System for administering electrical stimulation to treat cancer

Abstract

Embodiments herein relate to a medical device for treating a cancerous tumor, the medical device comprising an electric field generating circuit and a control circuit in communication with the electric field generating circuit, the electric field generating circuit being configured to generate one or more electric fields at or near the site of the cancerous tumor. The medical device comprises one or more supply wires in electrical communication with the electric field generating circuit and one or more supply electrodes. The supply electrode is configured to deliver the electric field to or near the site of the cancerous tumor. The medical device may comprise one or more sensing wires in electrical communication with the control circuit and one or more sensing electrodes. The sensing electrode may be configured to measure the impedance of the cancerous tumor at at least two different electric field strengths. Other embodiments are also included herein.

Description

[0001] This application is filed as a PCT International Patent Application on April 16, 2020 in the name of Boston Scientific Scimed, Inc., a U.S. company, as applicant in all designated countries, and Brian L. Schmidt, U.S. citizen, Benjamin Keith Stein, U.S. citizen, Keith R. Maile, U.S. citizen, William J. Linder, U.S. citizen, Ron A. Balczewski, U.S. citizen, Sarah Melissa Gruba, U.S. citizen, Tucker James Nelson, U.S. citizen, and Aleksandra Kharam, U.S. citizen (inventors in all designated countries). This application claims priority to U.S. Provisional Application No. 62 / 837,128, filed on April 22, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0002] Embodiments herein relate to electrical stimulation devices and methods for treating cancer. More specifically, the electrical stimulation devices and methods herein may include features related to measuring one or more electrical properties at or near the site of a cancerous tumor, including but not limited to: impedance, polarization, capacitance, or voltage. Background Art

[0003] Living organisms are composed of complex three-dimensional structures of biological tissues, including cells and extracellular matrices surrounded by intracellular fluid and extracellular fluid. The intracellular fluid found in the cells of an organism is usually ionic and includes various electroactive molecules, such as ions, proteins, macronutrients, and nucleic acids. Extracellular fluid includes various fluids found outside the cells of an organism. To name a few, examples of extracellular fluids may include plasma, lymph, cerebrospinal fluid, eye fluid, synovial fluid, and saliva. Extracellular fluid is usually ionic in nature and may include electroactive macronutrients, such as ions, sugars, fatty acids, and metabolic wastes. The cell membrane of an organism includes phospholipids and proteins, wherein the hydrophobic lipid tails are sandwiched between two layers of hydrophilic phosphate head groups and various proteins associated therewith.

[0004] Biological tissues in living organisms have an electrical impedance when placed in an alternating electric field. The electrical impedance of biological tissues in living organisms may depend on the type of tissue, the healthy or diseased state of the tissue, and the frequency of the applied electric field. The electrical impedance of each type of biological tissue is determined by the cell type, intracellular fluid, and extracellular fluid composition of each specific tissue.

[0005] The electroactive molecules in biological tissues also give rise to dielectric properties within the tissues. When placed in an electric field, biological tissues can store electromagnetic energy due to the displacement of positive or negative charges carried by the electroactive molecules therein. The displacement of positive and negative charges within the tissues can result in a net polarization of the tissues. Summary of the invention

[0006] In a first aspect, a medical device for treating a cancerous tumor is included. The medical device may include an electric field generating circuit and a control circuit in communication with the electric field generating circuit, the electric field generating circuit being configured to generate one or more electric fields at or near the site of the cancerous tumor, and the control circuit may be configured to control the delivery of the one or more electric fields from the electric field generating circuit. The control circuit may cause the electric field generating circuit to generate one or more electric fields with an electric field strength selected from the range of 0.25V / cm to 1000V / cm. The medical device may include one or more supply wires in electrical communication with the electric field generating circuit, wherein the one or more supply wires may each be in electrical communication with one or more supply electrodes. The one or more supply electrodes may be configured to deliver the electric field to or near the site of the cancerous tumor. The medical device may include one or more sensing wires in electrical communication with the control circuit, wherein the one or more sensing wires may each be in electrical communication with one or more sensing electrodes. The one or more sensing electrodes may be configured to measure the impedance of the cancerous tumor at at least two different electric field strengths.

[0007] In a second aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the control circuit is configured to generate at least a first electric field and a second electric field, and wherein the first electric field has a first electric field strength and the second electric field has a second electric field strength.

[0008] In a third aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the second electric field strength is greater than the first electric field strength.

[0009] In a fourth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the first electric field strength is selected from the range of 0.1 V / cm to 2 V / cm, and the second electric field strength is selected from the range of 1 V / cm to 100 V / cm.

[0010] In a fifth aspect, in addition to one or more of the preceding or following aspects, or in the alternative of certain aspects, a medical device comprises a memory containing one or more sets of treatment parameters.

[0011] In a sixth aspect, in addition to one or more of the preceding or following aspects, or in an alternative to certain aspects, the control circuit is further configured to implement the one or more treatment parameter sets to deliver a given therapy.

[0012] In a seventh aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the control circuit is configured to modulate the one or more electric fields if the impedance at or near the site of the cancerous tumor during therapy changes by at least 5% relative to the initial impedance at or near the site of the cancerous tumor at the beginning of a given therapy.

[0013] In an eighth aspect, in addition to one or more of the preceding or following aspects, or in an alternative to certain aspects, the one or more electric fields are modulated by increasing or decreasing the electric field strength.

[0014] In a ninth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the control circuit may cause the electric field generating circuit to generate one or more electric fields at a frequency selected from the range of 10 kHz to 1 MHz at or near the site of the cancerous tumor.

[0015] In a tenth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the control circuit can be further configured to generate one or more electric fields by sweeping across a range of frequencies, wherein sweeping across a range of frequencies includes sweeping upward from a first frequency to a second frequency and sweeping downward from the second frequency to the first frequency, and wherein the second frequency is higher than the first frequency.

[0016] In an eleventh aspect, in addition to one or more of the above or following aspects, or in the alternative of certain aspects, the frequency range includes a frequency range from 100 kHz to 500 kHz.

[0017] In a twelfth aspect, a method for treating a cancerous tumor in a subject is included. The method may include implanting a medical device at or near the site of the cancerous tumor. The method may include: applying at least two electric fields at or near the site of the cancerous tumor using one or more supply leads to deliver at least a first electric field having a first electric field strength and a second electric field having a second electric field strength, each supply lead including one or more supply electrodes. The method may include: measuring the impedance of the cancerous tumor at the at least two electric field strengths, wherein measuring the impedance includes using one or more sensing leads, the sensing leads including one or more sensing electrodes. The method may include: if the impedance changes, modulating the therapy according to at least one set of treatment parameters.

[0018] In a thirteenth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, modulating the therapy according to the at least one treatment parameter set includes: modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor during the therapy changes by at least 5% relative to an initial impedance measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0019] In a fourteenth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the at least one treatment parameter set further includes modulating the one or more electric fields by increasing or decreasing the strength of the one or more electric fields.

[0020] In a fifteenth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, modulating therapy according to the at least one treatment parameter set includes: terminating the at least one treatment parameter set if the impedance falls outside a predetermined range during a predetermined time period.

[0021] In a sixteenth aspect, in addition to one or more of the foregoing or following aspects, or in the alternative of certain aspects, the one or more electric fields comprise an electric field strength selected from the range of 0.25 V / cm to 1000 V / cm.

[0022] In a seventeenth aspect, in addition to or in the alternative to one or more of the foregoing or following aspects, the method may include classifying the subject as non-responsive to therapy if a decrease in impedance is measured over a predetermined period of time.

[0023] In an eighteenth aspect, in addition to or in the alternative to one or more of the foregoing or following aspects, the method may include classifying the subject as responsive to therapy if an increase in impedance is measured over a predetermined period of time.

[0024] In a nineteenth aspect, a method for treating a cancerous tumor in a subject is included. The method may include implanting a medical device at or near the site of the cancerous tumor. The medical device may include applying one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to the at least one treatment parameter set for a predetermined period of time, wherein applying the one or more electric fields includes using one or more supply leads, each supply lead including one or more supply electrodes; wherein applying the one or more electric fields further includes applying the one or more electric fields at at least two frequencies. The method may include measuring the impedance of the cancerous tumor during the application of the one or more electric fields at the at least two frequencies, wherein measuring the impedance includes using one or more sensing leads, the sensing leads including one or more sensing electrodes. The method may include modulating the therapy according to the at least one treatment parameter set if the impedance changes during the predetermined period of time.

[0025] In the twentieth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, applying one or more electric fields at at least two frequencies includes at least applying a first electric field at a first frequency and applying a second electric field at a second frequency.

[0026] The present invention is a summary of some teachings of the present application and is not intended to be an exclusive or exhaustive treatment of the subject matter of the present invention. Further details are present in the specific embodiments and the appended claims. Other aspects will be apparent to those skilled in the art by reading and understanding the following specific embodiments and viewing the accompanying drawings (each of which should not be considered to have a limiting meaning) that form a part of the specific embodiments. The scope of this article is limited by the appended claims and their legal equivalents. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Various aspects may be more fully understood in conjunction with the following drawings (Figures), in which:

[0028] Figure 1 is a schematic circuit diagram according to various embodiments herein.

[0029] Figure 2 is a schematic circuit diagram according to various embodiments herein.

[0030] Figure 3 is a schematic diagram of a medical device according to various embodiments herein.

[0031] Figure 4 is a schematic diagram of a medical device according to various embodiments herein.

[0032] Figure 5 is a schematic cross-sectional view of a medical device according to various embodiments herein.

[0033] Figure 6 is a schematic diagram of a medical device according to various embodiments herein.

[0034] Figure 7 is a schematic diagram of a medical device according to various embodiments herein.

[0035] Figure 8 is a schematic diagram of a medical device according to various embodiments herein.

[0036] Fig. 9 is a graph of exemplary dielectric relaxation of biological tissue according to various embodiments herein.

[0037] Fig.10 is a schematic diagram of components of a medical device according to various embodiments herein.

[0038] Fig.11 is a schematic diagram of a method according to various embodiments herein.

[0039] Fig.12 is a schematic diagram of a method according to various embodiments herein.

[0040] Fig.13 is a schematic diagram of a method according to various embodiments herein.

[0041] Fig.14 is a schematic diagram of a method according to various embodiments herein.

[0042] Fig.15 is a schematic diagram of a method according to various embodiments herein.

[0043] Fig.16 is a graph of exemplary electric fields according to various embodiments herein.

[0044] Fig.17 is a graph of exemplary electric fields according to various embodiments herein.

[0045] Although the embodiments are susceptible to various modifications and alternative forms, the details thereof have been shown by way of example and drawings and will be described in detail. However, it should be understood that the scope of this article is not limited to the specific aspects described. On the contrary, the present invention will cover modifications, equivalents, and alternatives that fall within the spirit and scope of this article. DETAILED DESCRIPTION

[0046] As discussed above, biological tissues in living organisms have electrical impedance when placed in an alternating electric field. Like any healthy tissue, a cancerous tumor including at least one cancer cell population may also exhibit an electrical impedance affected by its cell type, intracellular fluid, and the extracellular fluid associated therewith when placed in an electric field. However, the impedance of cancerous tissue may vary compared to healthy tissue. In addition, the impedance of cancerous tissue may change due to the treatment of cancerous tissue. In this way, measuring and monitoring the impedance of healthy tissue and cancerous tissue before, during, and after treatment (regardless of the treatment modality) can provide valuable clinical insights to guide further therapy.

[0047] In addition, the impedance of the device components themselves (including but not limited to electrodes, leads, and components electrically connected thereto) before, during, and after treatment (regardless of the treatment modality) can provide valuable insights to guide further therapy. In some embodiments, the impedance of the components can be monitored periodically or multiple times during a given therapy to ensure optimal performance of the components. In some components (such as electrodes), the impedance of the electrodes may degrade over time and therefore can be replaced or adjusted when providing a given therapy. In addition, it can be useful to be able to subtract the contribution of the device components themselves to the impedance to achieve a more accurate measurement of tissue impedance.

[0048] In addition, dielectric relaxation measurements can provide useful clinical insights to guide therapy. In various embodiments herein, amplitude and phase can be measured locally to identify increased or decreased polarization. Polarization measurements can provide valuable insights into healthy and unhealthy cell populations, each of which provides its own polarization signature. For example, a first cancerous cell population can have its own unique polarization signature, while a second cancerous cell population can have its own unique polarization signature. Similarly, a healthy muscle cell population can have its own unique polarization signature, while a healthy liver cell population can have its own unique polarization signature. And, electrical stimulation can be turned off, and relaxation time signatures can be measured.

[0049] Impedance in biological tissue can be measured using a variety of methods, including two-wire impedance measurement or four-wire impedance measurement. Figure 1 , a diagram of a two-wire circuit 100 for measuring impedance within biological tissue according to embodiments herein is shown. The two-wire circuit 100 includes a first wire 102 having a first wire resistance 104, and a first electrode 106 in electrical communication with the first wire 102. The two-wire circuit 100 also includes a second wire 114 having a second wire resistance 112, and a second electrode 110 in electrical communication with the second wire 114. The first electrode 106 and the second electrode 110 are placed in close proximity to a tissue to be treated 108. For example, the tissue to be treated 108 may include healthy body tissue, or diseased body tissue, such as a cancerous tumor.

