Application of pulsed electric fields in vascular therapy.

Abstract

Devices, systems, and methods are provided for treating damaged, diseased, abnormal, obstructive, unwanted, or potentially unwanted tissue by delivering specialized pulsed electric field (PEF) energy, and optionally a therapeutic agent, to a target tissue area, particularly within a vessel. The therapy can be used to treat a variety of conditions, particularly vascular conditions such as atherosclerosis and angina. Once a target tissue area is identified as being associated with vasospasm, the target tissue area is treated with PEF energy. Optionally, one or more agents can be delivered in conjunction with the therapy as well. Although the primary focus is to treat coronary arteries, such therapy may be applicable to other portions of the vessel, including peripheral vessels. Similarly, such therapy may be applicable to other body lumens.

Description

[Background technology]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 209,319, filed June 10, 2021, and entitled “APPLYING PULSED ELECTRIC FIELDS IN THE TREATMENT OF THE VASCULATURE,” the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] Angina is a type of chest pain characterized by discomfort, pressure, tightness, burning, or fullness. In addition, the pain may extend to the arms, neck, jaw, shoulders, or back. Other symptoms such as dizziness, fatigue, nausea, shortness of breath, and sweating may also be present. Angina is not a disease, but is a sign of an underlying heart problem.

[0003] There are several types of angina, including stable angina (thoracic angina), unstable angina, variant angina, and microvascular angina. Stable angina is the most common form of angina and is caused by coronary artery disease. Coronary artery disease develops when the major blood vessels that supply the heart become damaged or diseased. This is typically caused by cholesterol-containing deposits known as plaque, which build up over time and narrow the arteries. This reduces blood flow, and ultimately, the reduced blood flow causes angina and other symptoms. A complete blockage can cause a heart attack.

[0004] Unstable angina is caused by a blood clot that partially or completely blocks an artery. A blood clot may form, partially dissolve, and later form again, and angina may occur each time a blood clot blocks blood flow in an artery. Thus, unstable angina typically causes unexpected chest pain. A blood clot is typically caused by the rupture of a narrowed coronary artery, which causes injury to the coronary blood vessels and leads to a blood clot.

[0005] Variant angina is also known as Prinzmetal angina, variant Prinzmetal angina, and vasospastic angina. The pain from variant angina is caused by spasms in the coronary arteries that supply blood to the heart muscle. The coronary arteries may spasm as a result of exposure to cold weather, stress, drugs that constrict or narrow the blood vessels, smoking, and cocaine use.

[0006] Microvascular angina is typically a symptom of coronary microvascular disease (MVD). Coronary MVD (sometimes called small artery disease or small vessel disease) is a heart disease that affects the walls and medial lining of small coronary vessels that branch off from larger coronary arteries. In coronary MVD, the coronary vessels do not have plaque, but the inner wall of the vessel is damaged, which can lead to spasm and reduced blood flow to the heart muscle. In addition, abnormalities in the smaller arteries that branch off from the main coronary arteries can also contribute to coronary MVD.

[0007] There are various conventional treatment options for angina. In stable angina, the uncomfortable symptoms are usually predictable and manageable. Usually, this type of chest discomfort is relieved with rest, nitroglycerin, or both. Nitroglycerin relaxes the coronary arteries and other blood vessels, reducing the amount of blood returning to the heart and reducing the heart's workload. By relaxing the coronary arteries, this increases the blood supply to the heart.

[0008] Stable angina can develop into unstable angina, which is typically recognized as chest pain felt easier and more frequently. Treatment for unstable angina is an emergency and involves locating the clot or blocked artery and re-establishing blood flow through it. In some cases, percutaneous coronary intervention (PCI) may be required to open the blocked coronary artery. Briefly, the procedure involves undergoing cardiac catheterization for balloon angioplasty. Using a catheter with a small inflatable balloon at its tip, the balloon is inflated to compress fatty plaque deposits located on the medial lining of the coronary artery. The procedure is often followed by the insertion of a stent, which then holds the coronary vessel propped open, allowing improved blood flow to the myocardium. However, the increase in diameter can result in endothelial denudation, disruption of the internal elastic membrane and tunica media, and damage to approximately 20% of the smooth muscle cells (SMCs) within the tunica media. The stent is designed to be expanded within the stenotic area to hold it open. However, stents also lead to disruption of normal vasculature. The use of angioplasty to expand vascular walls with stents has a similar effect to that described above, and self-expanding stents continue to expand due to radial forces, which may prolong the disturbance to endothelial function. In addition, stents may disturb electrostatic equilibrium and prevent vasospasm and elastic recoil, two important mechanical properties of arteries.

[0009] The changes in vascular architecture and cells from angioplasty and stenting can lead to the development of restenosis, which is the re-narrowing of blood vessels at the site of intervention due to the iatrogenic injury response of the blood vessels. This problem also exists in peripheral vasculature. Restenosis involves two major processes: arterial remodeling and neointimal hyperplasia. Arterial remodeling is a natural compensatory response in which the artery widens in response to plaque formation, reducing vascular narrowing. However, in response to angioplasty, negative remodeling can lead to vasoconstriction, reducing the overall vessel lumen. This is believed to be the primary mechanism for angioplasty restenosis, while in-stent restenosis appears to result primarily from neointimal hyperplasia. Damaged endothelial cells from angioplasty and stenting may further contribute to smooth muscle cell proliferation and migration by decreasing their nitric oxide production, a chemical known to inhibit smooth muscle cell growth.

[0010] In other cases, coronary artery bypass graft surgery may be utilized depending on the extent of the coronary artery blockage and medical history. In this procedure, blood vessels are used to route blood around the blocked portion of the artery using a graft in an open chest surgical technique. Unfortunately, the graft source may have an improper vascular architecture for transplantation, causing donor site morbidity, or may be insufficient for multiple revascularization procedures. An additional open chest surgical technique is endarterectomy, where the diseased vascular area is exposed and the plaque is physically removed. However, this technique is also highly invasive and carries the risk of stroke, heavy bleeding, and damage to the cranial nerves.

[0011] Because variant angina and microvascular angina are caused by spasm, these conditions are typically treated with drugs to control spasm. Drugs such as calcium antagonists and nitrates are the mainstay of treatment.

[0012] Typical antianginal drug therapies include beta-adrenergic receptor blockers (beta-blockers), calcium channel blockers, and short-acting nitroglycerin. Beta-blockers can reduce the occurrence of anginal episodes, improve ischemic thresholds, and even improve endothelial function in some patients, possibly through antioxidant effects, although this remains widely unproven in clinical settings. The choice of drug class depends on the patient's tolerance and preference, contraindications, and the presence of comorbidities, and is not recommended for patients with vasospastic angina. Also, abrupt discontinuation may result in rebound myocardial ischemia.

[0013] Calcium channel blockers reduce afterload and increase myocardial blood flow while reducing heart rate and contractility. Systemic and coronary vasodilation is achieved through interaction with L-type Ca2+ receptors. It is preferred to use long-acting pharmaceuticals, and contraindications for non-dihydropyridine calcium channel blockers are similar to those for beta-blockers.

[0014] Organic nitrates can reduce myocardial oxygen demand while maintaining or increasing coronary flow and are a long-standing treatment for thoracic angina. Their safety profile allows them to be combined with both beta-adrenergic or calcium channel blockers, but some studies have reported no benefit in patients suffering from chest pain and without obstructive coronary artery disease. Treatment with oral nitrates requires an individualized approach. Usually, angina symptoms will improve with oral nitrate therapy, especially in patients who benefit from sublingual nitrates. In some patients, angina may worsen, possibly due to the steal phenomenon due to vasodilation of collateral vessels. Some patients may not tolerate statins due to side effects. Statins, angiotensin-converting enzyme inhibitors (ACE-I), and low-dose aspirin are also current pharmacologies for coronary microvascular dysfunction, with the goal of treating microvascular endothelial dysfunction. Patients with exercise-induced ischemia and flow-dependent vasodilation respond to statin therapy, and the observed beneficial effects are considered to be due to improved endothelial function. ACE-I medication is effective in patients with MVA, with improvement in coronary flow reserve in this patient population. If a patient cannot tolerate ACE-I, angiotensin receptor blockers are an alternative, but there is no data on the extent to which this therapy may be effective for the subgroup of patients with coronary microvascular dysfunction. In addition, for patients with insulin resistance, metformin administration is effective in increasing microvascular function. Imipramine, a tricyclic drug, also improved symptoms in patients with chest pain and no obstructive coronary artery disease, which was attributed to a visceral analgesic effect. Aspirin may be beneficial in patients with coronary artery disease, but once coronary artery disease is excluded, there is no evidence to support treatment with aspirin. In this case, the risk of bleeding events outweighs any theoretical benefits. For individuals with MVA, no definitive evidence exists supporting specific classes of drugs or combination therapies, or modalities and techniques, likely due to gaps in knowledge about the causes of MVA and inconsistencies in patient response to available drug treatments.

[0015] Most types of angina are chronic conditions, either by themselves or based on an underlying chronic disease. Similarly, atherosclerosis is typically chronic and progressive. Although various treatments are available for each of these conditions, either separately or in combination, such treatments involve risks, adverse effects, and are typically not curative and involve ongoing treatment. Thus, improvements in the treatment of these and vascular conditions are desirable. Such treatments should be safe, effective, and lead to reduced complications. At least some of these objectives will be met by the systems, devices, and methods described herein. Summary of the Invention [Means for solving the problem]

[0016] Described herein are embodiments of devices, systems, and methods for treating a target tissue. The present invention also relates to the following numbered clauses:

[0017] In a first aspect, a system for treating a blood vessel is provided, comprising an energy delivery catheter comprising an energy delivery body positionable within or near the blood vessel, and a generator in electrical communication with the energy delivery body, the generator including at least one energy delivery algorithm that provides pulsed electric field energy to the energy delivery body such that the energy treats cells of the blood vessel in a manner that reduces or eliminates the blood vessel's ability to vasoconstrict while preserving the blood vessel's extracellular matrix. It is understood that near is considered to be at a distance where a target tissue, such as a blood vessel or a targeted portion of a blood vessel, is capable of receiving energy delivered from the energy delivery body in such a manner as to achieve a desired outcome.

