Patent Grant
10959772
The present invention relates to the field of biomedical engineering and medical treatment of diseases and disorders. More specifically, the invention relates to devices and methods for destroying aberrant cell masses, including tumor tissues, such as cancerous tissues of the brain.
Treatment of abnormal cell growth in or on normal body tissues and organs can be achieved in many different ways to achieve reduced cell growth, reduction of the resulting aberrant cell mass, and even destruction of the aberrant cell mass. In general, treatments known in the art involve surgical intervention to physically remove the aberrant cell mass, radiation to kill the cells of the aberrant cell mass, exposure of aberrant cells to toxic chemicals (i.e., chemotherapy), or a combination of two or all three of these. While each treatment modality has shown significant effectiveness in treatment of various cell proliferative diseases, no one technique has been shown to be highly effective at treating all types of cell proliferative diseases and disorders. Furthermore, each technique has significant drawbacks. For example, surgical intervention is highly effective at removal of solid tumors on tissues and organs that are physically accessible and capable of sustaining physical damage or capable of regeneration. However, surgical intervention can be difficult to perform on tumors that are not readily accessible or on organs that do not regenerate (e.g., brain tumors), and can involve substantial physical damage to the patient, requiring extensive recuperation times and follow-on treatments. Likewise, treatment with radiation can result in collateral damage to tissue surrounding the tumor, and can cause long-lasting side-effects, which can lower the quality of life of the patient. Similarly, chemotherapeutic treatments cause systemic damage to the patient, and can result in significant side-effects that might require a long recuperation period or permanent damage to the patient.
In the treatment of tumors, including malignant tumors, it is recognized in the medical arts that it is important to achieve ablation of the undesirable tissue in a well-controlled and precise way without affecting the surrounding healthy tissue. The inventors and their colleagues recently developed a new method to treat tumors, known as irreversible electroporation (IRE). The procedure involves placing electrodes within or near the targeted region to deliver a series of low energy, microsecond electric pulses for approximately 1 minute. These pulses permanently destabilize the cell membranes of the targeted tissue (e.g., tumor), thereby killing the cells. IRE does not affect major blood vessels, does not require the use of drugs and non-thermally kills neoplastic cells in a precise and controllable manner, without significantly damaging surrounding tissue. The inventors and their colleagues also recently showed the complete regression in 12 out of 13 treated tumors in vivo using IRE on a type of aggressive sarcoma implanted in nude mice (Al-Sakere, B. et al., 2007, “Tumor ablation with irreversible electroporation.” PLoS ONE 2.).
Although advances have been made recently in the field of IRE and the concept of treatment of tumors with IRE has been established, the present inventors have recognized that there still exists a need in the art for improved devices and methods for ablating diseased or disordered tissues, such as tumor tissues, using IRE. The present invention addresses those needs.
The present invention provides an advancement over tissue ablation techniques previously devised by providing improved devices and methods for precisely and rapidly ablating diseased, damaged, disordered, or otherwise undesirable biological tissues in situ. As used herein, the term ablation is used to indicate destruction of cells, but not necessarily destruction of the underlying extracellular matrix. More specifically, the present invention provides new devices and methods for ablating target tissues for the treatment of diseases and disorders, and particularly tumors of the brain, using IRE. Use of IRE to decellularize diseased tissue provides a controlled, precise way to destroy aberrant cells of a tissue or organ, such as tumor or cancer cells or masses of the brain.
Non-thermal IRE is a method to kill undesirable cells using electric fields in tissue while preserving the ECM, blood vessels, and neural tubes/myelin sheaths. Certain electrical fields, when applied across a cell, have the ability to permeabilize the cell membrane through a process that has come to be called “electroporation”. When electrical fields permeabilize the cell membrane temporarily, after which the cells survive, the process is known as “reversible electroporation”. Reversible electroporation has become an important tool in biotechnology and medicine. Other electrical fields can cause the cell membrane to become permeabilized, after which the cells die. This deadly process is known as “irreversible electroporation”. According to the present invention, non-thermal irreversible electroporation is a minimally invasive surgical technique to ablate undesirable tissue, for example, tumor tissue. The technique is easy to apply, can be monitored and controlled, is not affected by local blood flow, and does not require the use of adjuvant drugs. The minimally invasive procedure involves placing needle-like electrodes into or around the targeted area to deliver a series of short and intense electric pulses that induce structural changes in the cell membranes that promote cell death. The voltages are applied in order to electroporate tissue without inducing significant Joule heating that would significantly damage major blood vessels and the ECM. For a specific tissue type and set of pulse conditions, the primary parameter determining the volume irreversibly electroporated is the electric field distribution within the tissue. Recent IRE animal experiments have verified the many beneficial effects resulting from this special mode of non-thermal cell ablation, such as preservation of major structures including the extracellular matrix, major blood vessels, and myelin sheaths, no scar formation, as well as its promotion of a beneficial immune response. Due to the nature of the function of the brain, in treatment of brain tissues, such as brain tumors, the total electrical charge delivered is at least as important as maintaining low temperature.
In a first aspect, the present invention provides a method for treating aberrant cell growth in animals. In general, the method comprises inserting one or more electrodes into or immediately adjacent to aberrant cell masses and applying IRE to cause irreversible cell death to the aberrant cells. In some embodiments, two or more electrodes are used to treat aberrant cell masses and effect cell death. The electrodes may be present on the same or different devices. Preferably, the parameters for IRE are selected to minimize or avoid excessive heating of the treated tissue and surrounding tissue, thus reducing collateral damage to healthy tissue near the aberrant cell mass. In addition, it is preferable to minimize the total electrical charge delivered when treating brain tissue to avoid complications. The methods are particularly well suited for treatment of aberrant cell growths in or on the brain, as it is important to avoid collateral damage to brain tissue during treatments of that organ. The methods also can be applied to treat a number of other of cancers, including liver cancer, prostate cancer, and pancreatic adenocarcinoma.
Viewed differently, the method for treating aberrant cell growth in animals can be considered a method of treating an animal (including humans) having an aberrant cell growth or mass in or on a tissue or an organ. In exemplary embodiments, the organ is a brain, and the aberrant cell mass is a benign or malignant tumor. Under this view, the method can be a method of treating an animal suffering from a disease or disorder resulting from aberrant cell growth by reducing or eliminating some or all of a mass (e.g., tumor) produced by the aberrant cell growth.
To effect the methods according to the invention, the present invention provides devices designed to treat aberrant cell masses using irreversible electroporation (IRE). While IRE devices have been disclosed prior to the priority date of this document, advanced surgical tools for in vivo IRE to treat diseased tissues and organs had not been developed. The present invention, for the first time, provides devices suitable for in vivo IRE treatment of diseases and disorders, particularly those associated with abnormal cell growth in or on a tissue or organ, which allow for minimally invasive treatment of patients suffering from such abnormal cell growth. The present inventors have designed microsurgical tools to treat currently inoperable tumors in humans and other animals through IRE, and in particular brain tumors. While not so limited, the designs provided herein are sufficient to ablate the majority of tumors smaller than about 3 cm in diameter, such as those about 14 cc in volume or less.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention, and together with the written description, 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, as broadly disclosed above. Rather, the following discussion is provided to give the reader a more detailed understanding of certain aspects and features of the invention.
Before embodiments of the present invention are described in detail, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Further, where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither, or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the term belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The present disclosure is controlling to the extent it conflicts with any incorporated publication.
As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pulse” includes a plurality of such pulses and reference to “the sample” includes reference to one or more samples and equivalents thereof known to those skilled in the art, and so forth. Furthermore, the use of terms that can be described using equivalent terms include the use of those equivalent terms. Thus, for example, the use of the term “patient” is to be understood to include the terms “subject”, “animal”, “human”, and other terms used in the art to indicate one who is subject to a medical treatment.
Electroporation is the phenomenon in which permeability of the cell membrane to ions and macromolecules is increased by exposing the cell to short (microsecond to millisecond) high voltage electric pulses. The application of the electric pulses can have no effect, can have a transient effect known as reversible electroporation, or can cause permanent permeation known as irreversible electroporation (IRE), which leads to non-thermal cell death by necrosis.
Davalos, Mir, and Rubinsky (Davalos, R. V. et al., 2005, “Tissue ablation with irreversible electroporation.” Annals of Biomedical Engineering, 3(2):223-231) recently postulated and demonstrated that IRE can be used as an independent drug-free tissue ablation modality for particular use in cancer therapy. This minimally invasive procedure involves placing electrodes into or around the targeted area to deliver a series of short and intense electric pulses to induce the irreversible structural changes in the membranes. To achieve IRE, the electric field in the targeted region needs to be above a critical value, which is dependent on a variety of conditions such as tissue type and pulse parameters.
The present invention extends and improves on prior techniques for IRE by providing new methods and devices for IRE treatment of solid tumors, including those associated with brain cancer. Because the brain is susceptible to small fluctuations in temperature, the present invention provides devices and techniques for non-thermal IRE to kill undesirable cells and tissues. In addition, because the brain functions by way of electrical charges, the present invention provides devices and techniques that limit or precisely control the amount of electrical charge delivered to tissue. To achieve the invention, a device has been developed that contains both conducting and non-conducting surfaces and that is capable of delivering controlled pulses of electricity to tumor tissues while substantially protecting surrounding healthy tissue. In exemplary embodiments, the device has a laminate structure of at least one electrically conductive and at least one electrically insulative material. In some exemplary embodiments, the device has at least two concentric disk electrodes separated by an insulating material similar in dimensions to those already used in deep brain stimulation (DBS). DBS is an FDA approved therapy that alleviates the symptoms of otherwise treatment-resistant disorders, such as chronic pain, Parkinson's disease, tremor, and dystonia. The Examples, below, present results demonstrating that an IRE procedure does not induce substantial thermal effects in the brain, and delivers electrical charges to highly defined regions of tissues, supporting the conclusion that IRE can be used as a minimally invasive surgical technique for the treatment of brain cancer and other diseases and disorders involving aberrant cell mass development. The methods employ the unique designs discussed herein, which provide improved controlled delivery of electrical pulses with controlled three-dimensional patterns and controlled thermal outputs. The present devices and systems provide surgical tools and methods for IRE treatment of subcutaneous tumors that expand the application space for this new technology, with the potential to treat a number of cancers, including brain, liver, prostate and pancreatic adenocarcinoma.
The following detailed description focuses on devices, systems, and methods for treatment of brain cancer. However, those of skill in the art will recognize that the concepts discussed have equivalent application to other diseases and disorders involving aberrant cell growth and/or production of deleterious cell masses on organs and tissues.
While the prognosis for many patients has improved with new drugs and radiosurgery, options to treat primary brain tumor patients are limited because of the need for techniques to be non-thermal, i.e., not propagate a convective hot spot in normal brain tissue not being treated. The current invention allows for IRE as an extremely useful, minimally invasive surgical technique for the treatment of brain cancer. The present designs for a surgical tool/treatment system for brain cancer is readily translated into the development of tools for other types of cancer.
As mentioned above, the present invention provides a method for treating aberrant cell growth in animals. The aberrant cell growth can be any type of aberrant cell growth, but in exemplary embodiments detailed herein, it is generally described in terms of tumors, such as brain tumors. In general, the method of treating comprises temporarily implanting one or more electrodes, which may be present on the same or different devices, into or immediately adjacent a tumor, and applying an electrical field to the tumor in multiple pulses or bursts over a prescribed or predetermined period of time to cause irreversible cell death to some or all of the tumor cells. Preferably, irreversible damage to non-tumor cells in proximity to the tumor is minimal and does not result in significant or long-lasting damage to healthy tissues or organs (or a significant number of cells of those tissues or organs). According to the method of the invention, cell killing is predominantly, essentially, or completely due to non-thermal effects of the electrical pulsing. The method further comprises removing the electrode(s) after suitable treatment with the electrical fields. As a general matter, because the method involves temporary implantation of relatively small electrodes, it is minimally invasive and does not result in the need for significant post-treatment procedures or care. Likewise, it does not result in significant ancillary or collateral damage to the subject being treated.
In practicing the method, the number of electrodes, either on a single or multiple devices, used can be selected by the practitioner based on the size and shape of the tumor to be treated and the size and shape of the electrode. Thus, embodiments of the invention include the use of one, two, three, four, five, or more electrodes. Each electrode can be independently sized, shaped, and positioned in or adjacent the tumor to be treated. In addition, the number and spacing of electrodes on a single device can be adjusted as desired. As detailed below, the location, shape, and size of electrodes can be selected to produce three-dimensional killing zones of numerous shapes and sizes, allowing for non-thermal treatment of tumors of varying shapes and sizes.
Surprisingly, it has been found that pulse durations for ablation of solid tumors can be relatively short, thus reducing the probability of generation of thermal conditions and excessive charges that cause collateral damage to healthy tissues. More specifically, the present invention recognizes for the first time that, in contrast to prior disclosures relating to IRE, the pulse length for highly efficient tissue ablation can be lower than 100 microseconds (100 us). Indeed, it has surprisingly been determined that a pulse length of 25 us or lower can successfully cause non-thermal cell death. Thus, in embodiments, the method of treatment uses pulse lengths of 10 us, 15 us, 20 us, 25 us, 30 us, 35 us, 40 us, 45 us, 50 us, 55 us, 60 us, 65 us, 70 us, 75 us, 80 us, 85 us, or 90 us. Preferably, to most effectively minimize peripheral damage due to heat, pulse lengths are limited to 90 us or less, for example 50 us or less, such as 25 us. By reducing the pulse length, as compared to prior art techniques for IRE, larger electric fields can be applied to the treatment area while avoiding thermal damage to non-target tissue (as well as to target tissue). As a result of the decreased pulse length and concomitant reduction in heat production, the methods of the invention allow for treatment of tissues having higher volumes (e.g., larger tumors) than possible if prior art methods were to be employed for in vivo treatment of tumors.
It has also been determined that voltages traditionally used for IRE are too high for beneficial treatment of tumors in situ. For example, typically, IRE is performed using voltages of between 4000 V/cm to 1500 V/cm. The present invention provides for use of voltages of much lower power. For example, the present methods can be performed using less than 1500 V/cm. Experiments performed by the inventors have shown that 2000 V/cm can cause excessive edema and stroke in patients when applied to brain tissue. Advantageously, for treatment of brain tumors, applied fields of about 500 V/cm to 1000 V/cm are used. Thus, in general for treatment of brain tumors, applied fields of less than 1000 V/cm can be used.
Further, it has been discovered that the number of electrical pulses that can be applied to successfully treat tumors can be quite high. Prior art methods of using IRE for various purposes included the use of relatively few pulses, for example 8 pulses or so. Reports of use of up to 80 pulses for IRE have been published; however, to the inventors' knowledge, a higher number of pulses has not been recommended. The present invention provides for the use of a relatively high number of pulses, on the order of 90 pulses or greater. For example, in exemplary embodiments, 90 pulses are used. Other embodiments include the use of more than 90 pulses, such as 100 pulses, 110 pulses, or more.
