Electric field cancer treatment device with feedback mechanism and diagnostic function

Abstract

Embodiments herein relate to a medical device system including an electric field shaping element for treating a cancerous tumor within body tissue. In an embodiment, a method for treating a cancerous tumor is provided. The method may include implanting one or more electrodes within a patient, and measuring an impedance of tissue within the patient along a vector across or near a cancerous tumor. The method may also include applying an electric field to a cancerous tumor of the patient based on the measured impedance. Other embodiments are also included herein.

Description

[0001] This application is a divisional application of patent application for invention 201880068852.0.

[0002] This application was filed as a PCT international patent application on October 23, 2018, in the name of Cardiac Pacemakers, Inc., a U.S. state-owned company, as the applicant designated for all countries, and U.S. citizens Brian L. Schmidt, Jacob M. Ludwig, Benjamin J. Haasl, and Michael J. Kane (as the inventors designated for all countries), and claims the priority of U.S. Patent Application No. 16 / 167,140 filed on October 22, 2018, and U.S. Provisional Patent Application No. 62 / 575,748 filed on October 23, 2017. The contents of these applications are incorporated herein by reference in their entirety. Technical Field

[0003] Embodiments herein relate to medical device systems including electrofield shaping elements for treating cancerous tumors within body tissue. More specifically, embodiments herein relate to the use of electrofield shaping elements configured to redirect or focus a treatment electrofield to a cancerous tumor site. Background Art

[0004] According to the American Cancer Society, cancer accounts for nearly 25% of the annual deaths in the United States. The current standard of care for cancerous tumors can include first-line treatments such as surgery, radiotherapy, and chemotherapy. Additional second-line treatments can include radioimmunotherapy, cryotherapy, hormone or biologic agent therapy, ablation, etc. Combinations of first-line and second-line treatments can also be beneficial to patients in cases where a particular treatment is ineffective on its own.

[0005] If a normal cell in any part of the human body mutates and then begins to grow and multiply too much and too fast, a cancerous tumor may form. Cancerous tumors may be the result of gene mutations in cellular DNA or RNA that occur during cell division, such as external stimuli like ionizing or non-ionizing radiation, exposure to carcinogens, or the result of genetic gene mutations. Regardless of the cause, many cancerous tumors are the result of unconstrained rapid cell division.

[0006] Mitosis is the process of cell division and is part of the cell cycle of all somatic cells in the body, including many types of cancer cells. Mitosis includes four basic stages: prophase, metaphase, anaphase, and telophase. Just before prophase, the cell will replicate its chromosomes to produce two identical sister chromatids. In prophase, the chromosomes begin to condense and the nuclear membrane surrounding the nucleus disappears. During prophase, the mitotic spindle also begins to form. The mitotic spindle consists of a self-organizing bipolar array of microtubules and centrosomes. Microtubules are typically formed by the polymerization of highly polar α-tubulin and β-tubulin. Centrosomes are similarly protein-based organelles, and the two organelles migrate to opposite sides of the dividing cell during this stage. The negatively charged ends of the microtubules attach to the centrosomes. The positively charged ends of the microtubules diverge towards the equator of the dividing cell and eventually attach to the centromere of each sister chromatid. Metaphase can be defined by all the chromosomes aligning at the equator of the dividing cell and being bound to the mitotic spindle. Then, an equal number of sister chromatids are pulled towards opposite ends of the cell during anaphase. Once all the chromosomes have been separated, the process of telophase begins, during which the cell membrane starts to form a cleavage furrow between the two newly formed sister cells, and cell division is complete once the cells are physically separated from each other in a process called cytokinesis. Summary of the Invention

[0007] Embodiments herein relate to a medical device system including an electric field shaping element for treating a cancerous tumor within body tissue. In a first aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, a method for treating a cancerous tumor is included. The method may include implanting one or more electrodes within a patient and measuring the impedance of tissue within the patient along a vector passing through or near the cancerous tumor. The method may further include applying an electric field to the patient's cancerous tumor based on the measured impedance.

[0008] In a second aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, the method may include applying an electric field to the patient's cancerous tumor based on the measured impedance.

[0009] In a third aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, the method may include electrodes, which include an electric field generating electrode and a passive electric field sensing electrode.

[0010] In a fourth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, a method may include implanting a passive electric field sensing electrode within the cancerous tumor.

[0011] In a fifth aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, the method may include implanting an electric field generating electrode near a cancerous tumor.

[0012] In a sixth aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, a method for treating a cancerous tumor is provided. The method may include: implanting one or more electrodes in a patient and measuring the impedance of tissue in the patient along a vector passing through or near the cancerous tumor. The method may further include evaluating tumor development based on the measured impedance.

[0013] In a seventh aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, the method may include applying an electric field to the cancerous tumor of the patient based on the measured impedance.

[0014] In an eighth aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, a decrease in impedance indicates tumor development.

[0015] In a ninth aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, the measured impedance includes the measured low-frequency impedance.

[0016] In a tenth aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, the low frequency may include frequencies from about 1 Hz to about 10 Hz.

[0017] In an eleventh aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, the measured impedance may include the measured high-frequency impedance.

[0018] In a twelfth aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, the high frequency may include frequencies from about 10 kHz to about 1 MHz.

[0019] In a thirteenth aspect, in addition to one or more of the foregoing or following aspects or in an alternative to some aspects, the high frequency may include frequencies from about 100 kHz to about 300 kHz.

[0020] In a fourteenth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, a method for treating a cancerous tumor is provided. The method may include implanting one or more electric field generating electrodes in a patient and implanting one or more electric field sensing electrodes in the patient. The method may further include delivering an electric field from the electric field generating electrodes to the cancerous tumor and measuring the electric field strength in or around the cancerous tumor using the electric field sensing electrodes. The method may further include adjusting the delivered electric field to a desired electric field strength based on the measured electric field strength.

[0021] In a fifteenth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, a method for treating a cancerous tumor is included. The method may include: implanting one or more electrodes in a patient and measuring the characteristics of an electric field delivered along a vector passing through or near the cancerous tumor, the characteristics being selected from the group including impedance, capacitance, and electric field strength. The method may further include delivering an electric field to the cancerous tumor based on the measured characteristics.

[0022] In a sixteenth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, the measured characteristics may include impedance.

[0023] In a seventeenth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, the measured characteristics may include capacitance.

[0024] In an eighteenth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, the measured characteristics may include field strength.

[0025] In a nineteenth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, the method may include adjusting the delivered electric field based on the measured characteristics.

[0026] In a twentieth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, wherein adjusting the delivered electric field may include changing one or more of the electric field strength, the waveform of the electric field, and the frequency of the electric field.

[0027] In a twenty - first aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, a method for treating a cancerous tumor is included. The method may include implanting one or more electric - field - generating electrodes in a patient and implanting an evoked - potential sensor in the patient. The method may include delivering an electric field from the electric - field - generating electrodes to the cancerous tumor. The method may include: using the evoked - potential sensor to monitor the evoked potential to determine whether the intensity of the delivered electric field is higher than a predetermined threshold for nerve or muscle recruitment, and if the electric - field intensity is higher than the nerve or muscle recruitment threshold, reducing the electric - field intensity.

[0028] In a twenty - second aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, a method for treating a cancerous tumor is provided. The method may include implanting one or more electric - field - generating electrodes in a patient and measuring the patient's heart rate. The method may include delivering an electric field from the electric - field - generating electrodes to the cancerous tumor. The method may include: monitoring a change in the patient's heart rate in response to the delivered electric field, and if a change in heart rate is detected, adjusting the electric field.

