The benefit of U.S. provisional patent application No. 60/825,660 (attorney docket No. 026533-.
The present invention relates generally to electric fields delivered to a tissue region. More particularly, the present invention relates to electric field delivery and non-thermal ablation of target tissue regions, including selective ablation of cancer cells and solid tumors.
Current tissue ablation techniques rely on the application of high frequency hyperthermo-inductive current to the tissue of a patient (e.g., human, animal, etc.) as a means of removing unwanted tissue or lesions, arresting bleeding, or cutting the tissue. There is increasing interest and activity in areas of high thermal ablation as a tool for treating cancer by heat-induced killing and/or removal of neoplastic tissue.
In hyperthermia ablation techniques, high frequency RF (radio frequency) (e.g., "RF thermal ablation") or microwave sources are used to heat tissue, causing histological damage to the target tissue. In RF thermal ablation techniques, for example, high frequencies, including about 500kHz and above, are used to ionically excite and frictionally (e.g., resistively) heat tissue surrounding a positioned electrode. Lethal damage to tissue (e.g., denaturation of tissue proteins) occurs at temperatures in excess of about 47 ℃, although heat generated near the electrodes in RF thermal ablation can reach temperatures up to or in excess of about 100 ℃.
A variety of different cancer ablation methods and devices have been proposed that rely on hyperthermic ablation or heat-induced tumor tissue destruction. One such example includes US patent No. 5,827,276, which teaches a device for volumetric tissue ablation. The apparatus includes a stylet having a plurality of wires journaled through a catheter, the stylet having a proximal end connected to an active terminal of a generator and a distal end protruding from a distal end of the catheter. The teachings include a method and probe deployable in a percutaneous procedure that produces a large volume of thermally ablated tissue with a single deployment.
Us patent No. 5,935,123 teaches an RF treatment device comprising a catheter having a catheter lumen. A detachable needle electrode is disposed within the catheter lumen and secured to the catheter. The treatment device is taught for ablating selected tissue masses, including but not limited to tumors, or treating tissue masses by hyperthermia. The tumor site is selectively treated by controlled delivery of RF energy by hyperthermia or ablation.
Various other methods and devices are taught that use hyperthermia or heat-induced cancerous tissue destruction. However, the significant limitations of RF-induced, hyperthermic ablation make it difficult to localize thermally-induced lesions of target cancerous tissue while limiting histological damage and destruction to surrounding healthy, non-target tissue.
Thus, there is a need for minimally invasive ablation techniques that selectively destroy cancerous cells while minimizing damage to healthy tissue.
Disclosure of Invention
The present invention provides devices and related methods for applying low-intensity electric fields for selective cancer cell destruction and non-thermal tissue ablation. The devices of the present invention are generally designed to introduce an electrode or electrodes into a target tissue region and apply an electric field to the target tissue region. The electrode or electrodes thereof are typically positioned such that the applied electric field radiates through the target tissue region, including, for example, where the electric field radiates outwardly in a plurality of radial directions from a location within the target tissue or an electrode positioned within the target tissue region. Furthermore, the energy applied to the target tissue region may be selected to minimize electrically generated heat and avoid an increase in tissue temperature. In particular embodiments, the applied electric field is typically a low intensity (e.g., less than about 50V/cm) and medium frequency (e.g., between about 50kHz and 300 kHz) alternating current sufficient to provide low power or non-thermal ablation of the target cells. The electrode positioning and electric field application (e.g., low power/non-thermal ablation electric field) of the present invention has proven to be unexpectedly effective in ablating cancerous cells, and the thermal effect is not a factor in the ablation process. Furthermore, the ablation process according to the present invention occurs mainly in abnormally proliferating cells or cells exhibiting irregular growth (e.g., cancer cells). Thus, the invention provides other advantages: provides minimally invasive, selective ablation or destruction of cancerous cells while leaving normal cells or tissue substantially intact.
Accordingly, in one aspect, the invention includes a method of delivering an electric field to tissue. The method includes positioning an electrode within a target tissue region including cancerous cells and applying an alternating electric field to the target tissue to non-thermally ablate the cancerous cells in the target tissue region surrounding the electrode.
In one embodiment, the target tissue region comprises a block or solid portion of tissue. Typically, the target tissue region comprises cancer cells, including for example a target tissue region comprising a solid tumor. The volume of tissue to be subjected to the methods of the invention may vary and depends, at least in part, on the size of the mass of cancer cells. The perimeter size of the target tissue region may be regular (e.g., spherical, ovoid, etc.) or may be irregular. The target tissue region may be determined and/or described using conventional imaging methods such as ultrasound, Computed Tomography (CT) scanning, X-ray imaging, nuclear species imaging, Magnetic Resonance Imaging (MRI), electromagnetic imaging, and the like. In addition, various imaging systems may be used to place and/or position the devices or electrodes of the present invention within the tissue of a patient or at or within a target tissue region.
As described above, the electrodes are positioned within the target tissue region and an alternating electric field is applied. Ablation techniques according to the present invention can be implemented in certain embodiments without increasing the local tissue temperature, and the thermal effect of the energy application is not a means by which ablation of the tissue occurs. Typically, the applied electric field comprises an alternating current of low strength and intermediate frequency. In one embodiment, for example, the current provides a voltage field of less than about 50V/cm. In another embodiment, the current comprises a frequency between about 50kHz and about 300 kHz. The voltage field and/or frequency of the applied current remains constant or varies during the application of energy. The electrodes are positioned within the target tissue region such that an electric field is applied from within the target tissue. In one embodiment, the electrodes are positioned within a target tissue region (e.g., a tumor), and the applied current provides an electric field extending radially outward from the electrodes. In certain embodiments, such localization may utilize tumor physiology, including, for example, the orientation of dividing/proliferating cells within the target tissue region, and ensure that the electric field provided by the electrodes is substantially aligned with the division axis of the dividing cancerous cells.
Accordingly, in another aspect, the invention includes a method of delivering an electric field to tissue, the method comprising disposing a plurality of electrodes within a target tissue having cancerous cells. The plurality of electrodes may include a first electrode and a plurality of second electrodes and at least partially define an ablation volume. The method also includes applying an alternating current to the volume to provide an electric field extending radially outward from within the volume to selectively destroy cancerous cells of the target tissue.