[0018] In some embodiments, treating comprises removing, destroying, or killing the cells. In some embodiments, the cells comprise vascular smooth muscle cells involved in vasoconstriction of blood vessels. In some embodiments, treating comprises disrupting local innervation to vascular smooth muscle cells. Optionally, disrupting local innervation comprises disrupting a neural pathway from the local area of ​​spasm through at least one vagus afferent fiber that contributes to angina pain symptoms. In other embodiments, the cells comprise endothelial cells, and maintaining the cellular outer layer leads to regeneration of the endothelial layer of the blood vessel.

[0019] In some embodiments, the energy delivery catheter is configured to deliver a fluid. Optionally, the fluid comprises a conductive solution. In some cases, the energy delivery catheter is configured to deliver the energy and the fluid in a manner such that the fluid acts as a virtual electrode. In some cases, an algorithm is configured to trigger the delivery of the energy and the fluid in a timing sequence such that the fluid acts as a virtual electrode.

[0020] In some embodiments, the fluid comprises an agent. In some embodiments, the agent comprises a chemical, a drug, a pharmaceutical, a chemotherapeutic agent, an immunotherapeutic agent, a micelle, a liposome, an embolic agent, a nanoparticle, a drug eluting particle, a gene, a plasmid, a protein, or a combination thereof. In some embodiments, treating comprises uptake of the agent by the cells. In some embodiments, uptake of the agent inhibits hyperplasia regrowth of the cells.

[0021] In some embodiments, the energy delivery body comprises an expandable member surrounding the at least one electrode, hi some embodiments, the energy delivery body comprises a shaft, the at least one electrode comprises a plurality of electrodes disposed along the shaft, and the expandable member comprises an elongated expandable member surrounding the plurality of electrodes.

[0022] In some embodiments, the expandable member is configured to exude a fluid. In some embodiments, the energy delivery body includes at least one port in the expandable member through which fluid is deliverable to exude from the expandable member. In some embodiments, the energy delivery body includes an electrode formed by a plurality of ribbons or wires. In some embodiments, the energy delivery body includes one or more protrusions, each protrusion bending radially outward from the longitudinal axis of the energy delivery catheter. In some embodiments, the one or more protrusions include one or more projections.

[0023] In some embodiments, the pulsed electric field energy is generated from a waveform comprising one or more of the following parameters: a) voltage in the range of 500-3,000 V; b) frequency in the range of 100-800 kHz; c) total on-time in the range of 25-250 μsec; and d) packets per electrode activation in the range of 1-30 packets.

[0024] In some embodiments, the voltage is in the range of 2,000-2,500V. In some embodiments, the frequency is in the range of 400-600kHz. In some embodiments, the total on-time is in the range of 50-150μsec. In some embodiments, the packets per electrode activation is in the range of 1-10 packets. In some embodiments, the pulsed electric field energy is generated from a waveform that includes one or more of the following parameters: a) a voltage in the range of 1,000-6,000V, b) a frequency in the range of 10-500kHz, c) a total on-time in the range of 50-500μsec, and d) a packet per electrode activation in the range of 1-30 packets. In some embodiments, the pulsed electric field energy causes disruption of calcification. In some embodiments, the voltage is in the range of 2,000-4,000V. In some embodiments, the frequency is in the range of 50-250kHz. In some embodiments, the total on-time is in the range of 75-150μsec.

[0025] In a second aspect, a system for treating vasospasm is provided comprising an energy delivery catheter comprising an energy delivery body positionable on or near muscle tissue, such as the cardiac myocardium, and a generator in electrical communication with the energy delivery body, the generator including at least one energy delivery algorithm that provides pulsed electric field energy to the energy delivery body such that the energy modifies the muscle tissue such that it replaces or eliminates the localized mechanical forces that cause the vasospasm. Again, it should be understood that near is considered to be at a distance where the target tissue, such as the cardiac myocardium or a targeted portion of the cardiac myocardium, is capable of receiving the energy delivered from the energy delivery body in such a manner as to achieve a desired outcome.

[0026] In some embodiments, the energy delivery catheter is configured to deliver a fluid. In some embodiments, the fluid comprises a conductive solution. In some embodiments, the energy delivery catheter is configured to deliver the energy and the fluid in a manner such that the fluid acts as a virtual electrode. In some embodiments, an algorithm is configured to trigger the delivery of the energy and the fluid in a timing sequence such that the fluid acts as a virtual electrode.

[0027] In some embodiments, the fluid comprises an agent. In some embodiments, the agent comprises a chemical, a drug, a pharmaceutical, a chemotherapeutic agent, an immunotherapeutic agent, a micelle, a liposome, an embolic agent, a nanoparticle, a drug eluting particle, a gene, a plasmid, a protein, or a combination thereof. In some embodiments, treating comprises uptake of the agent by the cells. In some embodiments, the pulsed electric field energy is generated from a waveform comprising one or more of the following parameters: a) a voltage in the range of 500-3,000 V, b) a frequency in the range of 100-800 kHz, c) a total on-time in the range of 25-250 μsec, and d) packets per electrode activation in the range of 1-30 packets.

[0028] In some embodiments, the voltage is in the range of 2,000-2,500 V. In some embodiments, the frequency is in the range of 400-600 kHz. In some embodiments, the total on-time is in the range of 50-150 μsec. In some embodiments, the packets per electrode activation is in the range of 1-10 packets.

[0029] In a third aspect of the present invention, a system for treating angina pain symptoms is provided comprising an energy delivery catheter comprising an energy delivery body positionable in or near a blood vessel, and a generator in electrical communication with the energy delivery body, the generator including at least one energy delivery algorithm that provides pulsed electric field energy to the energy delivery body such that the pulsed electric field energy disrupts a neural pathway through at least one vagus nerve afferent fiber that contributes to the angina pain symptoms. In some embodiments, the neural pathway innervates vascular smooth muscle cells of a blood vessel associated with the angina pain symptoms.

[0030] In a fourth aspect of the invention, a system is provided for treating a portion of a blood vessel comprising an electrode positionable proximate the portion of a blood vessel and a generator in electrical communication with the electrode, the generator including at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy treats the portion of the blood vessel. In some embodiments, the pulsed electric field energy is generated from a waveform that includes one or more of the following parameters: a) a voltage in the range of 500-3,000 V, b) a frequency in the range of 100-800 kHz, c) a total on-time in the range of 25-250 μsec, and d) packets per electrode activation in the range of 1-30 packets.

[0031] In some embodiments, the pulsed electric field energy is generated from a waveform comprising one or more of the following parameters: a) voltage in the range of 1,000-6,000 V, b) frequency in the range of 10-500 kHz, c) total on-time in the range of 50-500 μsec, and d) packets per electrode activation in the range of 1-30 packets. In some embodiments, the energy delivery body comprises an expandable member surrounding at least one electrode. In some embodiments, the energy delivery body comprises a shaft, the at least one electrode comprises a plurality of electrodes disposed along the shaft, and the expandable member comprises an elongated expandable member surrounding the plurality of electrodes.

[0032] In a sixth aspect of the invention, a method is provided for treating a blood vessel comprising positioning an energy delivery body of an energy delivery catheter within or near the blood vessel and delivering pulsed electric field energy to the energy delivery body such that the energy treats cells of the blood vessel in a manner that reduces or eliminates the ability of the blood vessel to vasoconstrict while preserving the extracellular matrix of the blood vessel.

[0033] In a seventh aspect of the invention, a method is provided for treating vasospasm comprising positioning an energy delivery body of an energy delivery catheter on or near the cardiac myocardium and delivering pulsed electric field energy to the energy delivery body such that the energy modifies the cardiac myocardium such that it replaces or eliminates localized mechanical forces causing vasospasm.

[0034] These and other embodiments are described in further detail in the following description taken in conjunction with the accompanying drawing figures.

[0035] (Incorporated by reference) All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0036] In the drawings, which are not necessarily drawn to scale, like numbers may describe similar components in different figures. Like numbers with different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

[0037] [Figure 1] FIG. 1 provides an overview illustration of an exemplary therapeutic system for use in delivering specialized PEF energy to a vessel.

[0038] [Diagram 2] FIG. 2 illustrates an embodiment of an energy delivery catheter having an energy delivery body comprised of an elongated expandable member that surrounds multiple electrodes.

[0039] [Diagram 3]FIG. 3 illustrates an embodiment of an energy delivery catheter having an energy delivery body with electrodes formed by multiple ribbons or wires.

[0040] [Figure 4] 4-5 illustrate embodiments of energy delivery bodies that include one or more protrusions, each protrusion bending radially outward from the longitudinal axis or shaft of the catheter. [Diagram 5] 4-5 illustrate embodiments of energy delivery bodies that include one or more protrusions, each protrusion bending radially outward from the longitudinal axis or shaft of the catheter.

[0041] [Figure 6A] 6A-6B illustrate embodiments of energy delivery bodies that include one or more protrusions that act as projections. [Figure 6B] 6A-6B illustrate embodiments of energy delivery bodies that include one or more protrusions that act as projections.

[0042] [Figure 7] FIG. 7 illustrates another embodiment of a catheter that includes an energy delivery body having a shape configured for intravascular treatment.

[0043] [Figure 8] 8-12 illustrate exemplary embodiments of catheters that deliver an agent through or near an energy delivery body. [Figure 9] 8-12 illustrate exemplary embodiments of catheters that deliver an agent through or near an energy delivery body. [Figure 10] 8-12 illustrate exemplary embodiments of catheters that deliver an agent through or near an energy delivery body. [Figure 11]8-12 illustrate exemplary embodiments of catheters that deliver an agent through or near an energy delivery body. [Figure 12] 8-12 illustrate exemplary embodiments of catheters that deliver an agent through or near an energy delivery body.

[0044] [Figure 13] FIG. 13 includes a schematic illustration of an embodiment of a coronary artery wall and an energy delivery body positioned adjacent to the wall.

[0045] [Figure 14] FIG. 14 illustrates an embodiment of a signal waveform prescribed by the energy delivery algorithm.

[0046] [Figure 15] FIG. 15 illustrates various examples of biphasic pulses (with a positive peak and a negative peak) with a switching time between them. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] Detailed Description Devices, systems, and methods are provided for treating damaged, diseased, abnormal, obstructed, unwanted, or potentially unwanted tissue by delivering specialized pulsed electric field (PEF) energy, and optionally a therapeutic agent, specifically to a target tissue area within a vessel. Although such devices, systems, and methods will be primarily focused on treating coronary arteries, such treatments may be applicable to other portions of the vessel, including peripheral vessels. Similarly, such treatments may be applicable to other body lumens.

