Damage focus optimization in use of pulsed electric fields

Abstract

Devices, systems, and methods are provided for treating a variety of conditions using PEF energy. The PEF energy is typically characterized as high voltage pulse energy configured to be delivered at one or more doses. One or more doses produce lesions in the tissue. The lesion size varies depending on parameters of PEF waveform and dose and other effects such as tissue type. Thus, different waveforms of PEF energies and different doses of PEF energies provide different results, in particular different lesion sizes and types. Systems, devices, and methods are provided that allow a physician or user to control delivered PEF energy to provide a desired outcome and / or to provide predictive information that the user may use to generate the desired outcome.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 336,197, filed on April 28, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Pulsed electric field (PEF) treatment uses the short application of electrical energy to the body to treat disease and pain. In some cases, this delivery is to the tissue in the body cavity, passage or similar anatomical structure, or can be reached in the cavity through these passages. This device usually includes a flexible elongated shaft to pass through the tortuous anatomical structure of the organ cavity, and this device usually includes an energy delivery element mounted thereon, to deliver this energy to a remote or closed position, such as a body cavity. This device has been developed as a blood vessel for treating, for example, a pulmonary passage or vascular system, or for treating various organs, such as the heart, stomach, intestines, etc. In other cases, delivery is directly performed by open surgery or by percutaneous methods. Different environments (such as airways and environments filled with blood) and different diseases (such as diseases affecting surface tissues and diseases affecting deeper layers or tissues) cause the designs of these devices to be different.

[0004] PEF energy destroys the integrity of target tissue cells, which triggers a series of biochemical processes that induce different forms of cell death, including necrosis, apoptosis, apoptotic necrosis, necroptosis and / or pyroptosis. Since PEF treatment does not rely on heat treatment, cells are killed within a certain volume of in vivo tissue without changing the matrix proteins and extracellular matrix within the volume, thereby helping to protect the function of those critical and sensitive anatomical structures (such as major vasculature, luminal systems (such as the common bile duct) and tissue structures (such as the pleura)). Therefore, PEF treatment provides better safety compared to other ablation methods. Due to these characteristics, PEF is being used more and more regularly in a variety of different disease states, including cancer, heart disease and lung disease.

[0005] There are differences between clinical PEF systems, including differences in waveform parameters and delivery polarity (i.e., bipolar or monopolar). In a bipolar electrode configuration, energy is delivered between effector devices placed within or adjacent to the target environment. In contrast, a monopolar system delivers energy from an effector device placed within or adjacent to the target environment to a remote dispersed electrode used as an electrical return. The surface area of ​​the dispersed electrode is sufficient to distribute the PEF energy wide enough so that the treatment effect is not encountered at its location. Traditionally, radiofrequency (RF) energy has been used to treat a variety of ailments, including cardiovascular disease. This energy can be applied to the heart and vascular system to treat a variety of conditions, including atherosclerosis (especially in the prevention of restenosis after angioplasty) and atrial fibrillation. Atrial fibrillation is the most common sustained arrhythmia and seriously increases the risk of death in affected patients, especially due to stroke. In this phenomenon, the heart deviates from normal sinus rhythm due to the generation of erroneous electrical impulses. Atrial fibrillation is believed to be caused in the myocardial sleeve of the pulmonary vein (PV) due to the presence of autonomy in the cells within the myocardial tissue of the PV. The pacemaker activity from these cells is thought to result in the formation of ectopic beats, which can initiate AF. The PVs are also thought to play an important role in maintaining AF because the chaotic architecture and electrophysiological properties of these vessels provide an environment in which AF can persist. Therefore, destruction or removal of these abnormal pacemaker cells within the myocardial sleeves of the PVs is a goal, and AF is often managed by delivering therapeutic energy to the pulmonary veins. However, due to reports of PV stenosis, this approach has routinely been modified to target the PV sinuses to achieve conduction block between the PVs and the left atrium. In addition to the pulmonary veins, the PV sinuses include the left atrium and posterior wall, and in the case of the right pulmonary vein sinuses, a portion of the atrial septum. In some cases, this technique offers higher success rates and lower complication rates compared with pulmonary vein ostium isolation.

[0006] Thermal ablation therapy, specifically radiofrequency (RF) ablation, is currently the "gold standard" for the management of symptomatic AF through localized 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 tissue desiccation by creating localized hot zones that result in discrete coagulative necrosis. The necrotic tissue acts as a conduction block, thereby electrically isolating the vein.

[0007] Although there have been improvements in reestablishing sinus rhythm using existing methods, the thermal properties of these surgeries limit success rates and safety. Complications include pulmonary vein stenosis, phrenic nerve injury, esophageal injury, atrioesophageal fistula, periesophageal vagus nerve injury, perforation, thromboembolic events, vascular complications, and acute coronary artery occlusion. Therefore, while maintaining this technology in clinical practice, safer and more versatile methods of removing abnormal tissues, such as pulsed electric field therapy (PEF), have been used. However, since PEF therapy has different cellular effects on tissues, the response of the tissues is different from when receiving RF ablation. Therefore, the conventional clues that doctors monitor throughout the ablation process are largely inapplicable and may lead to poor results, such as incomplete blocking of abnormal electrical rhythms. In addition, the different effects of PEF energy on tissues result in different lesion sizes from RF and a variety of other differences that doctors did not expect. Therefore, it is desirable to improve methods, devices, and systems to improve the availability of PEF systems and the final results of treatment. This treatment should be safe, effective, and result in reduced complications. The systems, devices, and methods described herein will meet at least some of these goals. Summary of the invention

[0008] Embodiments of devices, systems and methods for treating target tissue, particularly cardiac tissue, are described herein. Also, the present invention relates to the following numbered clauses:

[0009] 1. A system for generating a lesion in a tissue, comprising:

[0010] a treatment catheter having at least one delivery electrode; and

[0011] A generator electrically coupled to the treatment catheter, wherein the generator includes a processor that generates at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrode, wherein the processor generates the algorithm based on at least one of one or more inputs from a user.

[0012] 2. A system according to clause 1, wherein the processor dynamically generates the algorithm in real time based on the one or more inputs.

[0013] 3. The system of clause 1 , wherein the processor selects the algorithm based on the one or more inputs from a set of algorithms.

[0014] 4. A system according to any of the above clauses, wherein the one or more inputs include a desired size of the lesion.

[0015] 5. A system according to any of the preceding clauses, wherein the one or more inputs include a threshold value for temperature rise.

[0016] 6. A system according to any of the above clauses, wherein the one or more inputs include a threshold for muscle contraction.

[0017] 7. A system according to any of the above clauses, wherein the one or more inputs include a threshold dose time.

[0018] 8. A system according to any of the above clauses, wherein the one or more inputs include a plurality of the one or more inputs.

[0019] 9. The system of clause 8, wherein the at least one of the one or more inputs comprises a plurality of the one or more inputs.

[0020] 10. The system of clause 8, wherein the processor utilizes the plurality of the one or more inputs and is based on a ranking or weighting of the plurality of the one or more inputs.

[0021] 11. A system according to any of the above clauses, wherein the processor generates the algorithm using the one or more inputs and at least one default value.

[0022] 12. A system according to any of the preceding clauses, wherein at least one of the one or more inputs is selectable by the user from a menu.

[0023] 13. A system according to any of the preceding clauses, wherein at least one of the one or more inputs is programmable by the user using a user interface.

[0024] 14. A system according to any of the preceding clauses, wherein the processor associates the one or more inputs with an electric field strength threshold.

[0025] 15. The system of clause 14, wherein the processor determines the electric field strength of the at least one delivery electrode.

[0026] 16. The system of clause 15, wherein the processor associates the electric field strength with the electric field strength threshold.

[0027] 17. A system according to any of the preceding clauses, wherein the processor selects at least one parameter of the at least one algorithm to generate the electrical signal.

[0028] 18. A system according to any of the above clauses, wherein the processor modifies the algorithm based on tissue thickness.

[0029] 19. The system of clause 18, wherein tissue thickness is determined by ultrasound, magnetic resonance, or fluoroscopy.

[0030] 20. A system for providing treatment to a tissue, comprising:

[0031] a treatment catheter having at least one delivery electrode; and

[0032] a generator electrically coupled to the treatment catheter, wherein the generator includes a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrode to provide the treatment, wherein the processor generates a prediction of an outcome of the treatment based on at least one of one or more inputs from a user.

[0033] 21. The system of clause 20, wherein the prediction includes at least one of lesion size, temperature rise, muscle contraction and / or dose time.

[0034] 22. The system of clause 21, wherein the at least one lesion dimension comprises a lesion depth.

[0035] 23. The system of any of clauses 21-22, wherein the at least one lesion size comprises a lesion width.

[0036] 24. The system of any of clauses 20-23, wherein the one or more inputs comprises a threshold value for a temperature rise.

[0037] 25. A system according to any of clauses 20-24, wherein the one or more inputs include a threshold for muscle contraction.

[0038] 26. The system of any of clauses 20-25, wherein the one or more inputs comprises a threshold dose time.

[0039] 27. The system of any of clauses 20-26, wherein the one or more inputs comprises a plurality of inputs.

[0040] 28. The system of clause 27, wherein at least one of the one or more inputs comprises a plurality of the one or more inputs.

[0041] 29. The system of any of clauses 20-28, wherein at least one of the one or more inputs is selectable by the user from a menu.

[0042] 30. The system of any of clauses 20-29, wherein at least one of the one or more inputs is programmable by the user using a user interface.

[0043] 31. The system of clause 20, wherein the one or more inputs comprises a single input.

[0044] 32. A system according to clause 31, wherein the single input comprises a dosage time.

[0045] 33. A system for generating a lesion in a tissue, comprising:

[0046] a treatment catheter having at least one delivery electrode; and

[0047] A generator electrically coupled to the treatment catheter, wherein the generator includes a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrode to provide treatment, wherein the processor generates a separation distance recommendation between the lesion and a next lesion.

[0048] 34. The system of clause 33, wherein the tissue comprises cardiac tissue, and the delivery electrode is configured to deliver the energy to the surface of the cardiac tissue in a manner that produces a parabolic lesion.

[0049] 35. A system according to clause 34, wherein the parabolic lesion has a coma zone.

[0050] 36. A system according to clause 35, wherein the separation distance suggests positioning the next lesion sufficiently close to the lesion so that the coma zone at least partially overlaps with the next lesion.

[0051] 37. A system according to clause 36, wherein the next lesion has a coma zone, and wherein the spacing distance suggests at least overlapping the coma zone of the lesion with the coma zone of the next lesion so that the tissue between the centers of the lesions forms a continuous permanent lesion.

[0052] 38. A system according to any of clauses 33-37, wherein the processor dynamically generates a separation distance recommendation between the lesion and the next lesion based on local electrophysiological information.

[0053] 39. A system according to clause 38, wherein the local electrophysiological information is obtained from intraoperative voltage maps and post-application electrogram voltage changes.

[0054] 40. The system of clause 38, wherein the local electrophysiological information is obtained by including a voltage reduction observed in the tissue in response to energy delivery.

[0055] 41. The system of any of clauses 33-40, wherein the processor is configured to modify the separation distance recommendation based on tissue thickness.

[0056] 42. A system according to clause 41, wherein the tissue thickness is determined by ultrasound, magnetic resonance or fluoroscopy.

