Implantable arrays for delivering tumor-treating fields

Abstract

An implantable device can be positioned within a patient's body proximate a target site. The implantable device can generate an electric field across the target site at a frequency of about 50 kHz to about 500 kHz. The target site can be a tumor or a peritumoral region. The implantable device can include a thin substrate and at least one electrode coupled to the thin substrate, or an elongated body and a plurality of electrodes coupled to the elongated body.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 938,586, filed on November 21, 2019, and U.S. Provisional Application No. 63 / 085,658, filed on September 30, 2020. Each of the above-identified applications is incorporated herein by reference in its entirety. Technical Field

[0003] The present application relates generally to apparatus and methods for providing tumor treating fields, and more particularly to apparatus and methods for implanting electrodes within a patient for providing tumor treating fields. Background Art

[0004] Tumor Treating Fields, or TTFields, are low-intensity (e.g., 1-3 V / cm) alternating electric fields in the mid-frequency range (100-300 kHz). This non-invasive treatment targets solid tumors and is described in U.S. Patent No. 7,565,205, which is incorporated herein by reference in its entirety. TTFields disrupt cell division by physically interacting with key molecules during mitosis. TTFields therapy is an approved monotherapy for recurrent glioblastoma and an approved combination therapy with chemotherapy for newly diagnosed patients. Traditionally, these electric fields are induced non-invasively by a transducer array (i.e., an electrode array) placed directly on the patient's scalp. TTFields also appear to be beneficial for treating tumors in other parts of the body. Summary of the Invention

[0005] In one aspect, a method is described herein that can include positioning an implantable device within a patient's body proximate a target site. The implantable device can generate an electric field across the target site at a frequency of about 50 kHz to about 500 kHz. The target site can be a tumor or a peritumoral region. The implantable device can include a thin substrate and at least one electrode coupled to the thin substrate.

[0006] In other aspects, a method may include positioning an implantable device beneath a patient's skin proximate a target site. The target site may be a tumor or a peritumoral area. The implantable device may include an elongated body and a plurality of electrodes coupled to the elongated body. The implantable device may generate an electric field through the target site at a frequency of 50-500 kHz.

[0007] In a further aspect, a method may include positioning a first implantable device and a second implantable device within a patient's body proximate a target site. The target site may be a tumor or a peritumoral region. Each of the first implantable device and the second implantable device may include at least one electrode. The implantable devices may generate an electric field through the target site at a frequency of 50-500 kHz.

[0008] Additional advantages of the present invention will be set forth in part in the following description and, in part, will be obvious from the description, or may be learned by practice of the present invention. The advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] These and other features of the preferred embodiments of the present invention will become more apparent in the following detailed description, which proceeds with reference to the accompanying drawings, in which:

[0010] Figure 1 is a block diagram of a system for delivering tumor treating fields using implantable devices and systems as disclosed herein.

[0011] Figure 2 Schematic diagram of an implantable device placed within a resected cavity in a patient's skull and additional electrodes placed outside the skull.

[0012] Figure 3 Schematic diagram of an implantable device positioned within the resection chamber and additional electrodes positioned externally in the peritumoral region.

[0013] Figure 4 is a schematic diagram of a pair of implantable devices placed on opposite sides of a tumor.

[0014] Figure 5 is a perspective view of a plurality of implantable devices, each device comprising a thin substrate and a plurality of electrodes disposed thereon.

[0015] Figure 6A is a side view of an exemplary implantable device including an elongated body. Figure 6B yes Figure 6A Multiple cross-sectional views of an implantable device illustrating different electrode arrangements that may be employed within the implantable device.

[0016] Figure 7A is a side view of an exemplary implantable device including an elongated body. Figure 7B yes Figure 7A Cross-sectional view of an implantable device illustrating an exemplary electrode arrangement. DETAILED DESCRIPTION

[0017] The systems and methods of the present disclosure may be understood more readily by reference to the following detailed description of specific embodiments and the examples included therein, and by reference to the drawings and their previous and subsequent descriptions.

[0018] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0019] It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an electrode" includes one or more such electrodes, and so forth.

[0020] “Optional” or “optionally” means that the subsequently described event, circumstance, or material may or may not occur or exist, and that the description includes instances where the event, circumstance, or material occurs or exists and instances where it does not.

[0021] Scopes herein can be expressed as from "about" a specific value, and / or to "about" another specific value. When expressing such a range, unless the context specifically indicates otherwise, it is also specifically contemplated and considered that a range from a specific value and / or to another specific value is disclosed. Similarly, when a value is expressed as an approximation by using the antecedent "about", it will be understood that unless the context specifically indicates otherwise, the specific value forms another specifically considered embodiment that should be considered as disclosed. It will be further understood that unless the context specifically indicates otherwise, the endpoints of each range are significant with respect to the other endpoint and are independent of the other endpoint. Finally, it should be understood that all individual values ​​and sub-ranges of values ​​contained within the clearly disclosed range are also specifically contemplated and should be considered as disclosed, unless the context specifically indicates otherwise. Regardless of whether some or all of these embodiments are clearly disclosed in particular circumstances, the foregoing applies.