[0029] In a twenty - third aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, wherein adjusting the electric field may include reducing the intensity of the delivered electric field to a predetermined threshold.

[0030] In a twenty - fourth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, wherein adjusting the electric field may include increasing the intensity of the delivered electric field to a predetermined threshold.

[0031] In a twenty - fifth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, a method for treating a cancerous tumor is included. The method may include implanting one or more electric - field - generating electrodes in a patient and delivering an electric field from the electric - field - generating electrodes to the cancerous tumor. The method may include measuring at least one property selected from the group consisting of: temperature, blood flow, blood pressure, metabolite concentration, and systemic cancer - marker concentration.

[0032] In a twenty - sixth aspect, in addition to or as an alternative to one or more of the foregoing or following aspects, the method may include monitoring a change in at least one property.

[0033] The present invention content is an overview of some teachings of this application and is not intended to be an exclusive or exhaustive treatment of the subject matter. Further details will be found in the detailed description and the appended claims. After reading and understanding the following detailed description and viewing the accompanying drawings that form a part thereof, other aspects will be apparent to those skilled in the art, and each aspect should not be construed as restrictive. The scope herein is defined by the appended claims and their legal equivalents. Brief Description of the Drawings

[0034] In conjunction with the following drawings, various aspects can be more fully understood, in which:

[0035] Figure 1 is a schematic diagram of a medical system according to different embodiments herein.

[0036] Figure 2 is a schematic diagram of a medical system according to different embodiments herein.

[0037] Figure 3 is a schematic cross-sectional view of a medical device according to different embodiments herein.

[0038] Figure 4 is a schematic diagram of a medical device according to different embodiments herein.

[0039] Figure 5 is a schematic diagram of components of a medical device according to different embodiments herein.

[0040] Figure 6 is a schematic diagram of a medical device according to different embodiments herein.

[0041] Figure 7 is a schematic diagram of a wire according to different embodiments herein.

[0042] Figure 8 is a flowchart of a method for treating a cancerous tumor according to different embodiments herein.

[0043] Figure 9 is a flowchart of a method for treating a cancerous tumor according to different embodiments herein.

[0044] Figure 10 is a flowchart of a method for treating a cancerous tumor according to different embodiments herein.

[0045] Figure 11 is a flowchart of a method for treating cancer according to different embodiments herein.

[0046] Figure 12 is a flowchart of a method for treating a cancerous tumor according to different embodiments herein.

[0047] Figure 13 is a flowchart of a method for treating a cancerous tumor according to various embodiments herein.

[0048] Figure 14 is a flowchart of a method for treating a cancerous tumor according to various embodiments herein.

[0049] Figure 15 is a graph of exemplary treatment parameters according to various embodiments herein.

[0050] Although the embodiments are susceptible to various modifications and alternative forms, details of the embodiments have been shown by way of example and will be described in detail. However, it should be understood that the scope herein is not limited to the particular embodiments described. On the contrary, the intention is to cover modifications, equivalents, and alternatives falling within the spirit and scope herein. Detailed Description

[0051] As mentioned above, many cancerous tumors may be caused by unconstrained rapid cell division. Some conventional first-line treatments for treating cancerous tumors may include surgery, radiotherapy, and chemotherapy. However, many first-line treatments have adverse accompanying side effects such as fatigue, hair loss, immunosuppression, and long surgical recovery times, among others.

[0052] While not being bound by theory, it is believed that alternating electric fields can disrupt mitosis within a cancerous tumor by interfering with the dipole alignment of key proteins involved in cell division, particularly tubulin and septin. The polymerization of the protein tubulin that forms the microtubule spindle fibers can be disrupted, thereby preventing the formation of spindle fibers required for chromosome segregation. This can cause cell division to halt at the metaphase stage of mitosis. In some cases, if the cells are able to survive that long, the alternating electric field may cause the polymerization of already grown spindle fibers to stop, resulting in an incomplete spindle and unequal chromosome segregation in the anaphase. In each case, the halt in the formation of the microtubule spindle and unequal chromosome segregation due to incomplete microtubule polymerization in the anaphase may cause apoptosis (i.e., programmed cell death).

[0053] It is also believed that alternating electric fields may cause an increase in the electric field density near the cleavage furrow of dividing cells in the telophase. The increase in the electric field density in the region of the cleavage furrow may cause dielectrophoresis of charged macromolecules such as proteins and nucleic acids towards the high electric field density at the furrow. The unequal concentration of key macromolecules required for cell division at the cleavage furrow site may disrupt the final separation of sister cells in the telophase and ultimately cause cell apoptosis.

[0054] Feedback obtained during electric field therapy can be used to monitor the effectiveness of using such therapy to treat a cancerous tumor. Data on parameters such as impedance, capacitance, field strength, etc. can be measured to guide a particular treatment process. Without being bound by any particular theory, it is believed that a cancerous tumor has a particular impedance associated therewith. The impedance associated with the tumor can vary with changes in the size or cellular composition of the tumor. Thus, impedance can be monitored during electric field therapy to determine whether the cancerous tumor is responsive to the treatment. In some cases, an increase in the impedance of the tissue in the treatment area including the cancerous tumor can indicate tumor regression. In other cases, a decrease in the impedance of the tissue in the treatment area or no change being observed can indicate tumor progression or no change in the tumor, respectively. Other physiological characteristics associated with the cancerous tumor, such as blood flow, metabolite concentration, systemic cancer markers, and temperature, can also be used in combination with impedance analysis to monitor the progression or regression of the cancerous tumor in response to electric field therapy.

[0055] The treatment parameters of the electric field therapy can be modulated and / or changed, adjusted, or otherwise altered based on the measured value of at least one of impedance, capacitance, field strength, etc., and the treatment parameters include, but are not limited to, one or more of amplitude, frequency, pulse width, waveform, directionality, vector, and / or duty cycle.

[0056] Now refer to Figure 1 , which shows a schematic diagram of a medical device 100 according to different embodiments herein. The medical device 100 can be fully implanted into the body of a patient 101, at or near the site of a cancerous tumor within body tissue. Various implantation sites can be used, including areas such as the extremities, upper torso, abdominal region, head, etc.

[0057] Now refer to Figure 2 , which shows another schematic diagram of a medical device 200 according to different embodiments. The medical device 200 can be partially implanted into the body of a patient 101. In some embodiments, the medical device can be partially implanted and partially outside the patient's body. In other embodiments, the partially implanted medical device can include a percutaneous connection between components disposed inside and outside the body. The partially implanted medical device can communicate wirelessly with the part of the medical device outside the body via a wireless connection.

[0058] In some embodiments, a portion of a medical device may be fully implanted, while a portion of the medical device may be entirely external. For example, in some embodiments, one or more electrodes or leads may be fully implanted within the body, while a portion of the medical device that generates an electric field, such as an electric field generator, may be entirely external to the body. It should be understood that in some of the embodiments described herein, the 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 fully implanted and a portion of the medical device is entirely external, the portion of the medical device that is entirely external may communicate wirelessly with the portion of the medical device that is entirely internal. However, in other embodiments, a wired connection may be used.

