FIELD

[0001] The disclosure relates generally to therapeutic tissue modulation and, more specifically, to embodiments of devices, systems and methods for therapeutically effecting neuromodulation (e.g., hepatic denervation) of targeted nerve fibers innervating various organs (for example, the liver, pancreas, and/or small intestine) to treat metabolic diseases or conditions (e.g., diabetes melhtus, fatty liver conditions or factors of metabolic syndrome). Some implementations include automated/robotic elements for, as an example, facilitating robotically controlled laparoscopic access, navigation, imaging, and/or treatment.

BACKGROUND

[0002] Chronic hyperglycemia is one of the defining characteristics of diabetes melhtus. Hyperglycemia is a condition in which there is an elevated blood glucose concentration. An elevated blood glucose concentration may result from impaired insulin secretion from the pancreas and also, or alternatively, from cells failing to respond to insulin normally. Excessive glucose release from the liver is a significant contributor to hyperglycemia. The liver is responsible for approximately 90% of the glucose production and 33% of glucose uptake, and derangements in both in type 2 diabetes contribute to hyperglycemia in the fasting and post-prandial states.

[QQQ3] Type 1 diabetes mellitus results from autoimmune destruction of the pancreatic beta cells leading to inadequate insulin production. Type 2 diabetes mellitus is a more complex, chronic metabolic disorder that develops due to a combination of insufficient insulin production as well as cellular resistance to the action of insulin. Insulin promotes glucose uptake into a variety of tissues and also decreases production of glucose by the liver and kidneys; insulin resistance results in reduced peripheral glucose uptake and increased endogenous glucose output, both of which drive blood the glucose concentration above normal levels.

[0004] C Current estimates are that approximately 26 million people in the United

States (over 8% of the population) have some form of diabetes melhtus. Treatments, such as medications, diet, and exercise, seek to control blood glucose levels, which require a patient to closely monitor his or her blood glucose levels. Additionally, patients with type 1 diabetes mellitus, and many patients with type 2 diabetes meilitus, are required to take insulin every day. Insulin is not available in a pill form, however, but must be injected under the skm. Because treatment for diabetes meilitus is self-managed by the patient on a day-to-day basis, compliance or adherence with treatments can be problematic.

SUMMARY

[0005] In accordance with several embodiments, systems, devices and methods for accessing and modulating (e.g., denervating, ablating) nerves (e.g., nerves innervating a liver, nerves innervating a pancreas, nerves innervating a kidney, and/or nerves innervating a duodenum) surrounding a hepatic artery (e.g., common hepatic artery) or other artery, vein or vessel using a laparoscopic approach (e.g., via small percutaneous incisions or punctures made through a skin of the patient) are disclosed. Robotic, or automated, systems may be used to laparoscopically access and navigate treatment and/or imaging devices to target treatment locations. There can be many different tissues surrounding the hepatic artery and it can be difficult to locate and identify the nerves that one is attempting to modulate (e.g., ablate). In addition, the locations of the nerves and the arrangement and density of the nerves may vary significantly from patient to patient. In some patients, the nerves may be located a sufficiently large distance away from a lumen of a vessel (e.g., hepatic artery) that endovascular ablation may not be as effective as laparoscopic perivascular ablation at ablating all of the targeted nerves. If all of the targeted nerves are not completely ablated, there is a potential for the nerves to resume neural communications and reduce or reverse any improvement obtained from the neuromodulation (e.g., ablation) procedure. In some embodiments, an open surgical approach or an approach through a natural body orifice may be used. In accordance with several embodiments, laparoscopic approaches and tools described herein (1) do not require removal of fatty tissue, (2) provide effective treatment regardless of variations in anatomy (e.g., location, arrangement, density of nerves surrounding a hepatic artery or otherwise innervating a liver or pancreas) from patient to patient; (3) do not interfere wath blood flow wathin vessels; (4) reduce likelihood of damage to vessel lumens during treatment procedures; and/or (5) facilitate ease of confirmation of treatment via visualization of the nerves or use of electrophysiological mapping or stimulation systems to confirm efficacy of ablation of nerves.

[0006] In accordance with several embodiments, a system for laparoscopically modulating nerves to effect denervation of one or more organs or innervated tissue (e.g., liver, pancreas, duodenum, jejunum, kidney, adrenal gland, spleen, stomach, etc.) includes a laparoscopic denervation device having a proximal end and a distal end. The denervation device has a length sized to extend from an incision m an abdominal wall to a perivascular location adjacent or along a hepatic artery (e.g., common hepatic artery, proper hepatic artery, left hepatic artery, right hepatic artery) or other adjacent artery or vein (e.g., splenic artery, superior mesenteric artery, inferior mesenteric artery, gastroduodenal artery, gastric artery). The distal end of the denervation device is configured to effect ablation of one or more perivascular nerves surrounding the hepatic artery and/or other vessels or tissue sufficient to effect hepatic denervation, either alone or in combination with pancreatic denervation or denervation of other organs or glands.

[QQQ7] In some embodiments, the distal end of the laparoscopic denervation device includes a shaped tool configured to separate perivascular nerves from the hepatic artery or other vessel and deliver radiofrequency energy to the perivascular nerves sufficient to ablate the perivascular nerves. The shaped tool may include at least one ablation electrode. In one implementation, the shaped tool includes two hoop-shaped clamp arms sized and configured to extravascularly wrap around the hepatic artery or other vessel. In this implementation, each clamp arm may include one or more ablation electrodes. In one implementation, the shaped tool has a spiral configuration comprising one or more complete 360 degree spiral turns. In this implementation, there may be at least one ablation electrode on each of the one or more complete spiral turns.

[0008] In some implementations, the distal end of the laparoscopic denervation device includes a delivery portion configured to deliver ablation agents to target perivascular nerves surrounding the hepatic artery or other vessel. The delivery portion may include at least one outlet orifice or infusion port. The deliver portion may be configured to deliver liquid, solid, and/or gaseous ablation agents. The ablation agent may comprise foam material.

[0009] The system may further include an illumination device configured to provide illumination to the perivascular nerves and surrounding tissue. In one implementation, the illumination device is a catheter configured to wrap around the laparoscopic denervation device and to deliver illumination. In one implementation, the illumination device includes a malleable sheet configured to wrap around the laparoscopic denervation device and to deliver illumination. The system may optionally further include a camera or visualization scope configured to facilitate visualization of the distal end portion or the laparoscopic denervation device and/or the perivascular nerves. The camera or visualization scope (e.g., laparoscope, fiber optic camera) may be inserted through a minimally invasive incision in an abdominal or pelvic wall. Images captured by the camera or visualization scope may be displayed on a display device coupled (via wired or wireless connection) to the camera or visualization scope.

[0010] In accordance with several embodiments, a system for laparoscopically modulating nerves (e.g., to effect hepatic denervation, either alone or m combination with denervation of other organs or innervated tissue) includes a laparoscopic denervation device having a proximal end and a distal end. The device has a length sized to extend from an incision in an abdominal wall to a perivascular location surrounding a target vessel (e.g., hepatic artery). The distal end of the denervation device includes a treatment portion configured to effect denervation of perivascular nerves surrounding the target vessel (e.g., hepatic artery). The treatment portion is configured to transition from a straight configuration to a shaped, non-straight configuration. The treatment portion comprises shape memory material. The treatment portion includes a plurality of outlet orifices configured to deliver an ablation agent adapted to ablate the perivascular nerves surrounding the target vessel and/or a plurality of energy delivery elements configured to deliver energy sufficient to ablate the perivascular nerves surrounding the target vessel . The plurality of outlet orifices and/or the plurality of energy delivery elements are spaced apart along the treatment portion when the treatment portion is in the shaped, non-straight configuration. The system may include an outer sheath or an inner stylet or guidewire configured to be retracted toward the proximal end of the denervation device so as to allow the treatment portion to transition from the straight configuration to the shaped, non-straight configuration, and thereby be wrapped around the target vessel.

[0011] In various implementations, the shape of the shaped, non-straight configuration is a spiral, a hook, a loop, an angle, a hockey stick shape, or a hoop. In one implementation, the shaped, non-straight configuration is a spiral (e.g., pigtail, corkscrew') configuration that includes at least one complete 360-degree spiral turn. In some implementations, the spiral configuration includes 1.5 to 3 spiral turns (e.g., 1.5, 2, 2.5, 3).

[0012] In some embodiments, the treatment portion comprises a plurality of outlet orifices spaced apart along the treatment portion (e.g., 2-20 orifices per turn, 3-12 orifices per turn, 3-10 orifices per turn, 4-10 orifices per turn, overlapping ranges thereof, or any value within the recited ranges). For example, the plurality of outlet orifices may be spaced apart between 15 degrees and 30 degrees along a respective spiral turn when in the spiral configuration. The orifices or ports may be spaced at equal distances apart from each other or at different distances. The orifices or ports may be positioned on the treatment portion so as to be oriented to deliver ablation agents tow¾rd the perivascular nerves (e.g., toward an outer vessel wall of a hepatic artery) when the treatment portion is in the non-straight configuration (e.g., spiral configuration).

[QQ13] In some embodiments, the treatment portion includes a plurality of energy delivery elements (e.g., radiofrequency electrodes, ultrasound transducers, microwave antennae/emitters, laser emitters, etc.) spaced apart along the length of the treatment portion (e.g., 2-20 elements per turn, 3-12 elements per turn, 3-10 elements per turn, 2-6 elements per turn, overlapping ranges thereof, or any value within the recited ranges). For example, the energy delivery' elements may be spaced apart between 15 degrees and 30 degrees along a respective spiral turn when in a spiral configuration. The energy delivery' elements may be spaced at equal distances apart from each other (e.g., uniformly) or at different distances. The energy delivery elements may be positioned on the treatment portion so as to be oriented to deliver energy directed toward the perivascular nerves (e.g., toward an outer vessel wall of a hepatic artery) when the treatment portion is in the non-straight configuration (e.g., spiral configuration).

[0014] In accordance with several embodiments, a system for laparoscopically modulating nerves (e.g., to effect hepatic denervation, either alone or in combination with denervation of other organs or innervated tissue) includes a laparoscopic denervation device having a proximal end and a distal end. The device has a length sized to extend from an incision in an abdominal wall to a perivascular location surrounding a target vessel (e.g., hepatic artery). The distal end of the denervation device includes a treatment portion configured to effect denervation of perivascular nerves surrounding the target vessel (e.g., hepatic artery). The treatment portion is configured to transition from a straight configuration to a spiral configuration. The treatment portion comprises shape memory material (e.g., nitinol). The treatment portion includes a plurality of outlet orifices configured to deliver an ablation agent adapted to ablate the perivascular nerves surrounding the target vessel and/or a plurality of energy delivery elements configured to deliver energy sufficient to ablate the perivascular nerves surrounding the target vessel. The plurality of outlet orifices and/or the plurality of energy delivery elements are spaced apart along the treatment portion when the treatment portion is in the spiral configuration. The system may include an outer sheath or an inner stylet or guidewire configured to be retracted toward the proximal end of the denervation device so as to allow the treatment portion to transition from the straight configuration to the spiral configuration. When the treatment portion is in the spiral configuration, the treatment portion comprises at least one complete 360-degree spiral turn. The plurality of outlet orifices or the plurality of energy delivery elements may be located every 15 degrees to 60 degrees, every 15 degrees to 30 degrees, every 30 degrees to 60 degrees, every 45 degrees to 90 degrees, or every 60 degrees to 120 degrees along the treatment portion when the treatment portion is in the spiral configuration. The orifices or energy deliver _}? elements may be uniformly spaced or non-uniformly spaced

[0015] In some implementations, the treatment portion, when in the spiral configuration, has an internal spiral lumen diameter of between 0.4 cm and 0.9 cm so as to extravascularly contact or closely surround an external surface of a common hepatic artery. A system may include denervation devices having different internal spiral lumen diameters sized and configured to be used for different vessels.

[0016] In some implementations, the treatment portion comprises 1.5 to 3 complete 360-degree turns when in the spiral configuration (e.g., 1.5, 2, 2 5, 3 turns). The denervation device may comprise a catheter that is reinforced with one or more braided wires, coils, or slotted hypotubes to provide torqueability to the denervation device.

[0017] In some implementations, the treatment portion includes a plurality of outlet orifices and not a plurality of energy delivery elements. The plurality of outlet orifices may have a diameter of between 0.025 mm and 2 mm (e.g., between 0.025 mm and 0.20 mm, between 0.05 mm and 0.10 mm, between 0.10 mm and 0.50 mm, between 0.25 mm and 0.75 mm, between 0.50 mm and 1.0 mm, between 0.75 mm and 1.5 mm, between 1 mm and 2 mm, overlapping ranges thereof, or any value within the recited ranges) depending on the type of ablation agent. The outlet orifices may advantageously be uniformly or evenly distributed. The ablation agent may he in solid, liquid, or gaseous form upon delivery . The ablation agent may be a foam or water vapor (e.g., steam). When liquid agents are used, the diameter of the outlet orifices may be sized to deliver the liquid as a high velocity jet or as a slow trickle. For example, the liquid agent may comprise alcohol, phenol, and/or glycerol in some implementations, the ablation agent is a desiccating agent (e.g., a dry gas). The gas may be delivered at a pressure greater than 5 atm.

[0018] In accordance with several embodiments, a method of ablating nerves surrounding a target vessel (e.g., hepatic artery) includes forming a plurality of incisions m an abdominal area of a subject, inserting a visualization device through a first one of the plurality of incisions to facilitate visualization, and inserting a treatment device through a second one of the plurality of incisions. A distal end portion of the treatment device is configured to transition from a straight configuration to a non-straight configuration (e.g., spiral configuration). The distal end portion of the treatment device comprises shape memory' material. The distal end portion of the treatment device includes a plurality' of outlet orifices configured to del iver an ablation agent suffici ent to ablate nerves surrounding the target vessel and/or a plurality of energy delivery elements configured to del iver energy sufficient to ablate nerves surrounding the target vessel . The outlet orifices and/or the energy delivery elements are spaced apart along the distal end portion (e.g., located every 15 degrees to 30 degrees along the distal end portion when the distal end portion is in a spiral configuration).

