阅读说明：本技术 用于代谢紊乱中的血糖控制的联合失神经支配疗法 (Combination denervation therapy for glycemic control in metabolic disorders ) 是由 布莱恩·艾伦·克拉克 维杰·科亚 伊丽莎白·M·安诺尼 曹宏 于 2019-08-29 设计创作，主要内容包括：一种用于失神经支配的系统和方法,其中导管包括可径向扩张的构件,所述可径向扩张的构件包括：外表面；所述外表面上多个电极,所述多个电极被配置为在血管中在失神经支配程序过程中输送能量；以及所述外表面上的化学药剂涂层,其中,所述化学药剂抑制或阻止神经再生。所述可径向扩张的构件被配置为具有第一未扩张构型和第二已扩张构型,并且被配置为当其处于所述已扩张构型时使所述外表面与血管壁接触。(A system and method for denervation, wherein a catheter includes a radially expandable member comprising: an outer surface; a plurality of electrodes on the outer surface configured to deliver energy during a denervation procedure in a blood vessel; and a chemical agent coating on the outer surface, wherein the chemical agent inhibits or prevents nerve regeneration. The radially expandable member is configured to have a first, unexpanded configuration and a second, expanded configuration, and is configured to bring the outer surface into contact with a vessel wall when it is in the expanded configuration.)

1. A system for denervation, comprising a catheter comprising a radially expandable member, the radially expandable member comprising:

an outer surface;

a plurality of electrodes on the outer surface configured to deliver energy during a denervation procedure in a blood vessel; and

a coating of a chemical agent on the outer surface, wherein the chemical agent inhibits or prevents nerve regeneration;

wherein the radially expandable member is configured to have a first unexpanded configuration and a second expanded configuration, wherein the radially expandable member is configured to bring the outer surface into contact with a vessel wall when the radially expandable member is in the expanded configuration.

2. The system of claim 1, wherein the system is configured to cause current to flow between the plurality of electrodes.

3. The system of any of claims 1-2, wherein the radially expandable member is selected from the group consisting of: a balloon, an elongated balloon, a shape memory helix, a stent, a spline structure, a basket structure, and a wire frame structure.

4. The system of any of claims 1-2, wherein the radially expandable member is an elongate balloon and the system is configured to generate an elongate denervation treatment pattern.

5. The system of any of claims 1-4, wherein the catheter comprises an inflation lumen in fluid communication with the radially expandable member.

6. The system of claim 5, wherein the radially expandable member defines an opening, the system further comprising a fluid for filling the inflation lumen, inflating the radially expandable member, and for dispensing through the opening in the radially expandable member.

7. The system of any of claims 1-2, wherein the radially expandable member is a shape memory spiral having a first elongate linear configuration and a second radially expanded helical configuration.

8. The system of any one of claims 1-7, wherein the chemical agent is selected from the group consisting of: extracellular protein inhibitors, neurotrophin inhibitors, neuropeptide inhibitors, neurotrophin receptor inhibitors, cell adhesion molecule inhibitors, cell signaling molecule inhibitors, cytostatics, cytokine and chemokine inhibitors, sulfated proteoglycan inhibitors, enzyme inhibitors, arginase inhibitors, 13 secretase inhibitors, urokinase-type and tissue-type plasminogen activator inhibitors, myelin-derived molecule inhibitors, semaphorin-3A, paclitaxel, fibrin, brain-derived neurotrophic factor (BDNF), myelin-derived factor, phosphatase and tensin homolog (PTEN), cytokine signaling 3(SOCS3) gene suppressor, notch/lin12 protein, and ZnEgr protein.

9. The system of any one of claims 1-8, wherein the system is configured to measure impedance between the combination of electrodes.

10. The system of any of claims 1-9, wherein the radially expandable member is configured to contact a hepatic vessel wall when the radially expandable member is in the expanded configuration.

11. The system of any one of claims 1-10, wherein the radially expandable member comprises a wire frame structure having a plurality of wires extending from a proximal end to a distal end, wherein each wire comprises one of the electrodes, wherein each electrode defines a portion of the outer surface that contains the chemical agent coating.

12. The system of any of claims 1-2 and 8-10, wherein the radially expandable member comprises a shape-memory ribbon helix and has an outer side and an inner side, wherein the outer side defines the outer surface, wherein the electrode and the chemical agent coating are present on one side of the ribbon helix.

13. A method of treatment, comprising:

providing a catheter comprising a radially expandable member and a plurality of electrodes on an outer surface of the radially expandable member, the plurality of electrodes configured to deliver energy in a blood vessel during a denervation procedure, the catheter further comprising a chemical agent coating on the outer surface;

expanding the radially expandable member from a first unexpanded configuration to a second expanded configuration, wherein the radially expandable member is configured to bring the outer surface into contact with a vessel wall when the radially expandable member is in the expanded configuration;

performing a denervation procedure using electrical energy at a target site of a subject using the electrodes of the radially expandable member; and

introducing at least one chemical agent that inhibits or prevents nerve regeneration to the target site, wherein the chemical agent is present in a chemical agent coating on an outer surface of the radially expandable member.

14. The method of claim 13, wherein the denervation procedure is an irreversible electroporation procedure or a radiofrequency ablation (RFA) procedure.

15. The method of any one of claims 13-14, comprising measuring impedance between the combination of electrodes or between one of the electrodes and a combination of a ground pad.

Technical Field

The present disclosure relates to methods, devices, kits and systems for enhancing the efficacy and longevity of denervation procedures.

Background

Prior techniques for denervation mainly include radiofrequency ablation, which is typically performed in a monopolar configuration with current passing between the probe and the ground pad. Unfortunately, nerve fibers may regenerate over time, resulting in the need for repeated denervation procedures. The present disclosure relates to devices and methods for inhibiting nerve regeneration after performing a denervation procedure, including a radio frequency ablation denervation procedure.