[0050] The two-wire circuit 100 also includes a current source 116 and a voltmeter 118. The direction of current through the circuit is depicted by current arrows 120 and 122. The first electrode 106 and the second electrode 110 are each configured to perform the following functions: provide an electric field at or near the site of the tissue 108 to be treated, and sense the impedance at or near the site of the tissue 108 to be treated. Therefore, in this case, a known current is provided to the tissue 108, and the voltage drop is measured using the same electrode pair (or the potential difference between the two electrodes of the electrode pair). The impedance can then be calculated according to Ohm's law (V=IR or V=IZ). However, when measured in this manner, the current passing through the circuit experiences a voltage drop between the first wire resistance 104 and the second wire resistance 112. The current passing through the circuit may experience a voltage drop due to the impedance within the wires, electrodes, and any other components electrically connected thereto. Thus, the voltage 124 across tissue 108 measured by voltmeter 118 includes interference from voltage drops within components of two-wire circuit 100 and is different from the actual voltage drop 126 across tissue 108. As such, any impedance as measured through tissue 108 also includes the impedance of the components of two-wire circuit 100. While not intending to be bound by theory, it is believed that, in some circumstances, such interference with measuring the impedance of tissue 108 may be detrimental to the clinical value of measuring and / or monitoring the impedance of tissue 108 and render it less valuable for guiding treatment.

[0051] A four-wire system for measuring impedance may provide improved accuracy and, in particular, may reduce or eliminate interference with impedance measurements associated with a two-wire system. Figure 2 , a diagram of an exemplary four-wire circuit 200 for measuring impedance within biological tissue according to embodiments of the present invention is shown. The four-wire circuit 200 differs from the two-wire circuit 100 in that the four-wire circuit 200 includes two supply electrodes and two separate sensing electrodes. The four-wire circuit 200 includes a first wire 202 having a first wire resistance 204, and a first supply electrode 206 electrically connected to the first wire 202. The four-wire circuit 200 also includes a second wire 214 having a second wire resistance 212, and a second supply electrode 210 electrically connected to the second wire 214. The first supply electrode 206 and the second supply electrode 210 are placed in close proximity to the tissue 108 to be treated. For example, the tissue 108 to be treated may include healthy body tissue, or diseased body tissue, such as a cancerous tumor. The first supply electrode 206 and the second supply electrode 210 are configured to provide one or more electric fields to or near the site of the tissue 108.

[0052] The four-wire circuit 200 further includes a third wire 224 having a third wire resistance 226, and a first sensing electrode 228 in electrical communication with the third wire 224. The four-wire circuit 200 also includes a fourth wire 234 having a fourth wire resistance 232, and a second sensing electrode 230 in electrical communication with the fourth wire 234. The first sensing electrode 228 and the second sensing electrode 230 are placed in close proximity to the tissue 108 to be treated, and they are configured to measure impedance within the tissue 108.

[0053] The four-wire circuit 200 also includes a current source 116 and a voltmeter 118. The direction of current through the circuit is depicted by current arrows 220 and 222. The current is configured to flow through the first supply electrode 206, the tissue 108, the second supply electrode 210, and any wires and components in electrical communication therewith. Compared to the two-wire circuit 100, the four-wire circuit 200 is configured so that negligible current flows through the sensing electrode and the wires and components in electrical communication therewith. As such, the voltage 236 measured by the voltmeter 118 is substantially equal to the voltage 238 across the tissue 108. Any impedance within the first wire, the first supply electrode, the second wire, the second supply electrode, and any components in electrical communication therewith is not measured with the tissue sensed across the tissue 108 alone.

[0054] The impedance of a cancerous tumor can be measured using any of the medical devices described herein and can be accomplished using a two-lead, four-lead, or other system. Figure 3 and Figure 4 , shows a schematic diagram of a subject 301 having a cancerous tumor 310 according to embodiments herein. Figure 3 In FIG. 3 , a subject 301 has a medical device 300 fully implanted within the subject 301 at or near the site of a cancerous tumor 310. Various implantation sites may be used, including areas such as in a limb, upper torso, abdominal region, head, etc. In FIG. Figure 4 In the embodiment of the present invention, subject 301 has a medical device 400 at least partially implanted in subject 301 at or near the site of a cancerous tumor. In some embodiments, the medical device can be completely outside the subject's body. In some embodiments, the medical device can be partially outside the subject's body. In some embodiments, the medical device can be partially implanted in the subject and partially outside the subject's body. In other embodiments, the partially implanted medical device can include a percutaneous connection between components arranged inside the body and outside the body. The partially or completely implanted medical device can communicate wirelessly with a partially or completely external portion of the medical device via a wireless connection.

[0055] In some embodiments, a portion of the medical device may be completely implanted and a portion of the medical device may be completely external. For example, in some embodiments, one or more electrodes or leads may be completely implanted within the body, while the portion of the medical device that generates the electric field (such as an electric field generator) may be completely outside the body. It should be understood that in some embodiments described herein, the described electric field generator may include many of the same components as a pulse generator and may be configured to perform many of the same functions as a pulse generator. In embodiments where a portion of the medical device is completely implanted and a portion of the medical device is completely external to the body, the portion of the medical device that is completely external to the body may communicate wirelessly with the portion of the medical device that is completely internal to the body. However, in other embodiments, a wired connection may be used.

[0056] Medical device 300 may include a housing 302 and a head 304 coupled to housing 302, and medical device 400 may include housing 302. Various materials may be used. However, in some embodiments, housing 302 may be formed of materials such as metal, ceramic, polymer, composite material, etc. In some embodiments, housing 302 or one or more portions thereof may be formed of titanium. Head 304 may be formed of various materials, but in some embodiments, head 304 may be formed of a translucent polymer such as epoxy. In some embodiments, head 304 may be hollow. In other embodiments, head 304 may be filled with components and / or structural materials, such as epoxy or another material, so that it is not hollow.

[0057] In some embodiments where a portion of the medical device 300 or 400 is partially outside the body, the head 304 and the housing 302 may be surrounded by a protective casing made of a durable polymer material. In other embodiments, where a portion of the medical device 300 or 400 is partially outside the body, the head 304 and the housing 302 may be surrounded by a protective casing made of a combination of polymer materials, metal materials, and / or glass materials.

[0058] Head 304 can be coupled to one or more leads, such as lead 306. Head 304 can be used to provide fixation of the proximal end of one or more leads 306 and electrically couple one or more leads 306 to one or more components within housing 302. The one or more leads 306 can include one or more electrodes, such as electrode 308, arranged along the length of lead 306. In some embodiments, electrode 308 can include an electric field generating electrode, also referred to herein as a "supply electrode". In some embodiments, electrode 308 can include an electric field sensing electrode, also referred to herein as a "sensing electrode". In some embodiments, lead 306 can include both supply electrodes and sensing electrodes. In other embodiments, lead 306 can include any number of electrodes, which are both supply electrodes and sensing electrodes. It should be understood that although many embodiments of the medical device herein are designed to function with a lead, leadless medical devices that generate an electric field are also contemplated herein. In some embodiments, electrode 308 can be a tip electrode at the distal-most end of lead 306. In some embodiments, the medical device herein can include a drug eluting coating on the surface of the longitudinal axis of the lead in an area near the cancerous tumor 310. In some embodiments, the drug eluting coating may include an anti-neoplastic agent, a cytotoxic agent, or an antibiotic agent, as discussed in more detail below.

[0059] See now Figure 5 , a schematic cross-sectional view of an exemplary medical device 300 according to an embodiment of the present invention is shown. It should be understood that the features of the medical device 300 may be included in any medical device described herein. The housing 302 may define an internal volume 503, which may be hollow and, in some embodiments, be hermetically sealed and separated from an area 505 outside the medical device 300. In other embodiments, the housing 302 may be filled with components and / or structural materials so that it is not hollow. The medical device 300 may include a control circuit 506, which may include various components 508, 510, 512, 514, 516, and 518 arranged within the housing 302. In some embodiments, these components may be integrated, while in other embodiments, these components may be separate. In other other embodiments, there may be a combination of both integrated components and separate components. The medical device 300 may also include an antenna 524 to allow one-way or two-way wireless data communication. In some embodiments, components of medical device 300 may include an inductive energy receiver coil (not shown) communicatively coupled or attached thereto to facilitate transcutaneous recharging of the medical device via a recharging circuit.

[0060] The various components 508, 510, 512, 514, 516, and 518 of the control circuit 506 may include, but are not limited to, a microprocessor, a memory circuit (such as a random access memory (RAM) and / or a read-only memory (ROM)), a recorder circuit, a controller circuit, a telemetry circuit, a power circuit (such as a battery), a timing circuit and an application-specific integrated circuit (ASIC), a recharging circuit, and the like. The control circuit 506 may be in communication with an electric field generating circuit 520, which may be configured to generate an electric current to form one or more fields. The electric field generating circuit 520 may be integrated with the control circuit 506, or may be a separate component from the control circuit 506. The control circuit 506 may be configured to control the delivery of an electric current from the electric field generating circuit 520. In some embodiments, the electric field generating circuit 520 may be present in a portion of the medical device that is external to the body.

[0061] In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to deliver the electric field using one or more frequencies selected from the range of 10kHz to 1MHz. In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to deliver the electric field at one or more frequencies selected from the range of 300kHz to 500kHz. In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to deliver the electric field at one or more frequencies selected from the range of 100kHz to 300kHz. In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to periodically deliver the electric field using one or more frequencies greater than 1MHz.

[0062] In some embodiments, the electric field can effectively disrupt cell mitosis in cancer cells. The electric field can be delivered to the site of the cancerous tumor along more than one vector. In some instances, the electric field can be delivered along at least one vector (including at least one of the lead electrodes). In some embodiments, at least two vectors with spatial diversity between the two vectors can be used. The vectors can be separated in space and / or direction (e.g., the vectors can be arranged at an angle relative to each other) by at least about 10 degrees, 20 degrees, 30 degrees, 40 degrees, 50 degrees, 60 degrees, 70 degrees, 80 degrees, or 90 degrees.

[0063] The desired electric field strength can be achieved by delivering an electric current between the two electrodes. The specific current and voltage of the delivered electric field can vary and can be adjusted to achieve the desired electric field strength at the tissue site to be treated. In some embodiments, the control circuit 506 can be configured to guide the electric field generating circuit 520 to use a current in the range of 1 mAmp to 1000 mAmp to deliver the electric field to the site of the cancerous tumor. In some embodiments, the control circuit 506 can be configured to guide the electric field generating circuit 520 to use a current in the range of 20 mAmp to 500 mAmp to deliver the electric field to the site of the cancerous tumor. In some embodiments, the control circuit 506 can be configured to guide the electric field generating circuit 520 to use a current in the range of 30 mAmp to 300 mAmp to deliver the electric field to the site of the cancerous tumor.

[0064] In some embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to deliver an electric field using a current comprising: 1 mAmp, 2 mAmp, 3 mAmp, 4 mAmp, 5 mAmp, 6 mAmp, 7 mAmp, 8 mAmp, 9 mAmp, 10 mAmp, 15 mAmp, 20 mAmp, 25 mAmp, 30 mAmp, 35 mAmp, 40 mAmp, 45 mAmp, 50 mAmp, 60 mAmp, 70 mAmp, 80 mAmp, 90 mAmp, 300 mAmp, 125 mAmp, 150 mAmp, 175 mAmp, 400 mAmp, 225 mAmp, 250 mAmp, mAmp, 275mAmp, 300mAmp, 325mAmp, 350mAmp, 375mAmp, 400mAmp, 425mAmp, 450mAmp, 475mAmp, 500mAmp, 525mAmp, 550mAmp, 575mAmp, 600mAmp, 625mAm p, 650mAmp, 675mAmp, 700mAmp, 725mAmp, 750mAmp, 775mAmp, 800mAmp, 825mAmp, 850mAmp, 875mAmp, 900mAmp, 925mAmp, 950mAmp, 975mAmp or 1000mAmp. It should be understood that the control circuit can be configured to direct the electric field generating circuit 520 to deliver the electric field with a current falling within a certain range, where any of the aforementioned currents can be used as the lower limit or upper limit of the range, provided that the lower limit of the range is a value less than the upper limit of the range.

[0065] In some embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to use a 1V rms Up to 50V rmsIn some embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to use a voltage within the range of 5V to deliver the electric field to the site of the cancerous tumor. rms Up to 30V rms In some embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to use a voltage within the range of 10V to deliver the electric field to the site of the cancerous tumor. rms Up to 20V rms Voltages within a range deliver the electric field to the site of the cancerous tumor.

