阅读说明：本技术 带有热治疗或热监测的电刺激 (Electrical stimulation with thermal treatment or thermal monitoring ) 是由 布莱恩·L·施密特 本杰明·基思·斯坦 基思·R·梅勒 威廉·J.林德 亚历山德拉·哈拉姆 于 2020-04-22 设计创作，主要内容包括：本文的实施例涉及医疗装置以及使用该医疗装置来治疗身体组织内的癌性肿瘤的方法。包括一种医疗装置系统,该医疗装置系统具有被配置用于产生一个或多个电场的电场产生电路、和与该电场产生电路连通的控制电路。该控制电路被配置用于控制从电场产生电路递送一个或多个电场。该系统可以包括两个或更多个电极以将电场递送至患者体内的癌性肿瘤的部位、以及温度传感器以测量癌性肿瘤的部位处的组织的温度。该控制电路可以使电场产生电路以选自在10kHz至1MHz之间的范围的频率来产生一个或多个电场。该控制电路基于所计算的功率输出和电极之间的距离来估计电场内的组织的温度。该控制电路还可以基于阻抗测量值来估计电场内的组织的温度。(Embodiments herein relate to medical devices and methods of using the medical devices to treat cancerous tumors within body tissue. A medical device system is included having an electric field generating circuit configured to generate one or more electric fields, and a control circuit in communication with the electric field generating circuit. The control circuit is configured to control delivery of one or more electric fields from the electric field generating circuit. The system may include two or more electrodes to deliver an electric field to a site of a cancerous tumor within a patient's body, and a temperature sensor to measure a temperature of tissue at the site of the cancerous tumor. The control circuitry may cause the electric field generating circuitry to generate one or more electric fields at a frequency selected from a range between 10kHz and 1 MHz. The control circuit estimates a temperature of tissue within the electric field based on the calculated power output and a distance between the electrodes. The control circuit may also estimate the temperature of tissue within the electric field based on the impedance measurements.)

1. A medical device system, comprising:

an electric field generating circuit configured to generate one or more electric fields; and

control circuitry in communication with the electric field generation circuitry, the control circuitry configured to control delivery of the one or more electric fields from the electric field generation circuitry;

two or more electrodes for delivering the electric field to a site of a cancerous tumor within a patient; and

a temperature sensor for measuring a temperature of tissue at a site of the cancerous tumor, the temperature sensor in electronic communication with the control circuit;

wherein the control circuit causes the electric field generating circuit to generate one or more electric fields at a frequency selected from a range between 10kHz and 1 MHz.

2. The medical device system of any one of claims 1 and 3-7, further comprising

A first lead providing electrical communication between the control circuitry and at least one electrode;

wherein the temperature sensor is disposed on the first lead.

3. The medical device system of any of claims 1-2 and 4-7, wherein the electric field is delivered across at least one vector defined by the pair of electrodes.

4. The medical device system of any of claims 1-3 and 5-7, wherein the temperature sensor is positioned between the pair of electrodes.

5. The medical device system of any of claims 1-4 and 6-7, wherein the electric field is delivered across at least two vectors, wherein a first vector is defined by a first pair of electrodes and a second vector is defined by a second pair of electrodes.

6. The medical device system of any one of claims 1-5 and 7, wherein the electric fields along the at least two vectors are spatially and/or directionally separated from each other.

7. The medical device system of any one of claims 1-6, comprising at least two electric field generating circuits, wherein a first electric field generating circuit is implanted and a second electric field generating circuit is external.

8. A medical device system, comprising:

an electric field generating circuit configured to generate one or more electric fields; and

control circuitry in communication with the electric field generation circuitry, the control circuitry configured to control delivery of the one or more electric fields from the electric field generation circuitry;

two or more electrodes to form at least one electrode pair for targeting the electric field to a site of a cancerous tumor within a patient; and is

Wherein the control circuit causes the electric field generating circuit to generate one or more electric fields at a frequency selected from a range between 10kHz and 1 MHz;

wherein the control circuit calculates a power output of the electric field and estimates a temperature of tissue within the electric field based on the power output and a distance between electrodes of the electrode pair.

9. The medical device system of any one of claims 8 and 10, wherein the medical device system is configured to receive data regarding a distance between electrodes of the electrode pair.

10. The medical device system of any of claims 8-9, wherein the medical device system is configured to estimate a distance between electrodes of the pair of electrodes based on impedance data.

11. A medical device system, comprising:

an electric field generating circuit configured to generate one or more electric fields; and

control circuitry in communication with the electric field generation circuitry, the control circuitry configured to control delivery of the one or more electric fields from the electric field generation circuitry;

two or more electrodes to form at least one electrode pair for targeting the electric field to a site of a cancerous tumor within a patient; and is

Wherein the control circuit causes the electric field generating circuit to generate one or more electric fields at a frequency selected from a range between 10kHz and 1 MHz;

wherein the control circuit estimates a temperature of tissue within the electric field based on the impedance measurement.

12. The medical device system of any of claims 11 and 13-15, wherein the control circuitry estimates a temperature of tissue within the electric field based on impedance measurements and a distance between electrodes of the electrode pair.

13. The medical device system of any of claims 11-12 and 14-15, wherein the medical device system is configured to receive data regarding a distance between electrodes of the electrode pair.

14. The medical device system of any of claims 11-13 and 15, wherein the control circuitry estimates a change in temperature of tissue within the electric field based on a change in measured impedance.

15. The medical device system of any of claims 11-14, further comprising a heating element, wherein the control circuit causes the heating element to generate heat.

Technical Field

Embodiments herein relate to medical devices and methods of using the medical devices to treat cancerous tumors within body tissue.