[0022] Optionally, in some aspects, when values ​​are approximated by use of the antecedents "about," "substantially," "approximately," or "generally," it is contemplated that values ​​within up to 15%, up to 10%, up to 5%, or up to 1% (above or below) of the particularly stated value or property may be included within the range for those aspects.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the presently disclosed apparatus, systems, and methods belong. Although any apparatus, systems, methods, and materials similar or equivalent to those described herein can be used in the practice or testing of the present apparatus, systems, and methods, particularly useful methods, apparatus, systems, and materials are as described.

[0024] As used herein, the term "patient" refers to a human or animal subject in need of treatment using the disclosed systems and devices.

[0025] As used herein, the term "electrode" refers to any structure that permits the generation of an electric potential, current, or field as further disclosed herein. Alternatively, an electrode may comprise a transducer. Alternatively, an electrode may comprise a non-insulated portion of a conductive element.

[0026] Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", mean "including but not limited to", and are not intended to exclude, for example, other additives, components, integers, or steps. In particular, in a method recited as including one or more steps or operations, each step is specifically contemplated to include what is listed (unless the step includes a limiting term, such as "consisting of"), meaning that each step is not intended to exclude, for example, other additives, components, integers, or steps not listed in the step.

[0027] Figure 1 An example apparatus 10 for electrotherapy treatment is shown. Generally, apparatus 10 can be a portable, battery- or mains-operated device that generates an alternating electric field within the body with the aid of a transducer array or other electrodes. Apparatus 10 can include an electric field generator 12 and one or more electrode (e.g., transducer) arrays 104, each electrode array 104 including a plurality of electrodes 106. Apparatus 10 can be configured to generate tumor treatment fields (TTFields) via electric field generator 12 (e.g., at 150 kHz) and deliver the TTFields to a region of the body through one or more electrode arrays 104. Electric field generator 12 can be a battery- and / or mains-operated device.

[0028] The electric field generator 12 may include a processor 16 in communication with a signal generator 18. The electric field generator 12 may include control software 20 configured to control the performance of the processor 16 and the signal generator 18. Although depicted as being within the electric field generator 12, it is contemplated that the processor 16 and / or control software 20 may be provided separate from the electric field generator, so long as the processor is communicatively coupled to the signal generator and configured to execute the control software.

[0029] The signal generator 18 can generate one or more electrical signals in the form of a waveform or pulse train. The signal generator 18 can be configured to generate an AC voltage waveform (e.g., TTFields) at a frequency ranging from about 50 kHz to about 500 kHz (preferably from about 100 kHz to about 300 kHz). The voltage is such that the electric field strength in the tissue to be treated is typically in the range of about 0.1 V / cm to about 10 V / cm.

[0030] One or more outputs 24 of the electric field generator 12 can be coupled to one or more conductive leads 22, which are attached at one end to the signal generator 18. The opposite ends of the conductive leads 22 are connected to one or more electrode arrays 104, which are activated by an electrical signal (e.g., a waveform). The conductive leads 22 can comprise standard isolated conductors with flexible metal shields and can be grounded to prevent the electric field generated by the conductive leads 22 from spreading. One or more outputs 24 can be operated sequentially. Output parameters of the signal generator 18 can include, for example, the intensity of the field, the frequency of the wave (e.g., a therapeutic frequency), the maximum allowable temperature of one or more electrode arrays 104, and / or combinations thereof. In some aspects, a temperature sensor 107 can be associated with each electrode array 104. Once a temperature sensor measures a temperature above a threshold, current flow to the electrode array associated with the temperature sensor can be stopped until a second, lower threshold temperature is sensed. The output parameters can be set and / or determined by the control software 20 in conjunction with the processor 16. After determining the desired (eg, optimal) treatment frequency, the control software 20 may cause the processor 16 to send a control signal to the signal generator 18 , causing the signal generator 18 to output the desired treatment frequency to the one or more electrode arrays 104 .

[0031] The one or more electrode arrays 104 can be configured in a variety of shapes and positions to generate an electric field of a desired configuration, direction, and strength at a target site (also referred to herein as a "target volume" or "target area") for focused treatment. Alternatively, the one or more electrode arrays 104 can be configured to deliver two perpendicular field directions through the volume of interest.

[0032] Further disclosure regarding the use of such an electrotherapy system is provided in U.S. Provisional Patent Application No. 62 / 942,595, filed on December 2, 2019, the entire disclosure of which is hereby incorporated by reference herein.

[0033] While transducers are conventionally positioned external to the patient, the present disclosure recognizes that there are benefits to positioning electrodes within the patient's body to provide a localized electric field at the tumor site.

[0034] Alternatively, it is contemplated that administration of TTFields as disclosed herein could be beneficially combined with temozolomide chemotherapy. When dexamethasone, suspected of interfering with the effects of the tumor-toxic fields, is replaced with celecoxib to control tumor-associated inflammation, overall survival in some patients has now been extended to over 60 months. Given ongoing advances in deep brain stimulation (DBS) and transcranial electrical stimulation (TES), the transcranial approach to delivering tumor-toxic fields has remained unchanged. The resistivity of the skull is a barrier to placing therapeutic electric field strengths (e.g., at least 2 V / cm, at least 3 V / cm, or at least 4 V / cm) into the target tumor site, and variations in skull thickness can lead to inter-individual variability in TES efficiency. Finite element modeling (FEM) of the human head predicts that surgical craniectomy beneath the electrodes delivering the tumor-toxic fields can enhance field strength at the target tumor site. For example, using the methods disclosed herein, 2-4 V / cm can be reliably delivered to the tumor site using minimally invasive strip or ribbon electrode arrays combined with distal transcranial electrodes before and after resection. It is contemplated that using frequencies of approximately 200 kHz (e.g., 100-300 kHz), which are 1-3 orders of magnitude higher than the ion channel time constant, may be too high to stimulate axons in situ, thereby avoiding undesirable neurological side effects. Additionally, according to embodiments disclosed herein, field strengths can be maintained below levels that cause cell damage.

