WO2022192459A1

WO2022192459A1 - Pulse application for treatment and prevention of restenosis

Info

Publication number: WO2022192459A1
Application number: PCT/US2022/019636
Authority: WO
Inventors: Mitchell Elliott LEVINSON; Roman Turovskiy; David J. Danitz; Richard J. CONNOLLY
Original assignee: Pulse Biosciences, Inc.
Priority date: 2021-03-10
Filing date: 2022-03-09
Publication date: 2022-09-15

Abstract

Methods and apparatuses are disclosed for providing pulsed electrical treatment (including high voltage, sub-microsecond pulsed electric energy) to body lumens for treatment and/or prevention of restenosis.

Description

PULSE APPLICATION FOR TREATMENT AND PREVENTION OF RESTENOSIS

CLAIM OF PRIORITY

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 63/159,419, titled “PULSE APPLICATION FOR TREATMENT AND PREVENTION OF RESTENOSIS,” and filed on March 10, 2021, herein incorporated by reference in its entirety.

INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

BACKGROUND

[0003] Short, high-field strength electric pulses have been described for electromanipulation of biological cells. For example, electric pulses may be used in treatment of human cells and tissue including tumor cells, such as basal cell carcinoma, squamous cell carcinoma, and melanoma. The voltage induced across a cell membrane may depend on the pulse length and pulse amplitude. Pulses longer than about 1 microsecond may charge the outer cell membrane and may lead to permanent opening of pores. Permanent openings may result in instant or near instant cell death. Pulses shorter than about 1 microsecond may affect the cell interior without adversely or permanently affecting the outer cell membrane and result in a delayed cell death with intact cell membranes. Such shorter pulses with a field strength varying in the range, for example, of 10 kV/cm to 100 kV/cm may trigger apoptosis in some or all of the cells exposed to the described field strength and pulse duration. These higher electric field strengths and shorter electric pulses may be useful in manipulating intracellular structures, such as nuclei, endoplasmic reticulum and mitochondria. For example, such sub-microsecond (e.g., nanosecond) high voltage pulse generators have been proposed for biological and medical applications.

[0004] Patients that have been subjected to arterial or luminal therapies such as, but not limited to, angioplasty and stent implantation may suffer restenosis where the associated lumen becomes constricted and/or closes after treatment. The mechanism for restenosis involves the inflammation resulting from the damage to the vessel walls. The restenosis may adversely affect the patient and, in some cases, may place the patient at risk of stroke or other death caused by impeded flow through the lumen.

[0005] Thus, it would be beneficial to provide treatment for areas that have been or will be subject to arterial or luminal treatments in order to prevent or reduce restenosis of those areas. SUMMARY OF THE DISCLOSURE

[0006] Described herein are apparatuses and methods for treating within a body lumen using sub-microsecond pulsed electrical fields, including (but not limited to) nanosecond pulsed electrical fields. In particular, the methods and apparatuses described herein may be configured to selectively treat a portion of a wall of a body lumen, e.g., the innermost layer(s), with sub microsecond (e.g., nanosecond) pulsed electrical fields in a localized manner that limits or prevents damage to deeper, non-target regions. The use of sub-microsecond (e.g., nanosecond) pulsed electrical fields applied to a region of a vessel within a range of energy densities as described herein either before, during or after treatment within the same vessel region may prevent, reduce or eliminate restenosis of this region of the vessel lumen.

[0007] The method and apparatuses described herein may be particularly well suited for use in connection with angioplasty of vascular lumen. Thus, these methods may be used before, during and/or after an angioplasty procedure, and may be part of the angioplasty procedure or may be performed separate from the angioplasty procedure.

[0008] The methods and apparatuses described herein are not limited to vascular treatments, such as vascular angioplasty treatments, but may be used to treat other body lumen (also referred herein as “a lumen”) in which lumen narrowing may be a problem. For example, lungs (airways), gastric chambers, ducts, or the like may be treated as described herein. In some examples, the instruments and methods described herein are configured for otolaryngological use, e.g., for insertion and treatment by applying sub-microsecond (e.g., nanosecond) pulsed electrical fields within a lumen or other otolaryngological structure, such as an ear, nose, or throat, including anatomical structures, such as turbinates, tonsils, tongue, soft palate, parotid glands, as well as those structures that connect throat (pharynx) to the stomach. These instruments and devices may be configured for insertion into these structures, for example, they may be configured as elongate applicator tools, applicator catheters, tube, etc. sized and shaped to fit within an ear, nose, throat, and/or to treat an associated anatomical structure (e.g., turbinates, tonsils, tongue, soft palate, parotid gland, etc.). For example, described herein are methods and apparatuses configured for the delivery of sub-microsecond (e.g., nanosecond) pulsed electrical fields to a portion of the gastrointestinal tract, e.g., stomach, small intestine, large intestine, duodenum, colon, etc., including, but not limited to the esophagus. Also described herein are methods and apparatuses configured for the delivery of sub-microsecond (e.g., nanosecond) pulsed electrical fields to a portion of the respiratory tract, including the trachea, pharynx, larynx, bronchi and bronchioles. [0009] In general, these methods may include treatment of a patient by the application of therapeutic energy, including but not limited to short, high field strength electric pulses, while minimizing or avoiding the risk of harming non-target tissue. In some examples, these applicators may be referred to herein as applicator tools, and may be used for minimally invasive procedures, and may be particularly well suited, for example, for treatments that benefit from preventing, reducing or eliminating tissue in-growth into the body lumen and/or an implant (e.g., stent) within the body lumen. These applications may be also particularly well suited for use with various fully and partially automated systems, such as robotic systems. In particular, the apparatuses described herein may be configured as apparatuses (e.g., catheter apparatuses, catheter applicator tips, etc.) that can be used with a variety of different generator systems, as will be described in greater detail herein.

[0010] Thus, the apparatuses described herein may be configured for manual or automated (e.g., robotic-assisted) control. In some examples these apparatuses may be integrated into systems that are configured to be mounted onto or coupled to a movable (e.g., robotic) arm of a robotic system, such as robotic medical treatment system or robotic surgical system. For convenience of description the present disclosure may refer to these as robotic systems, however, it should be understood that such robotic systems are intended to cover any robotic medical treatment system (including surgical and non-surgical, e.g., cosmetic applications) and may include robotic systems having guidance. In some examples instruments can be guided and controlled by the robotic system during a medical or cosmetic procedure. For example, the devices described herein may be used through one or more operating channels of a robotic system.

[0011] The apparatuses described herein may include elongate applicator tools (e.g., applicator catheters) that may be inserted into a body lumen, including but not limited to a blood vessel (an artery, a vein, etc.) an esophagus, ear, nose, throat, trachea, pharynx, larynx, small intestine, large intestine, duodenum, colon, etc. These applicator tools may include an elongate, flexible body extending in a proximal-to-distal direction. One or more (e.g., a plurality) of electrodes configured for the delivery of high voltage, sub-microsecond electrical pulses (e.g., nanosecond) to a target tissue may be present at an end region of the flexible body. The body may include one or more channels, including a channel enclosing electrical connectors/contacts for the electrodes and one or more lumen for a vacuum. The vacuum may help secure the electrode(s) in contact with the wall of the vessel. In some cases, the body may include a channel or lumen for delivery of a material (e.g., a fluid material, including a therapeutic material) from the applicator tool. [0012] The applicator (“applicator tool”) may be configured to removably couple to a pulse generator configured to generate the sub-microsecond (e.g., nanosecond) pulsed energy, such coupling may be through a handle that is proximal to the distal end region including the electrodes. The electrodes may be deployable and may be on an expanding member that expands to contact the vessel wall. The handle may control the deployment. Alternatively, in some cases the applicator tool (also referred herein as apparatus or device) may be configured to couple to the pulse generator directly, without the need for an additional handle.

[0013] The applicator may be configured as a catheter. In some examples described herein the applicator may be flexible enough to easily bend within the confines of a tortuous body lumen but may have sufficient column strength so that it may be driven and inserted into the body lumen from the outer opening without collapsing or kinking. In some examples the walls of the apparatus may be reinforced with a support material (e.g., wire, braid, etc.).

[0014] When the applicator tool is coupled to a handle, the handle (proximal handle) may include one or more controls for activating one or more of: vacuum, electrodes, steering mechanisms and/or an expander for expanding a distal end region of the applicator including the electrodes for contacting a wall of the lumen into which the applicator has been inserted.

[0015] According to one example, apparatuses described herein comprise medical devices and instruments for use in procedures inserting the applicator tools into a lumen. These apparatuses (e.g., the applicator tools) may be introduced through a sheath into a blood vessel. [0016] Any of these apparatuses may include a scope (e.g., camera, etc.) or may be configured for use with a scope. For example, the apparatus may include a fiber optic for illuminating and/or imaging the surrounding region within the lumen of the body into which the apparatus is inserted. This may allow a user (e.g., physician) to image before, during and/or after a procedure within a body lumen using the applicator tool, such as applying sub-microsecond (e.g., nanosecond) pulsing to treat a region of a vessel lumen to prevent, reduce or eliminate restenosis within the vessel lumen. Examples of both applicator tools and methods of using them to treat restenosis are described in greater detail below. Thus, any of these apparatuses may, but does not necessarily have to, include one or more visualization components (e.g., a fiber optic, camera, lenses, filters, etc.).

[0017] In some cases, the electrodes on the applicator may be recessed into the outer surface of the applicator tool, flush with an outer surface of the applicator tool, or may stand proud of the applicator outer surface. Any of these applicators may include a suction or vacuum inlet at or adjacent to the location of the electrodes, to assist in making contact with the tissue by applying negative pressure to draw the tissue against the electrode(s). Any of the applicators may be configured to detect electrical impedance, either through the electrodes from which sub- microsecond (e.g., nanosecond) pulsing is applied, and/or through dedicated sensing electrodes; in some examples, the system may be configured to confirm that the electrodes are not in contact with an electrically conductive stent before treatment, which may otherwise damage the tissue and/or stent. Alternatively in some examples, the energy (e.g., sub-microsecond pulsed electrical field energy) may be applied to an electrically conductive stent specifically.

[0018] In some examples the applicator may include one or more contact projections (e.g., ribs, wires, springs, contact plates, contact posts, balloons, etc.) that may be manipulated to extend from the proximal end of the applicator by operation, for example, of the proximal handle to which the applicator tool is coupled. The contact projection may typically make contact with the wall of the lumen into which the applicator tool is inserted to enhance access and contact with the tissue against the electrodes. For example, the contact projection may be an inflatable element (e.g., balloon) or a mechanical element (e.g., a pair of plates or arms). In some examples multiple contact projections may be positioned along the length of the applicator and may be moved closer or farther apart along the length of the applicator distal end region. In some examples the contact projection(s) flank the electrodes; in some examples the contact projection(s) include the electrodes. The contact projections may be retractable/removable into the catheter, or simply relative to the catheter.

