Lesion optimization using pulsed electric fields

Abstract

Devices, systems, and methods are provided for treating various conditions with PEF energy. PEF energy is typically characterized as high-voltage pulsed energy configured to be delivered in one or more doses. The one or more doses generate a lesion in tissue. Lesion size varies depending on the parameters of the PEF waveform and dose, among other effects such as tissue type. Thus, different waveforms and doses of PEF energy provide different results, particularly different lesion sizes and types. Systems, devices, and methods are provided that allow a physician or user to control the PEF energy delivered to provide a desired result and / or provide predictive information that a user can utilize to generate a desired result.

Description

[Background technology]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 336,197, filed April 28, 2022, which is incorporated by reference in its entirety.

[0002] Pulsed electric field (PEF) therapy uses brief application of electrical energy to the body for the treatment of disease and pain. In some cases, such delivery is to tissues that are intraluminally accessible within or through a body lumen, passageway, or similar anatomical structure. Such devices typically include a flexible elongated shaft and an energy delivery element mounted thereon to traverse tortuous luminal anatomical structures and deliver such energy to remote or enclosed locations such as body lumens. Such devices have been developed, for example, to treat blood vessels in the pulmonary passageways or vasculature, or to treat various organs such as the heart, stomach, intestines, etc. In other cases, delivery is directed through open surgery or through a percutaneous approach. Different environments, such as airways versus blood-filled environments, and different diseases, such as those affecting superficial tissues versus those affecting deeper layers or tissues, lead to various designs for these devices.

[0003] PEF energy disrupts the integrity of target tissue cells, which initiates a cascade of biochemical processes that induce different forms of cell death, including necrosis, apoptosis, aponecrosis, necroptosis, and / or pyroptosis. Because PEF therapy does not rely on thermal processes, cells die within their volume of tissue in vivo without modifying the interstitial proteins and extracellular matrix within the volume, thus promoting the preserved function of their important and sensitive anatomical structures, such as major vasculature, luminal systems such as the common bile duct, and tissue structures such as the pleura. Thus, PEF therapy offers a superior safety profile versus other ablation modalities. As a result of their properties, PEF is being applied with increasing regularity in a variety of different disease conditions, including cancer, cardiac disease, and pulmonary disease.

[0004] Variations exist among clinical PEF systems, including differences in waveform parameters and delivery polarity (i.e., bipolar or unipolar). In a bipolar electrode configuration, energy is delivered between an effector device placed in or adjacent to the targeted environment. Conversely, unipolar systems deliver energy from an effector device placed in or adjacent to the targeted environment to a remote dispersive electrode that serves as electrical return. The dispersive electrode has sufficient surface area to distribute the PEF energy widely enough that no therapeutic effect is encountered at that location. Traditionally, radio frequency (RF) energy has been used to treat a variety of ailments, including cardiovascular conditions. Such energy can be applied to the heart and vessels for the treatment of a variety of conditions, including atherosclerosis (particularly in the prevention of restenosis following angioplasty) and atrial fibrillation. Atrial fibrillation is the most common sustained cardiac arrhythmia and significantly increases the risk of death in affected patients, particularly by causing stroke. In this phenomenon, the heart deviates from normal sinus rhythm due to the production of erroneous electrical impulses. Atrial fibrillation is believed to be initiated in the myocardial sleeve of the pulmonary veins (PVs) due to the presence of automaticity in cells within the myocardial tissue of the PVs. Pacemaker activity from these cells is believed to result in the formation of ectopic beats that initiate atrial fibrillation. The PVs are also believed to be important in the maintenance of atrial fibrillation because the disorganized architecture and electrophysiological properties of these vessels provide an environment in which atrial fibrillation can be perpetuated. Thus, destruction or removal of these abnormal pacemaker cells within the myocardial sleeve of the PVs is the goal, and atrial fibrillation is often treated by delivering therapeutic energy to the pulmonary veins. However, due to reports of PV stenosis, the approach has traditionally been modified to target the PV cavity to achieve a conduction block between the PVs and the left atrium. In addition to the pulmonary veins, the PV cavity encompasses the left atrial roof and posterior wall, and in the case of the right pulmonary vein cavity, a portion of the interatrial septum. In some cases, this technique results in higher success rates and lower complication rates compared to pulmonary vein ostium isolation.

[0005] Thermal ablation therapy, specifically radiofrequency (RF) ablation, is currently the "gold standard" for treating symptomatic atrial fibrillation due to focal tissue necrosis. Typically, RF ablation is used to create a ring of ablation lesions around the outside of the ostium of each of the four pulmonary veins. The RF current causes desiccation of the tissue by creating a localized area of ​​heat that results in discrete coagulation necrosis. The necrotic tissue acts as a conduction block, thereby electrically isolating the vein.

[0006] Despite improvements in re-establishing sinus rhythm using available methods, both success rates and safety are limited by the thermal nature of these procedures. Complications include pulmonary vein stenosis, phrenic nerve injury, esophageal injury, left atrioesophageal fistula, peresophageal vagus nerve injury, perforation, thromboembolism, vascular complications, and acute coronary artery occlusion, to name a few. Thus, while keeping the technique in clinical practice, safer and more versatile methods of removing abnormal tissue, such as pulsed electric field therapy (PEF), are being used. However, PEF therapy has different cellular effects on tissue, so tissue reacts differently than when subjected to RF ablation. As a result, traditional cues that physicians monitor throughout the ablation procedure are largely inapplicable and may lead to inferior outcomes, such as incomplete block of abnormal electrical rhythms. In addition, the different effects of PEF energy on tissue cause different lesion sizes than RF and various other differences not anticipated by physicians. Therefore, improvements in methods, devices, and systems that improve the usability of PEF systems and the outcome of the resulting treatment are desirable. Such treatment 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]

[0007] Described herein are embodiments of devices, systems, and methods for treating target tissue, particularly cardiac tissue. The present invention also relates to the following numbered clauses:

[0008] 1. A system for generating a lesion in tissue, comprising: a treatment catheter having at least one delivery electrode; a generator electrically coupleable to the treatment catheter, the generator being configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrodes, the generator including a processor that generates at least one algorithm, the processor generating the algorithm based on at least one of the one or more inputs by a user; A system comprising:

[0009] 2. The system of claim 1, wherein the processor dynamically generates the algorithm based on one or more inputs in real time.

[0010] 3. The system of claim 1, wherein the processor selects an algorithm from a group of algorithms based on one or more inputs.

[0011] 4. The system of any of the above clauses, wherein the one or more inputs comprise a desired dimension of the lesion.

[0012] 5. The system of any of the above clauses, wherein one or more inputs comprise a threshold for temperature rise.

[0013] 6. The system of any of the above clauses, wherein the one or more inputs comprise a threshold value for muscle contraction.

[0014] 7. The system of any of the above clauses, wherein the one or more inputs comprise a threshold administration time.

[0015] 8. The system of any of the above clauses, wherein the one or more inputs comprises a plurality of the one or more inputs.

[0016] 9. The system of claim 8, wherein at least one of the one or more inputs comprises a plurality of the one or more inputs.

[0017] 10. The system of claim 8, wherein the processor utilizes a plurality of one or more inputs and is based on a ranking or weighting of the plurality of one or more inputs.

[0018] 11. The system of any of the above clauses, wherein the processor utilizes one or more inputs and at least one default value to generate the algorithm.

[0019] 12. The system of any of the above clauses, wherein at least one of the one or more inputs is selectable by the user from a menu.

[0020] 13. The system of any of the above clauses, wherein at least one of the one or more inputs is user programmable via a user interface.

[0021] 14. The system of any of the above clauses, wherein the processor correlates one or more inputs to an electric field strength threshold.

[0022] 15. The system of claim 14, wherein the processor determines an electric field strength of at least one delivery electrode.

[0023] 16. The system of claim 15, wherein the processor correlates the electric field strength to an electric field strength threshold.

[0024] 17. The system of any of the above appended claims, wherein the processor selects at least one parameter of at least one algorithm and generates the electrical signal.

[0025] 18. The system of any of the above clauses, wherein the processor modifies the algorithm based on tissue thickness.

[0026] 19. The system of claim 18, wherein the tissue thickness is determined by ultrasound, magnetic resonance, or fluoroscopy.

[0027] 20. A system for delivering therapy to tissue, comprising: a treatment catheter having at least one delivery electrode; a generator electrically coupleable to the treatment catheter, the generator being configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode to provide treatment, the generator including a processor providing at least one algorithm, the processor generating a prediction of an outcome of the treatment based on at least one of the one or more inputs by a user; A system comprising:

[0028] 21. The system of claim 20, wherein the prediction comprises at least one of lesion size, temperature rise, muscle contraction, and / or administration time.

[0029] 22. The system of claim 21, wherein at least one lesion dimension comprises a lesion depth.

[0030] 23. The system of any of claims 21-22, wherein at least one lesion dimension comprises a lesion width.

[0031] 24. The system of any of claims 20-23, wherein one or more inputs comprise a threshold for temperature rise.

[0032] 25. The system of any of claims 20-24, wherein one or more inputs comprise a threshold value for muscle contraction.

[0033] 26. The system of any of claims 20-25, wherein one or more inputs comprise a threshold administration time.

[0034] 27. The system of any of Clauses 20-26, wherein the one or more inputs comprise a plurality of inputs.

[0035] 28. The system of claim 27, wherein at least one of the one or more inputs comprises a plurality of the one or more inputs.

[0036] 29. The system of any of claims 20-28, wherein at least one of the one or more inputs is selectable by the user from a menu.

[0037] 30. The system of any of claims 20-29, wherein at least one of the one or more inputs is user programmable using a user interface.

[0038] 31. The system of claim 20, wherein the one or more inputs comprise a single input.

[0039] 32. The system of claim 31, wherein the single input comprises a time of administration.

[0040] 33. A system for generating a lesion in tissue, comprising: a treatment catheter having at least one delivery electrode; a generator electrically coupleable to the treatment catheter, the generator being configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode to provide treatment, the generator including a processor providing at least one algorithm, the processor generating a spacing distance recommendation between a lesion and a next lesion; A system comprising:

[0041] 34. The system of claim 33, wherein the tissue comprises cardiac tissue and the delivery electrode is configured to deliver energy to a surface of the cardiac tissue in a manner to create a parabolic lesion.

[0042] 35. The system of claim 34, wherein the parabolic lesion has a stunning area.

[0043] 36. The system of claim 35, wherein the spacing distance recommendation positions a subsequent lesion sufficiently close to the subsequent lesion such that the stunning zone at least partially overlaps with the subsequent lesion.

[0044] 37. The system of claim 36, wherein the subsequent lesion has a stunning zone and the spacing distance recommendation at least overlaps the stunning zone of one lesion with the stunning zone of the subsequent lesion such that tissue between the centers of the lesions forms a continuous, permanent lesion.

[0045] 38. A system according to any of claims 33-37, wherein the processor dynamically generates spacing distance recommendations between lesions based on local electrophysiological information.

[0046] 39. The system of claim 38, wherein local electrophysiological information is obtained from intraprocedural voltage maps and post-application electrogram voltage changes.