[0048] PEF energy is delivered to the target tissue area in a manner that results in non-thermal treatment (i.e., the energy is below the threshold for causing thermal ablation or below the threshold for causing extracellular protein denaturation that is involved in the clinical morbidity of thermal therapy outcomes). As a result, when extracellular matrix is ​​present, it is preserved and the targeted tissue maintains its structural architecture. Thus, a portion of the vessel wall can be preserved, which is important for maintaining tissue integrity and functionality. This provides several benefits. First, it allows for the treatment of tissues that are often deemed untreatable by conventional methods. Target tissues that are in the vicinity of sensitive structures are typically deemed untreatable due to the proximity to the sensitive structures. Similarly, many conventional therapies are contraindicated due to the potential for damage to the sensitive structures by the therapy or because the therapy is deemed ineffective due to the proximity of the sensitive structures. Once the tissue is treated, the persistence of the structural architecture also allows for the natural influx of biological elements such as components of the immune system or the introduction of various agents to advance the therapeutic treatment. This provides several therapeutic benefits, which will be explained in more detail in a later section.

[0049] Therapeutic Systems and Devices FIG. 1 provides an overview illustration of an exemplary therapy system 100 for use in delivering specialized PEF energy to a vessel. In this embodiment, the system 100 includes an energy delivery catheter 102 comprising a shaft 106 having a distal end 103 and a proximal end 107. The catheter 102 includes an energy delivery body 108, generally illustrated as a dashed circle near the distal end 103 of the shaft 106. It should be understood that the energy delivery body 108 may take a variety of forms, with structural differences that prevent a single representational drawing, however, individual exemplary embodiments will be described and illustrated herein. The energy delivery body 108 may be mounted on or integral with the exterior of the shaft 106 so as to be visible from the outside. Alternatively, the energy delivery body 108 may be stored internally within the shaft 106 and exposed by advancing it out of the shaft 106 or retracting the shaft 106 itself. Similarly, there may be more than one energy delivery body 108, which may be external, internal, or both. In some embodiments, the shaft 106 is made of a polymer, such as an extruded polymer. It should be understood that in some embodiments, the shaft 106 is made of multiple layers of material with different durometer hardness to control flexibility and / or stiffness. In some embodiments, the shaft 106 is reinforced with various elements, such as individual wires or wire braids. In either case, such wires may be flat or round wires. The wire braids have a braid pattern, and in some embodiments, the braid pattern is tailored for the desired flexibility and / or stiffness. In other embodiments, the wire braids reinforcing the shaft 106 may be advantageously combined with multiple layers of material with different durometer hardness to provide additional control of flexibility and / or stiffness along the length of the shaft.

[0050] In some embodiments, the catheter 102 is delivered through a delivery device during a suitable access procedure. When accessing the coronary arteries, the heart is typically accessed via the femoral or radial artery by an access procedure such as the Seldinger technique. A sheath is inserted into the artery, acting as a conduit through which various catheters and / or tools may be advanced, including the treatment catheter 102 and, optionally, a device for delivering an agent. It should be understood that in some embodiments, the treatment catheter 102 and agent delivery are combined into a single device. Typically, the coronary vasculature is approached by the use of x-ray imaging. Once the desired treatment location is identified, the treatment catheter 102 is utilized to deliver the treatment energy.

[0051] Each energy delivery body 108 includes at least one electrode for delivery of PEF energy. Typically, the energy delivery body 108 includes a single delivery electrode and operates in a monopolar arrangement, which is achieved by supplying energy between the energy delivery body 108, disposed near the distal end 103 of the catheter 102, and a return electrode 140, positioned on the patient's skin. In some embodiments, the energy delivery body 108 includes a 32 mm diameter ... 21. It should be understood, however, that bipolar energy delivery and other arrangements may alternatively be used. When using bipolar energy delivery, the catheter 102 may include multiple energy delivery bodies 108 configured to function in a bipolar fashion, or may include a single energy delivery body 108 having multiple electrodes configured to function in a bipolar fashion. Similarly, multiple energy delivery bodies 108 may be on separate instruments. The catheter 102 typically includes a handle 110 disposed near the proximal end 107. The handle 110 is used to steer the catheter 102 and may include an actuator 132 for manipulating the energy delivery bodies 108. In some embodiments, the energy delivery body 108 transitions from a closed or retracted position (during access) to an open or exposed position (for energy delivery), which is controlled by the actuator 132. Thus, the actuator 132 typically has the form of a knob, button, lever, slide, or other mechanism. It should be appreciated that in some embodiments, the handle 110 includes a port 111 for the introduction of a fluid, agent, substance, tool, or other device for delivery through the catheter 102. Exemplary fluids include suspensions, mixtures, chemicals, liquids, agents, chemotherapeutic agents, immunotherapeutic agents, micelles, liposomes, embolic agents, nanoparticles, drug eluting particles, genes, plasmids, and proteins, to name a few.

[0052] As an added measure, it may be desirable to control any potential degree of temperature rise during therapy delivery. In some embodiments, this is accomplished by the use of internally cooled or perfused (open system) electrodes. Additionally, the cooling perfusion may optionally contain secondary biological compounds utilized by PEF therapy, such as genetic material, chemotherapy, or immunostimulants. The electrodes may be pre-cooled, cooled during delivery, or cooled thereafter. The coolant may be refrigerated, room temperature, normal temperature, or at an intentionally elevated temperature. In some embodiments, the perfusion material also contains calcium or other materials to increase therapeutic efficacy. In some embodiments, the perfusion material uses hypertonic solutions to locally increase electrical conductivity and acts as a virtual electrode to expand the applicable treatment zone.

[0053] The catheter 102 is in electrical communication with a generator 104 configured to generate PEF energy. In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / readout unit 156 (such as a memory and / or database), and an energy storage subsystem 158 that generates and stores the energy to be delivered. In some embodiments, the user interface 150 on the generator 104 is used to select a desired treatment algorithm 152. In other embodiments, the algorithm 152 is automatically selected by the generator 104 based on information acquired by one or more sensors, which will be described in more detail in a later section. Various energy delivery algorithms may be used. In some embodiments, one or more capacitors are used for energy storage / delivery, however, any other suitable energy storage elements may be used. In addition, one or more communication ports are typically included.

[0054] In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / retrieval unit 156 (such as a memory and / or database), and an energy storage subsystem 158 that generates and stores the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery, however, any other suitable energy storage elements may be used. Additionally, one or more communication ports are included.

[0055] In some embodiments, the generator 104 includes three subsystems: 1) a high energy storage system; 2) a high voltage mid-frequency switching amplifier; and 3) a system controller, firmware, and user interface. In some embodiments, the system controller includes a cardiac synchronization trigger monitor that allows the pulsed energy output to be synchronized to the patient's cardiac rhythm. In other embodiments, energy delivery is triggered by other monitoring mechanisms or simply by direct input from an operator. The generator draws on an alternating current (AC) mains power source to power multiple direct current (DC) power supplies. Alternatively, the generator may draw DC power from a battery or other electrical delivery system. The generator controller can cause the DC power supply or battery to charge the high energy capacitor storage bank before energy delivery begins. At the start of therapy energy delivery, the generator controller, high energy storage bank, and biphasic pulse amplifier can operate simultaneously to generate a high voltage mid-frequency output.

[0056] It should be understood that a number of generator electrical architectures can be employed to execute the energy delivery algorithm. In particular, in some embodiments, advanced switching systems are used that are capable of directing the pulsed electric field circuitry to the energy delivery electrodes separately from the same energy storage and high voltage delivery system. Furthermore, generators employed in advanced energy delivery algorithms that employ rapidly varying pulse parameters (e.g., voltage, frequency, etc.) or multiple energy delivery electrodes may utilize modular energy storage and / or high voltage systems, facilitating widely customizable waveforms and geographic pulse delivery paradigms. It should be further understood that the electrical architectures described herein above are merely examples, and that systems that deliver pulsed electric fields may or may not include additional switching amplifier components.

[0057] The user interface 150 may include a touch screen and / or more traditional buttons or mouse to allow an operator to enter patient data, select a treatment algorithm (e.g., energy delivery algorithm 152), initiate energy delivery, view records stored on the storage / readout unit 156, and / or otherwise communicate with the generator 104. The user interface 150 may include a voice activation mechanism for entering patient data, or may be capable of communicating with additional equipment in the suite such that control of the generator 104 is through a secondary, separate user interface.

[0058] In some embodiments, the user interface 150 is configured to receive operator-defined input. The operator-defined input may include duration of energy delivery, one or more other timing aspects of the energy delivery pulse, power, and / or mode of operation, or a combination thereof. Exemplary modes of operation may include (without limitation) system initiation and self-test, operator input, algorithm selection, pre-treatment system status and feedback, energy delivery, post-energy delivery display or feedback, treatment data review and / or download, software update, or any combination or subcombination or series of subcombinations thereof.

[0059] In some embodiments, the system 100 also includes a mechanism for obtaining an electrocardiogram (ECG), such as an external cardiac monitor 170. An exemplary cardiac monitor is available from AccuSync Medical Research Corporation. In some embodiments, the external cardiac monitor 170 is operatively connected to the generator 104. The cardiac monitor 170 can be used to continuously obtain an ECG signal. External electrodes 172 may be applied to the patient P to obtain the ECG. The generator 104 analyzes one or more cardiac cycles to identify the beginning of a time period during which it is safe to apply energy to the patient P, thus providing the ability to synchronize energy delivery with the cardiac cycle. In some embodiments, this time period is within a few milliseconds of the R wave (of the ECG QRS complex) to avoid induction of arrhythmias that may occur if an energy pulse is delivered over the T wave. Such cardiac synchronization is typically utilized when using unipolar energy delivery, however, it should be understood that it may be utilized as part of other energy delivery methods.

[0060] FIG. 2 illustrates an embodiment of an energy delivery catheter 102 having an energy delivery body 108 comprised of an elongated expandable member 202 surrounding one or more electrodes 200. In this embodiment, multiple electrodes 200 are disposed along the shaft 106 near its distal end. In this embodiment, multiple electrodes 200 are equally spaced apart, however, it should be understood that the electrodes 200 may be disposed with respect to any desired pattern of spacing therebetween. The electrodes 200 are surrounded by an expandable member 202, such as a balloon, which is expandable, such as to contact the wall of a blood vessel when inserted therein. In this embodiment, the expandable member 202 is inflatable with a conductive solution. Thus, when the expandable member 202 expands to contact the wall of a blood vessel, energy delivered through the one or more electrodes 200 can be transmitted to the wall of the blood vessel through the conductive solution. It should be understood that conduction to the wall of a blood vessel can also be achieved without contact or with minimal contact, such as when blood within the vessel acts as a conductive pathway to the wall of the vessel.