According to the method of the invention, cycle times for pulses are set generally about 1 Hz. Furthermore, it has been found that alternating polarity of adjacent electrodes minimizes charge build up and provides a more uniform treatment zone. More specifically, in experiments performed by the inventors, a superficial focal ablative IRE lesion was created in the cranial aspect of the temporal lobe (ectosylvian gyrus) using the NanoKnifeB (Angiodynamics, Queensbury, N.Y.) generator, blunt tip bipolar electrode (Angiodynamics, No. 204002XX) by delivering 9 sets of ten 50 us pulses (voltage-to-distance ratio 2000 V/cm) with alternating polarity between the sets to prevent charge build-up on the stainless steel electrode surfaces. These parameters were determined from ex-vivo experiments on canine brain and they ensured that the charge delivered during the procedure was lower than the charge delivered to the human brain during electroconvulsive therapy (an FDA approved treatment for major depression). Excessive charge delivery to the brain can induce memory loss, and thus is preferably avoided.
The method of the invention encompasses the use of multiple electrodes and different voltages applied for each electrode to precisely control the three-dimensional shape of the electric field for tissue ablation. More specifically, it has been found that varying the amount of electrical energy emitted by different electrodes placed in a tissue to be treated allows the practitioner to finely tune the three-dimensional shape of the electrical field that irreversibly disrupts cell membranes, causing cell death. Likewise, the polarity of electrodes can be varied to achieve different three-dimensional electrical fields. Furthermore, one of the advantages of embodiments of the invention is to generate electric field distributions that match complex tumor shapes by manipulating the potentials of multiple electrodes. In these embodiments, multiple electrodes are energized with different potential combinations, as opposed to an “on/off” system like radio frequency ablation, to maximize tumor treatment and minimize damage to surrounding healthy tissue.
According to the method of the invention, the separation of the electrodes within or about the tissue to be treated can be varied to provide a desired result. For example, the distance between two or more electrodes can be varied to achieve different three-dimensional electrical fields for irreversible disruption of cell membranes. The three-dimensional shape can thus be set to ablate diseased tissue, but partially or completely avoid healthy tissue in situations where the interface between healthy and diseased tissue shows a complex three dimensional shape.
The methods of the invention are well suited for treatment of tumors using non-thermal IRE. To better ensure that cell ablation is a result of non-thermal effect, and to better protect healthy tissue surrounding the site of treatment, the method can further comprise cooling the electrodes during the treatment process. By applying a heat sink, such as a cooling element in an electrode (discussed below), generation of heat in and around tissue in close proximity to the electrodes can be minimized, resulting in a more consistent application of non-thermal IRE to the tissue and a more controlled application of cell killing to only those tissues desired to be treated.
The method of the invention, in embodiments, includes the use of electrodes of different sizes and shapes. Studies performed by the inventors have shown that the electrical field distribution may be altered by use of electrodes having different diameters, lengths, and shapes. Thus, the use of different sizes and shapes of conducting surfaces can be used to control the electrical fields used for cell ablation. In certain embodiments, the method includes the use of a variable size electrode. For example, an electrode may be used that, in one configuration has a relatively small diameter, which is used for minimally invasive implantation of the electrode into the site to be treated. Once inserted, a sheath or other covering can be retracted to allow expansion of the electrode tip to a different size for application of the electric field. After treatment, the sheath can be moved to cover the tip again, thus reducing the size of the tip to its original size, and the electrode withdrawn from the treated tissue. The expandable element can be thought of as a balloon structure, which can have varying diameters and shapes, depending on original material shape and size.
The methods of the invention comprise, in embodiments, treatment of tissue surrounding tumor tissue. The surrounding tissue is treated by way of reversible electroporation. As such, bioactive agents can be introduced into the reversibly electroporated cells. In such embodiments, additional cell killing, under controlled conditions, can be effected in healthy tissue. Such a treatment is preferred when treating highly aggressive malignant tumors, which often show invasion of healthy tissue surrounding the tumor. Alternatively, the bioactive agents can provide a protective effect to cells in which they are introduced via reversible electroporation.
In embodiments, the method for treating aberrant cell growth in animals is a method of treating a subject suffering from a tumor. It thus may be a method of treating a subject suffering from cancer. Using different terminology, the method can be a method of treating a tumor or a method of treating cancer. As such, the method can be a method of treating either a benign tumor or a malignant tumor. In embodiments, the method is best suited for treatment of solid tumors. In exemplary embodiments, the method is a method of treating a subject suffering from a brain tumor, such as brain cancer.
In clinical settings, the method of treating according to the invention can have ameliorative effects or curative effects. That is, a method of treating a subject can provide a reduction in cell growth of a tumor, a reduction in tumor size, or total ablation of the tumor.
The method of the invention can include a single round of treatment or two or more rounds of treatment. That is, the method of cell ablation, either intentionally or as a result of tumor size or shape, can result in less than complete destruction of a tumor. In such a situation, the method can be repeated one or more times to effect the desired level of tumor reduction. As the method of the invention is relatively minimally invasive, multiple rounds of treatment are not as harmful to the patient than multiple rounds of traditional surgical intervention.
The method of the invention can be part of a multi-modal treatment. The method thus may comprise other cell-killing techniques known in the art. For example, the method may further comprise exposing the tumor to radiation, or treating the patient with a chemotherapeutic agent. It likewise may be performed after or between surgical intervention to remove all or part of a tumor. Those of skill in the art are fully aware of the parameters for treatment with other modalities; thus, details of those treatment regimens need not be detailed herein.
The method of the invention is implemented using devices and systems. The devices according to the invention are suitable for minimally invasive temporary implantation into a patient, emission of a tissue-ablating level of electricity, and removal from the patient. The device according to the invention thus may be used in the treatment of tumors and the treatment of patients suffering from tumors. The devices can take multiple forms, based on the desired three-dimensional shape of the electrical field for cell killing. However, in general, the devices include two or more regions of differing conductivity. In some embodiments, the device comprises alternating regions of conductivity, for example a region of electrical conductivity, which is adjacent a region of electrical non-conductivity, which is adjacent a different region of conductivity. In embodiments, the device comprises two or more layers of conductive and insulative materials, in a laminate structure with alternating conductive properties. To protect tissue that is not to be treated, the outer layer can be insulative except at the region where treatment is to be effected. According to embodiments of the device, the amount of conductive material exposed to the tissue to be treated can be adjusted by a movable non-conductive element disposed on the outer surface of the device.
Further, in general, the device takes a rod-like shape, with one dimension (i.e., length) being substantially longer than the other (i.e., width or diameter). While exemplary embodiments are configured in a generally cylindrical shape, it is to be understood that the cross-sectional shape of the electrode can take any suitable geometric shape. It thus may be circular, square, rectangular, oval, elliptical, triangular, pentagonal, hexagonal, octagonal, etc.
The devices of the invention comprise one or more electrodes, which are electrically conductive portions of the device. The devices are thus electrically conductive elements suitable for temporary implantation into living tissue that are capable of delivering an electrical pulse to the living tissue. The device of the invention has a proximal end and a distal end. The proximal end is defined as the end at which the device is attached to one or more other elements, for control of the function of the device. The distal end is defined by the end that contacts target tissue and delivers electrical pulses to the tissue. The distal end thus comprises an exposed or exposable electrically conductive material for implantation into a target tissue. Typically, the distal end is described as including a “tip” to denote the region of the distal end from which an electrical pulse is delivered to a tissue. The device further comprises at least one surface defining the length and circumference of the device.
In exemplary embodiments, the device comprises a laminate structure, with alternating conductive and non-conductive or insulative layers expanding outward from the proximal-distal center axis to the surface of the device. In typical embodiments, the center most layer, which shows the smallest diameter or width, is electrically conductive and comprises a part of the electrode tip. However, in alternative embodiments, the center-most layer is an open channel through which a fluid may be passed or through which additional physical elements may be placed. Yet again, the center-most layer may comprise an insulative material. In embodiments comprising a laminate structure, the structure can provide a more customizable electric field distribution by varying the separation distances between electrically conductive regions. Alternatively, in embodiments, certain electrically conductive regions can be exposed or concealed by movement of an outer, non-conductive sheath. In embodiments that do not comprise a laminate structure, the separation lengths can be achieved by disposing on the surface non-conductive materials at various regions.
In some embodiments, one or more substantially open channels are disposed along the center axis or in place of one of the conductive or insulative layers. The channel(s) may be used as heat sinks for heat produced by the device during use. In embodiments, water or another fluid is held or entrained in the channel to absorb and/or remove heat.
The device of the invention comprises an electrode tip at the distal end. The electrode tip functions to deliver electrical pulses to target tissue. The tip may be represented by a single conductive layer of the device or may be represented by two or more conductive layers that are exposed to the tissue to be treated. Furthermore, the tip may be designed to have any number of geometrical shapes. Exemplary embodiments include tips having a needle-like shape (i.e., electrical pulses emanate from a small cone-like structure at the distal end of the device) or having a circular shape (i.e., electrical pulses emanate from the cylindrical outer surface of the device, which is a section of the device where the outer insulative layer has been removed to expose the next layer, which is conductive). For use in treatment of brain tumors, the tip advantageously comprises a blunt or rounded end to minimize laceration of brain tissue. In embodiments, the rounded or blunt end comprises a hole that allows for a sharp or needle-like structure to be deployed into tumor tissue at the appropriate time.
The device comprises a proximal end, which generally functions for attachment of the device to a power source/controller and a handle. The proximal end thus may comprise connections for electrical wires that run from the power source/controller to the electrically conductive layers of the device. Standard electrical connections may be used to connect the conductive elements to the wires. In embodiments, the device is attached to a handle for ease of use by a human. While not limited in the means for attaching the device to the handle, in embodiments, the connection is made by way of a friction fit between the outer surface of the device and the handle, for example by way of an insulative O-ring (e.g., a Norprene O-ring) on the handle. In other embodiments, the device comprises, on its outer surface, ridges or other surface features that mate with surface features present on the handle. In yet other embodiments, the proximal end comprises one or more structures that allow for controlled movement of the outer surface along the length of the device. In such embodiments, the outer surface will comprise an outer sheath that is electrically non-conductive, and which surrounds an electrically conductive layer. Using the structures at the proximal end, the outer sheath may be moved, relative to the rest of the device, to expose or conceal varying portions of the electrically conductive material beneath it. In this way, the amount of surface area of the conductive material at the tip can be adjusted to provide a desired height of exposure of tissue to the electrode tip. Of course, other structures for securely fastening the device to a holder may be used, such as clips, set screws, pins, and the like. The device is not limited by the type of structure used to connect the device to the holder.
The device of the invention can be designed to have any desired size. Typically, it is designed to be minimally invasive yet at the same time suitable for delivery of an effective electrical field for IRE. The diameter or width is thus on the order of 0.5 mm to 1 cm. Preferably, the diameter or width is about 0.5 mm to about 5 mm, such as about 1 mm, 2 mm, 3 mm, or 4 mm. The length of the device is not particularly limited, but is generally set such that a surgeon can use the device comfortably to treat tumors at any position in the body. Thus, for human use, the device is typically on the order of 40 cm or less in length, such as about 30 cm, 25 cm, or 15 cm, whereas for veterinary use, the length can be much larger, depending on the size of animal to be treated. For treatment of human brain tumors, the length can be on the order of 40 cm.
In some embodiments, the device, or a portion of it, is flexible. A flexible device is advantageous for use in accessing tumors 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.
The device of the invention can be part of a system. In addition to the device, the system can comprise a handle into or onto which the device is disposed. The handle can take any of a number of shapes, but is generally designed to allow a surgeon to use the device of the invention to treat a patient in need. It thus typically has a connector for connecting the device to the holder, and a structure for the surgeon to grasp and maneuver the device. The handle further can comprise a trigger or other mechanism that allows the surgeon to control delivery of electrical pulses to the device, and thus to the tissue to be treated. The trigger can be a simple on/off switch or can comprise a variable control that allows for control of the amount of power to be delivered to the device. Additionally, the handle may be created in such a manner that it may be attached to additional pieces of equipment, such as ones that allow precise placement of the electrode relative to an inertial or the patient's frame of reference, allowing steady and accurate electrode positioning throughout an entire procedure, which may entail the application of electric pulses in addition to radiotherapy, imaging, and injections (systemically and locally) of bioactive agents. Furthermore, the handle may be attached to machines that are operated remotely by practitioners (e.g., the Da Vinci machine).
The system can further comprise a power source and/or a power control unit. In embodiments, the power source and control unit are the same object. The power source provides electrical power to the device, typically by way of an electrical connection through the handle. The power source can be any suitable source that can deliver the proper amount of electrical power to the device of the invention. Suitable power sources are commercially available, and the invention is not limited by the type or manufacturer. The power control unit provides the user with the ability to set the power output and pulse time for electrical pulses to be delivered to the device, and thus to the tissue to be treated. Suitable control units are commercially available, and the invention is not limited by the type or manufacturer. For example, an appropriate power source/controller is available from Angiodynamics (Queensbury, N.Y.).
The device of the invention can be disposable or reusable. Where the device is designed to be reusable, it is preferably fabricated from materials that can be sterilized multiple times without destruction of the device. For example, the device can be fabricated from rust-resistant metals or alloys, such as stainless steel, and plastic or other synthetic polymeric materials that can withstand cleaning and sterilization. Exemplary materials are those that can be subjected to detergents, steam heat (e.g., autoclaving), and/or irradiation for at least one cycle of sterilization. Those of skill in the art can select the appropriate materials without undue experimentation, based on materials used in other medical devices designed to withstand common sterilization techniques.
The invention will be further explained by the following Examples, which are intended to be purely exemplary of the invention, and should not be considered as limiting the invention in any way.
As a general background to the Examples, it is noted that the inventors and their colleagues have successfully demonstrated decellularization using IRE 1) in vivo and ex vivo, 2) to show that different tissues can be utilized, 3) to show that the area affected can be predicted using numerical modeling, 4) to show how numerical modeling can be used to ensure the ECM, blood vessels, and neural tubes are not thermally damaged, 5) while the organ was attached to a perfusion system, 6) while demonstrating preservation of major vasculature and ECM, and 7) with verification through imaging.
To illustrate 1) the possibility to monitor creation of a cell-free tissue section in brain in real-time using imaging techniques, 2) the variety of tissues that can be used, and 3) how to preserve vasculature, a healthy female purpose bred beagle was used. Nine sets of ten pulses were delivered with alternating polarity between the sets to minimize charge build-up on the electrode surfaces. The maximum voltage-to-distance ratio used was 2000 V/cm because the resulting current did not exceed 2 amps. The charge that was delivered to the brain during the IRE procedure was 22.5 mC, assuming ninety pulses (50 μs pulse durations) that would result from a maximum hypothetical current of 5 amps.