[0019] The apparatuses described herein may generally be configured to safely and reliably deliver microsecond, nanosecond, picosecond, etc. pulses, and may include an electric field with a pulse width of between 0.1 nanoseconds (ns) and less than 1000 nanoseconds, or shorter, such as 1 picosecond, which may be referred to as sub-microsecond pulsed electric field. This pulsed energy may have high peak voltages, such as 1 to 5 kilovolts per centimeter (kV/cm), 10 kV/cm, 20 kV/cm, 100 kV/cm or higher. In some applications, the pulsed energy may be less than lkV/cm. Treatment of biological cells may use a multitude of periodic pulses at a frequency ranging from 0.1 per second (Hz) to 100,000 Hz, and may trigger regulated cell death, for example, in the in-growing tissue causing restenosis. Selective treatment of vessel walls with high voltage, sub-microsecond pulsed energy can induce regulated cell death within the cells that are causing restenosis without substantially affecting normal cells in the surrounding tissue due to its non-thermal nature. A subject may be a patient (human or non-human, including animals). A user may operate the apparatuses described herein on a subject. The user may be a physician (doctor, surgeon, etc.), medical technician, nurse, or other care provider.

[0020] Thus, the application of high voltage, fast (e.g., microsecond or sub-microsecond) electrical pulses may include applying a train of electrical pulses having a pulse width, for example, of between 0.1 nanoseconds (ns) and 1000 nanoseconds. Applying high voltage, fast electrical pulses may include applying a train of sub-microsecond electrical pulses having peak voltages of between, for example, 1 kilovolt per centimeter (kV/cm) and 500 kV/cm. Applying high voltage, fast electrical pulses may include applying a train of sub-microsecond electrical pulses at a frequency, for example, of between 0.1 per second (Hz) to 100,000 Hz.

[0021] For example, described herein are apparatuses for treating a vessel lumen to treat restenosis. Treating restenosis may include preventing restenosis, reducing restenosis and/or substantially eliminating restenosis. Substantially eliminating may mean reducing to a negligible or near-negligible level, such as to less than 20%, less than 15%, less than 10%, less than 5%, e.g., of un-treated (or prior to treatment). Any appropriate tissue may be treated, including vascular tissue. In some examples the apparatuses and methods described herein may be used to treat one or more of these tissues, as part of a treatment therapy.

[0022] Any of these apparatuses may be used with a pulse generator. For example, described herein are systems for treating tissue that may include: an elongate applicator (e.g. applicator tool) as described herein, a connector, e.g., a high voltage connector adapted to couple the elongate applicator tool to a pulse generator; and a pulse generator configured to generate a plurality of electrical pulses having amplitude of at least 0.1 kV and a duration of less than 1000 nanoseconds, the pulse generator comprising a port configured to connect to the high voltage connector. In some examples the applicator tool includes an elongate body having a distal end region from which one or more electrodes are configured to extend. The distal end may be steerable (e.g., may articulate) in some examples.

[0023] Also described herein are methods for treating restenosis using any of the apparatuses (and systems that include such apparatuses) described herein. Generally, the elongate applicators described herein may be configured to treat within a vessel of a body by delivering, through the one or more electrodes, one or a train of fast (e.g., sub-microsecond, nanosecond, picosecond) pulses. For example, described herein are methods of treating tissue to reduce, prevent or eliminate restenosis within the vessel, the method comprising: inserting an applicator into a region of a vessel that has been surgically expanded or will be surgically expanded (e.g., via angioplasty, atherectomy or other medical intervention, including by implanting a stent), wherein the elongate applicator comprises one or more electrodes at a distal end region, and applying (in some examples using a proximal control, e.g., on handle) electrical energy to treat restenosis. Optionally as a preliminary step, the method may include identifying a target region within the vessel lumen that has been or will be surgically expanded. In some examples the electrical energy includes a plurality of electrical pulses having an amplitude of greater than 0.1 kV and a duration of less than 1000 nanoseconds from one or more electrodes to the target region. In some examples, after identifying the target region, suction may be applied around or adjacent to the one or more electrodes at the distal end region of the applicator tool. In some examples, an extendable contact projection of the applicator, which may be inflatable or mechanically deployed, may be actuated (for example, from the proximal end of the applicator tool, such as from the handle), to induce contact of the electrode(s) to the region of the vessel to be treated. [0024] In some examples the method includes applying the energy to a region including all or a portion of the medically expanded region. The method may also include a step of identifying the medically expanded region. In some examples this medically expanded region may include a stent, and the method may include positioning the applicator so that the electrodes do not contact the stent.

[0025] In general, any of these apparatuses may be used in conjunction with or be a part of the system that includes a pulse generator configured to generate a plurality of electrical pulses having amplitude of at least 0.1 kV and a duration, for example, of less than 1000 nanoseconds, the pulse generator may be configured to connect to the apparatus with a high voltage connector. [0026] Any of these apparatuses may include a suction inlet adjacent to the first and second electrodes.

[0027] As mentioned, any of these apparatuses may be configured so that the proximal end of the applicator tool is adapted to be coupled to a robotic or movable arm, for example, for computer-controlled activation of the set of electrodes. Alternatively, or additionally the proximal end of the applicator tool may be adapted to couple to a handle of the pulse generator which may in turn be adapted for connection to a robotic arm.

[0028] Any of these methods may be performed as part of a procedure to treat restenosis (e.g., prevent, reduce or substantially eliminate restenosis) prior to, simultaneous with and/or after stenting and/or balloon angioplasty. Thus these methods may be performed before the development of in-stent restenosis, e.g., proactively. In some examples, these methods may be performed after an in-stent restenosis has occurred. In some examples, the methods described herein may be part of a re-expansion procedure to reduce or remove narrowing of the vessel; this method may include re-stenting, additional balloon expansion, etc. Any of these methods may be done in addition to or instead of a pharmaceutical therapy, including local pharmaceutical therapy (such as sirolimus).

[0029] As mentioned, in general, these methods and apparatuses, e.g., systems, may be configured to prevent the electrodes applying the electrical energy from the applicator from touching the (e.g., metal) stent. If a metal implant, such as a stent is within the vessel lumen, contact with the energy-applying electrodes of the applicator may short or otherwise make unpredictable the energy applied by the system. In some examples the system may include (e.g., as software, firmware, and/or hardware) a low amplitude or low duration test signal subsystem to make sure that there is no short before delivering therapeutic pulsing. As mentioned above, in some examples the same electrodes used to apply the therapeutic energy may be used, and an electrical signal (e.g., impedance) may be determined between the electrodes applying the energy. Alternatively or additionally, sensors (e.g., sensing electrodes) separate from the therapy- applying energy may be used.

[0030] In some examples, as described above, the apparatus may be configured to adjust the distance between electrodes for applying the therapy at the distal end region of the applicator. In some examples the applicator includes at least two circumferentially arranged electrodes; one or more (e.g., all) of the at least two circumferentially arranged electrodes may be longitudinally adjustable so that the distance between the sets of circumferentially arranged electrodes may be increased or decreased to make sure that the electrodes are distal and proximal to the region to be treated for restenosis (e.g., stent). In some cases, the applicator may be adjustable to adjust the separation between the circumferentially arranged electrodes to be, for example, between 5 mm and 40 mm (e.g., between 10 mm and 20 mm, etc.). The circumferentially arranged electrodes may be an electrode ring (extending fully circumferentially around, or partially circumferentially around) or it may be a plurality of separate electrodes arranged circumferentially around the applicator.

[0031] In some examples the apparatus may be configured to contact the stent and may use the stent as one of the electrodes for delivering the therapy to the tissue. For example, the method may include contacting a stent already implanted (or being implanted) into the vessel lumen. Rather than having a second electrode, a stent contact (e.g., “grabber/contact”) on the applicator may be configured to convert the stent into one of the electrodes.

[0032] In some examples the applicator may include a balloon including one or more electrical contacts (electrodes). As mentioned, the electrical contacts may be arranged circumferentially. In some examples the electrical contacts may be metallic electrodes that are formed from a conductive ink (e.g. Ag-based, carbon black, etc.) or deposited using methods utilized for making flexible circuits onto the expandable structure (e.g., balloon).

[0033] The apparatuses described herein may be configured not to occlude flow through the vessel during the treatment. For example, the expandable member(s) holding the electrodes may be mesh and/or may be open (e.g., ring- or toroidal-shaped balloons) to allow, e.g., blood to flow through the vessel when a vascular lumen is being treated.

[0034] Sub-microsecond (e.g., nanosecond) pulsed fields may induce apoptosis in cellular structures. The methods described herein (and devices configured to perform them) may inhibit inflammation by inducing apoptosis in the cells of the arterial intima, media and in some examples the adventitia to render them unable to produce an inflammatory response to the structural damage caused by angioplasty and/or stenting. [0035] Thus, the methods described herein may include the insertion of a percutaneous arterial applicator device (e.g., which may be coupled to or configured as or to include a catheter) and may deliver it to the location of a stenosis, such as an arterial stenosis. The apparatus may then apply a pulsed electric field sufficient to induce apoptosis in all or some subset of the cellular tissue in the arterial wall before (or in some cases while or after) performing angioplasty and/or stenting, e.g., of an artery. The inflammatory process that would otherwise likely have resulted from the arterial trauma may therefore be significantly suppressed as the artery recovers from both the percutaneous arterial intervention (PAI), e.g., stenting, balloon expansion, etc., and the electrical energy application.

[0036] Alternatively or additionally, patients that have already received PAI and have clinically significant in-stent restenosis may be treated as described herein to clear smooth muscle tissue that has infiltrated the stent mesh as a result of the intimal hyperplasia. For example, a method as described herein may include inserting a catheter-based device percutaneously into an artery, advancing it into position such that the electrodes can apply energy (and in some examples, may contact) the smooth muscle tissue so that a pulsed electric field may be applied sufficient to induce apoptosis in the smooth muscle tissue causing the stenosis.

[0037] In some examples, in which a metal or otherwise electrically conductive stent is already in place within the vessel, a pulsed electric field may be conducted through the stent material as mentioned above. The applicator and electrodes on the applicator may be configured to accommodate the stent conductor.

[0038] The methods described herein may be particularly useful to treat arterial stenosis. [0039] As mentioned above, these methods may be used in addition to or in place of local drug administration at the site of the stent or angioplasty balloon to reduce intimal hyperplasia. Drugs that have been used with drug-eluting stents include rapamycin or taxol-related drugs. [0040] In addition to treatment of in-stent arterial restenosis, the methods and apparatuses described herein may be applicable to other areas of the body, including other areas that may face narrowing due to cell in-growth. For example, the walls of the bronchi in asthmatics may have thickened smooth muscle tissue as well as over-productive mucus glands. The methods and apparatuses described herein may be used to treat these lumens, in some examples by ablating the smooth muscle and the mucosa and submucosa, stimulating regrowth of normal tissue that may be unaffected by asthma. These methods and apparatuses may be used, e.g., to treat chronic bronchitis to reduce the size and prevalence of goblet cells and mucus glands, which could reduce mucous plugs that cause chronic bronchitis. The methods and apparatuses described herein may also be useful to treat patients with stents in the bile duct or ureter, which may also develop in-stent restenosis.

[0041] For example, described herein is an apparatus for treating or preventing restenosis while minimizing inflammation and/or fibrosis, the apparatus comprising: a pulse generator configured to generate a plurality of electrical pulses having amplitude of at least 0.1 kV; a controller configured to trigger regulated cell death by causing the pulse generator to limit a pulse width of the plurality of electrical pulses to less than 1000 nanoseconds; an applicator comprising a first electrical conductor, wherein the applicator is coupled to the pulse generator and configured to deliver the plurality of electrical pulses to a lumen; and a catheter configured to guide and position the first electrical conductor to a treatment area. Also described herein are separate applicators or separate pulse generators configured as described herein.