[0059] Medical device 100 or medical device 200 may include a housing 102 and a head 104 coupled to the housing 102. A variety of materials may be used. However, in some embodiments, the housing 102 may be formed of materials such as metal, ceramic, polymer, composite materials, etc. In some embodiments, the housing 102 or one or more of its parts may be formed of titanium. The head 104 may be formed of a variety of materials, but in some embodiments, the head 104 may be formed of a translucent polymer such as an epoxy resin material. In some embodiments, the head 104 may be hollow. In other embodiments, the head 104 may be filled with components and / or structural materials, such as epoxy resin or other materials, such that it is non-hollow.

[0060] In some embodiments where a portion of medical device 100 or 200 is partially external, the head 104 and the housing 102 may be surrounded by a protective outer shell made of a durable polymer material. In the case where a portion of medical device 100 or 200 is partially external, the head 104 and the housing 102 may be surrounded by a protective outer shell made of a combination of a polymer material, a metal material, and / or a glass material.

[0061] The head 104 may be coupled to one or more leads 106. The head 104 may be used to secure the proximal ends of one or more leads 106 and electrically couple one or more leads 106 to one or more components within the housing 102. One or more leads 106 may include one or more electrodes 108 disposed along the length of the electrical lead 106. In some embodiments, the electrodes 108 may include electric field generating electrodes, while in other embodiments, the electrodes 108 may include electric field sensing electrodes. In some embodiments, the lead 106 may include both an electric field generating electrode and an electric field sensing electrode. In other embodiments, the lead 106 may include any number of electric field sensing electrodes and electric field generating electrodes. It should be understood that although many embodiments of the medical devices herein are designed to operate with leads, leadless medical devices that generate electric fields are also contemplated herein.

[0062] Now referring Figure 3 , a schematic cross-sectional view of a medical device 100 in accordance with various embodiments herein is shown. The housing 102 may define an internal volume 302 that may be hollow and that in some embodiments is hermetically sealed from an area 304 external to the medical device 100. In other embodiments, the housing 102 may be filled with components and / or structural materials such that it is non-hollow. The medical device 100 may include control circuitry 306 that may include various components 308, 310, 312, 314, 316, and 318 disposed within the housing 102. In some embodiments, these components may be integrated, while in other embodiments, these components may be separate. In still other embodiments, there may be a combination of integrated and separate components. The medical device 100 may also include an antenna 324 to permit one-way or two-way wireless data communication. In some embodiments, the components of the medical device 100 may include an inductive energy receiving coil (not shown) that is communicatively coupled or attached to the medical device to facilitate transcutaneous charging of the medical device via a charging circuit.

[0063] The various components 308, 310, 312, 314, 316, and 318 of the control circuit 306 may include, but are not limited to, a microprocessor, a storage circuit (such as a random access memory (RAM) and / or a read-only memory (ROM)), a recording circuit, a controller circuit, a telemetry circuit, a power supply circuit (such as a battery), a timing circuit, and an application-specific integrated circuit (ASIC), a charging circuit, etc. The control circuit 306 may communicate with an electric field generating circuit 320, which may be configured to generate a current to form one or more fields. The electric field generating circuit 320 may be integrated with the control circuit 306 or may be a component separate from the control circuit 306. The control circuit 306 may be configured to control the delivery of the current from the electric field generating circuit 320. In some embodiments, the electric field generating circuit 320 may be present in a portion of the medical device that is external to the body.

[0064] In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver an electric field using one or more frequencies selected from a range between 10 kHz and 1 MHz. In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver an electric field at one or more frequencies selected from a range between 100 kHz and 500 kHz. In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver an electric field at one or more frequencies selected from a range between 100 kHz and 300 kHz. In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to periodically deliver an electric field using one or more frequencies greater than 1 MHz.

[0065] In some embodiments, the electric field may be effective in disrupting cell mitosis in cancer cells. The electric field may be delivered to the cancerous tumor site along more than one vector. In some examples, the electric field may be delivered along at least one vector, including at least one of the wire electrodes. In some embodiments, at least two vectors may be used, with spatial diversity between these vectors. The vectors may be spatially separated (e.g., the vectors may 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.

[0066] The desired electric field strength can be achieved by delivering an electric current between two electrodes. The specific current and voltage for delivering the 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 306 can be configured to direct the electric field generating circuit 320 to deliver an electric field to the cancerous tumor site using a current ranging from 1 mAmp to 1000 mAmp. In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver an electric field to the cancerous tumor site using a current ranging from 20 mAmp to 500 mAmp. In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver an electric field to the cancerous tumor site using a current ranging from 30 mAmp to 300 mAmp.

[0067] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver an electric field using a current including the following: 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, 100 mAmp, 125 mAmp, 150 mAmp, 175 mAmp, 200 mAmp, 225 mAmp, 250 mAmp, 275 mAmp, 300 mAmp, 325 mAmp, 350 mAmp, 375 mAmp, 400 mAmp, 425 mAmp, 450 mAmp, 475 mAmp, 500 mAmp, 525 mAmp, 550 mAmp, 575 mAmp, 600 mAmp, 625 mAmp, 650 mAmp, 675 mAmp, 700 mAmp, 725 mAmp, 750 mAmp, 775 mAmp, 800 mAmp, 825 mAmp, 850 mAmp, 875 mAmp, 900 mAmp, 925 mAmp, 950 mAmp, 975 mAmp or 1000 mAmp. It should be understood that the control circuit can be configured to direct the electric field generating circuit 320 to deliver an electric field with a current falling within a range where any of the foregoing currents can be used as the lower 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.

[0068] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to use a range from 1 V rms to 50 V rmsto deliver an electric field to a cancerous tumor site. In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to use a voltage ranging from 5V rms to 30V rms to deliver an electric field to a cancerous tumor site. In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to use a voltage ranging from 10V rms to 20V rms to deliver an electric field to a cancerous tumor site.

[0069] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to use one or more voltages including the following to deliver an electric field: 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 understood that the control circuit can be configured to direct the electric field generating circuit 320 to use a voltage belonging to the following range to deliver an electric field, where any one of the foregoing voltages can be used as the lower limit or the upper limit of the range, as long as the lower limit of the range is a value less than the upper limit of the range.

[0070] In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver an electric field using one or more frequencies including: 10 kHz, 20 kHz, 30 kHz, 40 kHz, 50 kHz, 60 kHz, 70 kHz, 80 kHz, 90 kHz, 100 kHz, 125 kHz, 150 kHz, 175 kHz, 200 kHz, 225 kHz, 250 kHz, 275 kHz, 300 kHz, 325 kHz, 350 kHz, 375 kHz, 400 kHz, 425 kHz, 450 kHz, 475 kHz, 500 kHz, 525 kHz, 550 kHz, 575 kHz, 600 kHz, 625 kHz, 650 kHz, 675 kHz, 700 kHz, 725 kHz, 750 kHz, 775 kHz, 800 kHz, 825 kHz, 850 kHz, 875 kHz, 900 kHz, 925 kHz, 950 kHz, 975 kHz, 1 MHz. It should be understood that the electric field generating circuit 320 may use frequencies within the following range to deliver an electric field, where any one of the foregoing frequencies may be used as the upper or lower limit of the range, as long as the upper limit is greater than the lower limit.

[0071] In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to generate one or more applied electric field strengths selected from the range between 0.25 V / cm and 1000 V / cm. In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to generate one or more applied electric field strengths greater than 3 V / cm. In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to generate one or more applied electric field strengths selected from the range between 1 V / cm and 10 V / cm. In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to generate one or more applied electric field strengths selected from the range between 3 V / cm and 5 V / cm.