[0035] Typically, a cancer patient's body has an anatomically well-defined mass of adjacent cancer cells, or a shell of cancer cells surrounding a "necrotic" area where the cells have died due to lack of nutrients. Such a tumor can be removed surgically ("resection"). The resected volume can be filled with cerebrospinal fluid in the brain or other body fluids in other body regions, which are conductive and significantly affect the electric field applied to the area. Typically, the tumor or resection cavity is surrounded by an anatomically undefined or loosely defined area containing stray cancer cells, as the extent of stray cancer cells near the tumor depends on the tumor cell type of each patient, as well as highly personalized medical history, anatomical structure, immune system, etc. The area containing stray, non-adjacent cancer cells is referred to herein as the "peritumoral area."

[0036] refer to Figure 2-3In some aspects, a method for treating tumor cells may include positioning an implantable device 100 within a patient's body proximate to a target site (e.g., less than 1 cm from the target site, less than 3 cm from the target site, or within 1-10 cm (or approximately 1 cm to approximately 10 cm) of the target site). Proximity to the target site can optionally be as close as possible (without causing damage to critical tissue) and no further than a distance at which the field strength is insufficient to kill tumor cells within the target site (i.e., a maximum effective distance). The maximum effective distance can be controlled by several factors. First, the field strength can be a function of the power supplied to the electrodes, and the maximum power threshold can be limited by a temperature threshold. Therefore, the implantable device 100 can be positioned proximate to the target site to provide sufficient field strength without exceeding a temperature threshold. For example, it is contemplated that the temperature threshold can be maintained below a temperature threshold at which the patient experiences pain (e.g., 41 degrees Celsius) or a temperature threshold before tissue damage occurs (which can be above the latter temperature threshold). The temperature contemplated to be achieved can depend on the thermal properties of the surrounding tissue. In a further aspect, the implantable device 100 can desirably generate sufficient heat (exceeding a temperature threshold at which tissue is damaged) to damage surrounding cells (e.g., ablate surrounding cells). Second, the configuration of the electrode array (further disclosed herein) can determine the shape of the field emitted from the implantable device 100, thereby affecting the maximum effective distance. Third, the frequency at which TTFields are applied to the target site can affect the maximum effective distance. Fourth, the geometry of the surrounding tissue and the properties of the surrounding tissue can affect the maximum distance. Thus, computational modeling can be used to determine the ideal position of the implantable device relative to the target site.

[0037] In some aspects, the implantable device 100 can be positioned in a tumor resection cavity 302, within a peritumoral region 304, or adjacent to a tumor or resection cavity, optionally within or adjacent to the peritumoral region 304. Figure 4In still further aspects, it is contemplated that at least two implantable devices 100 (optionally, three, four, or more implantable devices 100) can be positioned around a target site (e.g., around a resection cavity, or around a tumor 310). For example, optionally, two implantable devices 100 can be positioned on opposite or substantially opposite sides of the target site. In still further aspects, it is contemplated that one or more implantable devices 100 can be inserted directly into a tumor 310 or within a peritumoral region 304. For example, optionally, a first implantable device and a second implantable device can be positioned within the peritumoral region 204, and the first and second implantable devices can optionally generate TTFields between each other. According to various aspects, it is contemplated that by using TTField therapy, tumor resection can be avoided. Optionally, for generally spherical tumors or cancer cells, a single implantable device 100 can be used, while for heterogeneous and non-spherical cancer cells, two (or optionally, multiple) implantable devices 100 can be used to generate an electric field that overlaps with the tumor.

[0038] In some aspects, reference Figure 3One or more electrodes 200 can be positioned outside the peritumoral region such that the implantable device and the electrode(s) 200 positioned outside the peritumoral region can generate TTFields therebetween. For example, the implantable device 100 and the electrode(s) 200 can be positioned such that at least a portion of the tumor or peritumoral region is located therebetween (i.e., such that a line extending between the implantable device 100 and the electrode(s) 200 extends through the tumor or peritumoral region). Alternatively, the one or more electrodes 200 can be positioned outside the skull 306 (e.g., outside the patient's skin) or otherwise outside the patient's body (optionally, outside the skin) such that at least a portion of the peritumoral region is disposed between the implantable device and the one or more electrodes 200 outside the peritumoral region. For example, the OPTUNE device (NOVOCURE GmbH), as known to those skilled in the art, can be used to position the electrodes 200 against the patient's head. Alternatively, all of the peritumoral region can be disposed between the implantable device and the one or more electrodes 200. In a further aspect, in the event that the tumor has not yet been removed, one or more electrodes 200 can be positioned so that the tumor is between the implantable device and the one or more electrodes 200. It is contemplated that, based on the arrangement of the electrodes, different field patterns can be generated between the electrodes. As disclosed herein, computational modeling can be used to predict the activation pattern of the combined internal and external electrode arrays to most effectively deliver the effective field strength to the target area. Generally, the target area can be located between the internal activation electrode and the external activation electrode. However, changing the direction of the applied field can be desirable. Therefore, in some aspects, at least one electrode 200 can be positioned so that an imaginary line between the implantable device and the at least one electrode 200 extends through the target site, and a second pair of electrodes that is oblique or orthogonal to the imaginary line between the internal electrodes through the target area to the at least one electrode 200 can be desirable for applying the electric field from a different direction. Thus, general tumor locations can be modeled, for example, in different quadrants of tissue. In a further aspect, image scans for a given patient can be used to customize the optimal field shaping (e.g., different directional paths of TTFields through the target site) through various electrodes.