Method: After induction of general anesthesia, a routine parietotemporal craniectomy defect was created to expose the right temporal lobe of the brain. Two decelluarization sites were performed: 1) a deep lesion within the caudal aspect of the temporal lobe using a monopolar electrode configuration (6 mm electrode insertion depth perpendicular to the surface of the target gyms, with 5 mm interelectrode distance), and 2) a superficial lesion in the cranial aspect of the temporal lobe using a bipolar electrode (inserted 2 cm parallel to the rostrocaudal length of the target gyms, and 2 mm below the external surface of the gyrus). Intraoperative adverse effects that were encountered included gross microhemorrhages around the sharp monopolar electrode needles following insertion into the gyms. This hemorrhage was controlled with topical application of hemostatic foam. Subject motion was completely obliterated prior to ablating the superficial site by escalating the dose of atracurium to 0.4 mg/kg. Grossly visible brain edema and surface blanching of the gyrus overlying the bipolar electrode decelluarization site was apparent within 2 minutes of completion of IRE at this site. This edema resolved completely following intravenous administration of 1.0 g/kg of 20% mannitol. No adverse clinically apparent effects attributable to the IRE procedure, or significant deterioration in neurologic disability or coma scale scores from baseline evaluations were observed. However, the results indicated to the inventors that a lower voltage would provide adequate results but with less ancillary trauma to the brain.
Methods to monitor creation of cell-free tissues in vivo: A unique advantage of IRE to ablate tissues in vivo is its ability to be monitored in real-time using imaging techniques, such as electrical impedance tomography, MRI, and ultrasound. Below, this Example shows MRI examinations performed immediate post-operatively, which demonstrate that IRE decelluarization zones were sharply demarcated (
As shown in
Macrolevel and histologic verification of treating cells: The brain was collected within 2 hours of the time of death and removed from the cranium. Care was taken to inspect soft tissues and areas of closure created at the time of surgery. The brain was placed in 10% neutral buffered formalin solution for a minimum of 48 hours. Then, the brain was sectioned at 3 mm intervals across the short axis of the brain, in order to preserve symmetry and to compare lesions. Following gross dissection of fixed tissues, photographs were taken of brain sections in order to document the position and character of lesions, as shown in
Microscopic lesions correlated well with macroscale appearance. Areas of treatment are represented by foci of malacia and dissociation of white and grey matter. Small perivascular hemorrhages are present and there is sparing of major blood vessels (see
Analysis to determine IRE threshold: To determine the electric field needed to irreversibly electroporate tissue, one can correlate the lesion size that was observed in the ultrasound and MRI images with that in the histopathological analysis to determine the percentage of lesion growth. Decellularized site volumes can be determined after identification and demarcation of IRE decellularization zones from surrounding brain tissue using hand-drawn regions of interest (ROI). A representative source sample image is provided in
There are advantages to a strategy to treat cancer using IRE. IRE to treat cancer has advantages over existing thermal ablation, including the ability to: monitor what area has been irreversibly electroporated in real-time using ultra-sound or other imaging techniques; spare neural tubes and blood vessels, enabling treatment in otherwise inoperable areas; preserve the microvasculature, which promotes rapid healing of the treated volume; predict the affected area using numerical modeling for designing protocols; not be affected by blood flow as is the temperature distribution during thermal therapies; image the success of the treatment using MRI or other imaging techniques; and administer the electric fields in time periods of less than 5 minutes.
The present methods and devices provide a technology for treatment of tumors with IRE. Prior to the present invention, devices designed to irreversibly electroporate deep tissues did not exist. The experiments conducted and reported in the prior art utilized reversible electroporation systems. These devices usually consist of large plate electrodes (intended for transdermal drug delivery), needle electrodes with a large probe (intended for targeting in or for small animal studies), or cuvettes (used for in vitro applications). Applying an electric pulse over the skin presents challenges for deep tissue applications due to the significant voltage drop across the skin, generating considerable skin damage. (The same issue arises with an organ containing an epithelial layer.) Other devices that use needle electrodes are limited to superficial tumors. Furthermore, these tools have a large mechanical housing making the treatment of subcutaneous tumors impossible without invasive surgery. A tool designed specifically for IRE for subcutaneous delivery of the electric field dramatically enhances the application space of IRE for tissue ablation.
To provide an initial proof of concept, a device according to the invention was used to kill brain cells in vitro. Representing a unique pathobiological phenomenon, high-grade canine gliomas exhibit essentially the same properties as human gliomas, including pathology (markers), genetics, behavior (invasiveness), lack of metastases, and a similar clinical course of the disease. Dogs diagnosed with these tumors have poor prognosis and most are humanely euthanized to prevent further suffering from the progression of the disease. Primary brain tumors (PBTs) account for 1-3% of all deaths in aged dogs where necropsy is performed. The many similarities of glial tumors in people and dogs make these tumors in dogs an excellent translational approach for new diagnostic and treatment methods.
As shown in
The present invention provides simple and elegant minimally invasive microsurgical tools to treat currently inoperable tumors in humans and animals through IRE. Exemplary designs are shown in
The size and shape of the IRE area is dictated by the voltage applied and the electrode configuration and is readily predictable through numerical modeling. Therefore, different surgical tips can be fashioned to achieve the same therapeutic result. For example, tip 710 can comprises retractable conductive spikes 713 emanating from a blunt end tip 710 and disposed, when deployed, at an acute angle to tip 710 (see
The devices can comprise interchangeable surgical tips, allowing for versatility in creating a device well suited for different tissues or different sized or shaped tumors. Varying electrode diameters (varied in part by selection of the type and length of deployable spikes) and separation distances will be sufficient to ablate the majority of tumors about or smaller than 3 cm by selecting the appropriate voltages to match different tumor sizes and shapes. As shown in later figures, some of the embodiments of the device comprise an element at the tip to introduce anti-cancer drugs for ECT, cytotoxic proteins, or other bioactive agents into the targeted area.
While not depicted in detail, embodiments of the device comprise durable carbon coatings over portions of the device that act both to insulate normal tissue and to increase the efficiency of IRE pulsing.
With general reference to
Turning now to
As shown in the cut-away depiction in Panel B, device tip 810 has multiple alternating layers of conducting 820 and non-conducting 830 materials surrounding an non-conducting inner core 831. In Panel B, the top and bottom conducting regions 820 are energized electrodes while the middle conducting region 820 is a ground electrode. The present invention provides the conducting and non-conducting (insulative) regions in varying lengths to fine tune electrical field generation. More specifically, using imaging techniques directed at the tumor to be treated, a surgeon can determine what type of electrical field is best suited for the tumor size and shape. The device can comprise one or more movable elements on the surface of the tip (not depicted) or can be designed such that one or more of the alternating conducting 820 or non-conducting 830 elements is movable. Through movement and setting of the outer element(s) or inner elements 820 or 830, the surgeon can configure the device to deliver a three-dimensional electrical killing field to suit the needs of the particular situation.
In addition to changing charges, adapting the physical dimensions of the probe also allows flexibility in tailoring the treatment area to match the dimensions of the tumor. By altering the electrode parameters, including diameter, length, separation distance, and type, it is possible to conveniently tailor the treatment to affect only specific, targeted regions. In addition, developing an electrode capable of altering and adapting to these dimensional demands greatly enhances its usability and adaptability to treatment region demands.
Many IRE treatments may involve coupled procedures, incorporating several discrete aspects during the same treatment. One embodiment of the invention provides a device with a needle-like tip 910 with an incorporated hollow needle 990 with either an end outlet 991 (shown in Panel A) or mixed dispersion regions 961 (shown in Panel B). Such a configuration allows for highly accurate distribution of injectable solutions, including those comprising bioactive agents. Use of such a device limits the dose of treatment required as well as ensures the correct placement of the materials prior to, during, and/or after the treatment. Some of the possible treatment enhancers that would benefit from this technology are: single or multi-walled carbon nanotubes (CNTs); chemotherapeutic agents; conductive gels to homogenize the electric field; antibiotics; anti-inflammatories; anaesthetics; muscle relaxers; nerve relaxers; or any other substance of interest.
The schematics in
Irreversible Electroporation (IRE), a new minimally invasive technique we invented to treat tumors, can be enhanced using carbon nanotubes (CNTs). The technique can be used on a variety of tumors including liver, prostate, pancreatic adenocarcinoma and renal carcinoma. Focal ablation techniques, such as IRE, however, are not selective and thus cannot distinguish between healthy and cancerous cells. To overcome this limitation, nanoparticles can be incorporated into IRE therapy. Nanomaterials offer a potential means for energy focusing, because they present a toolset with a unique size range closely matching that of cells (1 to 1,000 nm), and substantial multi-functional capability. Some embodiments of nanoparticles exhibit a “lightning rod” effect when exposed to electric fields, amplifying the field at the nanoparticle's tip, thereby producing a significantly larger electric potential compared to its surroundings and reducing the possibility of sub-lethal joule heating. This localized amplification of electric fields could thus be used as a means to induce IRE from relatively small electric fields; residual adverse effects to surrounding tissue would subsequently be reduced. Targeting of nanoparticles through tumor specific antibodies to the desired tissue region will allow treatment up to and beyond the tumor margin using IRE, and offer the opportunity to lower the IRE applied field, thereby minimizing damage to surrounding, non-cancerous tissue during treatment. Integration of CNTs into IRE could more selectively localize the electric field and thermal profile to cancer cells through antibody targeting and more precisely control the induction of cell death and HSP expression.
When carbon nanotubes (CNTs) are immersed in an electric field, an induced dipole is generated that tends to align the axis of the CNT parallel to the electric field. Taking advantage of these effects can be used to reduce cell damage during treatment. For example, two sets of electric fields delivered subsequent to and at right angles to each other is a technique that can be used to align the CNTs and electroporate the cells. Under some circumstances, cells electroporated using CNTs may result in cells having a higher vitality than when electroporated without the use of CNTs. The use of CNTs injected into a region of tissue, with or without targeting antibodies, to mediate IRE for tumor ablation is another method covered by the present invention.
In N-TIRE therapy, the local electric field distribution dictates the treatment area. When electric field parameters are optimized, N-TIRE possesses a clear therapeutic advantage in that there is no induction of thermal injury in the ablated area, thereby preserving important tissue components such as the extracellular matrix, major blood vessels, myelin sheaths, and nerves. Since N-TIRE is a focal ablation technique, it does not selectively kill infiltrative cancer cells with the potential for re-growth and metastasis beyond the tumor margin without affecting the surrounding healthy cells. The ablation area can be enlarged without inducing joule heating and the selectivity of N-TIRE can be enhanced through the use of CNTs. Localized amplification of electric fields from CNTs could induce N-TIRE in adjacent cells from relatively small electric fields, without affecting healthy surrounding cells. Further, antibody targeting of CNTs to tumor cells could permit localized CNT-mediated electric field amplification at selected tumor cell membranes causing targeted cell death due to permanent membrane destabilization. Even further, it is advantageous to incorporate CNTs into N-TIRE protocols in order to simultaneously lower the voltage for N-TIRE and expand the treatable area.
Combinatorial CNT-mediated N-TIRE cancer therapies can include treatment of a number of cancers including prostate, liver, kidney, and pancreatic. Breast cancer is a particularly apt application since this combinatorial therapy can directly address the need of scar reduction and mitigate the likelihood of metastasis, which have proven in some circumstances to be helpful for improved treatment. Adapting N-TIRE treatments for breast carcinomas has several unique challenges. Among these are the diverse and dynamic physical and electrical properties of breast tissue. The fatty and connective tissues within the breast region surrounding a tumor have low water content, and thus significantly reduced electrical conductivity and permittivity than tumors. It has been shown that N-TIRE treatment area is highly predictable based on electric field distribution. CNTs will provide a means to raise the electric field magnitude within the tumor and increase N-TIRE treatment area in localized breast carcinomas.
Selective destruction of tumor cells with CNT-mediated N-TIRE therapy is dependent upon targeting CNTs to the tumor cells of interest. In physiological conditions, cells uptake folic acid across the plasma membrane using the folate carrier to supply the folate requirements of most normal cells. In contrast, folate receptor (FR), a high affinity membrane folate-binding protein, is frequently overexpressed in a wide variety of cancer cells. Since it is generally either absent or present at only low levels in most normal cells, the FR has been identified as not only a marker of cancers but also a potential and attractive target for tumor-specific drug delivery. Thus, bioconjugated nanoparticles, such as those conjugated with folic acid (FA-NP), can be synthesized and used as drug delivery tools for administering drugs into cancer cells.
In embodiments, the device comprises a cooling system within the electrode to reduce the highly localized temperature changes that occur from Joule heating. During the electric pulses for IRE, the highest quantity of heat generation is at the electrode-tissue interface. By actively cooling (for example, via water flow) the electrode during the procedure, these effects are minimized. Further, cooling provides a heat sink for the nearby tissue, further reducing thermal effects. This allows more flexibility in treating larger tissue regions with IRE while keeping thermal effects negligible, providing a greater advantage for IRE over conventional thermal techniques. Cooling can be achieved by placement of one or more hollow chambers within the body of the device. The cooling chambers can be closed or open. Open chambers can be attached at the proximal end to fluid pumping elements to allow for circulation of the fluid (e.g., water) through the device during use.
In embodiments, the device comprises an outer protector that is designed to be movable up and down along the length of the device.
The invention provides a system for performing IRE tumor tissue ablation. As depicted in
In this embodiment, device 1100 comprises further elements for use. More specifically, device 1100 comprises a height adjustment apparatus 1151 at its proximal end to effect movement of outer sheath 1160. Outer sheath 1160 further comprises markings or scores 1168 on its surface to indicate amount of movement of outer sheath 1160 after implantation of device 1100 into tumor tissue.
The invention provides a system for accurately controlling the distances between multiple electrodes of singular or multiple polarities during a charge. The device places electrode types within an adjustable part of a handle that may be maneuvered by a surgeon or attached to a harness system, as described above. The adjustable portion of the handle may be used to control the relative depths of penetration as well as separation distances of each electrode relative to one or more additional electrodes placed within the system.