[0072] In other embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 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, 100.0 V / cm, 125.0 V / cm, 150.0 V / cm, 175.0 V / cm, 200.0 V / cm, 225.0 V / cm, 250.0 V / cm, 275.0 V / cm, 300.0 V / cm, 325.0 V / cm, 350.0 V / cm, 375.0 V / cm, 400.0 V / cm, 425.0 V / cm, 450.0 V / cm, 475.0 V / cm, 500.0 V / cm, 600.0 V / cm, 700.0 V / cm, 800.0 V / cm, 900.0 V / cm, 1000.0 V / cm. It should be understood that the electric field generating circuit 320 may generate an electric field, and the electric field strength at the treatment site belongs to the following range, where any one of the foregoing electric field strengths may be used as the upper or lower limit of the range, as long as the upper limit is greater than the lower limit.

[0073] In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver an electric field via the wire 106 to a cancerous tumor site located within body tissue. In other embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver an electric field via the housing 102 of the medical device 100 to a cancerous tumor site located within body tissue. In other embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver an electric field between the wire 106 and the housing 102 of the medical device 100. In some embodiments, one or more wires 106 may be in electrical communication with the electric field generating circuit 320. In some embodiments, one or more wires 106 may include one or more electrodes 108 disposed along the length of the wire 106, wherein the electrodes 108 may be in electrical communication with the electric field generating circuit 320.

[0074] In some embodiments, various components within the medical device 100 may include an electric field sensing circuit 322, which is configured to generate a signal corresponding to the sensed electric field. The electric field sensing circuit 322 may be integrated with the control circuit 306, or it may also be separate from the control circuit 306.

[0075] The sensing electrodes can be disposed on or near the housing of the medical device, on one or more wires connected to the housing, on a separate device implanted near or in the tumor, or any combination of these locations. In some embodiments, the electric field sensing circuit 322 can include a first sensing electrode 332 and a second sensing electrode 334. In other embodiments, the housing 102 itself can be used as a sensing electrode of the electric field sensing circuit 322. The electrodes 332 and 334 can be in communication with the electric field sensing circuit 322. The electric field sensing circuit 322 can measure the potential difference (voltage) between the first electrode 332 and the second electrode 334. In some embodiments, the electric field sensing circuit 322 can measure the potential difference (voltage) between the first electrode 332 or the second electrode 334 and an electrode disposed along the length of one or more wires 106. In some embodiments, the electric field sensing circuit can be configured to measure the sensed electric field and record the electric field strength in V / cm.

[0076] It should be understood that the electric field sensing circuit 322 can additionally measure the potential difference between the first electrode 332 or the second electrode 334 and the housing 102 itself. In other embodiments, the medical device can include a third electrode 336, which can be an electric field sensing electrode or an electric field generating electrode. In some embodiments, one or more sensing electrodes can be disposed along the wire 106 and can be used as additional locations for sensing the electric field. According to the embodiments herein, many combinations can be envisioned for measuring the potential difference between an electrode disposed along the length of one or more wires 106 and the housing 102.

[0077] In some embodiments, one or more wires 106 can be in electrical communication with the electric field generating circuit 320. One or more wires 106 can include one or more electrodes 108, as Figure 1 and Figure 2 shown. In some embodiments, different electrical conductors (such as electrical conductors 326 and 328) can pass through the feedthrough structure 330 from the head 104 and into the internal volume 302 of the medical device 100. Thus, the electrical conductors 326 and 328 can be used to provide electrical communication between one or more wires 106 and the control circuit 306 disposed within the internal volume 302 of the housing 102.

[0078] In some embodiments, the recording circuit can be configured to record the data generated by the electric field sensing circuit 322 and record a timestamp for the data. In some embodiments, the control circuit 306 can be hardwired to perform various functions, while in other embodiments, the control circuit 306 can be instructed to execute instructions implemented on a microprocessor or other external computing device. A telemetry circuit can also be provided for communicating with external computing devices such as a programmer, a home-based unit, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smartphone, a tablet computer, etc.).

[0079] Now referring to Figure 4 , a leadless medical device 400 is shown in accordance with an embodiment herein. The leadless medical device 400 may include a housing 402 and a head 404 coupled to the housing 402. A variety of materials may be used. However, in some embodiments, the housing 402 may be formed of materials such as metal, ceramic, polymer, composite materials, etc. In some embodiments, the housing 402 or one or more of its parts may be formed of titanium. The head 404 may be formed of a variety of materials, but in some embodiments, the head 404 may be formed of a translucent polymer such as an epoxy resin material. In some embodiments, the head 404 may be hollow. In other embodiments, the head 404 may be filled with components and / or structural materials, such as epoxy resin or other materials, such that it is non-hollow. In some embodiments, the leadless medical device 400 may include a fixation element 406 for holding the leadless medical device 400 positioned at or near a site of a cancerous tumor in the body. In some embodiments, the fixation element 406 may include claws, barbs, helices, threads, etc.

[0080] In Figure 5 the elements of different embodiments of the medical devices described herein are shown. However, it should be understood that some embodiments may include additional elements in addition to Figure 5 the elements shown. Additionally, some embodiments may not have Figure 5 some of the elements shown. The medical device as implemented herein may collect information through one or more sensing channels and may output information through one or more field generating channels. The microprocessor 502 may communicate with the memory 504 via a bidirectional data bus. The memory 504 may include read only memory (ROM) or random access memory (RAM) for program storage and RAM for data storage. The microprocessor 502 may also be connected to a telemetry interface 518 for communicating with external devices such as a programmer, a home-based unit, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.) or directly connected to the cloud or another communication network with the help of a cellular network or other data communication network. In some embodiments, the medical device may include an inductive energy receiving coil interface (not shown) that is communicatively coupled or attached to the medical device to facilitate percutaneous charging of the medical device.

[0081] The medical device may include one or more electric field sensing electrodes 508, and one or more electric field sensor channel interfaces 506 that may communicate with ports of the microprocessor 502. The medical device may also include one or more electric field generating electrodes 512, and one or more electric field generating channel interfaces 510 that may communicate with ports of the microprocessor 502. The medical device may further include one or more physiological sensors, respiratory sensors, or chemical sensors 516, and one or more physiological / respiratory / chemical sensor channel interfaces 514 that may communicate with ports of the microprocessor 502. The channel interfaces 506, 510, and 514 may include different components, such as an analog-to-digital converter for digitizing the input signal, a sensing amplifier, a register that may be written by a control circuit to adjust the gain and threshold of the sensing amplifier, a source driver, a modulator, a demodulator, a multiplexer, and the like.

[0082] In some embodiments, the physiological sensors may include sensors for monitoring temperature, blood flow, blood pressure, and the like. In some embodiments, the respiratory sensors may include sensors for monitoring respiratory rate, peak respiratory amplitude, and the like. In some embodiments, the chemical sensors may measure the amount of analytes present in the treatment area surrounding the sensor, and these analytes include, but are not limited to, for example, blood urea nitrogen, creatinine, fibrin, fibrinogen, immunoglobulins, deoxyribonucleic acid, ribonucleic acid, potassium, sodium, chloride, calcium, magnesium, lithium, hydronium, hydrogen phosphate, bicarbonate, and the like. However, many other analytes are also contemplated herein. Exemplary chemical / analyte sensors are disclosed in U.S. Patent No. 7,809,441, jointly owned by Kane et al., and that patent is incorporated herein by reference in its entirety.