Background

According to the american cancer society, cancer accounts for nearly 25% of deaths annually in the united states. Current rescue criteria for cancerous tumors may include first line therapies such as surgery, radiation therapy, and chemotherapy. Additional second line therapies may include radiation seeding, cryotherapy, hormonal or biological therapy, ablation, and the like. A combination of first line therapy and second line therapy may also be beneficial to the patient if one particular therapy is not effective by itself.

Cancerous tumors may form if a normal cell in any part of the human body mutates and then begins to grow and multiply too much and too quickly. Cancerous tumors may be the result of genetic mutations in cellular DNA or RNA during cell division, external stimuli such as ionizing or non-ionizing radiation, exposure to carcinogens, or the result of genetic mutations. Regardless of the cause, many cancerous tumors are the result of rapid cell division that is uninhibited.

Disclosure of Invention

In a first aspect, a medical device system is included having an electric field generating circuit configured to generate one or more electric fields, and a control circuit in communication with the electric field generating circuit. The control circuit may be configured to control delivery of one or more electric fields from the electric field generating circuit. The system can include two or more electrodes to deliver an electric field to a site of a cancerous tumor within a patient's body, and a temperature sensor to measure a temperature of tissue at the site of the cancerous tumor, the temperature sensor in electronic communication with the control circuit. The control circuitry may cause the electric field generating circuitry to generate one or more electric fields at a frequency selected from a range between 10kHz and 1 MHz.

In a second aspect, in addition to, or in the alternative of, one or more of the preceding or following aspects, the system can include a first lead providing electrical communication between the control circuit and at least one electrode; wherein the temperature sensor is disposed on the first lead.

In a third aspect, the first lead may include at least one of a percutaneous lead and a fully implanted lead, in addition to, or in the alternative of, one or more of the preceding or following aspects.

In a fourth aspect, in addition to, or in the alternative of certain aspects to, one or more of the preceding or following aspects, at least two electrodes are configured to be implanted.

In a fifth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, the electric field is delivered across at least one vector defined by the pair of electrodes.

In a sixth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, the temperature sensor is positioned between the pair of electrodes.

In a seventh aspect, in addition to, or in the alternative of certain aspects to, one or more of the preceding or following aspects, the temperature sensor is adapted for insertion into a cancerous tumor.

In an eighth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, the electric field is delivered across at least two vectors, wherein a first vector is defined by a first pair of electrodes and a second vector is defined by a second pair of electrodes.

In a ninth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, wherein the electric fields along the at least two vectors are spatially and/or directionally separated from each other.

In a tenth aspect, in addition to, or in the alternative of, one or more of the preceding or following aspects, the system may comprise at least two electric field generating circuits, wherein a first electric field generating circuit is implanted and a second electric field generating circuit is external.

In an eleventh aspect, in addition to or in the alternative of one or more of the preceding or following aspects, or in the alternative of certain aspects, the system can further include an implanted housing defining an interior volume in which the electric field generating circuit and the control circuit are disposed.

In a twelfth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, or in certain aspects, the temperature sensor is selected from the group consisting of: thermistors, resistance thermometers, thermocouples, and semiconductor-based sensors.

In a thirteenth aspect, a medical device system is included having an electric field generating circuit configured to generate one or more electric fields, and a control circuit in communication with the electric field generating circuit, the control circuit configured to control delivery of the one or more electric fields from the electric field generating circuit. The system may include two or more electrodes to form at least one electrode pair for delivering an electric field to a site of a cancerous tumor within a patient. The control circuitry may cause the electric field generating circuitry to generate one or more electric fields at a frequency selected from a range between 10kHz and 1 MHz. The control circuit may calculate a power output of the electric field and estimate a temperature of tissue within the electric field based on the power output and a distance between electrodes of the pair of electrodes.

In a fourteenth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, or in the alternative of certain aspects, the medical device system is configured to receive data regarding a distance between electrodes of the electrode pair.

In a fifteenth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, or in the alternative of certain aspects, the medical device system is configured for estimating a distance between electrodes of the electrode pair based on impedance data.

In a sixteenth aspect, a medical device system is included having an electric field generating circuit configured to generate one or more electric fields, and a control circuit in communication with the electric field generating circuit, the control circuit configured to control delivery of the one or more electric fields from the electric field generating circuit. The system may further include two or more electrodes to form at least one electrode pair for delivering an electric field to a site of a cancerous tumor within a patient, and wherein the control circuit causes the electric field generating circuit to generate the one or more electric fields at a frequency selected from a range between 10kHz and 1 MHz. The control circuit may estimate a temperature of tissue within the electric field based on the impedance measurement.

In a seventeenth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, or in the alternative of certain aspects, the control circuit estimates a temperature of tissue within the electric field based on impedance measurements and distances between electrodes of the pair of electrodes.

In an eighteenth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, or in certain aspects, the medical device system is configured to receive data regarding a distance between electrodes of the electrode pair.

In a nineteenth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, the control circuit estimates a change in temperature of tissue within the electric field based on a change in measured impedance.

In a twentieth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, or in the alternative of certain aspects, the system can further comprise a heating element, wherein the control circuit causes the heating element to generate heat.

This summary is an overview of some of the teachings of the present application and is not intended to be an exclusive or exhaustive treatment of the present subject matter. Further details are present in the detailed description and the appended claims. Other aspects will be apparent to those skilled in the art from a reading and understanding of the following detailed description and a review of the drawings that form a part hereof, each of which is not to be taken in a limiting sense. The scope herein is defined by the appended claims and their legal equivalents.

Drawings

Aspects may be more completely understood in connection with the following drawings (figures), in which:

fig. 1 is a schematic illustration of a medical system according to various embodiments herein.

Fig. 2 is a schematic diagram of a medical system according to various embodiments herein.

Fig. 3 is a graph of exemplary therapy parameters according to various embodiments herein.

Fig. 4 is a graph of exemplary therapy parameters according to various embodiments herein.

