Pulse electric field energy delivery timing optimization

Abstract

Devices, systems, and methods are provided for treating target tissue with pulsed electric field energy in a manner that does not induce arrhythmia, such as tremor of the heart, and thus eliminates any need for cardiac synchronization of energy delivery. Cardiac synchronization is typically used to avoid delivery of energy during portions of the cardiac cycle that are susceptible to effect to induce fibrillation. Thus, parameters are manipulated herein to reduce the probability of inducing an arrhythmia. Typically, high voltage energy may trigger premature action potentials within the myocardium because the delivered energy increases myocardial cell membrane permeability, allowing ion transport, which may induce arrhythmias, especially ventricular fibrillation. However, shorter pulse durations (i.e., higher frequencies, e.g., 100 kHz to 600 kHz) and biphasic waveform shapes both theoretically and practically reduce the probability of inducing an arrhythmia.

Description

Cross-reference to related applications

[0001] This application claims priority and interest in U.S. Provisional Patent Application No. 63 / 491,025, filed March 17, 2023, entitled “Pulsed Electric Field Energy Delivery Timing of Optimization,” the disclosure of which is incorporated herein by reference in its entirety. background

[0002] Pulsed electric field (PEF) therapy uses the brief application of electrical energy to the body to treat illness and pain. In some cases, this delivery is to tissue within a body cavity, passageway, or similar anatomical structure, or can be reached within a cavity via these passageways. Such devices typically include a flexible, elongated shaft to traverse the tortuous luminal anatomy, and an energy delivery element mounted thereon to deliver this energy to remote or enclosed locations, such as body cavities. Such devices have been developed to treat passageways or blood vessels in the vascular system, such as the lungs, or to treat various organs, such as the heart, stomach, intestines, etc. In other cases, delivery is made directly through open surgery or percutaneously. Different environments (e.g., the airway versus a blood-filled environment) and different diseases (e.g., diseases affecting surface tissues versus diseases affecting deeper layers or tissues) lead to different purposes for these devices.

[0003] PEF energy disrupts the integrity of target tissue cells, initiating a series of biochemical processes that induce various forms of cell death, including necrosis, apoptosis, apoptotic-like necrosis, necroptosis, and / or pyroptosis. Because PEF therapy is not thermally dependent, cells within a specific volume of tissue are killed without altering the matrix proteins and extracellular matrix within that volume, thus promoting the preservation of function of critical and sensitive anatomical structures (e.g., major vascular systems, luminal systems such as the common bile duct) and tissue structures (e.g., the pleura). Therefore, PEF therapy offers better safety compared to other focal ablation modalities. Due to these characteristics, PEF is being increasingly used in a variety of disease states, including cancer, heart disease, and lung disease.

[0004] Differences exist between clinical PEF systems, including variations in waveform parameters and delivery polarity (i.e., bipolar or monopolar). In bipolar electrode configurations, energy is delivered between actuator devices placed within or near the target environment. Conversely, monopolar systems use a single end effector to deliver energy to the target location, where a remotely distributed electrode acts as the electrical loop. The distributed electrode has sufficient surface area to distribute PEF energy widely enough that no therapeutic effect is generated at its remote location.

[0005] An important consideration regarding the clinical use of PEF energy is its potential to stimulate cardiac tissue and disrupt the normal cardiac cycle, especially in the case of monopolar delivery arrangements, which penetrate the body more deeply than those using bipolar electrode arrangements. Furthermore, several other variables affect the arrhythmic potential of any given PEF therapy, including the location, extent, and timing of the stimulation. Many PEF techniques reduce the occurrence of arrhythmias by synchronizing PEF delivery with the cardiac refractory period (i.e., the ST segment). However, this synchronization involves additional instrumentation, such as an external cardiac monitor and a mechanism for acquiring an electrocardiogram (ECG). In some cases, a cardiac monitor is used to continuously acquire ECG signals via external electrodes positioned on the patient's chest. The PEF generator analyzes one or more cardiac cycles and identifies the start of a period during which it is safe to apply energy to the patient, thus providing the ability to synchronize energy delivery with the cardiac cycle. In some embodiments, this period is within milliseconds of the R wave (of the ECG QRS complex) to avoid inducing arrhythmias that could occur if an energy pulse is delivered on the T wave. This synchronization also complicates energy delivery, as it is limited to the time frame allowed by the synchronization.

[0006] Improved delivery of PEF energy is desired in terms of efficiency, simplicity, cost reduction, and improved patient outcomes. At least some of these goals will be achieved through the systems, devices, and methods described herein. Invention Overview

[0007] This document describes embodiments of devices, systems, and methods for treating target tissues within the body. Similarly, the invention relates to the following numbered clauses: 1. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the energy has a waveform comprising a plurality of pulses, each pulse having a voltage of at least 1000V and each pulse being below a threshold for inducing arrhythmia.

[0008] 2. The system according to Clause 1, wherein the plurality of pulses includes biphasic pulses.

[0009] 3. The system according to any one of the preceding clauses, wherein the voltage is in the range of 1000V to 10000V.

[0010] 4. The system according to any one of the preceding clauses, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during at least a portion of the T wave of the cardiac cycle.

[0011] 5. The system according to Clause 4, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the intermediate and / or terminal phases of the T wave of the cardiac cycle.

[0012] 6. The system according to any one of clauses 1 to 3, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during atrial contraction of the cardiac cycle.

[0013] 7. The system according to any one of clauses 1 to 3, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the peak contraction of atrial or ventricular contraction in the cardiac cycle.

[0014] 8. The system according to any one of the preceding clauses, wherein the plurality of pulses comprises at least one pulse group.

[0015] 9. The system according to Clause 8, wherein the at least one pulse group comprises at least six pulse groups, wherein each group comprises 40 biphasic pulses with an inter-pulse delay of 1000 microseconds.

[0016] 10. The system according to any one of the preceding clauses, wherein each pulse has a pulse duration of less than or equal to 10 µs.

[0017] 11. The system according to Clause 10, wherein each pulse has a pulse duration in the range of 0.5µs to 5µs.

[0018] 12. The system according to Clause 10, wherein each of the pulses has a voltage in the range of 1000V to 10000V.