[0047] 40. The system of claim 38, wherein local electrophysiological information is obtained through observed voltage reduction in tissue in response to energy delivery.

[0048] 41. The system of any of claims 33-40, wherein the processor is configured to modify the spacing distance recommendation based on tissue thickness.

[0049] 42. The system of claim 41, wherein the tissue thickness is determined by ultrasound, magnetic resonance, or fluoroscopy.

[0050] 43. The system of any of claims 33-41, further comprising an electroanatomical mapping system, wherein the spacing distance recommendation is visually displayed by the electroanatomical mapping system.

[0051] 44. A system for generating a lesion in tissue, comprising: A system comprising: a generator electrically coupleable to a treatment catheter, the system including a processor that generates at least one algorithm, the processor being configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode of the treatment catheter, the processor generating the algorithm based on at least one of one or more inputs by a user.

[0052] 45. A system for providing therapy to a tissue, comprising: 1. A system comprising: a generator electrically coupleable to a treatment catheter, the system being configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode of the treatment catheter to provide treatment; and a processor providing at least one algorithm, the processor generating a prediction of an outcome of the treatment based on at least one of one or more inputs by a user.

[0053] 46. ​​A system for generating a lesion in tissue, comprising: 1. A system comprising: a generator electrically coupleable to a treatment catheter, the system being configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode of the treatment catheter to provide treatment; and a processor providing at least one algorithm, the processor generating a spacing distance recommendation between an ablation lesion and a next ablation lesion.

[0054] These and other embodiments are described in further detail in the following description taken in conjunction with the accompanying drawing figures.

[0055] (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]

[0056] 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.

[0057] [Figure 1] FIG. 1 illustrates an embodiment of a tissue modification system.

[0058] [Diagram 2] 2A-2B illustrate an embodiment of a treatment catheter configured to deliver focused therapy.

[0059] [Diagram 3] FIG. 3 illustrates an embodiment of a signal waveform prescribed by the energy delivery algorithm.

[0060] [Figure 4] FIG. 4 illustrates a portion of the heart showing cuts in the right and left atria in which the treatment catheters are positioned.

[0061] [Diagram 5] FIG. 5 illustrates an embodiment of a signal waveform prescribed by the energy delivery algorithm.

[0062] [Figure 6] FIG. 6 is a schematic illustration of an ablation lesion generated by a catheter such as that illustrated in FIG. 2B.

[0063] [Figure 7] FIG. 7 illustrates an example of energy delivery at three different levels or doses.

[0064] [Figure 8] FIG. 8 illustrates the occurrence of two adjacent overlapping lesions.

[0065] [Figure 9] FIG. 9 illustrates the resulting continuous lesion formed from energy delivered by the catheter.

[0066] [Figure 10] FIG. 10 illustrates the effect of multiple administrations on lesion size.

[0067] [Figure 11] FIG. 11 illustrates the effect of overlapping lesions.

[0068] [Figure 12] FIG. 12 illustrates the area that received dual dosing from both catheter placements and is considered part of the treatment depth of the contiguous lesion.

[0069] [Figure 13] FIG. 13 illustrates the resulting continuous lesion having an increased treatment depth compared to FIG.

[0070] [Figure 14] FIG. 14 illustrates a lesion spacing that is larger than that of FIG. 11 and an area receiving dual dosing from both catheter placements that are offset upwards.

[0071] [Figure 15] FIG. 15 illustrates a continuous lesion as a result of the lesion of FIG.

[0072] [Figure 16]FIG. 16 illustrates an example correlation between treatment depth and lesion spacing at three different energy dosages.

[0073] [Figure 17] 17A-17B illustrate the use of two different treatment protocols on different areas of the heart.

[0074] [Figure 18] FIG. 18 illustrates an exemplary placement of anterior and posterior lesions.

[0075] [Figure 19] FIG. 19 illustrates the pulmonary vein isolation rate at 90-day remapping.

[0076] [Figure 20] FIG. 20 illustrates a system having user inputs that are used by the system to generate or select a particular energy delivery algorithm that optimizes the treatment waveform and / or administration for a desired treatment.

[0077] [Figure 21] 21A-21D illustrate exemplary individual relationships between treatment / lesion depth and the parameters of packet number, frequency, packet delivery rate, and packet duration.

[0078] [Figure 22] 22A-22D illustrate exemplary individual relationships between treatment / lesion width and the parameters of packet number, frequency, packet delivery rate, and packet duration.

[0079] [Figure 23] 23A-23D illustrate exemplary individual relationships between treatment / lesion width and the parameters of packet number, frequency, packet delivery rate, and temperature rise.

[0080] [Figure 24]24A-24D illustrate exemplary individual relationships between treatment / lesion width and parameters of packet number, frequency, packet delivery rate, and muscle contraction.

[0081] [Diagram 25] 25A-25C illustrate example electric field distributions for a catheter embodiment for delivering PEF energy into the heart.

[0082] [Figure 26] FIG. 26 illustrates a system that provides a prediction of lesion size.

[0083] [Figure 27] FIG. 27 illustrates a system that provides a prediction of lesion size based on desired administration time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0084] Detailed Description Devices, systems, and methods are provided for treating various conditions with PEF energy. PEF energy is typically characterized as high voltage pulsed energy configured to be delivered in one or more doses. Each energy dose delivered to the target tissue is configured to maintain the temperature at or within the target tissue below the threshold for thermal ablation. Instead of inducing damage from thermal ablation, described as extracellular protein coagulation, the effect is considered non-thermal, and such energy modifies or destroys cells within the tissue, but preserves the tissue's underlying protein extracellular matrix, which provides the tissue's interstitial architectural structure and structure-related functions. In some cases, this allows for tissue regeneration, such as by regrowth of the extracellular matrix. In addition, nearby sensitive tissues are spared damage. It is understood that the dose can be titrated or moderated over time to further reduce or eliminate heat accumulation during the treatment procedure. It is understood that in some embodiments, energy delivery is actuated by various mechanisms, such as by use of a foot switch operatively connected to an actuator or generator on the device. Such actuation typically provides a single energy deposition or activation.

[0085] Target tissue cells include, to name a few, cells of the digestive system (e.g., mouth, glands, esophagus, stomach, duodenum, jejunum, ileum, intestines, colon, rectum, liver, gallbladder, pancreas, anal canal, etc.), cells of the respiratory system (e.g., nasal cavity, larynx, trachea, bronchi, lungs, etc.), cells of the urinary system (e.g., kidney, ureter, bladder, urethra, etc.), cells of the reproductive system (e.g., genitalia, ovaries, fallopian tubes, uterus, cervix, vagina, testes, epididymis, vas deferens, seminal vesicles, prostate, glands, penis, scrotum, etc.), cells of the endocrine system (e.g., pituitary gland, pineal gland, etc.), and cells of the urinary system (e.g., kidney, ureter, bladder, urethra, etc.). Cells may be treated anywhere throughout the body, including cells of the circulatory system (e.g., heart, arteries, veins, etc.), cells of the lymphatic system (e.g., lymph nodes, bone marrow, thymus, spleen, etc.), cells of the nervous system (e.g., brain, spinal cord, nerves, ganglia, etc.), cells of the eye (e.g., retina, macula, rod and cone layer, retinal pigment epithelium, optic nerve, choroid, sclera, etc.), cells of the muscular system (e.g., muscle cells, etc.), and cells of the skin (e.g., epidermis, dermis, subcutaneous tissue, etc.).

[0086] The conditions treated include arrhythmias. When treating atrial fibrillation, a closed path of continuous ablation lesions, such as around the outer ostia of the pulmonary veins, is typically created by delivery of PEF energy with either a focused catheter or a single shot catheter. In addition, focused catheters can be used to create many other types of lesions, particularly lines along various surfaces of cardiac tissue. In one embodiment, an inferior vena cava-tricuspid annulus isthmus line is created for the treatment of typical atrial flutter in the right atrium. In another embodiment, a top and / or bottom line is created for a box lesion along the posterior wall of the left atrium for patients suffering from atrial fibrillation, particularly for persistent atrial fibrillation. In another embodiment, a mitral isthmus line is created along the anterior or lateral wall of the left atrium for atypical atrial flutter. In yet another embodiment, a ventricular line is created that connects two non-excitable boundaries that are important for the initiation or maintenance of reciprocal ventricular arrhythmias, typically in patients suffering from ventricular tachycardia resulting from ischemic heart disease. Other conditions to be treated include pulmonary disorders such as chronic obstructive pulmonary disease, chronic bronchitis, mucus hypersecretion, asthma, and cystic fibrosis, to name a few. Still other conditions comprise coagulation disorders. In some embodiments, the disorder comprises a neurological disorder, e.g., injury or disease. In some embodiments, the disorder comprises a cardiovascular disorder, such as degenerative heart disease, heart failure disease, coronary artery disease, ischemia, angina pectoris, acute coronary syndrome, peripheral vascular disease, peripheral arterial disease, cerebrovascular disease, or atherosclerosis. In some embodiments, the disorder comprises an immune disorder, e.g., an autoimmune disorder. In some embodiments, the disorder comprises a liver disease. In some embodiments, the disorder comprises a tumor or cancer, such as a hematological or solid tissue cancer.

[0087] The present devices, systems, and methods deliver therapeutic energy to tissue within the body and provide tissue modification, typically creating a lesion. A lesion is an area of ​​tissue damage, whether this is permanent or reversible. When treating a tumor, the lesion includes a portion of the tumor that is destroyed by the received PEF energy. When treating atrial fibrillation, the lesion includes a portion of the heart wall where cells have been killed by the received PEF energy. Such lesions are often positioned along the entrance to the pulmonary veins in the treatment of atrial fibrillation. Such tissue modification creates a conduction block in the tissue, preventing the transmission of abnormal electrical signals.

[0088] In general, the tissue modification system includes a specialized catheter, a high voltage biphasic waveform generator, and at least one distinct energy delivery algorithm. Additional accessories and devices may be utilized. It is understood that a variety of catheter designs may be utilized and specifically specialized for specific treatments. For illustrative purposes, simplified designs are provided when describing the overall system. Such simplified designs provide focused therapy. However, it is understood that various other types of catheters and delivery electrodes may also be used.

[0089] 1 illustrates an embodiment of a tissue modification system 100 used to treat cardiac tissue, comprising a treatment catheter 102, a mapping catheter 104, a return electrode 106, a waveform generator 108, and an external cardiac monitor 110. While this example is specific to treating cardiac tissue for the treatment of arrhythmias in particular, it should be understood that this is by way of example only. Such lesion characteristics and formation may be applicable to a variety of other tissue types and locations throughout the body as mentioned herein.