Fig. 5 is a schematic illustration of a medical device according to various embodiments herein.

Fig. 6 is a schematic illustration of a medical device according to various embodiments herein.

Fig. 7 is a schematic illustration of a medical device according to various embodiments herein.

Fig. 8 is a schematic illustration of a medical device according to various embodiments herein.

Fig. 9 is a schematic illustration of a medical device according to various embodiments herein.

Fig. 10 is a schematic illustration of a medical device according to various embodiments herein.

Fig. 11 is a schematic cross-sectional view of a medical device according to various embodiments herein.

Fig. 12 is a schematic illustration of components of a medical device according to various embodiments herein.

Fig. 13 is a flow diagram depicting a method according to various embodiments herein.

While the embodiments are susceptible to various modifications and alternative forms, specifics thereof have been shown by way of example and drawings and will be described in detail. It should be understood, however, that the scope herein is not limited by the particular aspects described. On the contrary, the intention is to cover modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure.

Detailed Description

As mentioned above, many cancerous tumors may be caused by rapid cell division that is not inhibited. Some traditional first-line therapies for treating cancerous tumors may include surgery, radiation therapy, and chemotherapy. However, many first-line therapies are associated with undesirable side effects such as fatigue, hair loss, immunosuppression, and long surgical recovery times, to name a few.

While not intending to be bound by theory, it is believed that the electric field may disrupt mitosis within the cancerous tumor, such as by interfering with the dipole arrangement of key proteins involved in cell division (tubulin and septal proteins in particular). Polymerization of tubulin to form microtubule spindle threads can be disrupted, thereby preventing the formation of spindle threads required for chromosome segregation. This can stop cell division during the metaphase stage of mitosis. In some cases, the electric field may stop the polymerization of the already growing spindle filaments, resulting in incomplete spindles and unequal chromosome segregation at a later stage (if the cell survives for that long time). In each case, cessation of microtubule spindle formation and unequal chromosome segregation at a later stage due to incomplete microtubule polymerization may lead to apoptosis (i.e., programmed cell death). It is also believed that the alternating electric field may result in an increase in the electric field density near the cleavage furrow of the dividing cell at the end stage. The increase in electric field density in the region of the cleavage groove can result in dielectrophoresis of charged macromolecules (such as proteins and nucleic acids) towards high electric field densities at the cleavage groove. Unequal concentrations of key macromolecules required for cell division at the site of the cleavage furrow may disrupt the eventual detachment of late stage sister cells and eventually lead to apoptosis.

Temperature can be an important parameter to measure during application of the electric field. In some cases, it may be desirable to limit and/or prevent thermal damage to tissue. In this way, the temperature of the tissue can be monitored (directly or indirectly) to prevent the temperature from rising to a level at which thermal destruction of the tissue may occur. However, in some embodiments, the degree of heating and application of the electric field may be therapeutic. Thus, in some embodiments, it may be desirable to apply heat to the tissue.

As such, various embodiments disclosed herein include a medical device system that can generate an electric field for treating cancer, which system can include or can control at least one electrode, and/or at least one temperature sensor or at least one heating element. In various embodiments, an electric field may be generated, and heat may be applied to treat a tumor, such as via a heating element. In various embodiments, a temperature sensor may be used to monitor the temperature of the tissue near or around the electric field or heating element to observe changes in the tissue during heating or electric field generation. In various embodiments, the medical device may be configured to turn off or stop therapy when the temperature of the tissue exceeds a threshold.

Referring now to fig. 1, a schematic diagram of a medical device 100 according to various embodiments herein is shown. The medical device 100 may be implanted entirely within the body of the patient 101 at or near the site of the cancerous tumor 110 located within the body tissue. Various implant sites may be used, including, for example, areas in the limbs, upper torso, abdominal area, head, etc.

Referring now to fig. 2, another schematic diagram of a medical device 200 according to various embodiments herein is shown. The medical device 200 may be external to the body, but may be connected to a component (such as a lead) that is at least partially implanted within the body of the patient 101. In some embodiments, the medical device 200 may be partially implanted within a patient and partially external to the patient. In some embodiments, the medical device 200 may include a percutaneous connection disposed between components inside and outside the body. In various embodiments, the medical device systems described herein may include an implanted medical device 100 and an external medical device 200. In other embodiments, the medical device systems described herein may include a partially implanted medical device.

The implanted portion of the medical device system (such as the implanted medical device 100 or a portion thereof) may wirelessly communicate patient identification data, diagnostic information, electric field data, physiological parameters, software updates, etc. with all or a portion of the external portion of the medical device 200 via a wireless connection. The implanted medical device 100 may also communicate wirelessly with an external device configured for wireless charging of the medical device using inductive, radio frequency, and acoustic energy transfer techniques, among others.

In some embodiments, a portion of the medical device or system may be fully implanted, and a portion of the medical device may be fully external. For example, in some embodiments, one or more electrodes or leads may be implanted entirely within the body, while the portion of the medical device that generates the electric field (such as the electric field generator) may be entirely outside the body. It will be appreciated that in some embodiments described herein, the described electric field generator may comprise many of the same components as the pulse generator and may be configured to perform many of the same functions as the pulse generator. In embodiments where a portion of the medical device is fully implanted and a portion of the medical device is fully external to the body, the portion of the medical device that is fully external to the body may wirelessly communicate with the portion of the medical device that is fully internal to the body. However, in other embodiments, a wired connection may be used for the implanted portion to communicate with the external portion.

The implanted medical device 100 and/or the medical device 200 may include a housing 102 and a head 104 coupled to the housing 102. Various materials may be used to form the housing 102. In some embodiments, the housing 102 may be formed from materials such as metals, ceramics, polymers, composites, and the like. In some embodiments, the housing 102, or one or more portions thereof, may be formed of titanium. The head 104 may be formed from a variety of materials, but in some embodiments, the head 104 may be formed from a translucent polymer such as an epoxy material. In some embodiments, the head 104 may be hollow. In other embodiments, the head 104 may be filled with a component and/or structural material, such as epoxy or another material, such that it is not hollow.