[0057] 43. The system of any of clauses 33-41, further comprising an electroanatomical mapping system, and wherein the separation distance suggestion is visually displayed by the electroanatomical mapping system.

[0058] 44. A system for generating a lesion in a tissue, comprising:

[0059] A generator electrically coupled to a treatment catheter, wherein the generator includes 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, wherein the processor generates the algorithm based on at least one of one or more inputs from a user.

[0060] 45. A system for providing treatment to a tissue, comprising:

[0061] A generator electrically coupled to a treatment catheter, wherein the generator includes 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, wherein the processor generates a prediction of an outcome of the treatment based on at least one of one or more inputs from a user.

[0062] 46. ​​A system for generating a lesion in a tissue, comprising:

[0063] A generator electrically coupled to a treatment catheter, wherein the generator includes 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 treatment, wherein the processor generates a separation distance recommendation between the lesion and a next lesion.

[0064] These and other embodiments are described in more detail in the following description associated with the accompanying drawings.

[0065] Incorporation by reference

[0066] 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

[0067] In the accompanying drawings, which are not necessarily drawn to scale, like numbers may describe similar components in different views. Like numbers with different letter suffixes may represent different instances of similar components. The accompanying drawings generally illustrate various embodiments discussed in this document by way of example and not by way of limitation.

[0068] Figure 1 Implementations of tissue modification systems are illustrated.

[0069] Figure 2A-2B An embodiment of a treatment catheter configured to deliver localized therapy is illustrated.

[0070] Figure 3 Embodiments of waveforms of signals dictated by an energy delivery algorithm are illustrated.

[0071] Figure 4 A portion of a heart is illustrated showing a cross-sectional view of the right and left atria with treatment catheters positioned therein.

[0072] Figure 5 Embodiments of waveforms of signals dictated by an energy delivery algorithm are illustrated.

[0073] Figure 6 It is caused by Figure 2B Schematic representation of the catheter-generated lesion is shown.

[0074] Figure 7 Examples of three different levels or doses of energy delivery are illustrated.

[0075] Figure 8 The diagram shows the creation of two overlapping adjacent lesions.

[0076] Fig. 9 The final continuous lesion formed by energy delivered through the catheter is illustrated.

[0077] Fig.10 The effect of various doses on lesion size is shown.

[0078] Fig.11 The effect of overlapping lesions is shown.

[0079] Fig.12 The region receiving double dose from both catheter placements and considered as part of the treatment depth of a continuous lesion is illustrated.

[0080] Fig.13 The resulting continuous lesion is shown with the depth of treatment and Figure 8 Compared to increase.

[0081] Fig.14 The diagram shows the Fig.11 The lesion intervals were larger and the zone receiving double dose from both catheter placements was shifted upward.

[0082] Fig.15 The diagram shows Fig.14 The lesions lead to continuous lesions.

[0083] Fig.16 An example correlation between treatment depth and lesion spacing at three different energy doses is illustrated.

[0084] Figure 17A-17B The diagram illustrates the use of two different treatment schemes for different regions of the heart.

[0085] Fig.18 Example placement of anterior and posterior lesions are illustrated.

[0086] Fig.19 Shown are the rates of pulmonary vein isolation at 90-day remapping.

[0087] Fig. 20 Illustrated is a system with user input that is used to generate or select a particular energy delivery algorithm that optimizes the treatment waveform and / or dosage for a desired treatment.

[0088] Figure 21A-Figure 21D Illustrated are example individual relationships between treatment / lesion depth and the parameters of pulse packet number, frequency, pulse packet delivery rate, and pulse packet duration.

[0089] Figure 22A-22D Illustrated are example individual relationships between treatment / lesion width and the parameters of pulse packet number, frequency, pulse packet delivery rate, and pulse packet duration.

[0090] Figure 23A-23D Example individual relationships between treatment / lesion width and the parameters of pulse packet number, frequency, pulse packet delivery rate, and temperature rise are illustrated.

[0091] Figure 24A-Figure 24D Example individual relationships between treatment / lesion width and parameters of pulse packet number, frequency, pulse packet delivery rate, and muscle contraction are illustrated.

[0092] Figure 25A-Figure 25C Example electric field distributions for catheter embodiments delivering PEF energy within the heart are illustrated.

[0093] Fig.26 A system for providing prediction of lesion size is illustrated.

[0094] Fig. 27A system is illustrated that provides a prediction of lesion size based on expected dose time. DETAILED DESCRIPTION

[0095] Provided are devices, systems and methods for treating a variety of diseases using PEF energy. PEF energy is generally characterized as high-voltage pulse energy, which is configured to be delivered with one or more doses. Each energy dose delivered to the target tissue is configured to keep the temperature at or in the target tissue below the thermal ablation threshold. These effects are considered to be non-thermal effects, rather than damage caused by thermal ablation (described as extracellular protein coagulation), where this energy changes or destroys cells in the tissue, but retains the underlying protein extracellular matrix of the tissue, which provides the interstitial framework structure and structural related functions of the tissue. In some cases, this allows tissue regeneration, such as by the re-increase of the extracellular matrix. In addition, nearby sensitive tissues will not be harmed. It is understood that the dose can be titrated or moderated over time to further reduce or eliminate heat accumulation during the treatment process. It is understood that in some embodiments, energy delivery is actuated by a variety of mechanisms, such as using an actuator on the device or a foot switch operably connected to the generator. This actuation generally provides a single energy dose or activation.

[0096] Target tissue cells can be processed anywhere in the body, including cells of the digestive system (e.g., oral cavity, glands, esophagus, stomach, duodenum, jejunum, ileum, intestines, colon, rectum, liver, gallbladder, pancreas, anal canal, etc.), cells of the respiratory system (e.g., nasal cavity, pharynx, trachea, bronchi, lungs, etc.), cells of the urinary system (e.g., kidneys, ureters, bladder, urethra, etc.), cells of the reproductive system (e.g., reproductive organs, ovaries, fallopian tubes, uterus, cervix, vagina, testicles, epididymis, vas deferens, seminal vesicles, prostate, glands, penis, scrotum, etc.), cells of the endocrine system (e.g., endocrine system ... The cells of the endocrine system (e.g., pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland), the cells of the circulatory system (e.g., heart, arteries, veins, etc.), the cells of the lymphatic system (e.g., lymph nodes, bone marrow, thymus gland, spleen, etc.), the cells of the nervous system (e.g., brain, spinal cord, nerves, ganglia, etc.), the cells of the eye (e.g., retina, macula, rod and cone cell layers, retinal pigment epithelium, optic nerve, choroid, sclera, etc.), the cells of the muscular system (e.g., myofilament layer, etc.), and the cells of the skin (e.g., epidermis, dermis, subcutaneous tissue, etc.), etc.

[0097] Conditions treated include arrhythmias. When treating atrial fibrillation, a closed path of connected ablation lesions (such as around the external ostium of the pulmonary veins) is usually created by delivering PEF energy using a local catheter or a single-shot catheter. In addition, local catheters can be used to create many other types of lesions, particularly lines along various surfaces of cardiac tissue. In one embodiment, a vena cava-tricuspid isthmus line is created to treat typical atrial flutter in the right atrium. In another embodiment, a roofline and / or floor line of a box-shaped lesion along the posterior wall of the left atrium is created for patients with atrial fibrillation (particularly persistent atrial fibrillation). In another embodiment, a mitral isthmus line along the anterior or lateral wall of the left atrium is created for atypical atrial flutter. In yet another embodiment, a ventricular line connecting two unexcitable boundaries is created, which is essential for the initiation or maintenance of reentrant ventricular arrhythmias, typically in patients with ventricular tachycardia caused by ischemic heart disease. Other conditions treated include pulmonary diseases, such as chronic obstructive pulmonary disease, chronic bronchitis, excessive mucus secretion, asthma and cystic fibrosis. Other conditions also include coagulation disorders. In some embodiments, the disease includes a nervous system disease, such as an injury or disease. In some embodiments, the disease includes a cardiovascular disease, such as degenerative heart disease, heart failure disease, coronary artery disease, ischemia, angina, acute coronary syndrome, peripheral vascular disease, peripheral arterial disease, cerebrovascular disease or atherosclerosis. In some embodiments, the disease includes an immune disease, such as an autoimmune disease. In some embodiments, the disease includes a liver disease. In some embodiments, the disease includes a tumor or cancer, such as a blood cancer or a solid tissue cancer.

[0098] The apparatus, system and method deliver therapeutic energy to tissues in the body for providing tissue remodeling, typically for creating lesions. Lesions are areas of tissue damage, whether permanent or reversible. When treating a tumor, the lesion includes the portion of the tumor destroyed by the received PEF energy. When treating atrial fibrillation, the lesion includes the portion of the heart wall where cells have been killed by the received PEF energy. In the treatment of atrial fibrillation, such lesions are typically located along the entrance of the pulmonary veins. Such tissue remodeling creates conduction blocks within the tissue to prevent the transmission of abnormal electrical signals.

[0099] In general, the tissue modification system includes a dedicated catheter, a high voltage biphasic waveform generator, and at least one different energy delivery algorithm. Additional accessories and equipment can be used. It is understood that a variety of catheter designs can be used, especially catheter designs specifically designed for specific treatments. For illustrative purposes, a simplified design is provided when describing the overall system. This simplified design provides local treatment. However, it is understood that a variety of other types of catheters and delivery electrodes can be used.

[0100] Figure 1 An embodiment of a tissue modification system 100 for treating cardiac tissue is illustrated, comprising a treatment catheter 102, a mapping catheter 104, a return electrode 106, a waveform generator 108, and an external cardiac monitor 110. It is understood that, although this example is specific to treating cardiac tissue, particularly for treating arrhythmias, this is merely an example. Such lesion features and formation can be applied to a variety of other tissue types and locations throughout the body as described herein.

[0101] In this embodiment, the heart is accessed via the right femoral vein FV through a suitable access procedure, such as the Seldinger technique. Typically, a sheath 112 is inserted into the femoral vein FV, which serves as a conduit through which various catheters and / or tools, including the treatment catheter 102 and the mapping catheter 104, can be advanced. It will be appreciated that in some embodiments, the treatment catheter 102 and the mapping catheter 104 are combined into a single device. Figure 1 As shown in , the distal ends of catheters 102, 104 are advanced through the inferior vena cava, through the right atrium, through the transseptal puncture and into the left atrium in order to gain access to the entrance of 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 cardiac muscle potentials during a particular cardiac rhythm. Cardiac mapping during abnormal cardiac rhythms is intended to elucidate the mechanisms of the rhythm, describe the propagation of activation from its initiation to its completion within a region of interest, and identify the starting site or critical site of conduction as a target for treatment. Once the desired treatment location is identified, the treatment catheter 102 is utilized to deliver treatment energy.

[0102] In this embodiment, the proximal end of the treatment catheter 102 is electrically connected to a waveform generator 108, wherein the generator 108 is software controlled and has a regulated energy output that creates high frequency, short duration energy that is delivered to the catheter 102. It will be appreciated 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 included in the generator 108. However, it will be appreciated that the mapping catheter 104 may alternatively be connected to a separate external device having the capability to provide a mapping procedure, such as an electroanatomical mapping (EAM) system (e.g., Biosense Webster / Johnson & Johnson's system, St.Jude Medical / Abbott's EnSite TM system, Philips' KODEX-EPD system, Boston Scientific's Rhythmia HDX TMSimilarly, in some embodiments, rather than using a separate mapping catheter 104, mapping features are built into the catheter 102.

