Apparatus and method for performing nerve blockade by local cooling to room temperature

Abstract

Provided herein are methods for blocking nerves, for example, for treating obesity, heart failure, cardiovascular disease, muscle spasms, chronic pain, or urinary retention in postoperative patients. The methods can include first heating the nerve to a temperature above physiological temperature (e.g., human body temperature of 37°C), for example, in the range of 43°C to 54°C, for a period of time, which results in reversible nerve blockade, which is the opposite of nerve damage. Second, reversible nerve blockade can be produced by cooling the nerve to a temperature below physiological temperature, where reversible nerve blockade can be achieved, for example, in the range of 15°C to 30°C.

Description

[0001] This application is a divisional application of application number 201680069689.0 filed on December 1, 2016, and the invention name is “Device and method for performing nerve blocking by local cooling to room temperature”.

[0002] Reference to related applications

[0003] This application claims the full benefit of U.S. Provisional Patent Application No. 62 / 262,445, filed December 3, 2015, which is incorporated herein by reference in its entirety.

[0004] Statement on Federal Funds

[0005] This invention was made with government support under Grant No. DK102427, with associated expenses paid by the National Institutes of Health. The federal government has certain rights in this invention. Technical Background

[0006] Myelinated nerves in mammals can be blocked by local cooling to below 15°C or heating to above 46°C. However, extreme cold or hot temperatures require a lot of energy to generate, and prolonged application (Jia J et al. (1999)) may also cause damage to nerve tissue. Cryogenic nerve damage may be aggravated by intermittent cooling. Muscle & Nerve 22, 1644-1652; Vujaskovic Z et al. (1994). The effects of hyperthermia during surgery on peripheral nerves include neuropathological and electrophysiological studies (Int J Hyperthermia 10, 41-49). Therefore, the current clinical application of cold / heat blockade for the treatment of chronic diseases remains difficult to resolve. If thermal blockade of nerve conduction were practically achievable, we would have broad clinical applications for a variety of chronic diseases, for example, blocking the vagus nerve in the abdomen to treat obesity, blocking sensory axons in the heel to treat chronic pain at peripheral nerve points, blocking sympathetic nerves to treat heart failure, and blocking the pudendal nerve to prevent the effects of spinal cord injury.

[0007] At present, what is commonly used in clinical applications is local anesthetics to carry out nerve conduction blocking. The injection of local anesthetics is mainly used as a first aid method of nerve blocking, and this is because it is difficult to deliver anesthetics in the application of chronic diseases. Recently, high-frequency (kHz) electrical stimulation generated by an implantable stimulator has been used clinically to block the vagus nerve, thereby treating obesity or chronic pain of the spinal cord roots. High frequency may also be suggested to restore bladder function by blocking the pudendal nerve after spinal cord injury. However, high-frequency stimulation always produces a nerve initial burn before it blocks nerve conduction. For most clinical applications, nerve initial burn is a big problem, for example, suppressing pain, this is because before nerve blockage occurs, initial pain is always sensed. Therefore, people need to produce a new method of reversibly blocking nerves. Summary of the Invention

[0008] As described herein, it has been discovered that mammalian myelinated nerves can be blocked by local cooling to room temperature (15°C to 30°C) following a brief, reversible thermal blockade. This thermal blockade is safe and provides a platform for developing implantable nerve blockade devices for treating a variety of conditions, such as obesity, pain, heart failure, and bladder dysfunction following spinal cord injury. Furthermore, thermal blockade, as described herein, provides a reversible nerve blockade without any initial response, offering advantages over electrical stimulation. Thermoelectric Peltier technology currently used (Aronov D et al. (2011). Analysis of dynamic force changes in brain circuits by temperature: Design and implementation of micro-thermoelectric devices J Neurosci Methods 197:32-47; Rothman S, et al. (2003). Local cooling: A therapy for intractable neocortical epilepsy. Epilepsy Currents 3:153-156) also makes it possible to design and develop implantable devices to form local temperature changes within the range of 15°C and 50°C. Therefore, the heat blocking technology described in this article has a variety of clinical applications, such as obesity, pain, heart failure and bladder dysfunction after spinal cord injury.

[0009] Provided herein is a method for reversibly blocking a nerve, comprising heating the nerve to a temperature greater than 37°C but less than a temperature and for a period of time that results in irreversible nerve blockade, and cooling the nerve to a temperature less than 37°C but greater than a temperature that results in irreversible nerve blockade, thereby producing reversible nerve blockade. In certain aspects, the nerve is heated to a temperature within a range of 42°C to 54°C. In certain aspects, the nerve is cooled to a temperature within a range of 15°C to 30°C.

[0010] In certain aspects, the method may further include, prior to heating the nerve, implanting a temperature controller in the nerve for heating or cooling the nerve, the temperature controller comprising a heating element, a cooling element, and a temperature sensor, wherein the temperature controller is wirelessly connected to a controller, the controller being adapted to control heating by the heating element, cooling by the cooling element, and monitoring the temperature of the nerve via the temperature sensor. In certain aspects, the heating element is a resistor, a thin film semiconductor, a Peltier heater, a microwave radiator, or an infrared heater, the cooling element is a coolant tube, a Peltier cooler, and / or the temperature sensor is a thermocouple or a thermoelectric regulator.

[0011] Likewise, the present invention also provides a method for treating excessive obesity in a patient, which is achieved by blocking the abdominal vagus nerve using the method described above.

[0012] Likewise, provided herein is a method for treating heart failure in a patient by blocking the patient's sympathetic nerves using the method described above, wherein the sympathetic nerves may be any one or more greater splanchnic nerves, lesser splanchnic nerves, or sympathetic trunks.

[0013] Further provided herein is a method for treating urinary incontinence in a patient by blocking the patient's pudendal nerve using the method described above.

[0014] Provided herein is a method for treating muscle spasms in a patient by blocking the nerves that control muscle activity in the patient using the method described above.

[0015] Likewise, provided herein is a method for treating cardiovascular disease in a patient by blocking the patient's vagus nerve using the method described above.

[0016] In addition, provided herein is a system for reversibly blocking nerves, the system comprising an implantable device and an external controller. The internal device comprises a temperature controller comprising a processor, a thermoelectric device that communicates with the temperature controller and is configured to be placed near the nerve, a temperature sensor that communicates with the temperature controller and is configured to be placed near the nerve, and a power source that provides power to the temperature controller and the thermoelectric device. The temperature controller also comprises a memory storing programming instructions that, when executed by the processor, can cause the processor to control the thermoelectric device to heat the nerve to a temperature above 37°C and below the temperature and time period for forming irreversible nerve blockade; and to cool the nerve to a temperature below 37°C and above the temperature for forming irreversible nerve blockade, thereby forming a reversible nerve blockade. The external controller of the system communicates with the temperature controller.

[0017] In some aspects, when executed by a processor, the programming instructions may further enable the processor to receive temperature information from a temperature sensor and adjust control of the thermoelectric device based on the temperature information.

