Electric field cancer therapy device with feedback mechanism and diagnostic capabilities

Abstract

Embodiments herein relate to medical device systems including electric field shaping elements for treating cancerous tumors within body tissue. In an embodiment, 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 also include applying an electric field to the cancerous tumor of the patient based on the measured impedance. Other embodiments are also included herein.

Description

[0001] This application was filed as a PCT international patent application on October 23, 2018 in the name of Cardiac Pacemakers, Inc., a U.S. government corporation, as designated applicant in all countries, and U.S. citizen Brian L. Schmidt, U.S. citizen Jacob M. Ludwig, U.S. citizen Benjamin J. Haasl, U.S. citizen, and Michael J. Kane, U.S. citizen, as designated inventors in all countries, and claims priority to 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 which are incorporated herein by reference in their entirety. Technical Field

[0002] Embodiments herein relate to medical device systems including electric field shaping elements for treating cancerous tumors within body tissue. More specifically, embodiments herein relate to using electric field shaping elements that are configured to redirect or focus a therapeutic electric field to a cancerous tumor site. Background Art

[0003] According to the American Cancer Society, cancer accounts for nearly 25% of deaths in the United States each year. The current standard of care for cancerous tumors can include first-line treatments such as surgery, radiation therapy, and chemotherapy. Additional second-line treatments can include radiotherapy, cryotherapy, hormone or biologic therapy, ablation, etc. In cases where a specific treatment is ineffective on its own, a combination of first-line and second-line treatments can also benefit the patient.

[0004] A cancerous tumor may form if a normal cell in any part of the body mutates and then begins to grow and multiply too much and too quickly. Cancerous tumors may be the result of genetic mutations in the cell's DNA or RNA produced during cell division, by external stimuli such as ionizing or non-ionizing radiation, by exposure to carcinogens, or as a result of inherited genetic mutations. Regardless of the cause, many cancerous tumors are the result of unchecked, rapid cell division.

[0005] Mitosis is the process of cell division, which is part of the cell cycle of all somatic cells in the body (including many types of cancer cells). Mitosis includes four basic periods: 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 includes a self-organized bipolar array of microtubules and centrosomes. Microtubules are usually formed by the polymerization of high polarity α-tubulin and β-tubulin. Centrosomes are similarly protein-based organelles, in which two organelles migrate to opposite sides of the dividing cell during this period. The negatively charged ends of the microtubules are attached to the centrosomes. The positively charged ends of the microtubules diverge toward the equator of the dividing cell and eventually attach to the centromere of each sister chromatid. Metaphase can be defined by all chromosomes arranging at the equator of the dividing cell and combining in the mitotic spindle. Then in anaphase, equal numbers of sister chromatids are pulled to opposite ends of the cell. Once all the chromosomes have been separated, the process of telophase begins where the cell membrane begins to form a division 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

[0006] Embodiments herein relate to medical device systems including electric field shaping elements for treating cancerous tumors within body tissue. In a first 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 included. The method may include implanting one or more electrodes in a patient's body and measuring the impedance of tissue in the patient's body along a vector passing through the cancerous tumor or in the vicinity thereof. The method may also include applying an electric field to the patient's cancerous tumor based on the measured impedance.

[0007] In a second aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, a method may include applying an electric field to a cancerous tumor of the patient based on the measured impedance.

[0008] In a third aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, a method may include electrodes including an electric field generating electrode and a passive electric field sensing electrode.

[0009] In a fourth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, a method may include implanting a passive electric field sensing electrode within a cancerous tumor.

[0010] In a fifth aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, a method may include implanting an electric field generating electrode proximate to a cancerous tumor.

[0011] 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 also include assessing tumor progression based on the measured impedance.

[0012] In a seventh aspect, in addition to or in the alternative of one or more of the preceding or following aspects, a method may include applying an electric field to a cancerous tumor of the patient based on the measured impedance.

[0013] In an eighth aspect, additionally or in the alternative of some aspects, one or more of the preceding or following aspects, wherein a decrease in impedance indicates tumor progression.

[0014] In a ninth aspect, additionally or in the alternative of some aspects, one or more of the preceding or following aspects, wherein the measured impedance comprises a measured low frequency impedance.

[0015] In a tenth aspect, additionally or in the alternative of some aspects, in addition to one or more of the foregoing or following aspects, the low frequency can include a frequency of about 1 Hz to about 10 Hz.

[0016] In an eleventh aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, the measured impedance may include a measured high frequency impedance.

[0017] In a twelfth aspect, additionally or in the alternative of some aspects, in addition to one or more of the foregoing or following aspects, the high frequency can include a frequency of about 10 kHz to about 1 MHz.

[0018] In a thirteenth aspect, additionally or in the alternative of some aspects, in addition to one or more of the foregoing or following aspects, the high frequency may include a frequency of about 100 kHz to about 300 kHz.

[0019] In a fourteenth 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 electric field generating electrodes in a patient's body, and implanting one or more electric field sensing electrodes in the patient's body. 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.

[0020] In a fifteenth aspect, in addition to or in 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's body and measuring a characteristic of an electric field delivered along a vector passing through or near the cancerous tumor, the characteristic selected from the group consisting of impedance, capacitance, and electric field strength. The method may also include delivering the electric field to the cancerous tumor based on the measured characteristic.