Disclosure of Invention

In one aspect, described herein is a system for denervation, comprising a catheter comprising a radially expandable member comprising: an outer surface; a plurality of electrodes on the outer surface configured to deliver energy during a denervation procedure in a blood vessel; and a chemical agent coating on the outer surface, wherein the chemical agent inhibits or prevents nerve regeneration. The radially expandable member is configured to have a first unexpanded configuration and a second expanded configuration and is configured to bring the outer surface into contact with a vessel wall when it is in the expanded configuration.

In one aspect, the system is configured to cause current to flow between the plurality of electrodes. In one aspect, the radially expandable member is selected from the group consisting of: a balloon, an elongated balloon, a shape memory helix, a stent, a spline structure, a basket structure, and a wire frame structure.

In one aspect, the radially expandable member is an elongate balloon and the system is configured to generate an elongate denervation treatment pattern. In one aspect, the catheter includes an inflation lumen in fluid communication with the radially expandable member. In one aspect, the radially expandable member defines an opening, and the system includes a fluid for filling the inflation lumen, inflating the radially expandable member, and for dispensing through the opening in the radially expandable member.

In one aspect, the radially expandable member is a shape memory spiral having a first elongate linear configuration and a second radially expanded helical configuration.

In one aspect, the chemical agent is selected from the group consisting of: extracellular protein inhibitors, neurotrophin inhibitors, neuropeptide inhibitors, neurotrophin receptor inhibitors, cell adhesion molecule inhibitors, cell signaling molecule inhibitors, cytostatics, cytokine and chemokine inhibitors, sulfated proteoglycan inhibitors, enzyme inhibitors, arginase inhibitors, 13 secretase inhibitors, urokinase-type and tissue-type plasminogen activator inhibitors, myelin-derived molecule inhibitors, semaphorin-3A, paclitaxel, fibrin, brain-derived neurotrophic factor (BDNF), myelin-derived factor, phosphatase and tensin homolog (PTEN), cytokine signaling 3(SOCS3) gene suppressor, notch/lin12 protein, and ZnEgr protein.

In one aspect, the system is configured to measure impedance between the combination of electrodes. In one aspect, the system is configured to measure the impedance of a reference patch and one or more electrodes on the skin of a patient.

In one aspect, the radially expandable member is configured to contact a hepatic vessel wall when the radially expandable member is in the expanded configuration.

In one aspect, the radially expandable member comprises a wire frame structure having a plurality of wires extending from a proximal end to a distal end, wherein each wire comprises one of the electrodes, wherein each electrode defines a portion of the outer surface that comprises the chemical agent coating.

In one aspect, the radially expandable member comprises a shape-memory ribbon helix and has an outer side and an inner side, wherein the outer side defines the outer surface, wherein the electrode and the chemical agent coating are present on one side of the ribbon helix.

In one aspect, described herein is a system for denervation, comprising a catheter including an inflation lumen and an elongate balloon in fluid communication with the inflation lumen, the elongate balloon comprising: an outer surface; a plurality of electrodes on the outer surface configured to deliver energy during a denervation procedure in a blood vessel; and a chemical agent coating on the outer surface, wherein the chemical agent inhibits or prevents nerve regeneration. The elongate balloon is configured to have a first, unexpanded configuration and a second, expanded configuration, wherein the elongate balloon is configured to contact the outer surface with a vessel wall when the elongate balloon is in the expanded configuration.

In one aspect, the radially expandable member is configured to contact a hepatic vessel wall when the radially expandable member is in the expanded configuration.

In one aspect, a method of treatment is described herein, including providing a catheter including a radially expandable member and a plurality of electrodes on an outer surface of the radially expandable member, the plurality of electrodes configured to deliver energy during a denervation procedure in a blood vessel. The catheter further includes a chemical agent coating on the outer surface. The method includes expanding the radially expandable member from a first, unexpanded configuration to a second, expanded configuration, wherein the radially expandable member is configured to bring the outer surface into contact with a vessel wall when the radially expandable member is in the expanded configuration. The method includes performing a denervation procedure using electrical energy at a target site of a subject using the electrodes of the radially expandable member. The method includes introducing at least one chemical agent that inhibits or prevents nerve regeneration to the target site, wherein the chemical agent is present in a chemical agent coating on an outer surface of the radially expandable member.

In one aspect, the denervation procedure is an irreversible electroporation procedure. In one aspect, the denervation procedure is a radiofrequency ablation (RFA) procedure.

In one aspect, the denervation procedure is performed while introducing the at least one chemical agent. In one aspect, the method includes measuring impedance between the combination of electrodes.

In one aspect, the radially expandable member is in contact with the hepatic vessel wall when the radially expandable member is in the expanded configuration.

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 of ordinary skill in the art from reading and understanding the following detailed description and viewing the drawings that form a part hereof, each of which should not be taken in a limiting sense. The scope herein is defined by the appended claims and their legal equivalents.

Drawings

Fig. 1 is a system for denervation according to some examples, including a balloon catheter.

Fig. 2 is a perspective view of a distal portion of the balloon catheter for denervation of fig. 1, according to some examples.

Fig. 3 is a schematic illustration of a distal portion of the balloon catheter of fig. 1 inserted into a hepatic vessel, according to some examples.

Fig. 4A is a side view of a shape-memory spiral in an expanded state, according to some examples.

Fig. 4B is a side view of the shape-memory spiral of fig. 4A in an unexpanded state, according to some examples.

Fig. 4C is a perspective view of the circular profile of the shape-memory spiral.

Fig. 4D is a perspective view of the band-like profile of the shape-memory spiral.

Fig. 5A is a side view of another shape-memory spiral in an expanded state, according to some examples.

Fig. 5B is a cross-sectional view of the shape-memory spiral of fig. 5A taken along line a in 5A.

Fig. 5C is a side view of another shape-memory spiral in an expanded state, according to some examples.

FIG. 5D is a cross-sectional view of the shape-memory spiral of FIG. 5C.

Fig. 6 is a schematic diagram of a wire-frame radially expandable denervation element having a surface coated with a nerve growth inhibitor, according to some examples.

Fig. 7 is a schematic diagram of an electrode assembly for denervation, according to some examples.