The present invention may include a variety of electrode compositions, configurations, geometries, and the like. In certain embodiments, each electrode may comprise a tissue-penetrating electrode comprising, for example, a small diameter wireThe wire has tissue piercing or sharpened distal ends that can penetrate tissue as the electrode is advanced within the target tissue region. The electrodes may be non-insulated or may include insulated portions. In one embodiment, the uninsulated portion of the electrode provides an electric field delivery surface for delivering electrical current to surrounding tissue. The electrodes may be substantially rigid, for example, to be more easily advanced through tissue, including hardened or denser tissue, or may be more flexible depending on the desired use. In an embodiment, the electrodes comprise needle or needle electrodes or electrodes having a substantially straight portion. In another embodiment, the electrodes may be curved, have a curved portion or a portion with a radius of curvature. The electrode composition may vary, and in some embodiments may include a memory metal (e.g., Nitinol, a commercially available memory metal)TMEtc.) or spring steel. Suitable electrode materials may include, for example, stainless steel, platinum, gold, silver, copper, or other conductive materials, metals, polymers, and the like. In certain embodiments, each electrode may be positioned within a lumen of a catheter and/or microcatheter or other means for introducing the electrode into tissue and may be deployed therefrom.
In one embodiment, the present invention includes a plurality of electrodes positioned or positionable within a target tissue region. A plurality of electrodes may form an array and may be deployed from, for example, a catheter lumen. In an embodiment, the plurality of electrodes includes one or more outer or secondary electrodes substantially defining the ablation volume and a primary or centrally disposed electrode, wherein the primary electrode is spaced apart from the secondary electrode and disposed within the ablation volume defined by the secondary electrode. The electrodes may be operated in a monopolar mode or in a bipolar mode. The device may be configured to switch polarity between the electrodes. In an embodiment where the electrodes are used in a bipolar mode and current is applied, for example, an electric field may be created that extends radially outward from the primary or centrally located electrode toward a circumferentially located or secondary electrode that substantially defines the ablation volume.
In another embodiment, the present invention may use one or more sensor mechanisms to provide feedback and/or control the ablation process. The sensor mechanism may include sensors or detectors that detect and measure parameters such as temperature, current, voltage, impedance, pH, and the like. Certain embodiments of the invention may include altering the applied current based at least in part on the detected characteristic or a change in the detected characteristic. In an embodiment, the applied current may be altered, for example, in response to a measured temperature, impedance, or the like. Altering may include, for example, altering the voltage, frequency, etc. of the applied current and/or discontinuing the application of the current upon, for example, a determination that the ablation process or a stage thereof is complete.
In yet another aspect of the present invention, a system for non-thermal tissue ablation is provided. The system includes a tissue ablation probe having one or more electrodes, each electrode positionable within a target tissue region including cancerous cells. The system also includes an energy source for providing an electrical current (e.g., an alternating current) to non-thermally ablate cancerous cells of the target tissue region.
In another aspect, the present invention provides a system for selectively destroying cancer cells. The system includes a probe having a plurality of electrodes that are positionable within a target tissue. The plurality of electrodes includes a first electrode and one or more second electrodes, and the ablation volume is at least partially definable by the second electrodes. A first electrode is positionable within the ablation volume. The system also includes an energy source for providing an alternating current and one or more electric fields extending radially from the first electrode and through the volume to selectively destroy cancerous cells within the target tissue.
For a fuller understanding of the nature and advantages of the present invention, reference should be made to the following detailed description and accompanying drawings. Other aspects, objects, and advantages of the invention will be apparent from the drawings and from the detailed description that follows.
Detailed Description
The present invention provides systems and devices for low power or non-thermal tissue ablation and related methods. In accordance with the present invention, one or more electrodes may be introduced into a target tissue region and an electric field applied to the target tissue region. The energy applied to the target tissue region may be selected to minimize the use of electrically generated heat and may avoid tissue temperature elevation, thereby providing low power or non-thermal ablation of the target cells. The devices and methods of the present invention have been shown to be effective in ablating cancerous cells without the need for thermal effects as a factor in the ablation process, ablation occurring primarily in abnormally proliferating cells or cells exhibiting irregular growth (e.g., cancerous cells). It is therefore an advantage of the present invention to provide minimally invasive, selective ablation or destruction of cancer cells while leaving normal cells or tissue substantially intact.
Referring to fig. 1, an apparatus according to an embodiment of the invention is depicted. The device 10 includes a delivery member 12 having a distal portion 14 and a proximal portion 16. The device 10 also includes a proximal end portion 18 of the device that is coupleable (e.g., detachably coupleable) to the delivery member 12. Further, the device 10 may include an electrically conductive cable 20 electrically coupled to an energy source (not shown). The device includes a plurality of electrodes 22 at the distal end portion 14 of the delivery member 12. The electrode 22 may be positioned or fixed, for example, at the distal end of the delivery member 12 or may be positioned and deployable from the lumen of the delivery member 12 and may extend and retract into the distal end of the delivery member 12. The electrodes 22 can include a non-deployed state in which the electrodes 22 can be disposed within the lumen of the delivery member 12 and a deployed state when advanced from the distal end of the delivery member 12. The electrode 22 is advanced distally and expanded to a deployed state that substantially defines an ablation volume.
The target tissue region may be positioned at any location within the body where it is desired or beneficial to employ the tissue ablation methods of the present invention. The target tissue is not limited to any particular type and non-limiting examples may include, for example, breast tissue, prostate tissue, liver, lung, brain tissue, muscle, lymph, pancreatic tissue, colon, rectum, bronchi, and the like. The target tissue region typically includes a tissue mass or a substantial portion of tissue. Typically, the target tissue region comprises cancer cells, including for example a target tissue region comprising a solid tumor. The term "cancer cell" as used herein generally refers to any cell that exhibits or is predisposed to exhibiting irregular growth, including, for example, a neoplastic cell such as a premalignant cell or a cancer cell (e.g., a cancer spreading cell or a sarcoma cell), and can be subjected to the ablation methods described herein. The volume of tissue to be subjected to the methods of the invention may vary depending on, for example, the size and/or shape of the mass of cancer cells, among other factors. The perimeter size of the target tissue region may be regular (e.g., spherical, ovoid, etc.) or may be irregular.