[0021] In a sixteenth aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, the measured characteristic may include impedance.

[0022] In a seventeenth aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, the measured characteristic may include capacitance.

[0023] In an eighteenth aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, the measured characteristic may include field strength.

[0024] In a nineteenth aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, the method may include adjusting the delivered electric field based on the measured characteristic.

[0025] In a twentieth aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, regulating the delivered electric field may include one or more of changing the strength of the electric field, changing the waveform of the electric field, and changing the frequency of the electric field.

[0026] In a twenty-first 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 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 delivered electric field strength is above a predetermined threshold for nerve or muscle recruitment, and reducing the electric field strength if the electric field strength is above the threshold for nerve or muscle recruitment.

[0027] In a twenty-second 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 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 changes in the patient's heart rate in response to the delivered electric field, and adjusting the electric field if changes in heart rate are detected.

[0028] In a twenty-third aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, wherein adjusting the electric field may include reducing the strength of the delivered electric field to a predetermined threshold.

[0029] In a twenty-fourth aspect, in addition to or in the alternative of one or more of the foregoing or following aspects, wherein adjusting the electric field may include increasing the strength of the delivered electric field to a predetermined threshold.

[0030] In a twenty-fifth aspect, in addition to or in 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 characteristic selected from the group consisting of: temperature, blood flow, blood pressure, metabolite concentration, and systemic cancer marker concentration.

[0031] In a twenty-sixth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, the method may include monitoring a change in at least one characteristic.

[0032] The present invention is an overview of some teachings of the present application and is not intended to be an exclusive or exhaustive treatment of the subject matter. Further details will be found in the specific embodiments and the appended claims. Other aspects will be clear to those skilled in the art after reading and understanding the following specific embodiments and viewing the accompanying drawings that form a part thereof, and each aspect should not be construed as limiting. The scope of this article is limited by the appended claims and their legal equivalents. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The various aspects may be more fully understood in conjunction with the following drawings, in which:

[0034] Figure 1 is a schematic diagram of a medical system according to various embodiments described herein.

[0035] Figure 2 is a schematic diagram of a medical system according to various embodiments described herein.

[0036] Figure 3 is a schematic cross-sectional view of a medical device according to various embodiments herein.

[0037] Figure 4 is a schematic diagram of a medical device according to various embodiments described herein.

[0038] Figure 5 is a schematic diagram of components of a medical device according to various embodiments herein.

[0039] Figure 6 is a schematic diagram of a medical device according to various embodiments described herein.

[0040] Figure 7 is a schematic diagram of a conductor according to various embodiments herein.

[0041] Figure 8 is a flow chart of a method of treating a cancerous tumor according to various embodiments herein.

[0042] Fig. 9 is a flow chart of a method of treating a cancerous tumor according to various embodiments herein.

[0043] Fig.10 is a flow chart of a method of treating a cancerous tumor according to various embodiments herein.

[0044] Fig.11 is a flow chart of a method of treating cancer according to various embodiments herein.

[0045] Fig.12 is a flow chart of a method of treating a cancerous tumor according to various embodiments herein.

[0046] Fig.13 is a flow chart of a method of treating a cancerous tumor according to various embodiments herein.

[0047] Fig.14 is a flow chart of a method of treating a cancerous tumor according to various embodiments herein.

[0048] Fig.15 is a graph of exemplary treatment parameters according to various embodiments herein.

[0049] Although the embodiments are susceptible to various modifications and alternative forms, the details of the embodiments 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 document is not limited to the specific embodiments described. On the contrary, it is intended to cover modifications, equivalents, and alternatives that fall within the spirit and scope of this document. DETAILED DESCRIPTION

[0050] As mentioned above, many cancerous tumors may be caused by unrestrained rapid cell division. Some traditional first-line treatments for treating cancerous tumors may include surgery, radiation therapy, and chemotherapy. However, many first-line treatments have adverse accompanying side effects, such as fatigue, hair loss, immunosuppression, and long recovery time from surgery, etc.

[0051] Although not bound by theory, it is believed that the alternating electric field can disrupt mitosis in cancerous tumors by interfering with the dipole arrangement of key proteins involved in cell division, especially tubulin and septin. The polymerization of tubulin proteins that form microtubule spindle fibers can be destroyed, thereby preventing the formation of spindle fibers required for chromosome separation. This can stop cell division in the metaphase stage of mitosis. In some cases, if the cell can survive for such a long time, the alternating electric field can stop the polymerization of the spindle fibers that have grown, resulting in incomplete spindles and unequal chromosome separation in the later stage. In each case, the formation of the microtubule spindle in the later stage caused by incomplete microtubule polymerization stops and unequal chromosome separation may cause apoptosis (i.e., programmed cell death).

[0052] It is also believed that the alternating electric field may lead to an increase in the electric field density near the cleavage furrow of dividing cells at telophase. The increase in electric field density in the region of the cleavage furrow may cause dielectrophoresis of charged macromolecules such as proteins and nucleic acids toward the high electric field density at the furrow. Unequal concentrations of key macromolecules required for cell division at the cleavage furrow site may disrupt the final separation of sister cells at telophase and ultimately cause apoptosis.