In some embodiments in which a portion of the medical device 100 or 200 is partially extracorporeal, the head 104 and the housing 102 may be surrounded by a protective shell made of a durable polymer material. In other embodiments, where a portion of the device is extracorporeal, the head 104 and the housing 102 may be surrounded by a protective shell made of one or more of a polymeric material, a metallic material, and/or a glass material.

The head 104 may be coupled to one or more leads 106. The head 104 may be used to provide fixation of the proximal end of the one or more leads 106 and electrically couple the 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 leads 106. In some embodiments, the electrodes 108 may comprise electric field generating electrodes, and in other embodiments, the electrodes 108 may comprise electric field sensing electrodes. In some embodiments, lead 106 may include both electric field generating electrodes and electric field sensing electrodes. In other embodiments, the leads 106 may include any number of electrodes for both electric field sensing and electric field generation. One or more conductors, such as wires, may be included in the lead 106 to provide electrical communication between the electrodes and the proximal end (or plug) of the lead. The wires may be present as a single strand or fiber, or may be multi-fiber, such as a cable. The lead 106 may include a shaft, typically formed of a polymer material or another non-conductive material, through which a conductor may pass. The proximal end of the lead 106 may be inserted into the head 104, thereby providing electrical communication between the electrode 108 and components within the housing 102. It should be understood that although many embodiments of the medical devices herein are designed to function with a lead, leadless medical devices that generate an electric field are also contemplated herein.

In various embodiments, the electrode 108 may be positioned around or near a tumor 110, such as a cancerous tumor. Tumor 110 may be positioned within the electric field generated by electrodes 108.

The electric field generated by the implanted medical device 100 and/or the medical device 200 may vary. In some embodiments, the implanted medical device 100 and/or the medical device 200 may generate one or more electric fields at a frequency selected from the range between 10kHz and 1 MHz.

In some embodiments, an electric field may be applied to a site of a cancerous tumor at a particular frequency or constant frequency range. However, in some embodiments, the electric field may be applied to the site of the cancerous tumor by sweeping through a range of frequencies. As one example, referring now to fig. 3, an exemplary graph 312 illustrates an alternating electric field delivered by the electrode 108, wherein the frequency increases over time. Similarly, fig. 4 shows the variation of frequency over time during programmed therapy parameters in an exemplary graph 414. In some embodiments, the frequency sweep may include sweeping up from a minimum frequency to a maximum frequency. In some embodiments, the frequency sweep may include sweeping down from a maximum frequency to a minimum frequency. In other embodiments, the sweep up from the minimum frequency to the maximum frequency and the sweep down from the maximum frequency to the minimum frequency may be repeated as many times as desired throughout the duration of the delivery of the electric field from the electric field generating circuit.

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

The frequency ranges for the first and second frequency ranges may be any range that includes the particular frequencies recited above or below, provided that the lower end of each range is a value that is less than the upper end of each range. Sometimes it may be beneficial to have a certain degree of overlap between the frequency ranges of the first and second frequency sweeps.

Medical device and system

Referring now to fig. 5, a schematic diagram of a medical device 500 according to various embodiments herein is shown. In various embodiments, the medical device 500 may include at least one electric field generating circuit configured to generate one or more electric fields. The electric field generating circuit may be disposed within the housing 102. The medical device 500 may further include a control circuit that may be in communication with the electric field generating circuit. The control circuit may be configured to control delivery of one or more electric fields from the electric field generating circuit. In various embodiments, the control circuit causes the electric field generating circuit to generate one or more electric fields at a frequency selected from a range between 10kHz to 1 MHz. In various embodiments, the medical device 500 may include an implanted housing 102. The implanted housing 102 may define an interior volume in which the electric field generating circuit and the first control circuit are disposed.

In some embodiments, the medical device 500 may include one or more leads 106, such as at least two leads 106 (although embodiments having three, four, five, six, or more leads are also directly contemplated herein). In some embodiments, the at least one lead 106 may be completely implanted or completely under the patient's skin 516, as shown in fig. 5. In some embodiments, the plurality of leads 106 are fully implanted, such as two leads 106, three leads 106, four leads 106, five leads 106, or six leads 106. In some embodiments, at least two electrodes 108 are implanted and disposed on the fully implanted lead 106. In various embodiments, the lead 106 may be a percutaneous lead that extends through the skin 516 of the patient, as shown in fig. 8.

In various embodiments, the medical device 500 may include two or more electrodes 108. The electrodes 108 may be configured to deliver an electric field to the site of the cancerous tumor 110. In various embodiments, the lead 106 can provide electrical communication between the control circuitry and the at least one electrode 108. In various embodiments, the electric field may be delivered across at least one vector 520 defined by a pair of electrodes 108 formed by two or more electrodes 108. In some embodiments, the electric field may be delivered across at least two vectors. In some embodiments, the first vector may be defined by a first pair of electrodes and the second vector may be defined by a second pair of electrodes.

Temperature sensor

In some embodiments, the medical device may include at least one temperature sensor 518. The temperature sensor 518 may be configured to measure the temperature of tissue at the site of the tumor 110, such as to monitor temperature changes that may result from the generation of an electric field, or changes that may result from heating of a heating element. The temperature sensor 518 may be in electronic communication with the control circuit. In some embodiments, the medical device may include at least one temperature sensor 519 disposed in tissue not within the treated region, such as within healthy tissue. A temperature sensor 519 (remote from the treatment area) may be used with the temperature sensor 518 to determine the temperature change achieved by the therapy.