[0018] In some ways, a temperature sensor is a thermistor. In other ways, a temperature sensor is a thermocouple.

[0019] In some aspects, a thermoelectric device includes a heating element and a cooling element. In some aspects, the heating element is a resistor, a thin-film semiconductor, a Peltier heater, a microwave radiator, or an infrared heater. In some aspects, the cooling element is a coolant tube or a Peltier cooler.

[0020] Further provided herein is the use of an implantable device suitable for reversibly blocking nerves. The implantable device includes a temperature controller having a processor; a thermoelectric device that communicates with the temperature controller and is configured to be placed near a nerve; a temperature sensor that communicates with the temperature controller and is configured to be placed near a nerve; and a power source that provides power to the temperature controller and the thermoelectric device. The device is used to provide a method for reversibly blocking nerves by heating the nerve to a temperature greater than 37°C and below a temperature and time period that results in irreversible nerve blockade, and then cooling the nerve to a temperature less than 37°C and above a temperature that results in irreversible nerve blockade, thereby forming a reversible nerve blockade. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Attachment Figure 1 Shown is a block diagram of an apparatus for localized heating and / or cooling of nerves according to one aspect of the present invention.

[0022] Attachment Figure 2 Shown is a schematic diagram of an embodiment of a configuration for cooling nerves to achieve blockade according to one aspect of the present invention. A urine catheter is inserted into the urethra through a small incision closest to the urethra, thereby achieving infusion and pressure recording inside the urethra. The pudendal nerves are bilaterally resected and immersed in a warm saline solution. The nerve passes through a copper tube coil. The temperature inside the coil can be changed by flowing water of different temperatures through it. A thermocouple is placed in the middle of the copper coil to record the temperature. The nerve is electrically stimulated by a hook electrode closest to the coil, thereby stimulating contraction of the external urethral sphincter (EUS) and causing an increase in pressure inside the urethra.

[0023] Attachment Figure 3 Shown are cold blockade of the urethral pressure response induced by pudendal nerve stimulation (PNS). In Figure A, the urethral pressure trace shows that complete nerve blockade is achieved at 5°C. The square wave below the trace indicates the duration of each short sequence (5 seconds) of PNS (50 Hz, 0.2 ms, 3.2 V). The black bars below the trace indicate the duration required for cooling by the copper coil. In Figure B, the average urethral pressure response to different temperatures (N = 20 nerves). The average pressure of the last response in each cooling cycle is normalized to the response value just before cooling began. In Figure C, cold blockade is fully reversible even after a long period of complete blockade (5 minutes).

[0024] Attachment Figure 4 Shown are thermal blockade of the urethral pressure response induced by pudendal nerve stimulation (PNS). In Figure A, the urethral pressure trace shows that complete nerve blockade is achieved at 52°C. The square wave below the trace indicates the duration of each short sequence (5 seconds) of PNS (50 Hz, 0.2 ms, 1.0 V). The black column below the trace indicates the duration required for heating by the copper coil. In Figure B, the average urethral pressure response to different temperatures (N = 14 nerves). The average pressure of the last response in each heating cycle was normalized to the response value just before heating began.

[0025] Attachment Figure 5 The reversibility of thermal blockade is shown as a function of heating time. In Figure A, nerve blockade is reversible after 1 minute of heating at 52°C, but irreversible after 3 minutes. Figure B, Results (N = 12 nerves). Heating temperature = 50-54°C. * indicates significant difference (p < 0.0001, paired t-test).

[0026] Attachment Figure 6Shown is a reversible heat block that raises the temperature to produce a cold block. In Figure A, in the same nerve, a temperature of 5°C was required to complete the cold block before heating. However, after a brief reversible heat block at 52°C, a complete cold block occurred at 20°C. In Figure B, the results (N=12 nerves) show that the cold block response curve shifts to higher temperatures at approximately 10°C. Reversible heat block at 50-54°C requires 0.5-1.5 minutes. *Indicates a significant (p<0.05) difference (two-way ANOVA) between before and after each heating.

[0027] Attachment Figure 7 Shown is the time-dependent recovery of the elevated temperature used for cooling block following a brief reversible heat block. In Panel A, after a brief heat block at 54°C, the onset of cooling block at 20°C gradually changes over time and ultimately has no effect on blocking nerve conduction. However, at 15°C, cooling block is achievable and persists for a longer period compared to 20°C. The second trace follows the first trace from the same animal. In Panel B, the duration of cooling block varies for each cold block temperature. *Indicates a significant difference (p < 0.05) compared to the 10°C data (one-way ANOVA). (N = 7 nerves). In Panel C, the temperature profile of cooling block after a brief reversible heat block shows complete recovery over time. Reversible cooling block lasted for 0.5–1.5 minutes within the temperature range of 50–54°C (N = 9 nerves).

[0028] Attachment Figure 8A and 8B Shown is the gradual increase in cold blocking temperature achieved by non-blocking heating. Figure 8A It was shown that when the nerve was heated at non-blocking temperature conditions (46-48°C) for 15 minutes, the threshold temperature for complete cold block increased from 5°C to 15°C. Figure 8B Shown are results (N=7 nerves) indicating that the threshold temperature for complete cold blockade increased with increasing temperature during the heating cycle. *Indicates an increase that is significantly different (p<0.05) from the blockade threshold temperature before heating (one-way ANOVA). DETAILED DESCRIPTION

[0029] Unless otherwise expressly stated, the various numerical ranges determined in this application are expressed as approximate values, and even the maximum and minimum values ​​within the specified range are preceded by the modifier "about". Therefore, values ​​slightly above or slightly below the specified range can essentially represent the same result value within the range. Similarly, unless otherwise expressly stated, the ranges disclosed in the present invention are directed to a continuous range that includes any value that varies between the maximum and minimum values. For the various definitions herein, they limit the word forms, cognates, and various grammatically different expressions of words or phrases.

[0030] The drawings corresponding to this application are representative in nature and should not be construed as implying any particular range or limitation unless expressly described. For the purpose of clarity in the following description, the terms "upper," "lower," "left," "right," "vertical," "horizontal," "top," "bottom," "side," "longitudinal," and their derivatives are used to indicate directions in the accompanying drawings. However, it is understood that the present invention is susceptible to various variations and step sequences unless expressly defined. Therefore, the specific dimensions and other physical characteristics of the embodiments disclosed herein should not be construed as limiting.

[0031] As used herein, the term "comprising" and similar terms are open ended. The term "consisting essentially of" limits the scope of the specific materials or steps in the claim and does not affect the basic and novel characteristics of the claimed invention. The term "comprising" is intended to exclude any elements, steps, or components not appearing in the claim.

[0032] As used herein, the terms "a" and "an" refer to one or more.

[0033] As used herein, the term "patient" can be any mammal, including humans, and "human patient" refers to any human.