[0053] Feedback obtained during electric field treatment can be used to monitor the effectiveness of using the treatment to treat cancerous tumors. Data such as impedance, capacitance, field strength and other parameters 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.

[0054] Therapeutic parameters of the electric field therapy may be modulated and / or changed, adjusted, or otherwise altered based on measurements of at least one of impedance, capacitance, field strength, etc., including but not limited to one or more of amplitude, frequency, pulse width, waveform, directionality, vector, and / or duty cycle.

[0055] Reference now Figure 1 , shows a schematic diagram of a medical device 100 according to various embodiments herein. The medical device 100 can be fully implanted in the body of a patient 101, at or near a cancerous tumor site within body tissue. Various implantation sites can be used, including areas such as the limbs, upper torso, abdominal area, head, etc.

[0056] Reference now Figure 2 , another schematic diagram of a medical device 200 according to various embodiments is shown. The medical device 200 can be partially implanted within the body of a patient 101. In some embodiments, the medical device can be partially implanted and partially external to 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 wirelessly communicate with a partially external portion of the medical device via a wireless connection.

[0057] In some embodiments, a portion of the medical device may be completely implanted, while a portion of the medical device may be completely external. For example, in some embodiments, one or more electrodes or wires 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 external to the body. It should be understood that in some 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 completely implanted and a portion of the medical device is completely external, the portion of the medical device that is completely external may communicate wirelessly with the portion of the medical device that is completely internal. However, in other embodiments, a wired connection may be used.

[0058] Medical device 100 or medical device 200 may include a housing 102 and a head 104 coupled to the housing 102. Various materials may be used. However, in some embodiments, the housing 102 may be formed of materials such as metal, ceramic, polymer, composite material, etc. In some embodiments, the housing 102 or one or more portions thereof may be formed of titanium. The head 104 may be formed of various materials, but in some embodiments, the head 104 may be formed of translucent polymers such as epoxy materials. 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 or other materials, so that it is non-hollow.

[0059] In some embodiments where a portion of the medical device 100 or 200 is partially external, the head 104 and the housing 102 may be surrounded by a protective shell made of a durable polymer material. In the case where a portion of the medical device 100 or 200 is partially external, the head 104 and the housing 102 may be surrounded by a protective shell made of a combination of polymer materials, metal materials, and / or glass materials.

[0060] The head 104 can be coupled to one or more wires 106. The head 104 can be used to fix the proximal end of the one or more wires 106 and electrically couple the one or more wires 106 to one or more components within the housing 102. The one or more wires 106 may include one or more electrodes 108 arranged along the length of the electrical wire 106. In some embodiments, the electrode 108 may include an electric field generating electrode, while in other embodiments, the electrode 108 may include an electric field sensing electrode. In some embodiments, the wire 106 may include both an electric field generating electrode and an electric field sensing electrode. In other embodiments, the wire 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 wires, wireless medical devices that generate electric fields are also contemplated herein.

[0061] Reference now Figure 3 , shows a schematic cross-sectional view of a medical device 100 according to various embodiments herein. The housing 102 may define an internal volume 302, which may be hollow and which, in some embodiments, is hermetically isolated from an area 304 outside 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 a control circuit 306, which 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 yet other embodiments, there may be a combination of integrated components and separate components. The medical device 100 may also include an antenna 324 to allow one-way or two-way wireless data communication. In some embodiments, 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.

[0062] 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 current to form one or more fields. The electric field generating circuit 320 may be integral to the control circuit 306, or may be a separate component from the control circuit 306. The control circuit 306 may be configured to control the delivery of 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 located outside the body.

[0063] In some embodiments, the control circuit 306 may be configured to direct the electric field generating circuit 320 to deliver the electric field using one or more frequencies selected from the 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 the electric field at one or more frequencies selected from the 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 the electric field at one or more frequencies selected from the 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 deliver the electric field periodically using one or more frequencies greater than 1 MHz.

[0064] In some embodiments, the electric field can effectively disrupt cell mitosis in cancer cells. The electric field can be delivered to the cancerous tumor site along more than one vector. In some examples, the electric field can be delivered along at least one vector (including at least one of the wire electrodes). In some embodiments, at least two vectors can be used with spatial diversity between the vectors. The vectors can be spatially separated (e.g., the vectors can be set at a certain 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.

[0065] The desired electric field strength can be achieved by delivering current between the two electrodes. The specific current and voltage of the delivered electric field can be varied 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 guide the electric field generating circuit 320 to deliver an electric field to the cancerous tumor site using a current ranging from 1mAmp to 1000mAmp. In some embodiments, the control circuit 306 can be configured to guide the electric field generating circuit 320 to deliver an electric field to the cancerous tumor site using a current ranging from 20mAmp to 500mAmp. In some embodiments, the control circuit 306 can be configured to guide the electric field generating circuit 320 to deliver an electric field to the cancerous tumor site using a current ranging from 30mAmp to 300mAmp.

[0066] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver the electric field using a current including the following: 1mAmp, 2mAmp, 3mAmp, 4mAmp, 5mAmp, 6mAmp, 7mAmp, 8mAmp, 9mAmp, 10mAmp, 15mAmp, 20mAmp, 25mAmp, 30mAmp, 35mAmp, 40mAmp, 45mAmp, 50mAmp, 60mAmp, 70mAmp, 80mAmp, 90mAmp, 100mAmp, 125mAmp, 150mAmp, 175mAmp, 200mAmp, 225mAmp, 250mAmp Amp, 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 320 to deliver an electric field with a current falling within the following range, wherein any of the aforementioned currents can be used as the lower limit or 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.