[0103] In this embodiment, the generator 108 is connected to an external cardiac monitor 110 to allow energy delivery coordinated with cardiac signals sensed from the patient P. The generator synchronizes the energy output with the patient's heart rhythm. The cardiac monitor provides a trigger signal to the generator 108 when it detects the R wave of the patient's cardiac cycle. The trigger signal and the generator's algorithm reliably synchronize the energy delivery with the patient's cardiac cycle to reduce the possibility of arrhythmias due to energy delivery. Typically, a foot switch allows the user to start and control the delivery of the energy output. The generator user interface (UI) provides the user with audio and video information about the energy delivery and the operating status of the generator.

[0104] In this embodiment, the treatment catheter 102 is designed to be monopolar, with the distal end of the catheter 108 having the delivery electrode 122 and the return electrode 106 positioned on the skin outside the body, typically on the thigh, lower back, or back. Figure 2A An embodiment of a treatment catheter 102 configured to deliver local treatment is illustrated. In this embodiment, the catheter 102 includes an elongated shaft 120 having a delivery electrode 122 located near its distal end 124 and a handle 126 located near its proximal end 128. The delivery electrode 122 is shown as a "solid tip" electrode having a cylindrical shape with a distal side having a continuous surface. In some embodiments, the cylindrical shape has a diameter of about 2-3 mm across its distal side and a length 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. along the shaft 120. It is understood that such electrodes are generally hollow, but are referred to as solid due to visual appearance. In some embodiments, the catheter 102 has a total length of 50-150 cm, preferably 100-125 cm, and more preferably 110-115 cm. Similarly, in some embodiments, it has a 7Fr outer diameter 3-15Fr, preferably 4-12Fr, and more preferably 7-8.5Fr. It will be appreciated that in some embodiments, the shaft 120 has a deflectable end 121, and optionally, the deflectable end 121 can have a length of 50-105mm, thereby producing a curve with a diameter ranging from about 15 to 55mm. Deflection can be achieved by a variety of mechanisms including a pull wire extending to the handle 126. Thus, the handle 126 is used to manipulate the catheter 102, particularly to guide the distal end 124 during delivery and processing. Energy is provided to the catheter 102 via a cable 130 that can be connected to the generator 108, and therefore to the delivery electrode 122.

[0105] Pulsed electric field (PEF) is provided by generator 108 and delivered to tissue by delivery electrode 122 placed on or near target tissue area. It is understood that in some embodiments, delivery electrode 122 is positioned to contact with conductive material, which is also in contact with target tissue. Such solution may include isotonic or hypertonic solution. These solutions may also include auxiliary materials, such as chemotherapy or calcium, to further enhance the treatment effect of local treatment and potential regional infiltration area of ​​target tissue type. Then high voltage, short duration biphasic electric pulses are delivered by electrode 122 near target tissue. These electric pulses are provided by at least one energy delivery algorithm 152. In some embodiments, each energy delivery algorithm 152 specifies a signal having a waveform including a series of energy pulse packets, wherein each energy pulse packet includes a series of high voltage pulses. In this embodiment, algorithm 152 specifies parameters of the signal, such as energy amplitude (e.g., voltage) and duration of energy application, which is composed of the number of pulse packets, the number of pulses in the pulse packet, and the fundamental frequency of the pulse sequence. Additional parameters may include switching times between polarities in biphasic pulses, quiet times between biphasic cycles, and rest times between pulse packets, which will be described in more detail in later sections. There may be fixed rest periods between pulse packets, or the pulse packets may be gated based on the cardiac cycle and thus vary with the patient's heart rate. There may be an intentionally variable rest period algorithm, or rest periods may not be applied between pulse packets. Feedback loops based on sensor information and automatic shut-off specifications and / or the like may be included.

[0106] It will be appreciated that in various embodiments, the treatment catheter 102 includes a variety of specialized features. For example, in some embodiments, the catheter 102 includes a mechanism for measuring the contact force applied by the catheter tip to the patient's heart wall in real time during surgery. In some embodiments, the mechanism is included within the shaft 120 and includes a three-axis optical force sensor using white light interferometry. By monitoring and modifying the applied force throughout the procedure, the user is able to better control the catheter 102 in order to create more consistent and effective lesions.

[0107] In some embodiments, Figure 2B As shown in , catheter 102 includes one or more additional electrodes 125 (e.g., ring electrodes) positioned along shaft 120 proximal to delivery electrode 122. In some embodiments, some or all of the additional electrodes can be used for stimulation and recording (for electrophysiological mapping), so that a separate cardiac mapping catheter is not required when catheter 102 is used to create lesions or for other purposes such as sensing.

[0108] In some embodiments, the catheter 102 includes a thermocouple temperature sensor, optionally embedded in 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 is connected to one or more ports along the distal end of the catheter 102, such as for injection of isotonic saline solution for irrigation or, for example, for removal of microbubbles.

[0109] In some embodiments, the catheter 102 includes one or more sensors that can be used to determine temperature, impedance, resistance, capacitance, conductivity, dielectric constant, and / or conductance, among others. In some embodiments, one or more of the electrodes act as one or more sensors. In other embodiments, one or more sensors are separate from the electrodes. The sensor data can be used to plan treatment, monitor treatment, and / or provide direct feedback via the processor 154, which in turn can change the energy delivery algorithm 152. For example, impedance measurements can be used not only to determine the initial dose to be applied, but also to determine whether further treatment is needed.

[0110] Return to reference Figure 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 a database), and an energy storage subsystem 158 that generates and stores energy to be delivered. In some embodiments, one or more capacitors are used to store / deliver energy, however, any other suitable energy storage element may be used. In addition, one or more communication ports are included.

[0111] In some embodiments, the generator 108 includes three subsystems: 1) a high energy storage system, 2) a high voltage, intermediate 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 with the patient's heart rhythm. The generator uses an alternating current (AC) power supply to power multiple direct current (DC) power supplies. The controller of the generator can cause the DC power supply to charge the high energy capacitor energy storage group before initiating energy delivery. When the therapeutic energy delivery is initiated, the controller of the generator, the high energy energy storage group, and the biphasic pulse amplifier can operate simultaneously to create a high voltage, intermediate frequency output.

[0112] It should be understood that a variety of generator electrical architectures can be used to implement energy delivery algorithms. In particular, in some embodiments, an advanced switching system is used that can direct the pulsed electric field circuit to an energy delivery electrode that is separate from the same energy storage and high voltage delivery system. In addition, the generator used in the advanced energy delivery algorithm that adopts rapidly changing pulse parameters (e.g., voltage, frequency, etc.) or multiple energy delivery electrodes can utilize modular energy storage and / or high voltage systems, thereby facilitating highly customizable waveforms and geographic pulse delivery paradigms. It should also be understood that the electrical architecture described above in this article is for illustration only, and the system that delivers the pulsed electric field may or may not include additional switching amplifier components.

[0113] The user interface 150 may include a touch screen and / or more traditional buttons to allow an operator to enter patient data, select a treatment algorithm (e.g., an energy delivery algorithm 152), initiate energy delivery, view records stored on a storage / retrieval unit 156, and / or otherwise communicate with the generator 108.

[0114] In some embodiments, the user interface 150 is configured to receive operator-defined inputs. The operator-defined inputs can include duration or dose time of energy delivery, one or more other timing aspects of energy delivery pulses, power and / or operation mode, one or more desired lesion sizes, type of treatment, treatment location, type of tissue, type of catheter or electrode configuration, temperature limits, muscle contraction limits, combinations thereof, and the like.

[0115] Example operating modes may include (but are not limited to): system startup 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 sub-combination thereof.

[0116] As described above, in some embodiments, the system 100 also includes a mechanism for collecting an electrocardiogram (ECG) when cardiac synchronization is required, such as an external cardiac monitor 110. Example cardiac monitors are available from AccuSync Medical Research Corporation and Ivy Biomedical Systems, Inc. In some embodiments, the external cardiac monitor 110 is operably connected to the generator 108. The cardiac monitor 110 can be used to continuously collect ECG signals. External electrodes 172 can be applied to the patient P to collect ECG. The generator 108 analyzes one or more cardiac cycles and identifies the beginning of a time period when energy can be safely applied to the patient P, thereby providing the ability to synchronize energy delivery with the cardiac cycle. In some embodiments, the time period is within a few milliseconds of the R wave (of the ECG QRS complex) to avoid inducing arrhythmias - if the energy pulse is delivered on the T wave, such a situation may occur. It should be understood that this cardiac synchronization is typically adopted when using unipolar energy delivery, but it can also be used as part of other energy delivery methods.

[0117] 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 operating 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.

[0118] The data storage / retrieval unit 156 stores data, such as data related to the delivered treatment, and can optionally be downloaded by connecting a device (e.g., a laptop or thumb drive) to the communication port. In some embodiments, the device has local software that directs the download of information, such as, for example, instructions stored on the data storage / retrieval unit 156 and executable by the processor 154. In some embodiments, the user interface 150 allows an operator to select to download data to a device and / or system, such as, but not limited to, a computer device, a tablet computer, a mobile device, a server, a workstation, a cloud computing device / system, etc. The communication port, which can allow wired and / or wireless connectivity, can allow data download as previously described, but can also allow data upload, such as uploading a custom algorithm or providing a software update.

[0119] As described herein, the various energy delivery algorithms 152 are programmable or may be pre-programmed into the generator 108, such as stored in a memory or data storage / retrieval unit 156. Alternatively, the energy delivery algorithms may be added to the data storage / retrieval unit for execution by the processor 154. Each of these algorithms 152 may be executed by the processor 154.

[0120] It will be appreciated that in some embodiments, system 100 includes an automated treatment delivery algorithm that dynamically responds and adjusts and / or terminates treatment 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 state.

[0121] As previously described, in some embodiments, the cardiac monitor provides a trigger signal to the generator 108 when it detects the R wave of the patient's cardiac cycle. The trigger signal and the generator's algorithm reliably synchronize energy delivery with the patient's cardiac cycle to reduce the possibility of arrhythmias due to energy delivery. The trigger occurs within a few milliseconds of the peak of the R wave (of the ECG QRS complex) to avoid inducing arrhythmias (which may occur if the energy pulse is delivered on the T wave), and also ensures that energy delivery occurs at a consistent phase of cardiac contraction. It should be understood that this cardiac synchronization is typically adopted when using unipolar energy delivery, but it can also be used as part of other energy delivery methods.

[0122] As previously described, the one or more energy delivery algorithms 152 are programmable or can be preprogrammed into the generator 108 for delivery to the patient P. The one or more energy delivery algorithms 152 specify electrical signals that provide energy delivered to the heart wall that is non-thermal (e.g., below the threshold for thermal ablation; below the threshold for inducing coagulative thermal injury), thereby reducing or avoiding inflammation, and / or preventing denaturation of matrix proteins in luminal structures. In general, the algorithms 152 are tailored to affect tissue to a predetermined depth and / or volume and / or for a specific type of cellular response to the delivered energy.

