Medical devices configured for therapeutic electroporation with adjustable sections of an elongate member

Abstract

A medical device includes an elongate member, the elongate member comprising a distal tip section, a first inflection section, a first elongate section, and a second inflection section, and at least a second elongate section, the first inflection section defining a pre-bent tip angle for the distal tip section of the elongate member, the second inflection section comprising an articulable bend of the first elongate section relative to the second elongate section. The medical device also includes one or more radiofrequency ablation electrodes disposed at a distal tip of the elongate member.

Description

MEDICAL DEVICES CONFIGURED FOR THERAPEUTIC ELECTROPORATION WITH ADJUSTABLE SECTIONS OF AN ELONGATE MEMBERTECHNICAL FIELD

[0001] The present disclosure relates to medical devices, such as delivery catheters, and to systems and methods for performing therapeutic electroporation of biologic tissues using such medical devices.BACKGROUND

[0002] Various approaches have been developed to deliver energy to target tissues within a subject, where the energy may be delivered for neuromodulation, denervation and / or ablation of the target tissues. Some approaches are catheter-based, and involve a deployable mechanical structure with hard, metallic electrodes that need to conform to the surface of the target tissues to be treated. As vessels narrow at the parenchyma of an organ, near to a tumor site, etc., it is challenging to reduce the size of the mechanical components and electrodes of a catheter-based medical device to reach the target tissue while also being able to maintain an effective treatment volume.SUMMARY

[0003] Illustrative embodiments provide medical devices configured for performing therapeutic electroporation of biologic tissues, the medical devices having an elongate member with one or more adjustable sections.

[0004] In some embodiments, a medical device comprises an elongate member, the elongate member comprising a distal tip section, a first inflection section, a first elongate section, and a second inflection section, and at least a second elongate section, the first inflection section defining a pre-bent tip angle for the distal tip section of the elongate member, the second inflection section comprising an articulable bend of the first elongate section relative to the second elongate section. The medical device also comprises one or more radiofrequency ablation electrodes disposed at a distal tip of the elongate member.

[0005] The elongate member may comprise a delivery catheter. The delivery catheter may be configured for deployment via a guide sheath. The medical device may further comprise a controller configured to advance the delivery catheter through the guide sheath, wherein on advancement of the distal tip section and the first inflection section past an end of the guidesheath, the distal tip section of the elongate member takes on the pre-bent tip angle. The controller may be further configured to actuate the second inflection section to provide the articulable bend of the first elongate section relative to the second elongate section. The articulable bend of the first elongate section relative to the second elongate section may bring the distal tip section into contact with a wall of a lumen in which the delivery catheter is deployed. The controller may be further configured to rotate the delivery catheter relative to the guide sheath to bring the distal tip section into contact with different portions of a circumference of a wall of the lumen in which the delivery catheter is deployed.

[0006] At least one of the first inflection section and the second inflection section may comprise a shape memory material. The second elongate section may have a higher rigidity than at least one of the first elongate section and the distal tip section.

[0007] The medical device may further comprise one or more temperature sensors disposed at the distal tip section of the elongate member proximate the one or more radiofrequency ablation electrodes. The medical device may further comprise a sheath tube isolating the one or more temperature sensors from the one or more radiofrequency ablation electrodes. The medical device may further comprise a controller configured to controllably advance the distal tip section and actuate the second inflection section to bring the one or more radiofrequency ablation electrodes into contact with a wall of a lumen, to monitor a temperature of target tissues in a vicinity of the wall of the lumen utilizing the one or more temperature sensors, and to control, based at least in part on the monitored temperature of the target tissues in the vicinity of the wall of the lumen, a current applied to the one or more radiofrequency ablation electrodes. The controller may be further configured to monitor a tissue impedance of the target tissues in the vicinity of the wall of the lumen, and the current applied to the one or more radiofrequency ablation electrodes may be further controlled based at least in part on the monitored tissue impedance.

[0008] The medical device may further comprise a radiofrequency wire extending along a length of the elongate member at and attached to the distal tip of the elongate member, at least a portion of the radiofrequency wire providing the one or more radiofrequency ablation electrodes. The medical device may further comprise a thermocouple wire extending along the length of the elongate member ending at a distance away from the distal tip of the elongate member. The portion of the radiofrequency wire providing the one or more radiofrequency ablation electrodes may comprise a portion of the radiofrequency wire extending past an endof the thermocouple wire. The medical device may further comprise a sheath tube isolating a distal section of the thermocouple wire and the radiofrequency wire from the distal tip of the elongate member.

[0009] The medical device may further comprise one or more return electrodes, wherein the one or more radiofrequency ablation electrodes and at least one of the one or more return electrodes are configured to perform bipolar radiofrequency ablation. The at least one of the one or more return electrodes may be disposed on the elongate member or on a guide sheath in which the elongate member is inserted.

[0010] The medical device may further comprise a pull wire coupled to the first elongate section of the elongate member, the pull wire being configured for actuating the articulable bend of the second inflection section.

[0011] In some embodiments, a method comprises delivering an elongate member of a medical device to a target site within a lumen, the elongate member comprising a distal tip section, a first inflection section, a first elongate section, and a second inflection section, and at least a second elongate section, the first inflection section defining a pre-bent tip angle for the distal tip section of the elongate member, the second inflection section comprising an articulable bend of the first elongate section relative to the second elongate section. The method also comprises actuating the second inflection section to provide the articulable bend of the first elongate section relative to the second elongate section to bring the distal tip section into contact with a wall of the lumen, and controlling a current applied to the one or more radiofrequency ablation electrodes to ablate target tissues in a vicinity of the wall of the lumen.

[0012] Delivering the elongate member of the medical device to the target site within the lumen may comprise advancing the elongate member through a guide sheath, wherein on advancement of the distal tip section and the first inflection section past an end of the guide sheath, the distal tip section of the elongate member takes on the pre-bent tip angle. The method may further comprise rotating the elongate member relative to the guide sheath to bring the distal tip section into contact with different portions of a circumference of the wall of the lumen.

[0013] At least one of the first inflection section and the second inflection section may comprise a shape memory material. The second elongate section may have a higher rigidity than at least one of the first elongate section and the distal tip section.