[0067] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to use a voltage ranging from 1V to rms Up to 50V rmsIn some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to use a voltage ranging from 5V to 10V. rms Up to 30V rms 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 to 10V. rms Up to 20V rms The voltage is delivered to the cancerous tumor site.

[0068] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver the 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 understood that the control circuit can be configured to direct the electric field generating circuit 320 to use a voltage within the following range to deliver the electric field, wherein any of the aforementioned voltages can be used as the lower limit or 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.

[0069] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver the electric field using one or more frequencies including: 10kHz, 20kHz, 30kHz, 40kHz, 50kHz, 60kHz, 70kHz, 80kHz, 90kHz, 100kHz, 125kHz, 150kHz, 175kHz, 200kHz, 225kHz, 250kHz, 275kHz, 300kHz, 325kHz, 350kHz 1 MHz. It should be understood that the electric field generating circuit 320 can use a frequency within the following range to transmit the electric field, wherein any of the aforementioned frequencies can be used as the upper limit or lower limit of the range, as long as the upper limit is greater than the lower limit.

[0070] 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 a 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 a 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 a range between 3 V / cm and 5 V / cm.

[0071] In other embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to generate one or more applied electric field strengths including: 0.25V / cm, 0.5V / cm, 0.75V / cm, 1.0V / cm, 2.0V / cm, 3.0V / cm, 5.0V / cm, 6.0V / cm, 7.0V / cm, 8.0V / cm, 9.0V / cm, 10.0V / cm, 20.0V / cm, 30.0V / cm, 40.0V / cm, 50.0V / cm, 60.0V / cm, 70.0V / cm, 80.0V / cm, 90.0V / cm, 100.0V / cm, 125.0V / cm, 150.0V / cm, 175.0V / cm, 200.0V / 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 320 can generate an electric field whose electric field strength at the treatment site belongs to the following range, wherein any one of the aforementioned electric field strengths can be used as the upper limit or lower limit of the range, as long as the upper limit is greater than the lower limit.

[0072] In some embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver an electric field to a cancerous tumor site located in body tissue via the wire 106. In other embodiments, the control circuit 306 can be configured to direct the electric field generating circuit 320 to deliver an electric field to a cancerous tumor site located in body tissue via the housing 102 of the medical device 100. In other embodiments, the control circuit 306 can 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, the one or more wires 106 can be in electrical communication with the electric field generating circuit 320. In some embodiments, the one or more wires 106 can include one or more electrodes 108 disposed along the length of the wire 106, wherein the electrodes 108 can be in electrical communication with the electric field generating circuit 320.

[0073] In some embodiments, various components within medical device 100 may include electric field sensing circuitry 322 configured to generate a signal corresponding to a sensed electric field. Electric field sensing circuitry 322 may be integral to control circuitry 306, or it may be separate from control circuitry 306.

[0074] The sensing electrodes may 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 a tumor, or any combination of these locations. In some embodiments, the electric field sensing circuit 322 may include a first sensing electrode 332 and a second sensing electrode 334. In other embodiments, the housing 102 itself may be used as a sensing electrode for the electric field sensing circuit 322. The electrodes 332 and 334 may be in communication with the electric field sensing circuit 322. The electric field sensing circuit 322 may measure the potential difference (voltage) between the first electrode 332 and the second electrode 334. In some embodiments, the electric field sensing circuit 322 may 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 may be configured to measure the sensed electric field and record the electric field strength in V / cm.

[0075] 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 set along the wire 106 and can be used as an additional location for sensing the electric field. According to the embodiments herein, many combinations can be conceived for measuring the potential difference between the electrodes set along the length of one or more wires 106 and the housing 102.

[0076] In some embodiments, the one or more wires 106 may be in electrical communication with the electric field generating circuit 320. The one or more wires 106 may include one or more electrodes 108, such as Figure 1 and Figure 2 In some embodiments, different electrical conductors (such as electrical conductors 326 and 328) can pass from the head 104 through the feed-through structure 330 and into the interior volume 302 of the medical device 100. In this way, the electrical conductors 326 and 328 can be used to provide electrical communication between the one or more wires 106 and the control circuit 306 disposed within the interior volume 302 of the housing 102.

[0077] In some embodiments, the recording circuitry can be configured to record data generated by the electric field sensing circuitry 322 and record a timestamp regarding the data. In some embodiments, the control circuitry 306 can be hardwired to perform various functions, while in other embodiments, the control circuitry 306 can be directed to implement instructions executed on a microprocessor or other external computing device. Telemetry circuitry can also be provided for communicating with external computing devices such as programmers, home-based units, and / or mobile units (e.g., cellular phones, personal computers, smart phones, tablet computers, etc.).