[0039] Alternatively, in an exemplary aspect, the one or more electrodes 200 outside of the peritumoral region may include one or more transducer arrays configured to apply TTFields through a portion of the patient's brain. For example, such a transducer array may be provided as a component of the OPTUNE system (NOVOCURE GmbH) for applying TTFields. In an exemplary aspect, it is contemplated that such a transducer array, when positioned externally to the patient (e.g., on the patient's head), may be used in combination with an implantable device including DBS electrodes as further disclosed herein.

[0040] Also refer to Figure 5 In some aspects, an implantable device may include a strip or belt-shaped electrode assembly comprising a thin substrate 102 having one or more electrodes 106 coupled thereto (optionally arranged in an array 104). Optionally, the thin substrate 102 may have a thickness of less than 2 mm, such as, for example, from 0.1 mm to 1 mm. Exemplary belt-shaped electrode assemblies suitable for use as disclosed herein include subdural grids or strip electrodes manufactured by AD-TECH Medical Devices. It is contemplated that the thin substrate 102 may be flexible to allow for selective positioning of the electrodes 106 within the resection cavity 302. For example, the tumor resection cavity may optionally be lined with an antimicrobial mesh or other surgical material 308. In some aspects, the antimicrobial mesh or other surgical material 308 may be a material used in conventional neurosurgery. In some aspects, the antimicrobial mesh or other surgical material 308 may have negligible electrical resistance or be designed to minimally interfere with or enhance an applied electric field. The implantable device 100 may be positioned within the mesh. Alternatively, the shape or contour of the implantable device 10 can be bent or otherwise modified to match the outer shape of the mesh. For example, the implantable device 100 can be pressed against the inner surface of the mesh 308.

[0041] In some aspects, the implantable device 100 can include a single electrode 106. In further aspects, the implantable device 100 can include a plurality of electrodes 106, which can be arranged in various configurations. For example, in some aspects, the plurality of electrodes 106 can include a single row of electrodes arranged along an axis. In further aspects, the plurality of electrodes 106 can be arranged on a rectangular grid and can be spaced apart from each other at equal or unequal intervals. In further aspects, the plurality of electrodes 106 can include multiple or multiple rows of electrodes, wherein the electrodes within each row are arranged along a corresponding axis.

[0042] refer to Figures 6A-7B In a further aspect, the implantable device 100 can include an elongated body 150 and a plurality of electrodes 106 coupled thereto. The elongated body 150 can optionally be rigid. Figures 6A-6B As shown in , the elongated body 150 may optionally define at least one cylindrical surface. In a further aspect, as Figures 7A-7BAs shown in , the elongated body can define a cross shape in a cross-section taken in a plane perpendicular to the longitudinal axis. Optionally, in these aspects, the elongated body 150 can include a first body portion 160, a second body portion 162, a third body portion 164, and a fourth body portion 166 that converge at a longitudinal axis 170, wherein the first and second body portions 160, 162 are aligned relative to a first transverse axis 172 that is perpendicular to the longitudinal axis 170, and wherein the third and fourth body portions 164, 166 are aligned relative to a second transverse axis 174 that is perpendicular to the longitudinal axis and the first transverse axis. Optionally, the first and second body portions can have equal or substantially equal dimensions relative to the first transverse axis, and the third and fourth body portions can have equal or substantially equal dimensions relative to the second transverse axis. Optionally, the dimensions of the first and second body portions relative to the first transverse axis can be equal or substantially equal to the dimensions of the third and fourth body portions relative to the second transverse axis.

[0043] The electrodes for the exemplary implantable device 100 may optionally have uniform or uneven sizes and may optionally have uniform or uneven spacing relative to the longitudinal axis. Alternatively, the electrodes may have a surface area size ranging from 0.1 mm x 0.1 mm to 1.5 mm x 1.15 mm. In a further aspect, depending on the application, the electrodes may be larger or smaller. Alternatively, the electrodes may be spaced 0.1 mm or less, between 0.1 and 0.5 mm, at least 0.5 mm, from 0.5 mm to 1 mm, or greater than 1 mm. The electrodes 106 may optionally be circular, a circular profile projected onto a cylindrical surface, rectangular, a rectangular profile projected onto a cylindrical surface, cylindrical, or any other suitable shape.