Many different types of sensors may be used as the temperature sensor herein. In some embodiments, the temperature sensor 518 may be selected from the group consisting of: thermistors, resistance thermometers, thermocouples, semiconductor-based sensors, bimetallic devices, thermometers, state change sensors, optical temperature sensors (such as infrared sensors), and the like.

In some embodiments, the temperature sensor 518 may be disposed on the lead 106. In some embodiments, multiple temperature sensors 518 may be disposed on a single lead 106. In some embodiments, at least one temperature sensor 518 is disposed on each lead 106. In some embodiments having multiple leads 106, at least two leads 106 may have temperature sensors 518 disposed on the leads 106.

In some embodiments herein, the temperature sensor may be chronically implanted. In some embodiments, the temperature sensor may be implanted for a duration of time greater than 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 52 weeks, or more, or an amount that falls within a range between any of the foregoing durations. However, in some embodiments, the temperature sensor may be temporarily implanted. In some embodiments, the temperature sensor may be implanted for a duration of time less than 2 days, 1 day, 12 hours, 4 hours, 2 hours, or 1 hour, or an amount falling within a range between any of the foregoing durations. In some embodiments, the temperature sensor 518 may be removable such that it may be removed after confirming that the medical device delivered therapy in a safe or desired manner. In various embodiments, a removable temperature sensor may be implanted during implantation of the electrode 108. The removable temperature sensor may be configured to measure a temperature of tissue proximate to the one or more electrodes, such as during implantation of the electrodes. The removable temperature sensor may be mounted on a temporarily inserted lead, introducer sheath, guidewire, delivery cannula, other type of cannula, or other type of surgical or implant instrument.

In some embodiments, such as after the medical device has been implanted, the patient may undergo a thermal scan. The thermal scan may be performed by an external device or component. The thermal scan may determine the temperature of tissue within the patient, such as tissue near the electrodes. Thermal scanning may allow for monitoring the temperature of various tissues within a patient, such as during therapy with a medical device, in a less invasive manner.

It should be appreciated that the thermal scan may be performed in various ways. For example, thermal scanning may be performed using infrared thermal Imaging (IRT), infrared thermometers, thermal imaging, thermal video, indium antimonide (InSb) devices, cadmium mercury telluride (MCT) devices, and the like.

Temperature estimation based on power output

In some embodiments, the control circuit may be configured to calculate the power output of the electric field. The control circuitry may also be configured to estimate the temperature of tissue within the electric field, such as based on the power output and the distance between the two electrodes 108 in the electrode pair. Power (in Watts) is related to current and resistance/impedance, P shown below_avg＝I² _rmsR. 1 watt equals 1 joule/second. The amount of heat transferred can be determined as q ═ mC_pΔ T or Δ T ═ q/mCp, where q is the energy in kilojoules, m is the mass, Cp is the specific heat capacity of the tissue, and Δ T is the temperature change. Thus, Δ T may be approximated as I ² _rmsR/mCp. In some embodiments, the distance (D) between the electrodes may be used to represent mass. Thus, in some embodiments, Δ T may be approximated as I² _rmsR/DCp. The specific heat capacity of the tissue may be about 3.6 to 3.9kJ kg^-1K^-1。

In some embodiments, the control circuit may be configured to estimate the power output based on temperature changes. In particular, the above equation may be reconfigured to solve for P based on Δ T_avg。

In some embodiments, the medical device 500 may be configured to receive data regarding the distance between two electrodes 108 in an electrode pair to estimate the temperature of tissue within the electric field. In some embodiments, the medical device 500 may receive data from the user regarding the distance between the two electrodes. As an example, the user may enter a distance during the programming phase. In some embodiments, a user (e.g., a physician) may use an imaging device (e.g., a fluoroscopic or ultrasound imaging device) to determine the distance between the two electrodes 108. This data may then be entered into the medical device 500. In further embodiments, the medical apparatus 500 may be configured to estimate the distance between the electrodes 108 of an electrode pair, such as based on impedance data between the two electrodes 108.

Temperature as a function of impedance

In some embodiments, the control circuit may be configured to estimate the temperature of tissue within the electric field, such as based on impedance measurements. In some embodiments, the control circuitry may be configured to estimate the temperature of tissue within the electric field, such as based on the impedance measurements and the distance between the electrodes 108 in the electrode pair. The medical device 500 may be configured to receive data regarding the distance between the electrodes 108 in an electrode pair. In further embodiments, the control circuit may be configured to estimate a change in temperature of tissue within the electric field, such as based on a change in measured impedance.

In various embodiments, the impedance of the tissue may vary as the temperature of the tissue varies. These impedance changes can be characterized and compared to known data for the therapy device. The impedance measurements may then be correlated with a temperature estimate of the tissue.

Referring now to fig. 6, a schematic diagram of a medical device 500 according to various embodiments herein is shown. In some embodiments, the medical device 500 may include a temperature sensor 518 positioned between a pair of electrodes 108. In some embodiments, the temperature sensor 518 may be adapted to be inserted into the tumor 110.

In some embodiments, the lead 106 on which the temperature sensor 518 is disposed does not include an electrode. In some embodiments, the lead 106 may include a plurality of temperature sensors 518.

Thermotherapy method

In some embodiments, the therapy delivered by the medical device 500 may include the generation of an electric field at the tumor 110 and the generation of heat. Fig. 7 is a schematic illustration of a medical device 500 according to various embodiments herein. In some embodiments, the medical device 500 may include a heating element 722. The heating element 722 may be configured to generate heat. In various embodiments, the heating element 722 may generate heat while the electrodes generate an electric field.