Fig. 8 is a schematic diagram of an electrode assembly for denervation, according to some examples.

Fig. 9 is a schematic diagram of an electrode assembly for delivering a chemical agent, according to some examples.

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

The present disclosure provides a liver denervation therapy for ameliorating metabolic disorders, wherein the liver denervation is performed using a first therapy such as radiofrequency ablation, irreversible electroporation, or other forms, followed by a second therapy such as nerve growth inhibitor delivery to prevent nerve regeneration. Specific nerve growth inhibitors are disclosed. In some examples, the system is self-contained in a single device. In alternative examples, the system may include multiple separate devices.

The disclosed technology provides a medical treatment for medical conditions including any condition requiring regulation of blood glucose levels, most notably diabetes, but also including insulin resistance, genetic metabolic diseases, hyperglycemia, obesity, hyperlipidemia, hypertension, endocrine diseases, and/or inflammatory diseases. The medical device and system include a first medical device capable of reducing sympathetic activity to control hepatic glucose production. The system also provides a nerve growth inhibitor or blocker. The medical device may be a catheter capable of delivering a nerve growth inhibitor or blocking agent to the neural tissue being treated to reduce the rate of nerve regeneration.

The disclosed technology provides a method comprising delivering a first treatment that at least temporarily reduces neural signals to the liver to reduce hepatic glucose production. The method further comprises delivering a second treatment that impairs the regenerative capacity of the nerve and/or prevents the nerve from restoring full function. A first treatment may include denervation of neural tissue of the liver using: electrical energy, radiofrequency energy, irreversible electroporation, microwave energy, ultrasound energy, focused ultrasound (e.g., High Intensity Focused Ultrasound (HIFU), Low Intensity Focused Ultrasound (LIFU)), laser energy, infrared energy, optical energy, thermal energy, steam or heated water, magnetic fields, reversible electroporation, cryotherapy, brachytherapy, ionization therapy, drug delivery, biological delivery, chemical ablation (e.g., ethanol), mechanical disruption, any other form of therapy that causes destruction or modulation of target tissue, or any combination thereof. The second treatment may include delivery of a nerve growth inhibitor to the tissue being treated.

In some examples, electroporation therapy is delivered concurrently with or at a similar time period to the nerve growth inhibitor treatment to increase penetration of the nerve growth inhibitor into the hepatic vessel wall. In some examples, the nerve growth inhibitor and optionally electroporation are delivered before, during, or after denervation therapy (such as radiofrequency ablation, irreversible electroporation, and other therapies). In some examples, the nerve growth inhibitor and optionally electroporation are first delivered via a first catheter, and then the second catheter delivers the denervation therapy. In some examples, the denervation therapy is delivered first via a first catheter, and then the nerve growth inhibitor and optionally electroporation are delivered by a second catheter.

Additionally or alternatively, in some examples, the period of time for delivery of both the denervation therapy and the nerve growth inhibitor treatment is within a period of one minimally invasive procedure, such as within five hours, within four hours, within three hours, within two hours, within one hour, within 45 minutes, within 30 minutes, or within 15 minutes.

Referring now to fig. 1, a schematic diagram of a absence distribution system is shown, according to some examples. The denervation system 100 includes a generator and control device 104, and a catheter assembly 108 having a radially expandable member 110 including an electrode 112 on an outer surface 114 of the radially expandable member 110. The system 100 and electrodes 112 are configured to deliver energy during a denervation procedure in a blood vessel, such as in a hepatic blood vessel. The system 100 may be used in other treatment areas, such as another lumen or vessel of the body, including the renal vessels. The radially expandable member 110 is configured to have a first unexpanded configuration and a second expanded configuration. In the expanded configuration, the radially expandable member 110 is configured to contact the outer surface 114 with the hepatic vessel wall of the patient. Fig. 2 shows a close-up view of the radially expandable member 110 in an expanded configuration.

In a number of different examples, the radially expandable member 110 is an expandable elongate balloon that is moved from an unexpanded configuration to an expanded configuration by expansion. As used herein, elongate means that the structure is longer than it is wide. To inflate the balloon, the catheter assembly 108 includes an inflation lumen and an inflation port 118, both in fluid communication with the interior of the balloon. In a number of different examples, the inflation fluid provided to inflate the balloon may be sterile water or saline solution. Additionally or alternatively, the inflation fluid may include a chemical agent that inhibits nerve growth, and the inflation fluid may be spread to the vessel wall, such as by oozing out of an opening in the balloon, to deliver the chemical agent to the vessel lumen.

Fig. 1 illustrates a radially expandable member as an expandable elongate balloon. In other examples of the system of fig. 1, the radially expandable member is a balloon, a shape memory helix, a stent, a basket structure, a spline structure, or a wire frame structure, and these structures may or may not be elongated. These examples will be described further herein. Other types of radially expandable members may also be used with the system of fig. 1 and other systems described herein.

The radially expandable member 110 further includes a chemical agent coating 116 on the outer surface, wherein the chemical agent inhibits or prevents nerve regeneration. In some examples, the chemical agent is a nerve growth inhibitor selected from the group consisting of: semaphorin-3A, paclitaxel, fibrin, brain-derived neurotrophic factor (BDNF), myelin-derived factor, phosphatase and tensin homolog (PTEN), cytokine signaling 3(SOCS3) gene inhibitor, notch/lin12 protein, and ZnEgr protein. Other examples of chemical agents may be used with the systems described herein, and some of these additional examples are described herein.

The catheter assembly 108 includes a catheter body 119 having a distal end 120 and a proximal end 122. The inflation lumen is a passage within the catheter body 108. Distal end 120 defines a distal guidewire port 124. The proximal end 122 of the catheter body 108 is attached to an outer housing 128 that includes the inflation port 118, a proximal guidewire port 130, and an electrical connector 134. The catheter body 108 can define a sheath such that the radially expandable member 110 can be contained within the sheath when the radially expandable member is in an unexpanded state.

