Conjunction with the AANS/CNS Section on Tumors, Nov. 17-20, 2011, Orange County California, Neuro-Oncology Supplement, vol. 13, Supplement 3, p. iii114. |
| Reber{hacek over (s)}ek, M. and D. Miklav{hacek over (c)}i{hacek over (c)}, “Advantages and Disadvantages of Different Concepts of Electroporation Pulse Generation,” AUTOMATIKA 52(2011) 1, 12-19. |
| Beebe, S.J., et al., “Diverse effects of nanosecond pulsed electric fields on cells and tissues”, DNA and Cell Biology, 22(12): 785-796 (2003). |
| Chang, D.C., “Cell Poration and Cell-Fusion Using an Oscillating Electric-Field”. Biophysical Journal, 56(4): p. 641-652 (1989). |
| Chen, M.T., et al., “Two-dimensional nanosecond electric field mapping based on cell electropermeabilization”, PMC Biophys, 2(1):9 (2009). |
| Co-pending U.S. Appl. No. 15/186,653, filed Jun. 20, 2016. |
| Co-Pending U.S. Appl. No. US 14/017,210, Non-Final Office Action dated Aug. 30, 2016, 11 pages. |
| De Vuyst, E. et al., “In situ bipolar Electroporation for localized cell loading with reporter dyes and investigating gap junctional coupling”, Biophysical Journal, 94(2): p. 469-479 (2008). |
| Esser, A.T., et al., “Towards solid tumor treatment by irreversible electroporation: intrinsic redistribution of fields and currents in tissue”. Technol Cancer Res Treat, 6(4): p. 261-74 (2007). |
| Esser, A.T., et al., “Towards Solid Tumor Treatment by Nanosecond Pulsed Electric Fields”, Technology in Cancer Research & Treatment, 8(4): p. 289-306 (2009). |
| Freeman, S.A., et al., Theory of Electroporation of Planar Bilayer-Membranes—Predictions of the Aqueous Area, Change in Capacitance, and Pore-Pore Separation. Biophysical Journal, 67(1): p. 42-56 (1994). |
| Gowrishankar T.R., et al., “Microdosimetry for conventional and supra-electroporation in cells with organelles”. Biochem Biophys Res Commun, 341(4): p. 1266-76 (2006). |
| Kotnik, T. and D. Miklavcic, “Theoretical evaluation of the distributed power dissipation in biological cells exposed to electric fields”, Bioelectromagnetics, 21(5): p. 385-394 (2000). |
| Kotnik, T., et al., “Cell membrane electropermeabilization by symmetrical bipolar rectangular pulses. Part II. Reduced electrolytic contamination”, Bioelectrochemistry, 54(1): p. 91-5 (2001). |
| Kotnik, T., et al., “Role of pulse shape in cell membrane electropermeabilization”, Biochimica Et Biophysica Acta-Biomembranes, 1614(2): p. 193-200 (2003). |
| Lackovic, I., et al., “Three-dimensional Finite-element Analysis of Joule Heating in Electrochemotherapy and in vivo Gene Electrotransfer”, Ieee Transactions on Dielectrics and Electrical Insulation, 16(5): p. 1338-1347 (2009). |
| Long, G., et al., “Targeted Tissue Ablation With Nanosecond Pulses”. Ieee Transactions on Biomedical Engineering, (2011). 58(8). |
| Nikolova, B., et al., “Treatment of Melanoma by Electroporation of Bacillus Calmette-Guerin”. Biotechnology & Biotechnological Equipment, 25(3): p. 2522-2524 (2011). |
| Nuccitelli, R., et al., “A new pulsed electric field therapy for melanoma disrupts the tumor's blood supply and causes complete remission without recurrence”, Int J Cancer, 125(2): p. 438-45 (2009). |
| PCT IPRP for PCT/US15/30429 (WO2015175570), dated Nov. 15, 2016. |
| Talele, S., et al., “Modelling single cell electroporation with bipolar pulse parameters and dynamic pore radii”. Journal of Electrostatics, 68(3): p. 261-274 (2010). |
| Vernier, P.T., et al., “Nanoelectropulse-driven membrane perturbation and small molecule permeabilization”, Bmc Cell Biology, 7 (2006). |