[0042] The same or a different controller may be configured to determine if the first electrical conductor is in contact with a stent within the lumen. The first electrical conductor may be configured for monopolar application of the plurality of electrical pulses to the lumen. Any of these apparatuses may include a second electrical conductor coupled to the pulse generator and configured to deliver the plurality of electrical pulses to the lumen between the first and second electrical conductors.

[0043] The apparatus may include an expandable member configured to position the first and second electrical conductors against a luminal wall. The expandable member may be a balloon.

In some examples, the balloon comprises grooves configured to allow fluid flow past the balloon and ridges configured to support the first and second electrical conductors. The first and second electrical conductors may be disposed radially or axially with respect to the balloon. For example, the first electrical conductor may be further configured to withdraw within the catheter. The first electrical conductor may be further configured to extend out of the catheter and expand to contact a wall of the lumen. The first electrical conductor may be disposed around a pigtail configured to extend beyond the catheter. The first electrical conductor may be part of an expandable wire mesh. The first electrical conductor may be disposed on a stent that is detachably /frangibly connected to the applicator. For example, the stent may be releasably coupled to the applicator so that it can be expanded within the lumen and energy applied from it, then the applicator withdrawn, leaving the stent behind. The connection to the stent may be configured to break or snap off.

[0044] The controller may be configured to minimize necrosis by limiting the pulse width of the plurality of electrical pulses to less than 900 nanoseconds. The controller may be configured to minimize necrosis by limiting the pulse width of the plurality of electrical pulses to less than 700 nanoseconds. [0045] Also described herein are methods for treating or preventing and/or inhibiting restenosis by applying electrical energy while minimizing inflammation and/or fibrosis, the method comprising: positioning an applicator within a treatment area; applying a plurality of sub-microsecond electrical pulses from the applicator to the treatment area and limiting a pulse length of the applied sub-microsecond electrical pulses to less than 900 ns to trigger regulated cell death; and concurrently, immediately prior to, or subsequently performing angioplasty and/or stenting to the treatment area.

[0046] Also described herein are methods for treating or inhibiting restenosis by applying electrical energy while minimizing inflammation and fibrosis, the method comprising: positioning an applicator within a treatment area of a lumen; applying a plurality of sub microsecond electrical pulses having amplitude of at least 0.1 kV from the applicator to the treatment area and limiting a pulse length of the applied sub-microsecond electrical pulses to less than 900 ns to trigger regulated cell death while minimizing immediate necrosis; and concurrently, immediately prior to, or subsequently performing angioplasty and/or stenting to the treatment area. The applicator may include a first conductor configured to contact the identified treatment area.

[0047] Applying the plurality of sub-microsecond electrical pulses may comprise applying monopolar electrical pulses from the applicator. The applicator may include a second conductor distinct from the first electrical conductor. Applying the plurality electrical pulses may comprise applying bipolar electrical pulses from the first conductor and the second conductor. The applicator may be removed from the treatment area prior to performing angioplasty and/or stenting. Positioning the applicator may comprise inserting a distal end region of an elongate applicator tool into an anatomical lumen, wherein the applicator is disposed at the distal end region of the elongate applicator tool.

[0048] In any of these methods, the pulse length of the applied sub-microsecond electrical pulses may be limited to less than 900 nanoseconds having an amplitude of greater than 0.1 kV to trigger regulated cell death while minimizing necrosis. For example, the pulse length of the applied sub-microsecond electrical pulses may be limited to less than 700 nanoseconds to trigger regulated cell death while minimizing necrosis. Applying the plurality electrical pulses from the applicator may comprise applying pulsed electrical treatment using an implanted stent as an electrode.

[0049] Also described herein are methods for treating or preventing restenosis by applying electrical energy while preventing at least one of inflammation and fibrosis, the method comprising: positioning a stent with embedded applicators within a treatment area of a lumen; and applying a plurality of sub-microsecond electrical pulses from the stent and limiting a pulse length of the sub-microsecond electrical pulses to less than 900 ns to trigger regulated cell death. [0050] Also described herein are methods for treating or preventing restenosis by applying electrical energy while preventing inflammation and/or fibrosis, the method comprising: positioning an applicator within a blood vessel and in electrical contact with a stent within the blood vessel; applying a plurality of sub-microsecond electrical pulses from the applicator to the stent and limiting a pulse length of the sub-microsecond electrical pulses to less than 900 ns to trigger regulated cell death. Positioning the stent may further comprise expanding the stent to cause the embedded applicators to contact the lumen. In some examples, positioning the stent further comprises positioning the stent via a catheter coupled thereto.

[0051] Any of these methods may include removing the catheter and leaving the stent with the embedded applicators in the lumen after applying the plurality of sub-microsecond electrical pulses. Applying the plurality of sub-microsecond electrical pulses may comprise limiting the pulse length of the applied sub-microsecond electrical pulses to less than 700 ns pulses each having an amplitude of greater than 0.1 kV to trigger regulated cell death and minimize necrosis. Applying the plurality of sub-microsecond electrical pulses may comprise applying monopolar electrical pulses from the applicator. In some examples applying the plurality of sub microsecond electrical pulses comprises applying bipolar electrical pulses from the applicator. Positioning the applicator within the blood vessel and in electrical contact with the stent may comprise contacting a first end region of the stent with a first electrical contact of the applicator and a second end region of the stent with a second electrical contact of the applicator and applying the plurality of sub-microsecond electrical pulses therebetween.

[0052] In any of these methods at least one electrode of the applicator may make electrical contact with the stent. For example, positioning the applicator within the blood vessel and in electrical contact with the stent may comprise contacting a first electrode of the applicator to the stent and contacting a wall of the blood vessel with a second electrode of the applicator, and applying the plurality of sub-microsecond electrical pulses between the first electrode and the second electrode of the applicator. The stent may be at least partially positioned between the first electrode and the second electrode when the first electrode is in electrical contact with the stent. [0053] In any of these methods, the stent may be positioned between the first and second electrodes. For example, positioning the applicator within the blood vessel and in electrical contact with the stent may comprise contacting a first electrode of the applicator to a first region of the stent and contacting a second electrode of the applicator to a second region of the stent, and applying the plurality of sub-microsecond electrical pulses between the first electrode and the second electrode of the applicator. In some examples, positioning the applicator within a blood vessel and in electrical contact with a stent within the blood vessel may comprise placing the stent between a first electrode of the applicator and a second electrode of the applicator. [0054] All of the methods and apparatuses described herein, in any combination, including any combination of various features and elements of different examples, are herein contemplated and can be used to achieve the benefits as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS [0055] A better understanding of the features and advantages of the methods and apparatuses described herein will be obtained by reference to the following detailed description that sets forth illustrative embodiments, and the accompanying drawings of which:

[0056] FIG. 1 illustrates one example of a system for delivering high voltage, fast pulses of electrical energy.

[0057] FIGS. 2A-2C illustrate examples of the distal end regions or applicators including electrodes on expandable member(s), e.g., balloons, that may form at least part of an applicator as described herein.

[0058] FIG. 3 shows an example of a distal end region of an applicator for treating restenosis as described herein.

[0059] FIG. 4 shows another example of a distal end region of an applicator for treating restenosis as described herein.

[0060] FIG. 5 shows a further example of a distal end region of an applicator for treating restenosis as described herein.

[0061] FIG. 6 shows yet another example of a distal end region of an applicator for treating restenosis as described herein.

[0062] FIG. 7 shows an example of a distal end region of an applicator for treating restenosis within a vessel including a stent.

[0063] FIG. 8 schematically illustrates one example of a method of applying pulsed electric fields (e.g., nanosecond pulses) to a patient prior to performing arterial treatment to treat restenosis.

[0064] FIG. 9 schematically illustrates an example of a method for applying pulsed electric fields (e.g., nanosecond pulses) to a patient after or during arterial treatment.

[0065] FIG. 10 schematically illustrates an example of an applicator delivering pulsed electric fields (e.g., nanosecond pulses) to vessel through a stent as described herein.

[0066] FIG. 11 shows one example of a model tissue treated as described herein. [0067] FIGS. 12A-12B illustrate examples of applicators for delivering energy to a body lumen as described herein. The devices shown by example in FIGS. 12A-12B all include two expandable members with electrodes on the expandable members.

[0068] FIGS. 13A-13C illustrate examples of applicators for delivering energy to a stent within a body lumen as described herein.

DETAILED DESCRIPTION

[0069] Described herein are systems and methods for treating and/or preventing restenosis. These methods may include applying sub-microsecond pulsed electrical energy using electrodes adapted to be inserted into a body lumen such as, for example, arteries and other vessels that may suffer from restenosis. In particular, the methods and apparatuses described herein are configured to treat and/or prevent restenosis using sub-microsecond electrical pulsing while minimizing necrosis (acute necrosis) which may cause inflammation and/or fibrosis. The inventors have determined that the application of pulsed electrical energy within a specific range of pulse parameters results in a regulated cell death pathway that minimizes (and sometimes prevents) inflammation, fibrosis or both that may otherwise occur at longer (e.g., microsecond or longer) pulsing regimens, including those in which the applied energy is applied at 1 microsecond (ps) or more.

[0070] In general, these methods may minimize necrosis and/or inflammation and/or fibrosis at or near the site. Minimizing necrosis, inflammation and/or fibrosis as described herein may result in a significant reduction in acute or immediate necrosis, inflammation and/or fibrosis at or near the site, as compared to other treatments that may result in acute necrosis of the target site (e.g., within 24 hours of delivering the energy), and an increase in inflammation and/or fibrosis at or near the treatment site. Instead, the primary effect seen by the methods and apparatuses described herein is regulated cell death (RCD). Immediate necrosis within the treated region may be less than 25%, less than 20%, less than 18%, less than 15%, less than 12%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, etc. In contrast, immediate necrosis following irreversible electroporation (IRE) may be greater than 25% (e.g., greater than 30%, etc.). The cells in the tissue undergoing regulated cell death may induce less inflammation as compared to IRE treatments (e.g., treatment with pulses having pulse widths greater than 1000 ns, such as in microsecond range and greater). In some cases, the amount of inflammation may be detected by a marker for inflammation, such as, for example, neutrophil adhesion molecules L-selectin and CD lib, IL-1, MCP-1, C-reactive protein, etc. In some cases these markers may be locally upregulated around the treatment region to a much greater degree following treatment resulting in IRE, including treatment with pulses having a pulse width greater than 1000 ns, etc. than following treatment with lower pulse width pulses (e.g., those inducing primarily or exclusively regulated cell death, e.g., having a pulse width of less than 1000 ns). In some examples one or more of any markers of inflammation (e.g., L-selectin and CDllb, IL-1, MCP-1, and/or C-reactive protein, etc.) may be increased, for example, by 25% or less (e.g., 20% or less, 15% or less, 10% or less, 7.5% or less, 5% or less, etc.) following the application of pulses having an amplitude of at least 0.1 kV and a pulse width limited to less than 1000 nanoseconds. In contrast, treatments with pulses longer than 1000 ns, inducing acute necrosis, may result in a local increase in one or more of these markers by significantly greater amounts (e.g., greater than 25%, greater than 30%, greater than 35%, greater than 40%, etc.) shortly after the application of energy.