[0078] Now refer to Figure 4 , a wireless medical device 400 is shown according to an embodiment herein. The wireless medical device 400 may include a housing 402 and a head 404 coupled to the housing 402. Various materials may be used. However, in some embodiments, the housing 402 may be formed of materials such as metals, ceramics, polymers, composite materials, and the like. In some embodiments, the housing 402 or one or more portions thereof may be formed of titanium. The head 404 may be formed of various materials, but in some embodiments, the head 404 may be formed of a translucent polymer such as an epoxy 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 or other materials, so that it is non-hollow. In some embodiments, the wireless medical device 400 may include a fixing element 406 for keeping the wireless medical device 400 positioned at or near a cancerous tumor site in the body. In some embodiments, the fixing element 406 may include claws, tines, spirals, twills, and the like.

[0079] exist Figure 5 2 shows elements of different embodiments of the medical device described herein. However, it should be understood that some embodiments may include Figure 5 Additional elements other than those shown. In addition, some embodiments may not have Figure 5 Some elements shown. As implemented herein, the medical device can collect information through one or more sensing channels, and can output information through one or more field generation channels. The microprocessor 502 can communicate with the memory 504 via a bidirectional data bus. The memory 504 may include a read-only memory (ROM) or a random access memory (RAM) for program storage and a RAM for data storage. The microprocessor 502 can also be connected to a telemetry interface 518 for communicating with external devices such as programmers, home-based units and / or mobile units (e.g., cellular phones, personal computers, smart phones, tablet computers, etc.), or directly connected to a 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), which is coupled or attached to the medical device in a communication manner to facilitate transcutaneous charging of the medical device.

[0080] The medical device may include one or more electric field sensing electrodes 508, and one or more electric field sensor channel interfaces 506 that can communicate with a port of a 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 can communicate with a port of a microprocessor 502. The medical device may also include one or more physiological sensors, respiratory sensors, or chemical sensors 516, and one or more physiological / respiratory / chemical sensor channel interfaces 514 that can communicate with a port of a microprocessor 502. The channel interfaces 506, 510, and 514 may include different 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, etc.

[0081] 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, respiratory peak 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 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. An exemplary chemical / analyte sensor is disclosed in U.S. Patent No. 7,809,441, co-owned by Kane et al., and the patent is incorporated herein by reference in its entirety.

[0082] Despite Figure 5 516 as part of the medical device, it should be appreciated that in some embodiments, one or more of the physiological sensor, respiratory sensor, or chemical sensor may be physically separate from the medical device. In different embodiments, one or more of the physiological sensor, respiratory sensor, or chemical sensor may be within another implanted medical device that is communicatively coupled to the medical device via telemetry interface 518. In still other embodiments, one or more of the physiological sensor, respiratory sensor, or chemical sensor may be external to the body and coupled to the medical device via telemetry interface 518.

[0083] Reference now Figure 6, a schematic diagram of a medical device 600 is shown according to an embodiment herein. The medical device 600 may include a housing 102 and a head 104 and one or more wires 106. The wire 106 may include one or more electrodes, such as electrodes 604, 606, 608, 610, 612, or 614, disposed along the length of the wire 106. 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 wire 106 may include both electric field generating electrodes and electric field sensing electrodes.

[0084] The proximal end of the lead 106 is disposed within the head 104. The distal end of the lead 106 can surround the cancerous tumor 602 so that the electrodes 604, 606, 608, 610, 612, or 614 are brought into proximity with the cancerous tumor 602. In some embodiments, the lead 106 can be positioned within the vasculature so that the electrodes 604, 606, 608, 610, 612, or 614 are adjacent to or within the cancerous tumor 602. However, it should be understood that the lead 106 can be positioned at different locations within or around the cancerous tumor 602. In some embodiments, the lead 106 can pass directly through the cancerous tumor 602.

[0085] 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 location of the electrode relative to the tumor. In some embodiments, the 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 radiographic material. In some embodiments, the tracking markers may be formed of a fluorographic material.

[0086] 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 the 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 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, round wires, clamp wires, cuff wires, paddle wires, or patch wires can be used.

[0087] Reference now Figure 7 , shows a wire 702 according to an embodiment herein. The wire 702 may include electrodes 704 disposed along the length of the wire 702. In some embodiments, the electrode 704 may be an electric field generating electrode. In some embodiments, the electrode 704 may be an electric field sensing electrode. In some embodiments, the electrode 704 may include a combination of an electric field generating electrode and an electric field sensing electrode. As discussed herein, an electrode may 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 may include one or more dedicated impedance monitoring electrodes (not shown).

[0088] In some embodiments, impedance can be measured by dividing voltage by current. In the body, impedance is affected by many factors, including but not limited to the components in contact with the electric field, such as cell type, 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, the following reference Fig. 9 Measuring impedance at one or more frequencies at any given location is contemplated and described in greater detail. 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.

[0089] 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 the one or more electrodes 704 and the proximal end 708 of the lead body 706. One or more leads 702 may be implanted at a cancerous tumor site. In some embodiments, one or more leads 702 may be implanted within a cancerous tumor. The lead 702 may be disposed within a head of a medical device implemented herein and may be configured to be in electrical communication with a control circuit within the medical device.