| Weaver, J.C., “Electroporation of cells and tissues”, IEEE Transactions on Plasma Science, 28(1): p. 24-33 (2000). |
| Co-Pending U.S. Appl. No. 14/017,210, Non-Final Office Action dated Dec. 15, 2016, 8 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response dated Aug. 30, 2016 Final Office Action, dated Nov. 30, 2016, 10 pages. |
| Co-Pending U.S. Appl. No. 12/906,923, Office Actions and Responses dated Jul. 2017, 55 pages. |
| Co-Pending U.S. Appl. No. 13/989,175, Office Actions and Responses dated Aug. 30, 2017, 172 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Non-Final Office Action dated Mar. 13, 2017, 10 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Response dated Mar. 13, 2017 Non-Final Office Action dated Jul. 13, 2017, 10 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, filed Nov. 10, 2016. |
| Co-pending U.S. Appl. No. 15/423,986, filed Feb. 3, 2017. |
| Co-pending U.S. Appl. No. 15/424,335, filed Feb. 3, 2017. |
| Co-Pending U.S. Appl. No. 14/012,832, Ex Parte Quayle Office Action dated Aug. 28, 2015, 6 pages. |
| Co-Pending U.S. Appl. No. 14/012,832, Notice of Allowance dated Nov. 4, 2015, 5 pages. |
| Co-Pending U.S. Appl. No. 14/012,832, Response to Ex Parte Quayle Office Action dated Aug. 28, 2015, filed with RCE on Oct. 28, 2015, 9 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Final Office Action dated May 1, 2017, 11 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response dated Dec. 15, 2016 Non-Final Office Action dated Mar. 20, 2017, 9 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response dated May 1, 2017 Final Office Action dated Aug. 1, 2017, 10 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Restriction Requirement dated Jul. 19, 2017, 7 pages. |
| Co-Pending U.S. Appl. No. 13/989,175, Notice of Allowance dated Sep. 1, 2017, 7 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Final Office Action dated Sep. 1, 2017, 9 pages. |
| Co-Pending U.S. Appl. No. 13/989,175, Supplemental Notice of Allowability, dated Dec. 6, 2017, 4 pages. |
| Co-Pending U.S. Appl. No. 13/989,175, Supplemental Notice of Allowability, dated Nov. 30, 2017, 4 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Non-Final Office Action dated Jan. 8, 2018, 5 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Response dated Jan. 8, 2018 Non-Final Office Action dated Apr. 9, 2018, 8 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Response dated Sep. 1, 2017 Final Office Action dated Dec. 1, 2017, 7 pages. |
| Co-Pending U.S. Appl. No. 14/940,863, Notice of Allowance dated May 25, 2018, 9 pages. |
| Co-pending U.S. Appl. No. 15/843,888, filed Dec. 15, 2017. |
| Co-pending U.S. Appl. No. 15/881,414, filed Jan. 26, 2018. |
| Co-Pending U.S. Appl. No. 14/017,210, Final Office Action dated Apr. 11, 2018, 10 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Non-Final Office Action dated Oct. 25, 2017, 9 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response dated Oct. 25, 2017 Non-Final Office Action dated Jan. 25, 2018, 11 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Final Office Action dated May 9, 2018, 14 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Non-Final Office Action dated Nov. 22, 2017, 11 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Response dated Jul. 19, 2017 Restriction Requirement, dated Sep. 15, 2017, 2 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Response dated Nov. 22, 2017 Non-Final Office Action dated Mar. 28, 2018, 11 pages. |