[0014] The method may further comprise monitoring a temperature of the target tissues in the vicinity of the wall of the lumen utilizing one or more temperature sensors disposed at the distal tip section of the elongate member proximate the one or more radiofrequency ablation electrodes. A sheath tube may isolate the one or more temperature sensors from the one or more radiofrequency ablation electrodes. Controlling the current applied to the one or more radiofrequency ablation electrodes may be based at least in part on the monitored temperature of the target tissues in the vicinity of the wall of the lumen. The method may further comprise monitoring a tissue impedance of the target tissues in the vicinity of the wall of the lumen, and the current applied to the one or more radiofrequency ablation electrodes may further be based at least in part on the monitored tissue impedance.

[0015] The medical device may further comprise one or more return electrodes, and wherein the one or more radiofrequency ablation electrodes and at least one of the one or more return electrodes may be configured to perform bipolar radiofrequency ablation.

[0016] The medical device may further comprise a pull wire coupled to the first elongate section of the elongate member, and wherein actuating the second inflection section to provide the articulable bend of the first elongate section relative to the second elongate section to bring the distal tip section into contact with a wall of the lumen may utilize the pull wire.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Several aspects of the disclosure can be better understood with reference to the following drawings. In the drawings, like reference numerals designate corresponding parts throughout the several views.

[0018] FIG. 1 shows aspects of a medical device configured for therapeutic electroporation of target tissues in an illustrative embodiment.

[0019] FIG. 2 shows a block diagram of hardware components of a medical device in an illustrative embodiment.

[0020] FIG. 3 shows a method for operating a medical device for therapeutic electroporation of target tissues in an illustrative embodiment.

[0021] FIG. 4 shows examples of locations in which medical devices may be deployed for therapeutic electroporation of target tissues in an illustrative embodiment.

[0022] FIGS. 5A-5D show examples of ganglia locations and spatial relationships between a celiac trunk and a superior mesenteric artery in an illustrative embodiment.

[0023] FIG. 6 shows a medical device with articulating elements configured for adjustable deflection of a distal tip in an illustrative embodiment.

[0024] FIG. 7 shows the medical device of FIG. 6 deployed within vessels and articulated such that the distal tip contacts a vessel wall in an illustrative embodiment.

[0025] FIG. 8 shows a medical device with articulating elements configured for adjustable deflection of a distal tip and including an integrated temperature sensor for enabling temperature-controlled therapeutic electroporation in an illustrative embodiment.

[0026] FIGS. 9 A and 9B show a guide sheath for a medical device with return electrodes positioned on the guide sheath to contact different regions of vessel walls in an illustrative embodiment.DETAILED DESCRIPTION

[0027] Particular embodiments of the present disclosure are described hereinbelow with reference to the accompanying drawings; however, the disclosed embodiments are merely examples of the disclosure and may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as an illustrative basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure. Like reference numerals may refer to similar or identical elements throughout the description of the figures.

[0028] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0029] As discussed above, various approaches have been developed to deliver energy to target tissues within a subject (e.g., for neuromodulation, denervation and / or ablation of target tissues), including catheter-based approaches that involve a mechanical structure (e.g., a distal tip of the catheter body) with hard, metallic electrodes that are configured to interface with thesurface of the target tissues to be treated. As vessels narrow at the parenchyma of an organ, near to a tumor site, etc., it is challenging to reduce the size of the mechanical components and electrodes of a catheter-based medical device to reach the target tissue while also being able to maintain an effective treatment volume.

[0030] Such challenges are exacerbated due to high vessel tortuosity of porcine and human subjects. Further, subjects with cancer present additional challenges as tumors may present some pressure against vessel structures resulting in very tight angles in which a catheter must be advanced. For example, there may be very tight angles between an aorta and a celiac artery. Some embodiments provide catheter-based approaches which are more flexible than conventional structures, and include flexible sensing tips or other deployable mechanical structures for managing tortuosity and reduced diameter of vessels near to target treatment regions. In some embodiments, guide sheaths are integrated with catheter-based approaches for delivery to difficult or hard-to-reach locations. Some embodiments also or alternatively utilize alternative insertion locations, possibly simultaneous insertion locations of multiple catheter-based devices, such as femoral and brachial, femoral and radial, etc. In some embodiments, a combined femoral and radial insertion approach is leveraged due to higher caseload and commonality among practitioners. This, however, may require increasing the length of the catheter-based devices which are used.

[0031] Another technical challenge is related to stenosis in vessels, which reduces their inner diameter and presents challenges for delivery of catheter-based devices. Stenosis may be a result of tumor growth. In some embodiments, these challenges are addressed through utilizing a compact construction of catheter-based devices. For example, catheter-based devices may be designed with an outer diameter that is 5 French gauge (Fr) or smaller. These challenges may also or alternatively be addressed through the use of alternative insertion locations as described above (e.g., brachial, radial, etc.), which may result in increasing the length of the catheter-based devices which are used.

[0032] Still further technical challenges are associated with the risk of perforation of vessels. Factors such as age and tumor stage can weaken the vessel walls of a subject, which increases the risk of perforation. These challenges may be addressed through the use of soft tip catheter-based devices. Such soft tip catheters may include a bulbous expanding nitinol electrode structure for blanket energy delivery. In other embodiments, combinations of electrode and chip structures may be utilized to address these challenges. Another approachwhich may be used in some embodiments includes a no irrigation approach, as even a small pressure at an outlet could stress the vessel wall. In some embodiments, catheter-based devices are further designed without any articulating structures, where steerability is achieved with small bends in the catheter tip.

[0033] In some embodiments, electroporation or other ablation techniques are utilized where both anterior and posterior walls of a vessel are ablated, which increases the chances of hitting the target ganglia. Such processing is achieved in some embodiments through the use of increased flexibility at the catheter tip level (e.g., a type “A” curvature), the use of a soft expandable tip to bring electrode structures (e.g., at or proximate a distal tip of a catheter body) into contact with the wall of a vessel, the use of electrode structures with at least a designated threshold length (e.g., 4 millimeter (mm) or longer electrode structures), etc.