The heating element 722 may generate heat and cause the tissue to be heated by various means. In some embodiments, the heating element 722 may be operable to heat tissue by conduction. For example, the heating element 722 itself may be heated by joule heating (also referred to as ohmic or resistive heating), which may be performed by passing a current through a component having a resistance. For example, a nichrome (nickel/chromium 80/20) wire, ribbon, or ribbon directly exposed or embedded within another material may be used as heating element 722, and when it is heated, it may heat the surrounding tissue by thermal conduction. Various other materials may also be used as heating elements. In some embodiments, heating element 722 may emit electromagnetic radiation that is then absorbed by surrounding tissue to heat the tissue. For example, heating element 722 may include an infrared emitter that generates electromagnetic radiation that is absorbed by surrounding tissue to raise the temperature of the tissue, which may be used as an example of radiant heating. In some embodiments, the heating element 722 may provide heat to the tissue by both conduction and radiation.

In some embodiments, the control circuit causes the heating element 722 to generate heat. In some embodiments, the control circuitry estimates the temperature of tissue within the electric field based on the impedance measurements. In some embodiments, the control circuitry estimates a temperature of tissue within the electric field based on the power measurement.

In various embodiments, one or more heating elements 722 may be disposed on the leads 106. In some embodiments, the lead 106 including the heating element 722 does not include the electrode 108.

In some embodiments, the lead 106 may include at least one heating element 722 and at least one electrode 108, as shown in fig. 8. Fig. 8 shows a schematic view of a medical device 500 according to various embodiments herein. The medical device 500 may include a housing 102 (which may be an outer housing in this example) and one or more leads 106.

The medical device 500 may include one or more percutaneous leads 106, such as leads 106 that pass through or across the skin 516 of the patient. In various embodiments, at least two electrodes 108 are implanted and disposed on the percutaneous lead 106. In various embodiments, at least two electrodes 108 are implanted and disposed on the percutaneous lead 106, such as at least one electrode 108 on two different percutaneous leads 106.

External power supply

In some cases, the device operation herein may consume a large amount of electrical power. For example, joule heating may consume a large amount of electrical power. The power capacity of a fully implanted component may be limited (e.g., the total power capacity provided by the implanted battery is limited). As such, in some embodiments, the system may be configured to deliver power from an external power source to the internal (implanted) component.

Fig. 9 shows a schematic view of a medical device 500 according to various embodiments herein. Medical device 500 may include an implanted housing 902 and one or more fully implanted leads 906. Implanted lead 906 may include electrode 108. The medical device 500 may include an outer housing 924. In some embodiments, an external power source may be disposed within the outer housing 924. In various embodiments, the implanted housing 902 can wirelessly communicate with the external housing 924 to exchange data or information regarding therapy delivery.

In some embodiments, the control circuitry may be disposed in one of the implanted housing 902 or the external housing 924. In some embodiments, the control circuitry may be disposed at least partially within the implanted housing 902 and the external housing 924.

In some embodiments, percutaneous lead 106 may include a wireless power transfer connection 940. A wireless power transfer connection 940 may be established transcutaneously between the outer housing 924 (such as a power source within the outer housing 924) and the implanted lead 106. In some embodiments, the medical device 500 may include an inductive power transfer link including paired inner 942 and outer 944 inductors for transferring power from outside the body to implanted components of the system. The inductive power transfer link may allow power to be transferred from an external power source to the internal components, which in turn may generate an electric field or generate heat without piercing the skin 516 or otherwise maintaining an opening or passageway through the patient's skin 516.

In various embodiments, a fully implanted lead 906 may include electrodes 108 and may lack heating elements 722, while percutaneous lead 106 may include one or more heating elements 722. In some embodiments, the outer housing 924 may include a power source to power the heating element 722.

Referring now to fig. 10, a schematic diagram of a medical device 500 according to various embodiments herein is shown. In some embodiments, the electric field may be delivered across at least two vectors 520, 920. The first vector 520 may be defined by the first pair of electrodes 108, and the second vector 920 may be defined by the second pair of electrodes 108. In various embodiments, the first vector 520 and the second vector 920 may be substantially orthogonal to each other.

In some embodiments, the medical device 500 may include at least two electric field generating circuits. In various embodiments, the first electric field generating circuit may be implanted, such as within housing 902, and the second electric field generating circuit may be external, such as within housing 924.

Referring now to fig. 11, a schematic cross-sectional view of a medical device 1100 according to various embodiments herein is shown. The housing 102 may define an interior volume 1102, which may be hollow and, in some embodiments, hermetically sealed from a region 1104 external to the medical device 1100. In other embodiments, the housing 102 may be filled with components and/or structural materials such that it is not hollow. The medical device 1100 may include control circuitry 1106, which may include various components 1108, 1110, 1112, 1114, 1116, and 1118 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 both integrated and separate components. The medical device 1100 may also include an antenna 1124 to allow one-way or two-way wireless data communication with, for example, an external device or an external power source. In some embodiments, the components of the medical device 1100 may include an inductive energy receiver coil (not shown) communicatively coupled or attached thereto to facilitate transcutaneous recharging of the medical device via a recharging circuit.

The various components 1108, 1110, 1112, 1114, 1116, and 1118 of the control circuitry 1106 can include, but are not limited to, microprocessors, memory circuits (such as Random Access Memory (RAM) and/or Read Only Memory (ROM)), recorder circuits, controller circuits, telemetry circuits, power supply circuits (such as batteries), timing and Application Specific Integrated Circuits (ASICs), recharging circuits, and the like. The control circuitry 1106 may be in communication with electric field generating circuitry 1120, which may be configured to generate electrical current to form one or more fields. The electric field generating circuit 1120 may be integrated with the control circuit 1106, or may be a separate component from the control circuit 1106. The control circuitry 1106 may be configured to control the delivery of electrical current from the electric field generation circuitry 1120. In some embodiments, the electric field generating circuit 1120 may be present in a portion of the medical device that is external to the body.