| Garcia, Paulo A., Robert E. Neal II and Rafael V. Davalos, Chapter 3, Non-Thermal Irreversible Electroporation for Tissue Ablation, In: Electroporation in Laboratory and Clinical Investigations ISBN 978-1-61668-327-6 Editors: Enrico R Spugnini and Alfonso Baldi, 2010, 22 pages. |
| Kotnik et al., “Sensitivity of transmembrane voltage induced by applied electric fields—A theoretical analysis”, Elioelectrochemistry and Bioenergetics,vol. 43, Issue 2, 1997, pp. 285-291. |
| Neal Re II, et al. (2013) Improved Local and Systemic Anti-Tumor Efficacy for Irreversible Electroporation in Immunocompetent versus Immunodeficient Mice. PLoS One 8(5): e64559. https://doi.org/10.1371/journal.pone.0064559. |
| Wimmer, Thomas, et al., “Planning Irreversible Electroporation (IRE) in the Porcine Kidney: Are Numerical Simulations Reliable for Predicting Empiric Ablation Outcomes?”, Cardiovasc Intervent Radiol. Feb. 2015 ; 38(1): 182-190. doi:10.1007/s00270-014-0905-2. |
| Co-Pending U.S. Appl. No. 14/558,631, Notice of Allowance dated Jun. 21, 2018, 7 pages. |
| Co-pending U.S. Appl. No. 15/881,414 dated Apr. 26, 2018 Non-Final Office Action, 8 pages. |
| Co-pending U.S. Appl. No. 15/843,888, Non-Final Office Action dated Sep. 14, 2018, 17 pages. |
| Co-pending U.S. Appl. No. 15/881,414 Amendment and Petition for Priority Claim dated Jul. 26, 2018, 26 pages. |
| Co-pending U.S. Appl. No. 15/881,414 Corrected Notice of Allowability dated Nov. 13, 2018, 2 pages. |
| Co-pending U.S. Appl. No. 15/881,414 Notice of Allowance dated Oct. 24, 2018, 7 pages. |
| Co-pending U.S. Appl. No. 15/881,414 Petition Decision dated Oct. 9, 2018, 9 pages. |
| Co-pending U.S. Appl. No. 16/177,745, filed Nov. 1, 2018. |
| Co-Pending U.S. Appl. No. 14/017,210 Acceptance of 312 Amendment dated Sep. 12, 2018, 1 page. |
| Co-Pending U.S. Appl. No. 14/017,210, AFCP dated Aug. 13, 2018, 9 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Notice of Allowance dated Sep. 12, 2018, 7 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Response dated May 9, 2018 Final Office Action with RCE, dated Aug. 30, 2018, 14 pages. |
| Co-pending U.S. Appl. No. 16/152,743, filed Oct. 5, 2018. |
| Co-Pending U.S. Appl. No. 12/432,295, Notice of Allowance and Interview Summary dated Nov. 3, 2016, 9 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Advisory Action and Examiner Interview Summary dated Feb. 9, 2016, 5 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Amendment with RCE dated Oct. 19, 2016, 9 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Appeal Brief and Appendices dated Jul. 25, 2016, 94 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Final Rejection dated Mar. 21, 2012, 14 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Non-Final Office Action dated Nov. 26, 2013, 15 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Non-Final Rejection dated Nov. 10, 2011, 10 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Requirement for Restriction/Election dated Aug. 9, 2011, 7 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Response dated Jun. 16, 2014 Final Rejection filed Oct. 16, 2014, 13 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Response dated Non-Final Office Action, dated Apr. 28, 2014, 14 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Response to Non-Final Rejection dated Jan. 23, 2012, 9 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Response to Requirement for Restriction/Election dated Sep. 2, 2011, 2 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Response with RCE to Final Rejection dated Jul. 23, 2012, 13 pages. |
| Co-Pending U.S. Appl. No. 12/757,901, File History 2018. |