[0019] 13. The system according to Clause 12, wherein the pulses each have a voltage in the range of 1000V to 5000V.

[0020] 14. The system according to any one of clauses 1 to 9, wherein each pulse has a voltage in the range of 1000V to 3000V, and wherein each pulse has a pulse duration in the range of less than or equal to 25µs.

[0021] 15. The system according to any one of clauses 1 to 9, wherein each pulse has a voltage in the range of 1000V to 1500V, and wherein each pulse has a pulse duration in the range of less than or equal to 50µs.

[0022] 16. The system according to any one of the preceding clauses, wherein the dose has a delivery time of at least the cardiac cycle.

[0023] 17. The system according to any one of the preceding clauses, wherein the target tissue is located in the lungs of the patient.

[0024] 18. The system according to any one of clauses 1 to 16, wherein the target tissue comprises the patient’s gastrointestinal system, urinary system or reproductive system.

[0025] 19. The system according to any one of clauses 1 to 16, wherein the energy is delivered at a constant delivery rate, and wherein the target tissue comprises heart tissue, the system further comprising a robotic device programmed to drag the energy delivery body along the heart tissue during energy delivery.

[0026] 20. The system according to any one of claims 1 to 18, wherein the target tissue comprises a tumor, and the energy delivery body comprises a probe.

[0027] 21. The system according to any one of the preceding claims, wherein the energy is delivered at a constant delivery rate.

[0028] 22. The system according to any one of the preceding claims further includes a robotic device for manipulating the energy delivery body within the patient.

[0029] 23. The system according to any one of the preceding clauses, wherein energy delivery is synchronized with the patient’s breathing, but not with the heart.

[0030] 24. The system according to Clause 23, wherein the energy delivery is actuated when the lungs are not moving.

[0031] 25. The system according to any one of clauses 1 to 22, wherein energy delivery is not associated with synchronization to the cardiac cycle and is actuated by feedback control.

[0032] 26. The system according to Clause 25, wherein the feedback control includes temperature monitoring, impedance monitoring, pH monitoring, contact detection and / or contact force.

[0033] 27. The system according to Clause 25 further includes one or more sensors configured to detect a drug in the body, and wherein energy delivery is actuated by feedback from the one or more sensors.

[0034] 28. The system according to Clause 27, wherein the agent comprises a drug, a molecule, a gene, or a chemotherapeutic agent.

[0035] 29. The system according to any one of clauses 27 to 28, wherein the energy delivery body includes at least one tip extending from the conduit, and wherein the system further includes one or more impedance sensors configured to measure the impedance between one of the at least one tip and another of the at least one tip or a portion of the conduit.

[0036] 30. The system according to Clause 29, wherein the one or more impedance sensors include a pH sensor, an optical fiber sensor, or a bipolar impedance sensor.

[0037] 31. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the dose consists of a plurality of pulses, wherein at least one of the pulses is arranged within the dose so as to be received by the target tissue during the T wave of the cardiac cycle, and wherein the dose does not induce arrhythmia.

[0038] 32. The system according to Clause 31, wherein the plurality of pulses includes biphasic pulses.

[0039] 33. The system according to any one of clauses 31 to 32, wherein the voltage is in the range of 1000V to 10000V.

[0040] 34. The system according to Clause 31, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the intermediate and / or terminal phases of the T wave of the cardiac cycle.

[0041] 35. The system according to any one of clauses 31 to 34, wherein the plurality of pulses comprises at least one pulse group.

[0042] 36. The system according to Clause 35, wherein the at least one pulse group comprises at least six pulse groups, wherein each group comprises 40 biphasic pulses with an inter-pulse delay of 1000 microseconds.

[0043] 37. The system according to any one of clauses 31 to 36, wherein each pulse has a pulse duration of less than or equal to 10 µs.

[0044] 38. The system according to Clause 37, wherein each pulse has a pulse duration in the range of 0.5µs to 5µs.

[0045] 39. The system according to Clause 37, wherein the pulses each have a voltage in the range of 1000V to 10000V.

[0046] 40. The system according to Clause 39, wherein the pulses each have a voltage in the range of 1000V to 5000V.

[0047] 41. The system according to any one of clauses 31 to 36, wherein each pulse has a voltage in the range of 1000V to 3000V, and wherein each pulse has a pulse duration in the range of less than or equal to 25µs.

[0048] 42. The system according to any one of clauses 31 to 36, wherein each pulse has a voltage in the range of 1000V to 1500V, and wherein each pulse has a pulse duration in the range of less than or equal to 50µs.

[0049] 43. The system according to any one of clauses 31 to 42, wherein the dose has a delivery time of at least the cardiac cycle.

[0050] 44. The system according to any one of clauses 31 to 43, wherein the target tissue is located in the lungs of the patient.

[0051] 45. The system according to any one of clauses 31 to 43, wherein the target tissue includes tissues located within the patient’s gastrointestinal system, urinary system, or reproductive system.

[0052] 46. ​​The system according to any one of clauses 31 to 45, wherein the energy is delivered at a constant delivery rate, and wherein the target tissue comprises heart tissue, the system further comprising a robotic device programmed to drag the energy delivery body along the heart tissue during energy delivery.

[0053] 47. The system according to any one of clauses 31 to 46, wherein the target tissue includes a tumor, and the energy delivery body includes a probe.

[0054] 48. The system according to any one of clauses 31 to 47, wherein the energy is delivered at a constant delivery rate.

[0055] 49. The system according to any one of clauses 31 to 48 further includes a robotic device for manipulating the energy delivery body within the patient.

[0056] 50. The system according to any one of clauses 31 to 49, wherein energy delivery is synchronized with the patient’s breathing, but not with the heart.

[0057] 51. The system according to Clause 50, wherein the energy delivery is actuated when the lungs are not moving.

[0058] 52. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the dose consists of a plurality of pulses, and wherein the dose has a delivery time of at least the cardiac cycle.

[0059] 53. The system according to clause 52, wherein the plurality of pulses comprises at least one pulse group.

[0060] 54. The system according to Clause 53, wherein the at least one pulse group comprises at least six pulse groups, wherein each group comprises 40 biphasic pulses with an inter-pulse delay of 1000 microseconds.