The electrical connector 134 connects the catheter assembly 108 to the generator and control device 104, which includes a plurality of electrical connections and is configured to deliver controlled energy to the electrodes 112. The generator and control device 104 includes a display 138, a user input device 140, an energy source 142, a controller 144, and a sensing circuit 146.

The energy source 142 may provide electrical energy, radiofrequency energy, irreversible electroporation, microwave energy, ultrasound energy, focused ultrasound (e.g., High Intensity Focused Ultrasound (HIFU), Low Intensity Focused Ultrasound (LIFU)), laser energy, infrared energy, optical energy, thermal energy, steam or heated water, magnetic fields, reversible electroporation, cryotherapy, brachytherapy, ionization therapy, drug delivery, biological delivery, chemical ablation (e.g., ethanol), mechanical disruption, any other form of therapy that causes disruption or modulation of target tissue, or any combination thereof. The sensing circuit 146 may be configured to determine an impedance between a combination of electrodes. The impedance information indicates whether the electrode is in contact with the vessel wall and indicates the progress of the treatment. The display 138 may include a graphical user interface that indicates which electrodes are in contact with the vessel wall, the wattage of the energy, the temperature of the temperature sensor, the seconds of treatment time remaining, and which electrodes are active. The user input device 140 includes buttons, switches, a touch screen, a keyboard, or other devices to provide input and instructions to the generator and control device 104.

Examples of generator and control devices, energy delivery structures, electrode configurations, and energy delivery methods that may be used with embodiments disclosed herein are disclosed in the following patents: U.S. patent No. 9,277,955 entitled "Power Generating and Control Apparatus for the Treatment of Tissue" published as U.S. patent application publication No. US 2012/0095461 and assigned to vestix Vascular corporation, which is incorporated herein by reference. Other examples are disclosed in the following patents: U.S. patent 9,037,259, entitled "Methods and apparatus for remodeling tissue of or adjacent to a body channel," is assigned to Vessix Vascular corporation and is incorporated herein by reference. Other examples that may be used with the embodiments disclosed herein are disclosed in the following patents: U.S. patent No. 7,742,795 entitled "Tuned RF Energy for Selective Treatment of aneurysms and Other Target Tissues and/or Structures" U.S. patent No. 7,291,146 entitled "Selective Eccentric Remodeling and/or Ablation of Atherosclerotic Material" and U.S. patent No. 2008/0188912 entitled "System for Inducing a desired Temperature effect on Body Tissue" are assigned to distributed vessel corporation, the entire disclosures of which are incorporated herein by reference. Combinations of the structures and methods described in this application and the incorporated documents may be used.

Referring now to fig. 2, a perspective view of the distal portion of the catheter assembly 108 of fig. 1 is shown. According to a number of different examples, the radially expandable member 110, in particular an expandable elongate balloon, includes an electrode 112 for energy delivery. The distal end 120 of the catheter assembly 108 defines a distal guidewire port 124. The radially expandable member 110 includes electrode pads 202 defined on an outer surface 114 thereof, wherein each electrode pad 202 supports a plurality of electrodes 112 that are each electrically connected to the generator and control device 104 via a conductor 204. Each electrode pad 202 also includes a temperature sensor 208.

In some examples, electrodes 112 are arranged on an elongate balloon to form an elongate denervation treatment pattern. In some examples, the system is configured to measure the impedance between the combination of electrodes 112. As shown in fig. 2, each electrode sheet includes three electrodes 112 on a first side and three electrodes 112 on a second side. In a number of different examples, the three electrodes 112 on one side are held at a different voltage potential than the three electrodes on the opposite side, such that an energy path is defined between the opposing electrodes on both sides of each electrode sheet. The arrangement of electrodes, the energy paths formed between combinations of electrodes, and other aspects of the energy delivery structure options for a number of different examples are described in previously incorporated U.S. patent 9,037,259 and other previously incorporated patent documents.

The outer surface 114 is provided with a chemical coating 116 containing a chemical that prevents or reduces nerve regeneration. The use of such chemicals may reduce the need for repeated denervation procedures and extend the time frame of beneficial effects of the denervation procedure. In a number of different examples, where it is desired that the radially expandable member 110 be in contact with the vessel wall when it is in the expanded configuration, a chemical coating is present, such as a portion of the radially expandable member that is cylindrical and has a maximum diameter when in the expanded configuration. In a number of different examples, the chemical coating is present on a portion of the outer surface of the radially expandable member 110. In a number of different examples, there is no chemical coating on the electrode 112. In a number of different examples, the chemical agent coating is present on portions of the radially expandable member 110 not occupied by the electrodes 112.

Fig. 3 is a schematic illustration of a catheter assembly for denervation inserted into a blood vessel, according to some examples. The catheter assembly 108 is shown with the radially expandable member 110 within the hepatic vessel 300, including the chemical coating 116 on the outer surface 114 of the radially expandable member 110. The radially expandable member 110 is shown in an expanded configuration such that the outer surface 114 is in contact with the vessel wall. The expanded configuration brings the electrodes 112 into contact with the vessel wall to assist in delivering energy to disrupt sympathetic nerves along the vessel. The expanded configuration also brings the outer surface 114 and the chemical coating 116 into contact with the vessel wall to assist in the transfer of the chemical into the vessel wall.

In some examples, the radially expandable member is a shape memory member having a first elongate linear configuration and a second radially expanded configuration. The shape memory member may include or be made of a shape retaining material or a shape memory material, such as a shape memory alloy. Examples of shape memory materials are nickel titanium alloy (also known as nitinol), copper aluminum nickel alloy, and stainless steel. Shape memory materials, as used herein, are materials that "remember" their original shape and return to their pre-deformed shape when deformed. Shape-retaining materials are materials that retain their shape once positioned.

In various examples, the radially expandable member is a shape memory spiral having a first elongate unexpanded configuration and a second radially expanded helical configuration.