[0061] 3 illustrates an embodiment of an energy delivery catheter 102 having an energy delivery body 108 with an electrode 200 formed by a plurality of ribbons or wires 120 mounted on a shaft 106 that extends through the energy delivery body 108. In this embodiment, the energy delivery body 108 has a basket shape that is constrained by a proximal end constraint 122 and a distal end constraint 124. In this configuration, for the energy delivery body 108 to collapse, either the proximal end constraint 122 or the distal end constraint 124 slides freely on the shaft 106 while the other end is fixedly attached to the shaft 106. Depending on the positioning of the energy delivery body 108 in the target treatment area, the sheath 126 is withdrawn by the operator, for example, via a lever or slider or plunger of the catheter handle 110 that is operatively connected to the sheath 126. Removal of the sheath 126 removes the constraint keeping the energy delivery body 108 in a collapsed state, thus allowing it to expand, leading to the wires 120 of the energy delivery body 108 contacting the vessel wall.

[0062] In some embodiments, the collapsed configuration of the energy delivery body 108 can be achieved by a mechanism that limits its expansion without the use of a sheath 126. For example, in some embodiments, a pull wire is attached to the proximal end constraint 122 of the energy delivery body 108 and extends through a lumen along the shaft 126 where it is operatively connected to a lever, slider, or plunger in the catheter handle 110. In this embodiment, the distal end constraint 124 is fixedly attached to the shaft 106 and the proximal end constraint 122 is configured to slide freely on the shaft 106. While the pull wire is under a pulling force, the proximal end constraint 122 is positioned such that the energy delivery body 108 is collapsed. The pull wire can be maintained in this position by a constraint within the handle 110. Releasing the pulling force, such as by reducing or removing the constraint within the handle 110, allows the pull wire to move, thus freeing the proximal end restraint 122 and allowing the self-expanding nature of the energy delivery body 108 to proceed closer to its distal end restraint 124 as it causes expansion.

[0063] In other embodiments, the proximal restraint 122 is affixed to the shaft 106 and the distal restraint 124 slides freely on the shaft 106. Additionally, a push rod (or tubing to achieve higher column strength) is attached to the distal restraint 124 and extends lumenally along the inner shaft 106 where it is operatively connected to a mechanism such as a lever, slider, or plunger in the catheter handle 110. When the push rod is pushed and subsequently constrained within the handle 110 of the catheter 102, the distal restraint 124 is moved away from the proximal restraint 122, which causes the energy delivery body 108 to collapse. When the energy delivery body 108 self-expands, release of the push rod allows the energy delivery body 108 to expand. Alternatively, the push rod may be retracted, pulling the distal end restraint 124 towards the proximal end restraint 122, which causes the energy delivery body 108 to expand.

[0064] In some embodiments, the energy delivery body 108 is formed from a braided metal tube that is constrained at both the proximal end constraint 122 and the distal end constraint 124 and configured to form a basket. The energy delivery body 108 can be controlled (i.e., collapsed, deployed) as described above. When the energy delivery body 108 comprises a braided metal tube, each wire within the braided tube is supported by the wires adjacent to it as well as by the interwoven nature of the braid itself. This support and interwoven configuration can ensure minimal variation in the space between the wires, otherwise known as the pore or opening size of the braid. In addition, this support and interwoven configuration can allow the braided tube to be constructed from very small wires and still have significant radial stability of the basket. This allows for the use of many wires (e.g., 12, 16, 18, 20, 22, 24, etc.), while maintaining a relatively small profile of the energy delivery body 108 in the collapsed / constrained state and optimizing the opening size of the braided tube when the electrodes are deployed / expanded. In this embodiment, the spaces between the wires are fairly small, leading to treatment that is essentially continuous across 360 degrees of the inner lumen of the blood vessel.

[0065] FIG. 4 illustrates another embodiment of the energy delivery body 108. In this embodiment, the energy delivery body 108 is not basket weave but rather includes one or more protrusions 850. Each protrusion 850 acts as an electrode and is formed by a wire or ribbon 120 that bends radially outward from the longitudinal axis or shaft 106 of the catheter 102. In this embodiment, each protrusion 850 is electrically isolated from each of the other protrusions. The protrusions 850 may be made of a variety of suitable materials to act as electrodes, such as stainless steel, spring steel, or other alloys, and may be, for example, round wires or ribbons. Each protrusion 850 is insulated with a section of insulation 852, such as a polymer (e.g., PET, polyether block amide, polyimide), over at least a portion of the proximal and distal ends of the energy delivery body 108. The exposed portion 854 of the wire or ribbon can then act as an electrode on each protrusion 850. In one embodiment, the exposed portion 854 of the protrusion 850 is completely free of the insulation 852. In another embodiment, the insulation 852 is removed only from the outer surface of the protrusion 850, leaving the side of the protrusion 850 that does not contact tissue (e.g., the inner surface facing the shaft 106 of the catheter 102) completely insulated. In one embodiment, each protrusion 850 is independently energized, with two protrusions 850 acting as neutral electrodes (return) and two protrusions 850 acting as active electrodes. The neutral and active electrodes can be positioned directly next to each other. The neutral electrodes (counter electrodes) located 180 degrees from each other can be electrically connected to each other and therefore can be active electrodes. In this embodiment, only two conductive wires (power lines) are needed to connect the two pairs of protrusions 850 to the generator 104. Additionally, the pairs of protrusions 850 utilized in the bipolar fashion can be further multiplexed to allow for any combination or rotation of active versus neutral electrodes. The generator 104 can be configured with sufficient channels (i.e., 1-4 channels) to support any of these approaches.This embodiment of the energy delivery body 108 can optionally be delivered in a collapsed configuration and expanded into tissue contact via a pullback wire and mechanism in the handle.

[0066] FIG. 5 illustrates another embodiment of the energy delivery body 108 comprising one or more protrusions 850, each of which bends radially outward from the longitudinal axis or shaft 106 of the catheter 102. However, in this embodiment, each of the protrusions 850 is formed from a non-conductive metal and carries, supports, and / or is otherwise coupled to a separate electrode 200. Each electrode 200 has a conductive wire 860 that connects the electrode 200 to the generator 104. The protrusions 850 position the electrode 200 against tissue upon expansion, such as via a pull wire and mechanism in a handle. In this embodiment, each electrode 200 is placed across or adjacent to each of the protrusions 850. If the protrusions 850 are made of metal, an insulator is provided to electrically isolate the electrode 200 from the protrusions 850 themselves. If the protrusions 850 are made of a polymer or other non-conductive material, additional insulation would not be required. In some embodiments, the protrusions 850 are made of round wire or ribbon and configured to form a straight basket as shown. In other embodiments (not shown), the protrusions 850 are configured in a helical shape. It should be understood that separate electrodes 200 as depicted in FIG. 5 may be similarly applied to other embodiments, such as where the basket is made of braided material. As with the embodiment of FIG. 4, each electrode 200 may be energized in various combinations. Additionally, each protrusion 850 may carry electrodes 200 that may be electrically connected to each other or electrically isolated from each other. To increase the surface area of ​​the electrodes 200, each can be constructed, for example, from a metal coil or in the form of a slotted (e.g., laser cut) tube. These configurations would allow for greater spatial coverage and also maintain the flexibility of the electrode 200, allowing the basket protrusions 850 to bend and straighten freely. As in FIG. 4, the surface of the protrusions 850 can be completely exposed or insulated over areas that do not contact tissue.

[0067] It should be understood that the energy delivery body 108 may be optimized for situations where a greater degree of control over the force applied on the vessel wall is desired. In this embodiment, the energy delivery body 108 is delivered into the vessel lumen via a three-step process. First, referring to FIGS. 6A-6B, the sheath 126 is proximally retracted, thus exposing one or more projections 900 that act as protrusions. This embodiment includes four projections 900 arranged symmetrically around a central lumen 902. It should be understood that there may be any number of projections 900, including one, two, three, four, five, six, or more. Each projection 900 includes at least one electrode 200. FIG. 6A illustrates an embodiment of the projection 900 having two electrodes 200 having an elongated shape (such as wires) attached to an insulating substrate 904, such as a polymeric substrate (e.g., ribbon, strip) therebetween, as a means to maintain the distance between the electrodes 200. It should be understood that the electrodes 200 may have a round or square / rectangular cross-section and are typically affixed to the insulating substrate 904 such that the electrodes 200 are generally parallel to one another. The manufacturing method for attaching the electrodes 200 to the insulating substrate 904 may employ (but is not limited to) co-extrusion, deposition, adhesive-based bonding, and thermal bonding. The width of the insulating substrate 904 may vary. The electrodes 200 may be electrically connected to one another, insulated from one another, or there may be different patterns of electrical interconnection between the electrodes, depending on the energy application algorithm controlled by the generator.

[0068] Once one or more protrusions 900 are exposed, the second step of the three-step process involves introducing a separate expandable member 910, such as a balloon, by advancing the expandable member 910 out of the lumen 902 while in a non-expanded state. The third step involves expanding the expandable member 910, such as by inflating a balloon, as illustrated in FIGS. 6A-6B, until a desired interface between the protrusions 900 (and thus the electrodes 200) and the vessel wall is achieved. In another embodiment, the protrusions 900 are positioned while the expandable member 910 is already positioned below the protrusions 900, thus their relative longitudinal position does not change. In this configuration, removal of the sheath 126 exposes both the expandable member 910 and the protrusions 900 simultaneously, thus eliminating the step of advancing the expandable member 910 out of the lumen 902. As explained above, the expandable member 910 is subsequently expanded (e.g., inflated) until a desired interface between the protrusions 900 and the vessel wall is achieved. The size (e.g., length, width) of the protrusions 900 can be the same or different. The number of protrusions 900 can vary from 1 (monopolar configuration) to 100 (monopolar and / or bipolar) configurations. The application of energy to the electrode 200 can vary widely depending on the algorithm of the energy delivery device (e.g., generator).