| Co-pending U.S. Appl. No. 13/550,307 Non-final office action dated Aug. 22, 2019, 19 pages. |
| Co-pending U.S. Appl. No. 13/550,307 Notice of panel decision from pre-appeal brief review dated May 16, 2019, 2 pages. |
| Co-pending U.S. Appl. No. 13/550,307 Pre-appeal brief request for review dated Apr. 4, 2019, 7 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Interview Summary, dated Apr. 26, 2019, 3 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Preliminary Amendment dated Jul. 24, 2015, 6 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Restriction Requirement dated Mar. 19, 2018, 7 pages. |
| Co-Pending U.S. Appl. No. 14/808,679 3rd Renewed Petition, Dec. 9, 2019 and Petition Decision Dec. 18, 2019, 11 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Final Office Action dated Jan. 11, 2019, 12 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Non-Final Office Action dated Sep. 10, 2018, 12 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Petition Decision, dated Oct. 1, 2019, 5 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Petition Decision, dated Oct. 23, 2019, 6 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Petition Decision, Dec. 3, 2019, 5 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Petition Supplement, dated Sep. 25, 2019, 10 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Petition, May 8, 2019, 2 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Preliminary Amendment, filed Jul. 27, 2015, 9 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, RCE filed Apr. 11, 2019, 8 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Renewed Petition, filed Oct. 9, 2019, 1 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Response to Mar. 19, 2018 Restriction Requirement dated May 21, 2018, 2 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Response dated Sep. 10, 2018 Non-Final Office Action dated Dec. 10, 2018, 9 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Second Renewed Petition, filed Oct. 31, 2019, 3 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Supplemental Response, dated May 8, 2019, 16 pages. |
| Co-pending Application No. 15/186,653, Notice of Allowance dated Aug 1, 2018, 7 pages. |
| Co-pending U.S. Appl. No. 15/186,653, Notice of Allowance dated Mar. 20, 2019, 14 pages. |
| Co-pending U.S. Appl. No. 15/186,653, Preliminary Amendment, dated Jun. 21, 2016, 5 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, Corrected notice of allowance dated Aug. 6, 2019, 9 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, Non-Final Office Action dated Mar. 6, 2019 Non-Final Office Action filed Jun. 4, 2019, 153 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, Notice of Allowance, dated Aug. 19, 2019, 3 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, Notice of Allowance, dated Jun. 21, 2019, 6 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, Preliminary Amendment, Nov. 10, 2016, 9 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, Response dated Mar. 6, 2019 Non-Final Office Action filed Jun. 4, 2019, 8 pages. |
| Co-pending U.S. Appl. No. 15/423,986 dated Apr. 10, 2018 Restriction Requirement, 8 pages. |
| Co-pending U.S. Appl. No. 15/423,986, Notice of allowance dated Jan. 2, 2019. |
| Co-pending U.S. Appl. No. 16/177,745, Applicant-initiated interview summary dated Dec. 16, 2019, 3 pages. |
| Co-pending U.S. Appl. No. 16/177,745, Non-final office action dated Aug. 20, 2019, 10 pages. |
| Co-pending U.S. Appl. No. 16/177,745, Response dated Aug. 20, 2019 Non-final office action dated Nov. 20, 2019, 10 pages. |