In some embodiments, the control circuitry 1106 may be configured to direct the electric field generating circuitry 1120 to deliver an electric field via the leads 106 to a site of a cancerous tumor located within body tissue. In other embodiments, the control circuitry 1106 may be configured to direct the electric field generating circuitry 1120 to deliver an electric field to a site of a cancerous tumor located within body tissue via the housing 102 of the medical device 1100. In other embodiments, the control circuitry 1106 may be configured to direct the electric field generating circuitry 1120 to deliver an electric field between the lead 106 and the housing 102 of the medical device 1100. In some embodiments, one or more leads 106 may be in electrical communication with the electric field generating circuit 1120.

In some embodiments, various components within the medical device 1100 may include an electric field sensing circuit 1122 configured to generate a signal corresponding to a sensed electric field. The electric field sensing circuit 1122 may be integrated with the control circuit 1106, or it may be separate from the control circuit 1106.

The sensing electrodes may be disposed on or near the housing of the medical device, on one or more leads connected to the housing, on a separate device implanted near or in the tumor, or any combination of these locations. In some embodiments, electric field sensing circuitry 1122 can include first sensing electrode 1132 and second sensing electrode 1134. In other embodiments, housing 102 itself may serve as the sensing electrode for electric field sensing circuit 1122. Electrodes 1132 and 1134 may be in communication with electric field sensing circuit 1122. The electric field sensing circuit 1122 can measure a potential difference (voltage) between the first electrode 1132 and the second electrode 1134. In some embodiments, electric field sensing circuit 1122 can measure the potential difference (voltage) between first electrode 1132 or second electrode 1134 and electrodes arranged along the length of one or more leads 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.

It should be appreciated that the electric field sensing circuit 1122 can additionally measure the potential difference between the first electrode 1132 or the second electrode 1134 and the housing 102 itself. In other embodiments, the medical device may include a third electrode 1136, which may be an electric field sensing electrode or an electric field generating electrode. In some embodiments, one or more sensing electrodes may be disposed along lead 106 and may serve as additional locations for sensing electric fields. Many combinations are contemplated for measuring the potential difference between electrodes disposed along the length of one or more leads 106 and the housing 102 according to embodiments herein.

In some embodiments, one or more leads 106 may be in electrical communication with the electric field generating circuit 1120. One or more leads 106 may include one or more electrodes 108, as shown in fig. 1 and 2. In some embodiments, various electrical conductors (such as electrical conductors 1126 and 1128) may pass from head 104 through feedthrough 1130 and into interior volume 1102 of medical device 1100. Accordingly, the electrical conductors 1126 and 1128 may be used to provide electrical communication between one or more leads 106 and the control circuitry 1106 disposed within the interior volume 1102 of the housing 102.

In some embodiments, the recorder circuit may be configured to record data generated by the electric field sensing circuit 1122 and to record a timestamp for the data. In some embodiments, the control circuitry 1106 may be hardwired to perform various functions, while in other embodiments, the control circuitry 1106 may be directed to implement instructions executing on a microprocessor or other external computing device. Telemetry circuitry may also be provided for communicating with external computing devices, such as programmers, room-mounted units, and/or mobile units (e.g., cellular phones, personal computers, smart phones, tablet computers, etc.).

The elements of the various embodiments of the medical devices described herein are shown in fig. 12. However, it should be understood that some embodiments may include additional elements than those shown in fig. 12. In addition, some embodiments may lack some of the elements shown in fig. 12. The medical devices embodied herein may collect information through one or more sensing channels and may output information through one or more field generating channels. The microprocessor 1202 may communicate with the memory 1204 via a bidirectional data bus. The memory 1204 may include Read Only Memory (ROM) or Random Access Memory (RAM) for program storage and RAM for data storage. The microprocessor 1202 may also be connected to a telemetry interface 1218 for communicating with external devices such as a programmer, room-mounted units, and/or mobile units (e.g., cell phones, personal computers, smart phones, tablet computers, etc.), or directly to the cloud or another communication network as facilitated by a cellular or other data communication network. The medical device may include a power circuit 1220. In some embodiments, the medical device may include an inductive energy receiver coil interface (not shown) communicatively coupled or attached thereto to facilitate transcutaneous recharging of the medical device.

The medical device may include one or more electric field sensing electrodes 1208 and one or more electric field sensor channel interfaces 1206 that may communicate with a port of the microprocessor 1202. The medical device may also include one or more electric field generating circuits 1222, one or more electric field generating electrodes 1212, and one or more electric field generating channel interfaces 1210 that may communicate with a port of the microprocessor 1202. The medical device may also include one or more temperature sensors 1216 and one or more temperature sensor channel interfaces 1214 that may be in communication with a port of the microprocessor 1202. Channel interfaces 1206, 1210, and 1214 may include various components such as analog-to-digital converters for digitizing signal inputs, sense amplifiers, registers that may be written to by control circuitry to adjust the gain and thresholds of the sense amplifiers, source drivers, modulators, demodulators, multiplexers, and so forth.

Although the temperature sensors 1216 are shown as part of the medical device in fig. 12, it should be appreciated that in some embodiments, one or more of the temperature sensors may be physically separate from the medical device. In various embodiments, one or more of the temperature sensors may be within another implanted medical device that is communicatively coupled to the medical device via telemetry interface 1218. In still other embodiments, one or more of the temperature sensors may be external to the body and coupled to the medical device via telemetry interface 1218.

Method

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

In an embodiment, a method for treating a cancerous tumor is included. The method can comprise the following steps: implanting at least two electrodes into a patient having a cancerous tumor of the patient; implanting a temperature sensor in the patient; generating an electric field between at least one pair of electrodes, the electric field having a frequency in the range between 10kHz and 1 MHz; and sensing the temperature with a temperature sensor.