[0069] FIG. 7 illustrates another embodiment of a catheter 102 comprising an energy delivery body 108 having a shape configured for intravascular treatment. In this embodiment, the energy delivery body 108 comprises an expandable member 202, such as an inflatable balloon, having at least one electrode 200 mounted thereon or incorporated therein. The energy delivery body 108 is delivered to the targeted area in a collapsed configuration. In this embodiment, the electrodes 200 have the form of a pad having a relatively wide surface area and a thin cross section. The pad shape provides a wider surface area than other shapes, such as a wire shape. Each electrode 200 is connected with a conductive wire 201, which electrically connects the electrodes 200 with a generator. In this embodiment, three electrodes 200 are visible, however, it should be understood that additional electrodes may be present around the expandable member 202. It should be understood that any number of electrodes 200 may be present and act as a single electrode or act independently or in combination. Placement of and / or selective energization of the electrodes 200 can direct energy towards specific target locations. In some embodiments, the electrodes 200 are comprised of flexible circuit pads or other materials attached to or formed into the expandable member 202. In some embodiments, the electrodes 200 are distributed radially around the circumference of the expandable member 202 and / or distributed longitudinally along the length of the expandable member 202. Such a design can promote improved deployment and retraction qualities, ease of user operation and compatibility with the introducer lumen.

[0070] In some embodiments, a fluid is delivered to the target vessel either before, during, or after the energy delivery. In some embodiments, the fluid includes one or more agents. Exemplary agents include drugs, pharmaceuticals, chemotherapeutic agents, immunotherapeutic agents, micelles, liposomes, embolic agents, nanoparticles, drug-eluting particles, genes, plasmids, and proteins, to name a few. The fluid may be delivered by any suitable method, such as systemically, locally, or locally, such as by injection through a separate device or through the catheter 102. Typically, the agent bathes the target tissue and is allowed to remain for biodistribution, if desired. In some embodiments, the effect of the energy delivered to the target vessel is enhanced by the presence of a fluid either before, during, or after the energy delivery. In other embodiments, the effect of the fluid delivered to the target vessel is enhanced by the delivery of energy either before, during, or after the agent delivery.

[0071] 8-12 illustrate exemplary embodiments of a catheter 102 that delivers a fluid, and optionally one or more active substances, through or near the energy delivery body 108. In particular, FIG. 8 illustrates an embodiment of the catheter 102 of FIG. 2 configured to deliver a fluid having one or more types of active substances. Here, the expandable member 202 can be filled with a fluid carrying one or more active substances, such as through a port in the shaft 106. Similarly, the expandable member 202 can leach or pass one or more active substances 110 to the surrounding environment (as indicated by the arrows) through pores in the expandable member 202, such as through pores. It should be understood that in some embodiments, a fluid, such as a conductive solution or saline solution, is passed through the expandable member 202 to act as a virtual electrode. Thus, energy delivered to the electrode 200 pad is transferred to the fluid and conducted to where the fluid has diffused. This increases the size, shape, and properties of the delivery electrode. It should be understood that the conductive solution may be used alone or in combination with one or more agents 110.

[0072] FIG. 9 illustrates an embodiment of the catheter 102 of FIG. 3 configured to deliver a fluid, such as having one or more types of active substances 110. In this embodiment, the shaft 106 includes multiple ports 131 and, optionally, a port 133 at the distal tip of the catheter 102 through which the active substances 110 flow. The energy delivery body 108 includes a wire basket, so that the active substances 110 can pass through the mesh of the basket into the surrounding environment. FIG. 10 illustrates an embodiment of the catheter 102 of FIG. 4 configured to deliver one or more types of active substances. In this embodiment, the active substances 110 can be delivered through a lumen in the shaft 106 to exit into the area of ​​the protrusion 850, as shown by the arrows. Thus, the active substances 110 can pass freely into the surrounding environment of the energy delivery body 108. FIG. 11 illustrates an embodiment of the catheter 102 of FIGS. 6A-6B configured to deliver one or more types of active substances. Here, the expandable member 910 includes multiple pores or ports 131 for the passage of the agent 110 therethrough to the surrounding environment as indicated by the arrows. In this embodiment, the expandable member 910 is expanded (e.g., inflated) until a desired interface between the protrusions 900 and the vessel wall is achieved in coordination with a desired flow rate of the agent 110 through the ports 131. FIG. 12 illustrates an embodiment of the catheter 102 of FIG. 7 configured to deliver one or more types of agents. Here, the expandable member 202 includes multiple pores or ports 131 for the passage of the agent 110 therethrough to the surrounding environment as indicated by the arrows. The ports 131 are located between the electrode 200 pads. Optionally, the catheter 102 includes a port 133 at the distal tip of the catheter 102 through which the agent 110 flows. It should be understood that in each of the above embodiments, a fluid such as a conductive solution may be used alone or in combination with one or more agents 110.

[0073] clinical method Therapy systems and devices may be used to treat a variety of conditions, particularly vascular conditions such as atherosclerosis and angina. As mentioned above, there are multiple types of angina, including stable angina (thoracic angina), unstable angina, variant angina, and microvascular angina. Both variant angina and microvascular angina involve spasms in the coronary arteries that supply blood to the heart muscle. During coronary spasms, the coronary arteries repeatedly contract or spasm, causing a temporary lack of blood supply to the heart muscle (ischemia). To diagnose coronary spasms, patients may wear portable monitors for up to 48 hours, etc. The monitor records the heart's electrical impulses, even while sleeping. Changes on an electrocardiogram (EKG) may indicate coronary spasms. However, not all patients show EKG changes during all episodes. To diagnose coronary spasms, an ergonovine stress test may be used. Ergonovine is a drug that is usually infused through an IV during cardiac catheterization. It can usually trigger a coronary artery spasm within a few minutes, at which point the coronary artery is visualized. Another drug is then infused into the coronary artery to relieve the spasm. The patient's EKG is recorded before, during, and after the test. If coronary artery spasm is present, it can be seen on the EKG as well as the angiogram. It should be understood that other similar tests may also be used. In some cases, acetylcholine is used to trigger coronary artery spasm. Ergonovine acts through serotonergic receptors, while acetylcholine acts through muscarinic cholinergic receptors. Different transmitters may have the potential to cause different coronary responses. Acetylcholine is hypersensitive to women, and the spasm induced by ergonovine is localized and proximal, while the spasm induced by acetylcholine is diffuse and distal. Therefore, both tests can be used as complements in the clinic.

[0074] Once a target tissue area is identified as being associated with coronary artery spasm, the target tissue area is treated with PEF energy. Optionally, one or more agents can be delivered in conjunction with the treatment as well. Typically, the catheter 102 is advanced through the vessel to the coronary artery, and the energy delivery body 108 is positioned at a desired location. In some embodiments, the energy delivery body 108 is actuated to expand within the vessel and contact at least a portion of the vessel wall. PEF energy is delivered through the energy delivery body according to an algorithm as will be described in a later section. Typically, the PEF energy is delivered in a monopolar manner. Monopolar delivery involves passing of current from the energy delivery body 108 to the target tissue and through the patient to a return pad 140 positioned against the patient's skin to complete the current circuit. Thus, in some embodiments, the catheter 102 includes only one energy delivery body 108 or electrode. This allows the catheter 102 to have a low profile so that it can be positioned within a smaller body lumen. This also allows for deep penetration of the tissue surrounding the energy delivery body 108. In some embodiments, energy is delivered in a bipolar manner, optionally with the use of more than one energy delivery body 108, however, it should be understood that in some instances a monopolar delivery design simplifies device and treatment design and provides superior treatment zones in the target tissue.

[0075] 13 includes a schematic illustration of an embodiment of the energy delivery body 108 (of FIG. 2) positioned adjacent to the wall W of the coronary artery CA. In this embodiment, the expandable member 202 is positioned against the endothelium E, and PEF energy is delivered from the electrodes 200 (as indicated by the wavy lines) through the expandable member 202 to the wall W. In some embodiments, the PEF energy treats cells within the tunica intima TI (e.g., endothelium, connective tissue, internal elastic tunica, etc.) and / or tunica media TM (e.g., elastic fibers, smooth muscle cells, fibroblasts, extracellular matrix, etc.) and preserves the tunica adventitia TA (e.g., external elastic tunica, connective tissue, etc.). Proposed mechanisms underlying susceptibility to coronary artery spasm include endothelial dysfunction, primary hyperresponsiveness of vascular smooth muscle cells (VSMCs), and other factors. Arterial spasm typically results from the interaction of at least two components: (1) a localized, but sometimes widespread, abnormality in the artery that causes an overreaction to vasoconstrictor stimuli, and (2) a vasoconstrictor stimulus that can induce spasm at the level of the overreactive vascular compartment. In some embodiments, the delivery of PEF energy interferes with one or more of these components. For example, in some cases, PEF energy treats vascular smooth muscle cells, which reduces or eliminates the ability of the blood vessel to vasoconstrict in response to stimuli. The extracellular matrix scaffold remains unaffected, preserving vascular patency and providing a suitable environment for regeneration of the vessel wall. In some cases, PEF energy disrupts local innervation to vascular smooth muscle cells, which reduces or eliminates the local triggering stimulus for vasospasm. In some embodiments, local denervation eliminates the nerve pathway from the local area of ​​spasm through vagus afferent fibers that contribute to the angina pain symptoms felt in the chest, neck, and jaw. In other embodiments, PEF energy treats the endothelium, leading to cell regeneration and healthy modification of the endothelial layer. In yet other embodiments, PEF energy is utilized to modify local cardiac myocardium, resulting in the replacement or elimination of local mechanical forces that may intensify or hasten contraction. It is understood that PEF energy may provide any combination or subcombination of these effects.

[0076] It is understood that treatment may include cell death, cell removal, and cell modification, to name a few. The adventitia is the outermost layer of the coronary artery CA and is the strongest of the three layers. It is composed of collagenous and elastic fibers. The adventitia provides a limiting barrier and protects the vessel from excessive expansion. This layer is maintained to preserve the integrity of the vessel.