[0083] Although the physiological sensors, respiratory sensors, or chemical sensors 516 are shown as part of the medical device in Figure 5 it should be appreciated that in some embodiments, one or more of the physiological sensors, respiratory sensors, or chemical sensors may be physically separate from the medical device. In different embodiments, one or more of the physiological sensors, respiratory sensors, or chemical sensors may be within another implanted medical device that is communicatively coupled to the medical device via a telemetry interface 518. In still other embodiments, one or more of the physiological sensors, respiratory sensors, or chemical sensors may be external to the body and coupled to the medical device via a telemetry interface 518.

[0084] Now refer to Figure 6, A schematic diagram of a medical device 600 is shown according to an embodiment in this document. The medical device 600 may include a housing 102, a head 104, and one or more leads 106. The lead 106 may include one or more electrodes disposed along the length of the lead, such as electrodes 604, 606, 608, 610, 612, or 614. In some embodiments, the electrodes 604, 606, 608, 610, 612, or 614 may include electric field generating electrodes, while in other embodiments, the electrodes 604, 606, 608, 610, 612, or 614 may include electric field sensing electrodes. In some embodiments, the lead 106 may include both electric field generating electrodes and electric field sensing electrodes.

[0085] The proximal end of the lead 106 is disposed within the head 104. The distal end of the electrical lead 106 may surround the cancerous tumor 602 such that the electrodes 604, 606, 608, 610, 612, or 614 are brought near the cancerous tumor 602. In some embodiments, the lead 106 may be positioned within the vasculature such that the electrodes 604, 606, 608, 610, 612, or 614 are adjacent to or positioned within the cancerous tumor 602. However, it should be understood that the lead 106 may be arranged at different positions within or around the cancerous tumor 602. In some embodiments, the lead 106 may pass directly through the cancerous tumor 602.

[0086] In some embodiments, the lead 106 may include one or more tracking markers 616 or 618 along the length of the lead for determining the precise position of the electrodes relative to the tumor. In some embodiments, one or more tracking markers may be disposed immediately distal or immediately proximal to one or more electrodes on the lead. In some embodiments, the tracking markers may be formed of a magnetic material. In some embodiments, the tracking markers may be formed of a radiopaque material. In some embodiments, the tracking markers may be formed of a fluoroscopic material.

[0087] It should be understood that multiple electric field vectors can be generated between various combinations of electrodes 604, 606, 608, 610, 612, or 614 disposed along wire 106 to form an electric field. For example, one or more electric field vectors can be generated between electrodes 604 and 610. Similarly, one or more electric field vectors can be generated between electrodes 606 and 612. It should also be understood that one or more electric field vectors can be generated between any combination of electrodes 604, 606, 608, 610, 612, or 614. In some embodiments, one or more electric field vectors can be generated between any combination of electrodes 604, 606, 608, 610, 612, or 614 and the housing 102 of the medical device 400. It should be understood that according to the embodiments herein, one or more monopolar wires or multipolar wires can be used. In some embodiments, a combination of monopolar wires and multipolar wires can be used. In other embodiments, circular wires, clamped wires, cuff wires, paddle wires, or patch wires can be used.

[0088] Now referring to Figure 7 , a wire 702 according to an embodiment herein is shown. The wire 702 can include electrodes 704 disposed along the length of the wire 702. In some embodiments, the electrodes 704 can be electric field generating electrodes. In some embodiments, the electrodes 704 can be electric field sensing electrodes. In some embodiments, the electrodes 704 can include a combination of an electric field generating electrode and an electric field sensing electrode. As discussed herein, an electrode can refer to an electric field generating electrode or an electric field sensing electrode unless specifically described as one or the other. In some embodiments, the wire 702 can include one or more dedicated impedance monitoring electrodes (not shown).

[0089] In some embodiments, impedance can be measured by dividing voltage by current. In the body, impedance is affected by a variety of factors, including but not limited to the 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, an electric field sensing electrode or an electric field generating electrode can be used as an impedance monitoring electrode. It should be understood that different tissues will have different impedances at a given frequency. Thus, in some embodiments, measuring impedance at one or more frequencies at any given location is contemplated and described in more detail below with reference to Figure 9 Impedance can be measured at frequencies within the treatment frequency range. In some embodiments, impedance can be measured at frequencies outside the treatment frequency. In some embodiments, impedance can be measured at two frequencies within the treatment frequency range and at a frequency outside the treatment frequency.

[0090] The lead 702 may include a lead body 706 having a proximal end 708 and a distal end 710. The lead body 706 may include one or more conductors (not shown) that pass through the lead body 706 and provide electrical communication between one or more electrodes 704 and the proximal end 708 of the lead body 706. One or more leads 702 may be implanted at the site of a cancerous tumor. In some embodiments, one or more leads 702 may be implanted within the cancerous tumor. The lead 702 may be disposed within the head of a medical device implemented herein and may be configured to be in electrical communication with a control circuit within the medical device.

[0091] In some embodiments, the lead 702 may be configured to generate an electric field at the site of a cancerous tumor within the patient's body via an electric field generation circuit (not shown). The lead 702 may be configured to generate an electric field by one or more electric field generation electrodes disposed thereon. In some embodiments, the lead 702 may include both an electric field generation electrode and an electric field sensing electrode. In some embodiments, a separate lead 703 having an electric field sensing electrode disposed thereon may be implanted at or near the site of the cancerous tumor to serve as an electric field sensing lead. In some embodiments, an inactive electric field generation electrode located on either the lead 702 or 703 and proximate to the generated electric field may be configured to indirectly sense the electric field strength by measuring the voltage across the electric field generation electrode. It should be understood that the medical device described herein may be in electrical communication with one or more electrodes 704 to serve as an electrode capable of generating an electric field itself.

[0092] The electric field sensing electrode may be used to sense the electric field strength within or around the tumor during any given treatment. A recording circuit within the medical device may be configured to record data generated by the electric field sensing electrode, and a clinician may use the data to adjust the electric field strength to maintain a desired electric field strength at the site of the cancerous tumor. In some embodiments, the electric field generation circuit may be configured to automatically adjust the electric field strength in response to one or more data values sensed by the electric field sensing electrode to maintain a desired electric field strength at the site of the cancerous tumor. The foregoing is referenced Figure 3 and the control circuit 306 and the electric field generation circuit 320 describe suitable electric field strengths for use herein.

[0093] Now referring Figure 8 , a method 800 for treating a cancerous tumor according to an embodiment herein is shown. The method 800 may include implanting one or more electrodes in the patient at 802. After implanting the one or more electrodes, the method 800 may include, at 804, measuring the impedance of tissue within the patient along a vector passing through or near the cancerous tumor. The method 800 may further include, at 806, applying an electric field to the cancerous tumor of the patient based on the measured impedance.

[0094] In some embodiments, method 800 may further include applying an electric field to a patient's cancerous tumor based on a change in the measured impedance. Without being bound by any particular theory, it is believed that the impedance within a cancerous tumor is relatively low compared to non-cancerous or necrotic tissue. This phenomenon enables monitoring of the impedance based on the treatment duration and can be used as a diagnostic tool to evaluate whether the tumor is responsive to electric field therapy. If the impedance within the treatment area increases (over a fixed distance or region, due to atrophy of the low-impedance tumor tissue and non-cancerous tissue occupying the remaining space), this can be considered an indication that the electric field therapy has effectively reduced the size of the cancerous tumor. However, if the impedance within the treatment area decreases or remains constant over a fixed distance or region, this can be considered an indication that the electric field therapy has not reduced the size of the cancerous tumor. Thus, the electric field therapy can be customized for a particular cancerous tumor in order to effectively reduce its size. By way of 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 varied.