[0044] In some optional aspects, it is contemplated that the implantable device 100 can be a deep brain stimulation (DBS) probe as known in the art. Exemplary DBS probes according to embodiments disclosed herein can include a MEDTRONIC 3387 DBS probe, a MEDTRONIC 3389 DBS probe, an ABBOT INFINITY probe, a BOSTON SCIENTIFIC probe, a DIRECTSTNACUTE probe, a MEDTRONIC-SAPIENS probe, a miniature DBS probe, an AD-TEC depth, strip, or ribbon ("grid") electrode, an AD-TEC subdural electrode, a WISE cortical strip, or a DBS probe as described in Anderson, Daria Nesterovich, et al., "Optimized programming algorithm for cylindrical and directional deep brain stimulation electrodes," Journal of Neural Engineering, 15.2 (2018): 026005, which is hereby incorporated by reference herein in its entirety. It is contemplated that the implantable device 100 can have any selected size or any electrode arrangement or distribution capable of providing electrical stimulation in the manner disclosed herein.

[0045] Alternatively, it is contemplated that the electrode 106 may comprise platinum iridium. In a further aspect, it is contemplated that the electrode may comprise ceramic. For example, ceramic may have a preferred impedance at certain beneficial frequencies (e.g., 50-500 kHz or 100-300 kHz).

[0046] It is contemplated that the electrodes 106 can be activated with selectable amplitudes. Advantageously, the electrodes disclosed herein can be used to generate TTFields in various combinations such that the direction of the field through the target site can be varied. TTFields can optionally be current or voltage controlled. It is contemplated that when a resistive fibrous material (e.g., scar tissue) is formed around the electrode(s), current-controlled TTFields can achieve higher fidelity in the desired waveform (e.g., a rectangular shape), as well as a more uniform field train over time. Current-driven waveforms can maintain current and field constant as resistance changes.

[0047] In some aspects, TTFields can be generated between different electrodes 106 of an implantable device 100. In further aspects, TTFields can be generated between an electrode 106 of an implantable device 100 and one or more electrodes 200. In further aspects, TTFields can be generated between electrodes 106 of two different implantable devices 100.

[0048] In some optional aspects, TTFields can be generated at one or more frequencies from 50-500 kHz, optionally from 100-300 kHz. The field strength through the target region (e.g., a tumor and / or peritumoral region) can be at least 2 V / cm, at least 3 V / cm, at least 4 V / cm, or between 2 V / cm and 4 V / cm.

[0049] It is contemplated that certain structures (such as microtubules and cellular organelles) may respond differently based on the orientation of the field passing therethrough. Therefore, it is contemplated that the direction of TTFields may be periodically varied. For example, the cathode and anode electrodes activated in an array may be periodically varied to achieve the goal of delivering the most effective field (optionally, the highest field intensity) to a given tumor / peritumoral target. In this manner, the pattern of cathode and anode electrodes activated in an array may be periodically varied to alter the direction of the field to optimally deliver the highest field intensity to target structures (such as microtubules and cellular organelles) that have different orientations relative to the applied field due to random cell axis orientations in the target tissue. For example, the direction of TTFields may optionally be varied at a frequency between 0.03 seconds and 0.5 seconds.

[0050] In some aspects, changing the direction of the TTFields can include switching the polarity of electrodes sensing the TTFields. For example, a first polarity can be induced between one or more electrodes of the implantable device 100 and electrode(s) 200 outside the peritumoral region 304 (optionally outside the skull 308 or otherwise outside the patient's skin); and, after a selected period of time, a second polarity, opposite the first polarity, can be induced between electrode(s) 106 of the implantable device and electrode(s) 200 outside the peritumoral region.

[0051] In further aspects, the electrodes between which the field is induced can be changed. For example, in some aspects, a field can be induced between at least two electrodes 106 of an implantable device, and to change direction, the field can be induced between different combinations of electrodes 106 of the implantable device 100. In further aspects, a field can be induced between at least two electrodes 106 of an implantable device, and to change direction, the field can be switched to being induced between at least one electrode 106 of the implantable device 100 and an electrode(s) 200 outside the peritumoral region. In still further aspects, a field can be induced between a first combination of at least one electrode 106 of the implantable device 100 and an electrode(s) 200, and a change in field direction can be caused by changing the electrode(s) of the implantable device 100 and / or the electrode(s) 200 in which the field is being induced. In a further aspect, a field can be induced between a first combination of at least one electrode 106 of a first implantable device 100 and at least one electrode 106 of a second implantable device 100, and a change in the direction of the field induced by a second combination of at least one electrode 106 of the first implantable device 100 and at least one electrode 106 of the second implantable device 100 can be caused.

[0052] In some aspects, the change in direction of the electric field before and after each direction change can be between 30 degrees and 90 degrees, or between 45 degrees and 90 degrees, or approximately 90 degrees. In still further aspects, during a single treatment session, the electric fields can be generated in directions that are at an angle of at least 30 degrees relative to each other, at an angle of at least 45 degrees relative to each other, or at an angle of at least 60 degrees relative to each other. It is contemplated that the mechanism of action of tumor-killing electric fields (i.e., TTFields) is their effect on polarized cell membranes and / or subcellular structures. Additionally, it is contemplated that TTFields can provide a significant tumoricidal (tumor-killing) effect when the field is aligned with the cell axis during mitosis, and secondarily when orthogonal to the cell axis. However, it is further contemplated that the tumoricidal (tumor-killing) effect of TTFields can be diminished (or even negligible) when aligned at 45 degrees (or approximately 45 degrees) to the cell axis. In some aspects, one orthogonal direction change of the applied field per second can provide a 20% increase in efficacy (compared to no direction change). Because cells are randomly arranged in living organisms, in order to achieve the benefits of applying a field aligned with or orthogonal to the cell axis, changes in field direction can be applied over time. It is contemplated that each change in field direction can reduce the variation in field strength experienced by polarized cell structures, thereby increasing the minimum field strength they experience, leading to the desired outcome. Additionally, each change in field direction can reduce the maximum field strength necessary to ensure delivery of sufficient field strength to the target.