[0061] 55. The system according to any one of clauses 52 to 54, wherein each pulse has a pulse duration of less than or equal to 10 µs.

[0062] 56. The system according to Clause 55, wherein each pulse has a pulse duration in the range of 0.5µs to 5µs.

[0063] 57. The system according to Clause 55, wherein the pulses each have a voltage in the range of 1000V to 10000V.

[0064] 58. The system according to Clause 57, wherein the pulses each have a voltage in the range of 1000V to 5000V.

[0065] 59. The system according to any one of clauses 52 to 58, wherein each pulse has a voltage in the range of 1000V to 3000V, and wherein each pulse has a pulse duration in the range of less than or equal to 25µs.

[0066] 60. The system according to any one of clauses 52 to 58, wherein each pulse has a voltage in the range of 1000V to 1500V, and wherein each pulse has a pulse duration in the range of less than or equal to 50µs.

[0067] 61. The system according to any one of clauses 52 to 60, wherein the dose has a delivery time of at least the cardiac cycle.

[0068] 62. The system according to any one of clauses 52 to 61, wherein the target tissue is located in the lungs of the patient.

[0069] 63. The system according to any one of clauses 52 to 61, wherein the target tissue comprises the patient’s gastrointestinal system, urinary system or reproductive system.

[0070] 64. The system according to any one of claims 52 to 61, wherein the energy is delivered at a constant delivery rate, and wherein the target tissue comprises heart tissue, the system further comprising a robotic device programmed to drag the energy delivery body along the heart tissue during energy delivery.

[0071] 65. The system according to any one of clauses 52 to 63, wherein the target tissue comprises a tumor, and the energy delivery body comprises a probe.

[0072] 66. The system according to any one of clauses 52 to 65, wherein the energy is delivered at a constant delivery rate.

[0073] 67. The system according to any one of clauses 52 to 66 further includes a robotic device for manipulating the energy delivery body within the patient.

[0074] 68. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the energy delivery is not associated with synchronization to the cardiac cycle and is actuated by feedback control.

[0075] 69. The system according to Clause 68, wherein the feedback control includes temperature monitoring, impedance monitoring, pH monitoring, contact detection and / or contact force.

[0076] 70. The system according to Clause 68 further includes one or more sensors configured to detect a drug in the body, and wherein energy delivery is actuated by feedback from the one or more sensors.

[0077] 71. The system according to Clause 70, wherein the agent comprises a drug, molecule, gene or chemotherapeutic agent.

[0078] 72. The system according to any one of clauses 70 to 71, wherein the energy delivery body includes at least one tip extending from the conduit, and wherein the system further includes one or more impedance sensors configured to measure the impedance between one of the at least one tip and another of the at least one tip or a portion of the conduit.

[0079] 73. The system according to Clause 72, wherein the one or more impedance sensors include a pH sensor, an optical fiber sensor, or a bipolar impedance sensor.

[0080] 74. A system for delivering energy to treat a target tissue in a patient's body, the target tissue being sufficiently close to the patient's heart to induce arrhythmia, the system comprising: At least one energy delivery subject configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue in a manner that is not synchronized with the cardiac cycle of the heart and does not induce arrhythmias.

[0081] 75. The system according to Clause 74, wherein the plurality of pulses includes biphasic pulses.

[0082] 76. The system according to any one of clauses 74 to 75, wherein the voltage is in the range of 1000V to 10000V.

[0083] 77. The system according to any one of clauses 74 to 76, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during at least a portion of the T wave of the cardiac cycle.

[0084] 78. The system according to Clause 77, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the middle and / or terminal phases of the T wave of the cardiac cycle.

[0085] 79. The system according to any one of clauses 74 to 76, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during atrial contraction of the cardiac cycle.

[0086] 80. The system according to any one of clauses 74 to 76, wherein the pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the peak contraction of atrial or ventricular contraction in the cardiac cycle.

[0087] 81. The system according to any one of clauses 74 to 80, wherein the plurality of pulses comprises at least one pulse group.

[0088] 82. The system according to Clause 81, wherein the at least one pulse group comprises at least six pulse groups, wherein each group comprises 40 biphasic pulses with an inter-pulse delay of 1000 microseconds.

[0089] 83. The system according to any one of clauses 74 to 82, wherein each pulse has a pulse duration of less than or equal to 10 µs.

[0090] 84. The system according to Clause 83, wherein each pulse has a pulse duration in the range of 0.5µs to 5µs.

[0091] 85. The system according to Clause 83, wherein the pulses each have a voltage in the range of 1000V to 10000V.

[0092] 86. The system according to Clause 85, wherein the pulses each have a voltage in the range of 1000V to 5000V.

[0093] 87. The system according to any one of clauses 74 to 82, wherein each pulse has a voltage in the range of 1000V to 3000V, and wherein each pulse has a pulse duration in the range of less than or equal to 25µs.

[0094] 88. The system according to any one of clauses 74 to 82, wherein each pulse has a voltage in the range of 1000V to 1500V, and wherein each pulse has a pulse duration in the range of less than or equal to 50µs.

[0095] 89. The system according to any one of clauses 74 to 88, wherein the dose has a delivery time of at least the cardiac cycle.

[0096] 90. The system according to any one of claims 74 to 89, wherein the target tissue is located in the lungs of the patient.

[0097] 91. The system according to any one of clauses 74 to 89, wherein the target tissue comprises the patient’s gastrointestinal system, urinary system or reproductive system.

[0098] 92. The system according to any one of clauses 74 to 89, wherein the energy is delivered at a constant delivery rate, and wherein the target tissue comprises heart tissue, the system further comprising a robotic device programmed to drag the energy delivery body along the heart tissue during energy delivery.

[0099] 93. The system according to any one of clauses 74 to 91, wherein the target tissue includes a tumor, and the energy delivery body includes a probe.

[0100] 94. The system according to any one of clauses 74 to 93, wherein the energy is delivered at a constant delivery rate.

[0101] 95. The system according to any one of clauses 74 to 94 further includes a robotic device for manipulating the energy delivery body within the patient.

[0102] 96. The system according to any one of clauses 74 to 95, wherein energy delivery is synchronized with the patient’s breathing, but not with the heart.