Imaging systems and devices may be included in the methods and systems of the present invention. For example, conventional imaging methods such as ultrasound, Computed Tomography (CT) scanning, X-ray imaging, nuclear species imaging, Magnetic Resonance Imaging (MRI), electromagnetic imaging, and the like may be used to determine and/or delineate the target tissue region. In certain embodiments, characteristics of the tumor, including features determined using imaging methods, may also be used to select ablation parameters such as energy application and shape and/or geometry of the electrodes. In addition, these or other known imaging systems may be used to position and place devices and/or electrodes within the tissue of a patient.
As described above, the electrodes are disposed within the target tissue region and the applied electric field is sufficient to provide low power or non-thermal ablation of the target cells. The term "non-thermal ablation" as used herein generally refers to the techniques of the present invention, including the removal or destruction of tissue function or cells of tissue by the application of an electric field, and wherein the energy application/delivery process occurs without substantial elevation of local tissue temperature, and the thermal effect of energy application is not a significant or primary means of tissue ablation. In many embodiments, localized tissue temperature increases may be avoided without causing detectable temperature increases in the target tissue region. However, in certain embodiments, minor changes/increases in temperature within the target tissue region can occur, but typically no more than a few degrees above body temperature (e.g., less than about 10 ℃, but typically no more than about 2 degrees above body temperature), and thermal effects are not the primary means of performing tissue ablation (e.g., no significant heat-mediated, lethal protein denaturation). Typically, the applied electric field comprises an alternating current of low and medium intensity. The intermediate frequency employed in accordance with the present invention is, for example, less than that typically required for frictional/resistive heating of tissue surrounding the electrode (e.g., less than about 400kHz, preferably about 300kHz or less). In one embodiment, for example, the current provides a voltage field of less than about 50V/cm. In another embodiment, the current comprises a frequency between about 50kHz to about 300 kHz.
The voltage field and/or the frequency and/or the magnitude of the applied current remain constant or vary during the energy application. In certain embodiments, it may be desirable to provide a non-constant or varying voltage and/or frequency and/or current by "sweeping" over a given range, for example, to ensure that an optimal ablation voltage/frequency/current is applied to the target tissue region. In another embodiment, a particular voltage and/or frequency and/or current may be selected prior to applying energy. Further, the electrodes are disposed within the target tissue region such that current is applied from within the target tissue and the target tissue is ablated from within to outside. In one embodiment, the electrodes are disposed within a target tissue region (e.g., a tumor), and the applied current provides an electric field extending radially outward from the electrodes. In certain embodiments, such an arrangement may take advantage of tumor physiology, including, for example, the orientation of dividing/proliferating cells within the target tissue region, and ensure that the electric field provided by the electrodes is substantially aligned with the axis of division of dividing cancerous cells that are dividing.
Fig. 2A to 2C show a device having a plurality of electrodes according to another embodiment of the present invention. As shown, the device 30 includes a plurality of electrodes extending from a distal portion of the device. Fig. 2A shows a three-dimensional side view of a device having a plurality of electrodes. Fig. 2B shows a top view of the device illustrating the electrode structure. The plurality of electrodes includes a centrally disposed electrode 32 and outer electrodes 34, 36, 38 laterally spaced from the central electrode 32. The electrodes shown include substantially linear needle-like portions or needle-like electrodes. These electrodes extend from the distal portion of the device and are oriented substantially parallel to the longitudinal axis of the device 30. Further, each electrode is substantially parallel to the other electrodes of the plurality of electrodes. The plurality of electrodes substantially define an ablation volume, the outer electrodes 34, 36, 38 substantially define a perimeter of the ablation volume and the electrode 32 is disposed within or about a center point of the defined perimeter. Each electrode may serve a different role during the ablation process. For example, the polarity may be changed and/or switched between different electrodes of the device. As with other devices of the invention, the electrodes may be electrically independently and separately addressable, or two or more electrodes may be electrically connected, for example, to effectively function as a unit. In one embodiment, for example, the outer electrodes 34, 36, 38 may be electrically connected and may include a polarity different from the polarity of the inner electrode 32 in operation. As shown in fig. 2C, the electrodes 32 and 34, 36 of the device may comprise opposite charges (e.g., bipolar). In such an example, the applied current may provide an electric field, shown by arrows, extending radially outward from the center electrode 32 and toward the peripherally disposed or outer electrodes 34, 36.
In certain embodiments, the devices and/or systems of the present invention comprise electrically floating systems or systems designed to operate without ground. In some cases, it has been found that electrode configurations that are electrically floating in this manner enable more accurate or more controllable application and/or delivery of electric fields. The low power requirements of the system according to certain embodiments allow for more design choices (e.g., battery operation) in the above-described electrically floating construction devices and systems, for example, as compared to known techniques such as thermal RF or microwave ablation, or high voltage irreversible electroporation that requires much higher power delivery and corresponding power sources.
Another embodiment of the device of the present invention is described with reference to fig. 3A and 3B. The device 40 includes a plurality of electrodes at or extending from the distal end 42 of the device 40. The plurality of electrodes includes an externally disposed electrode 44 that is curvilinear in shape and substantially defines an ablation volume. Electrode 46 is disposed within the volume defined by outer electrode 44 and spaced apart from electrode 44. The center electrode 46 is shown as being substantially linear and parallel to the longitudinal axis of the device 40, although other configurations may be used. Fig. 3B shows target tissue 48 within the perimeter defined by outer electrode 44, with current applied to target tissue 48, and shows the elongated or oval ablation volume defined by curved electrode 44. Accordingly, a target tissue region 48, such as a solid tumor, may be substantially enclosed within the volume defined by the outer electrode 44. The arrows show the electric field extending radially outward from the electrode 46 in a number of different directions.