| Co-Pending U.S. Appl. No. 14/940,863, Notice of Allowance dated Jan. 25, 2019, 5 pages. |
| Co-Pending U.S. Appl. No. 14/940,863, Notice of Allowance dated Sep. 19, 2018, 5 pages. |
| Co-pending U.S. Appl. No. 15/011,752 Final Office Action dated Dec. 19, 2018, 6 pages. |
| Co-pending U.S. Appl. No. 15/011,752 Non-Final Office Action dated May 11, 2018, 11 pages. |
| Co-pending U.S. Appl. No. 15/011,752 Notice of Allowance dated Mar. 22, 2019, 6 pages. |
| Co-pending U.S. Appl. No. 15/011,752 Preliminary Amendment, filed Feb. 2, 2016, 6 pages. |
| Co-pending U.S. Appl. No. 15/011,752 Response dated Dec. 19, 2018 Final Office Action, filed Mar. 5, 2019, 6 pages. |
| Co-pending U.S. Appl. No. 15/011,752 Response dated May 11, 2018 Non-Final Office Action dated Oct. 11, 2018, 11 pages. |
| Co-pending U.S. Appl. No. 15/536,333, filed Jun. 15, 2017. |
| Co-pending U.S. Appl. No. 15/536,333, Office Actions and Responses dated Jan. 2, 2020, 69 pages. |
| Co-pending U.S. Appl. No. 16/232,962 Applicant-initiated interview Summary dated Dec. 16, 2019, 3 pages. |
| Co-pending U.S. Appl. No. 16/232,962 Non-Final office action dated Aug. 20, 2019, 9 pages. |
| Co-pending U.S. Appl. No. 16/232,962 Response dated Aug. 20, 2019 Non-final office action dated Nov. 20, 2019, 10 pages. |
| Co-pending U.S. Appl. No. 16/275,429, filed Feb. 14, 2019, which published as 2019/0175260 on Jun. 13, 2019. |
| Co-pending U.S. Appl. No. 161275,429 Preliminary Amendment Filed Mar. 28, 2019, 6 pages. |
| Co-pending U.S. Appl. No. 16/280,511, filed Feb. 20, 2019. |
| Co-pending U.S. Appl. No. 16/372,520 Preliminary Amendment filed Apr. 9, 2019, 7 pages. |
| Co-pending U.S. Appl. No. 16/372,520, filed Apr. 2, 2019, which published as 20190223938 on Jul. 25, 2019. |
| Co-pending U.S. Appl. No. 16/375,878, filed Apr. 5, 2019, which published on Aug. 1, 2019 as US 2019-0233809 A1. |
| Co-Pending U.S. Appl. No. 16/375,878, Preliminary Amendment, filed Apr. 9, 2019, 9 pages. |
| Co-pending U.S. Appl. No. 16/404,392, filed May 6, 2019. |
| Co-pending U.S. Appl. No. 16/404,392, Non-Final Office Action dated Sep. 6, 2019, 8pgs. |
| Co-pending U.S. Appl. No. 16/404,392, Petition for Priority, filed Jun. 4, 2019, 2 pages. |
| Co-pending U.S. Appl. No. 16/404,392, Preliminary Amendment, filed Jun. 6, 2019, 5 pages. |
| Co-pending U.S. Appl. No. 16/404,392, Response to Non-Final Office action dated Sep. 6, 2019, filed Dec. 6, 2019, 8 pages. |
| Co-pending U.S. Appl. No. 16/443,351 filed Jun. 17, 2019 (published as 20190328445 on Oct. 31, 2019). |
| Co-pending U.S. Appl. No. 16/520,901, filed Jul. 24, 2019. |
| Co-pending U.S. Appl. No. 16/520,901, Preliminary Amendment filed Aug. 14, 2019. |
| Co-pending U.S. Appl. No. 16/535,451, filed Aug. 8, 2019. |
| Co-pending U.S. Appl. No. 16/535,451 Preliminary Amendment filed Aug. 8, 2019, 3 pages. |
| Co-pending U.S. Appl. No. 16/535,451 Second Preliminary Amendment filed Oct. 9, 2019, 15 pages. |
| Co-pending U.S. Appl. No. 16/535,451 Third Preliminary Amendment filed Nov. 5, 2019, 4 pages. |
| Co-Pending U.S. Appl. No. 16/655,845, filed Oct. 17, 2019. |
| Co-pending application No. PCT/US19/51731 filed Sep. 18, 2019. |
| Co-pending application No. PCT/US19/51731 Invitation to Pay Additional Search Fees dated Oct. 28, 2019, 2 pgs. |
| Co-Pending U.S. Appl. No. 12/432,295, Response dated Jun. 23, 2015 Non-Final Office Action dated Oct. 23, 2015, 46 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Final Office Action dated Jun. 16, 2014, 14 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Final Office Action dated Nov. 25, 2015, 14 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Non-Final Office Action dated Jun. 23, 2015, 12 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Response dated Nov. 25, 2015 Final Office Action, filed Jan. 25, 2016, 12 pages. |