[0053] In some aspects, the processor(s) 16 can be configured to control the polarity sensing between the electrodes. For example, the processor(s) can alternate the sensing polarity between two or more electrodes. Thus, optionally, in some aspects, the processor(s) 16 can be configured to switch the sensing polarity between the two or more electrodes so that the electrodes operating as electrodes and anodes and cathodes, respectively, can be reversed after a predetermined period of time. In some aspects, the processor(s) can repeatedly reverse the sensing polarity. In further aspects, the processor(s) can be configured to change which electrodes serve as anode(s) and cathode(s). For example, the processor(s) can cause the electric field generator 12 ( Figure 1 ) induces a field between a first pair of electrodes, and after a certain duration, the processor may cause the electric field generator 12 to induce a field between a second pair of electrodes. Optionally, the processor(s) may execute a protocol stored in memory that causes the processor to implement sequential changes in polarity and / or electrode combinations according to the stored protocol. For example, the stored protocol may include a predetermined sequence of electrode polarity sensing for a predetermined duration. Such a stored protocol may optionally be customized for general tumor locations and electrode arrays, or may be customized for a specific patient if the patient's tumor location and physical geometry are known. In some aspects, for general patients, a random order may be preferred for effectiveness, while for specific patients whose tumor location and physical geometry are known to the clinician, a customized order and / or arrangement may provide the best tumoricidal results.

[0054] Exemplary Apparatus and Methods

[0055] In some aspects, a single implantable device 100 can be inserted into or proximate a target area (e.g., a tumor or a tumor resection cavity). The single implantable device 100 can include an elongated rigid body 150 and a plurality of electrodes 106 spaced longitudinally along the length of the body. Alternatively, the single implantable device 100 can be a DBS probe. It is contemplated that generating the electric field between the most widely spaced electrodes can provide extensive (optionally, as extensive as possible) field coverage (e.g., through the resection cavity and peritumoral region).

[0056] In some aspects, two implantable devices 100 can be inserted into or near (e.g., on opposite sides of) a target area (e.g., a tumor or a tumor resection cavity). In further aspects, it is contemplated that the two implantable devices 100 can be positioned within a cavity (e.g., on opposite edges within a resection cavity). Each of the two implantable devices 100 can include an elongated rigid body and a plurality of electrodes 106 spaced longitudinally along the length of the body. Optionally, the two implantable devices 100 can be DBS probes. Different electrodes on each probe can be polarized sequentially to induce electric fields in different directions. In some aspects, each of the implantable devices 100 can have an inner electrode 106a and an outer electrode 106b, wherein the inner electrode is relatively closer to the other implantable device than the outer electrode. In some aspects, TTFields can be generated between the corresponding inner electrodes of each of the two implantable devices to deliver relatively high-intensity electric fields. In a further aspect, TTFields may be generated between respective external electrodes of each of two implantable devices to deliver more broadly reaching TTFields (ie, TTFields propagating further from the electrodes).

[0057] In some aspects, a band electrode array can be placed around a tumor or resection cavity. In some aspects, a band electrode array can provide a smaller and more densely packed electrode array than a conventional cylindrical DBS probe to more precisely deliver the strongest field to the tumor or resection cavity or peritumoral region. For example, electrodes can be activated sequentially around a tumor resection cavity to deliver the strongest dose to areas orthogonal to the electrode plane, while simultaneously delivering a weaker, but still therapeutic, dose to areas adjacent to the electrodes from different directions.

[0058] Alternatively, in exemplary aspects, it is contemplated that the implantable device 100 as disclosed herein can be configured to be removed from the patient's body before the patient's skin grows over the cavity therein to receive the implantable device (e.g., within approximately 3 to 4 weeks). Alternatively, in these aspects, it is contemplated that the cavity therein to receive the implantable device can be formed by a craniectomy or other similar procedure. It is further contemplated that, after removal of the implantable device, cells from the patient's body can be collected from the implantable device to permit analysis of the patient's cells remaining on the surface of the implantable device (e.g., a belt or strip electrode as disclosed herein), thereby permitting analysis of tumor cells or cells within the peritumoral area or other target area. Alternatively, in other exemplary aspects, it is contemplated that the implantable device 100 as disclosed herein can be configured to be powered by a battery or other power source located external to the patient, thereby providing a long-term implant configuration.

[0059] One advantage of using in situ TTFields with an external array is the ability to direct the electric field across the tumor / peritumoral region by changing the active electrodes on the external array. Another advantage of in situ tumor treatment fields is the ability to precisely control the field near the target tumor / peritumoral region, thereby avoiding or minimizing collateral damage to nearby, healthy, rapidly dividing cells. Still further, another advantage is the ability to optimize 1) the electrode static pattern at a given time point, 2) change the field direction so as to force alignment or orthogonality with the cell axis, and 3) change the field direction to obtain a maximum therapeutic dose region while minimizing hot spots, which can optionally be characterized by a temperature (e.g., 41 degrees Celsius) to avoid pain, and / or by a surface current density (such as 30 or 60 microcoulombs per square centimeter) to avoid undesirable biochemical reactions at the electrode-tissue interface.