The system and method of the invention can include the use of multiple devices for treatment of tumors. The devices can be implanted in the tumor at varying distances from each other to achieve desired cell killing. Alternatively, the system and method can include the use of a single device having multiple electrodes along its tip. Modeling of placement of multiple devices or a single device with multiple electrodes in tissue was performed, and exemplary electrical fields generated are depicted in
Numerical models representing two needles and an axis symmetric needle electrode configuration have been developed to compare the increase in treatment area shown by the electric field distribution for the same thermal effects between 100 and 50 us pulse lengths. The area/volume of tissue that increased by at least 1 degree Kelvin was determined for a 100 us pulse. This area/volume was then used for the 50 us pulse to determine the electric field magnitude that would cause the same increase in temperature. A contour line has been created within these models to represent the region treated with the IRE threshold of 700 V/cm. The results are shown in
To provide exquisite control of electrical fields, and thus cell killing, the size of the electrode tips may be adjusted. In addition to real-time electrode manipulation capabilities, integrating multiple electrode types within the same procedure can make a large impact on enhancing electric field distribution selectivity. This can be done by incorporating such variations as a needle electrode with a single probe or parallel needle electrodes with the conductive surface of one being a different dimension (e.g., longer) than the other. As shown in
We have discovered that a highly customizable electric field distribution may be attained by combining multiple electrode charges within the same pulse. This allows a highly customized and controllable treatment protocol to match the dimensions of the target tissue. In addition, the invasiveness of the treatment may be decreased by reducing the number of electrode placements required for treatment. In order to demonstrate the great flexibility in electric field distribution shape, 2-dimensional and axis symmetric models were developed with 3 and 4 electrode arrays along a single axis. The results are depicted in
We have done some preliminary studies and determined that the electric field distribution may be altered, and thus controlled, by changing the diameter and shape of the electrode between the conducting surfaces. This fact can be used to design and develop an electrode with an expandable/contractible interior and deformable exterior to change its size in real-time before or during a treatment to alter, and thus specify the electric field distribution in a manner that may be desirable during treatment. The ability to adjust this dimension in real-time is made additionally useful by the fact that a significantly smaller electrode may be inserted to keep it minimally invasive, and then expand the dimension once the electrode has reached the target tissue. In embodiments, the invention includes the use of a balloon between regions of charge that may be inflated/deflated during treatment to alter field distribution.
With the application of electric potentials, electrical forces may drive ions towards one electrode or the other. This may also lead to undesirable behavior such as electrolysis, separating water into its hydrogen and oxygen components, and leading to the formation of bubbles at the electrode-tissue interface. These effects are further exacerbated for multiple pulse applications. Such effects may cause interference with treatment by skewing electric field distributions and altering treatment outcomes in a relatively unpredictable manner. By altering the polarity between the electrodes for each pulse, these effects can be significantly reduced, enhancing treatment predictability, and thus, outcome. This alternating polarity may be a change in potential direction for each pulse, or occur within each pulse itself (switch each electrode's polarity for every pulse or go immediately from positive to negative potential within the pulse at each electrode).
Using a bipolar electrode with 4 embedded electrodes, one can use the middle two electrodes to inject a sinusoidal current (˜1-5 mA) that is low enough in magnitude to not generate electroporation and measure the voltage drop across the remaining two electrodes. From this setup one can calculate the impedance of the tissue and gather the conductivity of the tissue which is needed for treatment planning. One can do this analysis in a dynamic form after each electroporation pulse. Conductivity increases as a function of temperature and electroporation; therefore, for accurate treatment predictions and planning, the dynamic conductivity is needed and we can use the bipolar or unipolar electrodes to map the conductivity distribution before IRE treatment and during to adjust the pulse parameters.
According to the method, a tissue is exposed to an electrical field that is adequate in time and power to cause killing of cells of the tissue, but not adequate to significantly destroy the scaffolding upon and within which the cells exist. Furthermore, the electrical field does not cause irreversible tissue damage as a result of heating of the tissue. Various ways of providing such an electrical field are possible. General parameters follow; however, those of skill in the art are fully capable of devising alternative combinations to achieve the same end result without undue experimentation. In typical embodiments, one or more electrical pulses are applied to the tissue to cause cell membrane disruption as a result of the electricity and not substantially as a result of heat. Where two or more pulses are used, the pulses are separated by a period of time that allows, among other things, the tissue to cool so that thermal damage does not occur to a significant extent. For example, one or more electrical pulses can be applied to the tissue of interest for a duration in a range of from about 5 microseconds (μs) to about 62 seconds. For convenience, a short period of treatment might be desired. As such, in preferred embodiments, electrical pulses are applied for a period of about 1-10000 μs. Further, although there is no limit on the number of pulses to be delivered to the tissues, in preferred embodiments, from about 1 to about 100 pulses are applied to the tissue. For example, in an exemplary embodiment, about 10-1000 pulses of about 100 μs each in duration are applied to the tissue to cause cellular ablation.
The following are parameters that can be manipulated within the IRE treatments discussed herein.
Pulse length: 5 us-1 ms
Number of pulses: 1-10,000 pulses
Electric Field Distribution: 50-5,000 V/cm
Frequency of Pulse Application: 0.001-100 Hz
Frequency of pulse signal: 0-100 MHz
Pulse shape: square, exponential decay, sawtooth, sinusoidal, alternating polarity
Positive, negative, and neutral electrode charge pulses (changing polarity within probe)
Multiple sets of pulse parameters for a single treatment (changing any of the above parameters within the same treatment to specialize outcome)
Electrode Type
Needle diameter: 0.001 mm-1 cm
Electrode length (needle): 0.1 mm to 30 cm
Electrode separation: 0.1 mm to 5 cm
The methods used to model tissue ablation are similar to the ones described by Edd and Davalos for predicting IRE areas based on the electric field and temperature distribution in the tissue (Edd, J. F, et al., 2007, “Mathematical modeling of irreversible electroporation for treatment planning.”, Technology in Cancer Research and Treatment, 6:275-286.) The methods are disclosed in Garcia et al., “Irreversible electroporation (IRE) to treat brain cancer.” ASME Summer Bioengineering Conference, Marco Island, Fla., Jun. 25-29, 2008.
We have modeled a new electrode design for the application of IRE in brain tissue. According to our results, IRE can be an effective technique for minimally invasive brain tumor removal. The treatment does not induce substantial thermal effects in the brain, protecting the integrity of this organ, which is susceptible to small fluctuations in temperature. In an embodiment of the method of the invention, the method includes delivering electrical signal(s) through tissue to determine its electrical properties before administering IRE by monitoring the voltage and current. Following from that, one may apply intermittent and post-IRE pulse(s), which can be used to determine the success of the procedure and adjust IRE pulse parameters.
Specific conductivity can be important for treatment planning of irreversible electroporation (IRE). For many applications, especially when treating tumors in the brain, the volume (area) of IRE must be predicted to maximize the ablation of the tumorous tissue while minimizing the damage to surrounding healthy tissue. The specific electrical conductivity of tissue during an irreversible electroporation (IRE) procedure allows the physicians to: determine the current threshold; minimize the electric current dose; decrease the Joule heating; and reduce damage to surrounding healthy tissue. To measure the specific conductivity of tissue prior to an IRE procedure the physician must: establish the electrode geometry (shape factor); determine the physical dimensions of the tissue; apply a small excitation AC voltage signal (1 to 10 mV); measure the AC current response; calculate the specific conductivity (σ) using results from the prior steps. This procedure will not generate tissue damage (low amplitude AC signals) and will supply the physician (software) with the required information to optimize IRE treatment planning, especially in sensitive organs like the brain which is susceptible to high electrical currents and temperatures. Thus, the IRE procedure is well monitored and can also serve as a feedback system in between series of pulses and even after the treatment to evaluate the area of ablation.
Special Cases for electrode geometry:
Nomenclature (units in brackets):
Ve=voltage on the hot electrode (the highest voltage), [V]
R1=radius of electrode with highest voltage (inner radius), [m]
R2=radius at which the outer electrodes are arranged (outer radius), [m]
i=total current, [A]
L=length of cylindrical electrode, [m]
σ=electrical conductivity of tissue, [S/m]
Electrical conduction between a two-cylinder (needle) arrangement of length L in an infinite medium (tissue). It is important to note that this formulation is most accurate when L>>R1, R2 and L>>w. The electrical conductivity can be calculated from,
where the shape factor (S) corresponding to the electrode dimensions and configuration is given by,
The specific conductivity (σ) of the tissue can be calculated since the voltage signal (Ve) and the current responses (i) are known.
Explanation of electrical concepts: By using the bipolar electrode described in the priority document, one can apply a small excitation AC voltage signal (1 to 10 mV),
V(t)=V0 Sin(wt)
where V(t) is the potential at time t, V0 is the amplitude of the excitation signal and w is the frequency in radians/s. The reason for using a small excitation signal is to get a response that is pseudo-linear since in this manner we can determine the value for the impedance indicating the ability of a system (tissue) to resist the flow of electrical current. The measured AC current (response) that is generated by the excitation signal is described by
I(t)=I0 Sin(wt+q)
where I (t) is the response signal, I0 is the amplitude of the response (I01 V0) and q is the phase shift of the signal. The impedance (Z) of the system (tissue) is described by,
Z=(V(t))/(I(t))=(V0 Sin(wt))/(I0 Sin(wt+q))=Z0(Sin(wt))/(Sin(wt+q))
It is important to note that the measurement of the response is at the same excitation frequency as the AC voltage signal to prevent interfering signals that could compromise the results. The magnitude of the impedance |Z0| is the electrical resistance of the tissue. The electrical resistivity (W m) can be determined from the resistance and the physical dimensions of the tissue in addition to the electrode geometry (shape factor). The reciprocal of the electrical resistivity is the electrical conductivity (S/m). Therefore, after deriving the electrical resistivity from the methods described above, the conductivity may be determined.
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. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
The present application claims priority to and is a Continuation application of U.S. patent application Ser. No. 14/627,046, filed Feb. 20, 2015 and published as U.S. Patent Application Publication No. 2015/0164584 on Jun. 18, 2015 and issued as U.S. Pat. No. 10,245,105 on Apr. 2, 2019. The '046 application claims priority to and is a Continuation application of U.S. patent application Ser. No. 12/491,151, filed Jun. 24, 2009 and published as U.S. Patent Application Publication No. 2010/0030211 on Feb. 4, 2010 and issued as U.S. Pat. No. 8,992,517 on Mar. 31, 2015. The '151 application claims priority to and the benefit of the filing dates of U.S. provisional patent application No. 61/171,564, filed Apr. 22, 2009, U.S. provisional patent application No. 61/167,997, filed Apr. 9, 2009, and U.S. provisional patent application No. 61/075,216, filed Jun. 24, 2008. The '151 application is a Continuation-In-Part application of U.S. patent application Ser. No. 12/432,295, filed Apr. 29, 2009 and published as U.S. Patent Application Publication No. 2009/0269317 on Oct. 29, 2009 and issued as U.S. Pat. No. 9,598,691 on Mar. 21, 2017. The '295 application claims priority to and the benefit of the filing date of U.S. provisional patent application No. 61/125,840, filed Apr. 29, 2008. The entire disclosure of each of these patent applications is hereby incorporated herein by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1653819 | Northcott | 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 | Vu 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, III | 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 | Frattini | 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 et al. | 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 | Sander | 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 |
| 8361066 | Long et al. | Jan 2013 | B2 |
| D677798 | Hart et al. | Mar 2013 | S |
| 8425455 | Nentwick | Apr 2013 | B2 |
| 8425505 | Long | Apr 2013 | B2 |
| 8454594 | Demarais et al. | Jun 2013 | B2 |
| 8465464 | Travis et al. | Jun 2013 | B2 |
| 8465484 | Davalos et al. | Jun 2013 | B2 |
| 8506564 | Long | Aug 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 | 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, II et al. | Dec 2015 | B2 |
| 9283051 | Garcia et al. | Mar 2016 | B2 |
| 9414881 | Callas et al. | Aug 2016 | B2 |
| 9598691 | Davalos | Mar 2017 | B2 |
| 9764145 | Callas et al. | Sep 2017 | B2 |
| 9867652 | Sano et al. | Jan 2018 | B2 |
| 9943599 | Gehl et al. | Apr 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 | 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 |
| 10694972 | Davalos et al. | Jun 2020 | B2 |