[0090] In some embodiments, the lead 702 can be configured to generate an electric field at a cancerous tumor site in the patient's body through an electric field generating circuit (not shown). The lead 702 can be configured to generate an electric field by one or more electric field generating electrodes disposed thereon. In some embodiments, the lead 702 can include both an electric field generating electrode and an electric field sensing electrode. In some embodiments, a separate lead 703 on which an electric field sensing electrode is disposed can be implanted at or near the cancerous tumor site to serve as an electric field sensing lead. In some embodiments, an inactive electric field generating electrode located on any one of the leads 702 or 703 and close to the generated electric field can be configured to indirectly sense the electric field strength by measuring the voltage on the electric field generating electrode. It should be understood that the medical device described herein can be in electrical communication with one or more electrodes 704 to serve as an electrode capable of generating an electric field.

[0091] The electric field sensing electrodes can be used to sense the electric field strength in or around a tumor during any given treatment. Recording circuitry within the medical device can be configured to record data generated by the electric field sensing electrodes, and the clinician can use the data to adjust the electric field strength to maintain a desired electric field strength at the cancerous tumor site. In some embodiments, the electric field generating circuit can be configured to automatically adjust the electric field strength in response to one or more data values ​​sensed by the electric field sensing electrodes to maintain a desired electric field strength at the cancerous tumor site. Figure 3 As well as control circuit 306 and electric field generating circuit 320 describe suitable electric field strengths for use herein.

[0092] Reference now Figure 8 , a method 800 for treating a cancerous tumor according to embodiments herein is shown. The method 800 may include implanting one or more electrodes in a patient at 802. After implanting the one or more electrodes, the method 800 may include, at 804, measuring the impedance of tissue in the patient along a vector passing through or near the cancerous tumor. The method 800 may also include, at 806, applying an electric field to the cancerous tumor of the patient based on the measured impedance.

[0093] In some embodiments, method 800 may further include applying an electric field to a cancerous tumor of a patient 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 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 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.

[0094] Electrodes suitable for use in method 800 may include functionality that allows them to be used as active electric field generating electrodes or passive electric field sensing electrodes. In some embodiments, the electric field generating electrodes may be used as passive electric field sensing electrodes configured to measure the voltage of an electric field at a given point in time. In some embodiments, passive electric field sensing electrodes may be implanted within a cancerous tumor. In some embodiments, passive electric field sensing electrodes may be implanted near a cancerous tumor. In some embodiments, passive or active electric field generating electrodes may be implanted near a cancerous tumor. In various embodiments, including with respect to Figure 3 and Figure 5 A medical device having one or more components described herein may be configured to perform Figure 8 Describes one or more operations.

[0095] Reference now Fig. 9 , a method 900 for treating a cancerous tumor according to an embodiment of the present invention is shown. Method 900 may include: at 902, implanting one or more electrodes in a patient. After implanting the one or more electrodes, method 900 may include: at 904, measuring the impedance of tissue in the patient along a vector passing through the cancerous tumor or in the vicinity thereof. Method 900 may also include: at 906, assessing tumor progression based on the measured impedance. After assessing 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 area may indicate tumor regression. In other embodiments, a decrease in impedance may indicate tumor progression or resistance to electric field treatment.

[0096] Without being bound by any particular theory, it is believed that cancerous tumors have a specific impedance associated with them. In some embodiments, low frequency impedance through a specific 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 specific 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 Mz. 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 3 and Figure 5 A medical device having one or more components described herein may be configured to perform Fig. 9 Describes one or more operations.

[0097] Reference now Fig.10 , a method 1000 for treating a cancerous tumor according to an embodiment of the present invention is shown. 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's body. After implanting one or more electric field generating or electric field sensing electrodes, method 1000 may include: at 1004, delivering an electric field from the electric field generating electrode to the cancerous tumor. Method 1000 may include: at 1006, measuring the electric field strength in or around the cancerous tumor using the electric field sensing electrode. The electric field strength may be measured in different ways, but in some embodiments, may include calculating the electric field strength based on the measured voltage and the known spatial spacing between the measuring electrodes. 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, including regarding Figure 3 and Figure 5 A medical device having one or more components described herein may be configured to perform Fig.10 Describes one or more operations.

[0098] Reference now Fig.11, a method 1100 for treating a cancerous tumor according to an embodiment of the present invention is shown. The method 1100 may include: at 1102, implanting one or more electrodes in a patient's body. 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 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 one or more of changing 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 can be automatically adjusted by an electric field generating circuit regardless of local conditions such as tumor development or regression, local electrolyte concentration, electrode state, electrode encapsulation, electrode impedance, tissue impedance, etc. In different embodiments, including about Figure 3 and Figure 5 A medical device having one or more components described herein may be configured to perform Fig.11 Describes one or more operations.

[0099] Reference now Fig.12 , a method 1200 for treating a cancerous tumor according to an embodiment of the present invention is shown. 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 sensor may be a sensor configured to detect one or more potentials emitted by the nervous system, such as from the cerebral cortex, brainstem, spinal cord, and peripheral nerves. In some embodiments, the evoked potential sensor may be a sensor configured to detect one or more potentials emitted from other power sources in the body, such as from myocardium or skeletal muscle. In some embodiments, the electric field sensing electrodes and the electric field generating electrodes may be configured to be used as evoked potential sensors. The evoked potential sensor may include electrodes (such as electrodes on the wires described herein) to measure electrical properties such as potential, current, and / or impedance.