[0103] 97. The system according to Clause 96, wherein the energy delivery is actuated when the lungs are not moving.

[0104] 98. The system according to any one of Clauses 74 to 95, wherein energy delivery is actuated by feedback control.

[0105] 99. The system according to Clause 98, wherein the feedback control includes temperature monitoring, impedance monitoring, pH monitoring, contact detection and / or contact force.

[0106] 100. The system according to Clause 98 further includes one or more sensors configured to detect a drug in the body, and wherein energy delivery is actuated by feedback from the one or more sensors.

[0107] 101. The system according to Clause 100, wherein the agent comprises a drug, a molecule, a gene, or a chemotherapeutic agent.

[0108] 102. The system according to any one of clauses 100 to 101, wherein the energy delivery body includes at least one tip extending from the conduit, and wherein the system further includes one or more impedance sensors configured to measure the impedance between one of the at least one tip and another of the at least one tip or a portion of the conduit.

[0109] 103. The system according to clause 102, wherein the one or more impedance sensors include a pH sensor, an optical fiber sensor, or a bipolar impedance sensor.

[0110] These and other embodiments will be described in further detail in the following description in connection with the accompanying drawings. By incorporating references

[0111] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference. Brief description of the attached diagram

[0112] In the accompanying drawings, which are not necessarily drawn to scale, similar numbers may describe similar parts in different views. Similar numbers with different letter suffixes may represent different instances of similar parts. The accompanying drawings are illustrated in general terms by way of example and not by way of limitation, of the various embodiments discussed in this document.

[0113] Figure 1 An example of a tissue modification system is shown.

[0114] Figure 2 A to Figure 2 B illustrates another embodiment of the tissue modification system.

[0115] Figure 3 An example of a signal waveform defined by an energy transfer algorithm is shown.

[0116] Figure 4 A table is provided illustrating various example effects of parameter changes.

[0117] Figure 5A The variation of simulated tissue conductivity with electric field exposure is shown.

[0118] Figure 5B The simulation current and impedance are shown as a function of simulated applied voltages ranging from 500V to 5000V.

[0119] Figure 6 A to Figure 6 C shows A) reference data, B) a power-law curve fitted from (A) the “stimulus (coil)” curve, and C) a power-law curve fitted from (A) the “induction” curve; Note: “stimulus (coil)” is used for stimulation because it reflects the same electrode relationship used to generate the “induction” data.

[0120] Figure 7 An embodiment of a monopolar system for evaluating the energy of a dedicated PEF is shown.

[0121] Figure 8 A to Figure 8 D shows representative results from the numerical simulation; Figure 8 A) Numerical simulation of geometry and ( Figure 8 B to Figure 8 D) A cross-sectional view simulating the electrical conductivity, electric field, and voltage distribution in lung parenchyma. Mesh = 5mm.

[0122] Figures 9A to 9B The cardiac effect sensitivity of PEF in relation to basic treatment is shown.

[0123] Figure 10 A to Figure 10 D shows a fluorescence microscope image of a basket-deployed pig chest compared to a CT image.

[0124] Figure 11 A to Figure 11 D shows an example of cardiac effects caused by asynchronous PEF delivery; there may be no variation. Figure 11 A) Artificial changes in instantaneous heart rate ECG due to signal interference ( Figure 11 B) PAC without ventricular conduction, characterized by a brief delay in subsequent heartbeats. Figure 11 C) or PAC (premature ventricular contractions) that are conducted to the ventricles and cause premature ventricular contractions. Figure 11 D). Detailed description

[0125] Apparatus, systems, and methods are provided for treating body tissues using pulsed electric field (PEF) energy. PEF energy is generally characterized as high-voltage pulsed energy configured to be delivered in one or more doses. Each energy dose delivered to the target tissue is configured to maintain the temperature at or within the target tissue below a threshold for thermal ablation. These effects are considered non-thermal, rather than thermally ablated, thermal damage described as extracellular protein coagulation, where such energy modifies or destroys cells within the tissue but preserves the tissue's underlying extracellular matrix, which provides the tissue's interstitial structure and structure-related functions. In some cases, this allows tissue regeneration, for example, through the re-proliferation of the extracellular matrix. Furthermore, nearby sensitive tissue is not harmed. It is understood that the dose may be titrated over time or gradually reduced to further reduce or eliminate heat buildup during the treatment process. It is understood that in some embodiments, energy delivery is actuated by various mechanisms, such as the use of actuators on the device or foot switches operatively connected to the generator. Such actuation typically provides a single energy dose or activation.

[0126] It can treat target tissue cells in any part of the body, including cells of the gastrointestinal tract or digestive system (e.g., oral cavity, glands, esophagus, stomach, duodenum, jejunum, ileum, intestine, 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.), and cells of the reproductive system (e.g., reproductive organs, ovaries, fallopian tubes, uterus, cervix, vagina, testes, epididymis, vas deferens, seminal vesicles, prostate, glands, penis, scrotum, etc.). Cells of various organs and systems, including the endocrine system (such as the pituitary gland, pineal gland, thyroid gland, parathyroid gland, and adrenal gland), the circulatory system (such as the heart, arteries, and veins), the lymphatic system (such as lymph nodes, bone marrow, thymus, and spleen), the nervous system (such as the brain, spinal cord, nerves, and ganglia), the eyes (such as the retina, macula, rods and cones, retinal pigment epithelium, optic nerve, choroid, and sclera), the muscular system (such as muscle cells), and the skin (such as the epidermis, dermis, and subcutaneous tissue).

[0127] Conditions treated include cardiac arrhythmias, particularly atrial fibrillation. When treating atrial fibrillation, a lesion ring is typically created by delivering PEF energy (e.g., around the pulmonary vein orifice) using a focal catheter or a disposable catheter. Furthermore, focal catheters can be used to create many other types of lesions, particularly lines along various surfaces of the heart tissue. In one embodiment, creating a tricuspid isthmus line in the inferior vena cava is used to treat typical atrial flutter in the right atrium. In another embodiment, for patients with atrial fibrillation, particularly persistent atrial fibrillation, roof lines and / or floor lines are created along the posterior wall of the left atrium for box lesion. In yet another embodiment, for atypical atrial flutter, a mitral isthmus line is created along the anterior or lateral wall of the left atrium. In yet another embodiment, typically in patients with ventricular tachycardia caused by ischemic heart disease, a ventricular line connecting two inexcitable boundaries essential for the occurrence or maintenance of reentrant ventricular arrhythmias is created.