[0066] In some embodiments, control circuit 506 may be configured to direct electric field generating circuit 520 to deliver an electric field using one or more voltages including: 1V rms , 2V rms , 3V rms , 4V rms , 5V rms , 6V rms , 7V rms , 8V rms , 9V rms , 10V rms , 15V rms , 20V rms , 25V rms , 30V rms , 35V rms , 40V rms , 45V rms or 50V rms It should be appreciated that the control circuit 506 may be configured to direct the electric field generating circuit 520 to deliver the electric field using a voltage falling within a range, wherein any of the aforementioned voltages may be used as the lower limit or upper limit of the range, provided that the lower limit of the range is a value less than the upper limit of the range.

[0067] In some embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to deliver the electric field using one or more frequencies including: 10kHz, 20kHz, 30kHz, 40kHz, 50kHz, 60kHz, 70kHz, 80kHz, 90kHz, 300kHz, 125kHz, 150kHz, 175kHz, 400kHz, 225kHz, 250kHz, 275kHz, 300kHz, 325kHz, 350kHz Hz, 375kHz, 400kHz, 425kHz, 450kHz, 475kHz, 500kHz, 525kHz, 550kHz, 575kHz, 600kHz, 625kHz, 650kHz, 675kHz, 700kHz, 725kHz, 750kHz, 775kHz, 800kHz, 825kHz, 850kHz, 875kHz, 900kHz, 925kHz, 950kHz, 975kHz, 1MHz. It should be appreciated that the electric field generating circuit 520 can deliver the electric field using frequencies falling within a range, wherein any of the foregoing frequencies can be used as the upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

[0068] In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to generate one or more applied electric field strengths selected from the range of 0.25 V / cm to 1000 V / cm. In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to generate one or more applied electric field strengths greater than 3 V / cm. In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to generate one or more applied electric field strengths selected from the range of 1 V / cm to 10 V / cm. In some embodiments, the control circuit 506 may be configured to direct the electric field generating circuit 520 to generate one or more applied electric field strengths selected from the range of 3 V / cm to 5 V / cm.

[0069] In other embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to generate one or more applied electric field strengths including: 0.25 V / cm, 0.5 V / cm, 0.75 V / cm, 1.0 V / cm, 2.0 V / cm, 3.0 V / cm, 5.0 V / cm, 6.0 V / cm, 7.0 V / cm, 8.0 V / cm, 9.0 V / cm, 10.0 V / cm, 20.0 V / cm, 30.0 V / cm, 40.0 V / cm, 50.0 V / cm, 60.0 V / cm, 70.0 V / cm, 80.0 V / cm, 90.0 V / cm cm, 300.0V / cm, 125.0V / cm, 150.0V / cm, 175.0V / cm, 400.0V / cm, 225.0V / cm, 250.0V / cm, 275.0V / cm, 300.0V / cm, 325.0V / cm, 350.0V / cm , 375.0V / cm, 400.0V / cm, 425.0V / cm, 450.0V / cm, 475.0V / cm, 500.0V / cm, 600.0V / cm, 700.0V / cm, 800.0V / cm, 900.0V / cm, 1000.0V / cm. It should be understood that the electric field generating circuit 520 can generate an electric field at the treatment site having an electric field strength falling within a certain range, where any of the aforementioned field strengths can be used as the upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

[0070] In some embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to deliver the electric field to the site of the cancerous tumor located in the body tissue via the lead 507. In other embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to transmit the electric field to the site of the cancerous tumor located in the body tissue via the housing 502 of the medical device 300. In other embodiments, the control circuit 506 can be configured to direct the electric field generating circuit 520 to deliver the electric field between the lead 507 and the housing 502 of the medical device 300. In some embodiments, one or more leads 507 can be electrically connected to the electric field generating circuit 520. In some embodiments, one or more leads 507 can include one or more electrodes ( Figure 5 Not shown), wherein the electrodes may be in electrical communication with an electric field generating circuit 520.

[0071] In some embodiments, various components within medical device 300 may include electric field sensing circuitry 522 configured to generate a signal corresponding to a sensed electric field. Electric field sensing circuitry 522 may be integrated with control circuitry 506, or it may be separate from control circuitry 506.

[0072] The sensing electrodes may be arranged on or near the housing of the medical device, on one or more leads connected to the housing, on a separate device implanted near or in a tumor, or any combination of these locations. In some embodiments, the electric field sensing circuit 522 may include a first sensing electrode 532 and a second sensing electrode 534. In other embodiments, the housing 302 itself may be used as a sensing electrode for the electric field sensing circuit 522. The sensing electrodes 532 and 534 may be in communication with the electric field sensing circuit 522. The electric field sensing circuit 522 may measure the potential difference (voltage) between the first sensing electrode 532 and the second sensing electrode 534. In some embodiments, the electric field sensing circuit 522 may measure the potential difference (voltage) between the first sensing electrode 532 or the second sensing electrode 534 and an electrode arranged along the length of one or more leads 507. In some embodiments, the electric field sensing circuit may be configured to measure the sensed electric field and record the electric field strength in V / cm.

[0073] It should be appreciated that the electric field sensing circuit 522 can additionally measure the potential difference between the first sensing electrode 532 or the second sensing electrode 534 and the housing 302 itself. In other embodiments, the medical device may include a third electrode 536, which may be an electric field sensing electrode or an electric field generating electrode. In some embodiments, one or more sensing electrodes may be arranged along the lead 507 and may be used as an additional location for sensing an electric field. According to embodiments herein, many combinations are conceivable for measuring the potential difference between electrodes arranged along the length of one or more leads 507 and the housing 302.

[0074] In some embodiments, one or more leads 507 can be in electrical communication with the electric field generating circuit 520. The one or more leads 507 can include one or more electrodes arranged along the longitudinal axis or at the tip of the lead. In some embodiments, various electrical conductors (such as electrical conductors 526 and 528) can pass from the head 504 through the feed-through structure 530 and into the internal volume 503 of the medical device 300. In this way, the electrical conductors 526 and 528 can be used to provide electrical communication between the one or more leads 507 and the control circuit 506 arranged in the internal volume 503 of the housing 302.

[0075] In some embodiments, the recorder circuit can be configured to record data generated by the electric field sensing circuit 522 and record a timestamp about the data. In some embodiments, the control circuit 506 can be hardwired to perform various functions, while in other embodiments, the control circuit 506 can be directed to implement instructions executed on a microprocessor or other external computing device. Telemetry circuitry can also be provided for communicating with an external computing device, such as a programmer, a unit installed in a room, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.).

[0076] It should be understood that the components of the medical device that can form part of the circuit (including leads, electrodes, and any components electrically connected thereto) can apply impedance at any applied electric field strength discussed herein. It should be further understood that biological tissues that exist as part of the circuit created by the medical device described herein exhibit different impedances under different applied electric field strengths. Referring again to Ohm's law (V=IR or V=IZ), it should be understood that impedance Z is the ratio of voltage (V) to current (I) (i.e., Z=V / I). Therefore, the impedance of biological tissue is directly related to the strength of a given electric field. In this way, an electric field delivered at a high voltage produces a high impedance in biological tissue, while an electric field delivered at a low voltage produces a low impedance in biological tissue. Any impedance changes detected at a given electric field strength can provide valuable information related to the efficacy of the treatment, such as changes in tumor size and / or changes in surrounding healthy tissue.

[0077] See now Figure 6 , shows a medical device 600 for treating cancerous tumors according to an embodiment of the present invention. The medical device 600 may include a housing 302, a head 304 coupled to the housing 302, a first lead 602, and a second lead 608. The medical device 600 may include an electric field generating circuit arranged in the housing 302, such as Figure 5 The electric field generating circuit 520 shown. The electric field generating circuit of the medical device 600 can be configured to generate one or more electric fields at or near the site of the cancerous tumor 310. The medical device 600 can further include a control circuit disposed in the housing 302, such as Figure 5 The control circuit 506 shown. The control circuit of the medical device 600 can be in communication with the electric field generating circuit, wherein the control circuit is configured to control the delivery of the one or more electric fields from the electric field generating circuit. The control circuit can cause the electric field generating circuit to generate one or more electric fields with an electric field strength selected from the range of 0.25 V / cm to 1000 V / cm. The medical device 600 can further generate one or more electric fields at various currents, frequencies, and / or voltages, as described elsewhere herein.

[0078] The first lead 602 and the second lead 608 of the medical device 600 may include one or more supply wires and one or more sensing wires. For example, the first lead 602 may include a first supply wire 604, and the second lead 608 may include a second supply wire 610, wherein each supply wire is in electrical communication with an electric field generating circuit. The first supply wire 604 may be in electrical communication with a first supply electrode 614, and the second supply wire 610 may be in electrical communication with a second supply electrode 618. The first supply electrode 614 and the second supply electrode 618 may form a first supply electrode pair, which may be configured to deliver an electric field 622 to or near the site of the cancerous tumor 310.

[0079] The first lead 602 may include a first sensing wire 606, and the second lead 608 may include a second sensing wire 612, wherein each sensing wire is electrically connected to the electric field generating circuit. The first sensing wire 606 may be electrically connected to the first sensing electrode 616, and the second sensing wire 612 may be electrically connected to the second sensing electrode 620. The first sensing electrode 616 and the second sensing electrode 620 may form a first sensing electrode pair, which may be configured to measure the impedance 624 of the cancerous tumor 310. In other embodiments, the first sensing electrode 616 and the second sensing electrode 620 may be configured to measure the impedance 626 of the healthy tissue 601 surrounding the cancerous tumor 310, but not the impedance 624 of the cancerous tumor itself. It should be understood that although the medical device 600 is depicted as having only two leads, each having a single supply wire and a sensing wire, the medical device 600 may include more than two leads, wherein each lead may include one or more supply wires or sensing wires. In some embodiments, the supply wire and the sensing wire may be electrically insulated from each other.

[0080] In some embodiments, the sensing electrode may be configured to measure the impedance of the cancerous tumor under at least two different electric field strengths. In some embodiments, the sensing electrode may be configured to measure the impedance of the cancerous tumor under at least two different delivery voltages. For example, in some embodiments, the control circuit may be configured to generate at least a first electric field having a first electric field strength and a second electric field having a second electric field strength. In some embodiments, the second electric field strength is greater than the first electric field strength. In some embodiments, the first electric field strength partially overlaps with the second electric field strength. In some embodiments, the first electric field strength may be selected from a range of about 0.1V / cm to about 2V / cm, and the second electric field may be selected from a range of about 1V / cm to about 100V / cm. It should be understood that additional electric fields may also be used, such as a third electric field, a fourth electric field, a fifth electric field, a sixth electric field, a seventh electric field, etc., each of which includes a corresponding electric field strength. Various electric field strengths suitable for use in embodiments are described elsewhere herein.

[0081] The medical device 600 may further include a memory for storing one or more treatment parameter sets for delivering therapy at or near the site of the cancerous tumor 310. In some embodiments, the control circuit may be configured to implement the one or more treatment parameter sets to deliver a given therapy. In some embodiments, the control circuit may be configured to implement switching between the one or more treatment parameter sets to deliver a given therapy. In some embodiments, the control circuit may be configured to pause or interrupt the one or more treatment parameter sets to temporarily or permanently stop the delivery of a given therapy. In some embodiments, the control circuit may be configured to implement one or more treatment parameter sets configured to modulate the electric field by increasing or decreasing the electric field strength. In some embodiments, the control circuit may be configured to generate one or more electric fields by using a voltage control mode, wherein the voltage control mode includes modulating the voltage to maintain a substantially constant electric field strength. In some embodiments, the control circuit may be configured to generate one or more electric fields by using a current control mode, wherein the current control mode includes modulating the current to maintain a substantially constant electric field strength.

[0082] When the impedance of the cancerous tumor 310 changes during a given therapy, the control circuit can be configured to implement a set of treatment parameters to modulate one or more electric fields at or near the site of the cancerous tumor 310. In some embodiments, the one set of treatment parameters can be configured to modulate the one or more electric fields by increasing or decreasing the electric field strength in response to an increase or decrease in the impedance of the cancerous tumor 310. In some embodiments, at least one set of treatment parameters can include modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor during a given therapy changes by at least 5%, at least 15%, or at least 20% relative to an initial impedance at or near the site of the cancerous tumor at the beginning of the given therapy. In some embodiments, at least one set of treatment parameters can include modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor during a given therapy changes by at least 25%, at least 50%, or at least 75% relative to an initial impedance at or near the site of the cancerous tumor at the beginning of the given therapy. In some embodiments, the treatment parameter set may include modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by a percentage greater than or equal to 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, 750%, 1000%, or more, or an amount within a range between any of the foregoing percentages. In other embodiments, the treatment parameter set may include modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by a percentage greater than 100% relative to the initial impedance at or near the site of the cancerous tumor.

[0083] In some embodiments, if there are two or more electrodes on the lead of the medical device herein, each electrode can be spaced apart by at least 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.5, 0.75, 1, 2, 3, 4, 5, 10 cm (or an amount within a range between any of the foregoing) along the longitudinal axis of the lead. For example, the first supply electrode 614 and the first sensing electrode 616 of the first lead 602 are spaced apart by at least 0.25 cm along the longitudinal axis of the first lead 602; and the second supply electrode 618 and the second sensing electrode 620 of the second lead 608 are spaced apart by at least 0.25 cm along the longitudinal axis of the second lead 608.