[0034] As used herein, the terms "communication" and "communication" refer to the receipt, transmission, or transfer of one or more signals, messages, instructions, or other types of data. Communication between one unit or device and another unit or device refers to the ability of one unit or device to receive data and / or transmit data to the other unit or device. Communication can occur via direct or indirect links and can be wired and / or wireless in nature. Furthermore, two units or devices can communicate with each other, and even the data being transmitted can be modified, processed, tracked, and so on. Such communication can be between a first and a second unit or device. For example, a first unit can communicate with a second unit even if the first unit passively receives data and does not actively transmit data to the second unit. Alternatively, a first unit can communicate with a second unit if an intermediate unit processes data from the first unit and transmits the processed data to the second unit. It will be appreciated that numerous other arrangements are possible. Any known telecommunication protocol and / or logic algorithm may be used, for example, TCP / IP (including HTTP and other protocols), WLAN (including 802.11a / b / g / n and other radio frequency based protocols and methods), analog transmission, Global System for Mobile Communications (GSM), 3G / 4G / LTE, Bluetooth, ZigBee, EnOcean, TransferJet, Wireless USB, and similar protocols known to any person of ordinary skill in the art.

[0035] A method of blocking nerves for treating any disease in a patient, such as a human patient, including but not limited to obesity, heart failure, cardiovascular disease, chronic pain, muscle spasms, and urinary retention. The method comprises heating the patient's nerves to a temperature above body temperature (normal body temperature for the patient, such as 37°C) for a period and time that is less than the temperature and period that would cause irreversible nerve blockade in the patient. Heating can cause reversible nerve blockade or no nerve blockade. "Nerve blockade" refers to the loss or substantial loss of the ability of a nerve to stimulate action potential, conduct nerve signals, and / or release neurotransmitters. By "irreversible" effect, in the context of a nerve block, it is meant that the blockade of the nerve is well-retained beyond the blocking therapy (e.g., nerve injury), for example, for at least a day or a week after treatment, and by "reversible" effect, it is meant that the nerve can fully recover or substantially recover from the blocked state, either immediately or within a short period of time after the blockade period, for example, within a second, a minute, an hour, or a day, and increments therefrom.

[0036] The method may further include cooling the nerve to a temperature below body temperature (i.e., below 37°C in humans) and above a temperature at which irreversible nerve blockade is achieved, e.g., 15°C. The combined use of heating and cooling the nerve can result in reversible nerve blockade, thereby alleviating one or more symptoms of the health condition being treated by the nerve blockade. The heating temperature ranges from 42°C to 54°C and is continued for a period of time that does not result in irreversible nerve blockade in the nerve. For example, when the nerve is heated to 50°C and 54°C, the heating period is less than 1 minute. Heating at a lower temperature, e.g., from 42°C to 48°C, or from 46°C to 48°C, for a short period of time, e.g., 60 minutes, or less, 30 minutes, or less, e.g., 15 minutes, generally does not result in irreversible nerve blockade (e.g., nerve damage).

[0037] According to one aspect, a method for reversible nerve blockade is provided. The method comprises heating a nerve to a temperature greater than 37°C and less than a temperature and time period that would result in irreversible nerve blockade; and cooling the nerve to a temperature less than 37°C and greater than a temperature that would result in irreversible nerve blockade, thereby producing reversible nerve blockade. In one aspect, during the heating step, the nerve is heated to a temperature in the range of 42°C to 54°C, to a temperature in the range of 50°C to 54°C for a duration of less than 1 minute, to a temperature in the range of 43°C to 48°C for a duration of 60 minutes or less, or to a temperature and time period that does not result in nerve blockade (substantially or completely inactivating the nerve). In another aspect, during the cooling step, the nerve is cooled to a temperature in the range of 15°C to 30°C, for example, for a duration of 10 to 40 minutes. The duration of blockade can be extended by heating and cooling the nerve more than once or by repeating the steps. However, from another aspect, the method further includes implanting a device in the nerve before the heating step to heat or cool the nerve, the device including a temperature controller, and the thermoelectric device including a heating element, a cooling element and a temperature sensor.

[0038] According to one aspect, a method for treating obesity in a patient may be provided, comprising blocking the patient's abdominal vagus nerve by a nerve blockade, for example, as described above.

[0039] According to one aspect, provided herein is a method for treating chronic pain in a patient, comprising blocking a nerve in the patient by a nerve blockade, for example, as described above.

[0040] According to another aspect, provided herein is a method for treating heart failure in a patient, comprising blocking the patient's sympathetic nerves, such as one or more of the larger splanchnic nerves, smaller splanchnic nerves, or sympathetic trunks, for example, as described above, by a nerve blockade.

[0041] According to one aspect, provided herein is a method for treating cardiovascular disease in a patient, comprising blocking the patient's vagus nerve via a nerve blockade, for example, as described above.

[0042] According to another aspect, a method for treating urinary retention in a patient is also provided, comprising blocking the patient's pudendal nerve by a nerve block, for example, as described above.

[0043] According to one aspect, a method for treating muscle spasms in a patient may be provided, comprising blocking nerves of the patient's innervated muscles by a nerve blockade, for example, as described above.

[0044] Likewise, provided herein is a device and system that may be used to block a nerve by heating the nerve to a temperature greater than 37°C and then cooling the nerve to a temperature in the range of 15°C to 30°C, for example, as discussed above. The device and system include an implantable component and an external component. Figure 1 The device and system may include a temperature controller (10) in communication with a thermoelectric device (20) and a temperature sensor (30), wherein the thermoelectric device is adapted to transfer heat and cool nerves. The device and system receive power from an implantable power source (40) and is capable of receiving instructions from an external controller (50).

[0045] The temperature controller (10) is in wireless communication with an external controller (50). The external controller (50) may have a processor, memory, and a display, such as an LCD, LED, or OLED display, and an input device, such as a microphone, keyboard, mouse, touch screen, touchpad, or trackpad, and the like, which may be used to process data input into the external controller (50). The external controller (50) is described as being capable of sending and receiving wirelessly transmitted signals to the temperature controller (10), thereby allowing one or more parameters of the temperature controller (10), the thermoelectric device (20), the temperature sensor (30), and / or the power source (40) to be monitored, including but not limited to characteristics of the output signal (e.g., voltage, frequency, amplitude, etc. from the power source, transmitted to the temperature controller and the thermoelectric device; the temperature of the thermoelectric device being heated, the temperature measured by the temperature sensor, and / or any function / state of the implanted component).

[0046] The activities of the temperature controller (10) and the external controller (50) are controlled by the processor, and the software / firmware and hardware installed in the temperature controller (10) and the external controller (50) may be used to perform the described methods, and for example, and not limitation, an optional display GUI (graphical user interface) is provided in conjunction with the external controller (50) to facilitate the use of the device and system. Anyone skilled in the art of electronics can use the system using readily available electronic components and common programming techniques. Specialized chips, chipsets, etc. can also be designed and manufactured to implement the devices discussed herein.