[0123] Figure 3An embodiment of a waveform 400 of a signal specified by an energy delivery algorithm 152 is illustrated. Here, two pulse packets are shown - a first pulse packet 402 and a second pulse packet 404, wherein the pulse packets 402, 404 are separated by a rest period 406. In this embodiment, each pulse packet 402, 404 consists of a first biphasic cycle (including a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic cycle (including a second positive pulse peak 408' and a second negative pulse peak 410'). The first biphasic pulse and the second biphasic pulse are separated by a quiet time 412 (i.e., a pause) between each biphasic cycle. In this embodiment, the biphasic pulses are symmetrical, so the set voltage 416 is the same for the positive peak and the negative peak. Here, the biphasic symmetrical wave is also a square wave, so that the amplitude and time of the positive voltage wave are approximately equal to the amplitude and time of the negative voltage wave.

[0124] A. Voltage

[0125] The voltage used and considered can be the top of a square wave waveform, can be the peak in a sine or sawtooth waveform, or can be the RMS voltage of a sine or sawtooth waveform. In some embodiments, energy is delivered in a unipolar manner, and each high voltage pulse or set voltage 416 is between about 500V and 10,000V, particularly about 3500V to 4000V, about 3500V to 5000V, about 3500V to 6000V, including all values ​​and subranges therebetween, including about 250V, 500V, 1000V, 1500V, 2000V, 2500V, 3000V, 3500V, 4000V, 4500V, 5000V, 5500V, 6000V, etc. The voltage delivered to the tissue may be based on a set point on the generator 104 while accounting for electrical losses along the length of the device 102 due to the inherent impedance of the device 102 or without accounting for losses along the length, i.e., the delivered voltage may be measured at the generator or at the tip of the instrument.

[0126] It will be appreciated 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 a smaller, more directional electric field. The bipolar voltage selected for treatment depends on the spacing distance of the electrodes, while a monopolar electrode configuration using one or more remote dispersed pad electrodes may be delivered with less consideration of the exact placement of the catheter electrode and the dispersed electrode placed on the body. In a monopolar electrode embodiment, due to the dispersed behavior of the delivered energy through the body to the dispersed electrode, the effective spacing distance is approximately 10 cm to 100 cm, so a larger voltage is typically used. In contrast, in a bipolar electrode configuration, the relatively close active areas of the electrodes on the order of 0.5 mm to 10 cm, including 1 mm to 1 cm, have a greater impact on the concentration of electrical energy delivered to the tissue from the spacing distance and the effective dose. For example, if the target voltage to distance ratio is 3000 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 necessary increase in treatment voltage from 300 V to approximately 360 V, a change of 20%.

[0127] B. Frequency

[0128] It is understood that the number of biphasic cycles per second is the frequency when the signal is continuous. In some embodiments, biphasic pulses are used to reduce undesirable muscle stimulation, particularly myocardial stimulation. In other embodiments, the pulse waveform is monophasic and there is no clear natural frequency. Instead, the fundamental frequency can be considered by doubling the monophasic pulse length to derive the frequency. In some embodiments, the signal has a frequency in the range of 50kHz-1MHz, more specifically in the range of 50kHz-1000kHz. It is understood that at some voltages, a frequency at or below 100-250kHz may cause undesirable muscle stimulation. Therefore, in some embodiments, the signal has a frequency in the range of 300-800kHz, 400-800kHz or 500-800kHz, such as 300kHz, 400kHz, 450kHz, 500kHz, 550kHz, 600kHz, 650kHz, 700kHz, 750kHz, 800kHz. In addition, cardiac synchronization is usually used to reduce or avoid undesirable myocardial stimulation during sensitive rhythms. It will be appreciated that even higher frequencies may be used with components that minimize signal artifacts.

[0129] C. Voltage-Frequency Balance

[0130] The frequency of the delivered waveform can be varied synchronously with respect to the treatment voltage to maintain adequate treatment effect. Such synergistic variation will include a frequency reduction that causes a stronger effect combined with a voltage reduction that causes a weaker effect. For example, in some cases, treatment can be delivered in a monopolar manner using a waveform frequency of 3000V and 600kHz, while in other cases, treatment can be delivered using a waveform frequency of 2000V and 400kHz.

[0131] D. Pulse Packet

[0132] As previously described, the algorithm 152 generally provides for a signal having a waveform comprising a series of energy pulse packets, wherein each energy pulse packet comprises a series of high voltage pulses. The cycle count 420 is half the number of pulses in each biphasic pulse packet. Figure 3 , the cycle count 420 of the first pulse packet 402 is 2 (i.e., four biphasic pulses). In some embodiments, the cycle count 420 is set between 2 and 1000 per pulse packet, including all values ​​and subranges therebetween. In some embodiments, the cycle count 420 is 5-1000 per pulse packet, 2-10 per pulse packet, 2-20 per pulse packet, 2-25 per pulse packet, 10-20 per pulse packet, 20 per pulse packet, 20-30 per pulse packet, 25 per pulse packet, 20-40 per pulse packet, 30 per pulse packet, 20-50 per pulse packet, 30-60 per pulse packet, up to 60 per pulse packet, up to 80 per pulse packet, up to 100 per pulse packet, up to 1,000 per pulse packet, or up to 2,000 per pulse packet, including all values ​​and subranges therebetween.

[0133] The pulse packet duration is determined by factors such as the cycle count. For a matched pulse duration (or a positive pulse duration and a negative pulse duration sequence of a biphasic waveform), the higher the cycle count, the longer the pulse packet duration, and the greater the amount of energy delivered. In some embodiments, the pulse packet duration is in the range of about 50 to 1000 microseconds, such as 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 125 μs, 150 μs, 175 μs, 200 μs, 250 μs, 100 to 250 μs, 150 to 250 μs, 200 to 250 μs, 500 to 1000 μs, etc. In other embodiments, the pulse packet duration is in the range of about 100 to 1000 microseconds, such as 150 μs, 200 μs, 250 μs, 500 μs or 1000 μs.

[0134] The number of pulse packets delivered during treatment or the pulse packet count generally includes 1 to 250 pulse packets, including all values ​​and subranges therebetween. In some embodiments, the number of pulse packets delivered during treatment includes 10 pulse packets, 15 pulse packets, 20 pulse packets, 25 pulse packets, 30 pulse packets, or more than 30 pulse packets.

[0135] E. Rest period

[0136] In some embodiments, the time between pulse packets, referred to as the rest period 406, is set between about 0.001 seconds and about 5 seconds, including all values ​​and subranges therebetween. In other embodiments, the rest period 406 ranges from about 0.01-0.1 seconds, including all values ​​and subranges therebetween. In some embodiments, the rest period 406 is about 0.5 ms-500 ms, 1 ms-250 ms, or 10 ms-100 ms, etc.

[0137] F. Batch

[0138] In some embodiments, the signal is synchronized with the heart rhythm so that each pulse packet is delivered synchronously within a specified time period relative to the heartbeat, so that the rest period coincides with the heartbeat. It will be appreciated that the pulse packets delivered within each specified time period relative to the heartbeat can be considered as a batch or a bundle. Therefore, each batch has a desired number of pulse packets so that the desired total number of pulse packets is delivered at the end of the treatment period. Each batch can have the same number of pulse packets, however, in some embodiments, the batches have different numbers of pulse packets.

[0139] In some embodiments, only one pulse packet is delivered between heartbeats. In this case, the rest period can be considered to be the same as the time period between batches. However, when more than one pulse packet is delivered between batches, the rest time is usually different from the time period between batches. In this case, the rest time is usually much smaller than the time period between batches. In some embodiments, each batch includes 1-10 pulse packets, 1-5 pulse packets, 1-4 pulse packets, 1-3 pulse packets, 2-3 pulse packets, 2 pulse packets, 3 pulse packets, 4 pulse packets, 5 pulse packets, 5-10 pulse packets, etc. In some embodiments, the time period of each batch is 0.5ms-1sec, 1ms-1sec, 10ms-1sec, 10ms-100ms, etc. In some embodiments, the time period between batches is variable depending on the patient's heart rate. In some cases, the time period between batches is 0.25-5 seconds.

[0140] The tissue region is then processed until the batch of the desired number is delivered to the tissue region. In some embodiments, each process delivers 2-50 batches, wherein the process is considered to be the process of a specific tissue region. In other embodiments, the process comprises 5-40 batches, 5-30 batches, 5-20 batches, 5-10 batches, 5 batches, 6 batches, 7 batches, 8 batches, 9 batches, 10 batches, 10-15 batches, etc.

[0141] G. Switching time and quiet time

[0142] like Figure 3 As shown in , the switching time (also called the interphase delay) is the delay or time period without energy delivery between the positive peak and the negative peak of the biphasic pulse. In some embodiments, the switching time ranges from about 0 to about 1 microsecond, 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.

[0143] A delay may also be inserted between each biphasic cycle, referred to as a "quiet time" or inter-pulse delay. The quiet time occurs within the pulse packet, but between the biphasic pulses. This is in contrast to the rest period or inter-pulse packet delay that occurs between the pulse packets. In other embodiments, the range of the quiet time 412 is 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 range of the quiet time 412 is 0.2 to 0.3 microseconds. The quiet time can also be used to define the time period between the monophasic pulses spaced apart within the pulse packet.

[0144] Delays such as switching time and dead time are introduced into the pulse packet to reduce the dual phase cancellation effect within the waveform. In some cases, the switching time and dead time are increased together to enhance the effect. In other cases, only the switching time or only the dead time is increased to induce the effect.

[0145] G. Waveform

[0146] Figure 3An embodiment of a waveform 400 is illustrated, which has symmetrical pulses such that the voltage and duration of the pulses in one direction (i.e., positive or negative) are equal to the voltage and duration of the pulses in the other direction. It will be appreciated that in other embodiments, the waveform 400 has a voltage imbalance. For example, each pulse packet 402, 404 may be composed of a first biphasic cycle (including 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 (including 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 is greater than the second voltage V2. The first biphasic cycle and the second biphasic cycle are separated by a dead time 412 between each pulse. Therefore, the voltage in one direction (i.e., positive or negative) is greater than the voltage in the other direction, and thus the area under the positive portion of the curve is not equal to the area under the negative portion of the curve. This unbalanced waveform may produce a more significant treatment effect. It will be appreciated that in some embodiments, the imbalance includes pulses with pulse widths of unequal durations. In some embodiments, the biphasic waveform is unbalanced such that 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) is greater than the duration of the other direction, so that the area under the curve of the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

[0147] Figure 4 A portion of a heart H is illustrated, showing a cross-sectional view 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), with two draining from each lung to the left atrium LA of the heart H. Each pulmonary vein is connected to a network of capillaries in the alveoli of each lung and delivers oxygenated blood to the left atrium LA. Left atrial musculature extends from the left atrium LA and covers the proximal pulmonary veins. It is reported that the superior veins with longer muscle sleeves are more susceptible to arrhythmia induction than the inferior veins. In general, the length of the pulmonary vein sleeves varies between 13 mm and 25 mm. It is reported that the morphology of the pulmonary veins can affect the occurrence of arrhythmias. Similarly, the cellular electrophysiology and other aspects of the pulmonary veins are associated with the occurrence and propagation of arrhythmias.

[0148] A variety of methods are used to determine which tissues are targeted for treatment, such as anatomical indications and cardiac mapping. Typically, a mapping catheter is selected to fit the desired pulmonary vein anastomosis, thereby accommodating the size and anatomical form of the pulmonary vein. The mapping catheter allows electrograms to be recorded from the ostium of the pulmonary vein and from deep within the pulmonary vein; these electrograms are displayed and timed for the user. The treatment catheter 102 is initially placed deep within the pulmonary vein and gradually withdrawn to near the opening of the mapping catheter. Mapping and treatment then begin.