[0071] Stenosis refers to a partial or complete blockage of an artery or other lumen and may be caused by a build-up of plaque or other material. Performing angioplasty or stent implantation procedures may provide relief from arterial stenosis and restore, at least in part, blood circulation to one or more affected areas. In some cases, the lumen that has undergone treatment may be subject to a reclosing or restriction, referred to as restenosis. For example, the restenosis may be caused by local cells reacting to the initial treatment and producing an inflammatory response. In another example, restenosis may be caused by a clotting response to a surface of the lumen (such as the material used to form a stent).

[0072] The pulsed electrical treatment may be generally sub-microsecond pulsed treatment, including nanosecond pulses. For example, nanosecond or sub-microsecond pulsed electric fields treatment may refer to the application of relatively high voltages (in some cases 5kV or greater) for a relatively short amount of time (in some cases between about 1 nanosecond and 990 ns, 500 ns, 400 ns, 300 ns, 200 ns, 100h ns, etc.). These high voltages and short duration times create a pulsed electric field in the region that the voltages are applied. Treating an area that has undergone or will be undergoing angioplasty and/or stent implantation with pulsed electrical fields may reduce or prevent restenosis. In some cases, nanosecond pulsing may induce apoptosis within cellular structures which may reduce a cells’ inflammatory response. In some examples, pulsed electrical (e.g., nanosecond) treatment may be performed on tissue that has already undergone angioplasty, stent implantation, or other luminal treatment. In those cases, the nanosecond pulse energy treatment may clear smooth muscle tissue that has infiltrated the area, such as the area in and around an implanted stent. Clearing smooth muscle tissue may reduce inflammation and reduce or slow restenosis.

[0073] Pulsed electric fields may generally be applied to modify the permeability of cellular membranes. A voltage gradient of 500 mV across a bilayer membrane is sufficient to generate water- filled defects through the bilayer. Generally, the longer the pulse, the larger the pore size that it generates in a biological membrane. Molecular dynamics models of cellular membranes have demonstrated that fields of this magnitude push charged water dipoles into the hydrophobic lipid bilayer and form a water-filled defect that spans the membrane. Electrical pulses in the microsecond domain are used to permeabilize cells by generating pores large enough to allow the transport of small molecules across the plasma membrane. The microsecond pulses typically result in irreversible electroporation (IRE), depending on the amplitude of the pulsed electric field. IRE treatments generate pores that are “irreversible” or permanent and result in immediate cell death or necrosis in the treated tissue.

[0074] Although it has been suggested that pulsed energy may be applied to reduce restenosis following angioplasty, these efforts have been met with limited success. In particular, although such treatments typically included applying pulses having a pulse width in the microsecond range (e.g., pulsing between 1 ps and 900 ps or more) and/or induce irreversible electroporation (IRE), these treatments result in significant inflammation and/or fibrosis at or near the site of the treatment.

[0075] The methods and apparatuses described herein are based in part on the surprising finding that limiting the applied pulsed energy within a range that results predominantly or exclusively in regulated cell death rather than necrosis, effectively prevents or reduces restenosis with significantly less inflammation and/or fibrosis. This may be achieved in part by applying sub-microsecond (e.g., nanosecond) pulse width pulsing, for example, limiting pulsing to pulses having a pulse width of less than 900 ns, less than 800 ns, less than 700 ns, less than 600 ns, less than 500 ns, etc.

[0076] The inventors have found that there is a substantially and qualitative difference between nanosecond pulsing resulting in regulated cell death and microsecond pulsing (resulting in IRE and necrosis). For example, preliminary data indicates that inflammation is significantly reduced when the applied pulsed energy is limited to sub-microsecond pulsing, as compared with microsecond pulsing. Methods and apparatuses that apply IRE (e.g., in some cases by applying pulses of 1 ps or longer pulse width) may have a significantly higher inflammatory response, and/or fibrosis as compared to the methods and apparatuses described herein, which limit the applied energy (including limiting the pulse width to the sub-microsecond range) to result in a regulated cell death pathway in the target (e.g., luminal) tissues.

[0077] In general, the methods and apparatuses described herein may limit the applied energy to that which triggers a regulated cell death pathway while minimizing (or in some cases avoiding) irreversible electroporation (IRE) and necrosis. In some examples this may be achieved by limiting the apparatus and method to applying pulses having pulse width within the narrower sub-microsecond range; this narrow range is critical in order to achieve regulated cell death while minimizing necrosis, thereby reducing inflammation and/or fibrosis. By limiting the applied energy as described herein, including limiting to the sub-microsecond range (e.g., less than 900 ns), the methods and apparatuses described herein may achieve the new and unexpected result of reducing or preventing restenosis without significant inflammation and/or fibrosis, despite previous work suggesting pulsed electrical energy to trigger necrosis (e.g., IRE) to treat restenosis. In contrast, limiting the applied pulsed electric energy to trigger a regulated cell death pathway, rather than IRE (and necrosis), when treating restenosis results in a meaningful reduction in inflammation and/or fibrosis. This effect was unexpected and surprising, as prior work in the field did not suggest the link between either the pulse width and the reduction in inflammation or fibrosis.

[0078] Without being bound by a particular theory, one possible explanation for the surprising result that limiting the applied pulsing to a regulated cell death pathway (e.g., limiting the pulses to sub-microsecond pulses) may result in a significant reduction in restenosis/stenosis with minimal inflammation and/or fibrosis may be due to the subcellular effect of short pulse width energy. For example the use of shorter, faster sub-microsecond pulsing may result in the imposed field, particularly those having a rise time of less than one ps, penetrating the tissues to modify organelle membrane structure to trigger a regulated cell death pathway. Relatively higher field strengths may be used to permeabilize smaller organelles, such as mitochondria. For example, greater than 1 V/0.5 pm or 20 kV/cm may be used with the sub-microsecond pulsing described herein. For example, a 100 ns, 20 kV/cm pulse may be applied to a 200 ohm-cm load, and the energy may be about 0.2 Joules.

[0079] All of the cells in the body have a regulated cell death pathway to be utilized when they reach the end of their useful life or experience a problem with the replication of their DNA. This is referred to as a regulated cell death pathway and it involves shutting down ATP production, initiating DNA and protein degradation and the exposure of signaling molecules on the cell surface to attract dendritic cells to phagocytose the cell remains. Regulated cell death (sometimes referred to as RCD) is a commonly used pathway in cells and involves the fragmenting the DNA, hydrolyzing the cytoplasmic protein by activated caspase-3, translocating calreticulin to the cell surface and releasing DAMP molecules to attract dendritic cells. Dendritic cells phagocytose the dying cells in a manner that minimizes or avoids scarring by fibrosis and minimizes inflammation. In contrast, death by necrosis is associated with both inflammation and fibrosis. Therefore, when both nanosecond pulsing (resulting in RCD) and microsecond pulsing (resulting in IRE and necrosis) are applied to the same target, we would expect to detect higher levels of inflammation and fibrosis in microsecond-treated targets and more caspase-3 activation in nanosecond-treated targets. The main conclusion is that these two energy modalities are very different and the tissue response to each is also very different.

[0080] As mentioned, the methods described herein may be particularly useful to treat arterial stenosis. Arterial stenosis is a potentially fatal condition where blood flow is restricted inside an artery by the closing of the lumen due to ingress of plaque, typically over years of accumulation due to atherosclerosis. Early interventional procedures include angioplasty balloons which were inserted percutaneously into an artery and guided by medical imaging to the stenotic portion of the artery and inflated, stretching the walls of the artery and compressing the plaque to open the size of the lumen and allow restoration of normal blood flow. Partially as a result of remodeling of the tissue after damage to the vessel wall, inflammation, and proliferation of connective proteins such as elastin often result in subsequent narrowing of the vessel lumen (e.g., restenosis), due primarily to a phenomenon called “elastic recoil”. Although the use of intra-arterial stents has greatly improved the restenosis due to elastic recoil from balloon angioplasty, in some patients there is in-growth of smooth muscle tissue and fibrotic tissue through the stent mesh, which also can effectively narrow the arterial lumen. This process is called neointimal hyperplasia and is the commonest cause of in-stent restenosis (ISR). The methods and apparatuses described herein may be particularly helpful for treating restenosis due to neointimal hyperplasia.

[0081] Vascular smooth muscle cell proliferation into the stent mesh may also be caused by vessel injury following the mechanical damage from stretching the arterial wall during angioplasty, the rupturing of the internal elastic laminae, and damage to the arterial media and endothelium. Smooth muscle cells in the media of the arterial vessel express high levels of contractile proteins such as smooth muscle Alpha actin, and don’t produce significant levels of extracellular matrix; after injury from the angioplasty/stent procedure, the smooth muscle cells have been found to change to a different phenotype and express reduced levels of contractile proteins and increased levels of migration, proliferation and extracellular matrix synthesis. This smooth muscle cell proliferation jumps from a normal level of 0.06% before injury to a level of 10-40% in the injured arteries of animal subjects during the first 2 to 4 days following injury.

The methods and apparatuses described herein may be used to prevent this effect. Thus, in some cases, these methods may be performed within the first 2-4 days following angioplasty and/or stenting. Untreated, smooth muscle cells (SMCs) at the luminal surface in deendothelialized areas may continue to proliferate at a low rate. The methods and apparatuses described herein may prevent or reduce this.

[0082] FIG. 1 illustrates one example of a system 100 (also referred to herein as a high voltage system or a sub-microsecond generation system) for delivering high voltage, fast pulses of electrical energy that may include an elongate applicator tool 102, a pulse generator 107, footswitch 103, and user interface 104. Footswitch 103 is connected to housing 105 (which may enclose the electronic components) through a cable and connector 106. The elongate applicator tool 102 may include electrodes and is connected to housing 105 and the electronic components therein through a cable 137 and high voltage connector 112. The high voltage system 100 may also include a handle 110 and storage drawer 108. The system 100 may also include a holder (e.g., holster, carrier, etc.) (not shown) which may be configured to hold the elongate applicator tool 102. In some examples the system may be configured for monopolar treatment and may optionally include a dispersive electrode 133 (e.g., a return electrode pad).

[0083] In some cases, the elongate applicator tool 102 includes one or more imaging sensors, such as one or more cameras and/or fiber optics at or near the distal end of the elongate applicator tool 102. The camera(s) (not shown for simplicity) may be forward-facing and/or side facing. The system 100 may be configured to display images (in real time, and/or recorded) taken by the elongate applicator tool 102, in order to identify the target treatment region(s).

[0084] A human operator may select a number of pulses, amplitude, pulse duration, and frequency information, for example by inputting such parameters into a numeric keypad or a touch screen of interface 104. In some examples, the pulse width can be varied. A controller 144 (e.g., microcontroller) may send signals to pulse control elements within the system 100. In FIG. 1, the controller (which may include one or more processors and other control circuitry, including a memory) is shown within the housing 105, but it may be positioned anywhere within in the system. The controller may be coupled to the pulse generator and/or power supply and may receive input any of the input components.

[0085] In some examples, fiber optic cables are used which allow control signaling while also electrically isolating the contents of the metal cabinet (e.g., the housing 105) with a sub microsecond pulse generation system 100, e.g., the high voltage circuit, from the outside. In order to further electrically isolate the system, system 100 may be battery powered instead of being powered from a wall outlet. The system 100 may comprise one or more processors (not shown), which may be a separate processing unit or it may be incorporate with the controller.

The controller may comprise a plurality of controllers and the processor may comprise a plurality of processors.