[0060] In some aspects, the temperature increase caused by the interaction of current flowing through resistive tissue (e.g., "Joule heating") can be a limit on the maximum voltage, current, and power supplied to the device 100. In other aspects, where intentional damage to tumor cells in proximity to the device is desired, the implantable device 100 can be used to achieve temperatures that kill tissue cells. Thus, in some optional aspects, the implantable device 100 can be used for the dual purpose of destroying tumor cells via a tumor-killing electric field and killing cells using heat (tissue "ablation"). Given the voltage, current, or power parameters supplied to the device 100, in computer simulations, metrics such as the Arrhenius equation can be used to predict the 3-dimensional degree of tumor cell ablation. Optionally, the implantable device can include a temperature sensor (e.g., a thermocouple or thermistor). In further aspects, the temperature sensor can be positioned proximate to the implantable device to measure the temperature of the implantable device or tissue in proximity to the implantable device.

[0061] The devices and methods disclosed herein may optionally be used to treat glioblastoma or other cancers in the brain. In further optional aspects, the devices and methods disclosed herein may be used to treat cancer or tumor cells in other parts of the body, such as, for example, the torso. In these aspects, it is contemplated that the external arrays disclosed herein may be positioned on the patient's skin while also being proximal to a tumor or peritumoral area within the body. In exemplary aspects, it is contemplated that the implantable devices disclosed herein may include DBS electrodes (e.g., DBS probes) positioned within the patient's torso.

[0062] Although many of the exemplary embodiments disclosed herein are directed to treating brain tumors (such as glioblastomas), it should be understood that these examples are not meant to limit the use of the embodiments to treating brain tumors. Rather, applications and embodiments of the present disclosure may be used to treat various types of tumors throughout a patient's body. For example, although various embodiments disclose positioning electrodes outside the skull for treating brain tumors, it is contemplated that electrodes may be positioned at various locations in the body depending on the location of the target site. Exemplary target sites outside the brain include the lungs and other internal organs. In exemplary aspects, it is contemplated that electrodes may be positioned outside a portion of the torso for treating tumors within the lungs or other internal organs, or any other location within the torso where a tumor is identified.

[0063] Exemplary Aspects

[0064] In view of the described products, systems and methods and variations thereof, certain more particularly described aspects of the invention are described below. However, these particularly enumerated aspects should not be construed as having any limiting effect on any different claims incorporating different or more general teachings described herein, or that a "particular" aspect is limited in some manner other than by the inherent meaning of the literally used language therein.

[0065] Aspect 1: A method comprising: positioning an implantable device within a patient's body proximate a target site; and generating an electric field through the target site using the implantable device at a frequency from about 50 kHz to about 500 kHz, wherein the target site is a tumor or a peritumoral area, and wherein the implantable device comprises: a thin substrate; and at least one electrode coupled to the thin substrate.

[0066] Aspect 2: The method of aspect 1, wherein positioning the implantable device within the patient's body proximate to the target site comprises positioning the implantable device within a tumor resection cavity.

[0067] Aspect 3: A method according to Aspect 1 or Aspect 2, wherein positioning the implantable device near the target site in the patient's body includes positioning the implantable device in a tumor or peritumoral region, wherein the method further includes: positioning at least one electrode outside the peritumoral region, wherein generating the electric field includes generating an electric field between the implantable device and the at least one electrode outside the peritumoral region.

[0068] Aspect 4: A method according to Aspect 3, wherein positioning the at least one electrode outside the peritumoral region includes positioning the at least one electrode outside the patient's skin so that at least a portion of the peritumoral region is disposed between the implantable device and the at least one electrode outside the peritumoral region.

[0069] Aspect 5: The method according to aspect 1, wherein generating the electric field comprises periodically changing the direction of the electric field.

[0070] Aspect 6: The method of aspect 5, wherein periodically changing the direction of the electric field comprises changing the direction of the electric field at a frequency between 0.03 seconds and 0.5 seconds.

[0071] Aspect 7: A method according to Aspect 6, wherein the implantable device includes a plurality of electrodes, the plurality of electrodes including at least a first electrode and a second electrode, wherein changing the direction of the electric field includes inducing a first polarity at the first electrode and then inducing the first polarity at the second electrode.

[0072] Aspect 8: A method according to Aspect 3, wherein generating the electric field includes periodically changing the direction of the electric field, wherein changing the direction of the electric field includes: inducing a first polarity between the at least one electrode of the implantable device and the at least one electrode outside the peritumoral region; and inducing a second polarity opposite to the first polarity between the at least one electrode of the implantable device and the at least one electrode outside the peritumoral region.

[0073] Aspect 9: A method according to Aspect 4, wherein generating an electric field includes periodically changing the direction of the electric field, wherein changing the direction of the electric field includes: inducing a first polarity between at least one electrode of the implantable device and the at least one electrode outside the peritumoral region; and inducing a second polarity opposite to the first polarity between the at least one electrode of the implantable device and the at least one electrode outside the peritumoral region.

[0074] Aspect 10: The method of any of the preceding aspects, wherein the at least one electrode of the implantable device comprises ceramic.

[0075] Aspect 11: The method according to any one of the preceding aspects, wherein the target site is within the patient's brain.