Fig. 13 shows a flow diagram depicting a method 1300 according to various embodiments herein. Method 1300 may be a method for treating a cancerous tumor. Method 1300 may include step 1330: at least two electrodes are implanted in a patient having a cancerous tumor. Method 1300 may further include step 1332: the temperature sensor is implanted in the patient, such as near or within a cancerous tumor. Method 1300 may also include step 1334: an electric field is generated between at least one pair of electrodes. In various embodiments, the frequency of the electric field may be in a range between 10kHz and 1 MHz.

In some embodiments, method 1300 may include step 1336: a temperature sensor is used to sense a temperature, such as the temperature of tissue near the tumor or the temperature of the tumor. In some embodiments, method 1300 may include estimating a temperature of tissue within the electric field, such as based on the power output and a distance between the electrodes. In some embodiments, method 1300 may include estimating a distance between electrodes in an electrode pair, such as based on impedance data.

Electrical stimulation parameters

In various embodiments, the systems or devices herein (or components thereof, such as control circuitry) can be configured to direct the electric field generating circuitry to deliver an electric field using one or more frequencies selected from a range between 10kHz to 1 MHz. In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field at one or more frequencies selected from a range between 100kHz and 500 kHz. In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field at one or more frequencies selected from a range between 100kHz and 300 kHz. In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry to periodically deliver the electric field using one or more frequencies greater than 1 MHz.

In some embodiments, the electric field can be effective to disrupt cell mitosis in the cancer cell. The electric field may be delivered to the site of the cancerous tumor 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 lead electrodes). In some embodiments, at least two vectors having spatial diversity between the two vectors may be used. The vectors may be spatially and/or directionally separated (e.g., the vectors may be angularly disposed with respect 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.

The desired electric field strength can be achieved by delivering a current between the two electrodes. The particular current and voltage at which the electric field is delivered may be varied and adjusted to achieve a desired electric field strength at the tissue site to be treated. In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field to the site of the cancerous tumor using a current in a range of 1mAmp to 1000 mAmp. In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field to the site of the cancerous tumor using a current in the range of 20mAmp to 500 mAmp. In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field to the site of the cancerous tumor using a current in the range of 30mAmp to 300 mAmp.

In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field using a current comprising: 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, 275mAmp, 300mAmp, 325mAmp, 350mAmp, 375mAmp, 400mAmp, 425mAmp, 450mAmp, 475mAmp, 500mAmp, 525mAmp, 550mAmp, 575mAmp, 600mAmp, 625mAmp, 650mAmp, 675, 700mAmp, 725mAmp, 750mAmp, 775, 825mAmp, 800mAmp, 850mAmp, 900mAmp, or 1000 mAmp. It will be appreciated that the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field at a current falling within a range, where any of the aforementioned currents may be used as a lower limit or an upper limit of the range, provided that the lower limit of the range is a value less than the upper limit of the range.

In some embodiments, the control circuit may be configured to direct the electric field generating circuit to be used at 1V _rmsTo 50V_rmsVoltages within the range deliver an electric field to the site of a cancerous tumor. In some embodiments, the control circuit may be configured to direct the electric field generating circuit to be used at 5V_rmsTo 30V_rmsVoltages within the range deliver an electric field to the site of a cancerous tumor. In some embodiments, the control circuit may be configured to direct the electric field generating circuit to use at 10V_rmsTo 20V_rmsVoltages within the range deliver an electric field to the site of a cancerous tumor.

In some embodiments, the control circuitry may be configured to direct the electric field generating circuitry 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_rmsOr 50V_rms. It will be appreciated that the control circuitry may be configured to direct the electric field generating circuitry to deliver the electric field using voltages that fall within a range, where any of the foregoing voltages may be used as a lower limit or an upper limit of the range, provided that the lower limit of the range is a value that is less than the upper limit of the range.

In some embodiments, the control circuitry may be configured to direct the electric field generation circuitry 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, 375kHz, 400kHz, 425kHz, 450kHz, 475kHz, 500kHz, 525kHz, 550kHz, 575kHz, 600kHz, 625kHz, 650kHz, 675kHz, 700kHz, 725kHz, 750kHz, 775kHz, 800kHz, 825kHz, 850kHz, 875kHz, 900kHz, 925kHz, 950kHz, 975kHz, 1 MHz. It will be appreciated that the electric field generating circuit may deliver the electric field using frequencies that fall within a range, where any of the aforementioned frequencies may be used as an upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

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

In other embodiments, the control circuit may be configured to direct the electric field generating circuit to generate an applied electric field strength comprising one or more of: 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, 0V/cm, 350V/cm, 500.0V/cm, 450.0V/cm, 500V/cm, 600.0V/cm, 700.0V/cm, 800.0V/cm, 900.0V/cm, 1000.0V/cm. It will be appreciated that the electric field generating circuit may generate an electric field at the treatment site having an electric field strength that falls within a range, wherein any of the foregoing field strengths may be used as an upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

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

It should also be noted that, as used in this specification and the appended claims, the phrase "configured to" describes a system, device, or other structure that is constructed or arranged to perform a particular task or to 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).

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

As used herein, recitation of end-point logarithmic ranges of values is intended to include all numbers within that range (e.g., 2 to 8 includes 2.1, 2.8, 5.3, 7, etc.).

The headings used herein are provided to conform to the recommendations in 37CFR 1.77 or to otherwise provide organizational cues. These headings should not be taken as limiting or characterizing the invention(s) set forth in any claims that may be presented by this disclosure. By way of example, although the headings refer to a "realm," such claims should not be limited by the language chosen under this heading to describe the so-called realm of technology. Further, the description of technology in the "background" does not constitute an admission that the technology is prior art to any invention(s) in this disclosure. The "summary of the invention" should also not be considered a characterization of the invention(s) set forth in the issued claims.

The embodiments described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices. Thus, the various aspects have been described with reference to various specific and preferred embodiments and techniques. It will be understood, however, that many variations and modifications may be made while remaining within the spirit and scope of the disclosure.