[0047] In one aspect, the external controller (50) is a dedicated device that is specifically designed to perform a task, or, in another embodiment, the external controller (50) is a non-dedicated device, such as a smart phone, smart watch, or desktop computer. As described above, communication between the external controller (50) and the temperature controller (10) is achieved wirelessly. Such communication can also be achieved through any suitable wireless protocol, such as virtual domain communication, TCP / IP (including HTTP and other protocols), WLAN (including 802.11a / b / g / n and other radio frequency based protocols and methods), analog transmission, Global System for Mobile Communications (GSM), 3G / 4G / LTE, Bluetooth, ZigBee, EnOcean, TransferJet, Wireless USB, and any other protocol known to those of ordinary skill in the art.

[0048] One potential difficulty with wireless devices is identity. The external controller (50) can only control one temperature controller (10) to prevent accidental stimulation of an unconscious subject, or even intentional stimulation. In this simplest form, the transmission range of the device may also be limited to prevent transmission beyond a few feet, thereby limiting the possibility of unintentional stimulation (interference). Similarly, multiple identity recognition devices may be used to prevent interference. In one aspect, different transmission wavelengths are used for different devices, thereby reducing the possibility of interference. In another aspect, the temperature controller (10) is programmed to respond only to predefined signals contained in the transmission, so that the temperature controller (10) and the external controller (50) must first, and / or periodically, "handshake" to achieve communication. In another aspect, the temperature controller (10) and / or the external controller (50) transmit an encrypted signal that can only be interpreted by a key stored in the other temperature controller (10) and / or the external controller (50). However, in another aspect, RFID tag technology is used to ensure that the temperature controller and the external controller are matched. A combination of these proximity and / or identity recognition considerations can be used to prevent interfering crosstalk.Other useful techniques for ensuring security and identity are interconnected or may also be available and equally applicable.

[0049] Further reference Figure 1 The temperature controller (10) and / or the external controller (50) may include a memory having programmed instructions stored therein that, when executed by a processor (which may be contained in the temperature controller (10), the external controller (50), or both), may cause the thermoelectric device to heat or cool the nerve according to the methods described herein. The programmed instructions may be considered feedback from the temperature sensor that may relay the temperature to the heated or cooled nerve, and based on the feedback, the output of the temperature controller to the thermoelectric device may be adjusted. In one aspect, the programmed instructions are transmitted from the external controller (50) and stored in the memory of the temperature controller (10) so that the patient does not need to be in the vicinity of the external controller (50), for example, when the external controller (50) is a desktop computer or a laptop computer, in order to enable the device and system to perform the methods described herein.

[0050] Refer again to the attached Figure 1, the devices and systems may include a thermoelectric device (20) that can generate heat or cooling to block the target nerve. Suitable thermoelectric devices include, but are not limited to, resistors, thin film semiconductors, Peltier heaters and refrigerators, and coolers, microwave radiators, infrared heaters, and coolant pipes. The devices are commercially available (for example, Micropelt heat generators and Peltier coolers are commercially available from Micropelt GmbH of Freiburg, Germany). From several aspects of the present invention, the thermoelectric device is two or more thermoelectric devices, at least one of which is suitable for heating and at least another one is suitable for cooling. From several aspects of the present invention, the thermoelectric device (20) is one or more Peltier devices. For example, the device is described in the works of Imoto et al. (Use of a Peltier chip with a newly devised local brain-cooling system for neocortical seizures in the rat. J Neurosurg 104:150–156, 2006) and Long and Fee (Using temperature to analyse temporal dynamics in the songbird motor pathway. Nature 456:189–194, 2008). These devices convert voltage volts into temperature differences. Therefore, by applying different voltages to the thermoelectric device (20), heating or cooling can be generated, thereby affecting the target nerve accordingly. The thermoelectric device (20) communicates with the temperature controller (10) and receives power provided by the implantable power source (40), thereby generating a temperature difference to heat or cool the target nerve.

[0051] Refer again to the attached Figure 1The apparatus and system may include a temperature sensor (30) adapted to monitor the temperature of the target nerve. Suitable temperature sensors (30) include thermocouples and thermistors. A thermocouple is a pair of conductors that can be electrically connected at different temperatures, thereby producing a temperature-dependent voltage and temperature measurement. A thermistor is a resistor whose impedance changes with temperature, thereby providing a temperature measurement. A useful temperature sensor (30) in the apparatus and system may be a negative temperature coefficient thermistor (NTC), wherein the impedance decreases with increasing temperature. Such thermistors are commercially available, for example, from Vishay Intertechnology, Inc. (Shelton, CT) or TE Technologies, Inc. (Traverse City, MI). The temperature sensor (30) communicates with the temperature controller (10) and may provide feedback for adjusting the amount of energy applied to the thermoelectric device.

[0052] Further reference Figure 1 , the device and system may also include an implantable power source (40). The implantable power source (40) can provide power to the temperature controller (10) and the thermoelectric device (20), thereby heating / cooling the target nerve. The implantable power source (40) can be a battery, for example, a battery used in the field of pacemakers, such as a lithium-based battery or a zinc-based battery. The implantable power source (40) can be wirelessly rechargeable, for example, but not limited to, by an external wireless charging device (60). The external wireless charging device can charge the implantable power source (40), for example, but not limited to, inductive charging. The implantable power source (40) can also be recharged by a photovoltaic array.

[0053] Example

[0054] In this study, we demonstrated that the temperature of a cold block formed in a myelinated nerve of a mammal can be shifted from 5-15°C to room temperature (15-30°C) after a brief, reversible heat block. This heat block phenomenon raises numerous scientific questions regarding the effects of temperature on nerve conduction and blockade. More importantly, it offers the possibility of developing an implantable blockade device to treat a wide range of chronic diseases.

[0055] Currently, local anesthetics are commonly used in clinical practice to block nerve conduction. Local anesthetic infusion is primarily used as an emergency method for nerve blockade due to the difficulty in delivering anesthetics for chronic conditions. Recently, high-frequency (kHz) electrical stimulation, generated by implantable stimulators, has been used clinically to block the vagus nerve, thereby treating obesity or chronic spinal cord pain. High frequencies have also been proposed for restoring bladder function after spinal cord injury by blocking the pudendal nerve. However, high-frequency stimulation always produces an initial nerve burn before it blocks nerve conduction. This initial burn is a significant challenge for most clinical applications, such as pain suppression, because initial pain is always felt before nerve blockade occurs. The thermal blocking method disclosed herein provides a reversible nerve blockade without any initial reaction. Furthermore, current thermoelectric Peltier technology has made it possible to design and develop an implantable device that can vary the local temperature between 15°C and 50°C. Therefore, the thermal blocking technology described herein has substantial advantages for a wide range of clinical applications and can be used to treat chronic conditions such as obesity, pain, heart failure, and bladder dysfunction following spinal cord injury.