Fig. 4A is a side view of the distal end of a catheter including an embedded shape memory portion to define a shape memory spiral 400, wherein the shape memory spiral is in an expanded state in fig. 4A according to some examples. Fig. 4B is a side view of the shape-memory spiral 400 of fig. 4A in an unexpanded state, according to some examples. The shape-memory spiral 400 includes two or more electrodes 412. The shape-memory spiral 400 includes an outer side and an inner side, wherein the outer side defines an outer surface. An electrode 412 is present on the outer surface. The outer surface includes a chemical coating 416 on the outer surface. In a number of different examples, the chemical coating 416 is not present on the electrode 412. In a number of different examples, a chemical coating 416 is present on the portion of the shape-memory spiral 400 between the electrodes 412.

In fig. 4B, the shape-memory spiral 400 is shown in its unexpanded state, constrained within a sheath 460. In one example, the shape memory spiral 400 is delivered to the treatment site by being pushed within the sheath 460 until reaching the distal end of the sheath 460. By pushing the shape-memory spiral 400 out of the distal end of the sheath 460, the shape-memory spiral 400 is moved to its expanded configuration such that it protrudes from the distal end of the sheath. In some examples, once unconstrained by the sheath 460, the shape-memory spiral 400 springs into its expanded shape as shown in fig. 4A.

In a number of different examples, the radially expandable shape-memory helical member has a circular cross-section or a rectangular cross-section, such as a rectangular or ribbon-like cross-section. Fig. 4C is a perspective view of the circular profile of the shape-memory spiral 440. Fig. 4D is a perspective view of the band-like profile of the shape-memory spiral 450.

In a number of different examples, the diameter of the shape-memory spiral in its expanded state is sized to ensure intimate contact with the inner diameter of the lumen. Examples of diameters and other dimensions of radially expandable members, such as shape memory spirals, are provided herein.

Where the shape-memory spiral has a long square shape such as a ribbon shape, in various examples, the ribbon width or conduit cross-sectional diameter is at least about 0.05mm, at least about 0.3mm, at least about 0.5mm, at most about 5mm, at most about 3mm, at most about 2mm, at least about 0.05mm and at most about 5mm, at least about 0.3mm and at most about 3mm, or at least about 0.5mm and at most about 2 mm. In various embodiments, a shape-memory spiral having a circular cross-sectional shape may also have these cross-sectional diameters.

In a number of different examples, there is no chemical coating on the shape-memory spiral. Prior to or after denervation therapy, a separate device (such as a balloon device with a coated surface or a balloon device filled with a chemical agent, to name a few) may be used to apply the chemical agent to the treatment area.

Fig. 5A illustrates another example of a distal end of a catheter having a shape memory spiral 500, including an electrode 512 and an aperture 516 for delivering a chemical agent. In a number of different examples, the catheter has two or more lumens for delivering the chemical agent that terminate at one of the holes 516 in the shape-memory spiral 500. Fig. 5B is a cross-sectional view of the shape-memory spiral 500 along line a in fig. 5A. The shape memory spiral 500 includes a bore 516 and a plurality of lumens 518. In a number of different examples, the lumen may define a passageway for a chemical agent or may contain one or more conductors, such as shown in lumen 520. A conductor or lead is electrically connected to each electrode. A shape memory material such as nitinol may be present in the central lumen 522. The shape memory spiral 500 may further include an insulating material 524 surrounding the shape memory material in the central lumen 522 and defining the lumens 518 and 520.

Fig. 5C illustrates another example of the distal end of a catheter having a shape memory spiral 540 that includes an electrode 552 and a retracting needle 548 for delivering a chemical agent. The needle 548 may be advanced and retracted from the outer surface of the shape memory spiral 540 to inject the chemical agent into the tissue of the blood vessel. In various embodiments, the needle 548 can penetrate adjacent tissue to a depth of about 2mm, about 3mm, or about 4 mm. The injection of the chemical agent may be performed before, during, or after the denervation therapy, or a combination thereof.

Fig. 5D is a cross-sectional view of the shape memory spiral 540 and shows the lumen 554 for the retracting needle 548. In various embodiments, the needle 548 and corresponding lumen 554 are positioned along the outside of the shape memory spiral 540 such that the needle 548 deploys into the tissue surface of the blood vessel. The shape memory spiral 540 further includes a lumen 556 for a conductor, and a conductor or lead is electrically connected to each electrode. A shape memory material, such as nitinol, may be present in the central lumen 562. Shape-memory spiral 540 may further include an insulating material 564 surrounding central lumen 562 and defining lumens 554 and 556.

Fig. 6 is a schematic illustration of a nerve-denervation catheter assembly 600 having a wire-frame radially expandable member 610 with electrodes 612 and an outer surface 614 coated with a chemical coating containing a nerve growth inhibitor, according to some examples.

The wireframe structure 610 includes a plurality of wires 616 extending from a proximal end 618 of the structure to a distal end 620 of the structure. Each wire supporting at least one electrode. In a number of different examples, each wire 616 supports two electrodes, three electrodes, four electrodes, five electrodes, six electrodes, or another number of electrodes. Each electrode 612 defines a portion of the outer surface of the radially expandable member. Portions of the outer surface of the radially expandable member include a chemical coating.

The catheter body 608 can define a sheath such that the radially expandable member 610 can be contained within the catheter body 608 when the radially expandable member is in an unexpanded state. Wire 616 may comprise a shape memory material such as nitinol. In a number of different examples, the wireframe structure 610 is formed to have an expandable basket shape. In a number of different examples, a wire frame structure 610 is attached to the shaft within the catheter body 608 at its proximal end 618. In a number of different examples, a rod may be used to push the wire-frame structure 610 out of the catheter body 608, causing the wire-frame structure 610 to spring back to its expanded shape. When the rod is pulled in a proximal direction, the wireframe structure 610 is pulled, constrained, and assumes its unexpanded shape within the catheter body 608.

Additionally or alternatively, the distal rod may extend to the distal end 620 of the wireframe structure 610. The pushing and pulling of the distal lever may cause the basket to expand and fold. With such a design, the wire 616 may not need to rely on a shape memory material such as nitinol, but may instead be made of a shape retention material such as stainless steel. Additionally or alternatively, the wire 616 may be made of a flexible wire. An example of such flex circuitry is included in an INTELLAMAP ORIONTM mapping catheter available from Boston Scientific Corporation (Boston Scientific Corporation Inc., located headquarters in marberler, MA, USA).