[0086] The elongate applicator tool 102 may be hand-held (e.g., by a user) or it can be affixed to a movable arm of a robotic system, and its operation may be at least partially automated or fully automated, including computer controlled.

[0087] FIGS. 2A-2C illustrate an example of an applicator for applying pulse electrical energy within a vessel to treat restenosis. The applicator may include a balloon on at least part of a distal tip region of the elongate applicator 102 of FIG. 1 as described herein. FIG. 2A shows an applicator 200 for delivering pulsed electrical energy to treat restenosis. In this example, the applicator 200 may include a first conductive strip 201a, a second conductive strip 201b, an expandable portion (e.g., balloon) 202, and a catheter 203. The conductive strips may be formed as electrodes and may be printed (e.g., as a conductive ink) or otherwise attached to the balloon. The conductive strips may include a tissue-contacting surface that is exposed or partially exposed (and may be partially insulate). In some examples, just the region(s) over the midline of the expandable portion may be exposed, for contacting the wall of the lumen. The applicator may include (or may attach to) a catheter 203. The applicator may include a proximal handle (not shown). Although only two conductive strips 201a and 201b are shown, in other examples, the applicator 200 may include any feasible number of conductive strips. The conductive strips 201a and 201b may be positioned axially (e.g., in the direction of the axis of the balloon 202 and/or catheter 203). The conductive strips may form a circumferentially arranged set of electrodes around the expandable members.

[0088] In some examples the applicator is configured for bipolar operation, e.g., operation where pulse energy is transferred between two adjacent electrodes on the expandable portion.

The pulses may be biphasic or multi-phasic. The first conductive strip 201a may be associated with a signal having first polarity (e.g., a positive signal) and the second conductive strip 201b may be associated with a signal having second polarity (e.g., a negative signal). In other examples, the first conductive strip 201a may be associated with a signal having a negative signal and the second conductive strip 201b may be associated with a signal having a positive signal. Conductive strips carrying opposing polarity signals may enable electric fields associated with pulsed treatment to be produced between the conductive strips. Conductors to couple the first conductive strip 201a and the second conductive strip 201b to the pulse generator system 100 may be contained within the catheter 203. In some examples, the system (including the applicator 200) may be configured for monopolar operation. For example, the first and second conductors 201a and 201b may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 203 or a conductive pad or electrode that may be in contact with the patient.

[0089] The applicator 200 may be inserted into a blood vessel, such as an artery, or another lumen, or the like to provide pulsed electrical treatment (e.g., for example, to deliver high voltage, sub-microsecond electric energy) to an identified treatment area corresponding to a region where stenosis may occur or has already occurred or expanded (e.g., by angioplasty and/or stenting). In some examples, the applicator 200 may be guided to the identified treatment region by the catheter portion 203 of the elongate applicator tool. In some examples, the applicator 200 may also be guided by guide wires (not shown for simplicity) and the use of fluoroscopy equipment. The applicator may include a central lumen which may allow it to be delivered over a guidewire. Alternatively a rapid exchange lumen may be present on a side of the applicator distal end.

[0090] After position of the applicator 200 is verified, then the expandable member (e.g., balloon 202) may be inflated through the catheter 203. Inflation of the expandable member 202 may place the first and second conductive strips 201a and 201b in contact with the inner wall of the lumen. Pulsed electrical (e.g., nanosecond pulsed electrical) field may be applied to the tissue and the expandable member 202 may be deflated thereafter. The applicator 200 may be moved to another region of the vessel (e.g., artery) for additional treatment or may be withdrawn from the patient.

[0091] In some examples, the pulsed electrical field may be provided by the applicator 200 to one or more regions of an artery prior to angioplasty or stent implantation. In some other examples, pulsed electrical treatment may be provided by the applicator 200 to one or more regions of the artery during or after angioplasty or stent implantation.

[0092] FIG. 2B shows another example of an applicator 210. The applicator 210 may include a first conductive strip 21 la, a second conductive strip 211b, an expandable member (e.g., balloon) 212, and a catheter 213. The catheter 213 may couple the applicator 210 to a proximal handle (not shown) and/or to a pulse generator such as that shown in FIG. 1. Although only two conductive strips 211a and 211b are shown, in other examples, the applicator 210 may include any feasible number of conductive strips. The conductive strips 211a and 211b may be positioned radially (e.g., perpendicular to the direction of the axis of the balloon 212 and/or catheter 213). All or a portion of the conductive strips may be exposed. In some examples portions of the electrical strip may be insulated. For bipolar operation, the first conductive strip 211a may be associated with a signal having a first polarity and the second conductive strip 211b may be associated with a signal having a second polarity. For monopolar operation, the first and second conductors 211a and 211b may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 213 or a conductive pad or electrode that may be in contact with the patient. Conductors to couple the first conductive strip 211a and the second conductive strip 21 lb to the system 100 may be contained within the catheter 213 (conductors not shown for simplicity).

[0093] Similar to the applicator 200, the applicator 210 may be inserted into an appropriate vessel, lumen or the like and guided into position to provide treatment. After the position of the applicator 210 is verified, then the expandable member 212 may be expanded, e.g., by inflation through the catheter 213. In this example, inflation of the balloon 212 places the conductive strips 211a and 21 lb in contact with cells that form the inner wall of the lumen. Pulsed electrical treatment may be applied to these cells and the balloon 212 may be deflated thereafter. The applicator 210 may be moved to another region of the artery or may be withdrawn from the patient.

[0094] FIG. 2C shows another example of an applicator 220. The applicator 220 may include circumferentially arranged conductors (e.g., a first conductor 221a, a second conductor 221b, etc.), an expandable member 222 (e.g., balloon), and a catheter 223. For simplicity, only the first and second conductors 221a and 221b are shown. Any feasible number of conductors may be disposed radially and/or axially along the balloon 222. For example, additional conductors may be disposed opposite the first and second conductors 221a and 221b but may be obscured from view by the balloon 222. For bipolar operation, the first and second conductors 221a and 221b may be coupled to first and second signals, respectively. For monopolar operation, the first and second conductors 221a and 221b may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 223 or a conductive pad or electrode that may be in contact with the patient.

[0095] In this example the applicator apparatus may include optional wires 264, 264’ that may be attached to the shaft (e.g., catheter 223 shaft) and may lay over the balloon 222 to prevent the portions of the balloon from expansion (identical for all quadrants in this example), shaping the balloon so that it has channels when expanded.

[0096] The applicator 220 may be inserted into an appropriate artery, lumen, or the like (in need of treating restenosis) and guided into the position to provide treatment. For example, the applicator 220 may be guided by guide wires and/or the use of fluoroscopy equipment. Position of the applicator 220 may be verified and the expandable member 222 may be expanded through the catheter 223 (e.g., by inflation). Electrical conductors (e.g., wires) to couple the first and second conductors (electrodes) 221a and 221b to the pulse generator system 100 may also be contained within the catheter 223.

[0097] In some examples, the balloon 222 may include one or more axial grooves 225 that enable blood flow to continue in the artery after the balloon 222 is inflated. The first and second conductors 221a and 221b may be disposed away from the groves 225 and upon one or more ridges 224 allowing the first and second conductors 221a and 221b to contact the walls of the artery.

[0098] In some examples, the applicator 220 may be radially repositioned during treatment to enable additional regions of the artery to be treated. For example, the balloon 222 may be inflated and pulsed electrical treatment performed in a first region of the artery. Next, the balloon 222 may be partially or wholly deflated and the applicator 220 rotated so that the first and second conductors 221a and 221b can contract other regions of the artery. The balloon 222 may be reinflated and pulsed electrical treatment performed in a new region. This procedure may be repeated as many times as desired to increase the treated region.

[0099] FIG. 3 shows another example of an applicator 300 showing a portion of a distal tip region of the applicator. The applicator 300 may include a first deployable conductor 301a, a second deployable conductor 301b, and a catheter 303. The catheter 303 may couple the applicator 300 to the pulse generator and/or handle. Although two deployable electrodes (e.g., conductors 301a and 301b) are shown, in other examples, the applicator 300 may include any feasible number of deployable conductors. For bipolar operation, the first deployable conductor 301a may be coupled to a signal having a first polarity and the second deployable conductor 301b may be coupled to a signal having a second polarity. For monopolar operation, the first and second conductors 301a and 301b may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 303 or a conductive pad or electrode that may be in contact with the patient.

[0100] The applicator 300 may be inserted into a blood vessel, lumen, or the like with the first and second deployable electrodes 301a and 301b enclosed by the catheter 303. After the applicator 300 is positioned in the region of the lumen to receive treatment, the first and second deployable electrodes 301a and 301b may be extended (e.g., deployed) from the catheter 303 and form an annular shape that conforms and contacts the artery. For example, the deployable electrodes may be formed of a wire (e.g., stainless steel, shape memory alloy, etc.) that may expand outward to contact the vessel wall. The distance between the first and second deployable conductors 301a and 301b may be predetermined or may be varied during deployment.

[0101] After deployment of the deployable conductors 301a and 301b, pulsed electrical treatment may be performed, including but not limited to nanosecond pulsed electrical treatment. After treatment, the deployable conductors 301a and 301b may be retracted back into the catheter 303. Notably, the deployable conductors 301a and 301b may have a small cross- sectional area (for example, compared to the cross-sectional area of the artery), thereby have a minimal impact on blood flow within the artery. The deployable conductors may include electrically exposed regions (other regions may be electrically insulated) on an outer surface that may contact the tissue, forming electrodes through which energy may be applied.

[0102] FIG. 4 shows another example of an applicator 400 showing at least part of a distal tip region of the applicator. The applicator 400 may include a first set of conductors 401a (e.g., electrodes), a second set of conductors 401b (e.g., electrodes) and a catheter 403. Although two sets of conductors are shown, in other examples the applicator 400 may include any feasible number of sets of conductors. For bipolar operation, the first set of conductors 401a may be coupled to a signal having a first polarity and the second set of conductors 401b may be coupled to a signal having a second polarity. For monopolar operation, the first and second set of conductors 401a and 401b may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 403 or a conductive pad or electrode that may be in contact with the patient.

[0103] In some examples, the first and second set of conductors 401a and 401b may be withdrawn into and/or enclosed by the catheter 403 while the distal end of the catheter 403 is positioned into the region of the lumen to receive treatment. When the distal end of the catheter 403 is in position, the first and second set of conductors 401a and 401b may be deployed from the catheter 403 and expand to contact the walls of the lumen. Pulsed electrical treatment may be performed through the first and second set of conductors 401a and 401b. In some examples, the applicator 400 may be rotated axially to enable the first and second set of conductors 401a and 401b to contact other regions of the lumen. After pulsed electrical treatment, the first and second set of conductors 401a and 401b may be withdrawn into the catheter 403. Of note, the first and second set of conductors 401a and 401b may have a small cross-sectional area (compared to the cross-sectional area of the artery), thereby having a minimal impact on blood flow.

[0104] FIG. 5 shows another example of a distal end region of an applicator 500 that may form at least part of an elongate applicator tool. The applicator 500 may include a first conductor 501a (including one or more electrodes), a second conductor 501b (including one or more electrodes), a pigtail 502, and a catheter 503. The catheter 503 may couple the applicator 500 to the pulse generator. For bipolar operation, the first conductor 501a may be coupled to a signal having a first polarity and the second conductor 501b may be coupled to a signal having a second polarity. For monopolar operation, the first and second conductors 501a and 501b may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 503 or a conductive pad or electrode that may be in contact with the patient.