An electrode of an apparatus according to another embodiment of the present invention is described with reference to fig. 4. The device 50 includes a substantially linear electrode 52 extendable from and retractable into a microcatheter 54 and an electrode 56 having a curved portion, the electrode 56 being extendable from and retractable into a microcatheter 58. Microcatheters 58 and 54 may be included within a single delivery member, such as within the lumen of a delivery catheter, or may be independently positioned, for example, to individually access and address target tissue. One outer electrode (e.g., electrode 56) is shown, although multiple outer or secondary electrodes may be provided as shown in other embodiments (e.g., see below).
As shown in fig. 5A and 5B, the device may include a plurality of electrodes, each deployable or extendable and retractable into a microcatheter, each microcatheter/electrode assembly optionally disposed within the central lumen of a larger delivery member. The device 60 includes a delivery member 62 having a lumen 64, and microcatheters 66, 68, 70, 72 disposed within the lumen. Fig. 5B shows a top view of the device with microcatheters 60, 68, 70, 72 disposed within the lumen 62 of the delivery member 60. Electrodes 74, 76, 78, each having a curved portion, are deployable from the microcatheters 68, 70, 72 and substantially define an ablation volume in the deployed state. The electrode 80 is deployable from the microcatheter 66 and disposed within the ablation volume substantially defined by the electrodes 74, 76, 78.
In use, as shown in fig. 6, a device 82 of the present invention can be advanced through tissue 84 of a patient with electrodes 86 of the device 82 disposed within a target tissue region 88 (e.g., a tumor). Once the electrodes are disposed within the target tissue region 88, an electrical current is delivered to the target tissue region 88. Since the electrodes 86 are disposed within the target tissue region 88, the applied current may provide an electric field that radiates outwardly in multiple directions. The system or device of the present invention can be operated in either monopolar or bipolar mode. In a monopolar operational embodiment, the second electrode can be placed outside the patient's body, such as by placing the patient on a conductive pad or plate (e.g., a metal plate) and utilizing a conductive material, such as a conductive gel or adhesive, placed between the patient's skin and the second electrode. In a bipolar mode embodiment, an outer electrode substantially defining the ablation volume may be used as a return electrode, or in conjunction with an electrode disposed within the ablation volume to complete a circuit to flow an applied current through tissue in a target region between the outer electrode and the electrode disposed within the ablation volume. Fig. 7 illustrates a method of using the apparatus of the present invention according to another embodiment of the present invention. As described above, the device 90 is advanced through the tissue of the patient, and the delivery member 92 is disposed proximate the target tissue region 94. Once the delivery member 92 is positioned, the plurality of electrodes 96, 98, 100 may be deployed from the delivery member 92. The outer electrodes 96, 98 are deployed within or about the perimeter of the target tissue region 94, such as at about the edge of the target tissue region (e.g., tumor edge) and substantially define an ablation volume or target region. An inner electrode 100 is disposed within the ablation volume.
The present invention may include various means of accessing or addressing (addressing) the target tissue and positioning the electrodes/probes that deliver the ablation therapy. In general, positioning of the devices of the present invention includes minimally invasive access and positioning techniques, including, for example, access techniques commonly used for other types of tissue ablation (e.g., thermal RF ablation, microwave ablation, high voltage electroporation, etc.). For example, the device of the present invention may be percutaneously introduced through the skin and advanced through tissue and positioned at the target tissue. Although, the means for addressing and locating the target tissue may be performed in conjunction with more conventional surgical or laparoscopic techniques.
As described above, certain embodiments of the present invention include positioning an electrode within a target tissue region and applying an alternating current that provides an electric field that radiates outwardly from the positioned electrode. It was found that such applied electric fields are highly effective in disrupting and destroying cancer cells by low power ablation and have no thermal ablation effect. In certain embodiments, cancer cell disruption and resulting ablation according to the present invention is more effective where the electric field provided by the electrodes of the inventive device is substantially aligned with the axis of division of the dividing cancer cell or cells. Fig. 8A shows a simplified pattern of growth and physiology of a malignant tumor or solid mass of cancer cells, showing tumor growth with cancer cells dividing outward from the center of the region. Arrows indicate the division axis of cancer cells that divide from the center outward. Fig. 8B shows a focused and simplified view of dividing cells of the tumor of fig. 8A, also showing the concept of cell division axis. The illustrated dividing or proliferating cancer cell (shown in the metaphase stage of mitosis) includes a cell division axis 110 substantially perpendicular to a metaphase plate axis 112, wherein cell division occurs substantially along the plate axis 112 and cell proliferation and growth occurs along the cell division axis 110. Thus, in certain embodiments of the invention, the positioning of the electrodes within the tissue region (e.g., near the central region of a tumor or mass of cancer cells), and/or the configuration and arrangement of the electrodes of the device, may be selected such that the electric field radiates outward from about the central region and the electric field is substantially aligned with the axis of cell division of the growing tumor.
Furthermore, it was found that the application of an electric field as described above is particularly effective in selectively disturbing and destroying dividing cancerous cells, while having little or no effect on normal cells that do not exhibit irregular growth and proliferation. Without being bound by any particular theory, the application of an electric field as described above may specifically disrupt the cell division process (e.g., mitosis) or the progression of the cell cycle, or stages or processes thereof (e.g., mitotic spindle formation, microtubule polymerization, cytoplasmic organelle function or arrangement, cytokinesis, cell osmotic balance, etc.) and, thus, more specifically affect cells exhibiting irregular growth (e.g., cancer cells) and progress more rapidly through the cell cycle.
In accordance with the present invention, the target tissue region may be ablated in whole or in part. It will be appreciated that while it is generally desirable to ablate as much of the target area or tumor as possible, in certain embodiments, these methods may include ablating some or less than all of the target area. In some cases, partial tumor ablation may be sufficient to ultimately destroy or kill the entire tumor or cancerous tissue region.