In various examples, the diameter of the wireframe structure in its expanded state is sized to ensure intimate contact with the inner diameter of the lumen. Examples of diameters and other dimensions of radially expandable members, such as wire frame structures, are provided herein.

Fig. 7 is a schematic diagram of a denervation catheter assembly 700 having an inflatable balloon 710 with electrode strips 712 and defining apertures 714 for dispensing a chemical agent containing a nerve growth inhibitor, according to some examples. The inflatable balloon 710 is connected to the catheter body 708 at the proximal end 718 of the inflatable balloon. The catheter body 708 may include an inflation lumen to inflate the balloon 710 from the unexpanded configuration to the expanded configuration. The catheter body 708 may also include a sheath for retracting the balloon 710 into the sheath when the balloon 710 is in an unexpanded state.

Electrode strip 712 may include one electrode (such as for a monopolar device) or a plurality of electrodes. The one or more electrodes may be configured to deliver denervation therapy to the entire 360 degree circumference of the lumen or a circumferential range less than it, such as up to at least about 30 degrees, at least about 45 degrees, at least about 60 degrees, at least about 90 degrees, at least about 120 degrees, at least about 150 degrees, at least about 180 degrees, up to about 210 degrees, up to about 240 degrees, up to about 270 degrees, at least about 30 degrees and up to about 270 degrees, or at least about 45 degrees and up to about 180 degrees. The helical configuration of the electrode strip does not deliver therapy to the entire 360 degree circumference at the same axial location, thus reducing the likelihood of an acute response leading to complete constriction of the vessel.

The diameter of the holes 714 may range from 0.1 microns to 5 millimeters. In one example, hundreds of holes 714 are defined in the inflatable balloon 710, each hole having a diameter of about 0.5 microns. The holes may be oriented on one or both sides of the electrode strip, as shown in fig. 7, or may be in other patterns. The holes may cover the entire outer diameter of the balloon in contact with the luminal surface of the blood vessel.

Fig. 8 is a schematic diagram of a denervation catheter assembly 800 having an inflatable balloon 810 with electrodes 812 and an array of microneedles 814 for dispensing a chemical agent containing a nerve growth inhibitor, according to some examples. In various embodiments, holes may be provided in place of microneedles 814, wherein the holes may dispense nerve growth inhibitor or fluid.

In the example of fig. 8, a pair of microneedles 814 flank each electrode 812. The microneedles 814 may penetrate into the vessel wall to deliver the chemical agents. By increasing the depth of delivery of the chemical agent, the effectiveness of the chemical agent against nerve regrowth may be increased. The microneedles 814 may also be connected to sensing circuitry to detect the impedance of the tissue between each pair of microneedles 814.

The inflatable balloon 810 is connected to the catheter body 808 at the proximal end 818 of the inflatable balloon. The catheter body 808 may include an inflation lumen to inflate the balloon 810 from an unexpanded configuration to an expanded configuration. The catheter body 808 may also include a sheath for retracting the balloon 810 into the sheath when it is in its unexpanded state.

In one example, the microneedles deploy or more fully deploy when the balloon is pressurized. In other words, the needles protrude more completely from the outer surface of the balloon when pressure is applied internally. To avoid tissue damage (e.g., snagging of tissue with a needle) during delivery of the balloon catheter, the balloon will be in a folded state and within the delivery sheath during delivery of the balloon to the treatment site. The needles may protrude from the balloon surface in the range of 0.1mm to 1 mm. The needle may be used to measure electrical impedance of a local region, deliver denervation therapy (such as radiofrequency energy), or both.

The balloon may include one or more needles near each electrode. In various examples, the needles are spaced apart by at least about 1mm and at most about 10 mm. In various examples, the balloon includes at least about 2 microneedles and at most about 2000 microneedles, or preferably at least about 20 microneedles and at most about 200 microneedles, around the circumference of the balloon.

Fig. 9 is a schematic view of a catheter assembly 900 for delivering a chemical agent deployed within a blood vessel 902, the catheter assembly having a catheter body 908, a first inflatable balloon 910, and a second inflatable balloon 911. Catheter assembly 900 may be used to treat a length of blood vessel 902 with a nerve growth inhibitor after a denervation treatment to reduce nerve regrowth after the denervation treatment.

The catheter body 908 may include an inflation lumen to inflate the balloons 910, 911 from an unexpanded configuration to an expanded configuration. The catheter body 908 may also include a sheath for retracting the balloons 910, 911 into the sheath when it is in an unexpanded state. After the first and second balloons are deployed, spaced apart from each other, and inflated, a nerve growth inhibitor 916 may be injected into and circulated within the space 914 between the balloons. Residual nerve growth inhibitor may be removed prior to deflating the balloon.

In various examples, the balloon, when inflated, has a diameter of at least about 2mm, at least about 3mm, at most about 10mm, at most about 5mm, at least about 2mm and at most about 10mm, or at least about 3mm and at most about 5 mm. The distance between the balloons may range from at least about 10mm to at least about 50 mm.

Catheter assembly 900 may be configured to deliver electrical energy (e.g., electroporation) to the fluid between the two balloons to increase the permeability of the nerve growth inhibitor into the vessel wall. The balloon material may include polyethylene terephthalate (PET), thermoplastic elastomers such as PEBAXTM thermoplastic elastomer available from Arkema of akoma corporation of King of Prussia, Pennsylvania, USA at the service location, nylon, non-compliant balloon material, and semi-compliant balloon material.

Methods of denervation treatment

A method of treatment according to various examples described herein includes providing a catheter including a radially expandable member and a plurality of electrodes on an outer surface of the radially expandable member. The electrodes are configured to deliver energy during a denervation procedure in the blood vessel. The radially expandable member further includes a chemical coating on the outer surface.