[0090] In this embodiment, the heart is accessed via the right femoral vein FV by a suitable access procedure, such as the Seldinger technique. Typically, a sheath 112 is inserted into the femoral vein FV, acting as a conduit through which various catheters and / or tools may be advanced, including the treatment catheter 102 and the mapping catheter 104. It should be understood that in some embodiments, the treatment catheter 102 and the mapping catheter 104 are combined into a single device. As illustrated in FIG. 1, the distal ends of the catheters 102, 104 are advanced through the inferior vena cava, through the right atrium, through a transseptal puncture, and into the left atrium to access the entrance to the pulmonary veins. The mapping catheter 104 is used to perform cardiac mapping, which refers to the process of identifying the temporal and spatial distribution of myocardial potentials during a particular cardiac rhythm. Cardiac mapping during abnormal cardiac rhythms aims to elucidate the mechanics of the cardiac rhythm, describe the propagation of activation from its onset to its completion within a region of interest, and identify important sites of emergence or conduction to serve as targets for therapy. Once the desired treatment location has been identified, the treatment catheter 102 is utilized to deliver the treatment energy.

[0091] In this embodiment, the proximal end of the treatment catheter 102 is electrically connected to a waveform generator 108, which is software controlled with a regulated energy output that produces high frequency, short duration energy that is delivered to the catheter 102. It should be understood that in various embodiments, the output is controlled or modified to achieve a desired voltage, current, or combination thereof. In this embodiment, the proximal end of the mapping catheter 104 is also electrically connected to the waveform generator 108, and the electronics for performing the mapping procedure are contained within the generator 108. However, it is contemplated that the mapping catheter 104 may alternatively be coupled to an electroanatomical mapping (EAM) system (e.g., the CARTO® system by Biosense Webster / Johnson & Johnson, the EnSite TM by St. Jude Medical / Abbott, or the like). TMsystem, KODEX-EPD system by Philips, Rhythmia HDX by Boston Scientific TM It should be understood that the catheter 102 may be connected to a separate external device capable of providing a mapping procedure, such as a separate mapping catheter 104 (such as a CT system). Similarly, in some embodiments, a separate mapping catheter 104 is not used and mapping features are built into the catheter 102.

[0092] In this embodiment, the generator 108 is connected to an external cardiac monitor 110 to enable coordinated energy delivery with cardiac signals sensed from the patient P. The generator synchronizes the energy output to the patient's cardiac rhythm. The cardiac monitor provides a trigger signal to the generator 108 when it detects the patient's cardiac cycle R-wave. This trigger signal and the generator's algorithms ensure that the energy delivery is synchronized with the patient's cardiac cycle, reducing the potential for arrhythmia due to the energy delivery. Typically, a foot switch allows the user to initiate and control the delivery of the energy output. The generator user interface (UI) provides the user with both audible and visual information regarding the energy delivery and generator operating status.

[0093] In this embodiment, the delivery catheter 102 is designed to be monopolar, with the distal end of the catheter 108 having a delivery electrode 122 and a return electrode 106 positioned on the skin on the outside of the body, typically on the thigh, lower back, or back. FIG. 2A illustrates an embodiment of a treatment catheter 102 configured to deliver focused therapy. In this embodiment, the catheter 102 comprises an elongated shaft 120 having a delivery electrode 122 near its distal end 124 and a handle 126 near its proximal end 128. The delivery electrode 122 is shown as a "solid tip" electrode having a cylindrical shape with a distal face having a continuous surface. In some embodiments, the cylindrical shape has a diameter across its distal face of about 2-3 mm and a length along the shaft 120 of about 1 mm, 2 mm, 1-2 mm, 3 mm, 4 mm, 3-4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, etc. It should be understood that such electrodes are typically hollow, but are referred to as solid due to their visual appearance. In some embodiments, the catheter 102 has an overall length of 50-150 cm, preferably 100-125 cm, more preferably 110-115 cm. Similarly, in some embodiments, it has a 7 Fr outer diameter of 3-15 Fr, preferably 4-12 Fr, more preferably 7-8.5 Fr. It should be understood that in some embodiments, the shaft 120 has a deflectable end portion 121, and optionally, the deflectable end portion 121 may have a length of 50-105 mm, resulting in a curve with a diameter ranging from about 15-55 mm. Deflection may be accomplished by a variety of mechanisms, including a pull wire extending to the handle 126. The handle 126 is thus used to manipulate the catheter 102, and in particular to steer the distal end 124 during delivery and treatment. Energy is provided to the catheter 102 , and thus to the delivery electrode 122 , via a cable 130 that is connectable to the generator 108 .

[0094] A pulsed electric field (PEF) is provided by the generator 108 and delivered to the tissue through a delivery electrode 122 that is placed on or near the targeted tissue area. It should be understood that in some embodiments, the delivery electrode 122 is positioned in contact with a conductive material that also contacts the targeted tissue. Such solutions may include isotonic or hypertonic solutions. These solutions may further include adjuvant materials such as chemotherapy or calcium to further enhance the therapeutic efficacy both for the focused treatment and for the potential localized invasion area of ​​the targeted tissue type. High voltage short duration biphasic electrical pulses are then delivered through the electrodes 122 in the vicinity of the targeted tissue. These electrical pulses are provided by at least one energy delivery algorithm 152. In some embodiments, each energy delivery algorithm 152 prescribes a signal having a waveform that comprises a series of energy packets, each energy packet comprising a series of high voltage pulses. In such an embodiment, the algorithm 152 defines 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, and the fundamental frequency of the pulse sequence, to name a few. Additional parameters may include switching times between polarities in biphasic pulses, dead times between biphasic cycles, and pause times between packets, which will be explained in more detail in later sections. There may be fixed pause periods between packets, or the packets may be beat-synchronized to the cardiac cycle and thus variable with the patient's heart rate. There may be various deliberate pause period algorithms, or no pause periods may be applied between packets. Feedback loops and / or the like based on sensor information and auto-shutoff specifications may be included.

[0095] It should be appreciated that in various embodiments, the treatment catheter 102 includes various specialized features. For example, in some embodiments, the catheter 102 includes a mechanism for real-time measurement of the contact force applied by the catheter tip to the patient's heart wall during the procedure. In some embodiments, this mechanism comprises a three-axis optical force sensor contained within the shaft 120 and utilizing white light interferometry. By monitoring and modifying the applied force throughout the procedure, the user is able to better control the catheter 102 to create more consistent and effective lesions.

[0096] In some embodiments, catheter 102 includes one or more additional electrodes 125 (e.g., ring electrodes) positioned proximal to delivery electrode 122 and along shaft 120 as illustrated in FIG. 2B. In some embodiments, some or all of the additional electrodes can be used for stimulation (for electrophysiological mapping) and recording, and thus a separate cardiac mapping catheter is not required when using catheter 102 for lesion creation or for other purposes, such as sensing.

[0097] In some embodiments, the catheter 102 includes a thermocouple temperature sensor, optionally embedded within the delivery electrode 122. Similarly, in some embodiments, the catheter 102 includes a lumen that can be used for irrigation and / or aspiration. Typically, the lumen connects with one or more ports along the distal end of the catheter 102 for injection of an isotonic saline solution to irrigate or for removal of microbubbles, for example.

[0098] In some embodiments, the catheter 102 includes one or more sensors that can be used to determine temperature, impedance, resistance, capacitance, conductivity, permittivity, and / or conductance, to name a few. In some embodiments, one or more of the electrodes act as the one or more sensors. In other embodiments, the one or more sensors are separate from the electrodes. The sensor data can be used to plan therapy, monitor therapy, and / or provide feedback directly via the processor 154, which can then modify the energy delivery algorithm 152. For example, impedance measurements can be used to determine the initial dose to be applied, as well as whether there is a need for further therapy.

[0099] 1, in this embodiment, the generator 108 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.

[0100] In some embodiments, the generator 108 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 this embodiment, the system controller includes a cardiac synchronization trigger monitor that allows the pulsed energy output to be synchronized to the patient's cardiac rhythm. The generator takes an alternating current (AC) mains power source to power multiple direct current (DC) power supplies. The generator's controller can cause the DC power supplies to charge a high energy capacitor storage bank before energy delivery begins. At the start of therapy energy delivery, the generator's controller, high energy storage bank, and biphasic pulse amplifier can operate simultaneously to generate a high voltage mid-frequency output.

[0101] It should be understood that numerous generator electrical architectures can be employed to implement 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.

[0102] The user interface 150 may include a touch screen and / or more traditional buttons to enable an operator to enter patient data, select a treatment algorithm (e.g., the energy delivery algorithm 152), initiate energy delivery, view records stored on the storage / readout unit 156, and / or otherwise communicate with the generator 108.

[0103] In some embodiments, the user interface 150 is configured to receive operator-defined inputs that can include one or more timing aspects of the duration or administration time of energy delivery, energy delivery pulse, power, and / or mode of operation, one or more desired lesion dimensions, type of treatment, treatment location, type of tissue, type of catheter or electrode configuration, temperature limits, muscle contraction limits, and combinations thereof, to name a few.

[0104] Exemplary operational modes 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 thereof.

[0105] As mentioned, in some embodiments, the system 100 also includes a mechanism for obtaining an electrocardiogram (ECG), such as an external cardiac monitor 110, in situations where cardiac synchronization is desired. Exemplary cardiac monitors are available from AccuSync Medical Research Corporation and Ivy Biomedical Systems, Inc. In some embodiments, the external cardiac monitor 110 is operatively connected to the generator 108. The cardiac monitor 110 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 108 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.

[0106] In some embodiments, the processor 154 modifies and / or switches between energy delivery algorithms, monitors energy delivery and any sensor data, and reacts to the monitored data via a feedback loop, among other activities. In some embodiments, the processor 154 is configured to execute one or more algorithms for activating a feedback control loop based on one or more measured system parameters (e.g., current), one or more measured tissue parameters (e.g., impedance), and / or a combination thereof.

[0107] The data storage / readout unit 156 stores data related to the delivered treatment, etc., and can be downloaded, optionally, by connecting a device (e.g., a laptop or thumb drive) to the communication port. In some embodiments, the device has local software, for example, stored on the data storage / readout unit 156 and used to direct the download of information, such as instructions executable by the processor 154. In some embodiments, the user interface 150 allows the operator to select to download data to a device and / or system, such as, but not limited to, a computing device, tablet, mobile device, server, workstation, cloud computing device / system, and / or the like. The communication port, which may allow for wired and / or wireless connectivity, allows for data download, as thus described, but can also allow for data upload, such as uploading custom algorithms or providing software updates.

[0108] As described herein, various energy delivery algorithms 152 can be programmable or pre-programmed into the generator 108, such as stored in a memory or data storage / readout unit 156. Alternatively, the energy delivery algorithms can be added into the data storage / readout unit to be executed by the processor 154. Each of these algorithms 152 may be executed by the processor 154.

[0109] It should be appreciated that in some embodiments, the system 100 includes automated therapy delivery algorithms that dynamically respond to, adjust, and / or terminate therapy in response to inputs such as temperature, impedance at various voltages or AC frequencies, treatment duration, or other timing aspects of energy delivery pulses, treatment power, and / or system status.

[0110] As mentioned, in some embodiments, the cardiac monitor provides a trigger signal to the generator 108 when it detects the patient's cardiac cycle R wave. This trigger signal and generator algorithm ensures that the energy delivery is synchronized with the patient's cardiac cycle, reducing the potential for arrhythmia due to the energy delivery. This trigger is within a few milliseconds of the peak of the R wave (of the ECG QRS complex) to avoid induction of arrhythmia, which may occur if the energy pulse is delivered on the T wave, and to ensure that the energy delivery occurs at a consistent phase of the cardiac contraction. 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.