[0034] Electroporation or other ablation techniques may, in some cases, result in activation of the Vagus nerve of a subject which could fire temporary pain to posterior upper-level muscles like the shoulder blade, upper back, etc. Such undesirable activation of the Vagus nerve may be addressed, in some embodiments, through limiting the duration of the electroporation or other ablation process (e.g., to no longer than a minute or some other designated threshold, which may be shortened at the clinician’s discretion). Such challenges may also be addressed through the use of electroporation, pulsed field ablation (PF A) or other radio frequency (RF)-based nonthermal or thermal ablation processes which have less impact on the Vagus nerve during treatment.

[0035] In some embodiments, catheter-based devices are provided which facilitate electrode contact at various sections along a circumference of the vessels (e.g., the “top” and “bottom” sections of the vessels) in which the devices are deployed. The catheter-based devices advantageously have a small tip diameter (e.g., a 5Fr maximum), with a tip curve style that matches type “A”, which is non-irrigated, and has increased flexibility when compared with conventional catheter devices. For example, the catheter-based devices in some embodiments eliminate articulation, irrigation ports and extra stiffness.

[0036] Illustrative embodiments provide medical devices configured for therapeutic electroporation of biologic tissues which overcome these and other challenges of conventional approaches. A medical device may include a catheter body with one or more electrodes at or proximate to a distal tip thereof, with a curvature point some distance from the distal tip enabling bi-directional bending to reach different positions around a circumference of a wallof a lumen or other vessel in which the catheter is deployed. The catheter of the medical device may be deployed from a guide sheath. In some embodiments, the distal tip has an adjusted tip angle (e.g., achieved by a user pre-defining a shape memory material of the distal tip) to provide varying wall contact with familiar handling for users. The user manipulated tip bend configuration allows for easier access to challenging vessels. Further, the medical device may include or provide additional tip bend radius to facilitate steerability and eliminate or reduce the need for articulation.

[0037] Regions which may be accessed and / or targeted using the medical devices described herein include, but are not limited to: tubes or vessels (e.g., arteries, veins, lymphatic vessels, etc.) including bifurcated vessels, near to a bifurcation, between vessels near a bifurcation, between adjacent arteries and veins; vessels within an organ, within soft tissues, chamber walls (e.g., through the thickness of a chamber wall); into vessels within a wall of the heart; vessel entrances and / or exits to one or more chambers (e.g., of the heart or other organs or target tissues); microvasculature; within the vasculature and / or microvasculature of a bone; within the marrow of a bone; along a vessel as and down into an organ or other target tissues; a lobe of an organ, a region within an organ, a tumor, the vasculature serving a tumor, etc.

[0038] The medical device may include means for measuring the impedance of the tissue interface, where such measurement may be performed prior to and between delivery of therapeutic energy thereto. Such an approach may be used to limit the potential for arching and / or barotrauma in the vicinity of target treatment sites. In some embodiments, the medical device includes one or more sensors configured to determine impedance between a target treatment region and a return path. The impedance may be used to dictate or control the energy delivered during one or more PFA or other therapeutic pulses. The impedance may also be used to monitor for changes in the impedance of nearby tissues as pulse trains are delivered (e.g., to determine the changes from pulse to pulse in the train, during breaks between pulse trains, combinations thereof, etc.). The medical device may also or alternatively include one or more sensors configured to determine the local temperature near the target treatment region, such that the temperature may be used as feedback to limit and / or regulate delivery of therapy to the target treatment region. The medical device may further or alternatively include one or more sensors configured to tailor the energy delivery in a pulse (e.g., to the level needed to establish a therapeutic field gradient in the tissues adjacent to the target treatment region).

[0039] In some embodiments, a system may include means for measuring cardiac ventricular activity, the system including an algorithm configured to apply pulses in synchronization with the measured activity so as to prevent ventricular fibrillation or other proarrhythmic effects during therapy. The system may include an algorithm to tailor the pulses and pulse trains to minimize and / or eliminate local skeletal muscle contraction and pain associated with application of therapeutic pulses. Such pulse characteristics may be adjusted to a period of less than 100 microseconds (ps), less than 20ps, less than lOps, less than 5ps, less than 2ps, less than Ips, less than 0.4ps, or the like. The pulse width may be variable between 0.2ps and lOps throughout the pulse train. Each pulse may be formed as preferably an asymmetrical bipolar signal, the asymmetric bipolar signal changing in polarity throughout the pulse train, and the pulse spacing may be on the order of less than 1,000 milliseconds (ms), less than 100ms, less than 5ms, less than 1ms, less than 500ps, less than lOOps, less than 25ps, less than lOps, less than 2ps, or the like. Such pulse trains may be used to limit the need for general anesthesia / paralytics and intubation of patients prior to therapy.

[0040] The asymmetrical pulses may be applied in reverse polarity throughout the pulse chain, to minimize changes of muscle contraction while increasing the produced ablation volumes. The asymmetrical pulses may be adjusted throughout the train such that charge delivery is initially biased in a first polarity (e.g., a positive polarity), then in a second, opposite polarity (e.g., a negative polarity), with the timespan of the variation between first and second opposite polarities changing on a scale that is sufficiently rapid so as to minimize long-term charging of tissues, but yet long enough so as to maximize local electroporation of nearly tissues. Such an approach may be considered to introduce a changing polarity bias to the pulse train. The polarity bias may change at a rate of greater than 100Hz, greater than 1,000Hz, 10,000Hz or the like.

[0041] In some embodiments, the amplitude of the bias may be adjusted in real-time during pulse delivery to minimize long-term charging of remote tissues from the treatment site. The amplitude of the bias may be adjusted from + / -100% (e.g., essentially a monophasic pulse train), through to 0% (e.g., a balanced biphasic pulse train).

[0042] In some embodiments, the amplitude of the bias may be adjusted based on charge measurements made from one or more remote sites on and / or in the body of the subject (e.g., from a remote internally placed electrode, from a patch electrode on the body, etc.). The bias may be adjusted so as to prevent stimulation of nerves and / or muscles in such tissues, thuspotentially obviating the need for general anesthesia and / or application of paralytic agents during a procedure.