[0100] 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 adjusted down so that an evoked potential response is not generated by the nerve tissue or muscle tissue. The titration of the electric field strength may be performed manually by a clinician, or it may be performed automatically, such as by programming the titration process into a memory of a medical device and controlled by the medical device. Method 1200 may further include, if the electric field strength is above a 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 that the highest possible electric field strength is achieved before nerve or muscle recruitment is caused. In various embodiments, including with respect to Figure 3 and Figure 5 A medical device having one or more components described herein may be configured to perform Fig.12 Describes one or more operations.

[0101] Reference now Fig.13 , a method 1300 for treating a cancerous tumor according to an embodiment of the present invention is shown. Method 1300 may include: at 1302, implanting one or more electric field generating electrodes in a patient's body. Method 1300 may also include: at 1304, measuring the patient's initial heart rate. At 1306, an electric field may be delivered from the electric field generating electrodes to the cancerous tumor. Method 1300 may include: at 1306, monitoring changes in the patient's heart rate in response to the delivered electric field. Method 1300 may also 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, including with respect to Figure 3 and Figure 5 A medical device having one or more components described herein may be configured to perform Fig.13 Describes one or more operations.

[0102] Reference now Fig.14, a method 1400 for treating a cancerous tumor according to embodiments herein is shown. The method 1400 may include, at 1402, implanting one or more electric field generating electrodes in a patient. The method 1400 may include, at 1404, delivering an electric field from the electric field generating electrodes to the cancerous tumor. The method 1400 may include, at 1406, measuring at least one characteristic selected from the group consisting of: temperature, blood flow, blood pressure, metabolite concentration, and systemic cancer markers.

[0103] Temperature, blood flow and blood pressure can be monitored by temperature sensors and pressure sensors installed in or near the wires positioned at or in the cancerous tumor. The temperature sensor and pressure sensor can be configured to monitor the temperature, blood flow and blood pressure at or near the cancerous tumor site. An exemplary transthoracic impedance sensor capable of monitoring blood flow, heart rate, blood pressure, etc. is 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 by Kane et al., and the application is incorporated herein by reference in its entirety.

[0104] 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 (β-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 mutation, fibrin and fibrinogen, HE4, HER2 / neu gene and protein upregulation, immunoglobulins, KRAS gene mutation, lactate dehydrogenase, nonspecific enolase (NSE), nuclear matrix protein 22, programmed cell death ligand 1 (PD-L1), prostate specific antigen (PSA), thyroglobulin, urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1), etc.

[0105] Systemic cancer markers can be monitored by removing tissue or fluid samples from within or near the cancerous tumor site. In some embodiments, the guidewires described herein may include an open lumen extending over the entire longitudinal length of the guidewire or over a selected portion of the longitudinal length of the guidewire. The open lumen may include an integrated biopsy device suitable for periodically obtaining biopsy samples from the 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.

[0106] In some embodiments, method 1400 may include monitoring a change in at least one characteristic. If a change in at least one characteristic is detected, method 1400 may also include changing the delivered electric field based on the measured value of the at least one characteristic. Figure 3 and Figure 5 A medical device having one or more components described herein may be configured to perform Fig.14 Describes one or more operations.

[0107] Lead wires and electrodes

[0108] A variety of techniques may be used to place the leads described herein near a cancerous tumor site in the body. Placement of one or more leads may include use of techniques such as transvascular placement, penetration into the subcutaneous space, and / or surgical placement. In some embodiments, placement of one or more leads may include placement via one or more natural body orifices. The leads may be placed near or within a cancerous tumor. In some embodiments, multiple leads may be used near or away from a cancerous tumor.

[0109] In some embodiments, one or more wires described herein may be placed in the subcutaneous space. The electrodes on the wires 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 wires placed in the subcutaneous space may be used as the primary near-field generating electrodes, or in combination with the housing of the medical device as the far-field electric field generating electrodes. Similarly, one or more wires may be placed transvascularly to be combined with electrodes at or near the cancerous tumor site or in combination with the housing of the medical device as the far-field electric field generating electrodes.

[0110] 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.

[0111] 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.

[0112] 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 one or more electrodes along the length direction (e.g., the axis from the proximal side to the distal side) 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.

[0113] 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 electrode configurations and the housing of the medical device.

[0114] 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 insulator surrounding the electrodes can include a microporous insulator to prevent cell attachment but still allow current to flow. The microporous insulator 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 polyether block amides), and polyether block amides (such as polyether block amides). ), nylon, or its 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 parylene), etc.

[0115] According to the embodiments herein, a variety of wire fixation techniques and configurations can be used. Some non-limiting examples of wire fixation techniques can include biocompatible glue fixation, claw fixation, spiral wire fixation, passive centering of the wire in the vascular system, tooth fixation within the local vascular system, spiral twill fixation within the local vascular system, compression fixation, suture sleeve fixation, etc. In some examples, the wire implemented herein can be placed in the vascular system surrounding or adjacent to the cancerous tumor site. In other embodiments, the wire implemented herein can be placed at, within, or around the cancerous tumor site by surgical means.

[0116] The wire applicable to the present invention may also include one or more open lumens extending throughout the longitudinal length of the wire or in a selected portion of the longitudinal length. In some embodiments, the open lumen may include an integrated biopsy device suitable for periodically obtaining biopsy samples from the cancerous tumor site to monitor the progression and / or regression of the disease. The wire with 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 in a single bolus or periodically via a metered pump. The wire may include one or more ports disposed along the length of the wire to provide an outlet for delivering drugs to or near the cancerous tumor site.