[0019] The method further includes advancing the distal end portion of the treatment device toward the hepatic artery under visualization performed by the visualization device, positioning the distal end portion of the treatment device along a target ablation region of the hepatic artery comprising the nerves, causing the distal end portion of the treatment device to transition from the straight configuration to the non-straight (e.g., spiral) configuration such that the distal end portion of the treatment device wraps around the target ablation region of the target vessel (e.g., common hepatic artery), and ablating the target ablation region of the target vessel with the treatment device.

[0020] In some implementations, the non-straight configuration is a spiral configuration (e.g., pigtail, corkscrew shape) that includes at least one complete 360 degree turn (e.g., 1 turn, 1.5 turns, 2 turns, 2.5 turns, 3 turns). The nerves may include sympathetic nerves of a hepatic plexus. The treatment device may include any of the structural features of the denervation devices or other treatment devices described herein. [0021] In one implementation, the step of causing the distal end portion of the treatment device to transition from the straight configuration to the non-straight configuration includes retracting an inner stylet or guidewire from the distal end portion toward a proximal end portion of the treatment device, thereby allowing the distal end portion to transition from the straight configuration to the non-straight configuration. In another implementation, the step of causing the distal end portion of the treatment device to transition from the straight configuration to the spiral configuration includes retracting an outer sheath surrounding the distal end portion toward a proximal end portion of the treatment device, thereby allowing the distal end portion to transition from the straight configuration to the non-straight configuration.

[ 0022] In some implementations, the method includes confirming ablation of the nerves within the target ablation region. The method may further include providing enhanced visualization of the target ablation regi on of the target vessel (e.g , common hepatic artery) by advancing a light source to a location adjacent the target vessel, positioning the light source behind a section of perivascular ti ssue surrounding the target vessel, and illuminating the target vessel through the perivascular tissue using the light source.

[0023] The method may optionally include providing enhanced visualizati on of the target ablation region of the target vessel by delivering an index matching fluid into tissue surrounding the perivascular nerves, applying heat via a heat source to the tissue, and illuminating the tissue with a tight source. The method may optionally include providing enhanced visualization of the target ablation region of the target vessel by injecting a staining agent into perivascular nerves and tissue surrounding the target vessel.

[0024] The method may further include advancing the treatment device to a second target ablation region. The second target ablation region may be a different region along the same target vessel (e.g., common hepatic artery) or a different target vessel (e.g., a different hepatic artery, a gastric artery, a gastroduodenal artery, a renal artery , a mesentenc artery, or a splenic artery ). The second target ablation region may be designed to effect denervation of one or more organs, glands, or tissues other than the liver (e.g., pancreas, kidney, stomach, adrenal gland, spleen, duodenum) designed to address multiple factors or symptoms of metabolic syndrome.

[0025] In some implementations, automated/ robotic systems for accessing and/or treating (e.g., ablating, stimulating) nerves surrounding (e.g., m penvascular space or area of) vessels (e.g., hepatic arteries, gastroduodenal arteries, mesenteric arteries, renal arteries, and other arteries, veins or vessels disclosed herein) and/or organs (e.g., liver, pancreas, small intestine, stomach, spleen, kidney, or other organs disclosed herein) are provided. In accordance with several embodiments, robotically-enabled or robotically-controlled surgical, access, and/or treatment tools may provide a high level of control and precision of movement and increased dexterity and range of motion, thereby providing increased assurance that accessing and treating target locations will not cause injury to tissue not desired to be impacted. Robotically-controlled tools and techniques may also be used to facilitate navigation to, and surgical operation at, desired target treatment regions that may be difficult to access manually, thereby providing enhanced flexibility and possibilities thought not to be possible via open surgery performed manually by clinicians. Robotically-controlled tools and techniques may further be used to facilitate capture of images pre-operatively or intra-operatively without exposing the target treatment regions to radiation or without requiring large incisions to be made. Robotic, or automated, systems may be used to laparoscopically access and navigate treatment and/or imaging devices to target treatment locations, such as any of the devices and methods described herein.

[0026] In accordance with several embodiments, given the difficulty in identifying and isolating the nerves surrounding the hepatic artery, a mechanical method of constricting all the tissue surrounding the hepatic artery without the need to expose or identify the nerve fibers that leads to sympathetic and parasympathetic nerve disruption could be beneficial. This disclosure describes devices and methods of using loop constriction to denervate around the hepatic artery as well as combination laparoscopic tools to aid in the denervation process. One method to kill (e.g., destroy or render non-functional) the sympathetic and parasympathetic nerve fibers around an arterial lumen would be to completely encapsulate the lumen and surrounding tissue in a mechanical loop. This mechanical loop could then provide compressive forces that would acutely or chronically, over time, restrict the blood flow to the nerves causing the nerve fibers to die. Another loop method is to place a compression band or tool with two or more compression surfaces that are clamped around the vessel and surrounding tissue. The compression band(s) could be inflated, thereby providing restrictive pressure to kill the nerve fibers. A third method includes a catheter having a looped distal end that can be wrapped around the vessel and surrounding tissue and reconnected with itself, thereby forming a loop. Tins loop can be cinched down on the tissue to provide the compression.

[0027] In some embodiments, a laparoscopic neuromodulation device includes an elongate catheter shaft having a proximal end and a distal end. The elongate catheter shaft has a length sufficient to extend from an incision in an abdominal wall to a location adjacent a common hepatic artery. The device also includes a shaped tool emerging from (e.g., extending from) the distal end of the catheter shaft. The shaped tool is configured to separate perivascular nerves and tissue from a target vessel (e.g., common hepatic artery) and to deliver radiofrequency energy to the perivascular nerves sufficient to modulate (e.g., ablate) the perivascular nerves. The shaped tool may comprise at least one ablation electrode. In some embodiments, the shaped tool comprises hoop-shaped clamp arms configured to wrap around the target vessel (e.g., common hepatic artery, proper hepatic artery, renal artery). The shaped tool comprises one thermally-insulated surface. The possible shapes of the shaped tool include, but are not limited to, the following shapes: hook, loop, angled, hockey stick, and straight. In some embodiments, the shaped tool forms a spiral shape comprising at least one complete spiral turn (360 degrees). There may be at least one ablation electrode on each turn (e.g., 1 per turn, 1.5 per turn, 2 per turn, 2.5 per turn, 3 per turn, or any other integral or non-integral number of electrodes). The spiral turn may have uniform pitch and/or a constant, uniform internal spiral diameter.

[0028] In accordance with several embodiments, a laparoscopic neuromodulation device includes an elongate catheter shaft having a proximal end and a distal end and a delivery device emerging from the distal end of the catheter shaft. The elongate catheter shaft has a length sufficient to extend from an incision in an abdominal wall to a location adjacent a hepatic artery (e.g., common hepatic artery, right hepatic artery, left hepatic artery, proper hepatic artery). The delivery device is configured to deliver ablation agents to target perivascular nerves surrounding the hepatic artery. In some embodiments, the delivery device includes at least one outlet orifice. The delivery device may be configured to deliver (e.g., propel) liquid, solid and/or gaseous ablation agents. In some embodiments, the delivery device forms a spiral configuration comprising at least one complete spiral turn (360 degrees). There may be an integral or non-integral number of outlet orifices per turn of the spiral (e.g., 1. 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3 or more than 3). [0029] The correct identification/localization of the common hepatic artery or other artery or target vessel may be important to achieving desired therapeutic effects. The goal of surgical denervation is to resect (e.g., cut through the nerves) surrounding the common hepatic artery. The vascular/neural anatomy of the common hepatic artery can vary widely across the population in its length, diameter and curvature. A device can be used to augment a surgical or other denervation procedure (e.g., energy-based or chemical-based ablation) to ensure the completeness of nerve resection or destruction by providing illumination to assist in identification and localization of the common hepatic artery or other artery or target vessel. An illumination device can be used to identify the target vessel by shining light through or around the vessel. The appearance of nerves and other extravascular tissue will appear differently than the vessel if illuminated from behind tissue. The illumination device may include a deflectable light source for placing behind a section of tissue to illuminate through the target vessel. In some embodiments, the light source comprises a flexible optical tube configured to be positioned behind the section of perivascular tissue. In other embodiments, the light source comprises a stand-alone unit configured to remain m the location for the duration of the neuromodulation procedure. The light source may comprise light emitting diodes, electroluminescent wires, lamps, lasers, and/or other light sources. In some embodiments, an ultrasound probe may be used to identify the location of the target vessel (e.g., common hepatic artery) using Doppler ultrasound velocity or flow techniques. Laser Doppler techniques may also be used.

[0030] Methods may include performing photodynamic therapy of the perivascular nerves. In accordance with several embodiments, a system for performing photodynamic therapy on perivascular nerves and tissue includes an elongate delivery catheter shaft having a proximal end and a distal end. The delivery catheter shaft includes means configured to encircle a target vessel and its perivascular nerves and tissue. The system further includes an illumination device configured to provide illumination to the perivascular nerves and tissue. In some embodiments, the deliver} catheter shaft is configured to deliver an ablation agent to the perivascular nerves and tissue. In some embodiments, the illumination device is a catheter configured to wrap around the delivery catheter shaft and to deliver illumination. In some embodiments, the illumination device comprises a malleable sheet configured to wrap around the delivery catheter shaft and deliver illumination. The illumination device may be configured to be located at a distance of 0.1 mm to 5 mm from the circumference of the delivery catheter shaft or at distances greater than 5 mm from the circumference of the delivery catheter shaft.

[0031] In accordance with several embodiments, a method for visualizing perivascular nerves during a neuromodulation procedure by enhancing the clarity of surrounding tissue includes delivering an index matching fluid into tissue surrounding the perivascular nerves, applying heat via a heat source to the tissue, and illuminating the tissue with a light source. The index matching fluid may be pre-heated to a temperature of 20-30 degrees Celsius prior to being delivered to the target area. The index matching fluid may be delivered through an infusion channel in a delivery catheter. The heat source may be an infrared radiative heater or a hot gas source. The perivascular nerves may comprise perivascular nerves surrounding a common hepatic artery and/or other target vessel (e.g., gastroduodenal artery, mesenteric artery, gastric artery, splenic artery, other hepatic artery, and/or renal artery).

[0032] In accordance with several embodiments, a method for visualizing a target vessel during a neuromodulation procedure by illumination includes advancing a light source to a location adjacent the target vessel (e.g., common hepatic artery), positioning the light source behind a section of perivascular tissue surrounding the target vessel, and illuminating the target vessel through the perivascular tissue using the light source. In some embodiments, the light source comprises an internal power source (e.g., at least one battery) and is configured to operate without an external power source for at least as long as the duration of the neuromodulation (e.g., denervation) procedure.

[0033] In some embodiments, a staining element can be injected through laparoscopic, endovascular, or open surgical access. The staining element may advantageously help to identify nerves in the perivascular tissue prior to resection or destruction, thereby providing for a more complete and safer procedure. In accordance with several embodiments, a method for visualizing a target vessel (e.g., common hepatic artery) during a neuromodulation procedure includes delivering a delivery device to the perivascular nerves and tissue surrounding the target vessel, and injecting the staining agent into the perivascular nerves and tissue surrounding the target vessel via the deliver} device. The delivery device may be delivered endovascularly, laparoscopically or via an open surgical incision. In some embodiments, the delivery device comprises a guide catheter and a delivery needle configured for endovascular surgery. In such embodiments, the delivery device is advanced into the target vessel through normal endovascular means and passed through the wall of the target vessel to deliver the staining agent to the perivascular nerves and tissue surrounding the target vessel. Regardless of the approach or access used, the delivery device may comprise a deliver needle and a chamber containing the staining agent. The delivery device may be advanced to the location without entering the target vessel and the staining agent may be delivered directly to the perivascular nerves and tissue surrounding the target vessel.

[ 0034] In accordance with several embodiments, a method of delivering an ablation agent to a target vessel (e.g., common hepatic artery) includes embedding the ablation agent into a malleable biocompatible material and shaping the material into a shape suitable for delivery to the target vessel. For example, the shape may include a strip, a filament patch, or a film. The method also includes delivering the material with the embedded ablation agent to the target vessel and positioning the material with the embedded ablation agent along the length of the target vessel. Any of the above-recited methods may be performed in combination with each other.

[0035] For purposes of summarizing the disclosure, certain aspects, advantages, and novel features of embodiments of the invention have been described herein. It is to be understood that not necessarily all such advantages may be achieved in accordance with any particular embodiment of the invention disclosed herein. Thus, the embodiments disclosed herein may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught or suggested herein without necessarily achieving other advantages as may be taught or suggested herein. The term“embodiment” as used herein should not necessarily be interpreted as“invention” and can represent an example, an implementation, or aspect that can be combined with other“embodiments” to form an invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG. 1 A illustrates the anatomy of a target treatment location including the hepatic blood supply.

[0037] FIG. IB illustrates the anatomy of a target treatment location including an artery and the nerves in the perivascular space surrounding the artery. [0038] FIG. 1C illustrates the insertion of a laparoscopic tool into a region of interest, including the target vessel and surrounding perivascular tissue including nerves.

[0039] FIGS. 2A and 2B illustrate an embodiment of a combination dissection and ablation tool configured to facilitate modulation of nerves.

[0040] FIGS. 3A-3D illustrate embodiments of laparoscopic tools to facilitate modulation of nerves surrounding a target vessel.