[0084] It should be appreciated that the current passing through the first supply electrode 614 and the second supply electrode 618 does not pass significantly through the first sense electrode pair (including the first sense electrode 616 and the second sense electrode 620). Therefore, the current passing through the first sense electrode 616, the first sense wire 606, the second sense electrode 620, the second sense wire 612, and the components electrically connected thereto is negligible. In some embodiments, the current passing through the first sense electrode 616, the first sense wire 606, the second sense electrode 620, the second sense wire 612, and the components electrically connected thereto is less than 2000, 1000, 750, 500, 250, 100, 50, or 10 pA.

[0085] In some embodiments, the medical device herein may include four leads that are spatially separated from one another, wherein the supply wire or the sensing wire may be present in a separate lead. Figure 7 , shows a medical device 700 for treating a cancerous tumor 310 according to embodiments herein. The medical device 700 may include a first lead 702 (which includes a first supply wire 704), a second lead 706 (which includes a first sense wire 708), a third lead 710 (which includes a second supply wire 712), and a fourth lead 714 (which includes a second sense wire 716). The first supply wire 704 and the second supply wire 712 may be configured as supply wires for supplying an electric field at or near the site of the cancerous tumor 310. The first sense wire 708 and the second sense wire 716 may be configured as sense wires for measuring impedance at or near the site of the cancerous tumor 310.

[0086] The first lead 702 may include a first supply electrode 718 in electrical communication with the first supply wire 704. The second lead 706 may include a first sensing electrode 720 in electrical communication with the first sensing wire 708. The third lead 710 may include a second supply electrode 722 in electrical communication with the second supply wire 712. The fourth lead 714 may include a second sensing electrode 724 in electrical communication with the second sensing wire 716. The first supply electrode 718 and the second supply electrode 722 may be configured as a supply electrode pair to deliver an electric field to or near the site of the cancerous tumor 310. The first sensing electrode 720 and the second sensing electrode 724 are configured as a sensing electrode pair to measure the impedance 624 of the cancerous tumor 310, wherein the impedance 624 is independent of the impedance of the first supply electrode 718, the first supply wire 704, the second supply electrode 722, the second supply wire 712, and any components in electrical communication therewith. In some embodiments, more than four leads and / or more than four wires may be used.

[0087] The first supply electrode 718 and the second supply electrode 722 forming the first supply electrode pair can deliver the electric field to the site of the cancerous tumor or near the site along the first vector, and the first sensing electrode 720 and the second sensing electrode 724 forming the first sensing electrode can measure the impedance 624 of the cancerous tumor 310 at or near the site of the cancerous tumor 310 along the second vector. The first vector and the second vector can be separated from each other in space and or direction. In some embodiments, the first vector and the second vector can be separated in space and or direction (for example, the vectors can be arranged at an angle relative to each other) by at least about 10 degrees, 20 degrees, 30 degrees, 40 degrees, 50 degrees, 60 degrees, 70 degrees, 80 degrees, or 90 degrees. It should be understood that the first supply electrode pair can deliver the electric field to the site of the cancerous tumor or near the site along multiple vectors, and the first sensing electrode pair can similarly measure impedance along multiple vectors, which are separated in space from the vector used to deliver the electric field. In some embodiments, the sensing electrode can be configured to sense the impedance 624 within the cancerous tumor along one or more vectors of the non-therapy vector.

[0088] The medical device 700 may also include additional sensing wires and additional sensing electrodes. For example, the second lead 706 may further include a third sensing wire 726 electrically connected to the third sensing electrode 728, and the fourth lead 714 may include a fourth sensing electrode 730 electrically connected to the fourth sensing electrode 732. The third sensing electrode 728 and the fourth sensing electrode 730 may be used as a second sensing electrode pair that is configured to sense the impedance 626 of the healthy tissue 601 surrounding the cancerous tumor 310, but not the impedance 624 of the cancerous tumor itself. It should be understood that the medical device herein may include the following additional configurations: using multiple supply wires and multiple supply electrodes to deliver the electric field to or near the site of the cancerous tumor, and using multiple sensing wires and multiple sensing electrodes to measure the impedance within the cancerous tumor or healthy tissue.

[0089] In some embodiments herein, a medical device may include both an internal component and an external component. Figure 8, a schematic diagram of a medical device 800 according to an embodiment of the present invention is shown. The medical device 800 may include an inner portion at the inner side 850 of the subject's body and an outer portion at the outer side 852 of the subject's body. The inner portion of the medical device 800 may include an inner electrical lead 801, and the outer portion may include a housing 302 and an outer electrical lead 802. The medical device 800 may also include a percutaneous access port 820 that spans an outer surface 822 of the subject's body at or near the site of the cancerous tumor 310, suitable for receiving one or more leads or cannulas. For example, the percutaneous access port 820 may be configured to receive at least one of the following: an inner electrical lead 801, a drug delivery cannula for delivering one or more chemotherapeutic agents, an optical lead including one or more light emitters for delivering light energy, a biopsy device for obtaining a biopsy sample from a cancerous tumor, or a flushing cannula for flushing waste or body fluids from a cancerous tumor site.

[0090] Inner electrical lead 801 may include one or more electrodes, such as sensing electrodes 804 and 808 and supply electrodes 806 and 810, arranged along the length of inner electrical lead 801. Outer electrical lead 802 may include sensing electrodes 812 and 816 and supply electrodes 814 and 818 arranged along the length of outer electrical lead 802. In some embodiments, electrodes 804, 806, 808, 810, 812, 814, 816, and 818 may include any configuration of electric field generating electrodes and electric field sensing electrodes. In some embodiments, inner electrical lead 801 or outer electrical lead 802 may include any configuration of electric field generating electrodes and electric field sensing electrodes. It should be understood that although Figure 8 Not shown, but each supply electrode and each sense electrode has associated therewith a conductive line that is in electrical communication with the electric field generating circuit.

[0091] The proximal end of the inner electrical lead 801 or the outer electrical lead 802 is disposed within the housing 302. The distal end of the inner electrical lead 801 can surround the cancerous tumor 310 so that the electrodes 804, 806, 808, and 810 are brought near the cancerous tumor 310. The outer electrical lead 802 can be placed on the outside of the subject's body, near the cancerous tumor site, so that the electrodes 812, 814, 816, and 818 are in electrical communication with the electrodes 804, 806, 808, and 810 on the inner electrical lead 801. In some embodiments, the inner electrical lead 801 can be positioned within the vasculature so that the electrodes 804, 806, 808, and 810 are adjacent to the cancerous tumor 310 or positioned within the cancerous tumor. However, it should be understood that the inner electrical lead 801 can be disposed in a variety of places within or around the cancerous tumor 310. In some embodiments, the inner electrical lead 801 can pass directly through the cancerous tumor 310.

[0092] In some embodiments, the inner electrical lead 801 can include one or more tracking markers 826 along the length of the inner electrical lead 801 for determining the precise location of the electrode relative to the tumor. In some embodiments, the one or more tracking markers can be disposed directly distally or directly proximal to the one or more electrodes disposed on the inner electrical lead 801. In some embodiments, the tracking markers can be formed of a magnetic material. In some embodiments, the tracking markers can be formed of a radiographic material. In some embodiments, the tracking markers can be formed of a fluorographic material.

[0093] It should be understood that a plurality of electric field vectors can be generated between various combinations of supply electrodes 806, 810, 814, or 818 arranged along the inner electrical lead 801 and the outer electrical lead 802 to generate an electric field. For example, one or more electric field vectors can be generated between the supply electrodes 806 and 814. Similarly, one or more electric field vectors can be generated between the supply electrodes 810 and 818. It should also be understood that one or more electric field vectors can be generated between any combination of the supply electrodes 806, 810, 814, or 818. In some embodiments, one or more electric field vectors can be generated between any combination of the supply electrodes 806, 810, 814, or 818 and the housing 302 of the medical device 800.

[0094] It should be appreciated that the sensing electrodes 804, 808, 812, and 816 can sense impedance 624 within the cancerous tumor 310 along one or more vectors between any combination of the sensing electrodes 804, 808, 812, and 816, wherein the impedance 624 of sensing the cancerous tumor 310 can be independent of any impedance present in any of the supply electrodes 806, 810, 814, or 818, or any wires or components in electrical communication therewith. It should be further appreciated that the sensing electrodes 804, 808, 812, and 816 can sense impedance 626 within the healthy tissue 601 surrounding the cancerous tumor 310 along one or more vectors between any combination of the sensing electrodes 804, 808, 812, and 816. The impedance 626 of sensing the healthy tissue 601 can be independent of any impedance present in the cancerous tumor 310, or any of the supply electrodes 806, 810, 814, or 818, or any wires or components in electrical communication therewith. Sensing the impedance 626 of the healthy tissue 601 may be performed along one or more non-therapy vectors between any of the sensing electrodes 804 , 808 , 812 , and 816 .

[0095] It should be appreciated that the sensing electrodes may sense the impedance 824 of any supply electrode along one or more vectors between the sensing electrodes 804, 808, 812, and 816 and any combination of the supply electrodes 806, 810, 814, or 818. In some embodiments, the sensing electrodes 804, 808, 812, and 816 may sense the impedance 824 of any supply electrode along one or more non-therapy vectors. Each sensing electrode may be further configured to measure the impedance of any one of the supply electrodes 806, 810, 814, or 818 independently of the impedance created by the cancerous tumor 310, or by any of the other supply electrodes, leads, wires, or any components in electrical communication therewith. In some embodiments, the supply electrodes 806, 810, 814, or 818 may perform a monopolar impedance measurement to distinguish the impedance of each supply electrode.

[0096] In some embodiments, a coating 860 containing an active agent or drug can be disposed on a lead 801 (which can be partially implanted, such as Figure 8 as shown, or fully implanted, as Figure 6 to Figure 7 801 body or shaft of the implanted portion of the lead 801 shown in FIG. 801 . In various embodiments, the coating 860 may be a drug eluting coating. The length of the portion of the lead 801 covered by the coating 860 may be about 0.1, 0.5, 1, 1.5, 2, 3, 5, 7.5, 10, 15, 20, 40, 60, or 80 centimeters. In various embodiments, the coating 860 may completely surround the lead 801, thereby forming a 360-degree coating ring around the lead 801. For example, the coating 860 may include a polymer matrix (including one or more of the following hydrogels, poly (vinyl alcohol), poly (2-hydroxyethyl methacrylate), poly (methyl methacrylate), poly (ethylene-co-vinyl acetate), poly (methacrylic acid), etc.), wherein an active agent is arranged in the polymer matrix. In other cases, the coating 860 itself may be only an active agent, or together with an excipient, but without a polymer matrix. Exemplary active agents are described in more detail below. However, in some embodiments, the active agent may be a cytotoxic agent. While not intending to be bound by theory, a cytotoxic agent may be useful, particularly for leads that are in close proximity to or even within a cancerous tumor, to prevent cancerous cells from migrating from the tumor site using the lead as a pathway. Thus, in some embodiments, a cytotoxic agent coating may be placed at a point between the proximal end of the lead and the tumor site.

[0097] "Monopolar" impedance measurement refers to the following situation: the housing (or shell or container) of the implanted device itself is used as one of the two electrodes in a pair of electrodes required for the current to pass through to measure the voltage drop and deduce the impedance. "Bipolar" impedance measurement refers to the following situation: the housing (or shell or container) of the implanted device itself is not used as one of the two electrodes in a pair of electrodes required for the current to pass through to measure the voltage drop and deduce the impedance (for example, these two electrodes are arranged on the lead or other structure outside the housing of the implanted device). In some embodiments, the various impedance measurements herein can be monopolar impedance measurements, while in other embodiments, the various impedance measurements herein can be bipolar impedance measurements.

[0098] It should be understood that in addition to measuring the impedance of a cancerous tumor or healthy tissue, the medical device herein can also be used to measure the polarization of a cancerous tumor or healthy tissue. In some embodiments, the medical device herein can be implanted at or near the site of a cancerous tumor, and the electric field generating circuit can be configured to generate one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to at least one treatment parameter set for a predetermined period of time. The one or more electric fields can be delivered to or near the site of the cancerous tumor using one or more supply leads, each of which can include one or more supply electrodes. The control circuit of the medical device herein can be configured to measure the polarization of the cancerous tumor by measuring the amplitude and phase of the electric field over a certain frequency range. Measuring the polarization of the cancerous tumor can include using one or more sensing leads, which can include one or more sensing electrodes. The control circuit can also be configured to apply a DC electric field, suspend the therapy at the predetermined polarization of the cancerous tumor, and then measure the relaxation characteristic curve of the cancerous tumor. The control circuit can be further configured to: if the relaxation characteristic curve changes within a predetermined value range, then modulate the therapy according to the at least one treatment parameter set.