Methods of using devices according to embodiments of the present invention (e.g., the devices of fig. 2A-2C) are discussed with reference to fig. 9A-9D. The device 120 includes a plurality of electrodes, including outer electrodes 122, 124, 126 and at least one inner electrode 128 that substantially define an ablation volume. The device may be disposed at a target tissue region comprising a tumor or a portion thereof. The tumor 130 is shown positioned substantially within the ablation volume, the inner electrode 128 is positioned approximately through the center of the tumor, and the outer electrodes 122, 124, 126 are laterally spaced from the inner electrode 128 and positioned approximately at or slightly inside or outside of the tumor margin. Fig. 9A shows a top cross-sectional view and fig. 9B shows a side view of the tumor 130 and the positioned electrodes 122, 124, 126, 128. The electric field shown by the arrows in fig. 9C is provided by the electrodes positioned and the current applied. As shown, in the parallel straight needle electrode configuration shown in fig. 9A-9C, the electric field along the length of the ablation volume is oriented in a direction perpendicular to the longitudinal axis of the device. The electrical current emanating from the central electrode 128 toward the outer electrodes 122, 124, 126 provides an electric field that is substantially aligned with the direction of cell division of many tumor cells, particularly those within region 132, which divide in a direction outward from the center of the tumor (see, e.g., fig. 8A and 8B). It should be appreciated that the arrows are provided for illustrative purposes, and that embodiments of the present invention are not limited to any particular current and/or electric field direction, but may include directions other than and/or in addition to those specifically illustrated. The tumor includes a region 132 where the direction of tumor cell division is believed to align more closely with the electric field. In the illustrated configuration, the tumor may include regions 134, 136 at opposite ends of the tumor, which may include a greater proportion of cells whose cell division axes are not aligned with the provided electric field, or, in other words, at an angle relative to the magnetic field and may remain active after application of energy, while a greater proportion of the cells of region 132 are ablated. However, in one example, using tumor ablation in this manner, the tissue/cells of region 132 are ablated and material is subsequently removed from the treatment site (e.g., extruded by the application of pressure) and/or absorbed by surrounding tissue, and regions 134 and 136 are found to collapse inwardly to form a flat, "pancake-like" tissue residue (fig. 9D), which eventually dies after the application of energy. It is clear that various experimental (e.g., animal) models subjected to the ablation techniques described herein demonstrate complete removal of detectable tumors. These results indicate that the method of the present invention effectively ablates tumor tissue, can destroy solid tumors, even if less than all of the tumor tissue is ablated, and demonstrates improved tissue ablation with the electric field aligned with the direction of cell division of the cancer cells.
Fig. 10 shows another embodiment of the device of the present invention. As described above, the device configuration and electrode arrangement may be selected such that the electric field radiates outwardly from approximately the center of the target tissue region, and the electric field is substantially aligned with the division axis of certain cells of the growing tumor. More optimal electrical energy application and alignment of the electric field with the axis of division of the growing tumor can be achieved by positioning the electrodes within the target region and the selected electrode configuration and/or geometry of the device. In one embodiment, for example, the device may include an inner electrode 140 and a plurality of curved outer electrodes 142, 144. The inner electrode 140 may additionally include a curved or non-linear distal portion. Having a curved shape on the electrodes may help to select the applied electric field that radiates in multiple directions, including directions other than perpendicular to the longitudinal axis of the device or internal electrode. The outer curved electrode substantially defines an ablation volume, and the inner electrode is disposed within the ablation volume. The arrows show the electric field emanating in multiple directions from the center and substantially aligned with dividing cancerous cells of the target tissue region. In some cases, the electric field formed by this configuration may align with a larger portion of the cancerous cells of the target tissue region, for example, as compared to the straight needle electrode configuration shown in fig. 9A through 9D.
At the beginning of the ablation process, the electric field strength is highest at the inner or central electrode and within the tissue surrounding and adjacent to the inner or central electrode. As the ablation process continues, it is found that the cancer cells near the inner electrode are first damaged or ablated. The ablated cells effectively "liquefy" or take on the properties of a low impedance, liquid-like material. The term "liquefaction" is used herein for convenience and illustrative purposes, and does not necessarily imply any particular ablation or cell death mechanism, which may include cell effusion, apoptosis, cytolysis, or some other cellular process, and/or some combination thereof. Another possible cause of cell disruption may include disruption of cell membrane integrity, such as media disruption including one or more cell membranes (see, e.g., below). The liquid material surrounds the central electrode and effectively enlarges the higher electric field strength ablation zone, the highest electric field strength ablation zone being at the outer perimeter of the liquid material. Thus, the liquid material is said to become the "real electrode". As the ablation process continues, the outer perimeter of the fluid material or "real electrode" expands, ablating the target tissue region substantially from the inside to the outside. In certain embodiments, the target tissue region is found to be more pliable and soft or pasty after the ablation process. The ablated liquid tumor tissue is eventually removed from the treatment site and/or absorbed by surrounding tissue and is no longer detected.
The actual electrode effect is described with reference to fig. 11A to 11C, showing cross-sectional views of electrodes disposed within a target tissue region. The outer electrodes 150, 152, 154 are disposed at about the periphery or outer perimeter of the tumor 156, and the inner electrode 158 is disposed at about the center point of the volume defined by the outer electrodes 150, 152, 154. The ablation, or the start of the ablation process, is shown at T1 (fig. 11A); t2 is after ablation has begun, liquid tissue region 160 has expanded (fig. 11B); and at a subsequent time T3, liquid tissue region 162 expands further outward from central electrode 158 toward outer electrodes 150, 152, 154 (fig. 11C).
The ablation process, including its progress, can be monitored by detecting the associated changes in impedance within the ablated tissue. Once the outer perimeter of the ablated liquid tissue reaches the outer electrode defining the ablation volume, the impedance stabilizes or flattens. Thus, the progress of the ablation process can be monitored by measuring changes in impedance, and the application of the electric field interrupted as soon as it is found that the impedance no longer changes.
Feedback measurements can be used to ensure ablation of the target cancer cells by non-thermal ablation. In some cases, it may be desirable to generate as much electric field strength as possible at the inner electrode without creating high thermal effects or thermal ablation. Certain hyperthermic effects are discoverable and distinguishable from the claimed non-thermal ablation of the present invention, since thermal ablation causes destruction of surrounding cells without the "liquefaction" effect described above. For example, if the cells are destroyed by a thermal ablation process, the impedance of the treated tissue may not decrease, as the impedance of cells that are charred or necrotic due to thermal effects generally increases. In one embodiment, non-thermal ablation according to the present invention may include placing a sensor, such as a thermocouple, within the target tissue region (e.g., proximate the inner electrode) and selecting the applied electric field strength to be below a strength that would produce a thermal effect on the target cells.