[0105] The first and second conductors 501a and 501b may be disposed around the pigtail 502. In some examples, the pigtail 502 may have a spiral shape and be formed of a flexible material that enables the first and second conductors 501a and 501b to contact and conform to the walls of the lumen. In some other examples, the pigtail 502 may be drawn into a spiral shape allowing the first and second conductors 501a and 501b to contact the walls of the artery.

Control of the shape of the pigtail 502 may be through tendons or the like that may be contained within the catheter 503. This pigtail configuration is one example of a mechanically expandable member onto which the electrodes are held. [0106] The applicator 500 may be positioned within a region of the lumen indicated for treatment. The pigtail 502 may be manipulated to cause the first and second conductors 501a and 501b to contact walls of the artery and pulsed electric treatment may be performed (e.g., nanosecond pulsed electric treatment). In this example the first and second conductors 501a and 501b and the pigtail 502 may have a small cross-sectional area (compared to the cross-sectional area of the artery), thereby having a minimal impact on blood flow.

[0107] FIG. 6 shows another example of a distal end region of an applicator 600 that may form at least part of an elongate applicator tool. The applicator 600 may include a first conductor 601a (including one or more electrodes), a second conductor 601b (including one or more electrodes), a spacing element 602, and a catheter 603. The catheter 603 may couple the applicator distal end region (and electrodes) to a proximal handle and/or pulse generator. For bipolar operation, the first conductor 601a may be coupled to a signal having a first polarity and the second conductor 601b may be coupled to a signal having a second polarity. For monopolar operation, the first and second conductors 601a and 601b may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 603 or a conductive pad or electrode that may be in contact with the patient.

[0108] In some examples, the first and second conductors 601a and 601b may be an expandable wire mesh and may be held within the catheter 603 in a collapsed configuration while a distal end of the catheter 603 is being positioned within a relevant region, for example, the region of the artery, to receive treatment. After the catheter 603 is positioned, the first and second conductors 601a and 601b may be extended from the catheter 603 and may be expanded into an expanded configuration such that the conductors 601a and 601b come into contact with the walls of the lumen.

[0109] Pulsed electrical treatment (e.g., nanosecond pulses) may be performed through at least the first and second conductors 601a and 601b. The first electrical conductor is supported by a first expandable member or mesh 608 and the second electrical conductor is supported by the second expandable member 609. The distance between the first conductor 601a and the second conductor 601b may be determined at least in part by the spacing element 602. The spacing element may be, in some examples, a spring element 602. This spacing element in other examples may be a telescoping arm element coupled to the distal expandable member supporting the second conductor. In some examples, the spacing element 602 may provide a fixed spacing distance. In some other examples, spacing (including when provided by a spacing element 602) may be adjustable and may be controlled, for example, through a push rod, cable, tendons, etc. within the catheter 603 and coupled to the proximal handle. The first and second conductors 601a and 601b and the spacing element 602 may have a small cross-sectional area (compared to the cross-sectional area of the artery), thereby having a minimal impact on blood flow.

[0110] FIG. 7 shows an example of another applicator 700. The applicator 700 in this example may be coupled with a stent 701, a balloon 702, a catheter 703, and insulated conductors 704. In this example the same applicator that delivers the stent may also be used to deliver pulsed electrical (e.g., nanosecond pulsed electrical) field to treat restenosis. The stent 701 may include a first conductor 710 region and a second conductor 711 region. Thus, the stent 701 may include embedded conductors (electrodes) 710 and 711 that may be used to provide pulsed electric treatment. The first and second conductors 710 and 711 may be disposed on any feasible region of the stent 701. In some examples, the first conductor 710 and the second conductor 711 may be insulated from each other and/or the stent 701, particularly if the stent 701 is formed of a conductive material, to prevent shorting. The applicator may be releasably attached to these separate (in bipolar configurations) electrodes on the stent, so that once the balloon is expanded the applicator may disconnect from the stent. In some examples the applicator is releasably (e.g., breakably) connected to the stent.

[0111] For bipolar operation, the first conductor 710 may be coupled to a signal having a first polarity and the second conductor 711 may be coupled to a signal having a second polarity through the insulated conductors 704. For monopolar operation, the first and second conductors 710 and 711 may both be coupled to a first signal while a second signal may be coupled to another conductor such as a portion of the catheter 703 or a conductive pad or electrode that may be in contact with the patient.

[0112] The catheter portion of the applicator 700 may be positioned in the region of the lumen indicated for treatment. The stent 701 and balloon 702 may be extended from the catheter 703. As mentioned, the electrodes may be coupled to the stent and/or balloon. The balloon 702 may inflate placing the stent 701 and the first and second conductors (electrodes) 710 and 711 in contact with walls of the lumen. Pulsed electrical treatment may be delivered through at least the first and second conductors 710 and 711 and the insulated conductors 704. After treatment, the balloon 702 may be deflated, also removing the electrical connection to the electrical connectors on the stent, which may be left behind. In FIG. 7 the distal end region of the applicator is shown within a vessel 733.

[0113] As mentioned, in some examples the insulated conductors 704 may be coupled to the first and second conductors 710 and 711 through releasable/frangible connections 705. After pulsed electrical (e.g., nanosecond pulsed) treatment, the connections 705 may break as the balloon 702 and the insulated conductors 704 are withdrawn into the catheter 703. Thus, the connections 705 allow the stent 701 to remain in place after pulsed electrical treatment is delivered.

[0114] FIGS. 12A-12B illustrate another example of an applicator, similar to that shown in FIG. 6, in which the distal end of the applicator includes two expandable members (e.g., an expandable mesh or balloon region) that include electrodes 1201a, 1201b, which may be, e.g., circumferentially arranged around the expandable member (balloons 1205, 1206). In some examples electrodes may be placed over the expandable members. Alternatively or additionally, the electrodes may be integrated into the expandable members. For example, electrodes may be made from conductive wire that is braided into the expandable basket (shown in FIG. 12B). Electrodes do not have to be made from braided material and can have different forms including, but not limited to, conductive traces, struts/wires (placed longitudinally or radially), discrete electrodes, etc. The expandable members may expand electrodes, so they contact the targeted tissue.

[0115] In some examples the spacing distance 1212 between the two sets of electrodes may be adjustable. For example, the distal expandable member (shown in FIGS. 12B as an expandable mesh basket 1208 including the electrodes) may be coupled to a puller/pusher 1244, such as a hypotube, rod, wire, tendon, etc. that may be used to adjust the spacing 1212 between the distal expandable member and the proximal expandable member 1207. The spacing of the expandable members may be adjusted before deploying them (to expand). In some cases the expandable member includes a basket that is configured to expand or retract longitudinally so that the space between the electrodes is between 8 mm and 50 mm (e.g., between 10 mm and 40 mm, between 10 mm and 20 mm, etc.). This spacing may be sufficient so that the distance between the electrodes may encompass (but not contact) a stent that has been implanted. Any of these applicators may also include one or more inner member(s) 1245 (e.g., wire, rod, tendon, hypotube, etc. that is attached at a distal end of one or both expandable member(s) that may controllably allow expansion/retraction of the expandable member and therefore deployment/removal of the electrode(s). In some examples the region between the first and second expandable member may be connected by a telescoping member 1202 that may be controlled to increase or decrease the spacing distance between the electrodes (or sets of electrodes). In FIG. 12, the apparatus includes an atraumatic tip 1231. The distal balloon 1241 with the distal electrode 1208 may contact the luminal wall 1235; the proximal balloon 1243 with the proximal (e.g., second) electrode 1207 may also contact the luminal wall. Both balloons and electrode extend from the shaft 1247 of the applicator (e.g., catheter).

[0116] In general, the applicators described herein are not limited to those having a particular expandable member, e.g., balloons. In particular, applicators having adjustable longitudinal spacing distances between electrodes (or sets of electrodes) may be configured with other expandable members, such as coils, arms, baskets, etc. A proximal electrode or set of electrodes may be on a proximal one or more expandable member(s), and a distal electrode or set of electrodes may be on a distal one or more expandable member(s). In some examples, the proximal expandable member(s) may be a different type of expandable member than the distal expandable member(s).

[0117] The distance between the proximal electrode(s) and the distal electrode(s) may be adjusted, as described above, by coupling an inner member (e.g., pusher, hypotube, wire, tendon, etc.) coupled to the distal electrode(s). This inner member may be held within an outer member (e.g., catheter) that is coupled to the proximal electrode(s) and may slide proximally or distally relative to the outer catheter to adjust the distance. For example, a handle on the proximal end may adjust this spacing distance.

[0118] FIGS. 13A-13C illustrate examples of apparatuses described herein that may be used to prevent or reduce restenosis in combination with a stent. For example, in FIG. 13 A, which illustrates a variation in which the apparatus is configured to be positioned on either side (e.g., around) a stent 1349, an energy is applied to the tissue without contacting the stent. In this example, the apparatus includes a pair of expandable members (e.g., a proximal balloon 1207 and a distal balloon 1208) extending from an elongate member or shaft (catheter 1347). The expandable members (e.g., balloons) may expand outward with the electrodes formed thereon on either side of the stent, as shown. In FIG. 13B the apparatus contacts the stent 1349 at the proximal electrode region on the expandable member. Thus, the proximal electrode is in contact with the stent and the stent effectively, and electrically, becomes part of the proximal electrode. Similarly, FIG. 13C shows an example in which the stent is in contact with the distal electrode. The adjustable distance between the electrodes is shown as 1302 in FIGS. 13A-13C.

[0119] In any of these apparatuses, the spacer 1302 may be an adjustable spacer (adjustable spacing element) that may be configured to adjust to change the spacing between the first electrode 1207 and the second electrode 1208. For example, the adjustable spacer may include a telescoping structure that may expand or retract and/or be locked in position using a pusher and/or puller member extending through a lumen of the device (not visible in FIGS. 13A-13C). For example, a central shaft may be included that may be used to adjust the distance between the first expandable member and first electrode and the second expandable member and second electrode.

[0120] Although the apparatuses described herein, including those shown in FIGS. 13A-13C are primarily for use with sub-microsecond pulsing, in order to treat tissue while reducing or eliminating acute necrosis and/or causing regulated cell death as described herein, any of these apparatuses may also be used for treatment to induce acute necrosis (e.g., to induce IRE).

Methods to Treat or Prevent Restenosis

[0121] In general, the methods and apparatuses described herein may use pulsed electrical energy (e.g., sub-microsecond, nanosecond, etc., pulsed electrical energy) to treat restenosis within blood vessels, such as arterial pathways. As described above, treating may include preventing, reducing and/or at least partially eliminating restenosis.