[0111] As mentioned above, one or more energy delivery algorithms 152 can be programmable or preprogrammed into the generator 108 for delivery to the patient P. The one or more energy delivery algorithms 152 define electrical signals that provide energy delivered to the walls of the heart that is non-thermal (e.g., below the threshold for thermal ablation, below the threshold for inducing coagulative thermal damage), reduces or avoids inflammation, and / or prevents denaturation of interstitial proteins within luminal structures. Generally, the algorithms 152 are tailored to affect tissue to a predetermined depth and / or volume and / or to target specific types of cellular responses to the delivered energy.

[0112] FIG. 3 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 biphasic cycle. In this embodiment, the biphasic pulses are symmetric such that the set voltage 416 is the same for the positive and negative peaks. Here, the biphasic symmetrical wave is also a square wave such that the magnitude and duration of the positive voltage wave is approximately equal to the magnitude and duration of the negative voltage wave. A. Voltage

[0113] The voltages used and considered may be the crest of a square waveform, the peak in a sine or sawtooth waveform, or the RMS voltage of a sine or sawtooth waveform. In some embodiments, the energy is delivered in a monopolar manner and each high voltage pulse or set voltage 416 is between about 500V and 10,000V, including about 250V, 500V, 1,000V, 1,500V, 2,000V, 2,500V, 3,000V, 3,500V, 4,000V, 4,500V, 5,000V, 5,500V, 6,000V, particularly between about 3,500V and 4,000V, between about 3,500V and 5,000V, between about 3,500V and 6,000V (including all values ​​and subranges therebetween), to name a few. 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 device 102 due to the inherent impedance of the device 102, or not taking into account losses along the length, i.e., the voltage delivered can be measured at the generator or at the tip of the instrument.

[0114] 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 concentration and effective dosage of electrical energy 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%. B.Frequency

[0115] It should be understood that the number of biphasic cycles per second of time is the frequency at which 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. In some embodiments, the signal has a frequency in the range of 50 kHz to 1 MHz, more specifically, 50 kHz to 1,000 kHz. It should be understood that at some voltages, frequencies at or below 100 to 250 kHz may cause undesired muscle stimulation. Thus, in some embodiments, the signal has a frequency in the range of 300-800 kHz, 400-800 kHz, or 500-800 kHz, such as 300 kHz, 400 kHz, 450 kHz, 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, etc. In addition, cardiac synchronization is typically 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. C. Voltage-frequency balance

[0116] 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 600kHz, while in other cases, treatment may be delivered using 2,000V with a waveform frequency of 400kHz. D. Packet

[0117] As mentioned, the algorithm 152 typically 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. 3, the first packet 402 has a cycle count 420 of 2 (i.e., four biphasic pulses). In some embodiments, the cycle count 420 is set from 2 to 1,000 (including all values ​​and subranges therebetween) per packet. In some embodiments, the cycle count 420 is between 5 and 1,000 per packet, between 2 and 10 per packet, between 2 and 20 per packet, between 2 and 25 per packet, between 10 and 20 per packet, between 20 and 30 per packet, between 25 per packet, between 20 and 40 per packet, between 30 per packet, between 20 and 50 per packet, between 30 and 60 per packet, up to 60 per packet, up to 80 per packet, up to 100 per packet, up to 1,000 per packet, or up to 2,000 per packet (including all values ​​and subranges therebetween).

[0118] Packet duration is determined by cycle count, among other factors. For a matching pulse duration (or sequence of positive and negative pulse durations for a biphasic waveform), 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 within 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 within the range of about 100-1,000 microseconds, such as 150, 200, 250, 500, or 1,000 microseconds.

[0119] The number of packets or packet count delivered during a treatment typically comprises 1 to 250 packets, including all values ​​and subranges therebetween, in some embodiments, the number of packets delivered during a treatment comprises 10 packets, 15 packets, 20 packets, 25 packets, 30 packets, or more than 30 packets. E. Pause period

[0120] In some embodiments, the time between packets, referred to as the sleep period 406, is set to between about 0.001 seconds and about 5 seconds, including all values ​​and subranges therebetween. In other embodiments, the sleep period 406 ranges from about 0.01 to 0.1 seconds, including all values ​​and subranges therebetween. In some embodiments, the sleep period 406 is between about 0.5 milliseconds and 500 milliseconds, between 1 to 250 milliseconds, or between 10 to 100 milliseconds, to name a few. F. Batch

[0121] 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.

[0122] 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.

[0123] 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. G. Switching Times and Dead Times

[0124] The switching time, also known as the interphase delay, is the energy-free delay or period delivered between the positive and negative peaks of a biphasic pulse, as illustrated in FIG. 3. 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.

[0125] A delay may also be interposed between each biphasic cycle, referred to as a "dead time" or inter-pulse delay. Dead times occur between biphasic pulses, but within a packet. This is in contrast to a rest period or inter-packet delay, which occurs 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.

[0126] Delays such as switch times and dead times are introduced into the packets to reduce the effect of biphasic cancellation in the waveform. In some cases, both the switch times and dead times are increased together to enhance the effect. In other cases, only the switch times or only the dead times are increased to induce this effect. G. Waveform

[0127] FIG. 3 illustrates an embodiment of a waveform 400 having symmetrical pulses such that the voltage and duration of the pulse in one direction (i.e., positive or negative) is equal to the voltage and duration of the pulse in the other direction. It should be understood that in other embodiments, the waveform 400 has a voltage imbalance. For example, each packet 402, 404 may consist of a first biphasic cycle (comprising a first positive pulse peak 408 having a first voltage V1 and a first negative pulse peak 410 having a second voltage V2) and a second biphasic cycle (comprising a second positive pulse peak 408' having a first voltage V1 and a second negative pulse peak 410' having a second voltage V2). Here, the first voltage V1 exceeds the second voltage V2. The first and second biphasic cycles are separated by a dead time 412 between each pulse. Thus, the voltage in one direction (i.e., positive or negative) exceeds the voltage in the other direction, and therefore the area under the positive part of the curve is not equal to the area under the negative part of the curve. This unbalanced waveform may result in a more pronounced therapeutic effect. It should be understood that in some embodiments, the imbalance includes pulses having pulse widths of unequal duration. In some embodiments, the biphasic waveform is unbalanced, and therefore the voltage in one direction is equal to the voltage in the other direction, but the duration of one direction (i.e., positive or negative) exceeds the duration of the other direction, and therefore the area under the curve of the positive part of the waveform is not equal to the area under the negative part of the waveform.

[0128] FIG. 4 illustrates a portion of the heart H, showing the section of the right atrium RA and the left atrium LA. The largest pulmonary veins are the four main pulmonary veins (the right superior pulmonary vein RSPV, the right inferior pulmonary vein RIPV, the left superior pulmonary vein LSPV, and the left inferior pulmonary vein LIPV), two from each lung, which communicate into the left atrium LA of the heart H. Each pulmonary vein is connected to a capillary network within the alveoli of each lung and carries oxygenated blood to the left atrium LA. The left atrial musculature extends from the left atrium LA and envelops the proximal pulmonary veins. The superior vein, having a longer muscular sleeve, has been reported to be more arrhythmogenic than the inferior vein. In general, the length of the pulmonary vein sleeve varies from 13 mm to 25 mm. Pulmonary vein morphology has been reported to affect arrhythmogenesis. Similarly, the cellular electrophysiology and other aspects of the pulmonary veins are associated with arrhythmogenesis and propagation.

[0129] Various methods, such as anatomical indications and cardiac mapping, are used to determine the tissues targeted for treatment. Typically, a mapping catheter is selected to suit the size and anatomy of the pulmonary vein to suit the desired fit into the pulmonary vein. The mapping catheter allows recording of electrograms from the ostium of the pulmonary vein and from deep within the pulmonary vein, which are displayed and timed for the user. The treatment catheter 102 is first placed deep within the pulmonary vein and gradually withdrawn to the proximal ostium of the mapping catheter. Mapping and treatment are then initiated.

[0130] The current understanding of pulmonary vein electrophysiology is that the majority of fibers within the pulmonary veins are circular and do not carry conduction into the vein. The electrical conduction pathway is the longitudinal fibers that extend between the left atrium LA and the pulmonary veins. Pulmonary vein isolation is achieved by ablation of these connecting longitudinal fibers. For the left pulmonary veins, pacing the distal coronary sinus tends to increase the separation of the atrial signal and the pulmonary vein potentials, making them more electrically visible. Signals from within the pulmonary veins are evaluated. Each individual signal consists of a far-field atrial signal, which is generally of low amplitude, and a steep local pulmonary vein spike. The earliest pulmonary vein spike represents the site of pulmonary vein and atrium connection. If the pulmonary vein spike and atrial potentials are examined, on some of the poles of the mapping catheter, these electrograms will be widely separated, and on other sites there will be fused potentials of atrial and PV signals. The latter indicates the site of the longitudinal fibers and a potential site for treatment.

[0131] In some embodiments, tissue surrounding the opening of the left inferior pulmonary vein LIPV is treated in a sequential manner by use of the treatment catheter 102 (with the aid of mapping) to create a circular treatment zone around the left inferior pulmonary vein LIPV, as illustrated in FIG. 5. In some cases, specialized navigation software can be used to enable proper positioning of the treatment catheter 102. A delivery electrode 122 is positioned near or relative to the target tissue area, and energy is provided to the delivery electrode 122 to create a treatment area or lesion L. Because energy is delivered to a localized area (focused delivery), the electrical energy is concentrated over a smaller surface area, resulting in a stronger effect than delivery through electrodes that extend circumferentially around the lumen or ostium. This also forces the electrical energy to be delivered in a stepwise localized approach, mitigating the potential effect of preferential current paths through surrounding tissue. These preferential current paths are areas with electrical properties that induce locally increased current flow through them, rather than through adjacent areas. Such a path may result in an irregular current distribution around the circumference of the targeted lumen, which may thus distort the electric field and cause irregular increases in the therapeutic effect for some regions and lower therapeutic effect in other regions. This may be mitigated or avoided by the use of focused therapy, which stabilizes the therapeutic effect around the circumference of the targeted region. Thus, by providing energy to one region at a time, the electrical energy is "forced" across different regions of the circumference, ensuring an improved degree of therapeutic circumferential regularity. FIG. 5 illustrates the repeated application of energy in a sequential manner around the left inferior pulmonary vein LIPV by the use of the treatment catheter 102 to generate a circular treatment zone. As shown, in this embodiment, each lesion L overlaps with an adjacent lesion L to generate a continuous treatment zone. It should be understood that the number of lesions L may vary depending on various factors, particularly the unique conditions of each patient's anatomy and electrophysiology.In some embodiments, the number of lesions L includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, or more.