| 10702326 | Neal et al. | Jul 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 | Mavor 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 | Wei | 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, Jr. 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 | Robert 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 et al. | 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 |
| 20120090646 | Tanaka 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 |
| 20130184702 | Neal, II et al. | Jul 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 | Robert 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 |
| 20160338758 | Davalos et al. | Nov 2016 | A9 |
| 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 | 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 |
| 20190076528 | Soden 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 | Sano 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 |
| 20200093541 | Neal et al. | Mar 2020 | A9 |
| 20200197073 | Sano et al. | Jun 2020 | A1 |
| 20200260987 | Davalos et al. | Aug 2020 | A1 |
| 20200323576 | Neal et al. | Oct 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 |
| 2009243079 | Jan 2011 | 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 |
| 2722296 | Nov 2009 | CA |
| 2751462 | Nov 2010 | CA |
| 1525839 | Sep 2004 | CN |
| 101534736 | Sep 2009 | CN |
| 102238921 | Nov 2011 | CN |
| 102421386 | Apr 2012 | CN |
| 106715682 | May 2017 | CN |
| 863111TR | Jan 1953 | DE |
| 4000893TR | 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 |
| 2280741 | Feb 2011 | EP |
| 2381829 | Nov 2011 | EP |
| 2413833 | Feb 2012 | EP |
| 2488251 | Aug 2012 | EP |
| 2642937 | Oct 2013 | EP |
| 1791485 | Dec 2014 | EP |
| 2373241 | Jan 2015 | EP |
| 1962710 | Aug 2015 | EP |
| 1962708 | Sep 2015 | EP |
| 1962945 | Apr 2016 | EP |
| 3143124 | Mar 2017 | 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 |
| 2014501574 | Jan 2014 | JP |
| 6594901 | Oct 2019 | 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 |
| 0148153 | Jul 2001 | WO |
| 2001048153 | Jul 2001 | WO |
| 0170114 | Sep 2001 | WO |
| 0181533 | Nov 2001 | WO |
| 02078527 | Oct 2002 | WO |
| 02089686 | Nov 2002 | WO |
| 02100459 | Dec 2002 | WO |
| 2003020144 | Mar 2003 | WO |
| 2003047684 | Jun 2003 | WO |
| 03099382 | Dec 2003 | WO |
| 2004037341 | May 2004 | WO |
| 2004080347 | Sep 2004 | WO |
| 2005065284 | Jul 2005 | WO |
| 2006017666 | Feb 2006 | WO |
| 2006031541 | Mar 2006 | WO |
| 2006130194 | Dec 2006 | WO |
| 2007067628 | Jun 2007 | WO |
| 2007067937 | Jun 2007 | WO |
| 2007067938 | Jun 2007 | WO |
| 2007067939 | Jun 2007 | WO |
| 2007067940 | Jun 2007 | WO |
| 2007067941 | Jun 2007 | WO |
| 2007067943 | Jun 2007 | WO |
| 2007070361 | Jun 2007 | WO |
| 2007100727 | Sep 2007 | WO |
| 2007123690 | Nov 2007 | WO |
| 2008063195 | May 2008 | WO |
| 2008034103 | Nov 2008 | WO |
| 2009046176 | Apr 2009 | WO |
| 2007137303 | Jul 2009 | WO |
| 2009134876 | Nov 2009 | WO |
| 2009135070 | Nov 2009 | WO |
| 2009137800 | Nov 2009 | WO |
| 2010064154 | Jun 2010 | WO |
| 2010080974 | Jul 2010 | WO |
| 2010117806 | Oct 2010 | WO |
| 2010118387 | Oct 2010 | WO |
| 2010132472 | Nov 2010 | WO |
| 2010151277 | Dec 2010 | WO |
| 2011047387 | Apr 2011 | WO |
| 2011062653 | May 2011 | WO |
| 2011072221 | Jun 2011 | WO |
| 2012051433 | Apr 2012 | WO |
| 2012071526 | May 2012 | WO |
| 2012071526 | May 2012 | WO |
| 2012088149 | Jun 2012 | WO |
| 2015175570 | Nov 2015 | WO |
| 2016100325 | Jun 2016 | WO |
| 2016164930 | Oct 2016 | WO |
| 2020061192 | Mar 2020 | WO |
| Entry |
|---|
| Mulhall et al., “Cancer, pre-cancer and normal oral cells distinguished by dielectrophoresis.” Analytical and Bioanalytical Chemistry, vol. 401, pp. 2455-2463 (2011). |
| 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 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., “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). |
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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). |
| 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). |
| 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. |
| 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. |
| Organ, L.W., Electrophysiological principles of radiofrequency lesion making, Apply. Neurophysiol., 1976. 39: p. 59-76. |
| 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. |
| Paszek et al., “Tensional homeostasis and the malignant phenotype.” Cancer Cell, vol. 8, pp. 241-254 (2005). |
| 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). |
| Pavselj, N., et al., “A numerical model of skin electroporation as a method to enhance gene transfection in skin. 11th Mediterranean Conference on Medical and Biological Engineering and Computing”, vols. 1 and 2, 16(1-2): p. 597-601 (2007). |
| PCT International Preliminary Report on Patentability of Corresponding International Application No. PCT/2011/062067, dated May 28, 2013. |
| PCT International Preliminary Report on Patentability of Corresponding International Application No. PCT/2011/066239, dated Jun. 25, 2013. |
| 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. 22, 2012), and Written Opinion (dated Aug. 22, 2012) of PCT/US11/66239. |
| PCT International Search Report (dated Aug. 26, 2005), Written Opinion (dated Aug. 26, 2005), and International Preliminary Report on Patentability (dated Jun. 26, 2006) from PCT/US2004/043477. |
| 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/US2009/042100. |
| PCT International Search Report and Written Opinion (dated Jul. 25, 2012) of PCT/US2011/062067. |
| 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. |
| PCT IPRP for PCT/US15/30429 (WO2015175570), dated Nov. 15, 2016. |
| Phillips, M., Maor E. & Rubinsky, B. Non-Thermal Irreversible Electroporation for Tissue Decellularization. J. Biomech. Eng, doi:10.1115/1.4001882 (2010). |
| Piñero, 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. |
| 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). |
| Precision Office Tuna System, When Patient Satisfaction is Your Goal, VidaMed 2001. |
| Pucihar et al., “Numerical determination of transmembrane voltage induced on irregularly shaped cells.” Annals of Biomedical Engineering, vol. 34, pp. 642-652 (2006). |
| 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. |
| 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. |
| Rols, M.P., et al., Highly Efficient Transfection of Mammalian Cells by Electric Field Pulses: Application to Large Volumes of Cell Culture by Using a Flow System, Eur. J. Biochem. 1992, 206, pp. 115-121. |
| Ron et al., “Cell-based screening for membranal and cytoplasmatic markers using dielectric spectroscopy.” Biophysical chemistry, 135 (2008) pp. 59-68. |
| 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). |
| 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. |
| Rubinsky, B., “Irreversible Electroporation in Medicine”, Technology in Cancer Research and Treatment, vol. 6, No. 4, Aug. 1, 2007, pp. 255-259. |
| Jarm et al., “Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases.” Expert Rev Anticancer Ther. vol. 10, pp. 729-746 (2010). |
| Jaroszeski, et al., In Vivo Gene Delivery by Electroporation, Advanced Drug Delivery Review, vol. 35, pp. 131-137, 1999. |
| 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). |
| Jordan, D.W., et al., “Effect of pulsed, high-power radiofrequency radiation on electroporation of mammalian cells”. Ieee Transactions on Plasma Science, 32(4): p. 1573-1578 (2004). |
| 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. |
| Katsuki, S., et al., “Biological effects of narrow band pulsed electric fields”, Ieee Transactions on Dielectrics and Electrical Insulation,. 14(3): p. 663-668 (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. |
| Kinosita et al., “Electroporation of cell membrane visualized under a pulsed-laser fluorescence microscope.” Biophysical Journal, vol. 53, pp. 1015-1019 (1988). |
| 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. |
| 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). |
| Kolb, J.F. et al., “Nanosecond pulsed electric field generators for the study of subcellular effects”, Bioelectromagnetics, 27(3): p. 172-187 (2006). |
| 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). |
| Kotnik et al., “Sensitivity of transmembrane voltage induced by applied electric fields—A theoretical analysis”, Bioelectrochemistry and Bioenergetics,vol. 43, Issue 2, 1997, pp. 285-291. |
| 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). |
| 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). |
| 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). |
| Laufer et al., “Electrical impedance characterization of normal and cancerous human hepatic tissue.” Physiological Measurement, vol. 31, pp. 995-1009 (2010). |
| 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. |
| 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). |
| 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. |
| Liu, et al., Measurement of Pharyngeal Transit Time by Electrical Impedance Tomography, Clin. Phys. Physiol. Meas., 1992, vol. 13, Suppl. A, pp. 197-200. |
| Long, G., et al., “Targeted Tissue Ablation With Nanosecond Pulses”. Ieee Transactions on Biomedical Engineering, 58(8) (2011). |
| 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. |
| Ma{hacek over (c)}ek Lebar and Miklavc{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). |
| 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. |
| Malpica et al., “Grading ovarian serous carcinoma using a two-tier system.” The American Journal of Surgical Pathology, vol. 28, pp. 496-504 (2004). |
| 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, Sep. 2008, 55(9): p. 2268-74. |
| 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. |
| 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. |
| 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. |
| Co-pending U.S. Appl. No. 15/424,335 Examiner Interview Summary (dated Jul. 20, 2018), 3 pages. |
| Co-pending U.S. Appl. No. 15/424,335 Non-Final Office Action dated Apr. 26, 2018, 9 pages. |
| Co-pending U.S. Appl. No. 15/424,335 Notice of Allowance dated Sep. 21, 2018, 7 pages. |
| Co-pending U.S. Appl. No. 15/424,335 Notice of Allowance, dated Feb. 21, 2019, 7 pgs. |
| Co-pending U.S. Appl. No. 15/424,335 Preliminary Amendment filed Apr. 17, 2017, 17 pages. |
| Co-pending U.S. Appl. No. 15/424,335 Response to Non-Final Office Action dated Jul. 26, 2018, 13 pages. |
| Co-pending U.S. Appl. No. 15/536,333 Office Actions and Responses through dated Jan. 2, 2020, 69 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 Apr. 26, 2018 Non-Final Office Action, 8 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. 15/881,414 Response to Apr. 26, 2018 Non-Final Office Action, dated Jul. 26, 2018, 15 pages. |
| Co-pending U.S. Appl. No. 16/152,743 Preliminary Amendment filed Oct. 5, 2018, 7 pages. |
| 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, Final office action dated Jan. 9, 2020, 8 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, Preliminary Amendment dated Dec. 19, 2018, 7 pages. |
| Co-pending U.S. Appl. No. 16/177,745, Response to Aug. 20, 2019 Non-final office action dated Nov. 20, 2019, 10 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 Final office action dated Jan. 9, 2020, 7 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 to Aug. 20, 2019 Non-final office action dated Nov. 20, 2019, 10 pages. |
| Co-pending U.S. Appl. No. 16/372,520 Preliminary Amendment filed Apr. 9, 2019, 7 pages. |
| 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, 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. 4, 2019, 9 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, Preliminary amendment filed Feb. 3, 2020. |
| Co-pending U.S. Appl. No. 16/520,901, Preliminary Amendment filed Aug. 14, 2019. |
| Co-pending U.S. Appl. No. 16/520,901, Second Preliminary Amendment filed Feb. 4, 2020. |
| 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 Application No. PCT/US15/30429, International Search Report and Written Opinion dated Oct. 16, 2015, 19 pages. |
| Co-pending application No. PCT/US19/51731 International Search Report and Written Opinion dated Feb. 20, 2020, 19 pgs. |
| 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. 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, Final Office Action dated Apr. 11, 2018, 10 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Final Office Action dated Aug. 30, 2016, 11 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, Non-Final Office Action dated Dec. 15, 2016, 8 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, Non-Final Office Action dated Sep. 8, 2015, 8 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Notice of Allowance (after Dec. 12, 2018 RCE) dated Jan. 9, 2019, 5 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. 14/017,210, Petition dated Dec. 11, 2015, 5 pages. |
| (Arena, Christopher B. et al.) Co-pending U.S. Appl. No. 15/186,653, filed Jun. 20, 2016, and published as U.S. Publication No. 2016/0287314 on Oct. 6, 2016, Specification, Claims, Figures. |
| (Arena, Christopher B. et al.) Co-pending U.S. Appl. No. 16/372,520, filed Apr. 2, 2019, which published as 20190223938 on Jul. 25, 2019, Specification, Claims, Figures. |
| (Arena, Christopher B. et al.) Co-Pending Application No. PCT/US11/66239, filed Dec. 20, 2011, Specification, Claims, Figures. |
| (Arena Christopher B. et al.) Co-Pending U.S. Appl. No. 13/332,133, filed Dec. 20, 2011 and published as U.S. Publication No. 2012/0109122 on May 3, 2012, Specification, Claims, Figures. |
| (Davalos, Rafael et al.) Co-pending U.S. Appl. No. 10/571,162, filed Oct. 18, 2006 (published as 2007/0043345 on Feb. 22, 2007), Specification, Figures, Claims. |
| (Davalos, Rafael et al.) Co-Pending U.S. Appl. No. 12/757,901, filed Apr. 9, 2010, Specification, Claims, Figures. |
| (Davalos, Rafael et al.) Co-Pending Application No. PCT/US04/43477, filed Dec. 21, 2004, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al) Co-Pending Application No. PCT/US10/53077, filed Oct. 18, 2010, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending U.S. Appl. No. 12/491,151, filed Jun. 24, 2009, and published as U.S. Publication No. 2010/0030211 on Feb. 4, 2010, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending U.S. Appl. No. 12/609,779, filed Oct. 30, 2009, and published as U.S. Publication No. 2010/0331758 on Dec. 30, 2010, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending U.S. Appl. No. 13/919,640, filed Jun. 17, 2013, and published as U.S. Publication No. 2013/0281968 on Oct. 24, 2013, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 15/424,335, filed Feb. 3, 2017, and published as U.S. Publication No. 2017/0189579 on Jul. 6, 2017, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 15/536,333, filed Jun. 15, 2017, and published as U.S. Publication No. 2017/0360326 on Dec. 21, 2017, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 15/881,414, filed Jan. 26, 2018, and published as U.S. Publication No. 2018/0161086 on Jun. 14, 2018, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 16/177,745, filed Nov. 1, 2018, and published as U.S. Publication No. 2019/0069945 on Mar. 7, 2019, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 16/232,962, filed Dec. 26, 2018, and published as U.S. Publication No. 2019/0133671 on May 9, 2019, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 16/352,759, filed Mar. 13, 2019, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending U.S. Appl. No. 16/535,451, filed Aug. 8, 2019, and Published as U.S. Publication No. 2019/0376055 on Dec. 12, 2019, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending Application No. PCT/US09/62806, filed Oct. 30, 2009, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending Application No. PCT/US10/30629, filed Apr. 9, 2010, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-pending application No. PCT/US19/51731 filed Sep. 18, 2019, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending U.S. Appl. No. 14/017,210, filed Sep. 3, 2013, and published as U.S. Publication No. 2014/0039489 on Feb. 6, 2014, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending U.S. Appl. No. 14/627,046, filed Feb. 20, 2015, and published as U.S. Publication No. 2015/0164584 on Jun. 18, 2015, Specification, Claims, Figures. |