[0041] FIG. 4 illustrates an embodiment of a shaped tool configured to facilitate modulation of nerves surrounding a target vessel.

[0042] FIGS. 5A and 5B illustrate an embodiment of a spiral tool configured to facilitate modulation of nerves and tissue.

[0043] FIGS. 6-10 illustrate various embodiments of tools and methods configured to deliver ablation agents to nerves and tissue.

[0044] FIG. 11 illustrates an embodiment of a device and method configured to deliver desiccating agents to nerves and tissue.

[0045] FIGS. I2A and 12B illustrate an embodiment of a device and method configured to deliver photodynamic therapy to nerves and tissue.

[0046] FIG. 13 illustrates an embodiment of a device and method for enhancing visibility' of perivascular nerves.

[0047] FIGS. 14A-14D illustrate an embodiment of a device and method for identifying a common hepatic artery by illumination.

[0048] FIGS. 15A-15D illustrate an embodiment of a device and method for identifying the common hepatic artery by staining.

DETAILED DESCRIPTION

I. Introduction and Overview

[0049] In accordance with several embodiments of the disclosure, disruption of sympathetic nerve fibers innervating the liver is effective to reduce endogenous glucose production and increase hepatic and peripheral glucose storage. The liver is innervated along the structures of the portal triad, particularly the hepatic artery, along which both sympathetic and parasympathetic nerve fibers may course. The nature of the neuroanatomy in this region (e.g., the proximity of neural structures to the arterial lumens of the hepatic arteries such as the common hepatic artery and the proper hepatic artery) is amenable to endovascular approaches for disrupting sympathetic nervous activity, including but not limited to endovascular ablation. However, there are many different tissues surrounding the hepatic artery. In some anatomies, it can be difficult to locate and identify the nerves that one is attempting to modulate (e.g., ablate, denervate, stimulate). In methods incorporating ablation of nerves, if all of the nerves are not completely ablated, there is the potential that nerves may find a method of returning to function, thereby minimizing or reversing the effects of any improvement from the procedure.

[QQ50] In addition to endovascular ablation there is the potential for surgical approaches to modulating nerves within a subject (e.g., denervatmg the liver and/or pancreas by ablating nerves innervating those organs m the perivascular space around a hepatic artery'). Surgical approaches may be more invasive than an endovascular approach but can also be used to denervate the common hepatic artery (CHA), proper hepatic artery, left hepatic artery', right hepatic artery' ^· , superior mesenteric artery', inferior mesenteric artery, gastroduodenal artery', celiac artery, splenic artery', renal artery, and/or other vessels. The correct identification/localization of the CHA or other vessel is important to achieving desired therapeutic effect. The goal of surgical denervation is to resect (cut through the nerves) surrounding the CHA or other vessel. The vascular/neural anatomy of the CHA or other vessel can vary widely across the population in its length, diameter and curvature. Identification and targeting of perivascular nerves (e.g., nerves within a perivascular space surrounding an artery or other vessel) can be difficult in accordance with some embodiments, thereby hampering the safety' and effectiveness of neuromodulation procedures.

[0051] In some embodiments, a laparoscopic or endoscopic approach is used to access nerves in a perivascular space surrounding the common hepatic artery or other artery or blood vessel. The term“laparoscopic” shall be given its ordinary meaning and shall include, without limitation, any percutaneous access through one or more incisions through skin of a subject (e.g., through abdominal wall, torso, back). To sever the nerves surrounding the common hepatic artery (and/or a hepatic, splenic, gastroduodenal, renal, and/or superior mesenteric artery), a laparoscopic tool may be inserted through the abdominal wall or other tissue entry location. Any number of laparoscopic and/or endoscopic tools that enable visualization and treatment of the area of interest may be utilized. In accordance with several embodiments, the nerves of interest (e.g., the nerves to be modulated) reside in the perivascular space surrounding the vessel leading to the end organ of interest in both the radial and longitudinal directions. The nerves may vary in size and location and may be buried in the surrounding perivascular tissues. In some instances, the nerves are not easily identified visually, and therefore the operator separates and/or removes all or most of the perivascular tissues surrounding the vessel of interest. The operator may exercise special care to ensure the vascular wail of the target vessel is minimally damaged by the procedure in order to reduce potential vascular complications. In accordance with several embodiments, the systems, devices and methods described herein can be used to effect quick and circumferentially complete perivascular denervation. In some implementations, complete circumferential perivascular denervation is effected without causing complete circumferential ablation of a vessel wall (which could result in stenosis). Given the difficulty in identifying the nerves surrounding the CHA and/or other artery or vessel, a mechanical method of constricting all the tissue surrounding the CHA without the need to expose or identify the nerve fibers that leads to sympathetic and parasympathetic nerve disruption could be beneficial.

[0052] Embodiments of the invention described herein are generally directed to therapeutic neuromodulation of targeted nerve fibers to treat, or reduce the risk of occurrence or progression of, various metabolic diseases, conditions, or disorders, including but not limited to diabetes (e.g , diabetes mellitus) or fatty liver conditions, such as non-alcoholic fatty' liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), and/or factors associated with metabolic syndrome, such as hyperlipidemia, obesity and high blood pressure. While the description sets forth specific details in various embodiments, it will be appreciated that the description is illustrative only and should not be construed in any way as limiting the disclosure. Furthermore, various applications of the disclosed embodiments, and modifications thereto, which may occur to those who are skilled in the art, are also encompassed by the general concepts described herein. Although several figures set forth below' are described with respect to hepatic neuromodulation, the embodiments herein also contemplate neuromodulation or tissue modulation of regions other than the liver or hepatic vasculature. For example, the laparoscopic catheters, devices and systems described herein may also be used for renal denervation (e.g., by modulating the nerves in one or both renal arteries), for glucose or lipid regulation by modulating the nerves that innervate the pancreas, duodenum, jejunum and/or stomach, for cardiac ablation, for pulmonary tissue or vessel ablation or neuromodulation, as well as other targets and indications described herein. [0053] Several embodiments described herein relate generally to laparoscopic devices, systems and methods for accessing and therapeutically effecting neuromodulation of targeted nerve fibers to treat various medical conditions, disorders and diseases. In some embodiments, neuromodulation of targeted nerve fibers is used to treat, or reduce the risk of occurrence of symptoms associated with, a variety of metabolic diseases, or factors of metabolic syndrome. For example, neuromodulation of targeted nerve fibers can treat, or reduce the risk of occurrence of symptoms associated with, diabetes (e.g., diabetes mellitus) or other diabetes-related diseases. The methods described herein can advantageously treat diabetes without requiring daily insulin injection or constant monitoring of blood glucose levels. The treatment provided by the devices, systems and methods described herein can be permanent or at least semi-permanent (e.g., lasting for several weeks, months or years), thereby reducing the need for continued or periodic treatment. Embodiments of the laparoscopic devices described herein can be temporary (e.g., non-implantable) so as to effect a“one-and- done”-type procedure.

[0054] In some embodiments, neuromodulation of targeted nerve fibers as described herein can be used for the treatment of insulin resistance, genetic metabolic syndromes, ventricular tachycardia, atrial fibrillation or flutter, arrhythmia, inflammatory diseases, hypertension (arterial or pulmonary), obesity, hyperglycemia (including glucose tolerance), hyperlipidemia, eating disorders, and/or endocrine diseases. In some embodiments, neuromodulation of targeted nerve fibers treats any combination of diabetes, insulin resistance, or other metabolic diseases. In some embodiments, temporary or implantable neuromodulators may be used to regulate satiety and appetite (e.g., to promote weight loss). In several embodiments, modulation of nervous tissue that innervates (afferently or efferently) the liver is used to treat hemochromatosis, Wilson’s disease, NASH, NAFLD, and/or other conditions affecting the liver and/or liver metabolism. In some embodiments, modulation of nervous tissue that innervates (afferently or efferently) the liver (e.g., hepatic denervation) is effective for reducing whole-body sympathetic tone and resulting conditions such as hypertension, congestive heart failure, atrial fibrillation, obstructive sleep apnea, and/or renal failure, etc.

[0055] In some embodiments, sympathetic nerve fibers associated with the liver, pancreas, and/or other organs or tissue are selectively disrupted (e.g., ablated, denervated, disabled, severed, blocked, injured, desensitized, removed) to decrease hepatic glucose production and/or increase hepatic glucose uptake, thereby aiding m the treatment of, or reduction in the risk of, diabetes and/or related diseases or disorders. The disruption can be permanent or temporary (e.g., for a matter of several days, weeks or months). In some embodiments, sympathetic nerve fibers m the hepatic plexus are selectively disrupted. In some embodiments, sympathetic nerve fibers surrounding (e.g., within the perivascular space of) the common hepatic artery proximal to the proper hepatic artery, sympathetic nerve fibers surrounding the proper hepatic artery, sympathetic nerve fibers in the celiac ganglion adjacent the celiac artery, other sympathetic nerve fibers that innervate or surround the liver, sympathetic nerve fibers that innervate the pancreas, sympathetic nerve fibers that innervate fat tissue (e.g., visceral fat), sympathetic nerve fibers that innervate the adrenal glands, sympathetic nerve fibers that innervate the small intestine (e.g., duodenum), sympathetic nerve fibers that innervate the stomach (e.g., or portions thereof, such as the pylorus), sympathetic nerve fibers that innervate brown adipose tissue, sympathetic nerve fibers that innervate skeletal muscle, and/or sympathetic nerve fibers that innervate the kidneys are selectively disrupted or modulated (simultaneously or sequentially) to facilitate treatment or reduction of symptoms associated with hypertension, diabetes (e.g., diabetes mellitus), or other metabolic diseases or disorders. In some embodiments, the methods, devices and systems described herein are used to therapeutically modulate autonomic nerves associated with any diabetes relevant organs or tissues. For example, with respect to the pancreas and duodenum, the nerves that innervate one or both structures can be neuromodulated (e.g., ablated) in addition to or instead of the nerves that innervate the liver, wherein said neuromodulation affects one or more symptoms/characteristics associated with diabetes or other metabolic diseases or disorders. Such symptoms/characteristics include but are not limited to changes (e.g., increases or decreases) in glucose levels, cholesterol levels, lipid levels, triglyceride levels, norepinephrine levels, insulin regulation, etc. in the blood plasma or liver or other organs. The devices and methods disclosed herein with respect to hepatic modulation can be used for neuromodulatmg the pancreas, duodenum, stomach, or other organs and structures.

[0056] In accordance with several embodiments, any nerves containing autonomic fibers are modulated, including, but not limited to, the saphenous nerve, femoral nerves, lumbar nerves, median nerves, ulnar nerves, vagus nerves, and radial nerves. Nerves surrounding arteries or veins other than the hepatic artery may be modulated such as, but not limited to, nerves surrounding the hepatic veins, the superior mesenteric artery, the inferior mesenteric artery, the femoral artery, the pelvic arteries, the portal vein, pulmonary arteries, pulmonary veins, abdominal aorta, vena cavas, splenic arteries, the gastroduodenal artery , gastric arteries, the internal carotid artery, the internal jugular vein, the vertebral artery, renal arteries, and renal veins. Celiac arteries may also be modulated according to several embodiments herein.

[QQ57] In accordance with several embodiments, a laparoscopic therapeutic neuromodulation system is used to selectively disrupt sympathetic nerve fibers. The neuromodulation system can comprise a neuromodulation system (e.g., hollow, solid, partially hollow, catheter, probe, shaft or other delivery device with or without a lumen). A neuromodulation system may use radiofrequency (RF) energy supplied by an RF generator to ablate sympathetic nerve fibers to cause neuromodulation or disruption of sympathetic communication. In some embodiments, the neuromodulation system uses ultrasonic energy to ablate sympathetic nerve fibers. In some embodiments, the neuromodulation system uses ultrasound (e.g., high-intensity focused ultrasound or low-intensity focused ultrasound) energy to selectively ablate sympathetic nerve fibers. In other embodiments, the neuromodulation system uses electroporation to modulate sympathetic nerve fibers. A treatment device (e.g., neuromodulation or ablation device), as used herein, shall not necessarily be limited to causing ablation, but also includes devices that facilitate the modulation of nerves (e.g., partial or reversible ablation, blocking without ablation, stimulation). In some embodiments, the neuromodulation system delivers drugs or chemical agents to nerve fibers to modulate the nerve fibers (e.g., via chemoablation). Chemical agents used with chemoablation (or some other form of chemically-mediated neuromodulation) may, for example, include phenol, alcohol, or any other chemical agents that cause chemoablation of nerve fibers. In some embodiments, cryotherapy is used. For example, the neuromodulation system may use cryoablation to selectively modulate (e.g., ablate) sympathetic nerve fibers. In some embodiments, the neuromodulation system is used with hrachytherapy to modulate the nerve fibers. The neuromodulation systems may further utilize any combination of RF energy , ultrasonic energy, focused ultrasound (e.g., HIFU, LIFU) energy, ionizing energy (such as X- ray, proton beam, gamma rays, electron beams, and alpha rays), electroporation, drug delivery , chemoablation, cryoablation, brachytherapy, or any other modality to cause disruption or neuromodulation (e.g., ablation, denervation, stimulation) of autonomic (e.g., sympathetic or parasympathetic) nerve fibers. Microwave energy or laser energy for combinations of two, three or more energy sources) are used in some embodiments. In some embodiments, energy is used in conjunction with non-energy -based neuromodulation (e.g., drug delivery).