[0132] The size and depth of each lesion L may depend on various factors such as parameter values, treatment time, tissue characteristics, etc. It should be understood that the effect of energy on tissue is a function of both the strength of the waveform pulses and the cumulative damage incurred by the progressive series of those pulses caused by the administration. When considering generating a particular lesion size, the effective electric field threshold may be defined, for example, by the waveform characteristics (e.g., fundamental frequency, packet activity period, total number of packets) and a given electrode type or arrangement. This can be fine-tuned with changes in the delivered voltage, which affect the electric field strength and / or duration of the electric field pulse, to name a few. In addition to modifying the pulses, there is a contribution of secondary pulse parameters, including the number of pulses delivered and the cadence of their delivery. For cycles of a biphasic pulse waveform with alternating electric field polarity, the addition of multiple cycles with packets in rapid succession will modify the effective electric field threshold and induce the desired outcome.

[0133] When titrating PEF administration for cardiac ablation, it is important to consider the relative desirable and undesirable attributes associated with each treatment parameter. The basic waveform treatment parameters are briefly discussed herein. A summary table depicting the relative expected outcomes of each is provided in Table 1 below.

[0134] [Table 1]

[0135] Voltage: Voltage directly affects the electric field strength distribution. Increasing the voltage will directly increase the magnitude of treatment. However, higher voltages also increase the associated tissue heating, potentially resulting in undesirable thermal effects. Increased voltages also increase the muscle contraction associated with PEF, the volume of gaseous microemboli generated, and the likelihood of electrical arcing, potentially resulting in charring and coagulum formation or barotrauma.

[0136] Waveform Shape: PEF can use multiple waveforms to induce their effects, however, in practice, they are generally sinusoidal or square waveforms. The waveforms can be considered as essentially trains of pure monophasic pulses (a sequence of short (≦10 μsec) or long (>1 μsec) pulses, all of the same polarity, delivered with a relatively long (>1 ms) delay between them), alternating monophasic (a sequence of long pulses, delivered with alternating polarity, with a relatively long delay between them), and biphasic (short (≦10 μsec) pulses, delivered with a relatively short delay (<1 ms) between polarity changes). Monophasic waveforms produce the strongest therapeutic effects. However, they can also induce muscle contractions, pressure waves, and gaseous embolism formation. Biphasic waveforms can greatly reduce muscle contractions, but will generate weaker therapeutic effects for comparable total packet durations and applied electric fields. However, with optimization of waveform parameters, it is possible to balance reduced muscle contraction with therapeutic effect, allowing the therapy to develop clinically relevant lesions without excessive muscle contraction. For biphasic waveforms, the fundamental frequency influences the therapy, with higher frequencies (i.e., shorter individual pulse durations) monotonically reducing muscle contraction, but also resulting in progressively smaller therapeutic effects. Note that the PEF waveform is spectrally adjustable. The asymmetry and fundamental frequency of the waveform may be adjusted to further increase the effect, with more asymmetry or lower fundamental frequency increasing the therapeutic effect and muscle contraction until approaching a purely monophasic waveform.

[0137] Collective Pulse Duration: When multiple pulses are delivered in rapid succession (e.g., as a packet), their effect may be considered a collective pulse. As the packet duration increases, there is a corresponding increase in therapeutic effect, muscle contraction, gas formation, heating, and these effects may increase the potential for electrical arcing.

[0138] Total activation duration: When multiple packets are delivered to tissue, the accumulated damage increases. Thus, more packets will result in a stronger therapeutic effect, but will increase the therapeutic delivery time (with respect to the matched packet delivery rate) and increase the cumulative temperature rise if there is insufficient time for heat dissipation, such as between subsequent packets.

[0139] Packet Delivery Rate: When an interruption is provided between a sequence of pulses (e.g., a packet), the tissue has a chance to conduct heat away from the heated tissue, reducing the total temperature rise. However, during this interruption, the cells continue to expend energy trying to recover from the PEF effect. When a sequence of pulses is delivered with a relatively longer interruption (milliseconds to tens of seconds), cellular recovery is generally unaffected, but the total tissue temperature rise is reduced. This allows for the delivery of a strong cumulative therapy while maintaining an acceptable level of temperature rise. In some cases, delivering a series of pulses or packets spread over a longer period of time will increase the efficacy of the therapy.

[0140] As mentioned above, the size and depth of each lesion L may depend on a variety of factors. FIG. 6 is a schematic illustration of a lesion L generated by a catheter 102 as illustrated in FIG. 2B. Here, a delivery electrode 122 is positioned relative to tissue T, such as cardiac tissue, and energy is provided to the delivery electrode 122 to generate a lesion L. The delivery electrode 122 generates a lesion L having a three-dimensional paraboloidal or rounded cone shape. As illustrated, the lesion L has a lesion depth LD (extending from the tip of the delivery electrode 122 to the furthest depth of the paraboloidal shape) and a lesion width LW (extending across the base of the paraboloid). The lesion depth LD and lesion width LW vary depending on the energy delivered. In particular, the lesion dimensions vary depending on the waveform and administration parameters, among other effects, such as tissue type. The correlations between lesion size and changes in PEF energy parameters and administration described herein were analyzed to generate predictive algorithms. Such algorithms are used in various tissue modification systems 100 to improve clinical usability, treatment control, and patient outcomes. This will be described in more detail in a later section.

[0141] FIG. 7 illustrates energy delivery at three different levels or doses. In this example, a "low" dose is the combination of parameters that provides the smallest lesion size (e.g., 3-4 mm wide, 4-5 mm deep). In this example, a "medium" dose provides a medium level of size of the lesion (e.g., 7-8 mm wide, 5-6 mm deep). And in this example, a "high" dose results in the largest lesion size (9-10 mm wide, 7-8 mm deep). It should be understood that such terminology of low, medium, and high is simply relative to one another for the purposes of this example. Moving from low to high, both the peak amplitude (V or I) and the number of individual packets delivered increase for a given treatment. In some embodiments, such terminology correlates to values ​​as provided in Table 2 below.

[0142] [Table 2]

[0143] Referring again to FIG. 5, continuous lesions are formed by repeated application of energy in a sequential manner, typically with each lesion L overlapping an adjacent lesion L. The desired spacing between the lesions L, and therefore the amount of overlap, depends at least on the size of the lesions L to be generated. This, in turn, depends on various factors described herein. FIG. 8 illustrates the generation of two adjacent overlapping lesions L. In this embodiment, the lesions L are generated successively utilizing the same catheter 102. The actual treatment depth TD, which is considered the minimum depth of the lesions formed, is located between both focal lesions L at the overlap point. As shown, this is less than the lesion depth LD of either lesion L. FIG. 9 illustrates the resulting continuous lesions CL formed from the energy delivered by the catheter 102.

[0144] During treatment, physicians look at several clues to determine where they should next treat in the sequential sequence. For example, physicians may consider impedance measurements, electrogram signals, mapping system placement, fluoroscopy, etc. In the field of radiofrequency ablation, known protocols are often followed, such as the CLOSE protocol. However, such protocols are not applicable to PEF energy delivery and would erroneously direct the physician to utilize lesion placement that would result in a gap and therefore a failed conduction block. This is due to the transient effect of energy delivery at the lesion site, which is considered a "stunning" effect.

[0145] When PEF energy is used to create a lesion, a portion of the tissue receiving the energy will be killed by the PEF therapy and will eventually be replaced by a transmural fibrous scar. Another portion of the tissue will be stunned by the PEF therapy and will suddenly suffer a significant decrease in electrical conduction (i.e., be "stunned"), but will eventually survive the PEF therapy, at least in the short to medium term. The stunning phenomenon is likely the result of a border zone of damaged but not killed cells in the area surrounding the fatally affected tissue. This border zone effect may have significant predictive consequences on clinical outcomes by confounding the ability to accurately determine therapeutic efficacy during the procedure. To ensure durable clinical efficacy from PEF cardiac ablation procedures, it is important to ensure that the rapid electrical isolation does not rely on stunning tissue, but instead reflects dead tissue that will result in a durable fibrous scar.

[0146] Various measures were taken to determine the boundaries of the stunning and dead areas. In some cases, a pig heart model was utilized. In one example, a 7F treatment catheter 102 with a 3.5 mm ablation electrode 122 was connected to a pulsed electric field (PEF) generator 108 and positioned in the right ventricle RV and left ventricle LV under EnSite guidance in two closed-chest pigs. Biphasic PEF current was delivered between the ablation electrode and a skin patch at 13 RV sites (28 amps, 1.4 ms total pulse width, 4 pulses) and 19 LV sites (35 amps, 1.6 ms, 7 pulses). Two hours after ablation, triphenyltetrazolium chloride (TTC) was administered. The pigs were sacrificed and the hearts were excised and fixed in formalin. The hearts were sectioned and stained with hematoxylin-eosin (H&E) and Masson's trichrome. Cytochrome c oxidase (COX) staining was also performed to examine mitochondrial activity and to delineate stunning and dead lesion boundaries.

[0147] Ablation lesions were clearly demarcated with TTC staining and showed a dense central zone surrounded by a pale border. Histology showed disruption of myocyte architecture within the pale border. A highly stained (dark red) rim beyond the pale border indicated the stunning zone. COX staining showed little to no mitochondrial activity within the pale border, consistent with the ablation area. Enhanced activity of COX staining extended into unaffected normal myocardium, consistent with the stunning zone. Thus, the acute ventricular lesions produced by PEF ablation show clear demarcation with TTC staining. COX staining suggests that the dead portion of the lesion is surrounded by a stunning zone.

[0148] The stunning effect can be exploited in certain electrophysiological applications. For example, different types of cardiomyocytes may be more sensitive to stunning than others, which can help distinguish Purkinje origins from other types of cardiomyocyte origins. The stunning effect can also serve to sublethally test the ablation site prior to terminating it, ensuring that there will not be any inadvertent damage to the conduction system (similar to so-called "cryo-mapping" involving cryosurgery).

[0149] To increase the treatment depth TD, multiple doses may be utilized. FIG. 10 illustrates the effect of multiple doses on lesion size. Here, each dose initially extends toward the lesion boundary furthest from the delivery electrode 122. In this embodiment, the energy is delivered in a monopolar manner, and the energy intensity decreases as the distance from the delivery electrode 122 increases. The tissue in the outermost ring is simply the "stunned" tissue, while the tissue in the innermost ring receives enough energy to be killed. Thus, as illustrated, a single dose provides a first lesion size 200. Applying a dose again (Dose x 2) again treats the tissue, changing the tissue in the middle ring from a stunning to a dead state. Thus, a double dose increases the first lesion size 200 to a second lesion size 202. Applying a dose again (Dose x 3) repeats the process, now similarly changing the tissue in the outermost ring from a stunning to a dead state. This increases the second lesion size 202 to a third lesion size 204. It should be understood that additional doses may increase the incremental amount of lesion size up to a limit. Numerical approximations were employed to determine the effect of multiple delivery doses. The efficacy curve was found to increase with the number of packets.

[0150] It should be appreciated that overlapping lesions also advantageously increase the lesion treatment depth. FIG. 11 illustrates an embodiment of two overlapping lesions L. As in FIG. 8, the lesions L overlap when the catheter 102 is repositioned close enough to the first placement when creating the sequential lesions. Referring again to FIG. 11, the dose creates a larger potential lesion L' that reduces or reverses the lesion to the size of lesion L. However, as highlighted in FIG. 11, a region 210 is identified that receives a double dose from both catheter 102 placements. As a result, this region 210 transitions from a stunning state to a dead state. This region 210 is now considered part of the lesion treatment depth TD, as illustrated in FIG. 12, effectively increasing the treatment depth TD. In a similar manner, some tissue 212 surrounding the region 210 is affected by the fractional energy from both lesions, resulting in similar damage, and therefore can be considered part of the lesion. As a result, the resulting continuous lesion L is illustrated in Figure 13. As shown, the treatment depth TD has increased compared to Figure 8.