| (Davalos, Rafael V. et al.) Co-Pending U.S. Appl. No. 14/686,380, filed Apr. 14, 2015, and published on U.S. Publication No. 2015/0289923 on Oct. 15, 2015, Specification, Claims, Figures. |
| (Davalos, Rafael V.) Co-Pending U.S. Appl. No. 12/432,295, filed Apr. 29, 2009, and published as U.S. Publication No. 2009/0269317-A1 on Oct. 29, 2009, Specification, Figures, Claims. |
| (Davalos, Rafael V.) Co-pending U.S. Appl. No. 15/423,986, filed Feb. 3, 2017, and published as U.S. Publication No. 2017/0209620 on Jul. 27, 2017, Specification, Claims, Figures. |
| (Davalos, Rafael, V.) Co-Pending Application No. PCT/US09/42100, filed Apr. 29, 2009, Specification, Claims, Figures. |
| (Garcia, Paulo A. et al.) Co-Pending U.S. Appl. No. 14/012,832, filed Aug. 28, 2013, and published as U.S. Publication No. 2013/0345697 on Dec. 26, 2013, Specification, Claims, Figures. |
| (Garcia, Paulo A. et al.) Co-Pending U.S. Appl. No. 14/558,631, filed Dec. 2, 2014, and published as U.S. Publication No. 2015/0088120 on Mar. 26, 2015, Specification, Claims, Figures. |
| (Garcia, Paulo A. et al.) Co-Pending U.S. Appl. No. 15/011,752, filed Feb. 1, 2016, and published as U.S. Publication No. 2016/0143698 on May 26, 2016, Specification, Claims, Figures. |
| (Garcia, Paulo A. et al.) Co-Pending U.S. Appl. No. 16/655,845, filed Oct. 17, 2019, Specification, Claims, Figures. |
| (Garcia, Paulo A. et al.) Co-pending U.S. Appl. No. 16/152,743, filed Oct. 5, 2018, Specification, Claims, Figures. |
| (Latouche, Eduardo et al.) Co-pending U.S. Appl. No. 16/210,771, filed Dec. 5, 2018, and which published as US Patent Publication No. 2019/0232048 on Aug. 1, 2019, Specification, Claims, Figures. |
| (Mahajan, Roop L. et al.) Co-Pending U.S. Appl. No. 13/958,152, filed Aug. 2, 2013, Specification, Claims, Figures. |
| (Neal, Robert E. et al) Co-Pending U.S. Appl. No. 12/906,923, filed Oct. 18, 2010, Specification, Claims, Figures. |
| (Neal, Robert E. et al.) Co-Pending U.S. Appl. No. 14/808,679, filed Jul. 24, 2015 and Published as U.S. Publication No. 2015/0327944 on Nov. 19, 2015, Specification, Claims, Figures. |
| (Neal, Robert E. et al.) Co-pending U.S. Appl. No. 16/375,878, filed Apr. 5, 2019, which published on Aug. 1, 2019 as US 2019-0233809 A1, Specification, Claims, Figures. |
| (Neal, Robert E. et al.) Co-pending U.S. Appl. No. 16/404,392, filed May 6, 2019, and published as U.S. Publication No. 2019/0256839 on Aug. 22, 2019, Specification, Claims, Figures. |
| (Neal, Robert E. et al.) Co-Pending U.S. Appl. No. 13/550,307, filed Jul. 16, 2012, and published as U.S. Publication No. 2013/0184702 on Jul. 18, 2013, Specification, Claims, Figures. |
| (Neal, Robert E. et al.) Co-Pending U.S. Appl. No. 14/940,863, filed Nov. 13, 2015 and Published as US 2016/0066977 on Mar. 10, 2016, Specification, Claims, Figures. |
| (Neal, Robert et al.) Co-pending U.S. Appl. No. 16/280,511, filed Feb. 20, 2019, and published as U.S. Publication No. 2019/0175248 on Jun. 13, 2019, Specification, Claims, Figures. |
| (Pearson, Robert M. et al) Co-pending Application No. PCT/US2010/029243, filed Mar. 30, 2010, published as WO 2010/117806 on Oct. 14, 2010, Specification, Claims, Figures. |
| (Pearson, Robert M. et al.) Co-pending U.S. Appl. No. 12/751,826, filed Mar. 31, 2010 (published as 2010/0250209 on Sep. 30, 2010), Specification, Claims, Figures. |
| (Pearson, Robert M. et al.) Co-pending U.S. Appl. No. 12/751,854, filed Mar. 31, 2010 (published as 2010/0249771 on Sep. 30, 2010), Specification, Claims, Figures. |
| (Sano, Michael B. et al) Co-Pending Application No. PCT/US2015/030429, Filed May 12, 2015, Published on Nov. 19, 2015 as WO 2015/175570, Specification, Claims, Figures. |
| (Sano, Michael B. et al.) Co-Pending U.S. Appl. No. 13/989,175, filed May 23, 2013, and published as U.S. Publication No. 2013/0253415 on Sep. 26, 2013, Specification, Claims, Figures. |
| (Sano, Michael B. et al.) Co-Pending U.S. Appl. No. 15/310,114, filed Nov. 10, 2016, and published as U.S. Publication No. 2017/0266438 on Sep. 21, 2017, Specification, Claims, Figures. |
| (Sano, Michael B. et al.) Co-pending U.S. Appl. No. 15/843,888, filed Dec. 15, 2017, and published as U.S. Publication No. 2018/0125565 on May 10, 2018, Specification, Claims, Figures. |
| (Sano, Michael B. et al.) Co-pending U.S. Appl. No. 16/443,351, filed Jun. 17, 2019 (published as 20190328445 on Oct. 31, 2019), Specification, Claim, Figures. |
| (Sano, Michael B. et al.) Co-pending U.S. Appl. No. 16/520,901, filed Jul. 24, 2019 (published as U.S. Publication No. 2019/0351224 on Nov. 21, 2019), Specification, Claim, Figures. |
| Co-Pending U.S. Appl. No. 14/017,210, Petition Decision dated Aug. 12, 2019, 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, Priority Petition Dec. 11, 2015, 5 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, RCE dated Aug. 1, 2017, 13 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 Aug. 30, 2016 Final Office Action, dated Nov. 30, 2016, 10 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response to Dec. 15, 2016 Non-Final Office Action dated Mar. 20, 2017, 9 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response to May 1, 2017 Final Office Action dated Aug. 1, 2017, 10 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response to Non-Final Office Action dated Mar. 8, 2016, 16 pages. |
| Co-Pending U.S. Appl. No. 14/017,210, Response to Oct. 25, 2017 Non-Final Office Action dated Jan. 25, 2018, 11 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Amendment dated Jun. 29, 2017, 8 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Final Office Action dated Sep. 14, 2017, 11 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Interview Summary dated dated Apr. 27, 2018, 3 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Non-Final Office Action dated Feb. 15, 2018, 12 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Non-Final Office Action dated Mar. 29, 2017, 9 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Notice of Allowance dated Feb. 6, 2019, 5 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Notice of Allowance dated Sep. 19, 2018, 7 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Response to Mar. 29, 2017 Non-Final Office Action, dated Jun. 29, 2017, 8 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Response to Sep. 14, 2017 Final Office Action dated Dec. 14, 2017, 7 pages. |
| Co-Pending U.S. Appl. No. 14/627,046, Rule 132 Affidavit and Response to Feb. 15, 2018 Non-Final Office Action, dated Jun. 15, 2018, 13 pages. |
| 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. |
| 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. |
| Dahl et al., “Nuclear shape, mechanics, and mechanotransduction.” Circulation Research vol. 102, pp. 1307-1318 (2008). |
| Daskalov, I., et al, “Exploring new instrumentation parameters for electrochemotherapy—Attacking tumors with bursts of biphasic pulses instead of single pulses”, IEEE Eng Med Biol Mag, 18(1): p. 62-66 (1999). |
| 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, 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, 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). |
| Davalos, R.V., et al., “Electrical impedance tomography for imaging tissue electroporation,” IEEE Transactions on Biomedical Engineering, 51, 761-767, 2004. |
| 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. |
| 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). |
| Dean, Nonviral Gene Transfer to Skeletal, Smooth, and Cardiac Muscle in Living Animals, Am J. Physiol Cell Physiol 289: 233-245, 2005. |
| Demirbas, M. F., “Thermal Energy Storage and Phase Change Materials: An Overview” Energy Sources Part B 1(1), 85-95 (2006). |
| 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 fortreatment planning.”, Technology in Cancer Research and Treatment., 6:275-286. |
| 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). |
| Eppich et al., “Pulsed electric fields for selection of hematopoietic cells and depletion of tumor cell contaminants.” Nature Biotechnology 18, pp. 882-887 (2000). |
| 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. |
| Ermiolina 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. |
| 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). |
| Rubinsky, B., ed, Cryosurgery. Annu Rev. Biomed. Eng. vol. 2 2000. 157-187. |
| Rubinsky, B., et al., “Irreversible Electroporation: A New Ablation Modality—Clinical Implications” Technol. Cancer Res. Treatment 6(1), 37-48 (2007). |
| Sabuncu et al., “Dielectrophoretic separation of mouse melanoma clones.” Biomicrofluidics, vol. 4, 7 pages (2010). |
| 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). |
| 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., “Contactless Dielectrophoretic Spectroscopy: Examination of the Dielectric Properties of Cells Found in Blood.” Electrophoresis, 32, pp. 3164-3171, 2011. |
| 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). |
| 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. |
| Saur et al., “CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer.” Gastroenterology, vol. 129, pp. 1237-1250 (2005). |
| 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. |
| Schoenbach et al., “Intracellular effect of ultrashort electrical pulses.” Bioelectromagnetics, 22 (2001) pp. 440-448. |
| 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). |
| 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). |
| 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). |
| 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, A. , et al., “Review on Thermal Energy Storage with Phase Change Materials and Applications”, Renewable Sustainable Energy Rev. 13(2), 318-345 (2009). |
| 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. |
| Szot et al., “3D in vitro bioengineered tumors based on collagen I hydrogels.” Biomaterials vol. 32, pp. 7905-7912 (2011). |
| Talele, S. and P. Gaynor, “Non-linear time domain model of electropermeabilization: Effect of extracellular conductivity and applied electric field parameters”, Journal of Electrostatics,66(5-6): p. 328-334 (2008). |
| Talele, S. and P. Gaynor, “Non-linear time domain model of electropermeabilization: Response of a single cell to an arbitrary applied electric field”, Journal of Electrostatics, 65(12): p. 775-784 (2007). |
| 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). |
| Teissie, J. and T.Y. Tsong, “Electric-Field Induced Transient Pores in Phospholipid-Bilayer Vesicles”. Biochemistry, 20(6): p. 1548-1554 (1981). |
| 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. |
| Thomson, K. R., et al., “Investigation of the Safety of Irreversible Electroporation in Humans” J. Vascular Int. Radiol. 22(5), 611-621 (2011). |
| Tibbitt et al., “Hydrogels as Extracellular Matrix Mimics for 3D Cell Culture”, Jul. 2009, Biotechnol Bioeng, 103(4),655-663. |
| TUNA—Suggested Local Anesthesia Guidelines, no date available. |
| Verbridge et al., “Oxygen-Controlled Three-Dimensional Cultures to Analyze Tumor Angiogenesis.” Tissue Engineering, Part A vol. 16, pp. 2133-2141 (2010). |
| Vernier, P.T., et al., “Nanoelectropulse-driven membrane perturbation and small molecule permeabilization”, Bmc Cell Biology, 7 (2006). |
| Vidamed, Inc., Transurethral Needle Ablation (TUNA): Highlights from Worldwide Clinical Studies, Vidamed's Office TUNA System, 2001. |
| 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. |
| 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). |
| 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. |
| Weaver, J. C., Electroporation of biological membranes from multicellular to nano scales, IEEE Trns. Dielectr. Electr. Insul. 10, 754-768 (2003). |
| Weaver, J.C., “Electroporation of cells and tissues”, IEEE Transactions on Plasma Science, 28(1): p. 24-33 (2000). |
| Weisstein: Cassini Ovals. From MathWorld—A. Wolfram Web Resource; Apr. 30, 2010; http://mathworld.wolfram.com/ (updated May 18, 2011). |
| 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. |
| 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). |
| 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. |
| 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. |
| Zimmerman, 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. |
| Co-Pending U.S. Appl. No. 14/558,631, Response to Sep. 1, 2017 Final Office Action dated Dec. 1, 2017, 7 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, Final Office Action dated Sep. 3, 2019, 28 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Non-Final Office Action dated Feb. 13, 2020, 11 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Non-Final Office Action dated May 1, 2019, 18 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 to Jul. 19, 2017 Restriction Requirement, dated Sep. 15, 2017, 2 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Response to May 9, 2018 Final Office Action with RCE, dated Aug. 30, 2018, 14 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Response to Non-Final Office Action Filed Aug. 1, 2019, 11 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Response to Nov. 22, 2017 Non-Final Office Action dated Mar. 28, 2018, 11 pages. |
| Co-Pending U.S. Appl. No. 14/686,380, Restriction Requirement dated Jul. 19, 2017, 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 for Priority and Supplemental Response, filed May 8, 2019, 25 pages. |
| Co-Pending U.S. Appl. No. 14/808,679, Petition Supplement, 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 to 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 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 May 25, 2018, 9 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 to Dec. 19, 2018 Final Office Action dated Mar. 5, 2019, 6 pages. |
| Co-pending U.S. Appl. No. 15/011,752 Response to May 11, 2018 Non-Final Office Action dated Oct. 11, 2018, 11 pages. |
| Co-pending U.S. Appl. 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, NFOA dated Mar. 6, 2019, 13 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, dated Nov. 10, 2016, 9 pages. |
| Co-Pending U.S. Appl. No. 15/310,114, Response to Mar. 6, 2019 Non-Final Office Action filed Jun. 4, 2019, 8 pages. |
| Co-pending U.S. Appl. No. 15/424,335 Examiner Interview Request (dated Jul. 2, 2018), 1 page. |
| (Sano, Michael B. et al.) Co-Pending U.S. Appl. No. 16/747,219, filed Jan. 20, 2020, Specification, Claims, Figures. |