[0077] The tunica media TM varies based on the type of vessel being treated. In smaller arteries, it consists primarily of smooth muscle fibers in fine bundles arranged in lamellae and arranged in a circular fashion around the vessel. These lamellae vary in number according to the size of the vessel, with the smallest arteries having only a single layer, and the slightly larger having three or four layers, up to six layers. It is the medial capsule that determines most of the thickness of the artery's wall. In larger arteries, such as the iliac, femoral, and carotid arteries, elastic fibers and collagen combine to form lamellae that alternate with layers of smooth muscle fibers, which are interconnected by elastic fibers that pass between the smooth muscle bundles and are connected with the fenestrated membrane of the medial capsule. In the largest arteries, such as the aorta and brachiocephalic artery, the amount of elastic tissue is considerable, and in these vessels, several bundles of white connective tissue are also found in the medial capsule. The myofiber cells are arranged in five to seven layers of circular and longitudinal smooth muscle and often contain slightly curved, well-defined, rod-shaped nuclei. It should be understood that the devices, systems, and methods described herein are not limited to the treatment of coronary arteries, but include the treatment of intracranial arteries (e.g., cerebral arterial spasm), peripheral arteries (e.g., superficial femoral, popliteal, tibial arteries), and other peripheral targets, to name a few. Similarly, anatomical targets include diseased vascular compartments and / or adjacent compartments, venous structures adjacent to diseased vascular compartments and / or adjacent compartments, neural tissue adjacent to or controlling diseased vascular compartments and / or adjacent compartments, and muscle tissue (e.g., myocardium) adjacent to or controlling diseased vascular compartments and / or adjacent compartments, to name a few. Exemplary devices and systems for delivering energy to myocardium are provided in International Patent Application No. PCT / US2020 / 066205, filed December 18, 2020, and entitled "TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRIC FIELDS," which is incorporated herein by reference for all purposes.

[0078] Therapeutic systems and devices may also be used to treat atherosclerosis or coronary artery disease, particularly restenosis after percutaneous transluminal angioplasty (PTA) and / or stent placement. PTA uses the expansion of a balloon at the end of a catheter at the stenosis to increase the lumen of the blood vessel. However, the increase in diameter can result in endothelial denudation, disruption of the internal elastic membrane and the tunica media, and damage to approximately 20% of the smooth muscle cells in the tunica media. The stent is designed to be expanded within the stenosis area to hold it open using PTA, either during or prior to application, to expand the blood vessel with the stent. However, the stent also leads to disruption of normal vasculature. The use of PTA to expand the vessel wall with a stent has an effect similar to that described above, where a self-expanding stent continues to expand due to radial forces, prolonging the disturbance to endothelial function.

[0079] The vascular architecture and cellular changes from PTA and stenting can lead to the development of restenosis, which is the re-narrowing of the blood vessel at the site of intervention due to the iatrogenic injury response of the blood vessel. This problem also exists in the peripheral vasculature. Restenosis involves two major processes: arterial remodeling and neointimal hyperplasia. Arterial remodeling is a natural compensatory response in which the artery widens in response to plaque formation, reducing vascular narrowing. However, in response to angioplasty, negative remodeling can lead to vasoconstriction, reducing the overall vessel lumen. This is thought to be the primary mechanism for angioplasty restenosis, while in-stent restenosis appears to result primarily from neointimal hyperplasia, in which vascular injury releases mitogens and levels of mitogenic proto-oncogenes in smooth muscle cells are increased, modifying the phenotype of the smooth muscle cells from contractile to synthetic, with 20-40% of the medial smooth muscle cells entering the cell cycle within 3 days. Pro-migration proteins are also expressed, encouraging medial smooth muscle cells to migrate into the intima. Damaged endothelial cells from PTA and stenting may further contribute to smooth muscle cell proliferation and migration by decreasing their production of nitric oxide, a chemical known to inhibit smooth muscle cell growth.

[0080] The target region can be identified by any suitable method, such as by computed tomography, angiography, intravascular ultrasound (IVUS), optical coherence tomography (OCT), or any suitable imaging modality. Once the target tissue area is identified, the target tissue area is treated with PEF energy. In some cases, the PEF energy disrupts plaque layers, such as calcified deposits. In some embodiments, the plaque is treated by other methods and the PEF energy is utilized, such as to reduce or prevent restenosis. In some embodiments, one or more agents are delivered in conjunction with the PEF treatment. Typically, the catheter 102 is advanced through the vasculature to a coronary artery (although other blood vessels may also be targeted), and the energy delivery body 108 is positioned at a desired location. In some embodiments, the energy delivery body 108 is actuated to expand within the blood vessel and contact at least a portion of the vessel wall. PEF energy is delivered through the energy delivery body according to an algorithm as will be described in a later section. Typically, the PEF energy is delivered in a monopolar manner. Monopolar delivery involves passing current from the energy delivery body 108 to the target tissue and through the patient to a return pad 140 positioned against the patient's skin to complete the current circuit. Thus, in some embodiments, the catheter 102 includes only one energy delivery body 108 or electrode. It should be understood that in some embodiments, energy is delivered in a bipolar manner, optionally with the use of more than one energy delivery body 108.

[0081] In some embodiments, an agent 110 is also delivered to the target tissue area. Exemplary agents include anti-proliferative drugs that halt vascular smooth muscle cell proliferation and thus neointimal hyperplasia. Sirolimus and paclitaxel are two examples of such drugs. Paclitaxel inhibits microtubule disassembly, thus interfering with the cell cycle, leading to cell cycle arrest at G0-G1 and G2-M phases. Sirolimus binds to FKBP12, which in turn inhibits the mTOR and PI3 pathways, arresting the cell cycle at G1 phase. Similar drugs have been developed from sirolimus and include everolimus (SDZ RAD), ridaforolimus, zotarolimus, rapamycin agents, biolimus, and novolimus, etc., which have shown anti-atherosclerotic characteristics. Other therapeutic agents 110 include antiproliferatives, antithrombotic agents, which exhibit the same anti-inflammatory and antiproliferative effects as sirolimus in vitro and therefore may serve as an alternative to sirolimus, phytoncides (PTCs), which are useful for suppressing inflammatory changes that lead to restenosis, glucocorticoids, plasmid DNA for expressing proteins that are highly valued inside the cells, which arrest the cell cycle in the G0-G1 phase and upregulate p27KIP1, which inhibits proliferation of vascular smooth muscle cells, galangin, which reduces restenosis via the calcineurin / NFAT / IL-2 pathway, tacrolimus, stem cells to support healthy re-endothelialization, radioactive agents, actinomycin, probucol, and 7-hexanoyltaxol, to name a few.

[0082] As mentioned, the agent 110 may be delivered by any suitable method, such as systemically, locally, or locally, such as through a separate device or by injection through the catheter 102. The agent 110 bathes the target tissue and, optionally, is allowed to remain for biodistribution. In some embodiments, the PEF energy increases the uptake of the agent 110 by the wall W of the blood vessel targeted by the PEF treatment. Thus, the effect of the agent 110 delivered to the target vessel is enhanced by the delivery of energy either before, during, or after the agent delivery.

[0083] It should be understood that in some embodiments, the PEF energy optionally removes, destroys, or kills cells within the walls of the blood vessel. Similarly, in some embodiments, the PEF energy optionally disrupts calcified regions within the blood vessel, allowing for better expansion. If calcium disruption is part of the therapy protocol, the catheter 102 or a separate device can be used after PEF delivery to extend the blood vessel diameter beyond the normal range. In some embodiments, localized uptake of one or more agents 110 kills cells or inhibits hyperplastic regrowth of cells in the targeted region of tissue. In some embodiments, the locally increased concentration of absorbed agents 110 will induce cell death in the diseased region (the area exposed to the electric field distribution) and kill cells in the targeted region. Ultimately, tissue degradation and increased vascular flow occurs through the increased diameter lumen in the targeted region. The dead regions of tissue degrade, producing less physical restriction to lumen diameter and blood flow. Agent 110 also slows or prevents regenerative hyperplasia regrowth over long periods of time (eg, weeks to years).

[0084] Energy Algorithm The PEF energy is provided by one or more energy delivery algorithms 152. In some embodiments, the algorithm 152 prescribes a signal having a waveform comprising a series of energy packets, each energy packet comprising a series of high voltage pulses. In such embodiments, the algorithm 152 prescribes parameters of the signal such as the energy amplitude (e.g., voltage) and duration of the applied energy, consisting of the number of packets, the number of pulses in a packet, the fundamental frequency of the pulse sequence, to name a few. Additional parameters may include switching time or interphase delay between polarities in a biphasic pulse, dead time or cycle delay between biphasic cycles, pause time or interpacket delay between packets, or delay between groups or bundles of packets, which will be explained in more detail in later sections. There may be fixed pause periods between packets, or the packets may be gated to the cardiac cycle and thus variable with the patient's heart rate. There may be various intentional pause period algorithms, or no pause periods may be applied between packets. Feedback loops based on sensor information, and automatic shutoff specifications, and / or the like may be included.

[0085] FIG. 14 illustrates an embodiment of a signal waveform 400 prescribed by the energy delivery algorithm 152. Here, two packets are shown, a first packet 402 and a second packet 404, the packets 402, 404 being separated by a rest period 406. In this embodiment, each packet 402, 404 consists of a first biphasic cycle (comprising a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic cycle (comprising a second positive pulse peak 408' and a second negative pulse peak 410'). The first and second biphasic pulses are separated by a dead time 412 (i.e., pause) between each pulse. In this embodiment, the biphasic pulses are symmetric such that the set voltage 416 is identical for the positive and negative peaks. Here, the biphasic symmetric wave is also a square wave such that the magnitude and time of the positive voltage wave are approximately equal to the magnitude and time of the negative voltage wave. When using a bipolar configuration, the portions of the cells facing the negative voltage wave will undergo cell depolarization in those regions, and the normally negatively charged cell membrane regions will turn positive for a short period of time. Conversely, the portions of the wall W cells facing the positive voltage wave will undergo hyperpolarization, and the potential of the cell membrane regions will become extremely negative. It should be understood that in each positive or negative phase of the biphasic pulse, the portions of the wall W cells will experience the opposite effect. For example, the portions of the cell membrane facing the negative voltage will experience depolarization, while the portions 180° to this portion will experience hyperpolarization. In some embodiments, the hyperpolarized portions face the dispersion or return electrode 140.