As described above, in some cases, it may be desirable to increase the intensity of the electric field emanating from the location of the internal electrode within the target tissue region. In one embodiment of the present invention, the electric field strength may be increased by increasing the surface area of an internal electrode placed within the target tissue region. Various embodiments of the increased surface area electrode are shown in fig. 12A through 12F, although other configurations may be used. In one embodiment, the electrode includes a coiled distal end portion that may be further formed into a circular pattern (fig. 12A), a spiral (fig. 12B), or a simple coil (fig. 12C). In another embodiment, a small wire mesh may be included at the distal end of the electrode and expanded when placed within the target tissue region (fig. 12D). In other embodiments, the electrodes may comprise "twisted" wire-type electrodes, wherein the distal end comprises a plurality of small wires extending in an array (fig. 12E). In another embodiment, the distal portion may include a shape resembling a cone stacking two bases on top of each other, or have a diamond shape as viewed from the side (fig. 12F). The opposite distal and proximal portions of the pointed double taper/prism may facilitate insertion and retraction of the electrode within the tissue. A variety of other configurations are also available and include, for example, a loop, a ball, a spiral, a helix, a concentric helix, or a plurality thereof, an array of needles, a length of wire pushed out of the tube and formed into a non-elastic string-like shape similar to a wire ball in which the string is freely stacked within the capsule.
Another embodiment of the device of the present invention is shown in fig. 13. The device includes a delivery member 170 having a tissue-piercing distal portion 172. The delivery member includes a lumen and opening 174 in the body and an opening 176 in the distal end. A plurality of electrodes may be disposed within the lumen of the member. In the deployed state, the outer electrode 178 extends out of the opening 176 at the distal end of the member 170 and is inverted in an umbrella-like orientation. The deployed outer electrode 178 substantially defines an ablation volume. An electrode 180 extending out of the opening 174 of the body is spaced apart from the outer electrode 178 and positioned within the ablation volume.
Fig. 14 shows a device similar to the device shown in fig. 13. Referring to fig. 14, the device includes a delivery member 190 having a distal portion, an opening 192 on the body and at a distal end 194. An outer electrode 196 extends distally from the body opening 192 and defines a volume around the electrode 198 that extends out of the distal opening 194.
Another embodiment of the apparatus of the present invention is described with reference to fig. 15. The device includes a plurality of electrodes, each electrode disposed within a microcatheter, and each microcatheter disposed within a lumen of a delivery member. The delivery member or probe 300 may include a tissue piercing end that is sharpened or sharpened for easier insertion into the tissue of a patient. Similarly, the microcatheter may include a sharp or sharpened tissue-piercing end. In use, the delivery member 300 is advanced through the tissue of a patient with the distal end disposed adjacent a target tissue region (e.g., a tumor) and the microcatheter deployed from the delivery member. As shown in stage 1 deployment, microcatheter 310 is advanced distally from the distal end of the delivery member and into the target tissue region where the microcatheter's electrodes 320 may be deployed. The microcatheter 330 is also deployed from the delivery member 300 to target the electrode 340. In stage 2 deployment, the electrodes 340 are deployed in a direction aimed by the microcatheter 330, such as around the outer perimeter of the target tissue region (e.g., the tumor margin). The microcatheter and electrodes disposable therein can be made of a shape memory metal such as nitinol to assume a predetermined configuration upon deployment. Other stages may also be included.
A system according to an embodiment of the invention is described with reference to fig. 16. The system 200 may comprise any apparatus of the present invention for delivering energy to a patient and includes a power supply 210 for delivering energy to a drive unit 220 and then to the electrodes of the apparatus of the present invention. The components of the system may comprise an energy source for the inventive system, either individually or collectively, or in a combination of components. The power unit 210 may comprise any device that generates power for operating the device of the present invention and applying current to the target tissue as described herein. The power supply device 210 may include, for example, one or more generators, batteries (e.g., portable battery cells), and the like. One advantage of the system of the present invention is that the power required for the ablation process is low. Thus, in one embodiment, the system of the present invention may comprise a portable and/or battery operated device. The feedback unit 230 measures electric field delivery parameters and/or characteristics of the tissue of the target tissue region, including but not limited to current, voltage, impedance, temperature, pH, etc. One or more sensors (e.g., temperature sensors, impedance sensors, thermocouple sensors) may be included in the system and may be coupled with the device or system and/or separately disposed at or within the patient's tissue. These sensors and/or feedback units 230 may be used to monitor or control the delivery of energy to the tissue. The power supply apparatus 210 and/or other components of the system may be driven by a control unit 240, which may be coupled with a user interface 250 for input and/or control by, for example, a technician or physician. The control unit 240 and the system 200 may be coupled with an imaging system 260 (see above) to locate and/or describe a target tissue region and/or place or position a device during use.
The control unit may comprise, for example, a computer or a wide variety of proprietary or commercially available computers or systems having one or more processing structures, personal computers, or the like, typically comprising data processing hardware and/or software configured to perform any one (or combination) of the method steps described herein. Any software will typically include machine-readable code embodied as program instructions in a tangible medium such as a memory, a digital or optical recovery medium, an optical, electrical, or wireless telemetry signal, or the like, one or more of which may be used to transfer data and information between components of the system in any of a wide variety of distributed or central signal processing architectures.
Components of the system, including the controller, may be used to control the amount of power or electrical energy delivered to the target tissue. The energy may be delivered in a programmed or predetermined amount or may begin as an initial setting, with the electric field being modified during the energy delivery and ablation process. In one embodiment, for example, the system can deliver energy in a "sweep mode" where electric field parameters such as applied voltage, frequency, and the like include delivery across a predetermined range. A feedback mechanism may be used to monitor the electric field delivery in a scanning mode and select from delivery range parameters optimized for ablation of the target tissue.