[0095] The electrodes suitable for method 800 can include functionality that allows them to be used as active electric field generating electrodes or passive electric field sensing electrodes. In some embodiments, an electric field generating electrode can be used as a passive electric field sensing electrode configured to measure the voltage of the electric field at a given point in time. In some embodiments, passive electric field sensing electrodes can be implanted within the cancerous tumor. In some embodiments, passive electric field sensing electrodes can be implanted near the cancerous tumor. In some embodiments, passive or active electric field generating electrodes can be implanted near the cancerous tumor. In different embodiments, a medical device including one or more components described with respect to Figure 3 and Figure 5 can be configured to perform one or more operations described with respect to Figure 8 described.

[0096] Now referring to Figure 9 , a method 900 for treating a cancerous tumor according to an embodiment herein is shown. Method 900 may include: at 902, implanting one or more electrodes within a patient. After implanting the one or more electrodes, method 900 may include: at 904, measuring the impedance of tissue within the patient along a vector passing through or near the cancerous tumor. Method 900 may further include: at 906, evaluating tumor progression based on the measured impedance. After evaluating tumor progression, method 900 may further include applying an electric field to the patient's cancerous tumor based on the measured impedance. In some embodiments, an increase in impedance over a fixed distance or region may indicate tumor regression. In other embodiments, a decrease in impedance may indicate tumor progression or resistance to electric field therapy.

[0097] Not bound by any particular theory, it is believed that cancerous tumors have a specific impedance associated therewith. In some embodiments, the low-frequency impedance of a particular cancerous tumor can be used to measure the electrical conductivity of the tumor and can be used as an indicator of tissue development or regression. In some embodiments, the high-frequency impedance of a particular cancerous tumor can be used to measure the dielectric constant and capacitance characteristics of the tumor and can also be used as an indication of tissue development or regression. In some embodiments, the low-frequency impedance can be measured at a frequency of from about 1 Hz to about 10 Hz. In some embodiments, the high-frequency impedance can be measured at a frequency of from about 10 Hz to about 1 MHz. In some embodiments, the high-frequency impedance can be measured at a frequency of from about 100 kHz to about 300 kHz. In different embodiments, a medical device including one or more components described with respect to Figure 3 and Figure 5 can be configured to perform one or more operations described with respect to Figure 9 described.

[0098] Now referring to Figure 10 , a method 1000 for treating a cancerous tumor according to an embodiment herein is shown. The method 1000 may include: at 1002, implanting one or more electric field generating electrodes and one or more electric field sensing electrodes in a patient. After implanting one or more electric field generating or electric field sensing electrodes, the method 1000 may include: at 1004, delivering an electric field from the electric field generating electrodes to the cancerous tumor. The method 1000 may include: at 1006, measuring the electric field strength in or around the cancerous tumor using the electric field sensing electrodes. The electric field strength can be measured in different ways, but in some embodiments, it may include calculating the electric field strength based on the measured voltage and the known spatial separation between the measurement electrodes. The method 1000 may further include: at 1008, adjusting the delivered electric field to a desired electric field strength based on the measured electric field strength. In different embodiments, a medical device including one or more components described with respect to Figure 3 and Figure 5 described can be configured to perform one or more operations described with respect to Figure 10 described.

[0099] Now referring to Figure 11, shows a method 1100 for treating a cancerous tumor according to an embodiment herein. The method 1100 may include: at 1102, implanting one or more electrodes in a patient. The method 1100 may further include: at 1104, measuring a characteristic of an electric field delivered along a vector passing through or near the cancerous tumor, the characteristic being selected from the group consisting of impedance, capacitance, and electric field strength. The method 1100 may further include: at 1106, delivering an electric field to the cancerous tumor based on the measured characteristic. In some embodiments, the method 1100 may further adjust the delivered electric field based on the measured characteristic. Adjusting the delivered electric field may include changing one or more of the electric field strength, changing the waveform of the electric field, and changing the frequency of the electric field. In some embodiments, the delivered electric field may be automatically adjusted by an electric field generating circuit, independent of local conditions such as tumor growth or regression, local electrolyte concentration, electrode state, electrode encapsulation, electrode impedance, tissue impedance, etc. In different embodiments, a medical device including one or more components described with respect to Figure 3 and Figure 5 described may be configured to perform one or more operations described with respect to Figure 11 described.

[0100] Now referring to Figure 12 , shows a method 1200 for treating a cancerous tumor according to an embodiment herein. The method 1200 may include: at 1202, implanting one or more electric field generating electrodes and one or more evoked potential sensors in a patient. In some embodiments, the evoked potential sensors may be sensors configured to detect one or more potentials emitted by a nervous system such as from the cerebral cortex, brainstem, spinal cord, and peripheral nerves. In some embodiments, the evoked potential sensors may be sensors configured to detect one or more potentials emitted by other power sources within the body such as from the myocardium or skeletal muscle. In some embodiments, the electric field sensing electrodes and the electric field generating electrodes may be configured to function as evoked potential sensors. The evoked potential sensors may include electrodes (such as the electrodes on the wires described herein) to measure electrical characteristics such as potential, current, and / or impedance.

[0101] Method 1200 may further include: at 1204, delivering an electric field from the electric field generating electrode to the cancerous tumor. An evoked potential sensor may be used to monitor the evoked potential response. In some embodiments, at 1206, the evoked potential sensor may be used to determine whether the delivered electric field strength is above a predetermined threshold for nerve or muscle recruitment. In some embodiments, the predetermined threshold may be determined prior to treatment. In some embodiments, the delivered electric field strength may be titrated until an evoked potential response is observed by the evoked potential sensor, and the electric field strength may be turned down so that an evoked potential response is not generated by nerve tissue or muscle tissue. The titration of the electric field strength may be performed manually by a clinician, or it may also be performed automatically, such as by programming the titration process into the memory of a medical device and controlling it by that medical device. Method 1200 may further include: if the electric field strength is above the threshold for nerve or muscle recruitment, reducing the strength of the electric field. In some embodiments, the electric field strength may be determined empirically so as to reach the highest possible electric field strength before causing nerve or muscle recruitment. In different embodiments, a medical device including one or more components described with respect to Figure 3 and Figure 5 may be configured to perform one or more operations described with respect to Figure 12 described.

[0102] Now referring to Figure 13 , a method 1300 for treating a cancerous tumor according to an embodiment herein is shown. Method 1300 may include: at 1302, implanting one or more electric field generating electrodes in a patient. Method 1300 may further include: at 1304, measuring the patient's initial heart rate. At 1306, an electric field may be delivered from the electric field generating electrode to the cancerous tumor. Method 1300 may include: at 1306, monitoring a change in the patient's heart rate in response to the delivered electric field. Method 1300 may further include: at 1308, if a change in heart rate is detected, adjusting the electric field. In some embodiments, adjusting the electric field may include reducing the strength of the delivered electric field to a predetermined threshold that does not cause a change in the patient's heart rate. In some embodiments, adjusting the electric field may include increasing the strength of the delivered electric field to a predetermined threshold just before a change in the patient's heart rate is detected. In different embodiments, a medical device including one or more components described with respect to Figure 3 and Figure 5 may be configured to perform one or more operations described with respect to Figure 13 described.