| Co-Pending U.S. Appl. No. 12/432,295, Supplemental Response After RCE, filed Nov. 17, 2014, 9 pages. |
| Co-Pending U.S. Appl. No. 13/332,133, Amendment with RCE after Board Decision, dated Mar. 29, 2019, 16 pages. |
| Co-Pending U.S. Appl. No. 13/332,133, Board Decision dated Jan. 29, 2019, 13 pages. |
| Co-Pending U.S. Appl. No. 13/332,133, Notice of Allowance, dated May 31, 2019, 5 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Petition dated Dec. 11, 2015, 5 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Petition Decision dated Aug. 12, 2016, 9 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Petition Decision dated Aug. 2, 2016, 5 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, RCE dated Nov. 30, 2016, 13 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response to Non-Final Office Action dated Mar. 8, 2016, 16 pages. |
| Co-pending Chinese Application No. 201580025135.6 English translation of Sep. 25, 2019 Office action. |
| Wasson, Elisa M. et al. The Feasibility of Enhancing Susceptibility of Glioblastoma Cells to IRE Using a Calcium Adjuvant. Annals of Biomedical Engineering, vol. 45, No. 11, Nov. 2017 pp. 2535-2547. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 16/352,759 (VTIP-A1005), filed Mar. 13, 2019, Specification, Claims, Figures. |
| (Latouche, Eduardo et al.) Co-pending U.S. Appl. No. 16/210,771 (VTIP-A1006), filed Dec. 5, 2018, and which published as U.S. Pub. No. 2019/0232048 dated Aug. 1, 2019, Specification, Claims, Figures. |
| (Sano, Michael B. et al.) Co-Pending U.S. Appl. No. 16/747,219 (VTIP-48-DIV2), filed Jan. 20, 2020, Specification, Claims, Figures. |
| Co-pending U.S. Appl. No. 15/536,333 (VTIP-A1010-US), Notice of allowance dated Apr. 13, 2020, 9 pages. |
| Co-pending U.S. Appl. No. 15/881,414 (VTIP-80-CON) Response to Apr. 26, 2018 Non-Final Office Action, dated Jul. 26, 2018, 15 pages. |
| Co-pending U.S. Appl. No. 16/177,745 (VTIP-80-CON2), Final office action dated Jan. 9, 2020, 8 pages. |
| Co-pending U.S. Appl. No. 16/177,745 (VTIP-80-CON2), Preliminary Amendment dated Dec. 19, 2018, 7 pages. |
| Co-pending Application No. 16/232,962 (VTIP-80-CON3) Applicant initiated interview summary dated Dec. 16, 2019, 3 pages. |
| Co-pending U.S. Appl. No. 16/232,962 (VTIP-80-CON3) Final office action dated Jan. 9, 2020, 7 pages. |
| Co-Pending U.S. Appl. No. 16/375,878 (VTIP-35-CON), Second Preliminary Amendment, filed Feb. 5, 2020, 3 pages. |
| Co-pending U.S. Appl. No. 16/404,392 (VTIP35CON2), Final Office Action dated Mar. 20, 2020, 8pgs. |
| Co-pending U.S. Appl. No. 16/404,392 (VTIP35CON2), Preliminary Amendment, filed Jun. 4, 2019, 9 pages. |
| Co-pending U.S. Appl. No. 16/443,351 (VTIP97CON), Preliminary amendment filed Feb. 3, 2020. |
| Co-pending U.S. Appl. No. 16/520,901 (VTIP97CON2), Second Preliminary Amendment filed Feb. 4, 2020. |
| Co-pending U.S. Appl. No. PCT/US19/51731 (VTIP-A1001-PCT) International Search Report and Written Opinion dated Feb. 20, 2020, 19 pgs. |
| Shao, Qi et al. Engineering T cell response to cancer antigens by choice of focal therapeutic conditions, International Journal of Hyperthermia, 2019, DOI: 10.1080/02656736.2018.1539253. |
| Number | Date | Country | |
|---|---|---|---|
| 20130184702 A1 | Jul 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61508251 | Jul 2011 | US |