[0128] Other conditions being treated include lung diseases such as chronic obstructive pulmonary disease, chronic bronchitis, excessive mucus production, asthma, and cystic fibrosis, among others. In addition, various other conditions include coagulation disorders such as hemophilia (e.g., hemophilia A or hemophilia B), von Willebrand's disease, factor XI deficiency, fibrinogen deficiency, or vitamin K deficiency. Coagulation disorders may be characterized by mutations in the genes encoding fibrinogen, prothrombin, factor V, factor VII, factor VIII, factor X, factor XI, factor XIII, or enzymes involved in their post-translational modifications, or enzymes involved in vitamin K metabolism. In some embodiments, coagulation disorders are characterized by mutations in FGA, FGB, FGG, F2, F5, F7, F10, F11, F13A, F13B, LMAN1, MCFD2, GGCX, or VKORC1.

[0129] In some embodiments, the disorder includes a neurological disorder, such as a neurodegenerative disease. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, or multiple sclerosis. In some embodiments, neurodegenerative diseases include autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis, encephalomyelitis, paraneoplastic syndromes, autoimmune inner ear diseases, or opsoclonus myoclonus syndrome. A neurological disorder can be a stroke, spinal cord injury, a central nervous system disorder, a neuropsychiatric disorder, or a channelopathy (e.g., epilepsy or migraine). A neurological disorder can be an anxiety disorder, a mood disorder, a childhood disorder, a cognitive impairment, schizophrenia, a substance-related disorder, or an eating disorder. In some embodiments, a neurological disorder is a symptom of a stroke, traumatic brain injury, or spinal cord injury.

[0130] In some embodiments, the disorder includes lysosomal storage disorders such as Tay-Sachs disease, Gaucher disease, Fabry disease, Pompe disease, Niemann-Pick disease, or mucopolysaccharidosis (MPS).

[0131] In some embodiments, the disease includes cardiovascular diseases such as degenerative heart disease, coronary artery disease, ischemia, angina pectoris, acute coronary syndrome, peripheral vascular disease, peripheral artery disease, cerebrovascular disease, or atherosclerosis. Cardiovascular diseases can be degenerative heart disease selected from the group consisting of ischemic cardiomyopathy, conduction disorders, and congenital defects.

[0132] In some embodiments, the disorder includes an immune dysfunction, such as an autoimmune disease. Autoimmune diseases can be type 1 diabetes, multiple sclerosis, rheumatoid arthritis, lupus, encephalomyelitis, paraneoplastic syndrome, autoimmune inner ear disease or strabismus-clonic myoclonus syndrome, autoimmune hepatitis, uveitis, autoimmune retinopathy, neuromyelitis optica, psoriatic arthritis, psoriasis, myasthenia gravis, chronic Lyme disease, celiac disease, chronic inflammatory demyelinating polyneuropathy, peripheral neuropathy, fibromyalgia, Hashimoto's thyroiditis, ulcerative colitis, or Kawasaki disease.

[0133] In some embodiments, the condition includes liver diseases such as hepatitis, Alagille syndrome, biliary atresia, hepatocellular carcinoma, cirrhosis, cystic diseases, Caroli syndrome, congenital liver fibrosis, fatty liver, galactosemia, primary sclerosing cholangitis, tyrosinemia, glycogen storage disease, Wilson's disease, or endocrine deficiencies. Liver diseases can be hepatocellular carcinoma, such as hepatocellular hyperplasia, hepatocellular adenoma, focal nodular hyperplasia, or hepatocellular carcinoma.

[0134] In some embodiments, the disease includes tumors or cancers, such as blood cancers (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Hodgkin's disease, multiple myeloma and non-Hodgkin's lymphoma) or solid tissue cancers (e.g., lung cancer, liver cancer, kidney cancer, breast cancer, gastric cancer, esophageal cancer, stomach cancer, intestinal cancer, colorectal cancer, bladder cancer, prostate cancer, head and neck cancer, skin cancer or brain cancer, etc.).

[0135] In some embodiments, the disorder includes a recessive genetic disorder. In some embodiments, the disorder is a Mendelian-inherited disorder.

[0136] In some embodiments, the disorder includes ocular disorders that are retinal dystrophys (e.g., Mendelian retinal dystrophy). Retinal dystrophys can include Leber congenital amaurosis (LCA), Stargardt's disease, pseudoxanthoma elastica, rod-cone dystrophy, exudative vitreoretinopathy, Joubert syndrome, CSNB-1C, age-related macular degeneration, retinitis pigmentosa, Stickler syndrome, microcephaly and choroidoretinopathy, retinitis pigmentosa, CSNB-2, Usher syndrome, or Wagner syndrome.

[0137] Figure 1An example tissue modification system 100 for delivering PEF energy to target tissue in the heart is illustrated. In this embodiment, the tissue modification system 100 includes a dedicated catheter 102, a high-voltage waveform generator 104, and at least one different energy delivery algorithm 152. In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / retrieval unit 156 (e.g., a memory and / or database), and an energy storage subsystem 158 for generating and storing the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery; however, any other suitable energy storage element may be used. Additionally, one or more communication ports are included. In this embodiment, the treatment catheter 102 is designed to be monopolar, with at least one delivery body (e.g., an electrode) at the distal end of the catheter 102, and a return electrode 106 is positioned on the skin outside the body, typically in the thigh, lower back, or back. In this embodiment, a surgical approach (such as the Seldinger technique) is used to access the heart H via the right femoral vein FV. Typically, a guide sheath 112 is inserted into the femoral vein FV, which acts as a conduit through which various catheters and / or instruments (including treatment catheter 102) can be advanced. The distal end of catheter 102 is advanced through the inferior vena cava, through the right atrium, through a transatrial septal puncture, and into the left atrium to access the pulmonary veins. In this embodiment, catheter 102 is used to perform cardiac mapping, which is the process of identifying the temporal and spatial distribution of myocardial potentials during a specific cardiac rhythm. Cardiac mapping during abnormal rhythms aims to elucidate the rhythmic mechanisms, describe the propagation of activation within a region of interest from its initiation to its completion, and identify the initiation or key sites of conduction that serve as therapeutic targets. Once the desired treatment location is identified, therapeutic energy is delivered using catheter 102.