[0099] See now Fig. 9, shows an exemplary graph 900 of dielectric relaxation of biological tissue according to various embodiments herein. An electric field E may be applied to biological tissue, such as a cancerous tumor or healthy tissue, for a predetermined time t. During the application of the electric field, the biological tissue may become polarized within the electric field, as discussed elsewhere herein. Graph 902 shows a graph of the electric field E as a function of time. Curve 906 shows a graph of the polarization P of the biological tissue as a function of time. A constant electric field E may be applied to the biological tissue for a predetermined period of time 908. The electric field E may be turned off at 904, and the dielectric relaxation τ of the biological tissue may be measured during time 910, represented by decay 914. The final polarization of the biological tissue reaches a substantially zero value during time 912. In some embodiments, the applied electric field may be a DC electric field. In some embodiments, the applied DC electric field may be applied until a stable voltage is reached for a predetermined period of time. In some embodiments, after a stable voltage is achieved, the DC electric field may be removed, the relaxation characteristic curve of a given tissue or cell population may be monitored, and the relaxation time to reach zero voltage may be recorded. The time constant for relaxation to zero voltage can be used as a valuable insight into the capacitance of the system.

[0100] Elements of various embodiments of the medical devices described herein are Fig.10 However, it should be understood that some embodiments may include Fig.10 Additional elements beyond those shown. In addition, some embodiments may lack Fig.10 Some elements shown. The medical device embodied herein can collect information through one or more sensing channels, and can output information through one or more field generation channels. The microprocessor 1002 can communicate with the memory 1004 via a bidirectional data bus. The microprocessor 1002 can be electrically connected to the power supply circuit 1020. The memory 1004 may include a read-only memory (ROM) or a random access memory (RAM) for program storage and a RAM for data storage. The microprocessor 1002 can also be connected to a telemetry interface 1018 to communicate with an external device such as a programmer, a unit installed in a room, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.), or directly connected to a cloud or another communication network such as promoted by a cellular or other data communication network. In some embodiments, the medical device may include an inductive energy receiver coil interface (not shown) communicatively coupled or attached thereto to facilitate transcutaneous recharging of the medical device.

[0101] The medical device may include one or more electric field sensing electrodes 1008 and one or more electric field sensor channel interfaces 1006 that can communicate with a port of the microprocessor 1002. The medical device may also include one or more electric field generating electrodes 1012, and one or more electric field generating channel interfaces 1010 that can communicate with a port of the microprocessor 1002 and one or more electric field generating circuits 1009. The medical device may also include one or more other sensors 1016, such as physiological sensors, respiratory sensors, or chemical sensors; and one or more other sensor channel interfaces 1014 that can communicate with a port of the microprocessor 1002. The channel interfaces 1006, 1010, and 1014 may include various components, such as analog-to-digital converters for digitizing signal inputs, sense amplifiers, registers that can be written by control circuits to adjust the gain and threshold of the sense amplifiers, source drivers, modulators, demodulators, multiplexers, and the like.

[0102] In some embodiments, physiological sensors may include sensors that monitor temperature, blood flow, blood pressure, etc. In some embodiments, respiratory sensors may include sensors that monitor respiratory rate, peak respiratory amplitude, etc. In some embodiments, chemical sensors may measure the amount of analytes present in the treatment area around the sensor, including but not limited to analytes such as blood urea nitrogen, creatinine, fibrin, fibrinogen, immunoglobulins, deoxyribonucleic acid, RNA, potassium, sodium, chloride, calcium, magnesium, lithium, hydrated hydrogen, hydrogen phosphate, bicarbonate, etc. However, many other analytes are also contemplated herein. Exemplary chemical / analyte sensors are disclosed in co-owned U.S. Patent No. 7,809,441 to Kane et al., and the entire contents of that application are incorporated herein by reference.

[0103] Although other sensors 1016 are shown as Fig.10 1018, but it should be appreciated that in some embodiments, one or more of the other sensors may be physically separate from the medical device. In various embodiments, one or more of the other sensors may be within another implanted medical device that is communicatively coupled to the medical device via telemetry interface 1018. In still other embodiments, one or more of the other sensors may be external to the body and coupled to the medical device via telemetry interface 1018. In some embodiments, the other sensors may include drug delivery sensors, biopsy device sensors, optical sensors, or irrigation sensors.

[0104] method

[0105] Many different methods are contemplated herein, including, but not limited to, methods of manufacture, methods of use, etc. Aspects of the system / apparatus operations described elsewhere herein may be performed as operations of one or more methods according to various embodiments herein.

[0106] See now Fig.11 , a schematic diagram of a method 1100 for treating a cancerous tumor in a subject according to various embodiments herein is shown. The method 1100 may include implanting a medical device at or near the site of the cancerous tumor 1102. The method 1100 may include applying at least two electric fields at or near the site of the cancerous tumor to deliver at least a first electric field having a first electric field strength and a second electric field having a second electric field strength 1104. Applying the one or more electric fields may include using one or more supply leads, wherein each supply lead may include one or more supply electrodes. The method 1100 may include measuring the impedance of the cancerous tumor at the at least two electric field strengths 1106. Measuring the impedance may include using one or more sensing leads, each sensing lead including one or more sensing electrodes. The method 1100 may include modulating the therapy according to at least one set of treatment parameters if the impedance changes 1108.

[0107] See now Fig.12 , a schematic diagram of a method 1200 for treating a cancerous tumor in a subject according to various embodiments herein is shown. The method 1200 may include implanting a medical device at or near the site of the cancerous tumor 1202. The method 1200 may include applying one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to at least one set of treatment parameters for a predetermined period of time 1204. Applying the one or more electric fields may include using one or more supply leads, wherein each supply lead may include one or more supply electrodes. Applying the one or more electric fields 1204 may include applying the one or more electric fields at at least two different frequencies. The method 1200 may include measuring an impedance of the cancerous tumor during the application of the one or more electric fields at the at least two frequencies 1206. Measuring the impedance may include using one or more sensing leads, which may include one or more sensing electrodes. The method 1200 may include modulating the therapy according to the at least one set of treatment parameters if the impedance changes during the predetermined period of time 1208. In some embodiments, method 1200 may include repeatedly sweeping up from the first frequency to the second frequency and sweeping down from the second frequency to the first frequency throughout the duration of generating the one or more electric fields with the electric field generating circuit.

[0108] In some embodiments, method 1200 may include applying one or more electric fields at at least two frequencies, wherein a first electric field is applied at a first frequency and a second electric field is applied at a second frequency. In some embodiments, the first frequency is less than the second frequency. In some embodiments, the first frequency is selected from a range of about 10kHz to about 500kHz, and the second frequency is selected from a range of about 501kHz to about 1MHz. In some embodiments, method 1200 includes applying a first electric field and a second electric field having the same electric field strength but different frequencies. In other embodiments, method 1200 may include applying a first electric field and a second electric field having the same electric field strength but different frequencies. In some embodiments, the first electric field strength may be less than the second electric field strength, and the first frequency may be less than the second frequency. It should be understood that additional frequencies may also be used, such as a third frequency, a fourth frequency, a fifth frequency, a sixth frequency, a seventh frequency, etc. Various frequencies suitable for use in the methods implemented herein are described elsewhere herein.

[0109] See now Fig.13 , a schematic diagram of a method 1300 for treating a cancerous tumor in a subject according to various embodiments herein is shown. The method 1300 may include implanting a medical device at or near the site of the cancerous tumor 1302. The method 1300 may include applying one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to at least one set of treatment parameters for a predetermined period of time 1304. Applying the one or more electric fields may include using one or more supply leads, wherein each supply lead may include one or more supply electrodes. The method 1300 may include measuring an impedance of the cancerous tumor at predetermined intervals during the application of the one or more electric fields during the predetermined period of time 1306. Measuring the impedance of the cancerous tumor may include using one or more sensing leads, which may include one or more sensing electrodes. Measuring the impedance of healthy tissue at or near the site of the cancerous tumor at predetermined intervals during the application of the one or more electric fields 1308. Measuring the impedance of the healthy tissue may include using one or more sensing leads, which may include one or more sensing electrodes located at or near the site of the cancerous tumor. The method 1300 may include modulating 1310 the therapy according to the at least one set of treatment parameters if the impedance of the cancerous tumor or healthy tissue changes during a predetermined time period.

[0110] In some embodiments, at least method 1100, method 1200, or method 1300 may include modulating the therapy according to the at least one treatment parameter set by modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by at least 25%, at least 50%, or at least 75% during a given therapy relative to an initial impedance at or near the site of the cancerous tumor at the start of the given therapy. In some embodiments, modulating the therapy according to the at least one treatment parameter set may include modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by a percentage greater than or equal to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to an initial impedance at or near the site of the cancerous tumor, or an amount within a range between any of the foregoing percentages. In other embodiments, modulating the therapy according to the at least one treatment parameter set may include modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by a percentage greater than 100% relative to an initial impedance at or near the site of the cancerous tumor.

[0111] In some embodiments, at least method 1100, method 1200, or method 1300 may include modulating one or more electric fields by increasing or decreasing the electric field strength. In some embodiments, method 1100, 1200, or 1300 may include modulating therapy according to at least one therapy parameter set by terminating the therapy parameter set if the impedance falls outside of a predetermined range during a predetermined time period. In some embodiments, method 1100, 1200, or 1300 may include classifying the subject as a non-responsive class to therapy if a decrease in impedance is measured over a predetermined time period. In some embodiments, method 1100, 1200, or 1300 may include classifying the subject as a responsive class to therapy if an increase in impedance is measured over a predetermined time period. In some embodiments, if the subject is classified as a non-responsive class to therapy, therapy may be modulated by increasing the electric field strength delivered to the cancerous tumor. In some embodiments, if the subject is classified as a responsive class to therapy, therapy may be modulated by decreasing the electric field strength delivered to the cancerous tumor or terminating therapy altogether.

[0112] See now Fig.14, a schematic diagram of a method 1400 for treating a cancerous tumor in a subject according to various embodiments herein is shown. The method 1400 may include implanting a medical device at or near the site of the cancerous tumor 1402. The method 1400 may include applying one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to at least one set of treatment parameters for a predetermined period of time 1404. Applying the one or more electric fields may include using one or more supply leads, each of which may include one or more supply electrodes. The method 1404 may include measuring a polarization of the cancerous tumor by measuring amplitude and phase at predetermined intervals during the application of the one or more electric fields 1406. Measuring the polarization of the cancerous tumor may include using one or more sensing leads, which may include one or more sensing electrodes. The method 1400 may include pausing therapy at a predetermined polarization of the cancerous tumor and measuring a relaxation characteristic curve of the cancerous tumor 1408. The method may include modulating therapy according to the at least one set of treatment parameters if the relaxation characteristic curve changes within a predetermined value range 1410. In method 1400, the applied one or more electric fields include a DC electric field.

[0113] See now Fig.15 , a schematic diagram of a method 1500 for treating a cancerous tumor in a subject according to various embodiments herein is shown. The method 1500 may include implanting a medical device at or near the site of the cancerous tumor 1502. The method 1500 may include applying one or more DC electric fields at or near the site of the cancerous tumor to deliver therapy according to at least one set of treatment parameters for a predetermined period of time 1504. Applying the one or more DC electric fields may include using one or more supply leads, each of which may include one or more supply electrodes. The method 1500 may include measuring polarization of the cancerous tumor by measuring amplitude and phase at predetermined intervals during the application of the one or more DC electric fields 1506. Measuring the polarization of the cancerous tumor may include using one or more sensing leads, which may include one or more sensing electrodes. The method may include modulating therapy according to the at least one set of treatment parameters if the polarization of the cancerous tumor changes during the predetermined period of time 1508.

[0114] In some embodiments, modulating the therapy according to the at least one treatment parameter set included by at least methods 1400 and 1500 may include modulating the one or more electric fields if the polarization at or near the site of the cancerous tumor during a given therapy changes by at least 25%, at least 50%, or at least 75% relative to the initial polarization at or near the site of the cancerous tumor at the start of the given therapy. In some embodiments, modulating the therapy according to the at least one treatment parameter set included by at least methods 1400 and 1500 may include modulating the one or more electric fields if the polarization at or near the site of the cancerous tumor during a given therapy changes by at least 5%, at least 15%, or at least 20% relative to the initial polarization at or near the site of the cancerous tumor at the start of the given therapy. In some embodiments, modulating therapy according to the at least one treatment parameter set may include modulating the one or more electric fields if polarization at or near the site of the cancerous tumor changes by a percentage relative to an initial polarization at or near the site of the cancerous tumor that is greater than or equal to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or an amount within a range between any of the foregoing percentages. In some embodiments, modulating therapy according to the at least one treatment parameter set may include terminating the treatment parameter set if polarization falls outside of a predetermined range during a predetermined time period.