[QQ58] In some embodiments, a minimally invasive surgical technique is used to deliver devices or tools of the therapeutic neuromodulation system. For example, components of a catheter system (e.g., hollow, solid, partially hollow, catheter, probe, shaft or other delivery device wath or without a lumen) for the disruption or neuromodulation of sympathetic nerve fibers can be delivered intra-arterially (e.g., via a femoral artery, brachial artery, radial artery), laparoscopieaily (e.g., through a tissue wail such as the abdominal wall), or transiuininally (e.g., through a wall of a vessel, stomach or intestine). In some embodiments, one or more devices or tools of the neuromodulation system are advanced to a region of the common hepatic artery to ablate sympathetic nerve fibers surrounding the common hepatic artery. In some embodiments, devices or tools of the neuromodulation system are advanced to the celiac artery or celiac trunk to ablate sympathetic nerve fibers in the celiac ganglion or celiac plexus (e.g., including nerves downstream thereof). Devices or tools of the neuromodulation system can be advanced within or surrounding other arteries (e.g. , left hepatic artery, right hepatic artery, gastroduodenal artery, gastric arteries, splenic artery, renal arteries, etc.) in order to disrupt targeted sympathetic nerve fibers associated with the liver or other organs or tissue (such as the pancreas, fat tissue (e.g., visceral fat of the liver), the adrenal glands, the stomach, the small intestine, gall bladder, bile ducts, brown adipose tissue, skeletal muscle), at least some of which may be clinically relevant to diabetes.

[0059] In accordance with several embodiments, target regions for neuromodulation may be accessed through one or more natural body orifices. For example, an endoscope may be inserted through a natural orifice to access space adjacent to the vessel of interest. In some embodiments, an endoscope is inserted through the mouth and advanced through the esophagus to the stomach and/or the duodenum. A tool may be inserted through one of the lumens of the endoscope to enable penetration of the esophagus, stomach or duodenum. The endoscope may be advanced into the abdominal cavity adjacent to the vessel of interest. Alternatively, the endoscope can remain m the stomach or duodenum and tools could can be advanced to the site of interest. In some embodiments, an endoscope is inserted through the vagina. A tool may be inserted through one of the lumens of the endoscope that enables penetration of the vagina or uterus. The endoscope may be advanced into the abdominal cavity adjacent to the vessel of interest. Alternatively, the endoscope can remain m the vagina or uterus and tools can be advanced to the site of interest. In some embodiments, an endoscope is inserted through the anus. A tool may be inserted through one of the lumens of the endoscope that enables penetration of the rectum or large bowel. The endoscope may be advanced into the abdominal cavity adjacent to the vessel of interest. Alternatively, the endoscope can remain in the bowel and tools could then be advanced to the site of interest.

[QQ60] In some embodiments, minimally invasive (e.g., laparoscopic or endoscopic) surgical delivery of the neuromodulation system is accomplished in conjunction with image guidance techniques. For example, a visualization device such as a fiberoptic scope can be used to provide image guidance during minimally invasive surgical delivery of the neuromodulation system. In some embodiments, fluoroscopic, computerized tomography (CT), radiographic, stereotactic, optical coherence tomography (OCT), intravascular ultrasound (IVUS), Doppler, thermography, and/or magnetic resonance (MR) imaging is used in conjunction with minimally invasive surgical delivery of the neuromodulation system. The image guidance may be facilitated or carried out using a robotic-assisted surgical and/or navigation system.

[0061] In some embodiments, an open surgical procedure is used to access the nerve fibers to be modulated. In some embodiments, any of the modalities described herein, including, but not limited to, RF energy, ultrasonic energy, HIFU, thermal energy, light energy, electrical energy other than RF energy, drug delivery, chemoablation, cryoablation, steam or hot-water, ionizing energy (such as X-ray, proton beam, gamma rays, electron beams, and alpha rays) or any other modality are used in conjunction with an open surgical procedure to modulate or disrupt sympathetic nerve fibers. Neuromodulation via microwave energy and laser energy are also provided in some embodiments and discussed herein. In other embodiments, nerve fibers are surgically cut (e.g., transected) to disrupt conduction of nerve signals or otherwise cause nerve injury.

[0062] In some embodiments, neuromodulation of targeted autonomic nerve fibers treats diabetes (e.g., diabetes meilitus) and related conditions by decreasing systemic glucose. For example, therapeutic neuromodulation of targeted nerve fibers can decrease systemic glucose by decreasing hepatic glucose production. In some embodiments, hepatic glucose production is decreased by disruption (e.g., ablation) of sympathetic nerve fibers. In other embodiments, hepatic glucose production is decreased by stimulation of parasympathetic nerve fibers.

[QQ63] In some embodiments, therapeutic neuromodulation of targeted nerve fibers decreases systemic glucose by increasing hepatic glucose uptake. In some embodiments, hepatic glucose uptake is increased by disruption (e.g., ablation) of sympathetic nerve fibers. In other embodiments, hepatic glucose uptake is increased by stimulation of parasympathetic nerve fibers. In some embodiments, triglyceride or cholesterol levels are reduced by the therapeutic neuromodulation.

[0064] In some embodiments, disruption or modulation of the sympathetic nerve fibers of the hepatic plexus has no effect on the parasympathetic nerve fibers surrounding the liver. In some embodiments, disruption or modulation (e.g., ablation or denervation) of the sympathetic nerve fibers of the hepatic plexus causes a reduction of very low-density lipoprotein (VLDL) levels, thereby resulting in a beneficial effect on lipid profile. In several embodiments, the treatment comprises neuromodulation therapy to affect sympathetic drive and/or triglyceride or cholesterol levels, including high-density lipoprotein (HDL) levels, low- density lipoprotein (LDL) levels, and/or very-low-density lipoprotein (VLDL) levels. In some embodiments, denervation or ablation of sympathetic nerves reduces triglyceride levels, cholesterol levels and/or central sympathetic drive. For example, norepinephrine levels may ^¬ be affected in some embodiments.

[0065] In other embodiments, therapeutic neuromodulation of targeted nerve fibers (e.g., hepatic denervation) decreases systemic glucose by increasing insulin secretion. In some embodiments, insulin secretion is increased by disruption (e.g., ablation) of sympathetic nerve fibers (e.g., surrounding branches of the hepatic artery). In other embodiments, insulin secretion is increased by stimulation of parasympathetic nerve fibers. In some embodiments, sympathetic nerve fibers surrounding the pancreas may be modulated to decrease glucagon levels and increase insulin levels. In some embodiments, sympathetic nerve fibers surrounding the adrenal glands are modulated to affect adrenaline or noradrenaline levels. Fatty tissue (e.g., visceral fat) of the liver may be targeted to affect glycerol or free fatty acid levels. In some embodiments, insulin levels remain the same or increase or decrease by less than ± 5%, less 9 than ± 10%, less than ± 2.5%, or overlapping ranges thereof. In some embodiments, insulin levels remain constant or subs tantially constant when a portion of the pancreas is ablated, either alone or in combination with the common hepatic artery or other hepatic artery branch. In various embodiments, denervation of nerves innervating the liver (e.g., sympathetic nerves surrounding the common hepatic artery) does not affect a subject’s ability' to respond to a hypoglycemic event.

[QQ66] In accordance with several embodiments of the invention, a method of decreasing blood glucose levels within a subject is provided. The method comprises forming an incision m the abdomen of the subject to access the abdominal cavity (e.g., peritoneal space) and inserting a neuromodulation device (e.g., catheter or other tool) into the incision. In some embodiments, the method comprises advancing the neuromodulation device near a location of a common or proper hepatic artery' and causing a therapeutically effective amount of energy to thermally inhibit neural communication along one or more sympathetic nerves surrounding the common or proper hepatic artery', thereby decreasing blood glucose levels within the subject. Other incision or access points may be used as desired or required.

[0067] In some embodiments, the neuromodulation device (e.g., hollow, solid, partially hollow, catheter, probe, shaft or other delivery' device with or without a lumen) is a radiofrequency (RF) ablation catheter comprising one or more electrodes. In some embodiments, the neuromodulation device (e.g., hollow, solid, partially hollow, catheter, probe, shaft or other delivery device with or without a lumen) is a focused or unfocused ultrasound ablation catheter having one or more transducers. In some embodiments, the neuromodulation catheter is a high-intensity focused ultrasound ablation catheter. In some embodiments, the neuromodulation catheter includes one or more microwave antennas or emitters. In some embodiments, the neuromodulation catheter is a cryoablation catheter.

[0068] In accordance with several embodiments, a method of treating a subject having diabetes or symptoms associated with diabetes is provided. The method can comprise delivering an RF ablation catheter (e.g., hollow, solid, partially hollow, catheter, probe, shaft or other delivery device with or without a lumen) to a vicinity of a hepatic plexus of a subject and disrupting neural communication along one or more sympathetic nerves by' causing RF energy to be emitted from one or more electrodes of the RF ablation catheter. [0069] In some embodiments, disrupting neural communication comprises permanently disabling neural communication along the sympathetic nerves. In some embodiments, disrupting neural communication comprises temporarily inhibiting or reducing neural communication along the sympathetic nerves. In some embodiments, disrupting neural communication along a sympathetic nerve comprises disrupting neural communication along a plurality of sympathetic nerves of the hepatic plexus.

[QQ70] In accordance with several embodiments, a method of decreasing blood glucose levels within a subject is provided. The method comprises inserting an RF, ultrasound, etc. ablation catheter (e.g., hollow, solid, partially hollow, catheter, probe, shaft or other deliver device with or without a lumen) into the subject and advancing the RF ablation catheter to a location of (e.g., surrounding, in a perivascular space of) a branch of a hepatic artery (e.g., the proper hepatic artery or the common hepatic artery or right or left hepatic artery), a splenic artery, and/or a superior mesenteric artery. In one embodiment, the method comprises causing a therapeutically effective amount of RF, ultrasound, etc. energy to thermally inhibit neural communication within sympathetic nerves surrounding the one or more target arteries by the ablation catheter, thereby decreasing blood glucose levels within the subject. In some embodiments, the delivery of the therapeutically effective amount of RF, ultrasound, etc. energy to the common or proper hepatic artery also comprises delivery' of energy sufficient to modulate (e.g., ablate, denervate) nerves of the pancreas and/or duodenum, which may provide a synergistic effect. In various embodiments, blood glucose levels decrease by 30-60% (e.g., 40-50%, 30-50%, 35-55%, 45-60% or overlapping ranges thereof) from a baseline level.

[0071] In one embodiment, the therapeutically effective amount of RF energy at the location of the target artery or arteries is in the range of between about 100 J and about 2 kJ (e.g., between about 100 J and about lkJ, between about 100 J and about 500 J, between about 250 J and about 750 J, between about 300 J and about lkJ, between about 500 J and 1 kJ, or overlapping ranges thereof). In one embodiment, the therapeutically effective amount of RF energy has a power between about 0.1 W and about 14 W (e.g., between about 0.1 W and about 10 W, between about 0.5W and about 5 W, between about 3 W and about 8 W, between about 2 W and about 6 W, between about 5 W and about 10W, between about 8 W and about 12 W, between about 10 W and about 14 W, or overlapping ranges thereof). The ranges provided herein can be per electrode, per energy delivery location, or total energy delivery. The RF, ultrasound, microwave, etc. energy may be delivered at one location or multiple locations along the target vessel or within multiple different vessels. In some embodiments, the RF, ultrasound, etc. energy is delivered sufficient to cause fibrosis of the tissue surrounding the nerves, thereby resulting in nerve dropout.

[0072] The autonomic nervous system includes the sympathetic and parasympathetic nervous systems. The sympathetic nervous system is the component of the autonomic nervous system that is responsible for the body’s“fight or flight” responses, those that can prepare the body for periods of high stress or strenuous physical exertion. One of the functions of the sympathetic nervous system, therefore, is to increase availability of glucose for rapid energy metabolism during periods of excitement or stress, and to decrease insulin secretion.

[0073] The liver can play an important role in maintaining a normal blood glucose concentration. For example, the liver can store excess glucose within its cells by forming glycogen, a large polymer of glucose. Then, if the blood glucose concentration begins to decrease too severely, glucose molecules can be separated from the stored glycogen and returned to the blood to be used as energy by other cells. The liver is a highly vascular organ that is supplied by two independent blood supplies, one being the portal vein (as the liver’s primary blood supply) and the other being the hepatic artery (being the liver’s secondary blood supply).

[0074] Neuromodulation (e.g., denervation) of sympathetic and/or parasympathetic nerves surrounding other organs or tissues (such as the pancreas, small intestine, duodenum, kidneys, adrenal glands, and/or portions of the stomach) may also be performed in combination with modulation of nerves innervating the liver to treat diabetes or the symptoms associated with diabetes (e.g., high blood glucose levels, high triglyceride levels, high cholesterol levels, low insulin secretion levels), fatty liver conditions, or factors associated with metabolic syndrome (e.g., hyperlipidemia, high blood pressure, obesity, low high-density lipoprotein levels). Several embodiments described herein are adapted to modulate (e.g., ablate) the parasympathetic sy stem alone or m conjunction with the sympathetic system.

[0075] Several embodiments of the invention are particularly advantageous because they include one, several or all of the following benefits: (i) minimally invasive access through laparoscopic incisions without requiring navigation of tortuous vasculature, (ii)“one- and-done”-type procedure instead of chrome treatment over a long period of time, (hi) non implantable, (iv) can modulate (e.g., ablate) nerves directly rather than through a vessel wall, thereby reducing likelihood of potential damage to vessel walls, (v) more adap table to different anatomical variations between patients, (vi) facilitates less complex visualization of treatment and targets of treatment more readily, (vii) facilitates less complex confirmation of neuroniodulatioii efficacy due to direct access to nerves, and/or (viii) enables direct manipulation of organs or sensitive structures, thereby minimizing risk of damage during treatment.

[0076] FIG. 1A illustrates vasculature 100 of a target hepatic treatment location. The vasculature 100 includes the CHA 103, the proper hepatic artery 101, the gastroduodenal artery 102, the celiac artery 105, the splenic artery 106, the abdominal aorta 107, and the nerves 104 surrounding the CHA 103 located in a perivascular space (e.g., the space surrounding the CHA or other artery or vessel).