[0103] Now referring to Figure 14, shows a method 1400 for treating a cancerous tumor according to an embodiment herein. Method 1400 may include: at 1402, implanting one or more electric field generating electrodes in a patient. Method 1400 may include: at 1404, delivering an electric field from the electric field generating electrodes to the cancerous tumor. Method 1400 may include: at 1406, measuring at least one property selected from the group including: temperature, blood flow, blood pressure, metabolite concentration, and systemic cancer markers.

[0104] Temperature, blood flow, and blood pressure can be monitored by temperature sensors and pressure sensors mounted within or near a wire positioned at or within the cancerous tumor. The temperature sensors and pressure sensors can be configured to monitor the temperature, blood flow, and blood pressure at or near the site of the cancerous tumor. Exemplary transthoracic impedance sensors capable of monitoring blood flow, heart rate, blood pressure, etc. are described in co-owned U.S. Patent No. 8,795,189, which is incorporated herein by reference in its entirety. Exemplary chemical metabolites or analytes and methods for sensing them are disclosed in co-owned U.S. Patent No. 7,809,441 to Kane et al., and this application is incorporated herein by reference in its entirety.

[0105] Exemplary systemic cancer markers may include, but are not limited to: ALK gene overexpression, alpha-fetoprotein (AFP), beta-2-microglobulin (B2M), beta-human chorionic gonadotropin (beta-hCG), BRCA1 and BRCA2 gene mutations, BCR-ABL gene fusion, BRAF V600 mutation, BUN / creatinine, CD117 / C-kit, CA15-3 / CA27.29, CA19-9, CA-125, calcitonin, carcinoembryonic antigen (CEA), CD20, chromogranin A (CgA), cytokeratin fragment 21-1, epidural growth factor receptor (eGFR) gene mutation, estrogen receptor (ER) and progesterone receptor (PR) gene mutations, fibrin and fibrinogen, HE4, HER2 / neu gene and protein upregulation, immunoglobulins, KRAS gene mutation, lactate dehydrogenase, non-specific enolase (NSE), nuclear matrix protein 22, programmed death ligand 1 (PD-L1), prostate-specific antigen (PSA), thyroglobulin, urokinase plasminogen activator (uPA), and plasminogen activator inhibitor (PAI-1), etc.

[0106] Systemic cancer markers can be monitored by removing tissue or fluid samples from within or near a cancerous tumor site. In some embodiments, the lead described herein can include an open lumen extending along the entire longitudinal length of the lead or along a selected portion of the longitudinal length of the lead. The open lumen can 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 by analyzing the tissue or fluid for one or more systemic cancer markers.

[0107] In some embodiments, method 1400 can include monitoring for a change in at least one property. If a change in at least one property is detected, method 1400 can further include changing the delivered electric field based on the measured value of the at least one property. In different embodiments, a medical device including one or more components described with respect to Figure 3 and Figure 5 can be configured to perform one or more operations described with respect to Figure 14 described.

[0108] Conductor and electrode

[0109] A variety of techniques can be used to place the lead described herein near a cancerous tumor site within the body. Placement of one or more leads can include techniques such as transvascular placement, penetration into a subcutaneous space, and / or surgical placement. In some embodiments, placement of one or more leads can include placement via one or more natural body orifices. The lead can be placed near or within the cancerous tumor. In some embodiments, multiple leads can be used near or away from the cancerous tumor.

[0110] In some embodiments, one or more leads described herein can be placed in a subcutaneous space. Electrodes on the lead placed in the subcutaneous space can be used as primary near-field generating electrodes or far-field generating electrodes. In some embodiments, electrodes on the lead placed in the subcutaneous space can be used as primary near-field generating electrodes or, in combination with the housing of the medical device, as far-field electric field generating electrodes. Similarly, one or more leads can be placed transvascularly to be used as far-field electric field generating electrodes in combination with electrodes at or near the cancerous tumor site or in combination with the housing of the medical device.

[0111] The wires and electrodes described herein may include additional functional and structural features. In some embodiments, the wires may include wires compatible with imaging and treatment 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 wires 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 materials. The metal may include but is not limited to palladium, platinum, silver, gold, copper, aluminum, various alloys including stainless steel, nickel-cobalt alloys (such as ) etc. In some embodiments, the conductor core may be a multi-filament coil, including but not limited to a double-filament coil, a triple-filament coil, and a quad-filament coil.

[0112] In some embodiments, as described herein, the electrode can be arranged along the length of one or more wires. Suitable materials for the electrodes described herein may include metals such as palladium to minimize the coupling and artifact generation in the magnetic field. In some embodiments, the electrode may 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 may be in the form of a winding coil, which may provide an additional benefit of increasing the surface area without compromising the flexibility of the electrode. In some embodiments, an implantable device housing may be used as an electrode.

[0113] The wire described herein may also include one or more electrodes arranged along the length of the wire. The wire may include two or more electrodes arranged along the length of the wire. In some embodiments, the electrode may be a tip electrode found at the distal end of the wire. In other embodiments, the electrode may be a ring electrode found along the wire rather than at the tip of the wire. In some embodiments, the electrode may be a coil electrode. In some embodiments, the ring electrode or the tip electrode may be positioned in or near a tumor or cancerous tissue, and the coil electrode may be positioned away from the tumor or cancerous tissue to help the generated electric field have spatial diversity. In some embodiments, the length of the axis of the length direction of one or more electrodes (e.g., from the proximal to the distal axis) may be about 0.5, 1, 1.5, 2, 3, 4, 5, 7.5, 10, 15, 20, 30, 40, 50, 75, 100 mm or more. In some embodiments, the length of one or more electrodes may fall within the following range, wherein any of the aforementioned distances may be used as the upper or lower limit of the range, as long as the upper limit is greater than the lower limit.

[0114] The lead can be monopolar, bipolar, or multipolar. In some embodiments, a monopolar lead can include a wire that generates an electric field between one electrode and the housing of the medical device. In some embodiments, a bipolar lead can include a wire that generates an electric field between two electrodes disposed along the wire or between two electrodes and the housing of the medical device. In some embodiments, a multipolar lead can include a wire that generates an electric field between more than two electrodes disposed along the wire, between more than two electrodes and the housing of the medical device, or between any number of combinations of electrode configurations and the housing of the medical device.

[0115] The electrodes applicable here can be made of conductive polymers such as carbon-filled silicone, polyacetylene, polypyrrole, polyaniline, polythiophene, polyfuran, polyisoprene, polybutadiene, poly(p-phenylene), etc. In other embodiments, the electrodes can be insulating. In some embodiments, the insulator surrounding the electrode can include a microporous insulator to prevent cell attachment but still allow current flow. The microporous insulator can be made of various insulating materials described herein, including but not limited to expanded polytetrafluoroethylene (ePTFE), ethylene-tetrafluoroethylene copolymer (ETFE), polyurethane, silicone, poly(p-xylene) polymers (such as parylene polymers), polyether block amides (such as ), nylon, or derivatives thereof. 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, poly(p-xylene) polymers (such as parylene), etc.

[0116] According to the embodiments herein, a variety of lead fixation techniques and configurations can be used. Some non-limiting examples of lead fixation techniques can include biocompatible glue fixation, claw fixation, helical wire fixation, passive centering of the lead in the vascular system, tooth fixation within the local vascular system, helical thread fixation within the local vascular system, compression fixation, suture cannula fixation, etc. In some examples, the leads implemented herein can be placed within the vascular system surrounding or adjacent to the cancerous tumor site. In other embodiments, the leads implemented herein can be surgically placed at, within, or around the cancerous tumor site.