[0138] Additional exemplary embodiments of the energy delivery conduit 102 configured to provide local treatment to various parts of the body are provided in the following documents: International Patent Application No. PCT / US2018 / 067504 entitled “OPTIMIZATION OF ENERGY DELIVERY FOR VARIOUS APPLICATIONS”, which claims priority to Provisional Patent Application No. 62 / 610,430 filed December 26, 2017 and U.S. Provisional Patent Application No. 62 / 693,622 filed July 3, 2018, all of which are incorporated herein by reference for all purposes. In another example, in some embodiments, such as provisional patent application 63 / 159,331 filed March 10, 2021 entitled “DEVICES FORTHE DELIVERY OF PULSED ELECTRIC FIELDS IN THE TREATMENT OF CARDIAC TISSUE”, all of which are incorporated herein by reference for all purposes. Similarly, for example, according to the international patent application filed on December 18, 2020, entitled “TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRIC FIELDS” with application number PCT / US2020 / 066205, various catheter designs can be used, optionally with various accessories, to deliver therapeutic energy. This international patent application claims priority to provisional patent applications filed on December 18, 2019, with application number 62 / 949,633; provisional patent applications filed on March 26, 2020, with application number 63 / 000,275; and provisional patent applications filed on September 25, 2020, with application number 63 / 083,644, all of which are incorporated herein by reference for all purposes.

[0139] Figure 2 A to Figure 2 Figure B illustrates another embodiment of a tissue modification system 100 including an energy delivery conduit 102 connectable to a generator 104. As shown, the conduit 102 includes a shaft 106 having a distal end 103, a proximal end 107, and at least one lumen 105 extending at least partially therethrough. Similarly, the conduit 102 also includes at least one energy delivery body 108. In this embodiment, the energy delivery body 108 takes the form of a probe 700 disposed within the lumen 105 of the shaft 106. The probe 700 has a probe tip 702 that can be pushed through the lumen 105 and can extend from the distal end 103 of the shaft 106 (in...). Figure 2(A is enlarged to show details). In this embodiment, the tip 702 has a pointed shape configured to penetrate tissue, for example, similar to a needle. Therefore, in this embodiment, the probe tip 702 is used to penetrate the lumen wall W and surrounding tissue, allowing it to be inserted into target tissue outside the body cavity. Thus, the probe 700 has sufficient flexibility for delivery within the lumen, but sufficient columnar strength to penetrate the lumen wall W and target tissue. In some embodiments, the catheter 102 has markings to indicate to the user the distance the probe tip 702 has been pushed, thereby ensuring desired placement.

[0140] In some embodiments, the probe extends from the distal end 103 of shaft 106 by approximately less than 0.5 cm, 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, or more than 8 cm. In some embodiments, the probe extends from the distal end of shaft 106 by 1 cm to 3 cm or 2 cm to 3 cm. In some embodiments, the probe is 18 gauge, 19 gauge, 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, or 25 gauge. In some embodiments, the probe 700 is constructed of a conductive material for use as an electrode. Therefore, the electrode will have dimensions that expose the probe. Example materials include stainless steel, nitinol, cobalt-chromium alloy, copper, and gold. In some embodiments, the exposed probe conductive material is coated with different materials, examples including platinum-iridium, gold, platinum black, palladium, or other materials. The conductive material or conductive material coating may be designed to reduce biological interactions with tissues, reduce electrochemical effects resulting from PEF treatment, or more effectively distribute PEF energy to tissues, among other purposes. The material can be smooth, electropolished, sandblasted at various grit sizes, or treated with other mechanical or chemical agents to alter its surface roughness. Doing so can reduce biological interactions with tissues, facilitate easier electrode push-and-retract, reduce electrochemical effects generated by PEF treatment, or more effectively distribute PEF energy into the tissue, among other purposes. Therefore, in these embodiments, PEF energy can be transmitted from probe 700 to probe tip 702. Thus, shaft 106 is constructed of an insulating material or covered by an insulating sheath. Example insulating materials include polyimide, silicone, polytetrafluoroethylene, and polyether block amide. The insulating material can be uniform or varied along the length of shaft 106 or sheath. Again, in either case, the insulating material typically comprises complete electrical insulation. However, in some embodiments, the insulating material allows some leakage current to pass through.

[0141] When the probe 700 is energized, the insulating shaft 106 protects the surrounding tissue from the treatment energy and directs the energy to the probe tip 702 (and any exposed portion of the probe 700) capable of delivering the treatment energy to the surrounding tissue. Therefore, the tip 702 acts as a delivery electrode, and its size can be selected based on the amount of probe 700 exposed. A larger electrode can be formed by exposing a larger amount of probe 700, and a smaller electrode can be formed by exposing a smaller amount of probe 700. In some embodiments, the tip 702 exposed during energy delivery (measured from its distal end to the distal edge of the insulating shaft) has the following lengths: 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm, 0.8 cm, 0.9 cm, 1 cm, 2 cm, 3 cm, greater than 3 cm, up to 8 cm, less than or equal to 0.1 cm, less than or equal to 0.3 cm, less than or equal to 0.5 cm, less than or equal to 1 cm, 0.2 cm to 0.3 cm, 0.1 cm to 0.5 cm, 0.1 cm to 1 cm, and all ranges and subranges in between. In addition to altering the electrode size, the tip 702 can retract into the shaft 106 to allow delivery of atraumatic endoscopes and can then be pushed as needed to reach target tissue. In this embodiment, pushing and retracting are controlled by an actuator 732 (e.g., a knob, button, lever, slider, or other mechanism) attached to a handle 110 at the proximal end 107 of shaft 106. It is understood that shaft 106 itself can be pushed toward the target tissue, whether the probe is pushed out from the distal end 103 of shaft 106 or not. In some embodiments, the distal end of shaft 106 is advanced up to 20 cm into the tissue, for example, from the outer surface of a luminal structure or from the outer surface of the patient's body.