[0117] In some embodiments, a portion of the guide wire or the entire guide wire may include a drug 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, and the like. 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, and the like. In some embodiments, the drug eluting coating may be configured to release the drug from the coating in a time-release manner.

[0118] The wires herein can take a variety of shapes or configurations. In some embodiments, the wire can be linear, while in other embodiments, the wire can be circular. The circular wire can be a completely closed loop, or it can also be a semi-closed loop. In some embodiments, the wire can include a bendable core, which can allow the wire to be shaped into many configurations, including but not limited to U-shaped, S-shaped, spiral, semicircular, elliptical, etc.

[0119] In yet other examples, guidewires 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 guidewire 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 target chemical analyte.

[0120] Treatment parameters

[0121] Successful treatment of cancerous tumors may depend on many variables, including electric field strength, frequency, cellular heterogeneity, cell size, cancer cell type, tumor size, and location within the body. Various treatment parameters may be implemented using the medical devices described herein. One or more treatment parameter sets may be programmed into the memory of the medical device and controlled by the device. Figure 3 The control circuit 306 shown is implemented. An exemplary set of treatment parameters may include parameters that implement the following concepts: sweeping through a series of frequencies; simultaneously focusing one or more frequencies; sequentially stepping one or more frequencies; spatial or temporal delivery of one or more electric fields; sweeping through a series 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; manipulation of waveform shape and / or pulse sequence; and occasionally using high frequency or high electric field strength pulses.

[0122] The treatment parameter set can be programmed into the medical device to operate autonomously, or can be queried and manipulated by the patient or 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 other embodiments, the treatment parameter set can be wirelessly transmitted to the medical device from the external computing device. The above discussion of the electric field generating circuit 320 is applicable to the frequency and / or electric field strength in any treatment parameter set of this document. 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.

[0123] Reference now Fig.15 , exemplary graph 1502 illustrates an example of scanning through a range of frequencies at a cancerous tumor site. Graph 1502 illustrates an alternating electric field where the frequency increases over time as treatment is applied to the cancerous tumor. In some embodiments, the frequency sweep may include alternating between a first frequency sweep covering a range of approximately 100 kHz to 300 kHz and a second frequency sweep covering a range of approximately 200 kHz to 500 kHz. It should be understood that scanning through the first frequency range and the second frequency range as described above may be performed indefinitely throughout the treatment process.

[0124] Electric field generator

[0125] Medical devices implemented 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 electric field generators that have been treated with radiation hardening to render the components resistant to the damaging effects caused by radiation therapy treatments that are typically prescribed as the main line of treatment for cancerous tumors. The electric field generators may include, for example, the above referenced Figure 3 and Figure 5 Those parts described.

[0126] The electric field generators implemented herein can be programmed with any number of treatment parameter sets as described above. 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 a telemetry circuit. In some embodiments, the electric field generator can include a charging circuit that is communicatively coupled to a receiving coil to facilitate transcutaneous charging of the medical device. In some embodiments, the electric field generator can communicate wirelessly between the receiving coil and an external charging device.

[0127] 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. Thus, for example, reference to a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally used in a sense including "and / or" unless the content clearly dictates otherwise.

[0128] 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 particular task or adopt a particular configuration. The phrase "configured" may be used interchangeably with other similar phrases such as arranged and configured, constructed and arranged, constructed, manufactured and arranged, and the like.

[0129] 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 in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0130] Aspects have been described with reference to a number of different specific and preferred embodiments and techniques. However, it should be understood that numerous variations and modifications can be made without departing from the spirit and scope of the disclosure.

Claims

1. An implantable medical device for treating a cancerous tumor, comprising: wire; one or more electric field generating electrodes configured for implantation in a patient; as well as one or more impedance monitoring electrodes configured to measure impedance of tissue in the treatment region of the patient along a vector passing through the cancerous tumor; wherein the medical device is configured 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 a cancerous tumor of the patient based on the measured impedance, and wherein a decrease in impedance of the treatment area is indicative of tumor progression, The impedance monitoring electrode comprises a passive electric field sensing electrode, and The lead includes both the electric field generating electrode and the impedance monitoring electrode.

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

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

4. The medical device of any one of claims 1 to 2, wherein the medical device is configured to monitor changes 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 changes in heart rate are detected.

5. The medical device according to claim 4, wherein: The medical device is configured such that regulating the electric field includes reducing the strength 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 cancerous marker concentration; and Wherein the medical device is configured to monitor changes in the at least one characteristic.

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

8. The medical device of claim 7, the measured impedance comprising a measured low frequency impedance.

9. The medical device of claim 8, wherein the low frequency comprises a frequency of 1 Hz to 10 Hz.

10. The medical device of claim 7, the measured impedance comprising a measured high frequency impedance. The medical device of claim 10 , wherein the high frequency comprises a frequency of 100 kHz to 300 kHz.

12. The medical device according to any one of claims 1 to 2, The medical device is configured to measure electric field strength in or around the cancerous tumor using electric field sensing electrodes; and The delivered electric field is adjusted to a desired electric field strength based on the measured electric field strength.

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