[0043] Using an asymmetric pulse train, ablation volumes may be increased by a factor of at least 2x, and often up to 5x, that of a symmetric pulse train. Asymmetric pulses imply a biphasic pulse where a positive and negative amplitude and / or pulse width may be different from each other. In aspects, the pulse train may be configured such that asymmetry of the pulse train changes from primarily longer positive polarity pulses to primarily longer negative polarity pulses over the overall delivery period of the pulse train. The frequency with which the asymmetry shifts from positive to negative and back may be on the order of greater than 1kHz, greater than 10kHz, greater than 100kHz, or the like. The shifting asymmetry throughout the pulse train allows for the application of asymmetric pulses to the tissue (e.g., thus potentially lowering the ablation thresholds thereof), while providing short-term charge asymmetry to the target tissues, maintaining a long-term neutral overall energy delivery and minimizing long-term charge imbalance around the treatment site.

[0044] Combined with the device configurations herein, tailoring of the electrically applied pulses to focus on ultra-high frequency pulse application may significantly improve the field gradients around the intended target tissues, while limiting procedural times and risk to the patient during such procedures.

[0045] Electrical pulses may be applied in such a manner so as to establish field gradients in the target tissue of greater than 500 volts per centimeter (V / cm), greater than 700V / cm, greater than l,500V / cm, greater than 4,000V / cm, or the like. The pulses may be provided as bipolar pulses, and may be provided as asymmetrically bipolar pulses to maximize local charge fluctuations in adjacent tissues, thus potentially lowering the therapeutic threshold in such tissues and more easily establishing irreversible changes with minimal input energy.

[0046] In some embodiments, the medical devices described herein may be used in approaches for applying treatment to a tumor.

[0047] A medical device for treating a region of target tissue may include an elongate catheter, the elongate catheter shaped with a tip so as to be delivered into the local arterial supply of the target tissue. The medical device also includes one or more electrodes, the one or more electrodes attached to the tip of the catheter or an extendable component thereof (e.g., a guidewire). The one or more electrodes are positioned along the outer surface of the catheter tip (or the extendable component thereof) to couple electrically within a region surroundingthe catheter tip (or the extendable component thereof). The medical device may further include a fixed bent tip (e.g., that is user-adjusted or user set, such as via use of a shape memory material) that, provides an adjusted tip angle for delivery (e.g., from a guide sheath) to facilitating positioning of electrodes at or proximate the distal tip to touch and maintain contact with different sections around a circumference of a wall of vessel or another lumen in which the medical device is deployed.

[0048] The medical device may include or be coupled to a generator, configured to accommodate delivery of pulses (e.g., PFA pulses) through the generator to at least one of the one or more electrodes of the medical device during use.

[0049] In some embodiments, a system including the medical device provides a means (e.g., a generator) for controllably delivering electrical pulses to one or more of the electrodes. The generator may be coupled to deliver electrical pulses, through the one or more electrodes, to the adjacent target tissues.

[0050] In some embodiments, the system may include one or more sensing electrodes (e.g., which may be on the catheter or guidewire of the medical device) which are used, for example, in monitoring the local temperature at different locations, for monitoring an effect of an ablation process, etc.

[0051] Electric fields provide the principal therapeutic mechanism for biologic cell membrane modification. Electric fields across cell membranes result in membrane permeability, which is generally proportional to field strength and temporal duration of membrane-field exposure. Electric field strength may be measured in volts per meter (V / m), where one V / m is the electrical potential difference of 1 volt (V) at two points separated by one meter. Electric flux intensity measures may also be used. Electroporation may be ablative and / or therapeutic, allowing drugs or biomolecules to cross the cell membrane and interact with the cytosolic components and the nucleus. Electroporation may also initiate cell death if membrane pores are large enough and present long enough to allow intracellular and / or nucleus death. The systems and medical devices described herein enable creation and modification of electric fields in three spatial dimensions, and also enable application of time dependent electric field strength variation. The flexibility of these methods may be used to optimize field strength (e.g., in space and time), and result in vastly improved therapeutic effects. Such therapeutic effects may entail optimizing effective formation of pores in the target cells, affecting the size of the pores formed in the cells, increasing the number of pores formed in the cell walls, and / or-l ilengthening the time that pores remain open after application of the fields for either therapy or toxicity (e.g., resulting in degraded cell function or cell death).

[0052] Electric fields may be delivered to target tissues using spatial field shaping, allowing optimal field strength to be matched to create maximal therapeutic or toxic effect. The temporal field changes are independent of spatial changes, permitting time-varying electric fields of optimal shape. Biologic and medical applications may require therapy at a multiplicity of internal bodily sites, with different tissues to be treated. Electric fields for electroporation and other therapy must be delivered to various target sites within the body. Thus, the medical devices described herein provide catheter systems for traversing the required paths, with the catheter systems including one or more electrically conductive wires. Because the target biologic tissues may be of irregular 3D shapes, optimal delivery requires electric fields that can conform to and / or encompass the target tissue.

[0053] In some embodiments, systems and medical devices use one or more RF electrodes and return electrodes (possibly along with various sensing electrodes as described elsewhere herein), where such electrodes may have a multiplicity of components having opposite polarity (e.g., positive and negative). In some embodiments, electrodes of 3D configuration are used, where the RF electrodes are, for example, positioned at the terminus (e.g., the distal tip) of a delivery catheter. The medical device may include a guidewire configured to guide the delivery catheter and electrodes to a target site, provide electric potential to the distal tip (e.g., where the RF electrodes may be positioned), etc. The 3D configuration of the one or more RF electrodes, combined with complementary return electrodes, guides the pattern of delivery of energy (e.g., for PF A). The voltage applied controls the field strength, while temporal variation in field strength may be used to modulate biologic effects.

[0054] Various electrode configurations may be used, including front firing, lateral firing (e.g., where the field has a component perpendicular to the delivery catheter / guidewire), etc. The electrodes may also be positioned on flat opposing surfaces, which may or may not be parallel, including clamp configurations which can grasp tissue and apply an electric field. Additional electrode configurations which may be used include torus, spherical, ribbon and pyramidal configurations.