[0056] This study aimed to understand the impact of thermal effects on nerve conduction and to develop novel methods for creating a reversible thermal block in axonal conduction in myelinated mammalian nerves. Thirteen cats were treated with α-chloralose anesthetic. Conductive block of the pudendal nerve (N = 20 nerves) was achieved by cooling (5-30°C) or heating (42-54°C) a short segment of the nerve (9 mm). This process was monitored by muscle contraction of the striated urethral muscle and by an increase in urethral pressure induced by intermittent (5-second onset and 20-second end) electrical stimulation (50 Hz, 0.2 ms) to the nerve. Cold block was achieved within a temperature range of 5-15°C, while heat block was achieved within a temperature range of 50-54°C. A complete cold block was fully reversible after 10 minutes, but a complete heat block was reversible only if the heating period lasted less than 1.3 ± 0.1 minutes. A brief (<1 minute) reversible complete heat block is a 15-minute non-blocking mild heating at 50-54°C or 46-48°C, which significantly raises the temperature of the cold block to room temperature, i.e., 15-30°C. The effect of heating on the cold block can be completely reversed in about 40 minutes. This study has discovered a new method that can be used to block myelinated nerves in mammals at room temperature, providing the possibility of developing an implantable device that can be used to block axonal conduction and treat a large number of chronic diseases, such as obesity, pain, heart failure, and bladder dysfunction after spinal cord injury. The effect of heating on cold block is quite beneficial because it can raise a large number of basic scientific questions, which helps to show certain functions of axonal conduction under cold or heat block conditions.

[0057] Materials and Methods

[0058] Experimental plan

[0059] Thirteen cats (6 females and 7 males, 3.0-4.2 kg, Liberty Research Inc., Waverly, NY, USA) were used in this study. During surgery, the animals were anesthetized with isoflurane (2-5% in oxygen) and maintained with α-chloralose anesthesia (65 mg / kg iv supplemented as needed) during data collection. A pulse oximeter (9847V, NONIN Medical, Inc., Plymouth, MN, USA) was attached to the tongue to monitor heart rate and blood oxygen levels. A tracheotomy was performed and a flexible tube was inserted to maintain airway patency. A catheter was inserted into the right carotid artery to maintain systemic blood pressure. An additional catheter was inserted into the left cephalic vein for saline infusion and anesthetic administration. The ureters were isolated, dissected, and externally drained by laparotomy. The catheter was inserted into the urethra through a small incision located proximal to the urethra. The ureter was then catheterized via a T-connector (attached). Figure 2 ) catheter is connected to a pump and pressure transducer, which allows for slow (1 ml / min) instillation of the urethra and measurement of the increase in urethral pressure, which is caused by the neurogenic contraction of the striated muscle of the external urethral sphincter (EUS). At the end of the procedure, all incisions are closed with sutures.

[0060] The pudendal nerve, which has motor axons innervated by EUS, was exposed through a 3-4 cm incision between the caudal and coxal notches and the incisions were closed bilaterally with sutures distal to the distal end (see Appendix). Figure 2 The left or right pudendal nerve was studied separately. One of the pudendal nerves passed through a copper tube (attached Figure 2 ) in a small (9 mm long) coil (with an inner diameter of 2 mm). One end of the copper tube (with an outer diameter of 1.57 mm and an inner diameter of 0.36 mm) is connected to a syringe via plastic tubing, allowing manual injection of aqueous solutions at different temperatures to locally cool or heat the nerve segment within the coil. The temperature within the coil is monitored by a thermometer with the tip of a thermocouple inserted into the center of the coil (see attached). Figure 2 The target temperature was maintained within ±1°C, which was manually adjusted by the injection frequency. A bipolar hook electrode was placed on the nerve closest to the copper coil (see attached). Figure 2) to test whether temperature changes within the coil could limit the urethral contraction response induced by repetitive short sequences of stimulation (50 Hz, 0.2 ms, 5 seconds on and 20 seconds off). The stimulation intensity was sufficient to produce greater than 40 cmH2O, which increased the urethral pressure used during the experiment. The nerve, coil, and electrodes were all immersed in a pool of warm saline solution (35-37°C) created by retracting a flap using sutures.

[0061] Experimental Terms

[0062] In the first group of 9 cats, the nerve was first briefly cooled (50-60 second cycles), followed by temperatures set to 30, 25, 20, 15, 10, and 5°C, with a temperature change of -5°C per step. The nerve was then briefly heated (50-60 second cycles), followed by temperatures set to 42, 44, 46, 48, 50, 52, and 54°C, with a temperature change of +2°C per step. During these brief cooling / heating periods, EUS was given sufficient time (50-150 seconds) for the contraction response to fully recover. Once a reversible complete heat block was achieved (usually at 50-54°C), the temperature was not increased further. Instead, the brief cooling protocol was repeated so that changes in the cold block temperature could be detected; and, subsequently, the nerve was monitored for changes by repeating (50-150 intervals) and briefly cooling (50-60 seconds) the cycle until the cold block temperature returned to the control level. At the end of this set of experiments, different heating cycles (1-3 min) were tested at the reversible blocking temperature (50-54°C) to confirm that the heating cycles were suitable for irreversible blocking.

[0063] In the second group of four cats, the cooling protocol was repeated as described above to initially determine the temperature of the cold block. The nerve was then heated three times for 5 minutes, raising the temperature to 46°C or 48°C, which is just below the temperature required for the heat block (50-54°C). After each heating, the cold block temperature was measured by repeating the cooling protocol.

[0064] Data Analysis

[0065] To determine the possible effects of temperature on neural transmission, the mean amplitude of the minimal urethral contraction induced by a short train of pudendal nerve stimulation during each brief cooling / warming session was normalized to the mean amplitude of the urethral contraction immediately before cooling / warming. These results, obtained from nerves of different animals under the same experimental conditions, were averaged and expressed as mean ± standard error. Statistical significance (p < 0.05) was determined by t-test or analysis of variance followed by Dunnett (one-way) or Bonferroni (two-way) multiple comparisons.

[0066] in conclusion

[0067] Conductive blockade of the pudendal nerve using local cooling or heating

[0068] Pudendal nerve stimulation (50 Hz, 0.2 ms, 1-10 V) in short sequences (5 s on and 20 s off) resulted in brief EUS contractions that produced consistent urethral pressure increases with amplitudes greater than 40 cmH2O (see Appendix). Figure 3 , Figure A and attached Figure 4 , Figure A). Manually injected cold water (0-10°C) can pass through the copper coil quickly (5-10 seconds) and reduce the temperature inside the coil to 5-30°C as recorded by the thermometer, which can be maintained for 50-60 seconds (see Figure A). Figure 3 Once the infusion stops, the temperature quickly (5-10 seconds) returns to the saline bath temperature of 35-37°C. Similarly, brief heating of the nerve (see Figure 1) Figure 4 , Figure A) can be obtained by manually injecting hot water (50-60°C) into the copper coil.