[0076] Aspect 12: The method of any of the preceding aspects, wherein generating an electric field through the target site using an implantable device causes at least a portion of the target site to exceed a threshold temperature sufficient to cause damage to cells in the at least a portion of the target site.

[0077] Aspect 13: A method comprising: positioning an implantable device beneath the skin of a patient proximate a target site, wherein the target site is a tumor or peritumoral area, and wherein the implantable device comprises: an elongated body; and a plurality of electrodes coupled to the elongated body; and utilizing the implantable device to generate an electric field through the target site at a frequency of from 50-500 kHz.

[0078] Aspect 14: The method according to Aspect 13 further includes: positioning at least one electrode outside the patient's skin so that at least a portion of the target site is disposed between the implantable device and the at least one electrode, wherein generating an electric field through the target site using the implantable device includes generating an electric field between the implantable device and the at least one electrode outside the patient's skin at a frequency of from 50-500 kHz.

[0079] Aspect 15: The method of aspect 13 or aspect 14, wherein the elongated body is rigid.

[0080] Aspect 16: The method of any of Aspects 13-15, wherein the plurality of electrodes of the implantable device comprise ceramic.

[0081] Aspect 17: The method of any one of aspects 13-16, wherein generating the electric field comprises periodically changing the direction of the electric field.

[0082] Aspect 18: A method comprising: positioning a first implantable device and a second implantable device within a patient's body proximate a target site, wherein the target site is a tumor or a peritumoral area, and wherein each of the first implantable device and the second implantable device comprises at least one electrode; and generating an electric field between the at least one electrode of the first implantable device and the at least one electrode of the second implantable device at a frequency of from 50-500 kHz.

[0083] Aspect 19: The method of aspect 18, wherein generating the electric field comprises periodically changing the direction of the electric field.

[0084] Aspect 20: The method of aspect 19, wherein periodically changing the direction of the electric field comprises changing the direction of the electric field at a frequency between 0.03 seconds and 0.5 seconds.

[0085] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A system, characterized in that: include: electric field generator; and an implantable device comprising a transducer array having a plurality of electrodes, the implantable device being in electrical communication with the electric field generator and being configured for positioning proximate to or within a target site in a patient, wherein the electric field generator is configured to generate an electric field at a frequency from 50 kHz to 500 kHz using an implantable device, and wherein the electric field generator is configured to activate the plurality of electrodes as anode or cathode electrodes in a pattern, and periodically change the pattern of the plurality of electrodes activated as anode and cathode electrodes to periodically change the direction of the electric field.

2. The system of claim 1, wherein the implantable device comprises a thin substrate, wherein the plurality of electrodes are coupled to the thin substrate.

3. The system of claim 2, wherein the implantable device is configured for positioning in a tumor resection cavity.

4. The system according to claim 2, further comprising: at least one external electrode in electrical communication with the electric field generator and configured to be positioned remote from the target site, wherein the electric field generator is configured to generate an electric field between the implantable device and the at least one external electrode.

5. The system of claim 4, wherein the at least one external electrode is configured to be positioned externally to the patient's skin such that at least a portion of the target site is disposed between the implantable device and the at least one external electrode.

6. The system of claim 1, wherein the electric field generator is configured to change the direction of the electric field at a frequency between 0.03 seconds and 0.5 seconds.

7. The system of claim 6, wherein the plurality of electrodes comprises at least a first electrode and a second electrode, and the electric field generator is configured to change the direction of the electric field by inducing a first polarity at the first electrode and then inducing the first polarity at the second electrode.

8. The system of claim 4, wherein the electric field generator is configured to periodically change the direction of the electric field by: inducing a first polarity between at least one electrode of the plurality of electrodes of the implantable device and the at least one external electrode; and A second polarity opposite to the first polarity is induced between the at least one electrode of the plurality of electrodes of the implantable device and the at least one external electrode.

9. The system of claim 5, wherein the electric field generator is configured to periodically change the direction of the electric field by: inducing a first polarity between at least one electrode of the plurality of electrodes of the implantable device and the at least one external electrode; and A second polarity opposite to the first polarity is induced between the at least one electrode of the plurality of electrodes of the implantable device and the at least one external electrode.

10. The system of claim 2, wherein the plurality of electrodes of the implantable device comprises ceramic.

11. The system of claim 2, wherein the implantable device is configured to be positioned within the patient's brain.

12. The system of claim 2, wherein the electric field generator is configured to generate an electric field through the target site that causes at least a portion of the target site to exceed a threshold temperature sufficient to cause damage to cells in the at least a portion of the target site.

13. The system of claim 1 , wherein the implantable device comprises: An elongated body is provided, and the plurality of electrodes are coupled to the elongated body.

14. The system of claim 13, further comprising: at least one external electrode in electrical communication with the electric field generator and configured to be positioned remote from the target site, wherein the electric field generator is configured to generate an electric field between the implantable device and the at least one external electrode.

15. The system of claim 13, wherein the elongated body is rigid.

16. The system of claim 13, wherein the plurality of electrodes of the implantable device comprise ceramic.

17. A system according to claim 1, wherein the implantable device is a first implantable device, the system includes a second implantable device, the second implantable device includes at least one electrode, and the electric field generator is configured to generate an electric field between at least one electrode of the plurality of electrodes of the first implantable device and the at least one electrode of the second implantable device.

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