The system may include a guide wire, and the catheter may include a guide wire channel. The catheter may be introduced to a treatment site within a patient by advancing a guide wire to the treatment site, advancing a catheter assembly over the guide wire until a distal end of the catheter assembly is positioned adjacent the treatment site, and advancing an unexpanded, radially expandable member away from the catheter sheath. Other techniques for positioning the radially expandable member at the treatment site may also be used.

The radially expandable member is expanded from a first unexpanded configuration to a second expanded configuration. Many different types of radially expandable members may be used in this step, such as the examples described herein and in the incorporated documents. The radially expandable member is configured to contact the outer surface with a vessel wall when it is in the expanded configuration. In one example, the radially expandable member is configured to contact the outer surface with the hepatic vessel wall of the patient when it is in the expanded configuration.

The electrical energy is used at a target site of a subject using electrodes of a radially expandable member to perform a denervation procedure. The denervation procedure may be a radio frequency ablation procedure, an irreversible electroporation procedure, or another denervation procedure including other examples described herein and in the incorporated documents.

In a number of different examples, the treatment site is within a blood vessel, lumen, or other vasculature of the patient. In a number of different examples, the radially expandable member is advanced through the vasculature of the patient to the treatment site. In other words, the radially expandable member is delivered intravascularly.

At least one chemical agent that inhibits or prevents nerve regeneration is introduced to the target site proximate in time to the denervation procedure. In a number of different examples, the chemical agent is present in a chemical agent coating on an outer surface of the radially expandable member. In other examples, there is no chemical coating on the outer surface, and the chemical is injected into the vessel wall or circulates in the vessel at the target site. In some examples, a single catheter assembly is configured to perform a denervation procedure and deliver a chemical agent. In other examples, one catheter assembly provides a denervation procedure and another catheter assembly delivers a chemical agent.

In some examples, the chemical agent is delivered after denervation therapy. In some examples, the chemical agent is delivered concurrently with denervation therapy. In some examples, the nerve growth inhibitor is in contact with a surface of a vessel wall before the denervation therapy is delivered. For example, where a drug-coated balloon has electrodes on its surface, once the balloon is inflated, the drug will come into contact with the inner surface of the vessel prior to administration of the denervation therapy.

The method may further include measuring impedance between the combination of independent electrodes. The method may further include measuring an impedance between the one or more electrodes and a reference ground patch located on the skin of the patient. For example, the system may measure the impedance between the first electrode and the ground pad, between the second electrode and the ground pad, or both. The measurement of impedance may provide information about the progress of the denervation procedure, contact of the electrodes with the vessel wall, and other information.

Size and material of the radially expandable member

In various examples, the diameter of the radially expandable member in its expanded state is at least about 1mm, at least about 2mm, at least about 3mm, at most about 20mm, at most about 10mm, at most about 7mm, at least about 1mm and at most about 20mm, at least about 2mm and at most about 10mm, or at least about 3mm and at most about 7 mm.

In various examples, the length of the radially expandable member in its expanded state is at least about 10mm, at least about 20mm, at most about 30mm, at most about 50mm, at least about 10mm and at most about 50mm, at least about 20mm and at most about 30mm, or about 25 mm.

Where the radially expandable member is a balloon, the balloon material may include polyethylene terephthalate (PET), thermoplastic elastomers such as PEBAXTM thermoplastic elastomer available from Arkema of akoma corporation of Prussia, Pennsylvania, USA at the service location, nylon, non-compliant balloon material, and semi-compliant balloon material.

Examples of nerve growth inhibitors

The nerve growth inhibitor used with any of the example medical devices described herein may include one or a combination of the following agents. In a number of different examples, the nerve growth inhibitor may be provided as a coating, as a liquid, or may be encapsulated in microparticles or nanoparticles within a biodegradable shell. The encapsulated configuration may allow for the modulated release of the nerve growth inhibitor over a period of up to three months.

Classes of nerve growth inhibitors

Classes of nerve growth inhibitors include inhibitors of extracellular proteins such as laminin, fibronectin, tenascin, fibrinogen and fibrin. Nerve growth inhibitors may include inhibitors of neurotrophic factors such as Nerve Growth Factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3(NT-3), NT4-5, or glial-derived nerve growth factor (GDNF). Nerve growth inhibitors may include neuropeptide (neuroproteins) inhibitors such as Leukemia Inhibitory Factor (LIF) and ciliary neurotrophic factor (CNTF), oncostatin m (osm), and interleukin 6 (IL-6).

The nerve growth inhibitor may be an inhibitor of a neurotrophin receptor such as tyrosine kinase receptors (TrkA, TrkB and trkc), a common neurotrophin receptor (P75NTR), an ErbB receptor or a fibroblast growth factor receptor. The nerve growth inhibitor may be an inhibitor of Cell Adhesion Molecules (CAM) such as N-CAM, Ng-CAM/L1, N-cadherin, and L2-HWk-1. The nerve growth inhibitor may be an inhibitor of cell signaling molecules such as Ras, phosphatidylinositol 3-kinase, phospholipase c-gamma 1, mitogen-activated phosphokinase, protein kinase A, Janus kinase (JAKs), signal transducers, and transcriptional activators (JAKs/STATs signaling molecules). Kinase inhibitors include staurosporine, H89, dihydrochloride, cyclic adenosine monophosphate Rp (cAMPS-Rp), triethylammonium salt, KT 5720, wortmannin, LY294002, 1C486068, 187114, GDC-0941, gefitinib, erlotinib, lapatinib, AZ623, K252a, KT-5555, cyclotaraxin-B, lesotinib, tofacitinib, ruxotinib, SB1518, CYT387, LY3009104, TG101348, WP-1034, PD173074, and Sprouty RTK signal antagonist 4(SPRY 4). The nerve growth inhibitor may be an inhibitor of cytokines and chemokines, including interleukin-6, leukemia inhibitory factor, transforming growth factor 131, and monocyte chemotactic protein 1.