[0069] Under the effect of local cooling, as the temperature is gradually lowered, partial blockade of pudendal nerve conduction begins to appear at 15°C (see Appendix Figure 3 , Figures A and B). Of the 20 nerves tested, complete blockade was observed in 2 nerves at 15°C, in 6 nerves at 10°C, and in 8 nerves at 5°C. Figure 3 Figure B shows the average results. Once the low temperature returns to the temperature of the warm salt solution pool (see Figure 3 , Figure A), the urethral contractile response was completely restored, indicating that brief cold blockade (50-60 seconds) is fully reversible. Longer-term (4.5-10 minutes) complete cold blockade tested in the three nerves showed similar reversibility (Supplementary Figure 5). Figure 3 , Figure C).

[0070] In the case of local heating, the temperature gradually increases and partial blockage of nerve conduction occurs at 50°C (see Appendix Figure 4 , Figures A and B). Of the 14 tested nerves, complete blockade occurred in 2 nerves at 50°C, in 6 nerves at 52°C, and in 6 nerves at 54°C. Figure 4 , Graph B shows the average results. Although short-term (<1 minute) thermal blocking is fully reversible (see Appendix Figure 4 , Figure A and attached Figure 5 , Figure A), longer periods (3 minutes) can result in partial irreversible blockage or complete loss of urethral contraction (see Figure A). Figure 5 , Figure A). On average, reversible thermal blocking is achieved at a heating cycle of 1.3 ± 0.1 min, while irreversible thermal blocking (partial or complete) occurs at a heating cycle of 2.7 ± 0.2 min (see Appendix Figure 5 , Figure B) appears under the conditions of irreversible thermal blocking (attached Figure 4 , Panel A) Twelve nerves were monitored for 5-45 minutes (mean 17 ± 4 minutes) without recovery of urethral contraction.

[0071] The blocking temperature for local heating to cooling is 15-30℃

[0072] A reversible complete heat block raises the temperature to allow for a cold block. A partial cold block typically occurs at 15°C before any heating, while a complete cold block occurs at 5°C (approximately Figure 6 , Figure A). However, after a short period (50 seconds), a reversible complete thermal blockade occurs in the same nerve at 52°C, with partial blockade starting at 30°C and complete blockade occurring at 20°C (Figure 4A). Figure 6 , Figure A). From the average results, it can be seen that after a short period of time (0.5-1.5 minutes), the reversible complete thermal blockade occurs at 50-54°C, and the response curve of the cold blockade shifts to a temperature about 10°C higher than the control curve (see Appendix Figure 6 , Figure B). Under elevated temperature conditions, the cold block period was defined as the time when the mean pressure of the minimum urethral contraction during the cold block was maintained at <25% of the control pressure (Figure 5A). Figure 7 , Figure A). Compared with the cold blockade under high temperature conditions (20°C), the cold blockade under low temperature conditions (15°C) lasted for a longer period of time (see Figure A). Figure 7 , Figure A). Figure 7 The average cold blocking period under different elevated temperature conditions is shown in Figure B. The elevated temperature for cold blocking is fully recovered in about 40 minutes (see Appendix). Figure 7 , Figure B).

[0073] The temperature applied to the cold block may also be elevated to 46-48°C due to non-blocking heating. A 5°C low temperature is usually required to achieve complete nerve blockade before any heating (see first trace in Figure 8). However, repeated (3 times) heating to 46-48°C for 5 minutes each in the same nerve had no effect on the nerve-induced urethral pressure response. Increasing the temperature applied to the cold blockade stepwise to 15°C (see Figure 8) did not affect the nerve-induced urethral pressure response. Figure 8A ). Figure 8B Shown are the average results from 7 tested nerves.

[0074] Discussion

[0075] This study in cats showed that a myelinated nerve (pudendal nerve) in mammals could be cooled locally to below 15°C for 1-10 minutes (see Appendix). Figure 3 ), or by brief (<1 minute) local heating to above 50°C (with Figure 4 However, reversible thermal blocking (attached) is achieved at 50-54°C. Figure 6 ) or repeated non-blocking heating at 46-48°C (with Figure 8A and attached Figure 8B ) After that, the cold blocking temperature can be raised to room temperature 15-30 ° C. The elevated temperature for cold blocking will fully recover over time (see Figure 7 ). The interplay between heating and cooling in nerve conduction can be observed strikingly.

[0076] It is well known that external cooling (<15°C) or heating (>46°C) can block conduction in myelinated mammalian nerves. However, prolonged application of these extremely low or high temperatures can cause nerve damage. In cats, irreversible nerve block was achieved by locally heating the tibial nerve to 46.5°C for 10 minutes or to 51°C for 10 minutes. Although no conduction block was observed in cats' tibial nerves at temperatures below 46°C, local heating of the sciatic nerve to 45°C for 60 minutes in dogs has been reported to increase nerve conduction velocity and result in hindlimb sluggishness lasting 3–11 months. Nerve damage has also been reported in rodents when the sciatic nerve was cooled to 5°C for 120 minutes. Therefore, it is clear that these extremely low or high temperatures are not safe for prolonged application. However, these results demonstrate that blockade of nerve conduction can be achieved using a completely different approach, namely, by locally altering the temperature of the nerve. All that is required is a brief (<1 minute) fully reversible thermal block at 50-54°C (approximately Figure 6 ) or at 46-48°C for about 15 minutes (see Figure 8A and attached Figure 8B ), followed by gentle cooling to room temperature (15-30°C), thereby blocking nerve conduction for 5-40 minutes (see Figure 7 Room temperature is likely safe for myelinated mammalian nerves. The heating time periods used in this experiment are also likely safe because they produce complete and reversible nerve blockade (see Appendix). Figure 6 ) or has no effect on nerve conduction (Appendix Figure 8A and attached Figure 8B ). In addition, these heating time periods are only 10% of the time period required to achieve irreversible nerve blockade. However, the safety of repeated application of short periods of heating still needs to be determined.

[0077] The cumulative effects of repeated heating above the threshold for cold blocking are highly dependent on the frequency of application. For clinical applications requiring high frequency of application, the effects of non-blocking heating at 46–48°C may accumulate and reach unsafe levels. Therefore, it is possible that temperatures below 46°C may be used chronically to maintain the effects of non-blocking heating on cold blocking. Previous studies in rodents and dogs have shown that local heating of the sciatic nerve to 43–44°C for 30–60 minutes is safe and only induces reversible ultrastructural and electrophysiological changes in the nerve. Therefore, it is reasonable to hypothesize that a new approach for blocking myelinated nerves in mammals could be proposed that, after raising the threshold for cold blocking using the method used in this study, alternates the application of local heating and cooling between temperatures ranging from 45°C to 15°C.