[0117] The wire suitable for the present disclosure may further include one or more open lumens extending along the entire longitudinal length of the wire or in selected portions of the longitudinal length. In some embodiments, the open lumen may include an integrated biopsy device adapted to periodically obtain biopsy samples from a cancerous tumor site to monitor disease progression and / or regression. The wire having an open lumen may also be configured to include an integrated drug delivery lumen that can deliver one or more drugs, such as steroids or chemotherapeutic agents, to the tumor site either as a single bolus or periodically via a metering pump. The wire may include one or more ports disposed along the length of the wire to provide an outlet for delivering the drug to or near the cancerous tumor site.

[0118] In some embodiments, a portion or the entire wire may include a drug-eluting coating. In some embodiments, the drug-eluting coating may contain an anti-inflammatory agent such as a steroid. In some embodiments, the steroid may be dexamethasone. In other embodiments, the drug-eluting coating may contain a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent may include a taxane or its derivatives, including but not limited to paclitaxel, docetaxel, etc. In other embodiments, the drug-eluting coating may be configured to release additional 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 the drug from the coating in a time-release manner.

[0119] The wire in the present disclosure may assume a variety of shapes or configurations. In some embodiments, the wire may be linear, while in other embodiments, the wire may be circular. The circular wire may be a completely closed loop, or it may also be a semi-closed loop. In some embodiments, the wire may include a flexible core that allows the wire to be shaped into many configurations, including but not limited to U-shaped, S-shaped, helical, semi-circular, elliptical, etc.

[0120] In yet other examples, the wire suitable for the present disclosure may include a fluorescent or magnetic marker that can assist the clinician in precisely placing it at or near the cancerous tumor site. The wire may further include an integrated pH sensor for detecting changes in pH at or near the cancerous tumor, or other chemical sensors suitable for analyzing the concentration of a target chemical analyte.

[0121] Treatment parameters

[0122] Successful treatment of a cancerous tumor may depend on many variables, including electric field strength, frequency, cell heterogeneity, cell size, cancer cell type, tumor size, and location within the body. Various treatment parameters can be achieved using the medical devices described herein. One or more sets of treatment parameters can be programmed into the memory of the medical device andFigure 3 is implemented by the control circuit 306 shown. An exemplary set of treatment parameters can include parameters that implement the following concepts: through a series of frequency scans; simultaneously accumulating one or more frequencies; stepping through one or more frequencies sequentially; spatial or temporal delivery of one or more electric fields; through a series of electric field strength scans; 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; manipulation of waveform shape and / or pulse sequence; and occasional use of high-frequency or high electric field strength pulses.

[0123] The set of treatment parameters can be programmed into the medical device for autonomous operation, or can be queried and manipulated by a patient or clinician using an external computing device such as a programmer, a home-based unit, and / or a mobile unit (e.g., cellular phone, personal computer, smart phone, tablet computer, etc.). In other embodiments, the set of treatment parameters can be wirelessly transmitted from the external computing device to the medical device. The frequencies and / or electric field strengths in any set of treatment parameters applicable herein were discussed above with respect to the electric field generating circuit 320. In some embodiments, one or more sets of treatment parameters can be implemented simultaneously. In other embodiments, one or more sets of treatment parameters can be implemented in an alternating fashion.

[0124] Now referring to Figure 15 , the exemplary graph 1502 shows an example of scanning through a series of frequencies at the site of a cancerous tumor. The graph 1502 shows an alternating electric field, where the frequency increases over time when the treatment is applied to the cancerous tumor. In some embodiments, the frequency scan can include alternating between a first frequency scan that covers a range of approximately 100 kHz to 300 kHz and a second frequency scan that covers a range of approximately 200 kHz to 500 kHz. It should be understood that the scanning through the first frequency range and the second frequency range as described above can be performed indefinitely throughout the treatment process.

[0125] Electric field generator

[0126] The medical device implemented herein can include an electric field generator that is particularly suitable for treatment and diagnostic techniques used during the treatment of cancerous tumors. In some embodiments, the electric field generator applicable herein can include an electric field generator that has been radiation hardened to render the components resistant to the damaging effects caused by radiotherapy treatments that are typically designated for the primary treatment of cancerous tumors. The electric field generator can include components such as those described above with reference to Figure 3 and Figure 5 described.

[0127] Any number of sets of treatment parameters as described above can be utilized to program the electric field generator implemented herein. The electric field generator can be programmed prior to implantation or can be programmed by a clinician using an external computing device such as a programmer, a home-based unit, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.). In some embodiments, the treatment parameters can be delivered to the electric field generator via telemetry circuitry. In some embodiments, the electric field generator can include a charging circuit communicatively coupled to a receiving coil to facilitate percutaneous charging of the medical device. In some embodiments, the electric field generator can communicate wirelessly between the receiving coil and an external charging device.

[0128] 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 context clearly dictates otherwise. Thus, for example, a composition containing a "compound" includes a mixture of two or more compounds. It should also be noted that, unless the context clearly dictates otherwise, the term "or" is generally used in its inclusive sense of "and / or".

[0129] It should also be noted that, as used in this specification and the appended claims, the phrase "configured" describes a system, apparatus, or other structure that is constructed or configured to perform a particular task or adopt a particular configuration. The phrase "configured" can be used interchangeably with other similar phrases such as arranged and configured, constructed and arranged, constructed, manufactured and arranged, etc.

[0130] All publications and patent applications in this specification indicate the level of ordinary skill in the art to which the invention pertains. All of the disclosures and patent applications herein are incorporated by reference in their entirety as if each individual disclosure or patent application was specifically and individually indicated to be incorporated by reference.

[0131] Multiple 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 can be made without departing from the spirit and scope herein.

Claims

1. An implantable medical device for treating cancerous tumors, comprising: one or more electric field generating electrodes configured for implantation within a patient; one or more impedance monitoring electrodes configured to measure the impedance of tissue in a treatment area within the patient along a vector passing through the cancerous tumor; wherein the medical device is arranged to generate an electric field effective to disrupt cell mitosis in cancer cells; wherein the electrodes generating the electric field are configured to apply the electric field to the patient's cancerous tumor based on the measured impedance, and wherein a decrease in the impedance of the treatment area indicates tumor progression, the impedance monitoring electrodes including passive electric field sensing electrodes.

2. The medical device according to claim 1, wherein the medical device is configured to apply an electric field to the patient's cancerous tumor based on a change in the measured impedance.

3. The medical device according to any one of claims 1 to 2, wherein the passive electric field sensing electrodes are configured to be implanted within the cancerous tumor.

4. The medical device according to any one of claims 1 to 2, wherein the medical device is configured to monitor a change in the patient's heart rate in response to the delivered electric field; wherein the medical device is configured to adjust the electric field if a change in heart rate is detected.

5. The medical device according to claim 4, wherein, the medical device being configured to adjust the electric field includes reducing the intensity of the delivered electric field to a predetermined threshold.

6. The medical device according to any one of claims 1 to 2, wherein the medical device is configured to measure at least one characteristic selected from the group consisting of: temperature, blood flow, blood pressure, metabolite concentration, and systemic cancer marker concentration; and wherein the medical device is configured to monitor a change in the at least one characteristic.

7. The medical device according to any one of claims 1 - 2, further configured to: evaluate tumor progression based on the measured impedance.

8. The medical device according to claim 7, the measured impedance including the measured low-frequency impedance.

9. The medical device according to claim 8, the low frequency including a frequency from 1 Hz to 10 Hz.

10. The medical device according to claim 7, the measured impedance including the measured high-frequency impedance.

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