[0115] In the various methods described herein, applying the one or more electric fields may include at least applying the electric field at various electric field strengths. For example, the one or more electric fields may be applied to the cancerous tumor at an electric field strength selected from the range of electric field strengths between 0.25V / cm and 1000V / cm. In some embodiments, the one or more electric fields may be applied to the cancerous tumor at an electric field strength selected from the range of electric field strengths between 1V / cm and 10V / cm. In some embodiments, the one or more electric fields may be applied to the cancerous tumor at an electric field strength selected from the range of electric field strengths between 3V / cm and 5V / cm. In some embodiments, the electric field strength may be greater than or equal to 0.25 V / cm, 0.50 V / cm, 0.75 V / cm, 1.00 V / cm, 1.25 V / cm, 1.50 V / cm, 1.75 V / cm, 2.00 V / cm, 2.25 V / cm, 2.50 V / cm, 2.75 V / cm, 3.00 V / cm, 3.25 V / cm, 3.50 V / cm, 3.75 V / cm, 4.00V / cm, 4.25V / cm, 4.50V / cm, 4.75V / cm, 5.00V / cm, 5.25V / cm, 5.50V / cm, 5.75V / cm, 6.00V / cm, 6.25V / cm, 6.50V / cm, 6.75V / cm, 7.00V / cm, 7.25V / cm, 7.50V / cm, 7.75V / cm, 8.0 0V / cm, 8.25V / cm, 8.50V / cm, 8.75V / cm, 9.00V / cm, 9.25V / cm, 9.50V / cm, 9.75V / cm, 10V / cm , 20V / cm, 30V / cm, 40V / cm, 50V / cm, 60V / cm, 70V / cm, 80V / cm, 90V / cm, 300V / cm, 150V / cm, 400 In some embodiments, the present invention may be used in an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 400 V / cm, or an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 400 V / cm, or an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 400 V / cm, or an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 400 V / cm, or an amount within the range of 1 to 200 V / cm, or an amount within the range of 1 to 200 V / cm,

[0116] In the various methods described herein, applying the one or more electric fields may include at least applying the electric field at various frequencies. The one or more electric fields may be applied to the cancerous tumor at a frequency selected from the range of 10 kilohertz (kHz) to 1 megahertz (MHz). In some embodiments, the one or more electric fields may be applied to the cancerous tumor at a frequency selected from the range of 300kHz to 500kHz. In some embodiments, the one or more electric fields may be applied to the cancerous tumor at a frequency selected from the range of 100kHz to 300kHz. In some embodiments, the frequency of the applied electric field or fields may be greater than or equal to 10kHz, 20kHz, 30kHz, 40kHz, 50kHz, 60kHz, 70kHz, 80kHz, 90kHz, 300kHz, 125kHz, 150kHz, 175kHz, 400kHz, 225kHz, 250kHz, 275kHz, 300kHz, 325kHz, 350kHz, 375kHz, 400kHz, 425kHz, 450kHz, 475kHz, 500kHz, 525kHz, 550kHz, 575kHz, 600kHz, 625kHz, 650kHz, 675kHz, 700kHz, 725kHz, 750kHz, 775kHz, 800kHz, 825kHz, 850kHz, 875kHz, 900kHz, 925kHz, 950kHz, 975kHz, or 1MHz, or may be an amount falling within any of the foregoing ranges.

[0117] In various methods described herein, applying the one or more electric fields may include at least applying the electric fields for a plurality of different predetermined time periods. The one or more electric fields may be applied to or near the site of the cancerous tumor for a predetermined time period selected from a predetermined time period range from 1 minute to 24 hours. In some embodiments, the one or more electric fields may be applied to or near the site of the cancerous tumor for a predetermined time period, and the predetermined time period may be greater than or equal to 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, or 50 minutes, or 1.0 hour, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 5.5 hours, 6.0 hours, 6.5 hours, 7.0 hours, 7.5 hours, 8.0 hours, 8.5 hours, 9.0 hours, 9.5 hours, 10.0 hours, 10.5 hours, 11 .0 hours, 11.5 hours, 12.0 hours, 12.5 hours, 13.0 hours, 13.5 hours, 14.0 hours, 14.5 hours, 15.0 hours, 15.5 hours, 16.0 hours, 16.5, 17.0 hours, 17.5 hours, 18.0 hours, 18.5 hours, 19.0 hours, 19.5 hours, 20.0 hours, 20.5 hours, 21.0 hours, 21.5 hours, 22.0 hours, 22.5 hours, 23.0 hours, 23.5 hours, 24.0 hours, or 48 hours, or an amount falling within any of the foregoing ranges.

[0118] In various methods described herein, applying chemotherapeutic agents can include applying chemotherapeutic agents in a plurality of different predetermined time periods. Chemotherapeutic agents can be applied to or near the position of cancerous tumors in a predetermined time period selected from the range of a predetermined time period of less than 1 minute to 600 minutes. In certain embodiments, chemotherapeutic agents can be applied to or near the position of cancerous tumors in a predetermined time period, and this predetermined time period can be greater than or equal to 1 second, 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds or 60 seconds, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes, 420 minutes, 480 minutes, 540 minutes or 600 minutes or can be the amount falling in any aforementioned range.

[0119] In the various methods described herein, applying the one or more electric fields at or near the site of the cancerous tumor may include applying the one or more electric fields to the subject's body or body. In some embodiments, applying the one or more electric fields to the cancerous tumor may include applying the one or more electric fields entirely from outside the subject's body to the site of the cancerous tumor or near the site. In some embodiments, applying the one or more electric fields to the cancerous tumor may include applying the one or more electric fields entirely from inside the subject's body to the site of the cancerous tumor or near the site. In some embodiments, applying the one or more electric fields to the cancerous tumor may include applying the one or more electric fields at least partially from outside the subject's body to the site of the cancerous tumor or near the site. In some embodiments, applying the one or more electric fields to the cancerous tumor may include applying the one or more electric fields at least partially from inside the subject's body to the site of the cancerous tumor or near the site. In other embodiments, applying the one or more electric fields to the cancerous tumor may include applying the one or more electric fields partially from inside the subject's body and partially from outside the subject's body to the site of the cancerous tumor or near the site.

[0120] Impedance measurement

[0121] Feedback obtained during electric field treatment can be used to monitor the effectiveness of using the treatment to treat cancerous tumors. Data such as parameters such as impedance, capacitance, field strength, etc. can be measured to guide a specific treatment process. Without being bound by any particular theory, it is believed that cancerous tumors have a specific impedance associated with them. The impedance associated with the tumor can change with changes in the size or cell composition of the tumor. Therefore, impedance can be monitored during electric field treatment to determine whether the cancerous tumor responds to treatment. In some cases, an increase in the impedance of tissue in the treatment area including the cancerous tumor can indicate tumor regression. In other cases, a decrease in the impedance of tissue in the treatment area or no observed changes can indicate tumor development or no changes in the tumor, respectively. Other physiological characteristics associated with cancerous tumors, such as blood flow, metabolite concentrations, systemic cancer markers, and temperature, can also be used in conjunction with impedance analysis to monitor the development or regression of cancerous tumors in response to electric field treatment.

[0122] Ohm's law states that potential, current, and impedance are interrelated (V=IR or V=IZ). Therefore, by knowing one variable (e.g., such as the current supplied) and measuring another variable (e.g., such as measuring the voltage drop), a third variable can be calculated. In some embodiments herein, impedance (Z) can be measured by dividing voltage by current. In the body, impedance may be affected by a variety of factors, including but not limited to components in contact with the electric field, such as cell types, including muscle, fat, connective tissue, and bone; cell density, cell size; electrolyte concentration, etc. In some embodiments, electric field sensing electrodes or electric field generating electrodes can be used as impedance monitoring electrodes. It should be understood that different tissues will have different impedances at a given frequency. Thus, in some embodiments, it is contemplated that impedance is measured at one or more frequencies at any given location. In some embodiments, impedance can be measured at frequencies within the therapeutic frequency range. In some embodiments, impedance can be measured at frequencies outside the therapeutic frequency. In some embodiments, impedance can be measured at two frequencies within the therapeutic frequency range and at frequencies outside the therapeutic frequency.

[0123] In some embodiments, as the impedance changes within the cancerous tumor, an electric field can be applied to the cancerous tumor based on the measured impedance. Without being bound by any particular theory, it is believed that the impedance within the cancerous tumor is relatively low compared to non-cancerous tissue or necrotic tissue. This phenomenon makes it possible to monitor the impedance according to the duration of treatment and can be used as a diagnostic tool to assess whether the tumor is responsive to electric field treatment. If the impedance within the treatment area increases (at a fixed distance or area, due to the shrinkage of low-impedance tumor tissue and the occupation of the remaining space by non-cancerous tissue), this can be considered an indication that the electric field treatment effectively reduces the size of the cancerous tumor. However, if the impedance within the treatment area decreases or remains unchanged at a fixed distance or area, it can be considered that this is an indication that the electric field treatment does not reduce the size of the cancerous tumor. In this way, electric field treatment can be customized for a specific cancerous tumor in order to effectively reduce the size of the cancerous tumor. For example, one or more of the amplitude, frequency, pulse width, waveform, directionality and / or duty cycle of the electric field therapy can be modulated and / or changed.

[0124] In some embodiments, low frequency impedance through a particular cancerous tumor can be used to measure the conductivity of the tumor, and can be used as an indicator of tissue progression or regression. In some embodiments, high frequency impedance through a particular cancerous tumor can be used to measure the dielectric constant and capacitance properties of the tumor, and can also be used as an indicator of tissue progression or regression. In some embodiments, low frequency impedance can be measured at a frequency of about 1 Hz to about 10 Hz. In some embodiments, high frequency impedance can be measured at a frequency of about 10 Hz to about 1 MHz. In some embodiments, high frequency impedance can be measured at a frequency of about 100 kHz to about 300 kHz. In various embodiments, including with respect to Figure 1 and Fig.10 A medical device comprising one or more components described herein may be configured to perform Figures 11 to 15 An embodied method describes one or more operations.

[0125] Polarization measurement

[0126] Polarization can be measured by sweeping a sine wave over a range of frequencies (e.g., 1 Hz-10 Hz, 10 Hz-1 MHz, 100 kHz-300 kHz, 100 kHz-500 kHz) and measuring the complex impedance. Impedance consists of a real part and an imaginary part. This can be performed at the time of implantation, or after implantation by temporarily pausing treatment to repeat the impedance scan.

[0127] Polarization can be used as a measure to distinguish cancer cell populations from healthy cell populations based on the unique polarization characteristics of each cell population (i.e., healthy vs. cancerous). Polarization within a cell population depends on the frequency of the applied electric field. Polarized cell populations can exhibit charge asymmetry within a population of cells and across the entire cell population, which can be attributed to intracellular components, extracellular components, and the aqueous environment surrounding a given cell population.

[0128] Applied electric field

[0129] The electric field applied to the cancerous tumor using the methods of this article can be applied using a variety of ways. Exemplary treatment parameter sets may include those that implement the following concepts: sweeping through a range of frequencies; stacking one or more frequencies simultaneously; sequentially stepping through one or more frequencies; spatial or temporal delivery of one or more electric fields; sweeping through a range of electric field strengths; applying an effective rotating electric field; modulating a voltage control mode or a current control mode; implementing one or more duty cycles; pulse width modulation; manipulating the shape of the electrical waveform and / or the sequence of pulses; and occasionally using high frequency or high electric field strength pulses.

[0130] In some embodiments, the electric field can be modulated based on feedback from the biological tissue. As discussed above, the feedback can include data measuring parameters such as impedance, capacitance, field strength, etc. to guide a particular treatment process. The electric field can be modulated by increasing or decreasing the frequency of the electric field during the treatment process. In some embodiments, if the feedback causes the tumor to progress or the tumor does not change, the frequency of the applied electric field can be increased or decreased.

[0131] The treatment parameter set can be programmed into the medical device to operate autonomously, or can be queried and manipulated by the subject or clinician using an external computing device, such as a programmer, a unit installed in the room, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.). In other embodiments, the treatment parameter set can be wirelessly transmitted to the medical device from the external computing device. The above discussion of the frequency and / or electric field strength applicable to any treatment parameter set herein with respect to the electric field generating circuit. In some embodiments, one or more treatment parameter sets can be implemented simultaneously. In other embodiments, one or more treatment parameter sets can be implemented in an alternating manner. In some embodiments, the one or more electric fields can effectively prevent and / or destroy cell mitosis in cancer cells.

[0132] For example, an electric field can be applied to the site of a cancerous tumor by sweeping through a range of frequencies. Fig.16 , exemplary graph 1602 shows an alternating electric field where the frequency increases over time. Similarly, Fig.17 The change in frequency over time during the programmed therapy parameters is shown in exemplary graph 1702. In some embodiments, the frequency sweep may include sweeping upward from a minimum frequency to a maximum frequency. In some embodiments, the frequency sweep may include sweeping downward from a maximum frequency to a minimum frequency. In other embodiments, sweeping upward from a minimum frequency to a maximum frequency and sweeping downward from a maximum frequency to a minimum frequency may be repeated as many times as desired throughout the duration of delivering the electric field from the electric field generating circuit.

[0133] As therapy is performed during the frequency sweep, it may be desirable to alternate between frequency ranges so that more cells can be targeted as the cells in the population change size and number in response to therapy. For example, in some embodiments, the frequency sweep may include alternating between a first frequency sweep covering a range of about 100kHz to 300kHz and a second frequency sweep covering a range of about 200kHz to 500kHz. It should be understood that sweeping through the first frequency range and the second frequency range as described above can be performed indefinitely throughout the course of therapy. In some embodiments, the second frequency sweep (range) may be at a higher frequency than the first frequency sweep (range). In some embodiments, the first frequency sweep (range) may be at a higher frequency than the second frequency sweep (range).