[0078] Other methods currently used clinically to achieve nerve blockade. For many years, the infusion of local anesthetics was suitable for transient nerve blockade, due to the difficulty of slowly delivering anesthetics. More recently, high-frequency (kHz) electrical stimulation, generated by implantable stimulators, has been used clinically to slowly block the vagus nerve to treat obesity or to block the spinal cord roots to treat chronic pain. HF stimulation has been proposed for blocking the pudendal nerve to restore lower urinary tract function lost after spinal cord injury. However, when HF stimulation blocks nerve conduction, it invariably causes an initial nerve burn. This initial burn is a significant problem for most clinical applications of pain suppression because initial pain sensation is felt before nerve blockade occurs. The thermal blockade method proposed in this study offers a reversible nerve blockade method that does not produce an initial reaction. Furthermore, currently used thermoelectric Peltier technology could potentially enable the design and development of an implantable device that can generate localized temperature changes between 15 and 50°C. Therefore, the heat blocking technology based on this study has great potential for use in a wide range of clinical applications to treat certain conditions, such as obesity, pain, heart failure, and bladder dysfunction after spinal cord injury.

[0079] The underlying mechanisms of cold or heat block are currently unclear. However, it is known that temperature determines the kinetics of sodium and potassium channel activity. Therefore, it is possible that extremely low or high temperatures can cause significant changes in ion channel kinetics, resulting in conduction block. However, recent studies in rodents have demonstrated that the reduction in conduction velocity achieved by cooling the sciatic nerve is unaffected by dose-dependent sodium or potassium channel blockers, suggesting that the effects of hypothermia on conduction velocity may be related to the passive properties of myelinated axons. It is known that hypothermia can thicken the axonal septum in the sciatic nerve of toads and reduce conduction velocity. Conversely, the effects of hypothermia on action potential amplitude are sensitive to dose-dependent sodium channel blockers. Therefore, both ion channel kinetics and the passive properties of myelinated axons may play a role in cold blockade of myelinated nerves.

[0080] It is readily understood how prolonged heat blockage can lead to neuronal injury, as hyperthermia can cause edema, vascular occlusion, severe endothelial damage, and demyelination. However, the underlying mechanisms of reversible heat blockage are poorly understood. Based on our understanding of what occurs during cold blockage, it appears that both ion channel dynamics and the passive properties of myelinated axons may play a role in reversible heat blockage. Furthermore, it is known that the axonal diaphragm capacitance increases significantly at heat block temperatures. This locally increased capacitance can lead to charge redistribution along the axon, potentially resulting in localized depolarization that blocks axonal conduction.

[0081] In this study, it has been shown that brief or mild heating can increase the temperature of the cold block (see Figure 6 and attached Figure 8A and attached Figure 8B The effect of heating on the cold block can last for several minutes and is fully reversible (see Appendix). Figure 7 Because ion channel dynamics change immediately with temperature changes, they are unlikely to contribute to the prolonged effects of warming versus cold blockade. However, it is possible that brief or mild heating can induce changes in the passive properties of myelinated axons that are fully reversible over time. Further studies are needed to further understand the mechanisms of axonal blockade that can be induced by temperature changes and the interplay between hot and cold temperatures in conducting or blocking myelinated axons.

[0082] The results of this study regarding irreversible nerve blockade are consistent with those of previous studies. Cold blockade of sciatic nerve conduction in previous reports was achieved in cats at 5-15°C. Cold blockade of pudendal nerve conduction has also been observed in dogs at 2-10°C. In this study, the temperature was reduced rapidly (within 5-10 minutes) and then maintained for only 50-60 seconds. Previous studies on the sciatic nerve of rodents used a very slow cooling protocol, which reduced the temperature at a rate of approximately 0.1°C / min, which in this study corresponded to a time period of approximately 20 minutes per temperature reduction (±1°C). Even with such a slow temperature ramp, temperatures below 16°C were still required to block conduction in the rodent sciatic nerve, indicating that the cooling protocol used in this study was sufficient to accurately determine the response curve for cold blockade (see Appendix). Figure 3 , Figure B). It is noteworthy that cold block occurs over a wider temperature range (5-15°C) than heat block (50-54°C), which may indicate a very different structure in cold and heat block. In addition, it is known that the temperature of cold block does not correlate with the speed of nerve conduction. Therefore, the gradual blockade that occurs with decreasing temperature (see Appendix Figure 3 ) is more likely due to temperature gradients in the nerve, which are generated by the copper coil and are not related to the different diameters of the blocked axons.

[0083] Previous studies in cats have shown that temperatures above 46°C are required to achieve thermal blockade of myelinated axons. This temperature, which is suitable for thermal blockade, is slightly lower than the critical value for blockade in this study (Supplementary Figure 2). Figure 4 ) may be reflected in different experimental approaches. In previous studies, the heated nerve length was approximately 15 mm, but in this study, the nerve length was only 9 mm. The effects of cooling or heating nerves of varying lengths warrant investigation. The period of increased sensitivity to cold block may also be prolonged with additional intermittent gentle heating at 42–44°C.

[0084] In summary, the prolonged effects of brief heating within the threshold temperature range to produce cold block or axonal conduction are important observations that will lead to new insights into the physiology of myelinated axons and may lead to new clinical approaches to treat dysfunctions arising from neural tissue by exploiting thermally induced changes in axonal conduction.

[0085] Based on what has been described in the present invention, any ordinary technician in the field can understand that the same technical solution can be implemented under broad and equivalent range conditions without affecting the scope of the present invention or the conditions, formulas and other parameters of any embodiment therein.

[0086] The following clauses may be used to explain various aspects of the present invention:

[0087] Item 1: A method for reversibly blocking a nerve, comprising:

[0088] a. heating the nerve to a temperature greater than 37°C and below a temperature and time period that results in irreversible nerve blockade; and

[0089] b. Cooling the nerve to a temperature below 37°C and above the temperature at which irreversible nerve block is formed, thereby forming a reversible nerve block.

[0090] Clause 2: The method of clause 1, wherein in step a, the nerve is heated to a temperature within the range of 42°C to 54°C.

[0091] Clause 3: The method of any one of clauses 1 or 2, wherein in step a the nerve is heated to a temperature in the range of 50°C to 54°C for a period of less than 1 minute.

[0092] Clause 4: A method according to either clause 1 or clause 2, wherein in step a the nerve is heated to a temperature in the range of 43°C to 48°C for a period of 60 minutes or less, or 30 minutes or less.

[0093] Clause 5: A method according to any of clauses 1-4, wherein in step a the nerve is heated to a temperature and for a period of time which may or may not result in nerve blockade.

[0094] Clause 6: The method according to any one of clauses 1-5, wherein the nerve is cooled in step b, and the cooling temperature ranges from 15°C to 30°C.

[0095] Item 7: The method according to any one of items 1-6 further includes, before step a, implanting a temperature controller in the nerve for heating or cooling the nerve, the temperature controller including a heating device, a cooling device and a temperature sensor.