[0055] The medical devices described herein may be used for providing therapy to various target regions, including various organs, tissues, nerves, tumors, ganglion sites, etc. Therapy may include innervation along a target anatomy, innervation within the organ parenchyma,smooth muscle innervation in arteries, fluid transfer into the microvasculature around vessels, targeting organ resurfacing, ganglion access which may be combined with recordings for ganglia localization. Internal vessel and external approaches are enabled. The medical devices described herein may be used with methods for determining when a procedure or therapy is completed, for providing bipolar asymmetrically undulating PFA pulses, etc.

[0056] In some embodiments, a pulse train used for PFA includes asymmetric pulses of opposite polarity. Positive voltage pulses with amplitude Vpmay be applied for a time ti, with each of the positive voltage pulses being followed by a negative voltage pulse with amplitude Vnthat is applied for a time t2 (e.g., where t2 < ti). The negative voltage pulses are applied at a time t3 from a beginning of time ti. The time between the sets of asymmetric pulses is denoted time t4. The pulse train may include a changing polarity bias from an amplitude of Ebi (e.g., +100%) through to an amplitude of Eb2 (e.g., -100%) over a time period denoted ts. Negative voltage pulses with amplitude Vnare applied for a time te, with each of the negative voltage pulses being followed by a positive voltage pulse with amplitude Vpthat is applied for a time t? (e.g., where t? < te). The positive voltage pulses are applied at a time ts from a beginning of time te. The time between the sets of asymmetric pulses is denoted time t9.

[0057] Overall signal bias may be adjusted by altering the ratio between the positive pulse voltage and negative pulse voltage, by adjusting the ratio between the positive pulse width and negative pulse width, or the like. Such alterations may be completed at a frequency with which the bias shifts from positive to negative and back, and may be on the order of greater than 1kHz, greater than 10kHz, greater than 100kHz, or the like. The shifting asymmetry throughout the pulse train allows for the application of asymmetric pulses to the tissue (e.g., thus potentially lowering the ablation thresholds thereof), while providing short-term charge asymmetry to the target tissues, maintaining a long-term neutral overall energy delivery and minimizing long-term charge imbalance around the treatment site.

[0058] In some embodiments, one or more sensors may be applied to the body of the subject, the sensors configured to monitor for changes in local charge accumulation and / or electric field during the application of pulses to the subject. The bias of the pulse train may be adjusted to prevent the long-range charge accumulation and / or potential from increasing beyond a threshold, such as a threshold needed to stimulate muscles, muscle endplates, and / or nerves in the far field regions of the body of the subject.

[0059] In some embodiments, where the local electric field is to be extended beyond a therapeutic threshold in local tissues for a period, the applied pulses may be substantially square wave in nature.

[0060] In some embodiments, the shape and frequency content of the waveform may be adjusted to selectively target tissue types within the target tissues (e.g., stem cells, bone cells, blood cells, muscle cells, fat cells, skin cells, nerve cells, endothelial cells, sex cells, pancreatic cells, and / or cancer cells).

[0061] In some embodiments, in applications where heating is considered in conjunction with field generation, a more sinusoidal waveform may be applied to the tissues.

[0062] FIG. 1 shows a medical device 100 (e.g., a catheter-based medical device) which includes one or more lumens 121 which are coupled to a handle 110 and contained within catheter walls 123. The lumens 121 may include a catheter body, one or more guidewires (e.g., guidewire 126) configured to extend from the catheter body, etc. The lumens 121 include an inflection point 122 (e.g., an articulation) which is configured to provide shape memory for “remembering” its shape (e.g., angle) after being inserted through a guide sheath (not shown) and delivered to a target site. The lumens 121 further include a fixed-bend point 124 (e.g., a user-adjusted tip angle) which is memory shaped so as it exits a guide sheath (not shown) it takes on the pre-bent user-adjusted tip angle. The handle 110, in some embodiments, includes a connector that provides a mechanical and electrical interface between the medical device 100 and one or more other modules of a system, such as a control unit 130 configured to accept one or more signals from the medical device 100, communicate one or more control signals thereto, etc. The handle 110 may also or alternatively include or be coupled with one or more operator input devices (e.g., a foot pedal, an advancing slider, a torquing mechanism, a recording button, an ablation button, etc.). The control unit 130 may be connected to a display (not shown) configured to present one or more aspects of recorded signals from the medical device 100 to an operator. The control unit 130 may also or alternatively be coupled to a surgical subsystem (not shown) configured to perform a surgical procedure on a target region. Some non-limiting examples of surgical procedures include an ablation, such as electroporation, PFA or other RF- based nonthermal or thermal ablation procedures. The control unit 130 may be configured to influence, direct, control and / or provide feedback based on signals conveyed by the medical device 100 and / or other devices which are configured to monitor a subject.

[0063] FIG. 2 shows a hardware block diagram of a medical device 200, which includes a processor, memory, clock, peripherals, signal conditioning circuitry, power, a controller, one or more sensors, and a pulse generator (e.g., for applying pulses or energy to electrodes which are at or proximate to a distal tip of the lumens 121).

[0064] The medical devices described herein may be used for providing therapy to various target regions, including various organs, tissues, nerves, tumors, ganglion sites, etc. Therapy may include innervation along a target anatomy, innervation within the organ parenchyma, smooth muscle innervation in arteries, fluid transfer into the microvasculature around vessels, targeting organ resurfacing, ganglion access which may be combined with recordings for ganglia localization. Internal vessel and external approaches are enabled.

[0065] FIG. 3 shows a method 300 which may be performed using a medical device described herein. The method begins with accessing target tissues, such as by delivering a catheter via one or more vessels of a subject to access a region proximate the target tissues. The method continues with deflecting a distal tip of the catheter (e.g., such as by delivering the distal tip of the catheter through a guide sheath, using a pull wire, etc.), such that electrodes at or proximate the distal tip of the catheter contact the inner surface (e.g., a “top” or “bottom” surface) of a vessel proximate the target tissues. Energy is then applied to the electrodes on the expandable elements (e.g., application of energy pulses) to perform an ablation procedure. The distal tip may be repositioned or deflected in different directions in order to contact different portions of the inner surface of the vessel proximate the target tissues.