[0151] Changing the distance between lesion locations (i.e., changing the spacing between catheter placements) changes the amount of overlap of the lesions. In general, increasing the spacing would generally imply a reduction in the resulting treatment depth TD. FIG. 14 illustrates a lesion spacing (i.e., catheter spacing) that is larger than that of FIG. 11. Thus, the area 210 receiving double dosing from both catheter 102 placements has shifted upward. This in turn creates a shallower treatment depth for consecutive lesions as illustrated in FIG. 15. However, it is important that the lesion spacing is close enough that this area 210 is created; otherwise, gaps would appear between the lesions, leading to therapy failure.

[0152] To estimate the expected treatment depth TD for overlapping lesions, a simplified geometric approximation was adopted assuming ellipsoidal lesions. From this, the estimated treatment depth TD can be determined in relation to the lesion spacing to generate the desired treatment protocol. FIG. 16 illustrates an example correlation between treatment depth TD and lesion spacing at three different energy doses (low 250, medium 252, high 254). In some embodiments, these energy doses correlate to those in Table 2 above. A maximum lesion spacing can be determined from the graph to ensure the desired target treatment depth.

[0153] It should be appreciated that various measured atrial wall thicknesses were reported, particularly depending on the location within the heart. Based on a comparison of the data, it was determined that a 4 mm treatment depth TD was adequate for more than 99.42% of the expected wall thicknesses. Therefore, a minimum treatment depth TD of 4 mm is desired. To achieve this, lesion spacing is determined based on the dosage level. A reference dosage (e.g., 22 A, 400 kHz, 45 cycles, 12 packets) selected as the baseline intensity for therapy with 3 mm spacing resulted in a 4.0 mm treatment depth. Similarly, a dosage provided with a higher amperage delivered and more packets ("high" dosage) (e.g., 25 A, 400 kHz, 45 cycles, 21 packets) with 5 mm spacing resulted in a 4.4 mm treatment depth. This spacing worked well during the intervention. However, it was found that a high dosage with 3 mm spacing was utilized to achieve a 6 mm treatment depth.

[0154] 17A-17B illustrate the use of two different treatment protocols for different areas of the heart. FIG. 17A illustrates an exemplary lesion on the posterior surface of a heart H with a thinner wall thickness (approximately <3 mm). Here, energy was delivered through a catheter to create a lesion L along the posterior surface, with spacing of 5 mm and an average treatment depth of 5.8 mm. FIG. 17B illustrates an exemplary lesion on the anterior surface of a heart H with a thicker wall thickness (approximately 2-6 mm). Here, energy was delivered through a catheter to create a lesion L along the posterior surface, with spacing of 6 mm and an average treatment depth of 6 mm. The delivered energy was considered higher compared to the energy delivered to the posterior surface because three times as many packets were delivered. Thus, different anatomical regions may warrant different treatment dosing (i.e., stronger dosing in areas assessed or generally known to be thicker within the patient) to ensure transmural treatment effect thickness. Alternatively, strategies that space lesions closer together at different distances may be used to induce the same effect. For example, on thin tissue, a high dose embodiment may use 5 mm spacing to generate continuous transmural lesions. However, in the anterior or bifurcation region, the same dose may be combined with 3 mm spacing to obtain a similar transmural therapeutic effect in this thicker tissue.

[0155] It should be understood that therapy is terminated when all undesired electrical connections have been treated. When performing pulmonary vein isolation, the electrical connections between the atrium and the vein are treated until there is electrical quiescence in the pulmonary vein, and only the far-field atrial signal is recorded. From time to time, spikes of electrical activity are seen in the pulmonary vein, without any conduction to the rest of the atrium, which clearly demonstrate the electrical discontinuity of the vein from the rest of the atrial myocardium. Additional treatment areas can be created at other locations to treat arrhythmias in either the right or left atrium, depending on the clinical indication. Tests are then performed to ensure that each targeted pulmonary vein is effectively isolated from the body of the left atrium.

[0156] Lesions were evaluated to ensure longevity of results and therefore durability of the lesions. For example, a 90-day remapping study was conducted to evaluate the outcomes of lesions generated using three compatible focused cardiac ablation catheters. These ablation catheters were conventional catheters designed for delivery of radiofrequency energy, and the PEF energy described herein was delivered through the catheter utilizing specialized system components to enable such procedures. The objective was to study the safety and clinical performance to evaluate catheter ablation of atrial fibrillation using the systems and methods described herein. The study design was a prospective, single-arm, open-label, multicenter study. Patients were undergoing catheter ablation for the first time for the treatment of paroxysmal atrial fibrillation (PAF) or persistent AF (PerAF) of short duration (<1 year). The primary safety endpoint was the occurrence of system- and procedure-related serious adverse events of interest within 30 days of ablation. Acute secondary endpoints included pulmonary vein isolation during the index ablation procedure confirmed by both entrance and exit block. Chronic secondary endpoints included durability of pulmonary vein isolation at 90-day remapping.Additional safety assessments included intraprocedural gaseous emboli assessment with ICE and ST-segment changes assessment with ECG, phrenic nerve injury, preprocedural and postprocedural cranial MRI for assessment of brain lesions, preprocedural and postprocedural stroke assessment via NIHSS, postprocedural esophageal endoscopy, and PV imaging via cranial CT / MRI.

[0157] Three conventional RF catheter and mapping systems were used: 1) TACTICATH TM SE, ENSITE TM , Advisor TM HD-Grid 2) INTELLANV STABLEPOINT TM , RHYTHMIA HDx TM , INTELLAMAP ORION TM 3) THERMOCOOL SMARTTOUCH TM , CARTO(R) 3, PENTARAY(R)

[0158] Physicians selected one of three energy settings (low=19, medium=22, high=25 amps) and performed wide sinus circumferential ablation with a target contact force of ≥5 g. Acute success was assessed via entrance and exit block. Safety was assessed by independent evaluation of prespecified SAEs noted within 30 days. PVI durability was assessed for 90 days using high-density mapping and confirmation of entrance and exit block. The clinical energy setting strategy was a modification of the CLOSE protocol using PEF energy. Lesion tag diameters, representing lesion intervals, varied depending on the cohort. Patients were divided into five cohorts as presented in Table 3.

[0159] [Table 3-1]

[0160] In some instances, the anterior and posterior settings are different due to the thickness of the target tissue. The anterior site tends to be thicker while the posterior site tends to be thinner. Similarly, the posterior site is typically adjacent to anatomical features that may be more sensitive to energy delivery, such as the esophagus. Exemplary placement of anterior and posterior lesions is illustrated in FIG.

[0161] Pulmonary vein isolation was achieved in all subjects, with first-pass isolation in 92% (277 / 302) of PVs. Ninety days after treatment, high-density remapping of each pulmonary vein was performed using Advisor TMThis was achieved in 74 patients using HD-Grid or PENTARAY®. Circumferential mapping of the entire pulmonary vein was achieved to confirm durable continuous transmural ablation. Entry block was confirmed for every pulmonary vein. Exit block was confirmed for every pulmonary vein with high output pacing. Detailed mapping revealed local reconnections in some pulmonary veins that initially appeared isolated. Reconnections were treated with PEF energy as described herein. Pulmonary vein isolation rates at 90 days remap are illustrated in FIG. 19. Thus, cohorts 3, 4, and 5 achieved an overall pulmonary vein isolation durability of 87%. This is significantly better than that of cohorts 1 and 2, which ranged from 47 to 53%. Thus, in some embodiments, a high dose (25A) with 4-6mm spacing for anterior locations and a medium dose (22A) with 4-6mm spacing for posterior locations is desired. Thus, of the 73 subjects who were remapped, the energy settings were significantly higher in cohorts 1, 2, and 3 than in the TactiCath SE. TM The PV isolation rate improved from 47% to 84% after the optimized workflow was used in cohort 4 (STABLEPOINT TM ) and 5 (THERMOCOOL ST(R)), the PV isolation rates were 89% and 87%.

[0162] Effective PEF delivery was shown to be successfully integrated into standard PVI workflow with a limited learning curve. No intraprocedural gaseous emboli were observed with ICE. A favorable safety profile was found for the esophagus, phrenic nerve, pulmonary veins, and brain. Although 100% acute isolation was achieved, acute isolation is not a substitute for durable isolation or freedom from atrial fibrillation. A 90-day remap was desired to optimize administration and workflow. Very high compliance (96%) with the remap procedure was achieved with comprehensive durability assessment. Improvements in durable pulmonary vein isolation rates were achieved with energy setting optimization from cohorts 1-3. Sustained safety and efficacy was achieved with optimized settings across three solid-tip, contact force-sensing conventional RF-focused catheter platforms while using PEF energy. A preliminary 12-month freedom from atrial fibrillation was achieved.

[0163] It should be understood that focused therapy can be delivered using a variety of catheter designs and methods. For example, in some embodiments, the energy delivery catheter 102 is configured to provide focused therapy, such as in accordance with International Patent Application No. PCT / US2018 / 067504, entitled "OPTIMIZATION OF ENERGY DELIVERY FOR VARIOUS APPLICATIONS," which claims priority to Provisional Patent Application No. 62 / 610,430, filed December 26, 2017, and U.S. Provisional Patent Application No. 62 / 693,622, filed July 3, 2018, the entire contents of which are incorporated herein by reference for all purposes. Similarly, focused therapy may be delivered using various catheter designs, optionally with the use of various accessories, such as those described in International Patent Application No. PCT / US2020 / 066205, entitled "TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRIC FIELDS," filed December 18, 2020, which claims priority to Provisional Patent Application No. 62 / 949,633, filed December 18, 2019, Provisional Patent Application No. 63 / 000,275, filed March 26, 2020, and Provisional Patent Application No. 63 / 083,644, filed September 25, 2020 (all of which are incorporated by reference for all purposes).

[0164] As mentioned above, lesion size varies depending on the parameters of the PEF waveform and administration, among other influences such as tissue type. This is the case when delivering PEF energy to cardiac tissue as mentioned above, and to other tissue types throughout the body. Thus, different waveforms and administrations of PEF energy provide different results, in particular different lesion sizes and types. Systems, devices, and methods are provided that allow a physician or user to control the PEF energy delivered to provide a desired result, and / or provide predictive information that a user may utilize to generate a desired result.