[0134] The frequency ranges used for the first frequency range and the second frequency range can be any range including the specific frequencies described above with respect to the electric field generating circuit, provided that the lower end of each range is a value less than the upper end of each range. Sometimes, it may be beneficial to have a certain degree of overlap between the frequency ranges of the first frequency sweep and the second frequency sweep.

[0135] Leads and Electrodes

[0136] Leads described herein can be placed in the body at or near the site of a cancerous tumor using a variety of techniques. Placing one or more leads can include using techniques such as transvascular placement, penetration into the subcutaneous space and / or surgical placement. In some embodiments, placing one or more leads can include placing via one or more natural body orifices. The medical device herein can be configured to implant any of the first lead, the second lead, the third lead, the fourth lead, etc., through a natural body orifice or conduit into or near the site of a cancerous tumor. In some embodiments, a natural body orifice can include any of the nasal passage, the ear canal, the oral cavity, the esophagus, the trachea, the urethra, the vagina, the small intestine, the anus, or the colon. In some embodiments, suitable conduits can include those that can be reached via the gastrointestinal or urogenital system, including the common bile duct, the bile duct, the pancreatic duct, the common hepatic duct, the ureter, the eustachian tube, or the fallopian tube. Leads can be placed near or within a cancerous tumor. In some embodiments, multiple leads can be used near or away from a cancerous tumor.

[0137] In the medical devices described herein, it should be understood that, depending on the embodiments herein, one or more monopolar or multipolar leads may be used. In some embodiments, a combination of monopolar and multipolar leads may be used. In other embodiments, round leads, clamp leads, cuff leads, paddle leads, or patch leads may be used.

[0138] In some embodiments, one or more leads described herein may be placed in the subcutaneous space. The electrodes on the leads placed in the subcutaneous space may be used as the primary near-field generating electrodes or the far-field generating electrodes. In some embodiments, the electrodes on the leads placed in the subcutaneous space may be used as the primary near-field generating electrodes or the far-field generating electrodes in conjunction with the housing of the medical device. Similarly, one or more leads may be placed transvascularly to act as the far-field generating electrodes in conjunction with electrodes at or near the site of a cancerous tumor or in conjunction with the housing of a medical device.

[0139] The leads and electrodes described herein may include additional functional and structural features. In some embodiments, the leads may include leads compatible with imaging and therapeutic techniques, including but not limited to MRI (magnetic resonance imaging), X-ray imaging, deep brain stimulation techniques, and / or radiation therapy. In some embodiments, the leads may include one or more conductor cores made of a conductive material. The conductor cores may be formed of a conductive material including a metal and / or other conductive material. The metal may include but is not limited to palladium, platinum, silver, gold, copper, aluminum, various alloys (including stainless steel, such as In some embodiments, the conductor core may be a multi-winding coil, including but not limited to a double-winding coil, a triple-winding coil, and a quad-winding coil.

[0140] In some embodiments, as described herein, the electrode can be arranged along the length of one or more leads. The material suitable for the electrode described herein may include metals, such as palladium, to minimize the connection and artifact generation in the magnetic field. In some embodiments, the electrode can be made of other metals and / or other conductive materials. The metal may include but is not limited to palladium, platinum, platinum alloys (such as platinum-iridium alloys), gold, copper, tantalum, titanium, various alloys (including stainless steel), etc. In some embodiments, the electrode can be in the form of a winding coil, which can provide the additional benefit of increasing the surface area without compromising the flexibility of the electrode. In some embodiments, an implantable device housing can be used as an electrode.

[0141] The leads described herein may also include one or more electrodes arranged along the length of the lead. The lead may include two or more electrodes arranged along the length of the lead. In some embodiments, the electrode may be a tip electrode found at the distal end of the lead. In other embodiments, the electrode may be a ring electrode found along the lead but not at the tip of the lead.

[0142] In some embodiments, the electrode can be a coil electrode. In some embodiments, a ring or tip electrode can be positioned in or near a tumor or cancerous tissue, and the coil electrode can be positioned away from the tumor or cancerous tissue to help provide spatial diversity to the generated electric field. In some embodiments, the axis of one or more electrodes along the length direction (e.g., the axis from the proximal end to the distal end) can have the following lengths of about 0.5mm, 1mm, 1.5mm, 2mm, 3mm, 4mm, 5mm, 7.5mm, 10mm, 15mm, 20mm, 30mm, 40mm, 50mm, 75mm, 100mm or more. In some embodiments, the length of one or more electrodes can fall within the following range, wherein any of the aforementioned distances can be used as the upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

[0143] The lead may be monopolar, bipolar, or multipolar. In some embodiments, a monopolar lead may include a lead that generates an electric field between one electrode and the housing of the medical device. In some embodiments, a bipolar lead may include a lead that generates an electric field between two electrodes arranged along the lead or between two electrodes and the housing of the medical device. In some embodiments, a multipolar lead may include a lead that generates an electric field between two or more electrodes arranged along the lead, between two or more electrodes and the housing of the medical device, or between any number of combinations of configurations of electrodes and the housing of the medical device.

[0144] The lead of this article may include one or more light emitters along the length of the lead. Light emitters suitable for use herein may include those light emitters whose emitted light falls anywhere along the visible spectrum from about 350nm to 950nm. Suitable light emitters may include light emitting diodes or laser diodes. Suitable LEDs may be made of one or more of the following: gallium arsenide (GaAs), gallium phosphide (GaP), gallium arsenide phosphide (GaAsP), silicon carbide (SiC), or indium telluride nitride (GaInN). In some embodiments, LEDs suitable for use herein may include LEDs capable of emitting only one color, or monochromatic LEDs; LEDs capable of emitting two colors, or bicolor LEDs; LEDs capable of emitting three colors, or tricolor LEDs; or LEDs capable of emitting more than three colors. The LED may be electrically connected to a control circuit in the housing of the medical device described herein. In some embodiments, one or more laser diodes may be included along the lead of this article, and the laser diode may be optically communicated with one or more optical fibers disposed in the lead and used to transmit light from a laser source to the laser diode.

[0145] Electrodes suitable for use herein can be made of conductive polymers, such as carbon-filled silicone, polyacetylene, polypyrrole, polyaniline, polythiophene, polyfuran, polyisoprene, polybutadiene, polyparaphenylene, and the like. In other embodiments, the electrodes can be insulating. In some embodiments, the insulation surrounding the electrodes can include microporous insulators to prevent cell attachment but still allow current to flow. The microporous insulators can be made of a variety of insulating materials described herein, including but not limited to polytetrafluoroethylene (ePTFE), polyethylene-tetrafluoroethylene copolymer (ETFE), polyurethane, silicone, polyparaxylene polymers (such as polyparaxylene polymers), polyether block amides (such as ), nylon or their derivatives. In some embodiments, the electrodes can be coated with various materials, including but not limited to hydrogels or fractal coatings, such as iridium oxide, titanium oxide, tantalum pentoxide, other metal oxides, polyparaxylene polymers (such as polyparaxylene), etc.

[0146] According to embodiments of the present invention, a variety of lead fixation techniques and configurations may be used. Some non-limiting examples of lead fixation techniques may include biocompatible glue fixation, claw fixation, helical coil fixation, passive centering of the lead in the vascular system, tooth fixation within the local vascular system, helical offset fixation within the local vascular system, compression fixation, suture sleeve fixation, etc. In some examples, the leads embodied herein may be placed within the vascular system around or near the site of a cancerous tumor. In other embodiments, the leads embodied herein may be surgically placed at, within, or around the site of a cancerous tumor.

[0147] Leads suitable for use herein may also include one or more open cavities extending the entire longitudinal length of the lead or a selected portion of the longitudinal length. In some embodiments, the open cavity may include an integrated biopsy device adapted to periodically obtain biopsy samples from a cancerous tumor site to monitor the progression and / or regression of the disease. Leads with an open cavity may also be configured to include an integrated drug delivery cavity that may deliver one or more drugs (such as steroids or chemotherapy agents) to the tumor site in a single bolus or regularly via a metering pump. The lead may include one or more inlets arranged along the length of the lead to provide an outlet for delivering drugs at or near the site of a cancerous tumor.

[0148] In some embodiments, a portion or the entire lead may include a drug (or active agent) eluting coating. In some embodiments, the drug eluting coating may include an anti-inflammatory agent, such as a steroid. In some embodiments, the steroid may be dexamethasone. In other embodiments, the drug eluting coating may include a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent may include a taxane or a derivative thereof, including but not limited to paclitaxel, docetaxel, etc. In other embodiments, the drug eluting coating may be configured to release other types of chemotherapeutic agents, including but not limited to alkylating agents, plant alkaloids (such as vinca alkaloids), cytotoxic antibiotics, topoisomerase inhibitors, etc. In some embodiments, the drug eluting coating may be configured to release drugs from the coating in a delayed release manner. Cytotoxic agents may include alkylating drugs, anthracyclines, antimetabolites, vinca alkaloids, etoposide, protein kinase inhibitors, etc. Cytotoxic agents may specifically include cyclophosphamide, busulfan, and bleomycin.

[0149] The leads herein can take a variety of shapes or configurations. In some embodiments, the leads can be linear, while in other embodiments, the leads can be circular. A circular lead can be a fully enclosed ring or a semi-enclosed ring. In some embodiments, the leads can include a bendable core that can allow the leads to be formed into many configurations, including but not limited to U-shaped, S-shaped, spiral, semicircular, elliptical, etc.

[0150] In yet other examples, the leads suitable for use herein may include fluorescent or magnetic markers that can assist clinicians in accurately placing at or near a cancerous tumor site. The leads may also include an integrated pH sensor for detecting pH changes at or near a cancerous tumor, or other chemical sensors suitable for analyzing the concentration of a chemical analyte of interest.

[0151] Electric field generator

[0152] Medical devices embodied herein may include electric field generators that are particularly suitable for use in therapeutic and diagnostic techniques used in the treatment of cancerous tumors. In some embodiments, electric field generators suitable for use herein may include those that have been treated with radiation hardening to render the components resistant to the damaging effects of radiation therapy treatments that are often prescribed as the mainline treatment for cancerous tumors. Electric field generators may include, for example, those described above with reference to Figures 3 to 10 Those parts described.

[0153] The electric field generators embodied herein can be programmed with any number of treatment parameter sets as described. The electric field generators can be programmed prior to implantation, or they can be programmed by a clinician using an external computing device, such as a programmer, a unit installed in a room, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.). In some embodiments, the therapy parameters can be delivered to the electric field generator via a telemetry circuit. In some embodiments, the electric field generator may include a recharging circuit communicatively coupled to a receiver coil to facilitate transcutaneous recharging of the medical device. In some embodiments, the electric field generator may wirelessly communicate between the receiver coil and an external charging device.

[0154] Other embodiments

[0155] In an embodiment, a medical device for treating a cancerous tumor is included, the medical device having: an electric field generating circuit, the electric field generating circuit being configured to generate one or more electric fields at or near the site of the cancerous tumor; a control circuit, the control circuit being in communication with the electric field generating circuit, the control circuit being configured to control delivery of the one or more electric fields from the electric field generating circuit; wherein the control circuit causes the electric field generating circuit to generate one or more electric fields having an electric field strength selected from the range of 0.25 V / cm to 1000 V / cm; one or more supply wires electrically connected to the electric field generating circuit, the one or more supply wires being each electrically connected to one or more supply electrodes, wherein the one or more supply electrodes are configured to deliver the electric field to or near the site of the cancerous tumor; and one or more sensing wires electrically connected to the control circuit, the one or more sensing wires being each electrically connected to one or more sensing electrodes; and wherein the one or more sensing electrodes are configured to measure the impedance of the cancerous tumor at at least two different electric field strengths.

[0156] In an embodiment, the control circuit is configured to generate at least a first electric field and a second electric field, wherein the first electric field has a first electric field strength and the second electric field has a second electric field strength.

[0157] In an embodiment, the second electric field strength is greater than the first electric field strength.

[0158] In an embodiment, the first electric field strength is selected from the range from 0.1 V / cm to 2 V / cm, and the second electric field strength is selected from the range from 1 V / cm to 100 V / cm.

[0159] In an embodiment, the medical device may further include a memory which may include one or more sets of treatment parameters.

[0160] In an embodiment, the control circuit is further configured to implement the one or more sets of treatment parameters to deliver a given therapy.

[0161] In an embodiment, the control circuit is configured to modulate the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by at least 5% during therapy relative to an initial impedance at or near the site of the cancerous tumor at the start of the given therapy.

[0162] In an embodiment, the one or more electric fields are modulated by increasing or decreasing the electric field strength.

[0163] In an embodiment, the control circuit is configured to modulate the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by at least 50% during any given therapy relative to an initial impedance at or near the site of the cancerous tumor at the beginning of the given therapy.

[0164] In an embodiment, the one or more electric fields are modulated by increasing or decreasing the electric field strength.

[0165] In an embodiment, the control circuit causes the electric field generating circuit to generate one or more electric fields at a frequency selected from the range between 10 kHz and 1 MHz at or near the site of the cancerous tumor.