| (Sano, Michael et al.) Co-Pending Application No. PCT/US11/62067, filed Nov. 23, 2011, Specification, Claims, Figures. |
| (Sano, Michael et al.) Co-Pending Application No. PCT/US15/30429, filed May 12, 2015, Specification, Claims, Figures. |
| 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. |
| Abiror, I.G., et al., “Electric Breakdown of Bilayer Lipid-Membranes .1. Main Experimental Facts and Their Qualitative Discussion”, Bioelectrochemistry and Bioenergetics, 6(1): p. 37-52 (1979). |
| Agerholm-Larsen, B., et al., “Preclinical Validation of Electrochemotherapy as an Effective Treatment for Brain Tumors”, Cancer Research 71: 3753-3762 (2011). |
| Alberts et al., “Molecular Biology of the Cell,” 3rd edition, Garland Science, New York, 1994, 1 page. |
| Al-Sakere et al., “Tumor ablation with irreversible electroporation.” PLoS ONE, Issue 11, e1135, 8 pages, 2007. |
| 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. |
| Appelbaum, L., et al., “US Findings after Irreversible Electroporation Ablation: Radiologic-Pathologic Correlation” Radiology 262(1), 117-125 (2012). |
| 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. |
| 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. |
| Asami et al., “Dielectric properties of mouse lymphocytes and erythrocytes.” Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1010 (1989) pp. 49-55. |
| 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). |
| Baker, et al., Calcium-Dependent Exocytosis in Bovine Adrenal Medullary Cells with Leaky Plasma Membranes, Nature, vol. 276, pp. 620-622, 1978. |
| 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. |
| 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. |
| 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). |
| Barber, Electrical Impedance Tomography Applied Potential Tomography, Advances in Biomedical Engineering, Beneken and Thevenin, eds., IOS Press, pp. 165-173, 1993. |
| 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). |
| 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. |
| Beebe, S.J., et al. “Nanosecond, high-intensity pulsed electric fields induce apoptosis in human cells”, FASEB J, 17(9): p. 1493-5 (2003). |
| Belehradek, J., et al., “Electropermeabilization of Cells in Tissues Assessed by the Qualitative and Quantitative Electroloading of Bleomycin”, Biochimica Et Biophysica Acta-Biomembranes, 1190(1): p. 155-163 (1994). |
| Ben-David, E.,et al., “Characterization of Irreversible Electroporation Ablation in In Vivo Procine Liver” Am. J. Roentgenol. 198(1), W62-W68 (2012). |
| Benz, R., et al. “Reversible electrical breakdown of lipid bilayer membranes: a charge-pulse relaxation study”. J Membr Biol, 48(2): p. 181-204 (1979). |
| 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, Nov. 28, 2006, pp. 1061-1070. |
| 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). |
| Bower et al., “Irreversible electroporation of the pancreas: definitive local therapy without systemic effects.” Journal of surgical oncology, 2011. 104(1): p. 22-28. |
| 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. |
| 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. |
| 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). |
| 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. |
| Chang, D.C., “Cell Poration and Cell-Fusion Using an Oscillating Electric-Field”. Biophysical Journal, 56(4): p. 641-652 (1989). |
| 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). |
| Chen, M.T., et al., “Two-dimensional nanosecond electric field mapping based on cell electropermeabilization”, PMC Biophys, 2(1):9 (2009). |
| Clark et al., “The electrical properties of resting and secreting pancreas.” The Journal of Physiology, vol. 189, pp. 247-260 (1967). |
| 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. 12/491,151, Final Rejection dated Apr. 20, 2012, 8 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Non-Final Rejection dated Apr. 4, 2014, 12 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Non-Final Rejection dated Dec. 28, 2011, 7 pages. |
| Faroja, M., et al., “Irreversible Electroporation Ablation: Is the entire Damage Nonthermal?”, Radiology, 266(2), 462-470 (2013). |
| Fischbach et al., “Engineering tumors with 3D scaffolds.” Nat Meth 4, pp. 855-860 (2007). |
| 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). |
| Foster RS, “High-intensity focused ultrasound in the treatment of prostatic disease”, European Urology, 1993, vol. 23 Suppl 1, pp. 29-33. |
| Foster, R.S., et al., Production of Prostatic Lesions in Canines Using Transrectally Administered High-Intensity Focused Ultrasound. Eur. Urol., 1993; 23: 330-336. |
| Fox, et al., Sampling Conductivity Images via MCMC, Mathematics Department, Auckland University, New Zealand, May 1997. |
| 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). |
| Garcia et al., “Irreversible electroporation (IRE) to treat brain cancer.” ASME Summer Bioengineering Conference, Marco Island, FL, Jun. 25-29, 2008. |
| 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 Mlultimodal Therapy for Intracranial Malignant Glioma in a Canine Patient” Technol. Cancer Res. Treatment 10(1), 73-83 (2011). |
| Garcia, P. et al. Intracranial nonthermal irreversible electroporation: in vivo analysis. J Membr Biol 236, 127-136 (2010). |
| 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. |
| 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). |
| 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. |
| 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). |
| 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. |
| Golberg, A. and Rubinsky, B., “A statistical model for multidimensional irreversible electroporation cell death in tissue.” Biomed Eng Online, 9, 13 pages, 2010. |
| Gothelf, et al., Electrochemotherapy: Results of Cancer Treatment Using Enhanced Delivery of Bleomycin by Electroporation, Cancer Treatment Reviews 2003: 29: 371-387. |
| 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). |
| 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. |
| Helczynska et al., “Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ.” Cancer Research, vol. 63, pp. 1441-1444 (2003). |
| Heller, et al., Clinical Applications of Electrochemotherapy, Advanced Drug Delivery Reviews, vol. 35, pp. 119-129, 1999. |
| 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. |
| 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. |
| 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. |
| Hu, Q., et al., “Simulations of transient membrane behavior in cells subjected to a high-intensity ultrashort electric pulse”, Physical Review E, 71(3) (2005). |
| 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. |
| 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). |
| 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. |
| 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). |
| Ivorra, A., ed. “Tissue Electroporation as a Bioelectric Phenomenon: Basic Concepts. Irreversible Electroporation”, ed. B. Rubinsky., Springer Berlin Heidelberg. 23-61 (2010). |
| Co-Pending U.S. Appl. No. 12/491,151, Official Notice of Allowance dated Feb. 12, 2015, 2 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Official Notice of Allowance dated Nov. 6, 2014, 15 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Official Notice of Allowance dated Oct. 15, 2014, 5 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Requirement for Restriction/Election dated Dec. 2, 2011, 6 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Response to Apr. 4, 2014 Non-Final Rejection dated Aug. 22, 2014, 12 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Response to Non-Final Rejection dated Mar. 28, 2012, 10 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Response to Requirement for Restriction/Election dated Dec. 13, 2011, 2 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Response with RCE to Final Rejection dated Aug. 20, 2012, 14 pages. |
| Co-Pending U.S. Appl. No. 12/491,151, Supplemental Amendment dated Dec. 17, 2012, 6 pages. |
| Co-Pending U.S. Appl. No. 12/609,779, Final Rejection dated Oct. 26, 2012, 20 pages. |
| Co-Pending U.S. Appl. No. 12/609,779, Non-Final Rejection dated May 23, 2012, 17 pages. |
| Co-Pending U.S. Appl. No. 12/609,779, Notice of Allowance dated Feb. 12, 2013, 7 pages. |
| Co-Pending U.S. Appl. No. 12/609,779, Notice of Allowance dated May 23, 2013, 2 pages. |
| Co-Pending U.S. Appl. No. 12/609,779, Response to Non-Final Rejection dated Sep. 24, 2012, 37 pages. |
| Co-Pending U.S. Appl. No. 12/609,779, Response with RCE to Final Rejection dated Dec. 18, 2012, 20 pages. |
| Co-Pending U.S. Appl. No. 12/757,901, File History 2018. |
| Co-Pending U.S. Appl. No. 12/906,923, Office Actions and Responses dated Jul. 2017, 55 pages. |
| Co-Pending U.S. Appl. No. 12/906,923, Official Notice of Allowance and Examiner's Amendment, dated May 26, 2015, 21 pages. |
| Co-Pending U.S. Appl. No. 12/906,923, Response to Oct. 24, 2014 Office Action, filed Jan. 26, 2015, 11 pages. |
| Co-Pending U.S. Appl. No. 12/906,923, Non-Final Office Action dated Oct. 24, 2014, 11 pages. |
| Co-Pending U.S. Appl. No. 12/906,923, Requirement for Restriction/Election, dated Jan. 29, 2014, 9 pages. |
| Co-Pending U.S. Appl. No. 12/906,923, Response to Restriction Requirement, dated Mar. 19, 2014, 3 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. 13/332,133, Office Actions and Responses through Mar. 2018, 221 pages. |
| Co-Pending U.S. Appl. No. 13/550,307, Aug. 13, 2018 Applicant-Initiated Interview Summary, 3 pages. |
| Co-Pending U.S. Appl. No. 13/550,307, Final Office Action dated Dec. 5, 2018, 17 pages. |
| Co-Pending U.S. Appl. No. 13/550,307, Office Actions and Responses through Mar. 2018, 133 pages. |
| Co-Pending U.S. Appl. No. 13/550,307, Response to Mar. 14, 2018 Non-Final Office Action dated Jul. 16, 2018, 12 pages. |
| Co-pending U.S. Appl. No. 13/550,307 Interview Request and Summary, dated Dec. 13, 19, 2019, 4 pages. |
| 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. 13/550,307 Response to Aug. 22, 2019 Non-final office action dated Dec. 23, 2019, 10 pages. |
| Co-Pending U.S. Appl. No. 13/919,640, Notice of Allowance dated Mar. 17, 2014, 6 pages. |
| Co-Pending U.S. Appl. No. 13/919,640, Notice of Allowance dated Nov. 25, 2013, 15 pages. |
| Co-Pending U.S. Appl. No. 13/919,640, Response to Notice of Allowance with RCE dated Feb. 21, 2014, 5 pages. |
| Co-Pending U.S. Appl. No. 13/919,640, Supplemental Notice of Allowance dated Apr. 10, 2014, 5 pages. |
| Co-Pending U.S. Appl. No. 13/919,640, Supplemental Notice of Allowance dated Jul. 18, 2014, 2 pages. |
| 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. 14/558,631, Final Office Action dated Sep. 1, 2017, 9 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, Non-Final Office Action dated Mar. 13, 2017, 10 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Notice of Allowance dated Jul. 17, 2018, 2 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Notice of Allowance dated Jun. 21, 2018, 7 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Response to Jan. 8, 2018 Non-Final Office Action dated Apr. 9 2018, 8 pages. |
| Co-Pending U.S. Appl. No. 14/558,631, Response to Mar. 13, 2017 Non-Final Office Action dated Jul. 13, 2017, 10 pages. |
| (Davalos, Rafael V et al.) Co-pending U.S. Appl. No. 16/865,031, filed May 1, 2020, Specification, Claims, Figures. |
| (Davalos, Rafael V et al.) Co-pending U.S. Appl. No. 17/069,359, filed Oct. 13, 2020, Specification, Claims, Drawings. |
| (Davalos, Rafael V. et al.) Co-Pending Application No. AU 2009243079, filed Apr. 29, 2009 (see PCT/US2009/042100 for documents as filed), Specification, Claims, Figures. |
| (Davalos, Rafael V.) Co-Pending International Application No. PCT/US15/65792, filed Dec. 15, 2015, Amended C1aims, Specification, Drawings. |
| (Davalos, Rafael V.) Co-Pending Application No. CA 2,722,296, filed Apr. 29, 2009, Amended C1aims (7 pages), Specification, Figures (See PCT/US2009/042100 for Specification and figures as filed). |
| (Davalos, Rafael V.) Co-Pending Application No. EP 09739678.2 filed Apr. 29, 2009, Amended Claims (3 pages), Specification and Figures (See PCT/US2009/042100). |
| (Lorenzo, Melvin F. et al.) Co-pending U.S. Appl. No. 16/938,778, filed Jul. 24, 2020, Specification, Claims, Figures. |
| (Neal, Robert E. et al.) Co-pending U.S. Appl. No. 16/865,772, filed May 4, 2020, Specification, Claims, Figures. |
| (Neal, Robert et al.) Co-Pending Application No. EP 10824248.8, filed May 9, 2012, Amended Claims (3 pages), Specification and Figures (See PCT/US10/53077). |
| (O'Brien, Timothy J. et al.) Co-Pending U.S. Appl. No. 16/915,760, filed Jun. 29, 2020, Specification, Claims, Figures. |
| (Sano, Michael B. et al.) Co-Pending Application No. AU 2015259303, filed Oct. 24, 2016, Specification, Figures, Claims. |
| (Sano, Michael B. et al.) Co-Pending Application No. CN 201580025135.6, filed Nov. 14, 2016, Specification, Claims, Figures (Chinese language and English language versions). |
| (Sano, Michael B. et al.) Co-Pending Application No. EP 11842994.3, filed Jun. 24, 2013, Amended Claims (18 pages), Specification and Figures (See PCT/US11/62067). |
| (Sano, Michael B. et al.) Co-Pending Application No. EP 15793361.5, filed Dec. 12, 2016, Specification, Claims, Figures. |
| (Sano, Michael B. et al.) Co-pending Application No. HK 17112121.8, filed Nov. 20, 2017 and published as Publication No. HK1238288 on Apr. 27, 2018, Specification, Figures, Claims (see PCT/US15/30429 for English Version of documents as filed). |
| (Sano, Michael B. et al.) Co-Pending Application No. JP 2013-541050, filed May 22, 2013, Claims, Specification, and Figures (see PCT/US11/62067 for English Version). |
| (Sano, Michael B. et al.) Co-Pending Application No. JP 2016-567747, filed Nov. 10, 2016, Specification, Claims, Figures (see PCT/US15/30429 for English Version of documents as filed). |
| (Sano, Michael B. et al.) Co-Pending Application No. JP 2019-133057, filed Jul. 18, 2019, 155 pgs, Specification, Claims, Figures (see PCT/US15/30429 for English Version of documents as filed). |
| (Wasson, Elisa M. et al.) Co-Pending U.S. Appl. No. 17/000,049, filed Aug. 21, 2020, Specification, Claims, Figures. |
| Al-Sakere et al., “Tumor ablation with irreversible electroporation,” PLoS ONE, 2, e1135, 2007, 8 pages. |
| Beitel-White, N., S. Bhonsle, R. Martin, and R. V. Davalos, “Electrical characterization of human biological tissue for irreversible electroporation treatments,” in 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). IEEE, 2018, pp. 4170-4173. |
| Ben-David, E et al., “Irreversible Electroporation: Treatment Effect Is Susceptible to Local Environment and Tissue roperties,” Radiology, vol. 269, No. 3, 2013, 738-747. |
| Bhonsle, S. et al., “Characterization of Irreversible Electroporation Ablation with a Validated Perfused Organ Model,” J. Vasc. Interv. Radiol, vol. 27, No. 12, pp. 1913-1922.e2, 2016. |
| Bhonsle, S., M. F. Lorenzo, a. Safaai-Jazi, and R. V. Davalos, “Characterization of nonlinearity and dispersion in tissue impedance during high-frequency electroporation,” IEEE Transactions on Biomedical Engineering, vol. 65, No. 10, pp. 2190-2201, 2018. |
| Bonakdar, M., E. L Latouche, R. L. Mahajan, and R. V. Davalos, “The feasibility of a smart surgical probe for verification of IRE treatments using electrical impedance spectroscopy,” IEEE Trans. Biomed. Eng., vol. 62, No. 11, pp. 2674-2684, 2015. |