[0142] The handle 110 is connected to the generator 104 via a dedicated power plug 510. The power plug 510 has a first end 512 connected to the handle 110 and a second end 514 connected to the generator 104. The first end 512 is connected to the handle 110 at... Figure 2 B is described in detail. In this embodiment, the first end 712 has an adapter 716, which includes a connecting wire 718 extending therefrom. The connecting wire 718 can be inserted into the proximal end of the probe 700 within the handle 110. This allows energy to be transferred from the generator 104 to the probe 700 via the connecting wire 718. Thus, the probe 700 is capable of being charged along its entire length; however, due to the presence of the insulating shaft 106, only the exposed tip 702 delivers energy to the tissue.

[0143] In this embodiment, generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / retrieval unit 156 (e.g., a memory and / or database), and an energy storage subsystem 158 for generating and storing the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery; however, any other suitable energy storage element may be used. Additionally, one or more communication ports are included.

[0144] In some embodiments, generator 104 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 some embodiments, the system controller includes a synchronization trigger monitor that allows the pulsed energy output to be synchronized with a desired trigger. The generator uses an alternating current (AC) power supply to power multiple direct current (DC) power supplies. The generator's controller can cause the DC power supplies to charge the high-energy capacitor storage bank before energy delivery begins. At the start of therapeutic energy delivery, the generator's controller, high-energy storage bank, and biphase pulse amplifier can operate simultaneously to generate a high-voltage intermediate-frequency output.

[0145] It should be recognized that various generator electrical architectures can be employed to execute energy delivery algorithms. In particular, in some embodiments, advanced switching systems are used, capable of directing pulsed electric field circuitry to energy delivery electrodes separate from the same energy storage and high-voltage delivery system. Furthermore, in advanced energy delivery algorithms employing rapidly changing pulse parameters (e.g., voltage, frequency, etc.), the generator or multiple energy delivery electrodes can leverage modular energy storage and / or high-voltage systems, facilitating highly customizable waveform and geographic pulse delivery paradigms. It should also be recognized that the electrical architectures described above are merely exemplary, and systems delivering pulsed electric fields may or may not include additional switching amplifier components.

[0146] User interface 150 may include a touchscreen and / or more conventional buttons to allow the operator to input patient data, select a treatment algorithm (e.g., energy delivery algorithm 152), initiate energy delivery, view records stored on storage / retrieval unit 156, and / or otherwise communicate with generator 104. User interface 150 may include a voice-activated mechanism for inputting patient data, or may be able to communicate with additional instruments in the kit, such that control of generator 104 is performed through a separate, auxiliary user interface.

[0147] In some embodiments, the user interface 150 is configured to receive operator-defined input. Operator-defined input may include the duration of energy delivery, one or more other timing aspects of the energy delivery pulse, power and / or operating mode, or a combination thereof. Example operating modes may include (but are not limited to): system startup and self-test, operator input, algorithm selection, preprocessing system status and feedback, energy delivery, post-energy delivery display or feedback, processing data review and / or download, software update, or any combination or sub-combination thereof.

[0148] In some embodiments, processor 154 modifies the energy delivery algorithm 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, processor 154 is configured to execute one or more algorithms to run a feedback control loop based on one or more measured system parameters (e.g., current), one or more measured organizational parameters (e.g., impedance), and / or combinations thereof.

[0149] 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 a communication port. In some embodiments, the device has local software for guiding information download, such as instructions stored on the data storage / retrieval unit 156 and executable by the processor 154. In some embodiments, 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, tablet, mobile device, server, workstation, cloud computing device / system, etc. A communication port that can allow wired and / or wireless connections can allow data download, as just described, and can also allow data upload, such as uploading custom algorithms or providing software updates.

[0150] The data storage / retrieval unit 156 may be, for example, random access memory (RAM), a memory buffer, a hard disk drive, a database, an erasable programmable read-only memory (EPROM), an electrically erasable read-only memory (EEPROM), a read-only memory (ROM), flash memory, etc. The data storage / retrieval unit 156 may store instructions to cause the processor 154 to execute modules, processes, and / or functions associated with the system 100.

[0151] In some embodiments, the data storage / retrieval unit 156 includes a computer storage product having a non-transitory computer-readable medium (also referred to as a non-transitory processor-readable medium) having instructions or computer code on it for performing operations of various computer implementations. A computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not itself include transient propagation signals (e.g., electromagnetic waves carrying information propagating over transmission media such as space or cables). The medium and computer code (also referred to as code) can be those designed and constructed for one or more specific purposes. Examples of non-transitory computer-readable media include, but are not limited to: magnetic storage media such as hard disks, floppy disks, and magnetic tapes; optical storage media such as optical discs / digital video discs (CDs / DVDs), optical disc read-only memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical discs; carrier signal processing modules; and hardware devices specifically configured to store and execute program code, such as ASICs, programmable logic devices (PLDs), read-only memories (ROMs), and random access memory (RAM) devices. Other embodiments described herein relate to computer program products that may include, for example, the instructions and / or computer code discussed herein.

[0152] Examples of computer code include, but are not limited to, microcode or microinstructions, such as machine instructions generated by a compiler, code for generating web services, and files containing higher-level instructions executed by a computer using an interpreter. For example, embodiments may be implemented using imperative programming languages ​​(e.g., C, Fortran, etc.), functional programming languages ​​(Haskell, Erlang, etc.), logic programming languages ​​(e.g., Prolog), object-oriented programming languages ​​(e.g., Java, C++, etc.), or other suitable programming languages ​​and / or development tools. Other examples of computer code include, but are not limited to, control signals, encryption code, and compression code.

[0153] In some embodiments, system 100 may be communicatively coupled to a network, which may be any type of network implemented as a wired and / or wireless network, such as, for example, a local area network (LAN), a wide area network (WAN), a virtual network, a telecommunications network, a data network, and / or the Internet. In some embodiments, any or all communications may be protected using any suitable type and / or method of secure communication (e.g., Secure Sockets Layer (SSL)) and / or encryption. In other embodiments, any or all communications may be unprotected.