The methods and techniques of the present invention may be employed with a single device or with multiple devices. In one embodiment, for example, a device of the present invention (e.g., the device shown in fig. 2A-2C) may be disposed within a target tissue region as described above. The second device may then be positioned within the target tissue region or within another target tissue region, either within a portion of the same tumor or at a separate tumor. In one embodiment, for example, a first device is disposed within a target tissue region and a second device can be disposed within the target tissue region, wherein the second device is disposed at an angle (e.g., 90 degree angle) relative to the first device. Furthermore, the same device may be positioned in different orientations and/or locations at different points in time.
The systems and devices of the present invention may be used in conjunction with (although not necessarily) other systems, ablation systems, cancer treatment systems such as drug delivery, local or systemic delivery, radiation or nuclear medicine systems, and the like. Similarly, the device may be modified to incorporate components and/or aspects of other systems, such as drug delivery systems, including drug delivery needles, electrodes, and the like.
In some cases, it may be desirable to remove ablated tissue from a target tissue region at some stage of an ablation procedure as described herein. For example, it has been found that in some instances, removal of ablated tissue may improve treatment and/or recovery of a patient and may reduce stress and/or toxicity (e.g., local tissue toxicity, systemic toxicity, etc.) associated with the ablation process of the present invention.
Various devices and methods may be used to remove ablated tissue. In some cases, as described above, the ablated tissue may effectively "liquefy" or take on the properties of a liquid material. The liquid ablated tissue may then be drained or removed from the target tissue region. In one embodiment, removal of the ablated tissue may be as simple as allowing the ablated tissue to leak or leak out of the target tissue region (e.g., with or without application of force or pressure to the tissue at or near the target tissue region), such as by leaking through holes or perforations in the tissue, including, for example, an entry hole through which the device/electrode is introduced into the target tissue region. In other embodiments, removal of ablated tissue may be more discreet or controlled. Removal may be accomplished using a device or instrument separate from the ablation device, such as a syringe or other fluid removal device, or may be accomplished by using an ablation device that is also configured for tissue removal.
Although embodiments of the invention are discussed above with respect to the use of non-thermal ablation and destruction of cancer cells, in certain instances, the system and probe may be configured to deliver sufficient energy for other types of tissue ablation, such as thermal RF ablation, microwave ablation, irreversible electroporation by high voltage direct current, and the like. For example, the system of the present invention may include a power supply device configured to deliver energy suitable for any one or more types of tissue ablation. Indeed, certain probe configurations have designs (e.g., electrode arrangements) that can provide improved delivery of various types of tissue ablation, including, for example, improved delivery of thermal RF ablation and the like. And treatment according to the methods of the present invention may include delivery of one or more types of tissue ablation for a given treatment. In certain instances, for example, the treatment may include one or more ablation delivery modes, such as one mode that delivers non-thermal tissue ablation, which may precede or follow another ablation mode, such as thermal RF tissue ablation. For example, in one embodiment, treatment may include delivery of non-thermal tissue ablation followed by a shorter application or pulse of energy to produce a heat-mediated effect, e.g., to help "disinfect" one or more components of the probe for withdrawal from the target tissue through the entry track and reduce the risk of leaving any potentially viable cancer cells through the tissue during probe withdrawal.
In certain embodiments, the systems of the present invention may also include certain components and aspects for positioning and/or stabilizing the probe and other components during energy delivery. For example, in a treatment session, such as where energy application is expected to exceed several minutes, it may be desirable to include a positioning or stabilizing structure to maintain the probe at a desired position/location without specifically requiring a user (e.g., surgeon) to hold the probe. Thus, the system may include a harness, strap, clamp, or other structure to hold the probe in place. The system may be designed for ambulatory use to enable the patient to move (e.g., transfer, walk, etc.) during treatment. Indeed, the low power requirements and corresponding design options (e.g., battery powered systems) may make current systems particularly well suited for ambulatory systems.
In certain embodiments, the invention may include the use of aspects or techniques described herein in combination with certain known or commercially available components to provide improved systems and methods for destroying cancer cells. For example, certain available systems having ablation probe or electrode configurations, including those typically used for techniques such as thermal RF ablation, microwave ablation, high voltage electroporation, and the like, may be modified and used for the non-thermal ablation techniques of the present invention. In one example, the methods of the present invention include non-thermal ablation of cancer cells using probes such as "LeVeen probes" (see, e.g., U.S. patent No. 5,855,576) that are commonly used for thermal RF ablation. Referring to fig. 17, an embodiment of the present invention is described as using a probe for providing non-thermal tissue ablation. 270 can be introduced, for example, percutaneously (through the skin "S") such that a distal portion of the probe 272 is disposed at or within a target site or region ("TR"). Each electrode 274 is shown extending distally from a distal portion of the probe 272. The electrodes 274 may be advanced such that they first diverge radially outward from one another and eventually flip back in a proximal direction, as shown in FIG. 17. Each electrode 274 may be electrically connected to a power supply 280 or power source, such as by a cable 278, and may operate in a monopolar mode, as shown. The current may be applied from the power supply 280 at a level and for a period of time sufficient to non-thermally ablate or destroy cancerous cells within the target tissue region.
The following examples are intended to illustrate, but not to limit, the present invention.
Examples of the invention
A series of tests included breast cancer tumor treatment models. In one example, testing was performed on female Fisher-334 mice weighing 230-. Murine breast cancer cells (MTLn-3) were first cultured in culture medium and subcutaneous tumors were formed by displacing the cells from the medium into the abdomen of the animals. When the tumor grows to a diameter of about 1cm or more, ablation treatment is performed. 18 solid breast tumors were treated in mice.
Ablation therapy involves inserting an ablation probe comprising an array of stainless steel needle electrodes percutaneously through the skin and directly into the tumor, and then applying a therapeutic electric field to the tumor. The needle array comprises a central needle surrounded by three parallel outer needles approximately equally spaced. The probe design (including needle length and placement) was selected to traverse the approximate diameter of the tumor being treated and the needle was about 1cm long. The outer needles were spaced about 0.5cm from the central needle. The central needle is activated with the tumor treatment voltage and the surrounding needles provide a return path for the current. No ground (e.g., an electrical "floating" system) is provided, wherein the probe operates in a "bipolar mode" as described above, and the device includes a battery power supply.