[0066] FIG. 4 shows non-limiting examples of locations in which the medical devices described herein may be deployed, including the abdominal aorta, celiac trunk, common hepatic artery, left gastric artery, right gastric artery, hepatic artery proper, gastroduodenal artery, duodenal branch, superior pancreaticoduodenal artery, inferior pancreaticoduodenal artery, superior mesenteric artery, splenic artery (including the pancreatic branch of the splenic artery), left gastro-epiploic artery, and the right gastro-epiploic artery. Renal (both left and right) arteries are also examples of target anatomies.

[0067] The medical devices described herein may be used to provide unique ways of accessing, deploying and targeting specific anatomy, for example, in the abdominal vascular system (e.g., as illustrated in FIG. 4) that aim to ablate the ganglia that is responsible to transmit pain through the corresponding neuropaths of the anatomic location. FIGS. 5A-5D illustrate ganglia locations and spatial relationships between celiac ganglia (CG), both left (L-CG) andright (R-CG), the celiac trunk (CT) and the superior mesenteric artery (SMA). FIG. 5 A shows how the majority of the CG lay between the CT and the SMA. FIG. 5B shows how a portion of the CG protrudes below the origin of the SMA, sometimes reaching the level of the left renal vein. FIG. 5C shows that only a small number of CF protrude (markedly or slightly) above the level of the CT, sometimes extending also below the SMA (distinctly or slightly) as shown in FIG. 5D.

[0068] In some embodiments, a medical device includes a pre-bent distal tip having one or more RF ablation electrodes, along with integrated temperature sensors to monitor power- controlled, temperature-controlled and / or impedance-controlled RF during an ablation procedure (e.g., RF, PF A, etc.). In some embodiments, the medical device is configured to monitor temperature utilizing the temperature sensors, and it configured to measure tissue impedance between the “active” or RF ablation electrodes and the “return” electrodes. In the case of monopolar RF ablation, the tissue impedance measurement is taken between the active or RF ablation electrodes (e.g., at the pre-bent distal tip) and a return pad (e.g., placed on the patient’s back). In the case of bipolar RF ablation, the return electrode may be placed on the catheter body or on a guide sheath, and the tissue impedance measurement is taken between the active electrode and the return electrode (e.g., where there are multiple return electrodes, a closest one to the active electrode that is able to make the measurement). Thus, it is important to ensure an equivalent contact surface ratio, to ensure that the energy density through the tissue is safe and heating occurs only near the active electrode. The relative sizes of the active and return electrodes are also relevant. In the monopolar configuration, the return pads are significantly larger than the active electrode size, to prevent energy concentration at the return site and therefore prevent bums. By monitoring both temperature and tissue impedance, the medical device allows for a safety cutoff if one or both reach an associated threshold level (e.g., a maximum setup level, which may be predefined or manually set by an operator of the medical device).

[0069] FIG. 6 shows a medical device 600 including a catheter body with multiple sections 601, 603, 605, 607, 609 and 611, along with a distal tip 613 providing one or more RF electrodes configured for performing an ablation procedure. Different ones of the sections 601, 603, 605, 607 and 609 may be formed of different materials or with different rigidity. For example, the section 601 may be formed of a more rigid material, with the sections 603, 605, 607 and 609 being formed of more flexible materials. The section 603 is a curved section thatis coupled between the section 601 and the section 605. The section 605 provides an inflection point (e.g., enabling articulation) between the section 603 and the section 607, as an option to remember a shape after being inserted through a guide sheath (not shown). The sections 607 and 611 are coupled to the section 609 providing another inflection point. The section 609 may, in some embodiments, provide a memory-shaped adjusted tip angle (e.g., preset by a user) such that as the catheter body exits a guide sheath (not shown) it takes on the pre-bend, which may be selectable among different user-adjustable tip angles denoted 615-1, 615-2, 615-3 and 615-4 (collectively, user-adjustable tip angles 615). While FIG. 6 shows an example with just four user-adjustable tip angles 615, this is not a requirement and other embodiments may use more or fewer than four user-adjustable tip angles.

[0070] The distal tip 613, as discussed above, comprises one or more RF electrodes and one or more integrated temperature sensors (e.g., thermocouples) for monitoring temperature while a current is applied to the one or more RF electrodes during an ablation procedure. In some embodiments, one or more of the sections 601, 603, 605, 607, 609 and 611 includes a return electrode for enabling bipolar RF or PFA energy modes. RF energy is controllably delivered to the one or more RF electrodes at the distal tip 613 for performing an ablation procedure. The one or more temperature sensors at the distal tip are configured to monitor ablation temperatures around an inner circumference of a vessel or lumen in which the medical device 600 is deployed. This facilitates both power-controlled and temperature-controlled RF modes for application of RF energy to the one or more RF electrodes at the distal tip 613.

[0071] FIG. 7 shows an example where the medical device 600 is deployed within vessels 70 and 75 of a subject, where the distal tip 613 is bent at the user-adjustable tip angle 615-2 to contact a surface of a wall of the vessel 75. The medical device 600 includes a deployment mechanism with a biased deflection at the tip level to navigate tortuous vessel paths and constrictions (e.g., as shown by the path of the vessels 70 and 75). The deflection angle at the tip level is achieved by a combination of a memory shaped metal wire installed at one or more of the sections 603, 605, 607, 609 and 611 but disconnected from the section 601, allowing a most distal curvature without need of an articulation system. An external sheath (not shown) of the medical device 600, in some embodiments, is formed of a variant durometer to prevent buckling (e.g., more proximally rigid) and enable high flexibility at the sections 603, 605, 607, 609 and 611.

[0072] FIG. 8 shows a portion of a medical device 800 (e.g., a distal tip of a catheter body or other elongate member), including a dual lumen 801 for an articulating section of the elongate member. A coupling section 803 is provided (e.g., which may be formed of plastic), which is attached to a pull wire 805 facilitating articulation of the distal tip of the medical device 800. A RF wire 807 is provided through the dual lumen 801 and is attached to the distal tip. In some embodiments, the RF wire 807 is soldered to the distal tip, providing an RF electrode 809 at the distal tip. A thermocouple 811 is also provided through the dual lumen 801, and extends through to a sheath tube 813 providing isolation between the thermocouple 811 and the RF electrode 809 at the distal tip. The portion of the medical device 800 shown in FIG. 8 may represent the section 611 and distal tip 613 of the medical device 600.