[0077] FIG. IB illustrates a cross-sectional view of an artery 110 (e.g., CHA) and its arterial wall 111, surrounded by nerves 112 in a perivascular space 113. The nerves 112 in the perivascular space 113 are the nerves desired to be treated using the various embodiments of systems, devices and methods described herein.

[0078] FIG. 1€ illustrates an embodiment of a method of delivering a device (e.g. , laparoscopic tool) of a neuromodulation system to selectively disrupt target nerves in the perivascular space. In some embodiments, a laparoscopic tool 122 is advanced to the target site. The laparoscopic tool 122 (e.g., catheter) may be passed laparoscopically (e.g., through small incisions in an abdominal wall or other superficial tissue region) or translurmnally to the extravascular (e.g., perivascular) space or may create a virtual space between the vascular media 121 and adventitia of the vessel 120. In some embodiments, the tool (e.g., catheter or probe), once positioned at the desired location, is activated to selectively modulate or disrupt the target nerve or nerves. The selective disruption may be accomplished or performed through chemo-disruption, such as supplying any type of nerve destroying agent, including, but not limited to, neurotoxins or other drugs detrimental to nerve viability. The selective modulation or disruption may also be accomplished or performed through mechanical compression or physical cutting or severing of tissue (e.g., nerves). In some embodiments, selective disruption is performed through energy-induced disruption, such as thermal or light ablation (e.g., radiofrequency ablation, ultrasound ablation, microwave ablation, or laser ablation). In one embodiment, a camera or other visualization device (e.g., fiberoptic scope, charge-coupled device camera, ultrasound transducer array) is disposed on a distal end of the catheter to ensure that nerves are targeted and not surrounding tissue. In some embodiments, the catheter comprises a side port, opening or window, thereby allowing for delivery of fluid or energy to denervate or ablate nerves with the longitudinal axis of the catheter aligned parallel or substantially parallel to the target vessel portion. In some embodiments, the catheter is inserted percutaneously and advanced to the target location for extravascular delivery of energy or fluid.

II. Types of Neuromodulation

A. Mechanical and/or Electrical Neuromodulation

[0079] The selective modulation or disruption of nerve fibers may be performed by one or more tools or devices through mechanical or physical disruption, such as, but not limited to, cutting, severing, ripping, tearing, transecting, or crushing. Several embodiments of the invention comprise disrupting cell membranes of nerve tissue. Several embodiments involve selective compression of the nerve tissue and fibers. Nerves being subjected to mechanical pressure, such as, but not limited to, selective compression or crushing forces may experience effects such as, but not limited to, ischemia, impeded neural conduction velocity, and nervous necrosis. Such effects may be due to a plurality of factors, such as decreased blood flow.

[0080] In several embodiments, the disruption of the sympathetic and/or parasympathetic nerve fibers around an arterial or other vessel lumen is achieved by completely encapsulating the lumen and surrounding tissue in a mechanical loop. This mechanical loop could then provide compressive forces that would acutely or chronically (e.g., over time) restrict the blood flow to the nerves, thereby causing the nerve fibers to die. In one embodiment, a small band with a“zip tie” like interlocking closure could be placed around the vessel. The loop could then be tightened to provide enough restriction of the tissue to kill the nerve fibers. In some embodiments, a compression band or tool with two or more compression surfaces is clamped around the vessel and surrounding tissue. The compression band(s) could be inflated, thereby providing restrictive pressure to kill the nerve fibers. In some embodiments, a catheter with a looped distal end can be wrapped around the vessel and surrounding tissue. This looped distal end may he tightened and cinched down on the tissue to provide the compression.

[0081] FIGS. 2A, 2B, 3 A, 3B, 4, 5A, and 5B illustrate various embodiments of mechanical and/or electrical neuromodulation devices. FIGS. 2A and 2B illustrate embodiments of a combination ablation and dissection device configured for perivascular placement in proximity to one or more hepatic artery branches and/or adjacent artery branches. In some embodiments, the combination ablation and dissection device is used to separate the target tissue layers and ablate and/or cut the target tissue. FIG. 2A illustrates one view of the combination ablation and dissection device 200. In one implementation, the device 200 comprises at least one element configured to separate tissue layers and an ablative cutting element configured to perform neuromodulation (e.g., effect tissue ablation). In one implementation, the device 200 comprises a cauterizing hook 205 with at least one orifice 210 designed to eject pressurized fluid to separate tissue layers and an ablative element 201 (e.g., cutting element, electrode, transducer, laser emitter) that performs denervation or tissue ablation. The cauterizing hook 205 may comprise shape memory material having a pre-formed shape configuration (when not constrained by an outer sheath or an internal straightening stylet or guidewire) or the cauterizing hook 205 may be steerable or bendable (e.g., using one or more pull wires controlled by a proximal handle). In some implementations, the at least one orifice 210 that ejects pressurized fluid is located at the tip of the cauterizing hook 205. However, the at least one orifice may include one or more orifices alternatively or additionally placed at other locations. For example, FIG. 2B illustrates another implementation of a combination ablation and dissection device 200'. The combination ablation and dissection device 200' may include all or some of the features of the device 200. In some implementations, the at least one orifice 210 (e.g., one, two, three, four, or more than four orifices) adapted to eject pressurized fluid is alternatively or additionally located at the bottom distal most section of the cauterizing hook 205. There may be one orifice positioned at the location shown in FIG. 2A and one or more orifices positioned at the location shown in FIG. 2B on the same device. The devices 200, 200' may include a camera or other imaging element (not shown) configured to facilitate visualization of target tissue.

[0082] FIGS. 3A and 3B illustrate an embodiment of a tool 300 adapted to assist in hepatic and/or other tissue neuromodulation and accessibility along the length of a vessel, such as the common hepatic artery. The tool 300 may be inserted laparoscopieally and used to sever the nerves surrounding the common hepatic artery or other vessel. The tool 300 includes a clam-shell type clamp 302 formed by two clam-shell components that interact to form the complete clamp 302. The two clam-shell components may be coupled to articulating arms 304 extending out of a lumen of the shaft 303 or from a distal tip of the shaft 303. The claim-shell type clamp 302 is located at the distal end of a shaft 303 that is configured to extend into the abdominal (e.g., peritoneal) space. The proximal end of the tool 300 may be attached to a handle (not shown) that includes mechanical means (e.g., pull wires, spring actuation, gears and pins, torque shafts, actuator of a lever, and/or lead screw and lever to control operation of the articulating arms 304 to effect transitioning the clamp 302 between an“open” and“closed” configuration) or to otherwise change the shape or manipulate the distal shaft 303 or clamp 302. The handle may also have connectors for therapy delivery elements. The laparoscopic tool 300 may be delivered through a protective sheath so that the clamp 302 moves smoothly through the layers of tissue. The clamp 302 may be delivered such that the maximal dimension is oriented parallel to the shaft 303 when delivered and pivoted 90 degrees or so following delivery'. The longitudinal length of the clam shell clamp 302 could be adjusted to match or be of similar maximal dimension as the distal shaft, thereby eliminating the need for adjustment following delivery. The inside diameter of the clam shell clamp 302 may be increased or decreased to match more closely the diameter of the target vessel. Multiple elements and/or ports may be positioned along the inside of the outside surface of the clam shell 302 that are configured to completely denervate (e.g., sever, ablate) the nerves surrounding and along the vessel in the perivascular space. The elements and/or ports may be arranged to direct energy, fluid and/or gas toward the vessel, tangential to the vessel, away from the vessel, along the length of the vessel or in multiple directions along or at a specific point on the clamp 302. The tool 300 may be configured to deliver thermal energy (e.g., bipolar and/or monopolar radiofrequency energy, with or without irrigation), ultrasound energy, microwave energy, lasers, cryoablative fluid, and/or water vapor (e.g., steam)). The tool, or device, 300 may be configured to deliver a chemical and/or agent to denervate the nerves m the perivascular space. In one embodiment, the device 300 is configured to deliver dry air to desiccate the nerves, thereby ablating or otherwise denervatmg the nerves. [0083] FIGS. 3C and 3D illustrate an embodiment of a hoop device 300' adapted to assist in hepatic and/or other neuromodulation and accessibility along the length of a vessel, such as the common hepatic artery. FIG. 3C illustrates the hoop device 300’ in an open configuration, with the hoops 302 open in preparation for placement around the target vessel. FIG. 3D illustrates the hoop device 300' in a closed configuration, with hoops 302 closed after placement around the target vessel. In some embodiments, the apparatus 300' comprises at least two hoops 302 configured for intravascular placement around one or more hepatic artery branches or adjacent artery branches. In some embodiments, the hoops 302 open in a clamshell manner. In some embodiments, the hoops 302 are sized to the outer diameter of the target vessel(s). In some embodiments, the hoops 302 open in a clamshell manner away from the target vessel and strip tissue away from the vessel. In one embodiment, the hoops 302 include at least two ablation or cauterizing elements 304 located on the side of a hoop 302. In the illustrated embodiment, the hoops 302 include at least two ablation or cauterizing elements 304 located on the outer diameter of a hoop (not shown in figures). The ablation or cauterizing elements 304 further improve the stripping of the vessel. One, two, three, four, or more than four hoops may be used. Each hoop may have one, two, three, four, or more than four cauterizing elements. The cauterizing elements 304 may be located and positioned so as to effect localized and directional treatment (e.g., ablation). For example, the cauterizing elements 304 may be spaced apart along an arm of each hoop so as to provide circumferential treatment of the perivascular space surrounding the vessel. The cauterizing elements may be on the inner curved surface and/or the outer curved surface of the hoops 302 in addition to, or as an alternative, to being on the side of the hoops 302 as shown in FIGS. 3C and 3D. The tool 300’ shown in FIGS. 3C and 3D may incorporate any of the features of the tool 300 or the devices 200, 200’. In some embodiments, the hoops may be replaced with graspers (e.g., similar to pliers) configured to operate m a bipolar manner to ablate tissue between the two graspers or blades (e.g., similar to scissors) configured to cut or sever tissue.

[0084] FIG. 4 illustrates an embodiment of a shaped tool 400 to sever (e.g., mechanically or by compression) or ablate (e.g., by energy delivery or fluid deliver} ) nerves surrounding a target vessel (e.g., common hepatic artery). In one embodiment, a laparoscopic apparatus comprises the shaped tool 400 including a clamp located on the distal end of a shaft that extends into the a bdominal space. Possible shapes of a shaped treatment portion of the tool 400 include, but are not limited to, hook, loop, angled, hockey stick, and straight. The dimensions of the shaped treatment portion of the tool 400 can be adjusted according to the diameter of the vessel or dimensions of the area of interes t. In some implementations, the shape of the treatment portion, or shaped end, of the tool 400 can be adjusted by removal of a stiffening mandrel (e.g., internal) or an outer sheath. In one embodiment, the proximal end of the apparatus/tool 400 is attached to a handle which may include mechanical means (such as puli wires, spring actuators, gears and pins, torque shafts, actuator of a lever, and/or lead screw and lever) to manipulate and/or change the shape of the shaped end of the tool. In one aspect, the handle includes connectors for the delivery of therapeutic agents. In some aspects, the shaped tool 400 comprises an ablative surface 402 adapted to be positioned not in contact with the vessel, and an insulated surface 401 that is adapted to be in contact with the vessel. The ablative surface 402 performs neuromodulation of the nerves surrounding and/or along the vessel in the perivascular space. In one embodiment, the ablative surface 402 comprises a single continuous ablation element. In one embodiment, the ablative surface 402 comprises multiple ablation elements (e.g., two, three, four, more than four) that may be controlled independently (e.g., separately). The tool 400’ may incorporate any of the features of the tools 300, 300' or the devices 200, 200'.

[0085] FIGS. 5 A and 5B illustrate embodiments of a spiral tool 500 for ablating perivascular nerves surrounding a target vessel 120. FIG. 5A illustrates one view of the spiral tool 500. FIG. 5B illustrates the spiral tool 500 in use, after being wrapped around the target vessel 120 (e.g., a common hepatic artery). In some embodiments, the spiral tool 500 comprises a catheter having a spiral (e.g.,“pigtail”) shape 501 along the distal region of the catheter. Multiple ablation elements 502 are provided spaced at intervals along the spiral section 501. The ablation elements may compose energy delivery elements (e.g., radiofrequency electrodes, ultrasound transducers, laser emitters, microwave antennae, combinations of the same, and/or the like). In some embodiments, the ablation elements 502 span the circumference of the catheter. In some embodiments, the ablation elements 502 span a portion of the circumference of the catheter that is less than the entire circumference of the catheter so as to effect localized or directional energy delivery. In some embodiments, the ablation elements 502 are oriented towards the inner surface (towards the axis or centerline) of the catheter. In some embodiments, the orientation of the ablation elements 502 vary +/- 60 degrees (or by some range between 30-90 degrees, such as 30-60, 40-70, 50-80, 50-90, or any valise within the recited ranges) from the inward normal direction of the catheter centerline. In some embodiments, the ablation elements 502 are independently controlled. In some embodiments, the ablation elements 502 are arranged in bipolar pairs. The ablation elements 502 may be arranged in an alternating bipolar arrangement along the spiral catheter. In some embodiments, the bipolar pairs are configured to fall on opposite sides of the vessel. In some embodiments, the ablation area is irrigated with an electrolyte solution such as saline. In other embodiments, the ablation area is irrigated with a non-conductive fluid, such as 5% dextrose solution.