Using the probe and needle configuration described above, the therapeutic electric field is contained within a cylinder of approximately 1cm diameter by 1cm length whose volume is substantially occupied by the tumor. The peak applied AC voltage is about 10-12 volts, about 20-30mA (starting current). The frequency is about 98 KHz.
A feedback loop is included to measure the total current passed into the tumour during treatment. One hypothesis from preliminary experiments is that when a tumor cell begins to be destroyed by an applied electric field (e.g., cell lysis, disintegration, extravasation of cytoplasm, etc.), the current may actually increase due to, for example, increased conductivity within the tumor region because the contents of the destroyed cell (e.g., cytoplasm, etc.) are more conductive than the substantially intact cell. The results indicate that the circuit is operating as assumed. In all cases the current started to increase after the start of the treatment, indicating that the treatment was effectively ongoing. The observed current increase also provides an indication of when the process has reached a substantially complete phase. For example, observing that the current no longer increases indicates that treatment may be discontinued. A current plateau was observed to occur at about 40mA, and typically occurred within about 90 minutes of treatment.
The tumor began to show that cell destruction began almost immediately after power was applied. Significant destruction occurred within 30 minutes of entering treatment. In some cases, treatment was terminated after 30 minutes and tumors were barely detectable. In the other treatment groups, treatment was completed at about 90 minutes or within 3 hours. In all cases, the treated tumor was virtually undetectable under visual observation. A control (control) was included to confirm that tumor destruction was the result of the applied electric field. In one group, a needle without power was inserted as a control. Continued growth of the tumor was observed in the control.
A group of mice to be treated was selected for long-term survival studies and not killed after treatment. Survival was confirmed at a point greater than 12 months from the date of treatment, which was more than 17 times the expected survival of the animal model without any treatment (e.g., about 3 weeks). These mice are still alive at present. Survival observations and histological analysis (see below, for example) show that the majority, if not substantially all, of the cancer cells in the target tissue subjected to the treatment are destroyed.
As mentioned above, treatment usually results in a certain liquefaction of cancer cells/tissue. After treatment, it was clearly observed that a slightly pink coloured liquid appeared in the target tissue area subjected to treatment, which liquid could escape from the needle entry site and be further excreted when pressing or applying pressure to the treated area. Tissue analysis was performed on the fluid and tumor area after treatment. Histologically, the fluid was predominantly composed of destroyed cancer cells, and the destroyed cells essentially appeared necrotic and non-viable. PH testing has shown that the removed fluid has a higher alkalinity (e.g., a PH of about 7.8 or greater) than normal physiological fluids. Approximately 80-90% of the treated area was observed to be necrotic or non-viable cancer cells. The treatment area that is not necrosed (e.g., typically about 10-20% of the target tissue) appears to be part of an area of healthy, non-cancerous tissue. Thus, the results show that selective destruction of cancer cells substantially leaves healthy cells undamaged or viable.
The observed treatment showed no significant side effects. Surviving subjects that were not killed for further analysis showed no signs (viability, behavior, or otherwise) of weakness or negative side effects after treatment. No significant pain or discomfort or inflammation of the treatment area due to the application of energy was observed on the subject. During the treatment period, the rats appeared more comfortable, i.e. eating, drinking and sleeping, although they were not anesthetized during the treatment period.
The only potential side effects observed appear to be the result of not removing fluid or ablating tissue after treatment. When fluid was not removed from the treatment area after treatment, the subjects experienced several hours of lethargy and had an extended recovery period compared to rats that had fluid removed after ablation treatment.
As noted above, the treatment was observed to selectively destroy cancer cells within a defined target tissue region. Without being bound by any particular theory, there are one or more reasons that may explain the selective nature of the treatment. One reason for the observed selectivity appears to be due to the design of the ablation probe-the treatment is essentially limited to the treatment volume defined by the positioning electrodes. Only the tissue within the outer electrode of the probe appears to receive the transmitted energy and this is also the area of almost exclusive coverage of the electric field. The electric field does not appear to extend beyond the volume defined by the outer electrode.
Second, selectivity may be inherent to the cell destruction mechanism. Cell ablation is not unlike the main heat-mediated ablation carried out in known high frequency RF thermal ablation or microwave ablation techniques, nor is the effect due to high voltage irreversible electroporation by application of high voltage direct current as described elsewhere. All of these previously taught methods destroy both normal and cancerous tissue by design. The techniques of the present invention utilize voltage, power and frequency ranges that are not within the thermal or high voltage ablation range.
Furthermore, without being bound to any particular theory, the additional cellular level effects of current technology may result in the selective destruction of cancer cells as compared to non-cancer cells. The energy application described herein appears to mediate the breakdown of cell membrane integrity. One potential cause of cell membrane disruption and/or cancer cell destruction may include disruption of cell cycle progression and cell mitosis due to the applied electric field, which triggers cell destruction (e.g., necrosis, apoptosis, disintegration), as observed herein. Such energy application may be selectively performed on cancer cells as they actively divide and proliferate, and thus traverse the cell cycle/mitosis at a much faster rate than the magnitude of the slower rate of non-cancerous or healthy cells.
Another possible cause of cell damage may include dielectric breakdown of cell membranes. Cell membranes are known to have a dielectric breakdown threshold above which cells are destroyed. The threshold for normal cells is generally higher than for cancer cells. Thus, when the applied energy is above the dielectric breakdown threshold of cancer cells and below the dielectric breakdown threshold of normal/healthy cells, the cancer cell membrane can be selectively broken without harming normal cells. Membrane integrity failure, e.g., rupture of a component comprising lysosomes (e.g., a degrading enzyme), can occur on both the extracellular and intracellular membranes as a result of the treatment described herein, which further leads to cell destruction. Cell rupture and spillage of cell contents adversely affect nearby cells, causing a series of cell destruction. Treatment may also stimulate an immune response that can "clear" the treatment area and can further destroy any remaining/surviving cancer cells that are not destroyed or removed. Other perturbations and/or mechanisms of action may also occur. Whatever the specific mechanism of action, in the event that such cell disruption occurs, the resulting fluid appears to act in some cases also as a virtual electrode, making the electrode larger and larger in diameter and eventually covering substantially the entire target tissue area.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Many different combinations are possible and such combinations are also considered to be part of the present invention.