[0165] For example, in some instances, a user may type or input treatment profiles into the system 100, such as via a user interface 150, which are used by the system 100 (e.g., generator 108) to generate or select a particular energy delivery algorithm 152 that optimizes treatment waveforms and / or dosing for a desired treatment. FIG. 20 provides a schematic illustration of such a system 100. In this example, a user inputs one or more desired lesion dimensions as a first input 500. Such dimensions may include lesion depth, lesion width, lesion shape, or other dimensional characteristics. The user may have such preferences based on the type of treatment (e.g., tumor size, electrical block, etc.), the treatment location (e.g., endoluminal, along tissue edges, proximity to other anatomical features, etc.), or the type of tissue (which may also depend on the treatment location), to name a few. In this example, a user inputs a desired temperature characteristic, such as a maximum allowable temperature rise, as a second input 502. The user may have such preferences based on the type of treatment and the treatment location. For example, there may be different tolerances with respect to temperature in some types of treatments (e.g., higher temperatures may be more acceptable for tumor ablation). Similarly, some areas may be more sensitive to increased temperature or present increased risk in the presence of increased temperature (e.g., the posterior wall of the left atrium adjacent to the esophagus). Thus, preferences may be based on delivery electrode proximity to sensitive structures such as the phrenic nerve, esophagus, sinoatrial node, or atrioventricular node, where thermal damage to these structures may be irreversible and result in unacceptable patient morbidity or mortality. Similarly, in this embodiment, the user inputs a desired muscle contraction, such as a maximum allowable amount of muscle contraction, as a third input 504. The user may have such preferences based on delivery electrode proximity to the excitable tissue of interest. For example, when the delivery electrode is in the vicinity of the phrenic nerve, the patient will have a much higher likelihood of diaphragm contraction. In some cases, this range may be unacceptable in normal administration, and thus the clinician may choose to reduce the contraction and improve catheter stability during treatment delivery.In another example, if energy is being delivered near the vagus nerve, contraction excitability may also be correlated to stimulation of this nerve. Thus, by reducing the excitability of the waveform for this tissue, the user may reduce the likelihood of the patient coughing during the procedure and improve the accuracy of the electroanatomical mapping. Similarly, preferences for muscle contraction may be based on the surgical management of the patient (e.g., patients treated with conscious sedation versus general anesthesia). Alternatively, the user may have preferences based on the anatomical location and the effect that muscle contraction may have on the treatment itself (e.g., loss of tissue contact during delivery) or safety-related preferences (e.g., concerns about perforation when ablating on thinner tissue such as the posterior wall of the left atrium).

[0166] Additionally, in this embodiment, the user inputs a fourth input 506, a dosing time. The dosing time is the amount of time allowed for a particular application of energy. In some cases, a reduced dosing time is desired due to clinical circumstances that limit the allowable time to deliver energy, such as rapid contraction motion of the heart and delivery of energy to difficult to reach anatomical targets.

[0167] These inputs 500, 502, 504, 506 may be received by the system 100 in a variety of suitable ways, such as user selection from a menu or user input via a keypad. The inputs 500, 502, 504, 506 are utilized by the processor 154 to generate an appropriate energy delivery algorithm 152. The algorithm 152 then produces an appropriate energy waveform to provide the desired PEF energy. In some embodiments, the system 100 utilizes these inputs 500, 502, 504, 506 in coordination with various sensors or feedback systems to ensure that the waveform remains appropriate throughout the treatment procedure. For example, a temperature sensor may be utilized to ensure that any temperature rise does not exceed a maximum allowable temperature rise, provided as a second input 502. If a reading indicates that the maximum value is exceeded, a warning indication may be provided, a different energy delivery algorithm may be utilized, energy delivery may be automatically stopped, or other suitable protocol changes may follow.

[0168] It should be understood that any number of inputs 500, 502, 504, 506 may be utilized. Although four different inputs are shown in the above example, one, two, three, four, five, six, seven, eight, nine, ten, or more than ten inputs may be utilized. Other inputs may include type of catheter 102, type of energy delivery electrode 122, type of tissue, tissue thickness, activation pattern of energy delivery electrodes, location of other tissues, challenges suffered by the physician (e.g., too much coughing), proximity of non-target tissue, contact force, local tissue impedance, system impedance, etc. Similarly, if only a subset of inputs 500, 502, 504, 506 is desired to be selected, default inputs may be used for the remaining inputs. Values ​​of such default inputs may be based on clinical averages, preprogrammed information, or calculated based on the inputs provided or other available information. In some embodiments, the inputs may be ranked or weighted, for example, so that a suitable waveform may be generated even if each input is not absolutely matched. For example, in some cases there are primary inputs that are critical and secondary inputs that are desired but not critical. Thus, if a waveform cannot be generated based on all of the inputs (which may be the case particularly when selecting an algorithm from a given selection of algorithms), the primary inputs may be prioritized to ensure that at least the best fitting waveform is provided to the user. The ranking or weighting of the inputs may be based on a variety of factors, including the anatomical location of energy delivery, patient-specific anatomical variability, safety considerations, other procedure characteristics, and / or other information.

[0169] As mentioned, the system 100 includes a processor 154 that, among other things, generates an appropriate energy delivery algorithm 152 by use of a data storage / readout unit 156. The appropriate energy delivery algorithm 152 then produces the desired waveform for PEF energy delivery. The stored information utilized by the processor 154 to generate the algorithm 152 is generated by a series of steps. In one embodiment, the first step is to correlate the effect of different waveform parameters to treatment aspects such as the four inputs 500, 502, 504, 506 of FIG. 20. In this embodiment, this is accomplished by performing a parameter sweep in the model. A parameter sweep is when one parameter is changed through various values ​​while the other parameter is fixed and the effect is observed. Typically, a common baseline of the parameter is used as the fixed value. The sweep is performed to a value that achieves an effective lethal electric field threshold.

[0170] It should be understood that the model can be the final target tissue (e.g., a beating heart in vivo) or a surrogate model that reflects the same relationship to dose dependency (e.g., another organ such as a thigh, liver, an ex vivo perfused organ model, or a benchtop model such as a vegetable potato or apple). In some cases, a simple electrode geometry (e.g., a needle in a potato immersed in a saline bath or a bipolar electrode pair array in which both electrodes are placed in the potato at a standard separation distance and depth) can be used because the effect of the electrode geometry can be scaled. When using a benchtop model, a physical setup that mimics the energy delivery dynamics of the therapy is desired. For example, testing of a cardiac ablation device used to deliver therapy onto the surface of a target tissue may be simulated by delivering energy to the surface of a potato.

[0171] In this embodiment, the tissue is in a bath of fluid with a conductivity selected to best approximate the entire in vivo environment. For monopolar electrodes, this includes the heart, pericardium, lungs, muscle, fat, skin, and other tissues used clinically to conduct electrical pulse energy between the effector electrode and the remote distributed electrode. It should be understood that in bench models, a distributed ground electrode may be placed adjacent to, beneath, or within another environment to best represent the electrical PEF energy traveling through the tissue and reaching the ground electrode, such that the energy travels through the model in a similar manner. For bipolar electrodes, this may simply be the fluid between the active regions of the electrodes for a given bipolar electrode array pair.

[0172] An example of parameters and test sweeps are provided in Table 3. In this example, the baseline set of parameters included a 1,000 V applied voltage with a biphasic 100 kHz frequency baseline waveform with 10 cycles for 10 packets delivered at 1 packet per second.

[0173] [Table 3-2]

[0174] Following treatment delivery with all parameter combinations, a function is generated to determine the extent to which each parameter individually affects the treatment effect. In this example, inputs 500, 502, 504 of FIG. 20 are utilized as the treatment effect of interest. In particular, FIGS. 21A-21D, 22A-22D, 23A-23D, and 24A-24D illustrate the individual relationships between inputs 500, 502, 504 and parameters of packet number, frequency, packet delivery rate, and packet duration from which functions are mathematically generated. Input 500, which relates to lesion size, has been broken down into two measurements: treatment depth (i.e., lesion depth) and treatment width (i.e., lesion width). Input 502 refers to temperature rise and input 504 refers to muscle contraction, collected via an accelerometer (using an in vivo study). In particular, FIG. 21A illustrates the relationship between packet number and treatment depth. FIG. 21B illustrates the relationship between frequency and treatment depth. FIG. 21C illustrates the relationship between packet delivery rate and treatment depth. Also, FIG. 21D illustrates the relationship between packet duration and treatment depth. Similarly, FIG. 22A illustrates the relationship between packet number and treatment width. FIG. 22B illustrates the relationship between frequency and treatment width. FIG. 22C illustrates the relationship between packet delivery rate and treatment width. Also, FIG. 22D illustrates the relationship between packet duration and treatment width. Furthermore, FIG. 23A illustrates the relationship between packet number and temperature rise. FIG. 23B illustrates the relationship between frequency and temperature rise. FIG. 23C illustrates the relationship between packet delivery rate and temperature rise. Also, FIG. 23D illustrates the relationship between packet duration and temperature rise. Still further, FIG. 24A illustrates the relationship between packet number and muscle contraction. FIG. 24B illustrates the relationship between frequency and muscle contraction. Figure 24C illustrates the relationship between packet delivery rate and muscle contraction, and Figure 24D illustrates the relationship between packet duration and muscle contraction.

[0175] It should be appreciated that the resulting lesion size depends on the electrode array used in the model, therefore, numerical simulations of the electric field strength for the electrode array are performed to correlate lesion size to the electric field strength.

[0176] Following this, additional numerical simulations or multiple simulations may be constructed to represent different therapy delivery physical settings. For example, a focused monopolar catheter electrode may be modeled within the atrial chamber of the heart and placed relative to the myocardium. The electric field distributions of these simulations may be captured and retained. In this manner, applied voltage and lethal electric field threshold functions may be compiled to generate a look-up table or other method of capturing this data.

[0177] Additional numerical simulations can be made of other electrode arrangements. For example, a focused monopolar catheter electrode may be modeled within the atrial chamber of the heart and placed relative to the myocardium. Using the numerical model, the electric field distribution can be determined in each scenario. This can be captured in a look-up table or other method of capturing this data. Figures 25A-25C illustrate example electric field distributions for a catheter embodiment that delivers PEF energy into the heart.

[0178] The electric field data is then calibrated to ensure that the model reflects the clinical scenario. This is accomplished by testing a subset of treatment parameter combinations in clinical or in vivo models. Actual data captured from these studies (accelerometers, treatment effect sizes, etc.) are then used to generate new baseline electric field thresholds.

[0179] By these methods, a correlation between field strength and a treatment aspect such as lesion size is determined. Thus, referring again to FIG. 20, when a user inputs a particular desired lesion size (input 500), processor 154 uses the desired lesion size and correlates it to a field strength threshold. Processor 154 then uses the electrode array to determine the field strength and the field strength threshold corresponding to the desired lesion size. Processor 154 then determines parameter values ​​and generates the determined field strength, thereby generating the desired waveform. These same methods may be used with respect to any of the inputs to determine the desired waveform. Similarly, when combining the inputs, processor 154 considers the combined effect of various parameter influences to select the final parameters that lead to the generation of the most suitable waveform. It should be understood that processor 154 may also consider a ranking or weighting of the inputs to generate the most suitable waveform.

[0180] It should be appreciated that the methodology described above may also be used to allow a user to provide inputs to the system 100 and receive predictions of lesion size, temperature rise, muscle contraction, administration time, etc. In one embodiment, illustrated in FIG. 26, the generator 108 includes at least one algorithm 152 that generates a predetermined waveform. The algorithm 152 is modifiable by changing parameters based on the inputs 502, 504, 506, as described above. Based on the correlations described above, the user is provided with a lesion size. If such a lesion size is desired, the user may proceed to use a new modified waveform. If a different size is desired, the user may modify one or more inputs 502, 504, 506, such as in an iterative manner, until the desired lesion size is achieved. It should be appreciated that the inputs and outputs may have various combinations, as desired.