[0086] The desired treatment depth depends on the thickness of the target vessel's wall W and the type of treatment desired, to name a few. Blood vessels have a variety of wall thicknesses, such as approximately 2 mm (aorta), 1-4 mm (artery), 0.5-5 mm (vein), 1.5 mm (vena cava), 6 μm-30 μm (arteriole), 2 μm-10 μm (terminal arteriole), 0.5 μm-8 μm (capillary), 1 μm-20 μm (venule). Similarly, specific layers within a vessel will vary in depth depending on the type of vessel. In addition, layers of calcification within a vessel due to atherosclerosis also increase wall thickness, and a deeper penetration depth may be desired than would be desired in a non-calcified vessel. Thus, the target treatment depth will vary. In some embodiments, the treatment depth into the wall W is in the range of 0.05 mm to 5 mm, including 0.5 μm to 5 mm, particularly 0.5 μm to 30 μm, and more particularly 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.2 mm, 1.4 mm, 1.6 mm, 1.8 mm, 2 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.5 mm. In some embodiments, due to calcium deposits, the treatment depth into the wall W through the calcified plaque is in the range of 2 to 10 mm.

[0087] The energy delivered will depend on the desired treatment depth and the type of treatment desired, to name a few. For example, a treatment targeting cell disruption or cell death will generally be weaker than a treatment targeting disruption of calcium deposits in arteriosclerosis. The following parameters may be used in various treatment situations:

[0088] A. Voltage The voltages used and considered may be the apex of a square waveform, the peak in a sine or sawtooth waveform, the RMS voltage of a sine or sawtooth waveform or other suitable aspect. In some embodiments, the energy is delivered in a monopolar manner, with each high voltage pulse or set voltage 416 being approximately 100V to 10,000V. For cell death, the voltage may typically be in the range of 500 to 3,000V, particularly 2,000 to 2,500V. For disruption of calcium deposits, the voltage may typically be in the range of 1,000 to 6,000V, particularly 2,000 to 4,000V. The voltage delivered to the tissue may be based on a set point on the generator 104, either taking into account electrical losses along the length of the catheter 102 due to the intrinsic impedance of the catheter 102, or not taking into account losses along the length, i.e., the voltage delivered may be measured at the generator or at the tip of the catheter.

[0089] It should be understood that the set voltage 416 may vary depending on whether the energy is delivered in a monopolar or bipolar manner. In bipolar delivery, a lower voltage may be used due to the smaller, more directional electric field. While the bipolar voltage selected for use in therapy depends on the electrode separation distance, a monopolar electrode configuration using one or more separate dispersive pad electrodes may be delivered without much consideration of the exact placement of the catheter electrode and dispersive electrode placed on the body. In monopolar electrode embodiments, a larger voltage is typically used due to the dispersive behavior of the delivered energy through the body to reach dispersive electrodes with an effective separation distance of about 10 cm to 100 cm. Conversely, in a bipolar electrode configuration, the relatively close active area of ​​the electrodes of about 0.5 mm to 10 cm, including 1 mm to 1 cm, results in a larger effect on the electrical energy concentration and effective dose delivered to the tissue from the separation distance. For example, if the targeted voltage to distance ratio is 3,000 V / cm to induce the desired clinical effect at the appropriate tissue depth (1.3 mm), if the separation distance is changed from 1 mm to 1.2 mm, this will result in a required increase in treatment voltage from 300 to approximately 360 V, i.e., a change of 20%.

[0090] B.Frequency It should be understood that the number of biphasic cycles per second of time is the frequency when the signal is continuous. In some embodiments, biphasic pulses are utilized to reduce undesired muscle stimulation, particularly myocardial stimulation. In other embodiments, the pulse waveform is monophasic and does not have any distinct inherent frequency. Instead, the fundamental frequency may be considered by doubling the monophasic pulse length to derive the frequency.

[0091] In some embodiments, the signal has a frequency in the range of 10 kHz to 800 kHz. For cell death, the frequency may typically be in the range of 100 to 800 kHz, more specifically, 400 to 600 kHz. For calcium deposit disruption, the frequency may typically be in the range of 10 μsec to 100 μsec (monophasic) or 10 to 500 kHz (biphasic), more specifically, 50 to 250 kHz. In some embodiments, the signal has a frequency in the range of about 100 to 600 kHz, which typically penetrates the luminal wall to treat or affect certain cells located somewhat deeper, such as submucosal or smooth muscle cells. It should be understood that in some circumstances and at some voltages, frequencies at or below 100 to 250 kHz may cause undesired muscle stimulation. However, such muscle contractions may be mitigated by other techniques. Thus, in some embodiments, the signal has a frequency in the range of 400-800 kHz or 500-800 kHz, such as 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, etc. In particular, in some embodiments, the signal has a frequency of 600 kHz. In addition, cardiac synchronization may be utilized to reduce or avoid undesired myocardial stimulation during sensitive rhythmic periods. It should be appreciated that even higher frequencies may be used in conjunction with components that minimize signal artifacts.

[0092] C. Voltage-frequency balance The frequency of the delivered waveform may be varied synchronously with the treatment voltage to maintain the proper therapeutic effect. Such synergistic changes would include a decrease in frequency, which induces a stronger effect, combined with a decrease in voltage, which induces a weaker effect. For example, in some cases, treatment may be delivered using 3,000V in a monopolar manner with a waveform frequency of 800kHz, while in other cases, treatment may be delivered using 2,000V with a waveform frequency of 400kHz.

[0093] When used in the opposite direction, the treatment parameters may be manipulated in a way that makes it overly effective, which may increase the likelihood of muscle contraction or risky effects on undesired tissues. For example, if the frequency is increased and the voltage is decreased, such as using 2,000V at 800kHz, the treatment may not have sufficient clinical therapeutic benefit. Conversely, if the voltage is increased to 3,000V and the frequency is decreased to 400kHz, there may be an undesirable therapeutic effect range on collateral sensitive tissues. In some cases, overtreatment of these undesired tissues may result in morbidity or safety concerns for the patient. In other cases, overtreatment of non-targeted or undesired tissues may have a benign clinical outcome and not affect patient response or morbidity if they are overtreated.

[0094] D. Packet As mentioned, the algorithm 152 prescribes a signal having a waveform comprising a series of energy packets, each energy packet comprising a series of high voltage pulses. The cycle count 420 is half the number of pulses in each biphasic packet. With reference to FIG. 11, the first packet 402 has a cycle count 420 of 2 (i.e., 4 biphasic pulses). In some embodiments, the cycle count 420 is set to 1-100 (including all values ​​and subranges therebetween) per packet. In some embodiments, the cycle count 420 is up to 5 pulses, up to 10 pulses, up to 25 pulses, up to 40 pulses, up to 60 pulses, up to 80 pulses, up to 100 pulses, up to 1,000 pulses, or up to 2,000 pulses (including all values ​​and subranges therebetween). In some embodiments, the cycle count is adjusted to achieve a desired total on-time of the energy. For cell death, the total on-time for treatment may be 25-250 μsec, more specifically, 50-150 μsec. For disruption of calcific deposits, the total on-time for treatment may be from 50 to 500 μsec, more specifically, from 75 to 150 μsec.

[0095] Packet duration is determined by the cycle count, among other factors. Typically, the higher the cycle count, the longer the packet duration and the greater the amount of energy delivered. In some embodiments, the packet duration is in the range of about 50-1,000 microseconds, such as 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 100-250, 150-250, 200-250, 500-1,000 microseconds, to name a few. In other embodiments, the packet duration is in the range of about 100-1,000 microseconds, such as 150, 200, 250, 500, or 1,000 microseconds.

[0096] The number of packets or packet count delivered during treatment may vary. In some embodiments, the number of packets per electrode activation is in the range of 1 to 30, more specifically, 1 to 10. The number of packets delivered may be repeated or changed from one activated electrode to a subsequent activated electrode. This may be performed for both unipolar and bipolar electrode arrangements.

[0097] Exemplary parameter combinations include: [ka]

[0098] E. Interpacket Delay In some embodiments, the time between packets, referred to as the pause period 406 or inter-packet delay, is set to about 0.1 seconds to about 5 seconds, including all values ​​and subranges therebetween. In other embodiments, the pause period 406 ranges from about 0.001 seconds to about 10 seconds, including all values ​​and subranges therebetween. In some embodiments, the pause period 406 is about 1 second. In other embodiments, the pause period may reach 30 seconds, 1 minute, or 5 minutes. Notably, in some embodiments, the signal is synchronized with the cardiac rhythm such that each packet is delivered synchronously within a period specified relative to the heartbeat, and thus the pause period coincides with the heartbeat. In other embodiments where cardiac synchronization is utilized, the pause period 406 may vary since the pause period between packets may be affected by cardiac synchronization, as will be described in a later section.

[0099] F. Batch To ensure the safety of the therapy with respect to the cardiac rhythm, the therapy may be delivered synchronously, whereby the PEF is delivered in a safe ST interval of the cardiac rhythm. The therapy may be delivered with multiple packets per heartbeat (faster, more potential thermal effect) or with multiple heartbeats between packets (slower, but reducing potential thermal effect). Similarly, biphasic waveforms allow for asynchronous delivery with minimal cardiac arrhythmia risk, potentially delivering packets at a cadence that properly balances the time of therapy delivery (including considerations regarding the bioavailability of adjuvant materials in the blood or local-regional space) with the thermal load (temperature and time held at elevated temperature, which may affect the safety profile of the therapy).

[0100] In some embodiments, the signal is synchronized with the heart rhythm such that each packet is delivered synchronously within a designated period relative to the heartbeat, and thus the resting periods coincide with the heartbeat. It should be understood that the packets delivered within each designated period relative to the heartbeat may be considered a batch or bundle. Thus, each batch has a desired number of packets such that at the end of the treatment period, a desired total number of packets have been delivered. Each batch may have the same number of packets, however, in some embodiments, the batches have a varying number of packets.

[0101] In some embodiments, only one packet is delivered between heartbeats. In such cases, the pause period may be considered the same as the period between batches. However, when more than one packet is delivered between batches, the pause time is typically different from the period between batches. In such cases, the pause time is typically much smaller than the period between batches. In some embodiments, each batch includes 1-10 packets, 1-5 packets, 1-4 packets, 1-3 packets, 2-3 packets, 2 packets, 3 packets, 4 packets, 5 packets, 5-10 packets, to name a few. In some embodiments, each batch has a period of 0.5 ms to 1 s, 1 ms to 1 s, 10 ms to 1 s, 10 ms to 100 ms, to name a few. In some embodiments, the period between batches is variable depending on the patient's heart rate. In some cases, the period between batches is 0.25 to 5 s.