[0149] The current understanding of pulmonary vein electrophysiology is that most of the fibers in the pulmonary veins are rounded and do not carry conduction into the veins. The electrical pathways are longitudinal fibers that run between the left atrium LA and the pulmonary veins. Pulmonary vein isolation is achieved by ablating these connecting longitudinal fibers. For the left pulmonary vein, pacing of the distal coronary sinus tends to increase the separation of atrial signals and pulmonary vein potentials, making them more visible electrically. The signals from within the pulmonary veins are evaluated. Each individual signal contains far-field atrial signals (generally of low amplitude) as well as sharp local pulmonary vein spikes. The earliest pulmonary vein spikes represent the site of connection between the pulmonary veins and the atria. If the pulmonary vein spikes and atrial potentials are examined, at some poles of the mapping catheter, these electrograms are far apart, while at other sites there will be fusion potentials of atrial and PV signals. The latter indicates the location of the longitudinal fibers and potential processing sites.

[0150] In some embodiments, Figure 5 As shown in , a circular treatment zone around the left lower pulmonary vein LIPV is created using a treatment catheter 102 (with the aid of mapping) to treat the tissue around the opening of the left lower pulmonary vein LIPV in a point-by-point manner. In some cases, dedicated navigation software can be used to allow the treatment catheter 120 to be properly positioned. The delivery electrode 122 is positioned close to or against the target tissue area, and energy is provided to the delivery electrode 122 to create a treatment area A or a lesion L. Because the energy is delivered to a local area (local delivery), the electrical energy is concentrated on a smaller surface area, resulting in a stronger effect than delivery through electrodes extending circumferentially around the lumen or opening. This also forces the electrical energy to be delivered in a staged regional approach, thereby mitigating the potential impact of preferential current pathways through the surrounding tissue. These preferential current pathways are areas with electrical characteristics that cause locally increased current to flow through them rather than through adjacent areas. Such pathways can result in irregular current distribution around the perimeter of the target lumen, and may therefore distort the electric field and cause the treatment effect in some areas to increase irregularly while the treatment effect in other areas is reduced. This can be mitigated or avoided by using localized treatments that stabilize the treatment effect around the perimeter of the target area. Thus, by providing energy to a specific area at a time, the electrical energy is "forced" across different areas of the perimeter, thereby ensuring an increased degree of circumferential regularity of the treatment. Figure 5The diagram illustrates the repeated application of energy in a point-by-point manner around the left inferior pulmonary vein LIPV using a treatment catheter 102 to create a circular treatment zone. As shown in the figure, in this embodiment, each lesion L overlaps with an adjacent lesion L to create a continuous treatment zone. It will be appreciated that the number of lesions L may vary depending on a variety of factors, particularly depending on 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.

[0151] The size and depth of each lesion L may depend on a variety of factors, such as parameter values, treatment time, tissue characteristics, etc. It is understood that the effect of energy on tissue is a function of the intensity of the waveform pulse and the cumulative damage caused by a series of progressive pulses caused by the dose. When considering the generation of a specific lesion size, the effective electric field threshold can be defined by, for example, waveform characteristics (such as base frequency, pulse packet active time period, total number of pulse packets) and a given electrode type or arrangement. This can be fine-tuned as the delivery voltage changes, which can affect the field strength and / or duration of the electric field pulse, etc. In addition to changes to the pulse, there are contributions from secondary pulse parameters (including the number of pulses delivered and their delivery rhythm). For cycles of biphasic pulse waveforms in which the electric field polarity is alternated, adding multiple cycles (including pulse packets) in rapid succession will change the effective electric field threshold to result in the desired result.

[0152] When titrating PEF dose for cardiac ablation, it is important to consider the relative desirable and undesirable attributes associated with each processing parameter. This article briefly discusses the basic waveform processing parameters. Table 1 below provides a summary table describing the relative meaning of each parameter.

[0153] Table 1

[0154]

[0155] Voltage: Voltage directly affects the electric field strength distribution. Increasing voltage will directly increase the treatment amplitude. However, higher voltages will also increase the associated tissue heating, which may lead to undesirable thermal effects. Increasing voltage may also increase muscle contraction associated with PEF, increase the volume of generated gas microemboli, and increase the likelihood of arcing, which may lead to char and clot formation or barotrauma.

[0156] Waveform shape: PEF can use a variety of waveforms to produce its effects, however in practice they are typically either sinusoidal or square waveforms. Waveforms can be viewed fundamentally as a train of pure monophasic pulses (where sequences of short (≤10μs) or long (>10μs) pulses are delivered with relatively long (>1ms) delays between them, and they have the same polarity), alternating monophasic pulses (where sequences of long pulses are delivered with relatively long delays between them, with polarity alternating), and biphasic pulses (where short (≤10μs) pulses are delivered with relatively short delays (<1ms) between polarity changes). Monophasic waveforms create the strongest treatment effects. However, they may also induce muscle contractions, pressure waves, and gas embolism. Biphasic waveforms can greatly reduce muscle contractions, but will generate weaker treatment effects at equivalent total pulse packet duration and applied field. However, by optimizing waveform parameters, it is possible to balance muscle contraction reduction with treatment effects, allowing the generation of clinically relevant lesions without treatment-inhibiting muscle contractions. For biphasic waveforms, fundamental frequency affects treatment, where higher frequencies (i.e., shorter individual pulse durations) monotonically reduce muscle contraction, but also result in a diminishing treatment effect. It should be noted that the PEF waveform is adjustable as a spectrum. The asymmetry and fundamental frequency of the waveform can be adjusted to further titrate the effect, where greater asymmetry or lower fundamental frequency increases treatment effect and muscle contraction until approaching a pure monophasic waveform.

[0157] Collective Pulse Duration: When multiple pulses are delivered in rapid succession (e.g., as a pulse packet), their effects can be considered a collective pulse. As the pulse packet duration increases, processing effects, muscle contraction, gas formation, heating also increase accordingly, and these effects can increase the chance of arcing.

[0158] Total activation duration: When multiple pulse packets are delivered to tissue, the cumulative damage increases. Therefore, more pulse packets will produce a stronger treatment effect, but will increase the treatment delivery time (for matching pulse packet delivery rates) and will increase the cumulative temperature rise if there is not enough time for heat dissipation (such as between subsequent pulse packets).

[0159] Pulse Packet Delivery Rate: When a pause is provided between pulse trains (e.g., pulse packets), the tissue has an opportunity to conduct heat away from the warmed tissue, thereby reducing the overall temperature rise. However, during this pause, cells continue to expend energy in an effort to recover from the PEF effect. When pulse trains are delivered with relatively long pauses (a few milliseconds to tens of seconds), cell recovery is generally not affected, but the overall tissue temperature rise is reduced. This enables the delivery of a powerful cumulative treatment while maintaining an acceptable level of temperature rise. In some cases, delivering a series of pulses or pulse packets over a longer period of time will increase the effectiveness of the treatment.

[0160] As previously mentioned, the size and depth of each lesion L may depend on a variety of factors. Figure 6 It is caused by Figure 2B Schematic diagram of the lesion L generated by the catheter 102 shown. Here, the delivery electrode 122 is positioned against the tissue T (such as cardiac tissue), and energy is provided to the delivery electrode 122 to create the lesion L. The delivery electrode 122 creates a lesion L with a three-dimensional parabolic shape or a cone. As shown, the lesion L has a lesion depth LD (extending from the tip of the delivery electrode 122 to the farthest depth of the parabola shape) and a lesion width LW (extending across the bottom of the parabola). The lesion depth LD and the lesion width LW vary depending on the energy delivered. In particular, the lesion size varies depending on the parameters of the waveform and dose and other effects such as tissue type. The correlation between the lesion size and the parameters and dose changes of the PEF energy described herein has been analyzed to generate a prediction algorithm. This algorithm is used in a variety of tissue modification systems 100 to improve clinical usability, processing control and patient results. This will be described in more detail in the following section.

[0161] Figure 7 Energy delivery at three different levels or doses is illustrated. In this example, a "low" dose is a combination of parameters that provide a minimum lesion size (e.g., 3-4mm width, 4-5mm depth). In this example, a "medium" dose results in a medium lesion size (e.g., 7-8mm width, 5-6mm depth). And, in this example, a "high" dose results in a maximum lesion size (9-10mm width, 7-8mm depth). It will be appreciated that for the purposes of this example, the terms low, medium, and high are only relative to each other. Moving from low to high, both the peak amplitude (V or I) and the number of individual pulse packets delivered will increase for a given treatment. In some embodiments, these terms are associated with the values ​​provided in Table 2 below.

[0162] Table 2

[0163] Energy settings 19Amps 22Amps 25Amps Time per processing 1.4ms 2.4ms 3.4ms

[0164] Return to reference Figure 5 , successive lesions are formed by repeatedly applying energy in a point-by-point manner, typically wherein each lesion L overlaps an adjacent lesion L. The desired spacing between lesions L, and therefore the amount of overlap, depends at least on the size of the generated lesions L. This in turn depends on a variety of factors described herein. Figure 8The creation of two adjacent lesions L that overlap is illustrated. In this embodiment, the lesions L are created consecutively using the same catheter 102. The actual treatment depth TD (considered to be the minimum depth of the lesions formed) is located between the two local lesions L at the point of overlap. As shown, this is less than the lesion depth LD of either lesion L. Fig. 9 The final continuous lesion CL formed by the energy delivered through the catheter 102 is illustrated.

[0165] During treatment, the physician looks at several clues to determine where they should treat next in a point-by-point sequence. For example, the physician may consider impedance measurements, electrogram signals, mapping system placement, fluoroscopy, etc. In the field of radiofrequency ablation, known protocols such as the CLOSE protocol are often followed. However, this protocol is not suitable for PEF energy delivery and can mistakenly guide the physician to utilize lesion placement that can cause gaps and therefore conduction block failure. This is due to the transient effects of energy delivery in the lesion portion (considered a "coma" effect).

[0166] When PEF energy is used to create a lesion, a portion of the tissue receiving the energy will be killed by the PEF treatment and eventually replaced by a transmural fibrotic scar. Also, another portion of the tissue will be comatose due to the PEF treatment, acutely experiencing a significant decrease in electrical conduction (i.e., "coma"), but ultimately surviving the PEF treatment at least in the short to medium term. The coma phenomenon may be due to a penumbra of injured but not killed cells in the area surrounding the fatally affected tissue. This penumbra effect may have a significant impact on clinical outcomes by confusing the ability to accurately determine the effect of the treatment during surgery. In order to ensure the lasting clinical effect of PEF cardiac ablation surgery, it is important to ensure that acute electrical isolation does not rely on comatose tissue, but reflects killed tissue that will lead to a lasting fibrotic scar.

[0167] Various measures have been taken to determine the boundaries of the area of ​​coma and the area to be killed. In some cases, a pig heart model has been used. In one example, a 7F treatment catheter 102 with a 3.5mm ablation electrode 122 is connected to a pulsed electric field (PEF) generator 108 and positioned in the right ventricle RV and left ventricle LV of two closed chest pigs under the guidance of EnSite. At 13 RV sites (28Amp, total pulse width of 1.4ms, 4 pulses) and 19 LV sites (35Amp, total pulse width of 1.6ms, 7 pulses), a biphasic PEF current is delivered between the ablation electrode and the skin patch. Two hours after ablation, triphenyltetrazolium chloride (TTC) is applied. The pig is killed, and the heart is removed and fixed with formalin. The heart is sliced ​​and stained with hematoxylin and eosin (H&E) and Masson's trichrome. Cytochrome c oxidase (COX) staining was also performed to examine mitochondrial activity and thus delineate the boundaries of coma and killing lesions.