The nerve growth inhibitor may be an inhibitor of sulfated proteoglycans such as keratan sulfate proteoglycans. The nerve growth inhibitor may be an inhibitor of chondroitin sulfate proteoglycan such as proteoglycan, brevican, versican, phosphatase proteoglycan, aggrecan, and NG 2. The nerve growth inhibitor may be an inhibitor of enzymes including arginase I, chondroitinase ABC, 13-secretase BACE1, urokinase-type plasminogen activator, and tissue-type plasminogen activator. The nerve growth inhibitor may be an inhibitor of arginase including N-hydroxy-L-arginine and 2(S) -amino-6-borohexanoic acid. The nerve growth inhibitor may be an inhibitor of 13-secretase such as N-benzyloxycarbonyl-Val-Leu-leucine, H-Glu-Val-Asn-Statine-Val-Ala-Glu-Phe-NH2, and H-Lys-Thr-Glu-Glu-Ile-Ser-Glu-Val-Asn-Stat-Val-Ala-Glu-Phe-OH. The nerve growth inhibitor may be an inhibitor of urokinase-type and tissue-type plasminogen activators, including serine protease inhibitor El, tibiaxtinin, and plasminogen activator inhibitor-2.

The nerve growth inhibitor may be an inhibitor of myelin-derived molecules such as myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, Nogo-A/B/C, semaphorin 4D, semaphorin 3A, and ephrin-B3.

Specific examples of nerve growth inhibitors

Nerve growth inhibitors used in conjunction with the first medical treatment may include paclitaxel, semaphorin-3A, fibrin, brain-derived neurotrophic factor (BDNF), myelin-derived factors including NogoR and PirB, PTEN (dihydrogen phosphate and tendon homolog), SOCS3, Notch signaling (Notch/lin12), and ZnEgr.

Carriers and excipients in combination with nerve growth inhibitors

The carrier, excipient, or both may be combined with a nerve growth inhibitor for use with the systems described herein. The carrier may produce a delayed release, for example, such that the nerve growth inhibitor is released over a time course such as days, weeks or months. In various examples, the modulated release of the nerve growth inhibitor occurs at about one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, or six months.

In a number of different examples, the nerve growth inhibitor is encapsulated in microparticles, such as microspheres or nanoparticles, within a biodegradable shell or matrix, thereby allowing for the modulated release of the nerve growth inhibitor. In a number of different examples, the microparticles may be a solid with the drug mixed with the microparticle material. Biostable or biodegradable polymers are examples of particulate materials. The microparticles may be injected into the vessel wall or target tissue. The particulate material may be a biodegradable matrix material such as polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), poly-L-lactic acid (PLLA) or other biostable or biodegradable polymers.

Some excipients can help transport the nerve growth inhibitor deeper into the vessel wall (such as the hepatic vessel wall). The advantages obtained are similar to those obtained by electroporation. In various examples, the nerve growth inhibitor is combined with an excipient that promotes transfer to a target nerve location across the luminal surface of a hepatic artery or another blood vessel. Exemplary excipients include polysorbate, sorbitol, urea, iopromide, citrate excipients such as, for example, the transpax (tm) coatings available from Boston Scientific Corporation Inc, marberler, MA, USA, headquarters, tributyl citrate (BTHC), shellac, or keratin hydrogels.

Example of a denervation program

A first treatment may include denervation of neural tissue of the liver using: electrical energy, radiofrequency energy, irreversible electroporation, microwave energy, ultrasound energy, focused ultrasound (e.g., High Intensity Focused Ultrasound (HIFU), Low Intensity Focused Ultrasound (LIFU)), laser energy, infrared energy, optical energy, thermal energy, steam or heated water, magnetic fields, reversible electroporation, cryotherapy, brachytherapy, ionization therapy, drug delivery, biological delivery, chemical ablation (e.g., ethanol), mechanical disruption, any other form of therapy that causes destruction or modulation of target tissue, or any combination thereof.

During delivery of denervation therapy, such as radiofrequency ablation, saline or another fluid may be delivered to cool the inner surface of the lumen. Such cooling fluid may be provided to the inner surface of the lumen at the same time as the nerve growth inhibitor is delivered.

Parameters of radiofrequency ablation

In various examples, such as using the radially expandable member of fig. 2, the frequency of the energy is about 20kHz to 5MHz, or about 400kHz to 500kHz, e.g., 460 kHz. The target temperature for the embedded temperature sensor is about 60 ℃ to 95 ℃, or about 80 ℃. The duration of the application of the radiofrequency energy ranges from about 10 seconds to 5 minutes, or ranges from about 30 seconds to 2 minutes.

The energy may be applied (1) simultaneously, (2) sequentially, or (3) in a time-switched manner. Time-switched means that energy is applied to one or more selected electrodes for a short period of time (e.g. 20 milliseconds) and then to one or more other selected electrodes for another short period of time. The energy application is rapidly switched between the electrodes.

Parameters of irreversible electroporation

For irreversible electroporation, the pulse width ranges from 10 nanoseconds to 1 millisecond, or 1 microsecond to 75 microseconds. The pulses may be biphasic (having a positive and a negative phase) or monophasic. The voltage ranges from 200V to 5000V, or 1000V to 3000V, such that the electric field strength in the tissue is from 500V/cm to 2000V/cm, such as 1000V/cm to 1500V/cm, to cause cell damage.

Parameters of electroporation to facilitate drug permeation

For reversible electroporation, the pulse width ranges from 10 nanoseconds to 1 millisecond, preferably 1 microsecond to 75 microseconds. The pulses may be biphasic (having a positive and a negative phase) or monophasic. The voltage ranges from 50V to 5000V, such as 100V to 3000V, such that the electric field strength in the tissue is from 50V/cm to 800V/cm, such as 100V/cm to 400V/cm, to cause reversible cell damage to allow the drug to penetrate the membrane.

It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" includes mixtures of two or more compounds. 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, apparatus, or other structure that is constructed or arranged to perform a particular task or to adopt a particular configuration. The phrase "configured to" may be used interchangeably with other similar phrases (such as "arranged and configured to", "constructed and arranged to", "constructed to", "manufactured and arranged to", 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 in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

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.