[QQ86] In some embodiments, the number of turns (360 degrees per turn) in the spiral is about 1. In some embodiments, the number of turns is 1.5 to 3 (e.g., 1.5, 2, 2.5, 3 turns). In some embodiments, the number of turns is greater than 3. In some embodiments, the number of ablation elements 502 per turn is 4-16 (e.g., 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15 or 16). In some embodiments, the number of ablation elements 502 per turn is greater than 16. In other embodiments, the number of ablation elements 502 per turn is a non-integral multiple of the number of turns. In some embodiments, the number of ablation elements 502 is defined by degree spacing instead of number per turn. For example, the ablation elements 502 may be spaced apart from each other along a turn at between 15 degrees to 30 degrees, between 20 degrees and 40 degrees, between 30 degrees and 60 degrees, between 45 degrees and 90 degrees, between 60 degrees and 120 degrees, between 90 degrees and 180 degrees, between 100 degrees and 190 degrees, overlapping ranges thereof, or any value within the recited ranges. The spacing between ablation elements 502 may be uniform (e.g., equal) or non- uniform.

[0087] In some embodiments, the catheter is provided with pulling point features P (e.g., handle, loop or pull ring) to facilitate grabbing by an endoscopic instrument. The handle may be used to pass the tool/catheter 500 through multiple wraps around the vessel 120. In some embodiments, the catheter 500 is reinforced (e.g., with braid, coils, slotted hypotubes, etc. 503) to provide torqueability to“screw” the pigtail spiral portion 501 around the vessel 120. In some implementations, the spiral portion, when in the spiral configuration, has an internal spiral lumen diameter of between 0.4 cm and 0.9 cm so as to extravascular!y contact or closely surround an external surface of a common hepatic artery . The internal spiral lumen diameter may range from between 0.2 cm to 2.0 cm (e.g., 0.2 cm to 0.5 cm, 0.3 cm to 0.8 cm, 0.4 cm to 0.9 cm, 0.5 cm to 1.0 cm, 0.8 cm to 1.6 cm, 1.0 cm to 2.0 cm, overlapping ranges thereof, or any value within the recited ranges).

B. Chemical or Other Ablation Agents

1. Chemical A blation Agents

[QQ88] In accordance with several embodiments, a method for hepatic neuromodulation (e.g., denervation) via delivery of chemical or other ablation agents is provided. The method comprises inserting a delivery catheter (e.g., hollow, solid, partially hollow, probe, shaft or other delivery device with or without a lumen) into or toward vasculature of the subject (e.g., a location of a branch of a hepatic artery, such as the proper hepatic artery or the common hepatic artery). Suitable ablation agents include sclerosing agents such as alcohol, phenol, glycerol, sodium dodecyl sulfate, purified water, etc. Other suitable agents include nerve agents such as botu!inum toxin (BOTOX ^® ). Still other agents include phenolphtha!ein. In some implementations, the agents may be mixed with a carrier. Suitable carriers include water, saline, lipid emulsions such as lipiodol, solvents such as dimethyl sulfoxide, and other materials. In some implementations, visualization materials are mixed with the ablation agent. Suitable materials include dyes or stains such as indocyanine green, methylene blue, etc. In some embodiments, the dye is a fluorescent dye such as fluorescein. These ablation agents may be used in connection with any of the systems, tools, devices, catheters, and/or methods described herein.

[0089] FIG. 7 illustrates various embodiments of a system 700 for delivery of liquid ablation agents. In some embodiments, liquid ablation agents are applied using a gas sprayer 701, such as an air brush. In some embodiments, the gas sprayer (e.g., as shown in gas sprayer 701 A) comprises an outlet orifice 702A located at the distal end of the sprayer. In some embodiments, the gas sprayer (e.g., as shown in gas sprayer 701B) comprises outlet orifices 702B located along the length of the spray er. The system 700 may include one gas sprayer or multiple gas sprayers. The gas sprayers 701A, 701B may be alternative embodiments and not used concurrently. Gases such as carbon dioxide may be used as the propellant; these gases may be advantageous because their high solubility facilitates clearance of residual gas from the body. Other suitable propellants include, but are not limited to, helium, argon, xenon, and nitrous oxide. Some propellants provide analgesic effects that persist through a recovery period. In some embodiments, the liquid ablation agents are formulated as high viscosity fluids. In some embodiments, the liquid ablation agents are formulated as low viscosity fluids. In some embodiments, the liquid ablation agents are formulated using a co-solvent or carrier having a higher vapor pressure such that the solution viscosity is lower during delivery and higher after the high vapor pressure material evaporates. An advantage of this approach is reduced migration of agent after delivery. In some embodiments, the liquid ablation agent coalesces into a film on the tissue surface. In some embodiments, the ablation material exists as discontinuous regions of ablation agent dispersed on or m the tissue.

[ 0090] In some embodiments, the ablation agent may be provided in the form of a gel. Suitable gel materials include poly(vinyl alcohol), polyacrylamide, gelatin, collagen, agarose, methylcellulose, hyaluronan, dextrose, polyvinylphenol, amylopectin, polyethylene oxide, thrombin, agar and others. In some embodiments, the gel is a colloidal gel having a second liquid phase. In some embodiments, a first phase is a continuous phase and a second phase is a discontinuous phase. In some embodiments, both the first and second phases are continuous phases. In some embodiments, the ablation agent may comprise a first phase. In some embodiments, an ablation agent may comprise a second phase. In some embodiments, the gel is biodegradable. These ablation agents may be used in connection with any of the embodiments described herein. The system 700 may also optionally include a vessel loop catheter configured to perform diagnostic (e.g., treatment confirmation) and/or therapeutic (e.g , ablation or other denervation) procedures.

[0091] In some embodiments, the ablation agent is delivered as a strip, filament patch, or film. FIG. 8 illustrates an embodiment of the ablation agent 800 wrapped around the length of the target vessel 120. In some embodiments, the ablation agent comprises a tube. In some embodiments, the ablation agent comprises a detachable portion of a delivery catheter. For example, an ablation agent strip or filament may be wrapped around a distal portion of a catheter in such a way as to be slideably removed from the catheter. In other embodiments, a strip or film may be positioned alongside a catheter for release at the desired location. In some embodiments, a filament comprising an ablation agent may be extruded from a catheter. In some embodiments, the filament forms from a phase inverted gel extruded from a delivery- catheter (similar to“silly string”). In some embodiments, the strip, film, filament or patch may be biodegradable. Suitable biodegradable materials include polylactic acid, poly-L-lactide, poly-glutamic acid, polycaprolactone, poly(lactic-co-gly colic acid), polydioxanone, gelatin and other materials. In some embodiments, a film is wrapped around a catheter and unfurled to cover a tissue. In other embodiments, a film may be draped over the end of a catheter and to be positioned on a tissue. In other embodiments, multiple sections of film (patches) are delivered onto the tissue.

[QQ92] In some embodiments, the ablation agent is delivered as a powder. FIG. 6 illustrates an embodiment of a method and apparatus used to deliver a powdered ablation agent (e.g., powder spray or powder coating technique). In one embodiment, the powder is aerosolized and delivered from a catheter connected to a spray gas outlet 601 of a chamber 602 using high velocity gas jets or streams. In one embodiment, the powder is aerosolized using a fluidized bed 600. Fluidizing gas enters into an inlet at a bottom of the chamber 602. The chamber 602 may include a fluidizing gas distributor plate (shown as line with arrows pointing upward in FIG. 6). In some embodiments, on contact with the target tissue, the powder dissolves quickly, slowly, or not at all. In some embodiments, the powder is biodegradable. Suitable biodegradable materials include polylactic acid, poly-L-lactide, polyglutamic acid, polycaprolactone, poly(lactic~co-glycoiic acid), polydioxanone, gelatin, and other materials.

[0093] In some embodiments, the ablation agent is provided as a foam 900. FIG. 9 illustrates several embodiments of methods and devices configured to deliver a foam ablation agent to a target vessel 913, or perivascular space surrounding the vessel 913. In some embodiments, the foam 900 is formed from a compressed or condensed gas 903 mixed with the ablation agent 902, delivered via a delivery lumen 901 of a catheter or other delivery device. The gas expands upon exiting a delivery catheter, thereby causing foaming to occur. In some embodiments, a foaming agent is provided to form and/or stabilize the foam 900. Suitable foaming agents include sodium dodecyl sulfate, sodium tetradecyl sulfate, and sodium lauryl ether sulfate. In some embodiments, the foaming agent is an ablation agent. In some embodiments, the foam 900 is created by passing the ablation and /or foaming agent mixture 91 1 through an orifice or passageway 910 configured to entrain air, thereby creating a foam 900. In some embodiments, the material passes through multiple orifices or through a single orifice multiple times. Foam may advantageously be useful for evenly distributing small quantities of material over large areas. Foam may also provide ready visual assessment of the location of the material. [0094] In some embodiments, the ablation agent is provided m a form having controlled release characteristics whereby active components of an ablation agent are released from a carrier material over time. In some embodiments, controlled release carrier formulations include oils or other immiscible liquids, porous solids, biodegradable solids, multi-phase materials, permeable solids, closed cell foams, open cell foams and others. Some forms of controlled release materials described above may be deposited on the tissue using phase inversion methods. Phase inversion is a process whereby a carrier, solvent or cosolvent is replaced by or removed to a second solvent. For example, when a solution of polyurethane in dimethylacetamide (DMAC) is exposed to water, the DMAC disperses into the water, causing the polyurethane to precipitate. In this manner, a variety of porous structures can be created. In some embodiments, the solvent may disperse into the tissue on contact leaving concentrated solute on the surface of the tissue. In other embodiments, the solute (ablation agent) may be transported into the tissue along with the solvent. These ablation agents may be used in connection with any of the embodiments described herein.

2 Pigtail Ablation Agent Delivery Catheter

[0095] FIG. 10 illustrates an embodiment of a spiral apparatus 1000 for delivering ablation agents. In some embodiments, the apparatus 1000 comprises a catheter having a spiral (e.g.,“pigtail”) shape 1001 at a distal infusion region of the catheter. The distal infusion region of the catheter comprises shape memory material (e.g., nitinol) having the pre-formed spiral shape when in an unconstrained state. The distal infusion region may be configured to transition to the spiral shape when a constraint of an outer sheath or an internal mandrel or stiffening wire is removed. The distal infusion region may be positioned along a target vessel (e.g., common hepatic artery) and then the constraint may be removed so as to cause the distal infusion region to transition to the spiral shape and wrap around the target vessel. Infusion ports or outlet orifices 1002 are provided spaced at intervals along the spiral section. In some implementations, the ports 1002 are oriented towards the inner surface (towards a central longitudinal axis of the catheter when in a straight configuration) of the catheter, or toward the outer surface of the target vessel. In other implementations, the ports 1002 are oriented outward, depending on the location of the nerves surrounding the target vessel that are to be denervated (e.g., ablated). In some implementations, the orientation of the ports vary +/- 60 degrees (or by some range between 30-90 degrees, such as 30-60, 40-70, 50-80, 50-90, or any value within the recited ranges) from the inward normal direction of the catheter centerline. The infusion ports 1002 are substantially smaller in diameter than the infusion lumen to promote uniform delivery. The diameter of the ports 1002 may be between 0.025 mm and 2 mm (e.g., between 0.025 mm and 0.20 mm, between 0.05 mm and 0.10 mm, between 0.10 mm and 0.50 mm, between 0.25 mm and 0.75 mm, between 0.50 mm and 1.0 mm, between 0.75 mm and 1.5 mm, between 1 mm and 2 mm, overlapping ranges thereof, or any value within the recited ranges) depending on the type of ablation agent to be infused, injected, or otherwise delivered. In some implementations, the ports 1002 are sized to cause outflow at low' velocity' (e.g., seepage). In other embodiments, the ports 1002 are sized to cause outflow' at higher velocity (e.g., pressurized fluid jets). The ports 1002 may advantageously be uniformly or evenly distributed. The ports 1002 are fluidly coupled to a reservoir including the infusion fluid (e.g., via an infusion lumen). The ports 1002 may be configured to deliver any of the fluid ablation agents (e.g., liquid ablation agents, foam ablation agents, gaseous ablation agents), solid ablation agents, or other ablation agents described herein. For example, the ablation agent may be an alcohol, phenol, or glycerol. The catheter may optionally additionally include one or more energy delivery or diagnostic elements (e.g., electrodes, transducers, laser- emitting elements, microwave antennae, etc.) configured to provide therapeutic (e.g., ablation) or diagnostic procedures (e.g., confirmation of ablation).

[0096] In some embodiments, the number of turns (360 degrees per turn) of the spiral shape is about 1. In some embodiments, the number of turns is 1.5 to 3 (e.g., 1.5, 2, 2.5, 3 turns). In other embodiments, the number of turns is greater than 3. In some embodiments, the number of ports 1002 per turn is 4-16 (e.g., 4, 5, 6, 7, 8, 9, 10, 1 1 , 1 , 13, 14, 15, or 16) In some embodiments, the number of ports 1002 per turn is greater than 16 In other embodiments, the number of ports 1002 per turn is a non-integral multiple of the turns. In some embodiments, the number of ports 1002 is defined by degree spacing instead of number per turn. For example, the ports may be spaced apart from each other along a turn at between 15 degrees to 30 degrees, between 20 degrees and 40 degrees, between 30 degrees and 60 degrees, between 45 degrees and 90 degrees, between 60 degrees and 120 degrees, between 90 degrees and 180 degrees, between 100 degrees and 190 degrees, overlapping ranges thereof, or any value within the recited ranges. The spacing between ports 1002 may be uniform (e.g., equal) or non- uniform. [0097] In some embodiments, the catheter is provided with pulling point features (e.g., optional handle 1003) to facilitate grabbing by an endoscopic or laparoscopic instrument. The handle 1003 may be used to pass a portion of the catheter 1000 through multiple wraps around the vessel. In some embodiments, the catheter 1000 is reinforced (with braid, coils, slotted hypotubes, etc.) to provide torqueability to“screw” the pigtail spiral around the vessel 120. In some implementations, the spiral portion, when in the spiral configuration, has an internal spiral lumen diameter of between 0.4 cm and 0.9 cm so as to extravascularly contact or closely surround an external surface of a common hepatic artery or other target vessel. The internal spiral lumen diameter may range from between 0.2 cm to 2.0 cm (e.g., 0.2 cm to 0.5 cm, 0.3 cm to 0.8 cm, 0.4 cm to 0.9 cm, 0.5 cm to 1.0 cm, 0.8 cm to 1.6 cm, 1.0 cm to 2.0 cm, overlapping ranges thereof, or any value within the recited ranges). A kit including devices having different internal spiral lumen diameters adapted for different target vessels may be provided from which a clinician may select. Alternatively, the internal spiral lumen diameter of the spiral portion may be configured to be adjustable (e.g., made larger or smaller) by manipulation provide by a user or an automated control system (e.g., pull wires, gears and pulleys, etc). The apparatus 1000 may include a camera or other imaging and/or diagnostic device (or a lumen/port configured to receive such a separate device with the camera or other imaging device) to facilitate visualization of the target vessel or nerves and/or to confirm denervation of nerves. The apparatus 1000 may incorporate any of the features described in connection with the tools/catheters/devices/systems described above, such as in FIGS. 5 A and 5B but replacing the ablation elements 502 with the ports 1002.