[0168] The ablation lesion is clearly delineated by TTC staining, showing a dark central area surrounded by a light border. Histology shows that the myocardial cell architecture within the light border is destroyed. The overstained (dark red) edge outside the light border indicates the coma zone. COX staining shows that there is no mitochondrial activity or low mitochondrial activity within the light border, which is consistent with the ablation area. The enhanced activity of COX staining extends to the unaffected normal myocardium, which is consistent with the coma zone. Therefore, by TTC staining, the acute ventricular lesion produced by PEF ablation shows clear boundaries. COX staining shows that the killed part of the lesion is surrounded by the coma zone.

[0169] The coma effect can be used for certain electrophysiology applications. For example, different types of cardiomyocytes may be more sensitive to coma than others, which can help distinguish those of Purkinje origin from those of other origin. The coma effect can also be used to sublethally test ablation sites before finalizing them to ensure that no inadvertent damage to the conduction system is caused (similar to so-called "cryomapping" using cryotherapy).

[0170] To increase the treatment depth TD, multiple doses may be utilized. Fig.10The effect of multiple doses on lesion size is illustrated. Here, each dose initially extends from the delivery electrode 122 toward the farthest lesion boundary. In this embodiment, 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 just "coma" tissue, while the tissue in the innermost ring receives enough energy to be killed. Therefore, as shown, a single dose provides a first lesion size 200. Applying the dose again (dose x2) treats the tissue again, causing the tissue in the middle ring to change the balance from coma to being killed. Therefore, the double dose increases the first lesion size 200 to the second lesion size 202. Applying the dose again (dose x3) repeats the process, and now also causes the tissue in the outermost ring to change the balance from coma to being killed. This increases the second lesion size 202 to the third lesion size 204. It is understood that additional doses may increase the lesion size increment until a limit is reached. Numerical approximations have been used to determine the effect of multiple delivery doses. It has been found that the effect curve increases with the number of pulse packets.

[0171] It will be appreciated that advantageously overlapping lesions also increase the treatment depth of the lesions. Fig.11 The diagram shows an embodiment of two overlapping lesions L. Figure 8 Similarly, when the catheter 102 is repositioned close enough to the first placement when making the point-by-point lesion, the lesions L overlap. Fig.11 , the dose creates a larger potential lesion L', which reduces or reverses the lesion to the size of lesion L. However, if Fig.11 As highlighted in FIG. 1 , a zone 210 is identified that receives a double dose from the two catheter 102 placements. Thus, the zone 210 transitions from being unconscious to being killed. The zone 210 is now considered part of the treatment depth TD of the lesion, as shown in FIG. Fig.12 As shown, the treatment depth TD is effectively increased. In a similar manner, some tissue 212 surrounding the region 210 will be affected by part of the energy from both lesions, resulting in similar damage, and can therefore be considered part of the lesion. Therefore, Fig.13 The resulting continuous lesion L is shown in FIG. As shown in the figure, the treatment depth TD is Figure 8 Compared to the previous period, there has been an increase.

[0172] Changing the distance between lesion locations (ie, changing the spacing between catheter placements) will change the amount of lesion overlap. In general, increasing the spacing will generally mean reducing the resulting treatment depth TD. Fig.14 The diagram shows the Fig.11The lesion spacing of the lesions is larger than the lesion spacing (i.e., the catheter spacing). Therefore, the area 210 that receives the double dose from the two catheter 102 placements has been shifted upward. This in turn creates a shallower treatment depth for consecutive lesions, such as Fig.15 However, it is important that the lesions are spaced closely enough to create this zone 210, otherwise gaps will appear between the lesions, resulting in treatment failure.

[0173] To estimate the expected treatment depth TD of overlapping lesions, a simplified geometric approximation is used, which assumes that the lesions are ellipsoids. From this, the estimated treatment depth TD can be determined based on the lesion spacing, thereby generating the desired treatment plan. Fig.16 An example correlation between treatment depth TD and lesion spacing at three different energy doses (low 250, medium 252, high 254) is illustrated. In some embodiments, these energy doses are associated with the energy doses of Table 2 above. To ensure the desired target treatment depth, the maximum lesion spacing can be determined from the graph.

[0174] It is understandable that various measured atrial wall thicknesses have been reported, particularly depending on the position in the heart. Based on the comparison of data, it has been determined that a treatment depth TD of 4mm is sufficient to meet the expected wall thickness exceeding 99.42%. Therefore, a minimum treatment depth TD of 4mm is desired. To achieve this, the lesion interval is determined based on the dose level. The reference dose (e.g., 22A, 400kHz, 45 cycles, 12 pulse packets) selected as the baseline intensity of the treatment with 3mm intervals results in a treatment depth of 4.0mm. Similarly, the dose provided with higher amperage and more pulse packets ("high" dose) (e.g., 25A, 400kHz, 45 cycles, 21 pulse packets) delivered at 5mm intervals results in a treatment depth of 4.4mm. This interval performs well during the intervention period. However, in order to reach a treatment depth of 6mm, it is found that a high dose with a 3mm interval is utilized.

[0175] Figure 17A-17B The diagram shows the use of two different treatment protocols for different areas of the heart. Fig.17A An example lesion is shown on the posterior surface of a heart H, which has a thin wall thickness (typically <3 mm). Here, energy is delivered via a catheter to create lesions L along the posterior surface with 5 mm spacing and an average treatment depth of 5.8 mm. Fig. 17BAn example lesion on the front surface of heart H is illustrated, which has a thicker wall thickness (usually 2-6mm). Here, energy is delivered by catheter to create lesions L along the rear surface, wherein the interval is 6mm, and the average treatment depth is 6mm. Compared with the energy delivered to the rear surface, the energy delivered is considered to be higher because the number of pulse packets delivered is three times that of the rear surface. Therefore, different anatomical regions may require different treatment doses to ensure the thickness of the transmural treatment effect (that is, a stronger dose is used in the region assessed in the patient or in the region known to be thicker). Alternatively, the strategy of spacing the lesions closer together at different distances can be used to cause the same effect. For example, on thin tissue, a high dose example can use a 5mm interval and generate connected transmural lesions. However, in the anterior region or carina region, the same dose with a 3mm interval can be used to obtain a transmural treatment effect in the thicker tissue.

[0176] It will be appreciated that treatment is terminated when all undesired electrical connections have been addressed. When performing pulmonary vein isolation, the electrical connections between the atria and veins are addressed until electrical silence exists within the pulmonary veins and only far-field atrial signals are recorded. Occasionally, spikes of electrical activity may be seen within the pulmonary veins that are not conducted to the rest of the atria; these clearly indicate electrical disconnection of the veins from the rest of the atrial myocardium. Additional treatment areas may be created at other locations to address arrhythmias in the right or left atrium, depending on the clinical presentation. Testing is then performed to ensure that each targeted pulmonary vein is effectively isolated from the bulk of the left atrium.

[0177] The lesions have been evaluated to ensure the persistence of the results and, therefore, the durability of the lesions. For example, a 90-day re-mapping study was conducted to evaluate the results of lesions generated using three compatible local cardiac ablation catheters. These ablation catheters are conventional catheters designed to deliver radiofrequency energy, wherein the PEF energy described herein is delivered by a catheter utilizing a specialized system component to achieve this process. The purpose is to study safety and clinical performance to evaluate catheter ablation of atrial fibrillation using the systems and methods described herein. The study design is a prospective, single-group, open-label, multicenter study. Patients undergo catheter ablation for the first time to treat paroxysmal atrial fibrillation (PAF) or short-term (<1 year) persistent AF (PerAF). The primary safety endpoint is the occurrence of system- and process-related serious adverse events of interest within 30 days of ablation. Acute secondary endpoints include pulmonary vein isolation during the index ablation process confirmed by entry and exit blockade. Chronic secondary endpoints include the durability of pulmonary vein isolation at 90-day re-mapping. Additional safety evaluations included perioperative evaluation for gas embolism on ICE and ST-segment changes on ECG, phrenic nerve injury, preoperative and postoperative cranial MRI for evaluation of brain lesion foci, preoperative and postoperative stroke evaluation via NIHSS, postoperative esophageal endoscopy, and PV imaging via cardiac CT / MRI.

[0178] The following three conventional RF catheters and mapping systems are used:

[0179] 1) TACTICATH TM SE;ENSITE TM Advisor TM HD-Grid

[0180] 2)INTELLANAV STABLEPOINT TM ;RHYTHMIA HDx TM ;INTELLAMAP ORION TM

[0181] 3) THERMOCOOL SMARTTOUCH TM ; 3;

[0182] Physicians selected 1 of 3 energy settings (low = 19, medium = 22, high = 25 Amps) for wide sinus circumferential ablation with a target contact force ≥ 5 g. Acute success was evaluated via entry and exit block. Safety was evaluated by independent assessment of pre-specified SAEs of interest within 30 days. PVI durability was evaluated at 90 days using high-density mapping and confirmation of entry and exit block. The clinical energy setting strategy was a variation of the CLOSE protocol while using PEF energy. Lesion label diameter represented the lesion interval and varied depending on the group. Patients were divided into five groups as shown in Table 3:

[0183] Table 3

[0184]

[0185] In some cases, the anterior and posterior settings differ due to the thickness of the target tissue. The anterior site tends to be thicker, while the posterior site tends to be thinner. Likewise, the posterior site is often near anatomical features that may be more sensitive to energy delivery, such as the esophagus. Fig.18 Example placement of anterior and posterior lesions are illustrated.

[0186] Pulmonary vein isolation was achieved in all subjects, with 92% of PVs (277 / 302) being isolated on the first try. TM HD-Grid or High-density remapping of each pulmonary vein was achieved in 74 patients. Circumferential mapping of the entire pulmonary vein was performed to confirm durable, connected, transmural ablation. Entrance block of each pulmonary vein was confirmed. High-output pacing was used to confirm exit block of each pulmonary vein. Detailed mapping showed local reconnection in some pulmonary veins that initially appeared to be isolated. Reconnection was managed using the PEF energies described herein. Pulmonary vein isolation rates at 90-day remapping were as follows: Fig.19 As shown. Thus, Groups 3, 4, and 5 achieved an overall pulmonary vein isolation durability of 87%. This is significantly better than those of Groups 1 and 2, which ranged from 47% to 53%. Thus, in some embodiments, a high dose (25A) with 4-6 mm spacing in the anterior position and a medium dose (22A) with 4-6 mm spacing in the posterior position are desired. Thus, of the 73 subjects remapped, 18% of the subjects were treated with TactiCath SE in Groups 1, 2, and 3. TM The energy settings were optimized, so the PV isolation rate increased from 47% to 84%. Apply the optimized workflow to Group 4 (STABLEPOINT TM ) and 5(THERMOCOOL ), PV isolation rates were 89% and 87%.