| Bondarenko, A. and G. Ragoisha, Eis spectrum analyser (the program is available online at http://www.abc.chemistry.bsu.by/vi/analyser/. |
| Boussetta, N., N. Grimi, N. I. Lebovka, and E. Vorobiev, “Cold” electroporation in potato tissue induced by pulsed electric field, Journal of food engineering, vol. 115, No. 2, pp. 232-236, 2013. |
| Bulvik, B. E. et al. “Irreversible Electroporation versus Radiofrequency Ablation□: A Comparison of Local and Systemic Effects in a Small Animal Model,” Radiology, vol. 280, No. 2, 2016, 413-424. |
| Castellvi, Q., B. Mercadal, and a. Ivorra, “Assessment of electroporation by electrical impedance methods,” in Handbook of electroporation. Springer-Verlag, 2016, pp. 671-690. |
| Creason, S. C., J. W. Hayes, and D. E. Smith, “Fourier transform faradaic admittance measurements iii. comparison of measurement efficiency for various test signal waveforms,” Journal of Electroanalytical chemistry and interfacial electrochemistry, vol. 47, No. 1, pp. 9-46, 1973. |
| Davalos et al. “Electrical impedance tomography for imaging tissue electroporation,” IEEE Transactions on Biomedical Engineering, 51, pp. 761-767, 2004. |
| De Senneville, B. D. et al., “MR thermometry for monitoring tumor ablation,” European radiology, vol. 17, No. 9, pp. 2401-2410, 2007. |
| Frandsen, S. K., H. Gissel, P. Hojman, T. Tramm, J. Eriksen, and J. Gehl. Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis. Cancer Res. 72:1336-41, 2012. |
| Garcia-Sanchez, T., A. Azan, L Leray, J. Rosell-Ferrer, R. Bragos, and L M. Mir, “Interpulse multifrequency electrical impedance measurements during electroporation of adherent differentiated myotubes,” Bioelectrochemistry, vol. 105, pp. 123-135, 2015. |
| Gawad, S., T. Sun, N. G. Green, and H. Morgan, “Impedance spectroscopy using maximum length sequences: Applic.ation to single cell analysis,” Review of Scientific Instruments, vol. 78, No. 5, p. 054301, 2007. |
| Granot, Y., A Ivorra, E. Maor, and B. Rubinsky, “In vivo imaging of irreversible electroporation by means of electrical impedance tomography,” Physics in Medicine & Biology, vol. 54, no. 16, p. 4927, 2009. |
| Hoejholt, K. L et al. Calcium electroporation and electrochemotherapy for cancer treatment: Importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy. Scientific Reports (Mar. 18, 2019) 9:4758, pg. 1-12. |
| Ivey, J. W., E L Latouche, M. B. Sano, J. H. Rossmeisl, R. V. Davalos, and S. S. Verbridge, “Targeted cellular ablation based on the morphology of malignant cells,” Sci. Rep., vol. 5, pp. 1-17, 2015. |
| Kranjc, M., S. Kranjc, F. Bajd, G. Sersa, L Sersa, and D. Miklavcic, “Predicting irreversible electroporation-induced tissue damage by means of magnetic resonance electrical impedance tomography,” Scientific reports, vol. 7, No. 1, pp. 1-10, 2017. |
| Latouche, E L., M. B. Sano, M. F. Lorenzo, R. V. Davalos, and R. C. G. Martin, “Irreversible electroporation for the ablation of pancreatic malignancies: A patient-specific methodology,” J. Surg. Oncol., vol. 115, No. 6, pp. 711-717, 2017. |
| Lee, R. .' J.D. C D Canaday, and S. M. Hammer. Transient and stable ionic permeabilization of isolated skeletal muscle cells after electrical shock. J. Burn Care Rehabil. 14:528-540, 1993. |
| Martinsen, O0. G. and Grimnes, S., Bioimpedance and bioelectricity basics. Academic press, 2011. |
| Min, M., A. Giannitsis, R. Land, B. Cahill, U. Pliquett, T. Nacke, D. Frense, G. Gastrock, and D. Beckmann, “Comparison of rectangular wave excitations in broad band impedance spectroscopy for microfluidic applications,” in World Congress on Medical Physics and Biomedical Engineering, Sep. 7-12, 2009, Munich, Germany. Springer, 2009, pp. 85-88. |
| Min, M., U. Pliquett, T. Nacke, a. Barthel, P. Annus, and R. Land, “Broadband excitation for short-time impedance spectroscopy,” Physiological measurement, vol. 29, No. 6, p. S185, 2008. |
| Neal II et al., “Experimental Characterization and Numerical Modeling of Tissue Electrical Conductivity during Pulsed Electric Fields for Irreversible Electroporation Treatment Planning,” Biomedical Engineering, IEEE Transactions on 3iomedical Engineering, vol. 59, pp. 1076-1085, 2012. |
| Neal II, R. E. et al. In Vitro and Numerical Support for Combinatorial Irreversible Electroporation and Electrochemotherapy Glioma Treatment. Annals of Biomedical Engineering, Oct. 29, 2013, 13 pages. |
| O'Brien, T. J. et al., “Effects of internal electrode cooling on irreversible electroporation using a perfused organ model,” Int. J. Hyperth., vol. 35, No. 1, pp. 44-55, 2018. |
| Pakhomova, O. N., Gregory, B., Semenov I., and Pakhomov, A. G., BBA—Biomembr., 2014, 1838, 2547-2554. |
| PCT Application No. PCT/US15/65792, International Search Report (dated Feb. 9, 2016), Written opinion (dated Feb. 9, 2016), and International Preliminary Report on Patentability (dated Jun. 20, 2017), 15 pages. |
| PCT Application No. PCT/US2004/043477, International Search Report (dated Aug. 26, 2005), Written Opinion (dated Aug. 26, 2005), and International Preliminary Report on Patentability (dated Jun. 26, 2006). |
| Qiao et al. Electrical properties of breast cancer cells from impedance measurement of cell suspensions, 2010, Journal of Physics, 224, 1-4 (2010). |
| Ringel-Scaia, V. M. et al., High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunity. EBioMedicine, 2019, 44, 112-125. |
| Rossmeisl, John H. et al. Safety and feasibility of the NanoKnife system for irreversible electroporation ablative treatment of canine spontaneous intracranial gliomas. J. Neurosurgery 123.4 (2015): 1008-1025. |
| Sai Infusion Technologies, “Rabbit Ear Vein Catheters”, https://www.sai-infusion.com/products/rabbit-ear-catheters, Aug. 10, 2017 webpage printout, 5 pages. |
| Sanchez, B., G. Vandersteen, R. Bragos, and J. Schoukens, “Basics of broadband impedance spectroscopy measurements using periodic excitations,” Measurement Science and Technology, vol. 23, No. 10, p. 105501, 2012. |
| Sanchez, B., G. Vandersteen, R. Bragos, and J. Schoukens, “Optimal multisine excitation design for broadband electrical impedance spec-troscopy,” Measurement Science and Technology, vol. 22, no. 11, p. 115601, 201t. |
| 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. |
| Thomson et al., “Investigation of the safety of irreversible electroporation in humans,” J Vasc Intery Radio!, 22, pgs. 511-21,2011. |
| U.S. Appl. No. 12/432,295 (now U.S. Pat. No. 9,598,691), file history through Jan. 2017, 334 pages. |
| U.S. Appl. No. 12/491,151 (now U.S. Pat. No. 8,992,517), file history through Feb. 2015, 113 pages. |
| U.S. Appl. No. 12/609,779 (now U.S. Pat. No. 8,465,484), file history through May 2013, 100 pages. |
| U.S. Appl. No. 12/757,901 (now U.S. Pat. No. 8,926,606), file history through Jan. 2015, 165 pages. |
| U.S. Appl. No. 12/906,923 (now U.S. Pat. No. 9,198,733), file history through Nov. 2015, 55 pages. |
| U.S. Appl. No. 13/332,133 (now U.S. Pat. No. 10,448,989), file history through Sep. 2019, 226 pages. |
| U.S. Appl. No. 13/550,307 (now U.S. Pat. No. 10,702,326), file history through May 2020, 224 pages. |
| U.S. Appl. No. 13/919,640 (now U.S. Pat. No. 8,814,860), file history through Jul. 2014, 41 pages. |
| U.S. Appl. No. 13/958,152, file history through Dec. 2019, 391 pages. |
| U.S. Appl. No. 13/989,175 (now U.S. Pat. No. 9,867,652), file history through Dec. 2017, 200 pages. |
| U.S. Appl. No. 14/012,832 (now U.S. Pat. No. 9,283,051), file history through Nov. 2015, 17 pages. |
| U.S. Appl. No. 14/017,210 (now U.S. Pat. No. 10,245,098), file history through Jan. 2019, 294 pages. |
| U.S. Appl. No. 14/558,631 (now U.S. Pat. No. 10,117,707), file history through Jul. 2018, 58 pages. |
| U.S. Appl. No. 14/627,046 (now U.S. Pat. No. 10,245,105), file history through Feb. 2019, 77 pages. |
| U.S. Appl. No. 14/940,863 (now U.S. Pat. No. 10,238,447), file history through Oct. 2019, 23 pages. |
| U.S. Appl.No. 15/011,752 (now U.S. Pat. No. 10,470,822), file history through Jul. 2019, 54 pages. |
| U.S. Appl. No. 15/186,653 (now U.S. Pat. No. 10,292,755), file history through Mar. 2019, 21 pages. |
| U.S. Appl. No. 15/310,114 (now U.S. Pat. No. 10,471,254), file history through Aug. 2019, 44 pages. |
| U.S. Appl. No. 15/423,986 (now U.S. Pat. No. 10,286,108), file history through Jan. 2019, 124 pages. |
| U.S. Appl. No. 15/424,335 (now U.S. Pat. No. 10,272,178), file history through Feb. 2019, 57 pages. |
| U.S. Appl. No. 15/536,333 (now U.S. Pat. No. 10,694,972), file history through Apr. 2020, 78 pages. |
| U.S. Appl. No. 15/843,888 (now U.S. Pat. No. 10,537,379), file history through Sep. 2019, 33 pages. |
| U.S. Appl. No. 15/881,414 (now U.S. Pat. No. 10,154,874), file history through Nov. 2018, 43 pages. |
| U.S. Appl. No. 16/177,745 (Patented), file history through Jun. 2020, 57 pages. |
| U.S. Appl. No. 16/232,962 (Patented), file history through Jun. 2020, 44 pages. |
| Van Den Bos, W. et al., “MRI and contrast-enhanced ultrasound imaging for evaluation of focal irreversible electroporation treatment: results from a phase I-II study in patients undergoing ire followed by radical prostatectomy,” European radiology, vol. 26, No. 7, pp. 2252-2260, 2016. |
| Voyer, D., A. Silve, L. M. Mir, R. Scorretti, and C. Poignard, Dynamical modeling of tissue electroporation, Bioelectrochemistry, vol. 119, pp. 98-110, 2018. |
| Zhao, Y., S. Bhonsle, S. Dong, Y. Lv, H. Liu, a. Safaai-Jazi, R. V. Davalos, and C. Yao, “Characterization of conductivity changes during high-frequency irreversible electroporation for treatment planning,” IEEE Transactions on 3iomedical Engineering, vol. 65, No. 8, pp. 1810-1819, 2017. |
| Pending U.S. Appl. No. 14/686,380, Final Office Action dated Oct. 6, 2020, 14 pages. |
| Pending U.S. Appl. No. 14/686,380, Response to Feb. 13, 2020 Non-Final Office Action, filed Jul. 1, 2020, 8 pages. |
| Pending U.S. Appl. No. 14/686,380, Response to Sep. 3, 2019 Final Office Action, filed Jan. 3, 2020, 10 pages. |
| Pending U.S. Appl. No. 14/808,679, Non-Final Office Action dated Jun. 12, 2020, 10 pages. |
| Pending U.S. Appl. No. 14/808,679, Response to Non-Final Office Action dated Jun. 12, 2020, filed Sep. 14, 2020, 9 pages. |
| Pending U.S. Appl. No. 16/152,743, Non-Final Office Action dated Sep. 25, 2020, 10 pages. |
| Pending U.S. Appl. No. 16/152,743, Second Preliminary Amendment filed May 2, 2019, 6 pages. |
| Pending U.S. Appl. No. 16/210,771, Non-Final Office Action dated Sep. 3, 2020, 9 pages. |
| Pending U.S. Appl. No. 16/210,771, Preliminary Amendment filed Dec. 5, 2018, 8 pages. |
| Pending U.S. Appl. No. 16/210,771, Response to Restriction Requirement, filed Jul. 8, 2020, 7 pages. |
| Pending U.S. Appl. No. 16/210,771, Restriction Requirement, dated Jun. 9, 2020, 7 pages. |
| Pending U.S. Appl. No. 16/210,771, Second Preliminary Amendment filed Oct. 14, 2019, 7 pages. |
| Pending U.S. Appl. No. 16/280,511, Preliminary Amendment filed Nov. 2, 2020, 6 pages. |
| Pending U.S. Appl. No. 16/375,878, Second Preliminary Amendment, filed Feb. 5, 2020, 3 pages. |
| Pending U.S. Appl. No. 16/404,392, Final Office Action dated Mar. 20, 2020, 8pgs. |
| Pending U.S. Appl. No. 16/404,392, Response to Final Office action dated Mar. 20, 2020, filed Sep. 18, 2020, 7 pages. |
| Pending U.S. Appl. No. 16/655,845, Preliminary Amendment filed Oct. 16, 2020, 6 pages. |
| Pending U.S. Appl. No. 16/747,219, Preliminary Amendment filed Jan. 20, 2020, 5 pages. |
| Pending U.S. Appl. No. 16/865,031, Preliminary Amendment filed May 1, 2020, 7 pages. |
| Pending U.S. Appl. No. 16/865,772, Preliminary Amendment filed May 4, 2020, 6 pages. |
| Pending U.S. Appl. No. 16/915,760, Preliminary Amendment filed Jul. 6, 2020, 5 pages. |
| Pending Application No. AU 2009243079, First Examination Report, Jan. 24, 2014, 4 pages. |
| Pending Application No. AU 2009243079, Voluntary Amendment filed Dec. 6, 2010, 35 pages. |
| Pending Application No. AU 2015259303, First Examination Report dated Oct. 26, 2020, 6 pages. |
| Pending Application No. CA 2,722,296 Examination Report dated Apr. 2, 2015, 6 pages. |
| Pending Application No. CN 201580025135.6 English translation of Apr. 29, 2020 Office action, 7 pages. |
| Pending Application No. CN 201580025135.6 English translation of Sep. 25, 2019 Office action. |
| Pending Application No. CN 201580025135.6 Preliminary Amendment filed with application Nov. 14, 2016. |
| Pending Application No. CN 201580025135.6 Response to Sep. 25, 2019 Office action, filed Feb. 10, 2020, English language version and original document. |
| Pending Application No. EP 09739678.2 Extended European Search Report dated May 11, 2012, 7 pages. |
| Pending Application No. EP 09739678.2, Communication pursuant to Rule 94.3, dated Apr. 16, 2014, 3 pages. |
| Pending Application No. EP 09739678.2, Office Action dated Apr. 16, 2014, 3 pages. |
| Pending Application No. EP 09739678.2, Response to Extended European Search Report and Communication pursuant to Rules 70(2) and 70a(2) EPC, dated Dec. 10, 2012. |
| Pending Application No. EP 10824248.8, Extended Search Report (dated Jan. 20, 2014), 6 pages. |
| Pending Application No. EP 10824248.8, Invitation Pursuant to Rule 62a(1) EPC (dated Sep. 25, 2013), 2 pages. |
| Pending Application No. EP 10824248.8, Communication Pursuant to Rule 70(2) dated Feb. 6, 2014, 1 page. |
| Pending Application No. EP 10824248.8, Response to Invitation Pursuant to rule 62a(1) EPC (Sep. 25, 2013), Response filed Nov. 18, 2013. |
| Pending Application No. EP 11842994.3, Communication Pursuant to Rules 70(2) and 70a(2) EPC dated Apr. 28, 2014, 1 page. |
| Pending Application No. EP 11842994.3, Extended European Search Report dated Apr. 9, 2014, 34 pages. |
| Pending Application No. EP 15793361.5, Claim amendment filed Jul. 18, 2018, 13 pages. |
| Pending Application No. EP 15793361.5, European Search Report dated Dec. 4, 2017, 9 pages. |
| Pending Application No. JP 2013-541050, Voluntary Amendment filed Oct. 29, 2013, 4 pages (with English Version of the Claims, 2 pages). |
| Pending Application No. JP 2016-567747 Amendment filed Jul. 18, 2019, 7 pgs. |
| Pending Application No. JP 2016-567747 English translation of amended claims filed Jul. 18, 2019, 6 pgs. |
| Pending Application No. JP 2016-567747, First Office Action (Translation) dated Feb. 21, 2019, 5 pages. |
| Pending Application No. JP 2016-567747, First Office Action dated Feb. 21, 2019, 4 pages. |
| Pending Application No. JP 2016-567747, Decision to Grant with English Version of allowed claims, 9 pages. |
| Pending Application No. JP 2019-133057, amended claims (English language version) filed Aug. 14, 2019, 5 pages. |
| Pending Application No. JP 2019-133057, Office Action dated Sep. 14, 2020, 5 pages (and English translation, 6 pages). |
| Number | Date | Country | |
|---|---|---|---|
| 20190175260 A1 | Jun 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61171564 | Apr 2009 | US | |
| 61167997 | Apr 2009 | US | |
| 61075216 | Jun 2008 | US | |
| 61125840 | Apr 2008 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14627046 | Feb 2015 | US |
| Child | 16275429 | US | |
| Parent | 12491151 | Jun 2009 | US |
| Child | 14627046 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12432295 | Apr 2009 | US |
| Child | 12491151 | US |