[0102] Treatment of the tissue area continues until the desired number of batches have been delivered to the tissue area. In some embodiments, between 2 and 50 batches are delivered per treatment, with a treatment being considered treatment of a particular tissue area. In other embodiments, a treatment may include between 5 and 40 batches, between 5 and 30 batches, between 5 and 20 batches, between 5 and 10 batches, 5 batches, 6 batches, 7 batches, 8 batches, 9 batches, 10 batches, 10 and 15 batches, etc.

[0103] G. Phase Delay and Intercycle Delay The switching time or phase delay is a delay or period of no energy delivered between the positive and negative peaks of a biphasic pulse, as illustrated in FIG. 15. FIG. 15 illustrates various examples of biphasic pulses (comprising a positive peak 408 and a negative peak 410) having a switching time 403 therebetween (however, when the switching time 403 is zero, it does not appear). In some embodiments, the switching time ranges from about 0 to about 1 microseconds (including all values ​​and subranges therebetween). In other embodiments, the switching time ranges from 1 to 20 microseconds (including all values ​​and subranges therebetween). In other embodiments, the switching time ranges from about 2 to about 8 microseconds (including all values ​​and subranges therebetween).

[0104] A delay may also be interposed between each cycle of the biphasic pulses, referred to as an inter-cycle delay or "dead time." Dead times occur between biphasic pulses, but within a packet. This is in contrast to the rest periods that occur between packets. In other embodiments, the dead time 412 is within the range of about 0 to 0.5 microseconds, 0 to 10 microseconds, 2 to 5 microseconds, 0 to 20 microseconds, about 0 to about 100 microseconds, or about 0 to about 100 milliseconds, including all values ​​and subranges therebetween. In some embodiments, the dead time 412 is within the range of 0.2 to 0.3 microseconds. Dead times may also be used to define periods between separate monophasic pulses within a packet.

[0105] Some PEF waveforms induce strong pressure waves and potential electrical arcing events. Examples of such waveforms include single pulse PEF waveforms or stack cycle PEF waveforms (back-to-back cycles with a duty cycle of more than 50%) durations (current dependent) of more than about 10 μs. This can also occur into well-connected high conductivity solutions. This typically occurs when the current density is too high due to concentration at a singular point or small electrodes. Both effects can induce serious adverse events for patients, and therefore treatment must generally be titrated to an intensity below that which induces these phenomena. However, it should be understood that in some cases, certain levels of pressure waves and external arcing effects may be tolerated or even beneficial. For example, when disrupting calcium deposits in the treatment of atherosclerosis, the external discharge may deliver pressure waves similar to tissue fracturing that may mechanically pulverize the calcium deposits. Thus, in some embodiments, the phase delay or inter-cycle delay may be short, minimal, or zero. In some embodiments, this will support lower frequencies (below 100 kHz, up to monophasic waveforms of 100 μsec or 1 ms or 10 ms length). In some embodiments, asymmetric to monophasic waveforms may be used for pressure wave generation.

[0106] In some embodiments, a safe PEF waveform is provided that includes strategically timed energy delivery by splitting packets into smaller subcomponents with significantly smaller duty cycles of very short duration. This is accomplished by the introduction of specifically placed and timed delays such as inter-pulse delay 14, inter-cycle delay 16, inter-phase delay 18, inter-packet delay 22, inter-bundle delay 26, etc. It should be understood that a combination of delays may be utilized within a therapy to obtain a desired outcome. In particular, these delays may be specifically manipulated to obtain a particular desired outcome. For example, one, some, or all of these delays may be manipulated to control various aspects of the PEF therapy to mitigate any associated risks such as gas formation, discharge, cavitation, muscle contraction, and temperature rise, to name a few. In some embodiments, the delays distribute the periods over which the (high) voltage PEF energy is delivered, resulting in significant changes and optimization of the therapy delivery outcome. In some embodiments, the range of delays described herein is 0 seconds to 100 milliseconds.

[0107] In some embodiments, the delay period is manipulated to distribute the pace of energy delivery and allow certain effects to decompose and decay before they induce effects from their accumulation. When applying PEF for biological cell and tissue manipulation, where charge accumulation and decay are on a different timescale than other effects, it is possible to accumulate therapeutic effects on cells using multiple cycles or series of pulses without triggering various secondary therapeutic effects such as gas formation, discharge, cavitation, muscle contraction, and temperature increase, to name a few. In other cases, these secondary accumulated therapeutic effects may be desirable to initiate or enhance a therapy outcome, and therefore the delay is selected to encourage these effects, again in a manner that does not alter the primary purpose of inducing a cell and tissue response to PEF. These examples of secondary effects are not an exhaustive list, and other secondary effects desired to be manipulated may also be controlled by selecting an appropriate delay. Exemplary delay and secondary effect relationships are provided in International Patent Application No. PCT / US2021 / 026221, filed April 8, 2021, and entitled "PULSED ELECTRIC FIELD WAVEFORM MANIPULATION AND USE," which is incorporated herein by reference for all purposes.

[0108] Overall, the sensitivity and sensitivity to each secondary therapeutic effect, such as gas formation, discharge, cavitation, muscle contraction, and temperature rise, for a given therapy will vary. Table 1 below summarizes the most applicable ranges of potential delays that can be used to mitigate these effects for various targeted tissue types. Notably, this table focuses on applications for mitigating secondary effects, but there are other cases where it may be desirable to promote these effects, and therefore different ranges of delays may be applicable for a given therapy target.

[0109] [Table 1-1] [Table 1-2]

[0110] The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples." Such examples may include elements in addition to those shown or described. However, the inventors also contemplate examples in which only those elements shown or described are provided. The inventors also contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof) or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0111] In the event of a conflicting usage between this document and any document so incorporated by reference, the usage in this document shall control.

[0112] The terms "a" or "an" are used herein to include "one or more than one," as is common in patent documents, independent of any other instance or usage of "at least one" or "one or more." The term "or" is used herein to refer to a non-exclusive or, such that "A or B" includes "A but not B," "B but not A," and "A and B," unless otherwise indicated. The terms "including" and "in which" are used herein as the plain English equivalents of the respective terms "comprising" and "wherein." Also, in the following claims, the terms "including" and "comprising" are open-ended, i.e., systems, devices, articles, compositions, formulations, or processes that include elements in addition to those recited after such terms in a claim are still considered to fall within the scope of that claim. Also, in the following claims, the terms "first," "second," and "third," etc. are used merely as labels and are not intended to impose numerical requirements on their objects.

[0113] The above description is intended to be illustrative, not restrictive. For example, the above described embodiments (or one or more aspects thereof) may be used in combination with each other. Other embodiments may also be used by those skilled in the art upon review of the above description. The Abstract is provided to comply with 37 C.FR §1.72(b) to enable the reader to quickly ascertain the nature of the present technical disclosure. It should be considered with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above detailed description, various features may be grouped together to simplify the disclosure. This should not be construed as intending that an unclaimed disclosed feature is essential to any claim. Rather, the subject matter of the invention may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are incorporated herein as examples or embodiments into the detailed description, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments may be combined with each other in various combinations or permutations. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. A system for treating a blood vessel, comprising: An energy delivery catheter, the energy delivery catheter comprising an energy delivery body positionable within or in the vicinity of the blood vessel; A generator in electrical communication with the energy delivery body, the generator including at least one energy delivery algorithm, the at least one energy delivery algorithm providing energy to the energy delivery body such that pulsed electric field energy comprising packets of biphasic pulses treats cells of the blood vessel while maintaining the extracellular matrix of the blood vessel in a manner that reduces or eliminates the blood vessel's ability to vasoconstrict; A system comprising the above.

2. The system according to claim 1, wherein treating comprises removing, destroying, or killing the cells.

3. The system according to claim 1, wherein the cells comprise vascular smooth muscle cells involved in vasoconstriction of the blood vessel.

4. The system according to claim 3, wherein treating comprises interrupting local innervation to the vascular smooth muscle cells.

5. The system according to claim 4, wherein interrupting local innervation comprises interrupting the neural pathway from a local area of constriction through at least one vagal afferent fiber contributing to angina symptoms.

6. The system according to claim 1, wherein the cells comprise endothelial cells, and maintaining the extracellular layer leads to regeneration of the endothelial layer of the blood vessel.

7. The energy delivery catheter is configured to deliver a conductive solution, and the algorithm is configured to trigger delivery of the energy and the conductive solution in a timing sequence such that the conductive solution acts as a virtual electrode, the system of claim 1. **Claim 8**: The system of claim 1, wherein the energy delivery catheter is configured to deliver an agent. **Claim 9** The agent includes a chemical substance, a drug, a medicine, a chemotherapeutic agent, an immunotherapeutic agent, a micelle, a liposome, an embolizing agent, a nanoparticle, a drug eluting particle, a gene, a plasmid, a protein, or a combination thereof, the system of claim 8. **Claim 10** Treating includes causing the cell to incorporate the agent, the system of claim 8. **Claim 11** Incorporation of the agent inhibits hyperplastic regrowth of the cell, the system of claim 10. **Claim 12** The energy delivery body includes an expandable member surrounding at least one electrode, the system of claim 1. **Claim 13** The energy delivery body includes a shaft, the at least one electrode includes a plurality of electrodes disposed along the shaft, and the expandable member includes an elongatable expandable member surrounding the plurality of electrodes, the system of claim 12. **Claim 14** The expandable member is configured to exude a fluid, the system of claim 12. **Claim 15** The energy delivery body includes an electrode formed by a plurality of ribbons or wires, the system of claim 1. **Claim 16** The energy delivery body according to claim 1, comprising one or more protrusions, each protrusion bending radially outward from the longitudinal axis of the energy delivery catheter.

17. The system according to claim 16, wherein the one or more protrusions comprise one or more protrusions.

18. The pulsed electric field energy is generated from a waveform including one or more of the following parameters, namely, a) a voltage in the range of 500 to 3,000 V, and b) a frequency in the range of 100 to 800 kHz, and c) a total on-time in the range of 25 to 250 μs, and d) a packet per electrode activation in the range of 1 to 30 packets The system according to claim 1.

19. The pulsed electric field energy is generated from a waveform including one or more of the following parameters, namely, a) a voltage in the range of 1,000 to 6,000 V, and b) a frequency in the range of 10 to 500 kHz, and c) a total on-time in the range of 50 to 500 μs, and d) a packet per electrode activation in the range of 1 to 30 packets The system according to claim 1.

20. The system according to claim 19, wherein the pulsed electric field energy causes interruption of calcification.

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