[0187] Effective PEF delivery was shown to be successfully integrated into a standard PVI workflow with a limited learning curve. No intraoperative gas embolism was observed on ICE. Good safety performance was found for the esophagus, phrenic nerves, pulmonary veins, and brain. 100% acute isolation was achieved, but acute isolation does not replace durable isolation or freedom from AF. 90-day remapping is expected to optimize dose and workflow. Very high compliance (96%) with the remapping process was achieved through comprehensive durability evaluation. Improved rates of durable pulmonary vein isolation were achieved through optimization of energy settings from Group 1 to Group 3. Safety and effectiveness were maintained while using PEF energy through optimized settings across three solid-tip, contact force sensing conventional RF local catheter platforms. Initial 12-month freedom from AF was achieved.

[0188] It will be appreciated that localized treatments 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 localized treatments, such as according to 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 on December 26, 2017 and U.S. Provisional Patent Application No. 62 / 693,622 filed on July 3, 2018, all of which are incorporated herein by reference for all purposes. Similarly, a variety of catheter designs may be used, optionally through the use of a variety of accessories, to deliver localized treatments, such as according to International Patent Application No. PCT / US2020 / 066205, entitled “TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRICFIELDS,” filed on December 18, 2020, which claims priority to Provisional Patent Application No. 62 / 949,633, filed on December 18, 2019, Provisional Patent Application No. 63 / 000,275, filed on March 26, 2020, and Provisional Patent Application No. 63 / 083,644, filed on September 25, 2020, all of which are incorporated herein by reference for all purposes.

[0189] As previously described, lesion size varies depending on the parameters of the PEF waveform and dose, as well as other influencing factors such as tissue type. This is the case when PEF energy is delivered to cardiac tissue (as described above) and other tissue types throughout the body. Therefore, different waveforms of PEF energy and different 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 delivered PEF energy to provide a desired result and / or provide predictive information that a user can use to generate a desired result.

[0190] For example, in some cases, such as via the user interface 150, a user may type or input treatment aspects into the system 100, which the system 100 (e.g., the generator 108) uses to generate or select a particular energy delivery algorithm 152 that optimizes the treatment waveform and / or dose for the desired treatment. Fig. 20A schematic diagram of such a system 100 is provided. In this example, a user inputs one or more desired lesion sizes as a first input 500. Such sizes 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 disconnection, etc.), treatment location (e.g., within a cavity, along a tissue edge, proximity to other anatomical features, etc.), or tissue type (which may also depend on the treatment location), etc. In this example, the 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, different temperature tolerances may exist in some types of treatment (e.g., higher temperatures may be more suitable for tumor ablation). Similarly, some areas may be more sensitive to temperature increases or present a higher risk in the event of temperature increases (e.g., the posterior wall of the left atrium near the esophagus). Therefore, preferences may be based on the proximity of the delivery electrode 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. Likewise, in this example, the user inputs the desired muscle contraction (such as the maximum allowed amount of muscle contraction) as a third input 504. The user may have such a preference based on the proximity of the delivery electrode to the excitable tissue of interest. For example, when the delivery electrode is near the phrenic nerve, the patient's diaphragm is much more likely to contract. In some cases, this degree may be unacceptable at normal doses, so the clinician may choose to reduce the contraction, thereby improving catheter stability during treatment delivery. In another example, if energy is delivered near the vagus nerve, the contraction excitability may also be associated with the stimulation of the nerve. Therefore, by reducing the excitability of the waveform of the tissue, the user can reduce the likelihood of the patient coughing during surgery, thereby improving the accuracy of electroanatomical mapping. Likewise, the preference for muscle contraction may be based on the surgical management of the patient (e.g., the patient is treated with conscious sedation versus general anesthesia). Or the user may have a preference 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 a safety-related preference (e.g., worrying about perforation when ablating on thinner tissues such as the posterior wall of the left atrium).

[0191] Additionally, in this example, the user enters a dose time as a fourth input 506. The dose time is the amount of time allowed for a particular energy application. In some cases, the dose time needs to be shortened due to clinical circumstances that limit the time allowed for delivering energy, such as rapid contractile movements of the heart and delivering energy to difficult-to-reach anatomical targets.

[0192] These inputs 500, 502, 504, 506 can be received by the system 100 in a variety of suitable ways, such as selections made by a user from a menu or inputs made by a user via a keyboard. The processor 154 uses the inputs 500, 502, 504, 506 to generate an appropriate energy delivery algorithm 152. The algorithm 152 then generates an appropriate energy waveform to provide the desired PEF energy. In some embodiments, the system 100 uses these inputs 500, 502, 504, 506 to coordinate with various sensors or feedback systems to ensure that the waveform continues to be appropriate throughout the treatment process. For example, a temperature sensor can be used to ensure that any temperature rise does not exceed the maximum allowable temperature rise provided as the second input 502. If the reading indicates that the maximum value is exceeded, a warning indication can be provided, a different energy delivery algorithm can be used, energy delivery can be automatically stopped, or other suitable changes in the regimen can occur.

[0193] It is understood that any number of inputs 500, 502, 504, 506 can 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 can be utilized. Other inputs may include the type of catheter 102, the type of energy delivery electrode 122, the type of tissue, the thickness of the tissue, the activation mode of the energy delivery electrode, the location of other tissues, the challenges that the doctor is experiencing (e.g., excessive coughing), the proximity of non-target tissues, contact forces, local tissue impedance, system impedance, etc. Similarly, if only a subset of the inputs 500, 502, 504, 506 is desired to be selected, a default input can be used for the remaining inputs. The value of such a default input can be based on a clinical average, pre-programmed information, or a calculation based on the input provided or other available information. In some embodiments, the inputs can be sorted or weighted so that, for example, even if each input is not fully met, a suitable waveform can be generated. For example, in some cases, there are critical primary inputs and expected but unimportant secondary inputs. Thus, if a waveform cannot be generated based on all inputs (which may be particularly true when selecting an algorithm from a predetermined selection of algorithms), the primary inputs may be prioritized to ensure that at least the best fit 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 surgical characteristics, and / or other information.

[0194] As described above, the system 100 includes a processor 154 that generates an appropriate energy delivery algorithm 152 using a data storage / retrieval unit 156 or the like. The appropriate energy delivery algorithm 152 then generates the desired waveform for PEF energy delivery. The stored information used by the processor 154 to generate the algorithm 152 is generated by a series of steps. In one embodiment, the first step is to compare the effects of different waveform parameters with treatment aspects (such as Fig. 20 The four inputs 500, 502, 504, 506 of the model are associated. In this embodiment, this is achieved by performing a parameter sweep in the model. A parameter sweep is when one parameter is changed through a series of values ​​while other parameters are fixed and the effect is observed. Typically, a general baseline of the parameters is used as a fixed value. The sweep is completed to achieve a value that achieves an effective lethal electric field threshold.

[0195] It will be appreciated that the model can be the ultimate target tissue (e.g., a beating heart in vivo), or a surrogate model that reflects the same relationship with respect to dose dependence (e.g., another organ such as a thigh, liver, etc., an in vitro perfused organ model, or a benchtop model such as a plant potato or apple). In some cases, a simple electrode geometry can be used (e.g., a needle in a potato immersed in a saline bath, or a bipolar electrode couplet array with two electrodes placed in a potato at a standard distance and depth apart) because the effects of the electrode geometry can be scaled. When a benchtop model is used, it is desirable to simulate the physical setup of the energy delivery dynamics of the treatment. For example, testing of a cardiac ablation device used to deliver treatment to the surface of the target tissue can be simulated by delivering energy to the surface of a potato.

[0196] In this embodiment, the tissue is in a fluid bath, and the conductivity of the fluid is selected to best approximate the entire in vivo environment. For monopolar electrodes, this clinically includes the heart, pericardial sac, lungs, muscles, fat, skin, and other tissues for conducting electrical pulse energy between effector electrodes and remote dispersed electrodes at a distance. It is understood that in a benchtop model, the dispersed ground electrode can be placed adjacent to another environment, placed below another environment, or placed in another environment to best represent the electrical PEF energy that passes through the tissue to the ground electrode, so that the energy passes through the model in a similar manner. For bipolar electrodes, this can be just the fluid between the activation areas of the electrodes of a given bipolar electrode array couplet.

[0197] An example of parameters and test scans is provided in Table 3. In this example, the baseline parameter set includes a 1000 V applied voltage with a baseline waveform of a biphasic 100 kHz frequency with 10 cycles of 10 pulse packets delivered at 1 pulse packet per second.

[0198] Table 3

[0199]

[0200] After treatment delivery using all parameter combinations, a function is generated to determine how each parameter individually affects the treatment effect. In this example, Fig. 20 The inputs 500, 502, 504 of are used as processing effects of interest. In particular, Figure 21A-Figure 21D , Figure 22A-22D , Figure 23A-23D , Figure 24A-Figure 24D The individual relationships between the parameters of pulse packet number, frequency, pulse packet delivery rate, and pulse packet duration and the inputs 500, 502, 504 from which functions are mathematically generated are illustrated. The input 500 regarding lesion size has been separated 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 accelerometers (using in vivo studies). In particular, Fig.21A The relationship between the number of pulse packets and the processing depth is shown. Fig. 21B The relationship between frequency and processing depth is illustrated. Fig. 21C The relationship between the pulse packet delivery rate and the processing depth is shown. And, Fig.21D The relationship between pulse packet duration and treatment depth is shown. Fig.22A The relationship between the number of pulse packets and the processing width is shown in the figure. Fig. 22B The relationship between frequency and process width is illustrated. Fig. 22C The relationship between the pulse packet delivery rate and the processing width is shown. Fig.22D The relationship between the pulse packet duration and the processing width is shown. Fig.23A The relationship between the number of pulse packets and the temperature rise is shown in the figure. Fig. 23B The relationship between frequency and temperature rise is shown in the graph. Fig.23C The relationship between the pulse packet delivery rate and the temperature rise is shown in the figure. And, Fig.23D The relationship between pulse packet duration and temperature rise is shown in the figure. Fig.24A The relationship between the number of pulse packets and muscle contraction is shown. Fig. 24B The relationship between frequency and muscle contraction is shown graphically. Fig.24C The relationship between pulse packet delivery rate and muscle contraction is shown. And, Fig.24D The relationship between pulse packet duration and muscle contraction is shown.

[0201] It is understood that the final lesion size depends on the electrode arrangement used in the model. Therefore, numerical simulations of the electric field strength of the electrode arrangement were performed to correlate the lesion size with the electric field strength.

[0202] Following this, additional numerical simulations or multiple simulations can be constructed to represent different physical setups for treatment delivery. For example, a localized monopolar catheter electrode can be modeled within the atrial chamber of the heart and placed against the myocardium. The electric field distributions from these simulations can be captured and retained. In this way, applied voltage and lethal electric field threshold functions can be compiled to generate a lookup table or other method of capturing this data.

[0203] Additional numerical simulations can be performed for other electrode arrangements. For example, a localized monopolar catheter electrode can be modeled within the atrial chamber of the heart, placed against the myocardium. Using the numerical model, the electric field distribution can be determined for each case. This can be captured in a lookup table or other method of capturing this data. Figure 25A-Figure 25C Example electric field distributions for catheter embodiments delivering PEF energy within the heart are illustrated.

[0204] The electric field data is then calibrated to ensure the model reflects the clinical situation. 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.