[0073] Fixed-bend tips (e.g., pre-adjusted by a user) allows access to narrow angles between vessels or other lumens (e.g., between the aorta vessel and the celiac trunk). The addition of the fixed-bend tip (e.g., an adjusted tip angle) with a guide sheath facilitates the position of RF electrodes at the distal tip of a catheter body to touch and maintain contact with a desired section of a wall of a vessel, while also allowing a clinician to easily retract both the guide sheath and the catheter body to ensure bottom level contact with the vessel and through produce an ablation around a circumference of the vessel (e.g., targeting the celiac trunk in an example where the catheter body is insert between the aorta vessel and the celiac trunk). Such medical devices with fixed-bend tips (e.g., formed used memory shaped materials) also enables further insertion and ablation into different target regions (e.g., different branches of the celiac trunk, such as the common hepatic, splenic and left gastric arteries). When inserted into the different target regions, rotation of the catheter body relative to the guide sheath will enable ablations around a circumference of the wall of the vessel or other lumen in which the catheter is deployed. This advantageously eliminates the need for articulation.

[0074] Nonetheless, articulation may be achieved in some embodiments to ensure a deflection of the distal tip of the catheter body (e.g., by a few millimeters) from the fixed bend angle (e.g., where the user created the original deflection angle) and eliminates the long bonding radius that is formed a few centimeters from the distal tip. This articulation method may be achieved by two distinct articulation points (e.g., sections 605 and 609 in the medical device 600) made by a semi-rigid filling wire that prevents deflection at a lower level but allows deflection closer to the top, along with a secondary filling wire (e.g., pull wire 805 in the medical device 800) that pulls on a distal articulation point to create a second pivot point thathelps the catheter to reach different portions of an inner surface of a vessel or other lumen when the catheter is rotated relative to the guide sheath.

[0075] As discussed above, in some embodiments a catheter-based medical device may utilize a guide sheath (e.g., surrounding at least a portion of a catheter body shown in FIGS. 6, 7 or 8). Local and return electrodes are arranged so as to target specific ganglia (e.g., near the base of the celiac trunk) enabling bipolar RF or PFA ablation. In some embodiments, the return electrodes are installed at the guide sheath level, biasing the current to the root of the trunk and further focusing the target (e.g., the celiac ganglia). Return electrodes at the guide sheath level may be deployable to ensure surface contact with inner walls of the vessels in which the guide sheath is placed (e.g., the root of the celiac trunk), as the guide sheath is placed to enable entry for a catheter-based medical device (e.g., medical device 600 or 800) into more distal vessel structures. The return electrodes may thus be expanded along the root of the ostium of the celiac trunk or other vessel in which the guide sheath is positioned.

[0076] FIGS. 9 A and 9B show an example of a guide sheath device 900 including a guide sheath body 901 on which a set of return electrodes 903-1, 903-2 and 903-3 (collectively, return electrodes 903) are attached. By placing the return electrodes 903 at multiple locations on the guide sheath body 901, this enables flexibility for allowing contact of at least one of the return electrodes 903 with inner walls of different vessels based on the placement and advancement of the guide sheath device 900. FIGS. 9A and 9B also show a catheter device 950 which is routed through the guide sheath body 901, with a distal tip of the catheter device 950 providing an active electrode 955 for performing bipolar RF or PFA ablation using the active electrode 955 and one or more of the return electrodes 903 of the guide sheath device 900.

[0077] As shown in FIG. 9A, in a first placement of the guide sheath device 900, the return electrode 903-3 contacts an inner wall of vessel 95 and the return electrode 903-2 contacts the inner wall where the vessel 90 and vessel 95 branch. As shown in FIG. 9B, in a second placement of the guide sheath device 900, the return electrode 903-1 contacts the inner wall of vessel 90. This approach will maximize energy delivery to the regions of the ganglia around the celiac trunk (e.g., vessel 90) as well as along the vessels (e.g., dual targeting of nerves along the vessel trunk and direct targeting of ganglia).

[0078] In some embodiments, such a system (e.g., a combination of one of the medical devices 600 or 800 and the guide sheath device 900) allows for targeting energy delivery toganglia which are not located along the celiac artery and distal arterial branches. Further, the overall system is simplified as no return patch electrodes are needed on the subject. The construction of the catheter body is designed to minimize impact on flexibility and tortuous vessel maneuvering, and enables easy integration of RF / PFA and a sensing electrode array. In some embodiments, the distal tip of the catheter body provides a full contact electrode enabling directed energy delivery to regions of ganglia in which associated devices are deployed. For PFA ablation, such systems will also advantageously reduce muscular spasm as the current delivery is collocated along the catheter body and does not deviate to form inductive pathways.

[0079] For subjects with cancer, having the ability to target desired ganglia opens various opportunities, depending on where a tumor is located and which nerve pathways are being engaged by the tumor. Ganglia are often organized along the aorta near the target plexuses, so the ability to bring energy delivery to those regions in an easy way will help with these and other types of therapies (e.g., including therapies for cancer treatment, for treatment of cancer pain, etc.).

[0080] It will be appreciated that additional advantages and modifications will readily occur to those skilled in the art. Therefore, the disclosures presented herein and broader aspects thereof are not limited to the specific details and representative embodiments shown and described herein. Accordingly, many modifications, equivalents, and improvements may be included without departing from the spirit or scope of the general inventive concept as defined by the appended claims and their equivalents.

Claims

CLAIMSWhat is claimed is:

1. A medical device, comprising: an elongate member, the elongate member comprising a distal tip section, a first inflection section, a first elongate section, and a second inflection section, and at least a second elongate section, the first inflection section defining a pre-bent tip angle for the distal tip section of the elongate member, the second inflection section comprising an articulable bend of the first elongate section relative to the second elongate section; and one or more radiofrequency ablation electrodes disposed at a distal tip of the elongate member.