[0166] In an embodiment, the control circuit is further configured to generate one or more electric fields by sweeping through a range of frequencies, wherein sweeping through the range of frequencies includes sweeping up from a first frequency to a second frequency and sweeping down from the second frequency to the first frequency, wherein the second frequency is higher than the first frequency.

[0167] In an embodiment, the range of frequencies includes a frequency range from 100 kHz to 500 kHz.

[0168] In an embodiment, the control circuit is further configured to generate the one or more electric fields by using a voltage control scheme comprising modulating the voltage to maintain a substantially constant electric field strength.

[0169] In an embodiment, the control circuit may be configured to generate one or more electric fields by using a current control scheme that includes modulating the current to maintain a substantially constant electric field strength.

[0170] In an embodiment, the one or more supply leads and / or the one or more sensing leads include a therapeutic coating proximate to the cancerous tumor.

[0171] In embodiments, the therapeutic coating is a cytotoxic coating.

[0172] In an embodiment, the medical device is configured to be fully implanted within a subject.

[0173] In an embodiment, the medical device is configured to be partially implanted within a subject.

[0174] In an embodiment, the medical device is configured to be entirely external to the subject.

[0175] In an embodiment, the control circuit is further configured to generate one or more electric fields by sweeping through a range of frequencies, wherein sweeping through the range of frequencies includes sweeping up from a first frequency to a second frequency and sweeping down from the second frequency to the first frequency, wherein the second frequency is higher than the first frequency.

[0176] In an embodiment, sweeping up from the first frequency to the second frequency and sweeping down from the second frequency to the first frequency is repeated throughout the duration of generating the one or more electric fields with the electric field generating circuit.

[0177] In an embodiment, the range of frequencies includes a frequency range from 10 kHz to 1 MHz. In an embodiment, the range of frequencies includes a frequency range from 100 kHz to 500 kHz. In an embodiment, the range of frequencies includes a frequency range from 300 kHz to 500 kHz.

[0178] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: implanting a medical device at or near the site of the cancerous tumor; applying at least two electric fields at or near the site of the cancerous tumor using one or more supply leads to deliver at least a first electric field having a first electric field strength and a second electric field having a second electric field strength, each supply lead may include one or more supply electrodes; measuring the impedance of the cancerous tumor at the at least two electric field strengths, wherein measuring the impedance includes using one or more sensing leads, which may include one or more sensing electrodes; and if the impedance changes, modulating the therapy according to at least one set of treatment parameters.

[0179] In an embodiment, modulating the therapy according to the at least one set of treatment parameters includes modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by at least 5% during the therapy relative to an initial impedance measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0180] In an embodiment, the at least one set of treatment parameters further comprises modulating the one or more electric fields by increasing or decreasing the strength of the one or more electric fields.

[0181] In an embodiment, modulating the therapy according to the at least one set of treatment parameters includes modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by at least 50% during the therapy relative to an initial impedance measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0182] In an embodiment, the at least one set of treatment parameters further comprises modulating the one or more electric fields by increasing or decreasing the strength of the one or more electric fields.

[0183] In an embodiment, modulating therapy according to the at least one therapy parameter set comprises terminating the at least one therapy parameter set if the impedance falls outside of a predetermined range during a predetermined time period.

[0184] In an embodiment, the one or more electric fields comprise an electric field strength selected from the range of 0.25 V / cm to 1000 V / cm.

[0185] In an embodiment, the method may further comprise classifying the subject as non-responsive to therapy if a decrease in impedance is measured over a predetermined period of time.

[0186] In an embodiment, the method may further comprise classifying the subject as responsive to therapy if an impedance increase is measured over a predetermined period of time.

[0187] In embodiments, the medical device is fully implanted within the subject.

[0188] In embodiments, the medical device is partially implanted within the subject.

[0189] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: implanting a medical device at or near the site of the cancerous tumor; applying one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to the at least one treatment parameter set for a predetermined time period, wherein applying the one or more electric fields comprises using one or more supply leads, each supply lead may include one or more supply electrodes; wherein applying the one or more electric fields further comprises applying the one or more electric fields at at least two frequencies; measuring impedance of the cancerous tumor during applying the one or more electric fields at the at least two frequencies, wherein measuring impedance comprises using one or more sensing leads, the sensing leads may include one or more sensing electrodes; and if the impedance changes during the predetermined time period, modulating the therapy according to the at least one treatment parameter set.

[0190] In an embodiment, applying the one or more electric fields at at least two frequencies comprises at least applying a first electric field at a first frequency and applying a second electric field at a second frequency.

[0191] In an embodiment, applying the one or more electric fields at at least two frequencies comprises at least applying a first electric field at a first frequency and applying a second electric field at a second frequency.

[0192] In an embodiment, the first frequency is less than the second frequency.

[0193] In an embodiment, the first frequency is selected from the range from 10 kHz to 500 kHz and the second frequency is selected from the range from 501 kHz to 1 MHz.

[0194] In an embodiment, the first electric field has a first electric field strength and the second electric field has a second electric field strength.

[0195] In an embodiment, the first electric field strength is the same as the second electric field strength.

[0196] In an embodiment, the first electric field strength is less than the second electric field strength.

[0197] In an embodiment, applying the one or more electric fields further comprises applying the one or more electric fields at at least two frequencies by sweeping through a range of frequencies, wherein sweeping through the range of frequencies comprises sweeping upward from a first frequency to a second frequency and sweeping downward from the second frequency to the first frequency, wherein the second frequency is higher than the first frequency.

[0198] In an embodiment, sweeping up from the first frequency to the second frequency and sweeping down from the second frequency to the first frequency is repeated throughout the duration of applying the one or more electric fields.

[0199] In an embodiment, the range of frequencies includes a frequency range from 10 kHz to 1 MHz. In an embodiment, the range of frequencies includes a frequency range from 100 kHz to 500 kHz. In an embodiment, the range of frequencies includes a frequency range from 300 kHz to 500 kHz.

[0200] In an embodiment, modulating the therapy according to the at least one set of treatment parameters includes modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by at least 25% during the therapy relative to an initial impedance measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0201] In an embodiment, the at least one set of treatment parameters further comprises modulating the one or more electric fields by increasing or decreasing the strength of the one or more electric fields.

[0202] In an embodiment, modulating the therapy according to the at least one set of treatment parameters includes modulating the one or more electric fields if the impedance at or near the site of the cancerous tumor changes by at least 50% during the therapy relative to an initial impedance measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0203] In an embodiment, the at least one set of treatment parameters further comprises modulating the one or more electric fields by increasing or decreasing the strength of the one or more electric fields.

[0204] In an embodiment, modulating therapy according to the at least one therapy parameter set comprises terminating the at least one therapy parameter set if the impedance falls outside of a predetermined range during a predetermined time period.

[0205] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: implanting a medical device at or near the site of the cancerous tumor; applying one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to the at least one treatment parameter set for a predetermined time period, wherein applying the one or more electric fields comprises using one or more supply leads, each supply lead may comprise one or more supply electrodes; measuring impedance at the cancerous tumor at predetermined intervals during the application of the one or more electric fields, wherein measuring the impedance of the cancerous tumor comprises using one or more sensing leads, which may comprise one or more sensing electrodes; measuring impedance of healthy tissue at or near the site of the cancerous tumor at predetermined intervals during the application of the one or more electric fields, wherein measuring the impedance of the healthy tissue may comprise using one or more sensing leads, which may comprise one or more sensing electrodes located at or near the site of the cancerous tumor; and modulating the therapy according to the at least one treatment parameter set if the impedance of the cancerous tumor or the healthy tissue changes during the predetermined time period.

[0206] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: implanting a medical device at or near the site of the cancerous tumor; applying one or more electric fields at or near the site of the cancerous tumor to deliver therapy according to the at least one treatment parameter set for a predetermined period of time, wherein applying the one or more electric fields comprises using one or more supply leads, each supply lead may include one or more supply electrodes; measuring polarization of the cancerous tumor by measuring amplitude and phase at predetermined intervals during application of the one or more electric fields, wherein measuring the polarization of the cancerous tumor comprises using one or more sensing leads, the sensing leads may include one or more sensing electrodes; pausing the therapy at a predetermined polarization of the cancerous tumor and measuring a relaxation characteristic curve of the cancerous tumor; and modulating the therapy according to the at least one treatment parameter set if the relaxation characteristic curve changes within a predetermined value range.

[0207] In an embodiment, modulating the therapy according to the at least one set of treatment parameters includes modulating the one or more electric fields if a polarization at or near the site of the cancerous tumor during the therapy changes by at least 25% relative to an initial polarization measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0208] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: implanting a medical device at or near the site of the cancerous tumor; applying one or more DC electric fields at or near the site of the cancerous tumor to deliver therapy according to at least one treatment parameter set for a predetermined time period, wherein applying the one or more DC electric fields comprises using one or more supply leads, each of which may comprise one or more supply electrodes; measuring polarization of the cancerous tumor by measuring amplitude and phase at predetermined intervals during applying the one or more DC electric fields, wherein measuring the polarization of the cancerous tumor comprises using one or more sensing leads, which may comprise one or more sensing electrodes; if the polarization of the cancerous tumor changes during the predetermined time period, modulating the therapy according to the at least one treatment parameter set.

[0209] In an embodiment, modulating the therapy according to the at least one set of treatment parameters includes modulating the one or more DC electric fields if a polarization at or near the site of the cancerous tumor changes by at least 25% during the therapy relative to an initial polarization measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0210] In an embodiment, the at least one set of treatment parameters further comprises modulating the one or more DC electric fields by increasing or decreasing the strength of the one or more DC electric fields.

[0211] In an embodiment, modulating the therapy according to the at least one set of treatment parameters includes modulating the one or more DC electric fields if during any given therapy the polarization at or near the site of the cancerous tumor changes by at least 50% relative to an initial polarization measured at or near the site of the cancerous tumor at the beginning of the therapy.

[0212] In an embodiment, the at least one set of treatment parameters further comprises modulating the one or more DC electric fields by increasing or decreasing the strength of the one or more DC electric fields.

[0213] In an embodiment, modulating therapy according to the at least one set of therapy parameters comprises terminating the at least one set of therapy parameters if, during a predetermined time period, the polarization falls outside of a predetermined range.

[0214] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in a sense including "and / or" unless the content clearly dictates otherwise.

[0215] It should also be noted that, as used in this specification and the appended claims, the phrase "configured" describes a system, device, or other structure that is constructed or configured to perform a specific task or adopt a specific configuration. The phrase "configured" may be used interchangeably with other similar phrases such as "arranged and configured," "constructed and arranged," "constructed," "manufactured and arranged," etc.

[0216] All publications and patent applications in this specification are indicative of the levels of ordinary skill in the art to which the invention pertains. All publications and patent applications are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0217] The embodiments described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, these embodiments are selected and described so that those skilled in the art can understand and appreciate these principles and practices. Thus, various aspects have been described with reference to a number of different specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of this article.

Claims

1. A medical device for treating cancerous tumors, comprising: an electric field generating circuit configured to generate one or more electric fields at or near the site of the cancerous tumor; a control circuit in communication with the electric field generating circuit, the control circuit being configured to control delivery of the one or more electric fields from the electric field generating circuit; wherein the control circuit is configured to generate at least a first electric field and a second electric field, wherein the first electric field has a first electric field strength and the second electric field has a second electric field strength; a first supply lead in communication with a first supply electrode and a second supply lead in communication with a second supply electrode, the first supply lead and the second supply lead being in electrical communication with the electric field generating circuit, wherein an electric current generated by the electric field generating circuit flows through the first supply lead and the second supply lead, wherein the first and second supply electrodes are configured to deliver the first and second electric fields to at or near the site of the cancerous tumor; as well as a first sensing wire in communication with the first sensing electrode and a second sensing wire in communication with the second sensing electrode, the first and second sensing wires being in electrical communication with a control circuit, wherein current generated by the electric field generating circuit does not substantially flow through the first sensing wire and the second sensing wire; as well as Wherein, the first sensing electrode and the second sensing electrode are configured to measure the impedance of the cancerous tumor under the first electric field strength and the second electric field strength during the application of the first electric field and the second electric field; Wherein, the first electric field strength is selected from the range from 0.1 V / cm to 2 V / cm, and the second electric field strength is selected from the range from 3 V / cm to 100 V / cm.

2. The medical device of claim 1, further comprising a memory containing one or more sets of treatment parameters.

3. The medical device according to claim 2, wherein: The control circuitry is further configured to implement the one or more sets of treatment parameters to deliver a given therapy.

4. The medical device according to claim 3, wherein: The control circuit is configured to modulate the one or more electric fields if an impedance at or near the site of the cancerous tumor changes by at least 5% during therapy relative to an initial impedance at or near the site of the cancerous tumor at the start of a given therapy.

5. The medical device according to claim 1, wherein: The one or more electric fields are modulated by increasing or decreasing the electric field strength.

6. The medical device according to claim 1, wherein: The frequency range for delivering the electric field includes a frequency range from 100 kHz to 500 kHz.

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