[0181] It should be appreciated that the methodology described above may also be used to allow a user to provide a single input to the system 100 and receive a prediction of lesion size, etc. In one embodiment, illustrated in FIG. 27, the generator 108 includes at least one algorithm 152 that generates a predetermined waveform. In this embodiment, the user provides an input 506, such as a dosing time. Thus, the user has a desired dosing time based on various clinical constraints. Based on the correlations described above, the user is provided with a lesion size that would result from delivering the predetermined waveform. If such a lesion size is desired, the user may proceed with using the waveform. This aids the user in determining the placement of the lesion to provide a desired level of overlap, etc. This is particularly useful in cardiac applications, such as when generating an electrical interruption.

[0182] It should be appreciated that in some embodiments, the system of FIG. 27 is reversed, with the user providing an input 500 of the desired lesion size, and the predicted dose time provided by the system 100. When doses are delivered manually, such as by a foot switch, the user may provide the appropriate dose time or number of doses. When doses are delivered automatically, the user can determine if the dose time is appropriate for the clinical situation and activate delivery as desired.

[0183] Control over lesion size is desirable when determining lesion spacing. As mentioned above, successive lesions can be formed by repeated application of energy in a sequential manner, typically with each lesion L overlapping an adjacent lesion L. The desired spacing between lesions L, and therefore the amount of overlap, depends at least on the size of the lesion L to be generated. Once the lesion size is known, spacing can be determined by the user, either alone or assisted by the system 100. A default or known dimension of the stunning zone for each given lesion size may determine how closely the lesions should be placed together to ensure durable, successive lesions. In some embodiments, the system 100 indicates the desired spacing, such as in a numerical readout or graphical format, to name a few.

[0184] In some embodiments, the system 100 uses local electrophysiological responses to provide dynamic intervals. In such embodiments, a dose of PEF energy is delivered through a catheter having at least one delivery electrode. The same or a different catheter then maps the spatial extent of the voltage reduction. The lesion interval or PEF application location interval may be driven by the actual voltage reduction observed in response to the dose and electrode configuration. In some embodiments, the interval takes the form of a fixed overlap, while in other embodiments, the interval is user selectable based on desired safety factors, etc. This can be performed manually or automated through software that interprets the intraprocedural map and post-application electrogram voltage changes.

[0185] It should also be appreciated that pre-procedure imaging data may be used to dynamically control safety factors / spacing. For tissue areas known or suspected to be thicker, the dynamic spacing recommendation would be smaller to ensure transmural lesions. For example, intracardiac echocardiography may be used to measure the thickness of the tissue adjacent to the electrode. This may be measured manually and entered into the system, or ultrasound may communicate directly with the generator to feed any thickness data. In another embodiment, an ultrasound transducer may be incorporated onto a catheter electrode, which may measure tissue thickness locally prior to energy delivery, or throughout the organ chamber, or at the site of intended energy delivery immediately prior to energy delivery. In another embodiment, 3D magnetic resonance (MR)-ultrasound (US) fusion or MR mapping system fusion may be used to correlate anatomy with targeted tissue thickness. In this way, MR may be used to visualize and compartmentalize chamber wall thickness in 3D. This data may be coupled to mapping or ultrasound data via a series of fiducial landmarks to orient them. The thickness data may then be projected onto an electroanatomical mapping system, either directly for MR mapping fusion or with an interface of an ultrasound machine for MR-US fusion. This thickness data may be used to establish treatment administration parameters to be used in the region or to assist the clinician in setting the parameters. In another approach, optical coherence tomography may be used to measure tissue thickness. In each case of these described embodiments, thickness data may be generated and interpreted in real time at the site of interest where energy will be delivered, is being delivered, or has been delivered. The data may also be used to generate a global targeted reconstruction of thickness prior to energy delivery, whereby measurements are not made in real time immediately prior to energy delivery. In some cases, 3D mapping may be performed retrospectively after energy delivery to determine any areas where treatment may be inadequate.This may be done with knowledge of the dose being used, or with a PEF or mapping system that logs each specific dose at each specific activation, records this data and later compares it with the thickness data to assess any areas of undertreatment.

[0186] In some embodiments, the generator 108 generates "smart tag" information that is incorporated into any type of display of the generated lesion. In cardiac applications, the smart tag may appear on a mapping system's display, or the smart tag may be stored or displayed through the generator or other data collection system used to assist in the ablation procedure. In some embodiments, the smart tag includes information such as treatment depth and width, predicted thermal rise, predicted muscle stimulation, and other relevant parameters of interest to the operator when administering or reviewing the treatment.

[0187] 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.

[0188] In the event of a conflicting usage between this document and any document so incorporated by reference, the usage in this document shall control.

[0189] 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.

[0190] 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. 1. A system for generating a lesion in tissue, comprising: a treatment catheter having at least one delivery electrode; a generator electrically coupleable to the treatment catheter, the generator including a processor that generates at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrodes, the processor generating the algorithm based on at least one of one or more inputs by a user; A system comprising:

2. The system of claim 1 , wherein the processor dynamically generates the algorithm based on the one or more inputs in real time.

3. The system of claim 1 , wherein the processor selects the algorithm from a group of algorithms based on the one or more inputs.

4. The system of any preceding claim, wherein the one or more inputs comprise a desired dimension of the lesion.

5. 2. A system as claimed in any preceding claim, wherein the one or more inputs comprise a threshold for temperature rise.

6. 20. The system of claim 1 , wherein the one or more inputs comprise a threshold for muscle contraction.

7. 20. The system of claim 19, wherein the one or more inputs comprise a threshold administration time.

8. 2. A system according to any preceding claim, wherein the one or more inputs comprise a plurality of the one or more inputs.

9. The system of claim 8 , wherein at least one of the one or more inputs comprises a plurality of the one or more inputs.

10. The system of claim 8 , wherein the processor utilizes the plurality of one or more inputs and is based on a ranking or weighting of the plurality of one or more inputs.

11. 20. A system according to any preceding claim, wherein the processor utilises the one or more inputs and at least one default value to generate the algorithm.

12. 20. A system according to any preceding claim, wherein at least one of the one or more inputs is selectable by the user from a menu.

13. 20. A system according to any preceding claim, wherein at least one of the one or more inputs is programmable by the user by means of a user interface.

14. 20. The system of claim 19, wherein the processor correlates the one or more inputs to an electric field strength threshold.

15. The system of claim 14 , wherein the processor determines an electric field strength of the at least one delivery electrode.

16. The system of claim 15 , wherein the processor correlates the electric field strength to the electric field strength threshold.

17. 2. The system of claim 1, wherein the processor selects at least one parameter of the at least one algorithm to generate the electrical signal.

18. 20. The system of claim 19, wherein the processor modifies the algorithm based on tissue thickness.

19. 20. The system of claim 18, wherein the tissue thickness is determined by ultrasound, magnetic resonance, or fluoroscopy.

20. 1. A system for delivering therapy to tissue, comprising: a treatment catheter having at least one delivery electrode; a generator electrically coupleable to the treatment catheter, the generator including a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrodes to provide the treatment, the processor generating a prediction of an outcome of the treatment based on at least one of one or more inputs by a user; A system comprising:

21. The system of claim 20 , wherein the prediction comprises at least one lesion size.

22. The system of claim 21 , wherein the at least one lesion dimension comprises a lesion depth.

23. The system of any of claims 21-22, wherein the at least one lesion dimension comprises a lesion width.

24. A system according to any of claims 20-23, wherein the one or more inputs comprise a threshold value for temperature rise.

25. The system of any of claims 20-24, wherein the one or more inputs comprise a threshold value for muscle contraction.

26. The system of any of claims 20-25, wherein the one or more inputs comprise a threshold administration time.

27. The system of any of claims 20-26, wherein the one or more inputs comprise a plurality of inputs.

28. 30. The system of claim 27, wherein at least one of the one or more inputs comprises a plurality of the one or more inputs.

29. A system according to any of claims 20-28, wherein at least one of the one or more inputs is selectable by the user from a menu.

30. A system according to any of claims 20-29, wherein at least one of the one or more inputs is programmable by the user via a user interface.

31. 21. The system of claim 20, wherein the one or more inputs comprise a single input.

32. 32. The system of claim 31, wherein the single input comprises a time of administration.

33. 1. A system for generating a lesion in tissue, comprising: a treatment catheter having at least one delivery electrode; a generator electrically coupleable to the treatment catheter, the generator including a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrodes to provide the treatment, the processor generating a spacing distance recommendation between the lesion and a next lesion; A system comprising:

34. 34. The system of claim 33, wherein the tissue comprises cardiac tissue and the delivery electrode is configured to deliver the energy to a surface of the cardiac tissue in a manner to create a parabolic lesion.

35. 35. The system of claim 34, wherein the parabolic lesion has a stunning area.

36. 36. The system of claim 35, wherein the spacing distance recommendation positions the subsequent lesion sufficiently close to the subsequent lesion such that the stunning zone at least partially overlaps the subsequent lesion.

37. 37. The system of claim 36, wherein the subsequent lesion has a stunning zone, and the spacing distance recommendation at least causes the stunning zone of the lesion to overlap with the stunning zone of the subsequent lesion such that the tissue between centers of the lesions forms a continuous permanent lesion.

38. A system according to any of claims 33-37, wherein a processor dynamically generates the spacing distance recommendation between the lesion and a next lesion based on local electrophysiological information.

39. 40. The system of claim 38, wherein the local electrophysiological information is obtained from intra-procedural voltage maps and post-application electrogram voltage changes.

40. 40. The system of claim 38, wherein the local electrophysiological information is obtained through observed voltage reduction in the tissue in response to energy delivery.

41. The system of any of claims 33-40, wherein the processor is configured to modify the spacing distance recommendation based on tissue thickness.

42. 42. The system of claim 41, wherein the tissue thickness is determined by ultrasound, magnetic resonance, or fluoroscopy.

43. 42. The system of any of claims 33-41, further comprising an electroanatomical mapping system, wherein the spacing recommendation is visually displayed by the electroanatomical mapping system.

44. 1. A system for generating a lesion in tissue, comprising: a generator electrically coupleable to a treatment catheter, the generator including a processor that generates at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode of the treatment catheter, the processor generating the algorithm based on at least one of one or more inputs by a user; A system comprising:

45. 1. A system for delivering therapy to tissue, comprising: a generator electrically coupleable to a treatment catheter, the generator including a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode of the treatment catheter to provide the treatment, the processor generating a prediction of an outcome of the treatment based on at least one of one or more inputs by a user; A system comprising:

46. 1. A system for generating a lesion in tissue, comprising: a generator electrically coupleable to a treatment catheter, the generator including a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through a delivery electrode of the treatment catheter to provide the treatment, the processor generating a spacing distance recommendation between the lesion and a next lesion; A system comprising:

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