[0122] For example, these methods and apparatuses may prevent in-stent restenosis, and/or may treat restenosis once it has occurred. These methods may apply to coronary arteries as well as peripheral arteries. In addition, these methods and apparatuses may be used in other areas of the body that would benefit from treating stenosis and/or restenosis, such as the bronchi, to ablate thickened mucosa and smooth muscle. Stents in the bile duct and ureter can also develop in-stent restenosis, and therefore could be additional places where this invention could be useful. [0123] For example, the methods and apparatuses described herein may be configured to treat arterial regions to prevent or reduce inflammation that may occur as the result of angioplasty or stent implantation. In some examples, arterial regions that have been identified for subsequent angioplasty or stent implantation may first be treated with pulsed electrical treatment (e.g., nanosecond pulsed electrical field) as described herein. In some examples, arterial regions that have previously been subjected to angioplasty or stent implantation may receive subsequent pulsed electrical treatment. In still other examples, these methods of applying pulsed electrical energy to treat restenosis may be applied as the stenosis is treated (e.g., by balloon angioplasty and/or stent). In one example a stent with integrated electrodes can be implanted with a catheter and pulsed electrical treatment may be provided through the embedded electrodes and the catheter removed.

[0124] Pulsed electrical (e.g., nanosecond pulsed) treatment may include a pulse profile having a rise and/or fall time for pulses that may be less than 20 ns, about 20 ns, about 25 ns, about 30 ns, about 40 ns, about 50 ns, about 60 ns, about 75 ns, or greater than 75 ns. In some examples, the pulse voltage may be less than lkV, less than 5 kV, about 5 kV, between about 5 kV and about 10 kV, about 15 kV, about 20 kV, about 25 kV, about 30 kV, greater than 5 kV, greater than 10 kV, greater than 15 kV, greater than 20 kV, greater than 30 kV, etc. In some examples, the current may be less than 10 A, about 10 A, about 25 A, about 40 A, about 50 A, about 60 A, about 75 A, about 100 A, about 125 A, about 150 A, about 175 A, about 200 A, or more than 200 A. In some examples, the pulse duration may be less than 10 ns, about 10 ns, about 15 ns or less, about 20 ns or less, about 25 ns or less, about 30 ns or less, about 40 ns or less, about 50 ns or less, about 60 ns or less, about 75 ns or less, about 100 ns or less, about 125 ns or less, about 150 ns or less, about 175 ns or less, about 200 ns or less, about 300 ns or less, about 400 ns or less, about 500 ns or less, about 750 ns or less, about 900 ns or less, etc. The apparatuses (e.g., systems) described herein may include, in addition to the instrument (e.g., the elongate applicator tool), a pulse generator such as the one shown schematically in FIG. 1, configured to emit pulses, e.g., in the sub-microsecond range.

[0125] In general, the systems of the present disclosure may comprise additional elements, such as power supplies, and/or a high voltage connector for safely connecting the elongate applicator tool device to a high voltage power source. As described above, these systems and devices are configured to apply high voltage, sub-microsecond pulsed electrical energy.

[0126] FIG. 8 is a flowchart depicting an example of one method 800 for applying pulsed electrical treatment to a patient prior to performing luminal treatment (e.g., expansion of a stenotic region of a vessel, for example by balloon angioplasty and/or stenting). Some examples may perform the operations described herein with additional operations, fewer operations, operations in a different order, operations in parallel, and some operations differently.

[0127] In FIG. 8, operation 800 may begin as a treatment area is identified in the optional block 802. For example, one or more diagnostic tests for a patient may identify a region of an artery suffering from stenosis. In other examples, the treatment area may be any technically feasible lumen. The diagnostic tests may include radiological, vascular, ultrasound, or any other feasible tests that enable the identification of a treatment area. In some examples the method may include identifying an implanted stent that is at risk for restenosis or has restenosed. For example, imaging may be used to identify the treatment area by identifying the location of a stent. The stent may have been implanted in a previous procedure (e.g., days, weeks, months or years before the current procedure). As mentioned, this step may be optional (as shown by dashed lines in FIGS. 8-10).

[0128] In block 804 an applicator is positioned within the identified treatment area. For example, the system 100 of FIG. 1 may be used to position an applicator (such as, but not limited to, any of the applicators of FIGS. 2-7 and 12A-12B) within the identified treatment area. In some examples, the applicators may extend and expand from a catheter used to position the applicator. Thus, the applicators may be made to contact and conform to the lumen. In some examples the user may adjust the spacing between the applicators to adjust the treatment region. [0129] When positioning the distal end region of the applicator within the identified treatment area, the spacing (e.g., longitudinal spacing) between the electrodes (e.g., sets of electrodes) on the applicator may be adjusted in some examples. For example, and especially in reference to the methods provided by example in FIGS. 9 and 10, the spacing between the electrode(s) on the applicator may be adjusted so that the stent is positioned on either side of first electrode (or first set of electrodes) and the second electrode (or second set of electrodes). The spacing may be adjusted so that the electrodes do not contact the stent. In some cases, such as where the stent includes an electrically conductive metal, contacting the electrically conductive stent with the electrodes may result in shorting.

[0130] Alternatively in some examples (including those of FIGS. 9 and 10) it may be desirable to contact an implanted electrically conductive stent with one of the electrodes (configured as an electrical contact) through which the pulsed treatment may be applied into the tissue. For example, positioning the distal end region of the applicator may include positioning one of the electrodes of the applicator on the electrically conductive stent. In some examples a second electrode or set of electrodes of the applicator may be positioned apart from the electrically conductive stent.

[0131] In block 806, pulsed electrical treatment is applied to the identified treatment area through the applicator. In some examples, the system 100 may deliver energy through applicators. In some examples the energy may be provided by a pulse generator configured to provide electrical pulses having an amplitude of greater than 0.1 kV and a duration of less than 1000 nanoseconds.

[0132] In block 808 subsequent treatment of stenosis/restenosis is provided in the identified treatment area. For example, the applicator may be removed from the patient and angioplasty and/or stenting may be performed in the identified treatment area, such as an affected artery. In another example, after the applicator is removed a stent may be implanted in the identified treatment area. In still other examples, any other feasible arterial or luminal treatment may be provided.

[0133] FIG. 9 is a flowchart depicting an example operation 900 for applying pulsed electrical treatment to a patient during or after luminal treatment in an identified treatment area. The operation 900 may optionally begin by identifying a treatment area 902. Block 902 may be another example of block 802 of FIG. 8. In FIG. 9, the treatment area may be identified by identifying a stenosed region or a region within a vessel that is at risk for stenosis.

[0134] The identified region of the vessel may then be treated to treat the stenosis, for example by angioplasty (e.g., balloon expansion and/or stenting) 904. This treatment (referred to herein as a luminal treatment) may be provided to the identified treatment area and may be part of the same procedure for treating restenosis as described herein or as part of a separate procedure. For example, angioplasty may be performed, or a stent may be implanted in the identified treatment area using the same applicator or a different applicator, and/or may be performed concurrently or separately (e.g., separated by minutes hours or days). In other examples, any other feasible arterial or luminal treatment may be provided.

[0135] In block 906, a distal end region of an applicator is positioned within the identified treatment area. For example, the system 100 of FIG. 1 may be used to position an applicator (such as, but not limited to, any of the applicators of FIGS. 2-7 and 12A-12B) within the identified treatment area. In some examples the spacing between the sets of electrodes may be adjusted as described above. In some examples, the applicators may extend and expand from a catheter used to position the applicator. Alternatively or additionally, the applicators may be expanded by applying pressure (e.g., fluid pressure) and/or a mechanical expanding member. Thus, the applicators may be made to contact and conform to the lumen so that the electrodes are in contact with the lumen wall. In still other examples, the applicator is positioned after other luminal devices are removed. For example, the applicator may be positioned within the identified treatment area after angioplasty or stent implantation equipment used to provide the luminal treatment of block 904 is removed from the lumen.

[0136] In block 908, pulsed electrical treatment is applied to the identified treatment area through the applicator. In some examples, the system 100 may deliver energy for the pulsed electrical treatment. The energy may be provided by a pulse generator configured to provide electrical pulses having an amplitude of greater than 0.1 kV and a duration, for example, of less than 1000 nanoseconds. After application of the pulsed electrical treatment, the applicator may be withdrawn from the patient.

[0137] FIG. 10 is a flowchart depicting an example operation 1000 applying pulsed electrical treatment with a stent that includes one or more embedded applicators. In some examples, operation 1000 may be performed with the applicator 700 of FIG. 7. In other examples, any feasible applicator may be used.

[0138] In some examples the method may optionally include identifying a treatment area, as described above. For example, as shown in FIG. 10, treatment may begin by identifying a treatment area 1002. Block 1002 may be another example of block 802 of FIG. 8 or block 902 of FIG. 9.

[0139] In block 1004 the stent with embedded applicators is positioned in the identified treatment area. For example, the system 100 of FIG. 1 may position the stent within the identified treatment area via the elongate applicator tool 102. In some examples, the stent may be coupled to the elongate applicator tool 102 via a catheter.

[0140] In block 1006, the stent including the embedded applicators is implanted. In some examples, a balloon may be inflated to implant the stent and cause the embedded applicators to contact the identified treatment area. [0141] In block 1008, pulsed electrical treatment is applied to the identified treatment area.

In some examples, the system 100 may deliver energy for the pulsed electrical treatment through the embedded electrodes. The energy may be provided by a pulse generator configured to provide electrical pulses having an amplitude of greater than 0.1 kV.

[0142] In block 1010, the stent is disconnected from the catheter and the catheter removed.

In some examples, a balloon may be deflated prior to catheter removal. In some other examples, frangible connections may be used to couple the embedded applicators to the catheter. These frangible connections may be broken as the catheter is removed.

[0143] FIG. 11 illustrates the effects of nanosecond pulse treatment with an applicator similar to the applicator of FIG. 6, demonstrated on a model of a lumen vessel. In particular, the applicator has been used to apply pulsed electrical treatment of test tissue model (e.g., a potato) submerged in saline. In this example, darker regions of the test tissue show penetration of the nanosecond pulse electric field.

[0144] As mentioned above, any of the apparatuses described herein may be implemented in robotic systems that may be used to position and/or control the electrodes during a treatment. For example, a robotic system may include a movable (robotic) arm to which elongate applicator tool is coupled. Various motors and other movement devices may be incorporated to enable fine movements of an operating tip of the elongate applicator tool in multiple directions. The robotic system and/or elongate applicator tool may further include at least one image acquisition device (and preferably two for stereo vision, or more) which may be mounted in a fixed position or coupled (directly or indirectly) to a robotic arm or other controllable motion device. In some examples, the image acquisition device(s) may be incorporated into the elongate applicator tool. [0145] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits described herein.

[0146] The process parameters and sequence of steps described and/or illustrated herein are given by way of example only and can be varied as desired. For example, while the steps illustrated and/or described herein may be shown or discussed in a particular order, these steps do not necessarily need to be performed in the order illustrated or discussed. The various example methods described and/or illustrated herein may also omit one or more of the steps described or illustrated herein or include additional steps in addition to those disclosed.

[0147] Any of the methods (including user interfaces) described herein may be implemented as software, hardware or firmware, or a combination thereof, and may be described as a non- transitory computer-readable storage medium storing a set of instructions capable of being executed by a processor (e.g., computer, tablet, smartphone, etc.), that when executed by the processor causes the processor to perform or control performing of any of the steps, including but not limited to: displaying, communicating with the user, analyzing, modifying parameters (including timing, frequency, intensity, etc.), determining, alerting, or the like. For example, any of the methods described herein may be performed, at least in part, by an apparatus including one or more processors having a memory storing a non-transitory computer-readable storage medium storing a set of instructions for the processes(s) of the method.