[0096] Item 8: A method according to Item 7, wherein the temperature controller is connected, for example, electrically or wirelessly to a controller, the controller being adapted to control the heating process of the heating device, to control the cooling process of the cooling device, and to monitor the temperature of the nerve via a temperature sensor.

[0097] Item 9: A method according to any one of Item 7 or Item 8, wherein the heating device is a resistor, a thin film semiconductor, a Peltier heater, a microwave radiator or an infrared heater, and the cooling component is a coolant tube, the Peltier cooler and / or the temperature sensor is a thermocouple or a thermoelectric regulator.

[0098] Item 10: A method for treating excessive obesity in a patient, comprising blocking the patient's abdominal vagus nerve by any of the methods described in Items 1-9.

[0099] Item 11: A method for treating chronic pain in a patient, comprising blocking the patient's nerves by any of the methods of Items 1-9.

[0100] Clause 12: A method for treating heart failure in a patient, comprising blocking the patient's sympathetic nerves by any of the methods of clauses 1-9.

[0101] Clause 13: The method of clause 12, wherein the sympathetic nerve is one or more greater splanchnic nerves, lesser splanchnic nerves, or a sympathetic trunk.

[0102] Clause 14: A method for treating urinary incontinence in a patient, comprising blocking the patient's pudendal nerve by any of the methods of clauses 1-9.

[0103] Item 15: A method for treating muscle spasms in a patient, comprising blocking the patient's nerves that control muscle activity by any of the methods described in Items 1-9.

[0104] Clause 16: A method for treating cardiovascular disease in a patient, comprising blocking the patient's vagus nerve by any of the methods of clauses 1-9.

[0105] Item 17: A system suitable for reversibly blocking a nerve, comprising:

[0106] An implantable device comprising:

[0107] A temperature controller including a processor;

[0108] a thermoelectric device in communication with a temperature controller and configured to be placed in proximity to a nerve;

[0109] a temperature sensor in communication with the temperature controller, configured to be placed proximate to the nerve; and

[0110] A power source for powering the temperature controller and the thermoelectric device; and

[0111] An external controller that communicates with the temperature controller,

[0112] The temperature controller includes a memory storing programming instructions, which, when executed by a processor, can cause the processor to control the thermoelectric device to perform the following instructions:

[0113] heating the nerve to a temperature greater than 37°C and below a temperature and for a period of time that would produce an irreversible nerve block; and

[0114] The nerve is cooled to a temperature below 37°C and above a temperature at which an irreversible nerve block is formed, thereby forming a reversible nerve block.

[0115] Clause 18: The system of clause 17, wherein the programming instructions, when executed by a processor, further enable the processor to receive temperature information from a temperature sensor and, based on the temperature information, adjust control of the thermoelectric device.

[0116] Clause 19: A system according to either clause 17 or clause 18, wherein the temperature sensor is a thermistor.

[0117] Clause 20: A system according to any of clauses 17-19, wherein the temperature sensor is a thermocouple.

[0118] Clause 21: A system according to any of clauses 17-20, wherein the thermoelectric device includes a heating device and a cooling device, and wherein the heating device is a resistor, a thin film semiconductor, a Peltier heater, a microwave radiator or an infrared heater, and the cooling device is a coolant tube, a Peltier cooler.

[0119] Clause 22: A system according to any of clauses 17-21, wherein the power source is a rechargeable battery.

[0120] Clause 23: The system of clause 22, wherein the rechargeable battery is wirelessly rechargeable.

[0121] Clause 24: The system of clause 23, wherein the rechargeable battery is configured to be charged inductively.

[0122] Clause 25: The system of any of clauses 17-24, wherein the external controller is in wireless communication with the temperature controller.

[0123] Clause 26: A system according to any of clauses 17-25, wherein the external controller is a mobile phone, a tablet computer, a smart watch, a laptop computer or a desktop computer.

[0124] Article 27: Use of implantable devices, including:

[0125] A temperature controller including a processor;

[0126] a thermoelectric device in communication with a temperature controller and configured to be placed in proximity to a nerve;

[0127] a temperature sensor in communication with the temperature controller, configured to be placed proximate to the nerve; and

[0128] A power source that provides power to temperature controllers and thermoelectric devices;

[0129] To achieve reversible nerve blocking, the method includes heating the nerve to a temperature above 37°C and below the temperature and time period at which irreversible nerve blockade is formed; and cooling the nerve to a temperature below 37°C and above the temperature at which irreversible nerve blockade is formed, thereby forming a reversible nerve blockade.

Claims

1. A system for reversibly blocking a nerve, comprising: a device configured to heat and cool nerves; a temperature sensor configured to be placed in proximity to the nerve; a power source for providing power to the device; a processor in communication with the temperature sensor and the device; A memory storing programming instructions which, when executed by a processor, can cause the processor to control the device to perform the following instructions: First, heating the nerve to a temperature within the range of 42-54° C. for a period of time sufficient to increase the threshold temperature for producing cold conduction blockade within the nerve and below a temperature and time period that produces irreversible nerve blockade; and The nerve is then cooled to a temperature within the range of 15-30°C to produce a reversible nerve block at a higher temperature than would be required without the heating step.

2. The system of claim 1, wherein the programming instructions, when executed by the processor, further cause the processor to receive temperature information from the temperature sensor and to modify control of the device based on the temperature information.

3. The system of claim 1, wherein the temperature sensor is a thermistor or a thermocouple.

4. The system of claim 1 , wherein the device comprises a heating element and a cooling element, wherein the heating element is a fluid tube, a resistor, a thin film semiconductor, a Peltier heater, a microwave radiator, or an infrared heater, and the cooling element is a coolant tube or a Peltier cooler.

5. The system of claim 1, wherein the device comprises a heating element and a cooling element, and wherein the heating element is a fluid tube and the cooling element is a fluid tube.

6. The system of claim 1, wherein the device is implantable.

7. The system of claim 1, wherein the processor is in wireless communication with the device.

8. The system of claim 7, wherein the processor sends an encrypted signal to the device.

9. The system of claim 7, further comprising a display and / or input device in communication with the processor.

10. The system according to claim 1, wherein: When executed by the processor, the programmed instructions may cause the processor to control the device to heat the nerve to a temperature within the range of 42-48°C.

11. The system according to claim 1, wherein: When executed by the processor, the programmed instructions may cause the processor to control the device to heat the nerve to a temperature within the range of 43-48°C.

12. The system according to claim 1, wherein: When executed by the processor, the programmed instructions may cause the processor to control the device to heat the nerve to a temperature within the range of 46-48°C.

13. The system of claim 1, wherein: When executed by the processor, the programmed instructions may cause the processor to control the device to heat the nerve to a temperature within the range of 50-54°C.

14. The system according to claim 1, wherein: When executed by the processor, the programmed instructions may cause the processor to control the device to heat the nerve for 60 minutes or less.

15. The system of claim 1, wherein: When executed by the processor, the programmed instructions may cause the processor to control the device to heat the nerve for a duration of 10-40 minutes.

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