3. Desiccating Agents

[0098] In some embodiments, an ablation agent is delivered as a stream of dry gas towards a tissue surface (e.g., vessel surface or surface of nerves in perivascular space surrounding a vessel). FIG. 11 illustrates an embodiment of a method and apparatus 1100 for delivering the stream of dry gas. Water from the tissue is evaporated into the gas, thereby desiccating and ablating the cells. Suitable gases for desiccation include, but are not limited to: carbon dioxide, helium, nitrous oxide, etc. In some embodiments, the gas is heated to increase the partial pressure of water both m the gas and to warm the tissue, thereby speeding evaporation. In various embodiments, the gas stream is substantially cylindrical, conical, or planar. In some embodiments, the gas stream exits from an opening 1102 in a catheter 1101. The opening 1102 may be 0.001-0.005” in diameter, 0.004-0.020” in diameter, greater than 0.010” in diameter, or less than 0.005” in diameter in some embodiments, the gas opening 1 102 may be an orifice in some embodiments, the gas opening 1 102 may be a slit. In some embodiments, the gas opening 1102 may include a diffuser. Gas may be delivered at high pressure (e.g., greater than 5 atm, between 5-8 atm, between 6-12 atm, or higher than 12 atm). In some embodiments, the gas is delivered through a shaft (of the catheter 1101 or a separate shaft). The shaft diameter may be 0.005”- 0.020” in diameter, less than 0.010” m diameter, or more than 0.02” in diameter. The shaft length may be 6-12", more than 10”, or less than 10”. The shaft may be constructed of metal (e.g. stainless steel) hypotubing, nitmol tubing, or polymer tubing (e.g., polyimide, polyethylene, nylon, poly ether ether ketone, pebax, etc.). In some embodiments, the gas opening 1102 is located at the end of the catheter 1101. In some embodiments, the gas opening 1 102 is located at the side of the catheter 1 101. In some embodiments, the gas outflow is directed at an angle to the catheter 1101. In some embodiments, the gas outflow is substantially normal (e.g., perpendicular) to the catheter 1101 (e.g., a centerline or longitudinal axis). FIG. 11 illustrates two embodiments of catheters or shafts 1 101 (one that forms a spiral shape around the vessel 120 and one that is straight and positioned adjacent the vessel 120 with the opening 1102 positioned such that the gas is delivered toward the vessel 120. The catheter wrapped around the vessel in FIG. 1 1 may include any or all of the features of the catheter 1000 of FIG 10 The catheter wrapped around the vessel in FIG. 11 is shown with multiple openings or orifices 1102.

[0099] In some embodiments, the ablation agent is a strongly hygroscopic material (e.g., desiccant) delivered into contact with the tissue. The desiccant may be presented in solid or liquid form. Suitable desiccant materials include, but are not limited to: alcohol, dehydrated hydrogels, silica gel, salts (e.g. sodium chloride), dextrose, and other materials. The desiccant material may be applied as powder, film, or patch. In some embodiments, the desiccant is delivered temporarily and removed after desiccation is accomplished. In some embodiments, the desiccant is left in place after desiccation is accomplished. In some embodiments, the desiccant material is separated from the target tissue by a thin osmosis membrane. Multiple applications of the material may be necessary to accomplish desiccation. These ablation agents may be used in connection with any of the embodiments described herein. 4. Photodynamic Therapy

[0100] FIGS. 12A and 12B illustrate embodiments of methods and devices for hepatic or other neuromodulation utilizing photodynamic therapy. Photodynamic therapy involves administering a photosensitizing agent 1201 (FIG. 12A) and illuminating a target tissue. When exposed to light, the photosensitizing agent produces singlet oxygen (or other reactive oxygen species) which are short lived, but highly cytotoxic. This causes cell death to occur with little to no effect on the extracellular matrix. Photosensitizing agents may be selective or non-selective. Tissue ablation is accomplished by selectively or non-selectively illuminating perivascular nerves or tissue exposed to the photosensitizing agent. The photosensitizing agents may include variations on porphyrin molecules, such as metallo- porphyrms. Non-therapeutic examples of metallo-porphyrins include heme and chlorophyll. Therapeutic photosensitizing agents include verteporfin and lutetium texaphyrin. In some embodiments, the photosensitizing agent is delivered systemically via intravenous injection hours to days prior to the procedure (e.g., 2 - 6 hours, 4-8 hours, 6-12 hours, 10-20 hours, 12- 24 hours, 1-3 days prior). In other embodiments, the photosensitizing agent is delivered via selective intra-arterial injection or topically to the exposed perivascular (e.g., periarterial) tissues. This latter approach has the advantage of reducing post-procedural photosensitivity that may otherwise require the patient to avoid light for a period after the procedure. Topical administration can be accomplished by irrigating, spraying or soaking a region in a solution of photosensitizer agent. Excess solution may be removed before illumination is delivered. Penetration of the photosensitizing agent into the tissue may be enhanced by use of solvents, such as dimethyl sulfoxide. In some embodiments, the photosensitizing agent is delivered via a catheter (inserted through an endoscopic port) adapted to encircle the target vessel. In some embodiments, the photosensitizing agent is delivered through standard endoscopic irrigation devices. In some embodiments, the photosensitizing agent is contained m a wrap, sponge or pad applied to a target tissue. In some embodiments, non-target tissues are masked, shielded or otherwise protected from exposure to the photosensitizing agent. In one embodiment, suction is used to remove excess photosensitizing agent as it is delivered. In some embodiments, the photosensitizing agent is incorporated and delivered in a foam, film or other carrier, in order to improve exposure time. [0101] In some embodiments, an illumination device is configured to provide illumination to the target tissue. In one embodiment, the illumination device is a light source delivered through an endoscopic port. The light source may be positioned outside of the body and include a laser, light emitting diode, superluminescent diode, halogen or xenon lamp, or other light sources. In some embodiments, light transmission is achieved through optical fibers, mirrors, and lenses. Filters may be used to limit the bandwidth of broad spectrum sources to only the wavelengths necessary for excitation of the photosensitizing agent. In some embodiments, the wavelength of the illumination includes green light. In other embodiments, the wavelength of the illumination includes ultraviolet light.

[0102] FIG. 12A illustrates an embodiment of a spiral illumination device 1201. In some embodiments, the illumination device 1201 is a catheter wrapped around the target vessel 120. Diffuse illumination is administered along the length of the catheter by an exposed, etched optical fiber 1202. In some embodiments, the light emitting portion of the catheter is shielded to restrict illumination substantially towards the perivascular nerve tissue. In some embodiments, the illumination device 1201 is also the photosensitizing agent delivery' catheter. FIG. 12 B illustrates an embodiment of an illumination device 1210 providing diffuse illumination from various angles around the target vessel, substantially avoiding shadowing of both perivascular nerve tissue or nerves in the surrounding fascia.

[0103] In some embodiments, the photosensitizing agent has a distinctive color or spectrum of colors that indicates which tissues have been exposed. In some embodiments, the color photobieaches with exposure to light, indicating that therapy has been delivered.

IIL Visualization of Common Hepatic Artery and Perivascular Nerves

A. Index Matching Liquids for Tissue Transparency

[0104] FIG. 13 illustrates an embodiment of a method and device for enhancing visibility of perivascular nerves 131 1 by clarification of surrounding connective tissue 1310. Tissues surrounding the blood vessels and nerves are translucent, but not transparent due to light scattering from fat and connective tissue. Light scattering is caused by variation in index of refraction on a length scale comparable to the wavelength of light. Elevated temperature can change the optical properties of fat to reduce light scattering. Administration (e.g., via a catheter, cannula, needle) of index matching fluids 1301 such as glycerol or dimethyl sulfoxide further reduces scatter and improves visibility. It has been observed that elevated temperature improves the transparency of fatty tissues. In some embodiments, the exposed tissues are heated moderately to improve nerve visualization. For example, heat may be applied via infrared radiative heaters. In some implementations, the tissue temperature is monitored by infrared thermometry. In some implementations, infrared thermometry is interlaced with infrared heating. In some embodiments, heat is applied by hot gas delivery 1302. In some embodiments, hot carbon dioxide is delivered to the area of interest (e.g., target vessel 120 or perivascular area or space surrounding the target vessel 120).

[010S] In some embodiments, heat is applied via hot liquid irrigation. The hot liquid may be an index matching fluid. It has also been observed that impregnation or immersion of materials having substantially matched indices of refraction can improve the transparency of the material. In some embodiments, an indexed matching fluid is provided to the perivascular tissue. In some embodiments, the index matching fluid is delivered through an infusion channel in a delivery' catheter. The catheter may be formed in a spiral fashion to wrap around the vessel. In one embodiment, the index matching fluid is injected into the tissue. In another embodiment, the indexed matched fluid is flowed over the tissue. Suitable index matching fluids include dimethyl sulfoxide, glycerol, dextrose, and/or the like.

[0106] In some embodiments, a system for visualizing and treating perivascular nerves comprises a green light or near infrared light illuminator, an optical imaging sensor filtered to substantially limit sensitivity to the illumination wavelength, a tissue grasping or manipulation device, and/or a tissue electrocautery device for transecting or ablating nerves. It has been observed that tissues are more transparent at certain wavelengths of light, for example, green and near infrared wavelengths. In one embodiment, the illuminator provides green light. In one embodiment, the illuminator provides near infrared light. In another embodiment, the illuminator is capable of providing green and/or near infrared light.

B. Physical Light Sources for Illumination

[0107] FIGS. 14A-D illustrate several embodiments of methods and devices for identifying the CHA or other vessel (e.g., proper hepatic artery, right hepatic artery, left hepatic artery, superior mesenteric artery, inferior mesenteric artery, gastric artery, splenic artery, renal artery, gastroduodenal artery) by illumination. Nerves and other extravascular tissue will appear differently than the CFIA if illuminated from behind tissue. FIG. 14A illustrates an embodiment of a flexible light source 1400 that is advanced to the area of interest to provide illumination of the CHA 100. FIG. 14B illustrates another view of the flexible light source 1400 that is positioned behind a section of perivascular tissue to provide illumination of the CHA 100. FIG. 14C illustrates an embodiment of a stand-alone light source 1420. FIG. 14D illustrates the positioning of the stand-alone light source 1420 behind a section of perivascular tissue to provide illumination of the CHA 100. In some embodiments, the light source is comprised of light emitting diodes. In some embodiments, the light source is powered by batteries 1421 (FIG. 14C) or other power sources. The light source can be positioned in the area of interest through an open incision or through minimally invasive means (e.g., laparoscopically or endoscopically).

C. Visualizing with Staining Agents

[Q1Q8] In some embodiments, the CHA or other target vessel (e.g., proper hepatic artery, right hepatic artery, left hepatic artery, superior mesenteric artery, inferior mesenteric artery, gastric artery, splenic artery, renal artery, gastroduodenal artery) is identified by injecting a staining agent such as sterile surgical ink, methylene blue, fluorescing material (e.g., eosin, ffuorescite fluorescein injection) that glo ' when a certain wavelength of light is delivered to the tissue through or around the vessel. FIGS. 15A-D illustrate the delivery of staining agent to the nerves of interest. The staining agent can be injected from an endovascular or surgical (e.g., laparoscopic) location. The location of the CHA can be approximated by using a small diameter hollow device (e.g., needle) with a reservoir loaded with a staining agent that is injected into the perivascular tissue. The appearance of the tissue surrounding the CHA can thus be visualized directly during a surgical procedure (e.g., laparoscopic or open surgery). In accordance with several embodiments, the surgical procedure would need to be performed in a timeframe that the injected endovascular stain remains visible. In some embodiments, the staining agent is injected during a single surgical procedure. This co uld occur nearer the beginning of the s urgery after a surgical dissection to get near the CHA with conventional open or minimally invasive laparoscopic surgical procedures. After the injection of the staining agent and allowance of a short period of time to elapse (e.g., 30 seconds to 5 minutes, 5 minutes to 15 minutes, 1 5 minutes to 30 minutes, 30 minutes to 1 hour), the staining agent could soak into the surrounding tissue and nerves at different rates or concentrations, leaving the nerves either darker or lighter than the surrounding tissues. This would provide the surgeon additional feedback about the presence or absence of the remaining nerves and guide surgical resection. FIGS. 15A and 15B illustrate one method of delivering the staining agent. FIG. 15A illustrates one view of the area of interest 1500 surrounding a vessel. FIG. 15B illustrates an embodiment of an endoscopic method of delivering the staining agent. In one embodiment, the device delivering the staining agent comprises a guide catheter 1510 encasing a delivery needle 1511 which is advanced into a target vessel (e.g., CHA) 2100 through normal endovascular means and passed through the wall of the target vessel (e.g., CHA) 2100 to deliver the staining agent 1512 to the perivascular nerves or tissue. FIG. 15C illustrates a surgical incision 1520 used to access the area of interest. FIG. 15D illustrates an embodiment of a surgical incision method of delivering the staining agent. In one embodiment, the device 1530 is delivered via surgical incision 1520 directly to the perivascular nerves or tissue 1531 to inject the staining agent 1512 without entering the target vessel (e.g., CHA 2100).