[0148] While various examples have been described and/or illustrated herein in the context of fully functional computing systems, one or more of these example embodiments may be distributed as a program product in a variety of forms, regardless of the particular type of computer-readable media used to actually carry out the distribution. The examples disclosed herein may also be implemented using software modules that perform certain tasks. These software modules may include script, batch, or other executable files that may be stored on a computer-readable storage medium or in a computing system. In some examples, these software modules may configure a computing system to perform one or more of the examples disclosed herein.

[0149] As described herein, the computing devices and systems described and/or illustrated herein broadly represent any type or form of computing device or system capable of executing computer-readable instructions, such as those contained within the modules described herein. In their most basic configuration, these computing device(s) may each comprise at least one memory device and at least one physical processor.

[0150] The term “memory” or “memory device,” as used herein, generally represents any type or form of volatile or non-volatile storage device or medium capable of storing data and/or computer-readable instructions. In one example, a memory device may store, load, and/or maintain one or more of the modules described herein. Examples of memory devices comprise, without limitation, Random Access Memory (RAM), Read Only Memory (ROM), flash memory, Hard Disk Drives (HDDs), Solid-State Drives (SSDs), optical disk drives, caches, variations or combinations of one or more of the same, or any other suitable storage memory. [0151] In addition, the term “processor” as used herein, generally refers to any type or form of hardware-implemented processing unit capable of interpreting and/or executing computer- readable instructions. In one example, a processor may access and/or modify one or more modules stored in the above-described memory device. Examples of physical processors comprise, without limitation, microprocessors, Central Processing Units (CPUs), Field- Programmable Gate Arrays (FPGAs) that implement softcore processors, Application-Specific Integrated Circuits (ASICs), portions of one or more of the same, variations or combinations of one or more of the same, or any other suitable physical processor.

[0152] Although illustrated as separate elements, the method steps described and/or illustrated herein may represent portions of a single application. In addition, in some examples one or more of these steps may represent or correspond to one or more software applications or programs that, when executed by a computing device, may cause the computing device to perform one or more tasks, such as the method step.

[0153] In addition, one or more of the devices described herein may transform data, physical devices, and/or representations of physical devices from one form to another. Additionally or alternatively, one or more of the modules recited herein may transform a processor, volatile memory, non-volatile memory, and/or any other portion of a physical computing device from one form of computing device to another form of computing device by executing on the computing device, storing data on the computing device, and/or otherwise interacting with the computing device.

[0154] The term “computer-readable medium,” as used herein, generally refers to any form of device, carrier, or medium capable of storing or carrying computer-readable instructions. Examples of computer-readable media comprise, without limitation, transmission-type media, such as carrier waves, and non-transitory-type media, such as magnetic-storage media (e.g., hard disk drives, tape drives, and floppy disks), optical- storage media (e.g., Compact Disks (CDs), Digital Video Disks (DVDs), and BLU-RAY disks), electronic- storage media (e.g., solid-state drives and flash media), and other distribution systems.

[0155] A person of ordinary skill in the art will recognize that any process or method disclosed herein can be modified in many ways. The process parameters and sequence of the steps described and/or illustrated herein are given by way of example only and can be varied as desired. For example, while the steps illustrated and/or described herein may be shown or discussed in a particular order, these steps do not necessarily need to be performed in the order illustrated or discussed.

[0156] The various exemplary methods described and/or illustrated herein may also omit one or more of the steps described or illustrated herein or comprise additional steps in addition to those disclosed. Further, a step of any method as disclosed herein can be combined with any one or more steps of any other method as disclosed herein.

[0157] The processor as described herein can be configured to perform one or more steps of any method disclosed herein. Alternatively or in combination, the processor can be configured to combine one or more steps of one or more methods as disclosed herein. [0158] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one example, the features and elements so described or shown can apply to other examples. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0159] Terminology used herein is for the purpose of describing particular example only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0160] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0161] Although the terms “first” and “second” may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention. [0162] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[0163] Any of the apparatuses and methods described herein may include all or a sub-set of the components and/or steps, and these components or steps may be either non-exclusive (e.g., may include additional components and/or steps) or in some variations may be exclusive, and therefore may be expressed as “consisting of’ or alternatively “consisting essentially of’ the various components, steps, sub-components, or sub-steps.

[0164] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/- 0.1% of the stated value (or range of values), +/- 1% of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. [0165] Although various illustrative examples are described above, any of a number of changes may be made to various examples without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative examples, and in other alternative examples one or more method steps may be skipped altogether. Optional features of various device and system examples may be included in some examples and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0166] The examples and illustrations included herein show, by way of illustration and not of limitation, specific examples in which the subject matter may be practiced. As mentioned, other examples may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such examples of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific examples have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific examples shown. This disclosure is intended to cover any and all adaptations or variations of various examples. Combinations of the above examples or some features of the described examples, and other examples not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

Claims

CLAIMS What is claimed is:

1. An apparatus for treating or inhibiting restenosis while minimizing inflammation and/or fibrosis, the apparatus comprising: a pulse generator configured to generate a plurality of electrical pulses having amplitude of at least 0.1 kV; a controller configured to trigger regulated cell death by causing the pulse generator to limit a pulse width of the plurality of electrical pulses to less than 1000 nanoseconds; an applicator comprising a first electrical conductor, wherein the applicator is coupled to the pulse generator and configured to deliver the plurality of electrical pulses to a lumen; and a catheter configured to guide and position the first electrical conductor to a treatment area.

2. The apparatus of claim 1, wherein the apparatus is configured to determine if the first electrical conductor is in contact with a stent within the lumen.

3. The apparatus of claims 1 or 2, wherein the first electrical conductor is configured for monopolar application of the plurality of electrical pulses to the lumen.

4. The apparatus of claims 1 or 2, further comprising a second electrical conductor coupled to the pulse generator and configured to deliver the plurality of electrical pulses to the lumen between the first and second electrical conductors.

5. The apparatus of claim 4, further comprising an expandable member configured to position the first electrical conductor or the first and second electrical conductor against a luminal wall.

6. The apparatus of claim 5, wherein the expandable member comprises a balloon.

7. The apparatus of claim 6, wherein the balloon comprises grooves configured to allow fluid flow past the balloon and ridges configured to support the first and second electrical conductors.

8. The apparatus of claim 5, wherein the first or the first and second electrical conductors are disposed radially or axially with respect to the expandable member.

9. The apparatus of claim 4, further comprising an adjustable spacer between the first electrode and the second electrode configured to adjust the separation between the first electrode and the second electrode.

10. The apparatus of any one of claims 1-9, wherein the first electrical conductor is further configured to withdraw within the catheter.

11. The apparatus of any one of claims 1-10, wherein the first electrical conductor is further configured to extend out of the catheter and expand to contact a wall of the lumen.

12. The apparatus of any one of claims 1-11, wherein the first electrical conductor is disposed around a pigtail configured to extend beyond the catheter.

13. The apparatus of any one of claims 1-5 wherein the first electrical conductor is part of an expandable wire mesh.

14. The apparatus of any one of claims 1-13, wherein the first electrical conductor is disposed on a stent that is releasably connected to the applicator.

15. The apparatus of any of claims 1-14, wherein the controller is configured to minimize necrosis by limiting the pulse width of the plurality of electrical pulses to less than 900 nanoseconds.

16. A method for treating or inhibiting restenosis by applying electrical energy while minimizing inflammation and/or fibrosis, the method comprising: positioning an applicator within a treatment area; applying a plurality of sub-microsecond electrical pulses from the applicator to the treatment area and limiting a pulse length of the applied sub-microsecond electrical pulses to less than 900 ns to trigger regulated cell death; and concurrently, immediately prior to, or subsequently performing angioplasty and/or stenting to the treatment area.

17. A method for treating or preventing restenosis by applying electrical energy while minimizing inflammation and/or fibrosis, the method comprising: positioning an applicator within a treatment area of a lumen; applying a plurality of sub-microsecond electrical pulses having amplitude of at least 0.1 kV from the applicator to the treatment area and limiting a pulse length of the applied sub-microsecond electrical pulses to less than 900 ns to trigger regulated cell death; and concurrently, immediately prior to, or subsequently performing angioplasty and/or stenting to the treatment area.

18. The method of claims 16 or 17, wherein the applicator includes a first conductor configured to contact the treatment area.

19. The method of claims 16 or 17, wherein applying the plurality of sub-microsecond electrical pulses comprises applying monopolar electrical pulses from the applicator.

20. The method of any one of claims 16-19, wherein the applicator includes a second conductor distinct from the first electrical conductor.

21. The method of claim 20, wherein applying the plurality electrical pulses comprises applying bipolar electrical pulses from the first conductor and the second conductor.

22. The method of any one of claims 16-21, wherein the applicator is removed from the treatment area prior to performing angioplasty and/or stenting.

23. The method of any one of claims 16-22, wherein the pulse length of the applied sub microsecond electrical pulses is limited to less than 700 nanoseconds to trigger regulated cell death and minimize necrosis.

24. The method of any one of claims 16-23, wherein applying the plurality electrical pulses from the applicator comprises applying pulsed electrical treatment using an implanted stent as an electrode.

25. A method for treating or preventing restenosis by applying electrical energy while minimizing inflammation and/or fibrosis, the method comprising: positioning a stent with embedded applicators within a treatment area of a lumen; and applying a plurality of sub-microsecond electrical pulses from the stent; and triggering regulated cell death and minimizing necrosis by limiting a pulse length of the sub-microsecond electrical pulses to less than 900 ns.

26. A method for treating or preventing restenosis by applying electrical energy while minimizing inflammation and/or fibrosis, the method comprising: positioning an applicator within a blood vessel and in electrical contact with a stent within the blood vessel; and applying a plurality of sub-microsecond electrical pulses from the applicator to the stent; and triggering regulated cell death and minimizing necrosis by limiting a pulse length of the sub-microsecond electrical pulses to less than 900 ns.

27. The method of claim 25, wherein positioning the stent further comprises expanding the stent to cause the embedded applicators to contact the lumen.

28. The method of claims 25 or 27, wherein positioning the stent further comprises positioning the stent via a catheter coupled thereto.

29. The method of claim 28, further comprising removing the catheter and leaving the stent with the embedded applicators in the lumen after applying the plurality of sub microsecond electrical pulses.

30. The method of any one of claims 25-29, comprising positioning electrodes of the applicator on either side of the stent within the treatment area so that the electrodes do not contact the stent.

31. The method of any one of claims 25-30, wherein applying the plurality of sub microsecond electrical pulses comprises applying bipolar electrical pulses from the applicator.

32. The method of claim 26, wherein positioning the applicator within the blood vessel and in electrical contact with the stent comprises contacting a first electrode of the applicator to the stent and contacting a wall of the blood vessel with a second electrode of the applicator, and applying the plurality of sub-microsecond electrical pulses between the first electrode and the second electrode of the applicator.

33. The method of claim 32, wherein the stent is at least partially positioned between the first electrode and the second electrode when the first electrode is in electrical contact with the stent.

34. The method of claim 26, wherein positioning the applicator within the blood vessel and in electrical contact with the stent comprises contacting a first electrode of the applicator to a first region of the stent and contacting a second electrode of the applicator to a second region of the stent, and applying the plurality of sub-microsecond electrical pulses between the first electrode and the second electrode of the applicator.

5. The method of claim 26, wherein positioning the applicator within a blood vessel and in electrical contact with a stent within the blood vessel comprises placing the stent between a first electrode of the applicator and a second electrode of the applicator.