2. The medical device of claim 1, wherein the elongate member comprises a delivery catheter.

3. The medical device of claim 2, wherein the delivery catheter is configured for deployment via a guide sheath.

4. The medical device of claim 3, further comprising a controller configured to advance the delivery catheter through the guide sheath, wherein on advancement of the distal tip section and the first inflection section past an end of the guide sheath, the distal tip section of the elongate member takes on the pre-bent tip angle.

5. The medical device of claim 4, wherein the controller is further configured to actuate the second inflection section to provide the articulable bend of the first elongate section relative to the second elongate section.

6. The medical device of claim 5, wherein the articulable bend of the first elongate section relative to the second elongate section brings the distal tip section into contact with a wall of a lumen in which the delivery catheter is deployed.

7. The medical device of claim 4, wherein the controller is further configured to rotate the delivery catheter relative to the guide sheath to bring the distal tip section into contact with different portions of a circumference of a wall of a lumen in which the delivery catheter is deployed.

8. The medical device of claim 1, wherein at least one of the first inflection section and the second inflection section comprises a shape memory material.

9. The medical device of claim 8, wherein the second elongate section has a higher rigidity than at least one of the first elongate section and the distal tip section.

10. The medical device of claim 1, further comprising one or more temperature sensors disposed at the distal tip of the elongate member proximate the one or more radiofrequency ablation electrodes.

11. The medical device of claim 10, further comprising a sheath tube isolating the one or more temperature sensors from the one or more radiofrequency ablation electrodes.

12. The medical device of claim 10, further comprising a controller configured: to controllably advance the distal tip section and actuate the second inflection section to bring the one or more radiofrequency ablation electrodes into contact with a wall of a lumen; to monitor a temperature of target tissues in a vicinity of the wall of the lumen utilizing the one or more temperature sensors; and to control, based at least in part on the monitored temperature of the target tissues in the vicinity of the wall of the lumen, a current applied to the one or more radiofrequency ablation electrodes.

13. The medical device of claim 12, wherein the controller is further configured to monitor a tissue impedance of the target tissues in the vicinity of the wall of the lumen, and wherein the current applied to the one or more radiofrequency ablation electrodes is further controlled based at least in part on the monitored tissue impedance.

14. The medical device of claim 1, further comprising a radiofrequency wire extending along a length of the elongate member at and attached to the distal tip of the elongate member, at least a portion of the radiofrequency wire providing the one or more radiofrequency ablation electrodes.

15. The medical device of claim 14, further comprising a thermocouple wire extending along the length of the elongate member ending at a distance away from the distal tip of the elongate member.

16. The medical device of claim 15, wherein the portion of the radiofrequency wire providing the one or more radiofrequency ablation electrodes comprises a portion of the radiofrequency wire extending past an end of the thermocouple wire.

17. The medical device of claim 16, further comprising a sheath tube isolating a distal section of the thermocouple wire and the radiofrequency wire from the distal tip of the elongate member.

18. The medical device of claim 1, further comprising one or more return electrodes, wherein the one or more radiofrequency ablation electrodes and at least one of the one or more return electrodes are configured to perform bipolar radiofrequency ablation.

19. The medical device of claim 18, wherein said at least one of the one or more return electrodes is disposed on the elongate member.

20. The medical device of claim 18, wherein said at least one of the one or more return electrodes is disposed on a guide sheath in which the elongate member is inserted.

21. The medical device of claim 1, further comprising a pull wire coupled to the first elongate section of the elongate member, the pull wire being configured for actuating the articulable bend of the second inflection section.

22. A method, comprising: delivering an elongate member of a medical device to a target site within a lumen, the elongate member comprising a distal tip section, a first inflection section, a first elongate section, and a second inflection section, and at least a second elongate section, the first inflection section defining a pre-bent tip angle for the distal tip section of the elongate member, the second inflection section comprising an articulable bend of the first elongate section relative to the second elongate section; andactuating the second inflection section to provide the articulable bend of the first elongate section relative to the second elongate section to bring the distal tip section into contact with a wall of the lumen; and controlling a current applied to one or more radiofrequency ablation electrodes to ablate target tissues in a vicinity of the wall of the lumen.

23. The method of claim 22, wherein delivering the elongate member of the medical device to the target site within the lumen comprises advancing the elongate member through a guide sheath, wherein on advancement of the distal tip section and the first inflection section past an end of the guide sheath, the distal tip section of the elongate member takes on the prebent tip angle.

24. The method of claim 23, further comprising rotating the elongate member relative to the guide sheath to bring the distal tip section into contact with different portions of a circumference of the wall of the lumen.

25. The method of claim 22, wherein at least one of the first inflection section and the second inflection section comprises a shape memory material.

26. The method of claim 25, wherein the second elongate section has a higher rigidity than at least one of the first elongate section and the distal tip section.

27. The method of claim 22, further comprising monitoring a temperature of the target tissues in the vicinity of the wall of the lumen utilizing one or more temperature sensors disposed at the distal tip of the elongate member proximate the one or more radiofrequency ablation electrodes.

28. The method of claim 27, wherein a sheath tube isolates the one or more temperature sensors from the one or more radiofrequency ablation electrodes.

29. The method of claim 27, wherein controlling the current applied to the one or more radiofrequency ablation electrodes is based at least in part on the monitored temperature of the target tissues in the vicinity of the wall of the lumen.

30. The method of claim 29, further comprising monitoring a tissue impedance of the target tissues in the vicinity of the wall of the lumen, and wherein the current applied to the radiofrequency ablation electrode is further controlled based at least in part on the monitored tissue impedance.

31. The method of claim 22, wherein the medical device further comprises one or more return electrodes, and wherein the one or more radiofrequency ablation electrodes and at least one of the one or more return electrodes are configured to perform bipolar radiofrequency ablation.

32. The method of claim 22, wherein the medical device further comprises a pull wire coupled to the first elongate section of the elongate member, and wherein actuating the second inflection section to provide the articulable bend of the first elongate section relative to the second elongate section to bring the distal tip section into contact with a wall of the lumen utilizes the pull wire.

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