[0205] By these methods, correlations between electric field strength and treatment aspects such as lesion size were determined. Fig. 20 , when the user enters a specific desired lesion size (input 500), the processor 154 uses the desired lesion size and associates it with the electric field strength threshold. The processor 154 then uses the electrode arrangement to determine the electric field strength and determines the electric field strength threshold corresponding to the desired lesion size. The processor 154 then determines the parameter values ​​to generate the determined electric field strength to generate the desired waveform. These same methods can be used for any input to determine the desired waveform. Similarly, when combining the inputs, the processor 154 considers the combined effects of the various parameter influences to select the final parameters that result in the generation of the most appropriate waveform. It will be appreciated that the processor 154 may also consider the sorting or weighting of the inputs to generate the most appropriate waveform.

[0206] It will be appreciated that the above method may also be used to allow a user to provide input to the system 100 and receive predictions, such as lesion size, temperature rise, muscle contraction, dose time, etc. Fig.26In one embodiment shown, the generator 108 includes at least one algorithm 152 that generates a predetermined waveform. The algorithm 152 can be modified by changing parameters based on inputs 502, 504, 506 similar to the inputs described above. Based on the above correlations, the lesion size is provided to the user. If such a lesion size is desired, the user can continue to use the new modified waveform. If a different size is desired, the user can change one or more inputs 502, 504, 506, such as in an iterative manner, until the desired lesion size is achieved. It will be appreciated that the inputs and outputs can have a variety of combinations as desired.

[0207] It will be appreciated that the above method may also be used to allow a user to provide a single input to the system 100 and receive a prediction such as lesion size. Fig. 27 In one embodiment shown, the generator 108 includes at least one algorithm 152 that generates a predetermined waveform. In this embodiment, the user provides input 506, such as a dose time. Therefore, the user has an expected dose time based on various clinical constraints. Based on the above correlation, the user is provided with the lesion size caused by delivering the predetermined waveform. If this lesion size is desired, the user can continue to use the waveform. This helps the user determine the placement of the lesion, such as to provide a desired overlap level. This is particularly useful in cardiac applications (such as when generating a resistor disconnect).

[0208] It is understood that in some embodiments, Fig. 27 The system of is the reverse, wherein the user provides an input 500 of the desired lesion size, and the predicted dose time is provided by the system 100. When the dose is delivered manually (such as by a foot switch), the user can then provide the appropriate dose time or dose quantity. When the dose is delivered automatically, the user can decide whether the dose time is appropriate for the clinical situation and actuate the delivery as needed.

[0209] When determining the lesion spacing, it is desirable to control the lesion size. As previously described, continuous lesions can be formed by repeatedly applying energy in a point-by-point manner, typically wherein each lesion L overlaps an adjacent lesion L. The desired spacing between lesions L and therefore the amount of overlap depends at least on the size of the generated lesions L. Once the lesion size is known, the spacing can be determined by the user alone or with the assistance of the system 100. The default or known size of the coma zone for each given lesion size can determine how close the lesions should be placed to each other to ensure a lasting continuous lesion. In some embodiments, the system 100 indicates the desired spacing, such as in a digital readout or graphical format.

[0210] In some embodiments, system 100 uses local electrophysiological response to provide dynamic intervals. In this embodiment, a dose of PEF energy is delivered by a catheter having at least one delivery electrode. Then, the same or different catheters map the spatial extent of voltage reduction. The lesion interval or PEF application position interval can be driven by the actual voltage reduction observed in response to the dose and electrode configuration. In some embodiments, the interval adopts the form of fixed overlap, and in other embodiments, the interval is user-selectable (such as based on the expected safety factor). This can be performed manually or automatically by software that interprets the diagram in the operation and the change in the voltage of the electrogram after application.

[0211] It can also be understood that the safety factor / interval can be dynamically controlled using preoperative imaging data. For known or suspected thicker tissue areas, the dynamic interval suggestion will be smaller to ensure transmural lesions. For example, intracardiac echography can be used to measure the thickness of tissue near the electrode. This can be measured manually and entered into the system, or the ultrasound can communicate directly with the generator to feed any thickness data. In another embodiment, an ultrasound transducer can be incorporated into the catheter electrode, and it can measure tissue thickness locally or throughout the organ chamber before energy delivery, or measure tissue thickness at the site of expected energy delivery immediately before energy delivery. In another embodiment, 3D magnetic resonance (MR)-ultrasound (US) fusion or MR-mapping system fusion can be used to associate anatomical structures with target tissue thickness. In this way, MR can be used to visualize and segment chamber wall thickness in 3D. This data can be combined with mapping or ultrasound data via a series of fiducial markers to orient them. Then, the thickness data can be projected to the electroanatomical mapping system, which can be used directly for MR-mapping fusion, or for MR-US fusion through the interface of the ultrasound machine. This thickness data can be used to establish treatment dose parameters used in the area, or to assist clinicians in setting parameters. In another method, optical coherence tomography can be used to measure tissue thickness. In each instance of these described embodiments, thickness data can be generated and interpreted in real time at the site of interest to determine where energy will be delivered, energy is being delivered, or energy has been delivered. The data can also be used to generate an entire target thickness reconstruction before energy delivery, thereby not performing real-time measurements immediately before energy delivery. In some cases, 3D mapping can be performed retrospectively after energy delivery to determine any areas that may be undertreated. This can be done by understanding the dose being used, or by recording each specific dose at each specific activation by a PEF or mapping system, and recording the data for later comparison with the thickness data to assess any undertreated areas.

[0212] 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 display of a mapping system, or the smart tag may be stored or displayed by the generator or other data collection system used to support the ablation procedure. In some embodiments, the smart tag includes information such as treatment depth and width, predicted heat rise, predicted muscle stimulation, and other relevant parameters of interest to the operator when performing or reviewing the treatment.

[0213] The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The accompanying drawings illustrate specific embodiments in which the present invention may be practiced. These embodiments are also referred to as "examples" in this article. Such examples may include elements other than those shown or described. However, the inventors also contemplate examples that only provide those shown or described elements. In addition, the inventors also contemplate examples using any combination or arrangement of those shown or described elements (or one or more aspects thereof), whether with respect to a specific example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0214] In the event of an inconsistent usage between this document and any document incorporated by reference, the usage in this document controls.

[0215] In this document, as is common in patent documents, the terms "a" or "an" are used to include one or more than one, independent of any other instance or usage of "at least one" or "one or more." In this document, the term "or" is used to represent a non-exclusive or, so that "A or B" includes "A but not B," "B but not A," and "A and B," unless otherwise noted. In this document, the terms "including" and "wherein" are used as the plain English equivalents of the respective terms "comprising" and "wherein." In addition, in the appended claims, the terms "including" and "comprising" are open-ended, that is, systems, devices, articles, compositions, preparations, or processes that include elements other than those listed after the term in a claim are still deemed to fall within the scope of the claim. In addition, in the appended claims, the terms "first," "second," and "third," etc. are used merely as labels and are not intended to impose numerical requirements on their objects.

[0216] The above description is intended to be illustrative, not restrictive. For example, the above examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments may be used, such as by a person of ordinary skill in the art after reading the above description. An abstract is provided to comply with 37 CFR § 1.72 (b), enabling readers to quickly determine the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. In addition, in the above detailed description, various features may be combined together to simplify the disclosure. This should not be interpreted as meaning that the disclosed features that are not claimed for protection are essential to any claim. On the contrary, the subject matter of the invention may not lie in all the features of a particular disclosed embodiment. Therefore, the attached claims are incorporated into the detailed description as examples or embodiments herein, each claim exists independently as a separate embodiment, and it is contemplated that these embodiments can be combined with each other in various combinations or arrangements. The scope of the present invention should be determined with reference to the attached claims and the full scope of equivalents enjoyed by these claims.

Claims

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

2. The system of claim 1, wherein the processor dynamically generates the algorithm in real time based on the one or more inputs. 3 . The system of claim 1 , wherein the processor selects the algorithm based on the one or more inputs from a group of algorithms.

4. The system of any of the preceding claims, wherein the one or more inputs include a desired size of the lesion.

5. A system according to any one of the preceding claims, wherein the one or more inputs comprises a threshold value for a temperature rise.

6. A system according to any of the preceding claims, wherein the one or more inputs include a threshold for muscle contraction.

7. The system of any of the above claims, wherein the one or more inputs include a threshold dose time.

8. The system of any one of the preceding claims, wherein the one or more inputs comprises a plurality of the one or more inputs.

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

11. The system of any one of the preceding claims, wherein the processor generates the algorithm using the one or more inputs and at least one default value.

12. 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. The system of any preceding claim, wherein at least one of the one or more inputs is programmable by the user using a user interface.

14. The system of any preceding claim, wherein the processor associates the one or more inputs with an electric field strength threshold.

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

16. The system of claim 15, wherein the processor associates the electric field strength with the electric field strength threshold.

17. The system of any of the preceding claims, wherein the processor selects at least one parameter of the at least one algorithm to generate the electrical signal.

18. The system of any of the above claims, wherein the processor modifies the algorithm based on tissue thickness.

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

20. A system for providing treatment to tissue, the system comprising: a treatment catheter having at least one delivery electrode; as well as a generator electrically coupled to the treatment catheter, wherein the generator includes a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrode to provide the treatment, wherein the processor generates a prediction of an outcome of the treatment based on at least one of one or more inputs from a user.

21. The system of claim 20, wherein the prediction includes 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 one of claims 21-22, wherein the at least one lesion size comprises a lesion width.

24. The system of any one of claims 20-23, wherein the one or more inputs include a threshold for a temperature rise.

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

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

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

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

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

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

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

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

33. A system for generating a lesion in a tissue, the system comprising: a treatment catheter having at least one delivery electrode; as well as A generator electrically coupled to the treatment catheter, wherein the generator includes a processor providing at least one algorithm configured to provide an electrical signal of pulsed electric field energy deliverable through the delivery electrode to provide treatment, wherein the processor generates a separation distance recommendation between the lesion and a next lesion.

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

35. The system of claim 34, wherein the parabolic lesion has a coma zone.

36. The system of claim 35, wherein the separation distance suggests positioning the next lesion sufficiently close to the lesion such that the coma zone at least partially overlaps the next lesion.

37. A system according to claim 36, wherein the next lesion has a coma zone, and wherein the spacing distance suggests at least overlapping the coma zone of the lesion with the coma zone of the next lesion so that the tissue between the centers of the lesions forms a continuous permanent lesion.

38. The system of any one of claims 33-37, wherein a processor dynamically generates the separation distance suggestion between the lesion and a next lesion based on local electrophysiological information.

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

40. The system of claim 38, wherein the local electrophysiological information is obtained by including a voltage drop observed in the tissue in response to energy delivery.

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

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

43. The system of any one of claims 33-41, further comprising an electroanatomical mapping system, and wherein the separation distance suggestion is visually displayed by the electroanatomical mapping system.

44. A system for creating a lesion in a tissue, the system comprising: A generator electrically coupled to a treatment catheter, wherein the generator includes 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, wherein the processor generates the algorithm based on at least one of one or more inputs from a user.

45. A system for providing treatment to tissue, the system comprising: A generator electrically coupled to a treatment catheter, wherein the generator includes 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, wherein the processor generates a prediction of an outcome of the treatment based on at least one of one or more inputs from a user.

46. ​​A system for creating a lesion in a tissue, the system comprising: A generator electrically coupled to a treatment catheter, wherein the generator includes 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 treatment, wherein the processor generates a separation distance recommendation between the lesion and a next lesion.

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