[0109] The hepatic or other arteries disclosed herein may lend themselves to robotic or automated treatments based on a predetermined or preselected treatment. The automated treatment may minimize or reduce trauma and risk of deviation from protocol. The preselected treatment may incorporate treatment parameters (e.g , target locations, spacing between treatment locations, duration, frequency, etc.) and may be based, at least in part, on pre-operative and/or intra-operative images or other intraoperative feedback. Feedback ma ^¬ be based on artificial intelligence feedback received from one or more processors executing instructions of artificial intelligence programs or algorithms designed to analyze medical data (of the patient and/or stored data based on research or past imaging or treatment of other patients) and provide decisions and actions based on the analysis to adjust movement of navigation instruments and/or adjust parameters of treatment devices. Any of the methods described herein may be implemented using one or more robotic or automated systems.

[0110] In an embodiment, an automated system (e.g , robotic controller or robotic control and/or navigation system) may be used for automated access to and/or treatment (e.g., laparoscopic access and treatment) of a nerve. The automated system may include memory that includes a recipe or protocol. The memory may include a plurality of recipes (e.g., different body parts to be treated, different treatments of such body parts) that may be selected by an input device. The recipe can include information about, for example, how to navigate to the body part (e.g., blood vessel or organ) and what type of energy (e.g., energy modality, power level, treatment duration, continuous versus intermittent) to apply to effect certain treatment.

[Q111] The system may include memory that includes information, for example related to the patient, the components of the system, the user, environmental factors, etc. The system may use the information to modify the recipe before, during, and/or after a procedure. The memory may include program instructions stored on a non-transitory computer-readable storage medium (e.g., solid state storage drive, magnetic storage drive, other memory)

[0112] A computing device (e.g., operator workstation or control console) such as a laptop or tablet may include the memory, input device, a display device, communications devices, and the like to operate as a control center for the procedure. For example, a procedure may start by selecting via an input device of the control center a recipe (e.g., hepatic denervation) and a patient from menus displayed by the control center. The control center may visibly and/or audibly provide instructions for initial setup of the procedure after which the procedure is substantially automated, or the procedure may begin immediately or soon after menu selection. The computing device includes one or more specialized processors.

[0113] The system may include a steerable component such as a guidewire, endoscope, laparoscope, or a guide catheter. The steerable component may be inserted into a patient’s body laparoscopically and advanced adjacent to the nerve(s) to be treated, for example nerves surrounding a liver, pancreas, kidney, intestine, adrenal grand, spleen, stomach, etc. A portion of the steerable component inside the body may include a monitoring device such as IVUS, RFID, etc. to monitor position of the catheter. The control center may receive information from the monitoring device via wired and/or wireless communication. Alternatively or additionally, a portion of the steerable component inside the body may include a radiopaque element (e.g., marker band) and/or other means for monitoring the position of the steerable component external to the body. The steerable component may include one or more robotic arms. The robotic arms may be configured to move with six or more degrees of freedom and to support or carry access tools and/or treatment or diagnostic devices (e.g., the mechanical and/or electrical neuromodulation devices or other tools or devices described herein). The robotic arms may be coupled to a support system and controlled by one or more instrument drive systems that are m turn controlled by the computing device. The instrument drive systems may include electro-mechanical components and advancement mechanisms (e.g., gears, pulleys, joints, hydraulics, wires, etc.) configured to actuate and move the robotic arms.

[0114] Outside of the body, the steerable component may be engaged with an advancement mechanism. For example, one or more motors may advance, retract, and/or rotate the steerable component in response to instructions from the control center. A curvature of at least part of the steerable component may be modified to provide navigability within the body (e.g., to avoid obstacles or sensitive structures). The robotic system may also include one or more imaging devices (e.g., cameras, endoscopes, laparoscopes, ultrasound imaging modality, fluoroscopic imaging modality, MR imaging modality, and/or the like). The imaging devices may be supported or carried by one or more of the robotic arms. The imaging devices may include stereotactic cameras and/or electromagnetic field sensors. The imaging devices may be calibrated to patient anatomy or using reference pins or trackers positioned at one or more locations of the patient’s body by a registration, or localization, system. The registration system may include multiple computing devices (e.g., processors and computer-readable memory for storing instructions to be executed by the processor! s)). Imaging modalities may be used to monitor the surroundings of the steerabl e component. The advancement mechanism may advance the steerable component to a body part (e.g., vessel or organ) as indicated in the recipe. For example, the steerable component may be longitudinally distally advanced until the steerable component reaches a vessel, for example indicated by a dark, non-walled spot on an imaging output that can be detected by the control center. Based on the recipe, which may include a map of the vasculature, the steerable component can be advanced to a vessel or organ (e.g., by modifying curvature of the steerable component). If the steerable component is a guidewire, a catheter may be advanced over the gmdewire. If the steerable component is a guide catheter, a catheter may be advanced in the guide catheter, or the guide catheter itself may include a treatment tool such as an energy emitter. In a partially automated system, a user may advance a steerable component to a location at or proximate to the body part, and the system can be automated thereafter.

[0115] Once the treatment tool is in a position, the recipe may call for an initial diagnosis, for example of a bodily parameter. The bodily parameter may be used as a baseline to evaluate the treatment and/or as a variable to adjust a treatment parameter. The treatment tool can be automatically positioned, for example via longitudinal advancement and/or retraction, rotation, and/or biasing to a side (e.g., via shape-memory wire, balloon, anchor, and/or the like), to modulate a nerve. The recipe may call for denervation or stimulation and may adjust energy application parameters (e.g., frequency, tune, cooling, focus, etc.) accordingly. The treatment tool may be moved to a plurality of sites, for example advancing a known or calculated distance in a particular direction. The recipe may call for an ongoing diagnosis, for example of the same or a different bodily parameter, during the treatment. The bodily parameter may be used to adjust a treatment parameter and/or repeat a treatment mid procedure. The recipe may call for a final or post-procedure diagnosis, for example of the same or a different bodily parameter. The bodily parameter may be used to confirm completion of the procedure. The bodily parameter may be used to adjust a treatment parameter and/or repeat a treatment after the initial completion of the procedure. Feedback may be based on artificial intelligence feedback received from one or more processors executing instructions of artificial intelligence programs or algorithms designed to analyze medical data (e.g., bodily- parameters, images, measurements, etc.) and provide decisions and actions based on the analysis to adjust movement of navigation instruments and/or adjust parameters of treatment devices.

[0116] A user of the system may be standing by in case non-automated action may be needed. Action may be indicated by the system itself, for example via a warning (e.g., visual or audible alert or alarm) on a control center.

V. Certain Terminology

[0117] Terms of orientation used herein, such as“top,”“bottom,”“horizontal,” “vertical,”“longitudinal,”“lateral,” and“end” are used m the context of the illustrated embodiment. However, the present disclosure should not be limited to the illustrated orientation. Indeed, other orientations are possible and are within the scope of this disclosure. Terms relating to circular shapes as used herein, such as diameter or radius, should be understood not to require perfect circular structures, but rather should be applied to any suitable structure with a cross-sectional region that can be measured from side-to-side. Terms relating to shapes generally, such as“circular” or“cylindrical” or“semi-circular” or“semi-cylindrical” or any related or similar terms, are not required to conform strictly to the mathematical definitions of circles or cylinders or other structures, but can encompass structures that are reasonably close approximations.

[0118] Conditional language, such as“can,”“could,”“might,” or“may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include, while other embodiments do not include, certain features, elements, and/or steps. Thus, such conditional language is not generally intended to imply that features, elements, and/or steps are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding, with or without user input or prompting, whether these features, elements, and/or steps are included or are to be performed in any particular embodiment.

[0119] Various embodiments of the invention have been presented m a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. The ranges disclosed herein encompass any and all overlap, sub-ranges, and combinations thereof, as well as individual numerical values within that range. For example, description of a range such as from about 2W to about 6W should be considered to have specifically disclosed subranges such as from 2 to 4 W, from 3 to 5 W, from 3 to 6 W, from 4 to 6 W, etc., as well as individual numbers within that range, for example, 2, 2.5, 3, 4, 4.5, 5, 6, and any whole and partial increments therebetween. Language such as“up to,”“at least,” “greater than,”“less than,”“between,” and the like includes the number recited. Numbers preceded by a term such as“about” or“approximately” include the recited numbers (for example,“about 1” includes 1 ).

[0120] The terms“approximately,”“about,” and“substantially” as used herein represent an amount close to the stated amount that still performs a desired function or achieves a desired result. For example, m some embodiments, as the context may permit, the terms “approximately”,“about”, and“substantially” may refer to an amount that is within less than or equal to 10% of the stated amount. The term“generally” as used herein represents a value, amount, or characteristic that predominantly includes or tends toward a particular value, amount, or characteristic. As an example, in certain embodiments, as the context may permit, the term“generally parallel” can refer to something that departs from exactly parallel by less than or equal to 15 degrees. As another example, in certain embodiments, as the context may permit, the term“generally perpendicular” can refer to something that departs from exactly perpendicular by less than or equal to 15 degrees.

V. Conclusion

[Q121] In some embodiments, the systems comprise one or more of the following: means for tissue modulation (e.g., an ablation or other type of modulation catheter or deliver _} ' device), means for laparoseopicaliy accessing a tissue location within a body of a subject (e.g., incision tools and/or an ablation or other type of modulation catheter or deliver _} ' device having a sufficient length and diameter to enter through an incision in an abdominal or other superficial tissue wall and extend to a target location such as a location surrounding a common hepatic artery or other blood vessel described herein), etc.

[0122] While the embodiments described herein have primarily addressed the treatment of diabetes (e.g., diabetes meilitus), other conditions, diseases, disorders, or syndromes (e.g., factors of metabolic syndrome) can be treated using the devices, systems and methods described herein, including but not limited to ventricular tachycardia, atrial fibrillation or atrial flutter, high blood pressure, hyperlipidemia, obesity, inflammatory diseases, endocrine diseases, hepatitis, pancreatitis, gastric ulcers, gastric motility disorders, irritable bowel syndrome, autoimmune disorders (such as Crohn’s disease), Tay-Sachs disease, Wilson’s disease, fatty liver conditions (such as NASH and NAFLD), leukodystrophy, polycystic ovary syndrome, gestational diabetes, diabetes insipidus, thyroid disease, and other metabolic disorders, diseases, or conditions.

[0123] Although certain embodiments and examples have been described herein, aspects of the methods and devices shown and described in the present disclosure may be differently combined and/or modified to form still further embodiments. Additionally, the methods described herein may be practiced using any device suitable for performing the recited steps. Further, the disclosure (including the figures) herein of any particular feature, aspect, method, property, characteristic, quality, attribute, element, or the like m connection with various embodiments can be used in all other embodiments set forth herein. The section headings used herein are merely provided to enhance readability and are not intended to limit the scope of the embodiments disclosed in a particular section to the features or elements disclosed in that section. [0124] Furthermore, certain features that are described in this disclosure in the context of separate implementations can also be implemented in combination in a single implementation. In some embodiments, the systems comprise various features that are present as single features (as opposed to multiple features). Conversely, various features that are described in the context of a single implementation can also be implemented m multiple implementations separately or in any suitable subcombination. Multiple features or components are provided in some embodiments. Moreover, although features may be described above as acting in certain combinations, one or more features from a claimed combination can, in some cases, be excised from the combination, and the combination may be claimed as a subcombination or variation of a subcombination.

[0125] Features, materials, characteristics, or groups described in conjunction with a particular aspect, implementation, embodiment, or example are to be understood to be applicable to any other aspect, embodiment or example described in this section or elsewhere in this specification unless incompatible therewith. The term“embodiment” as used herein should not necessarily be interpreted as“invention” and can represent an example, an implementation, or aspect that can be combined with other“embodiments” to form an invention. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings) may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The protection is not restricted to the details of any foregoing embodiments. The protection extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination so disclosed.

[0126] For purposes of this disclosure, certain aspects, advantages, and novel features are described herein. Not necessarily all such advantages may be achieved in accordance with any particular embodiment. Thus, for example, those skilled in the art will recognize that the disclosure may be embodied or carried out in a manner that achieves one advantage or a group of advantages as taught herein without necessarily achieving other advantages as may be taught or suggested herein.

[0127] Some embodiments have been described in connection with the accompanying drawings. The figures are drawn to scale where appropriate, but such scale should not be limiting, since dimensions and proportions other than what are shown are contemplated and are within the scope of the disclosed invention. Distances, angles, etc. are merely illustrative and do not necessarily bear an exact relationship to actual dimensions and layout of the devices illustrated. Components can be added, removed, and/or rearranged. Further, the disclosure herein of any particular feature, aspect, method, property, characteristic, qualify, attribute, element, or the like in connection with various embodiments can be used in ail other embodiments set forth herein. Additionally, any methods described herein may be practiced using any device suitable for performing the recited steps. Any methods disclosed herein need not be performed in the order recited. The methods disclosed herein include certain actions taken by a practitioner: however, they can also include any third-party instruction of those actions, either expressly or by implication.