[0154] As described herein, the various energy delivery algorithms 152 are programmable or can be pre-programmed into the generator 104, such as by storing them in memory or data storage / retrieval unit 156. Alternatively, the energy delivery algorithms can be added to the data storage / retrieval unit for execution by the processor 154. The processor 154 can be, for example, a general-purpose processor, a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), a digital signal processor (DSP), etc. The processor 154 can be configured to run and / or execute application processes and / or other modules, processes, and / or functions associated with system 100 and / or the network associated with system 100. As used herein, the term "module" refers to any component and / or collection of electrically coupled components that may include, for example, memory, a processor, traces, optical connectors, software (executed in hardware), and / or the like. For example, a module executed in a processor can be any combination of hardware-based modules (e.g., FPGA, ASIC, DSP) and / or software-based modules (e.g., modules of computer code stored in memory and / or executed at the processor) capable of performing one or more specific functions associated with that module.

[0155] Each of these algorithms 152 can be executed by processor 154. In some embodiments, device 102 includes one or more sensors 160 that can be used to determine temperature, impedance, resistance, capacitance, conductivity, pH, optical properties (coherence, echogenicity, fluorescence), electrical or optical dielectric constant and / or conductivity, etc. In some embodiments, one or more electrodes serve as one or more sensors. In other embodiments, one or more sensors are separate from electrodes. It is understood that one or more sensors 160 can be positioned in various locations, particularly depending on the parameter being sensed. For example, sensors can be positioned along energy delivery body 108, along the interior of the device, along axis 106, along elements protruding from the device, etc. Multiple sensors 160 can be present for sensing the same parameter at multiple locations, sensing different parameters at different locations, or sampling parameters at different locations to compile a single metric measurement result (e.g., average temperature, average voltage exposure, average conductivity, etc.). One or more sensors 160 can alternatively or additionally be located on a separate device. Sensor data can be used to plan treatment, monitor treatment, and / or provide direct feedback via processor 154, which can then modify energy delivery algorithm 152. For example, impedance measurement results can be used not only to determine the initial dose to be applied but also to determine whether further treatment is needed.

[0156] It should be understood that system 100 may include an automatic treatment delivery algorithm that can dynamically respond to and adjust and / or terminate 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.

[0157] Figure 3 An embodiment of the waveform 400 of the signal defined by the energy transfer algorithm 152 is shown. Here, two groups, a first group 402 and a second group 404, are shown, wherein groups 402 and 404 are separated by a rest period or an inter-group delay 406. In this embodiment, each group 402 and 404 includes a first biphase cycle (including a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphase cycle (including a second positive pulse peak 408' and a second negative pulse peak 410'). The first and second biphase pulses are separated by a dead time or an inter-cycle delay 412 (i.e., a pause) between each pulse. In this embodiment, the biphase pulses are symmetrical, such that the set voltage 416 for the positive and negative peaks is the same. Here, the biphase symmetrical wave is also a square wave, such that the amplitude and duration of the positive voltage wave are approximately equal to the amplitude and duration of the negative voltage wave.

[0158] It is understandable that manipulation of various parameters (e.g., voltage, fundamental frequency, number of pulses per group, number of groups, and various delays) has a variety of effects on the resulting damage and the body itself. In some cases, parameter changes can balance each other, and the effect of a change in one or more parameters can be balanced by changes in one or more different parameter values ​​that lead to the same or similar results. In other cases, parameter values ​​can be adjusted to generate or produce different effects, such as different damage characteristics (e.g., the presence, size, and / or nature of different regions) and / or different effects on the body. These effects on the body can be immediate (e.g., muscle stimulation) or delayed (e.g., generating a specific immune response).

[0159] Figure 4A table (Table 1) is provided illustrating various example effects of parameter variations. Typically, the electrode type is monopolar rather than bipolar. In a monopolar arrangement, one or more delivery electrodes are positioned near the target tissue site, and at least one remote return electrode is positioned against the patient's skin. By utilizing a monopolar electrode configuration, the intensity of muscle contraction increases. To counteract this effect, a biphasic waveform, or a waveform consisting of sufficiently short individual pulse durations, including groupings with appropriate delays between pulses, is typically used to counteract the degree of muscle contraction. This waveform variation results in a reduced therapeutic effect, but this reduction is less pronounced compared to the reduction in muscle contraction, resulting in a still effective PEF treatment application. The monopolar configuration also reduces the risk of arcing compared to bipolar or multipolar configurations, where all actuator electrodes are placed in similar areas that allow arcing between them. Typically, the waveform utilizes biphasic pulses instead of monophasic pulses. The use of biphasic pulses reduces the treatment size, reduces muscle contraction, and also reduces the risk of arcing. Therefore, the use of biphasic pulses counteracts the increase in muscle contraction caused by the monopolar electrode type. Since both monopolar electrode type and biphasic pulses reduce the treatment size, it can be increased by varying other variables. For example, increasing voltage, group duration, and the number of groups increases the treatment size. However, increasing these parameters has various other effects. For example, increasing voltage and group duration both increase the risk of muscle contraction, temperature rise, and arcing. Increasing the fundamental frequency can reduce muscle contraction but also reduces the treatment size. Similarly, increasing the number of groups increases the treatment size but also increases temperature rise and treatment delivery time. Treatment delivery time can be reduced by increasing the group delivery rate; however, this increases temperature rise. Therefore, managing the effects of various parameter variations is a complex task. This is further complicated by making these variations incremental. Once the number of parameters and increments that can be changed, related to the PEF waveform and the dose itself, is considered, the number of combinations is staggering. This is exacerbated by the effects of electrode geometry, such as the fact that a large electrode delivering a specific voltage will have different characteristics than a smaller electrode, or monopolar versus bipolar and multipolar arrangements (and the spacing between electrodes in these arrangements). These characteristics also include temperature rise, therapeutic effect magnitude, delivered current, muscle contraction, risk of arcing, and time required to achieve coverage of the target therapeutic effect magnitude. Furthermore, certain conditioning solutions provided to patients can be specifically designed to target and reduce induced muscle contraction. For example, neuromuscular blocking agents containing pancuronium bromide, vecuronium bromide, succinylcholine, and other blockers can be used. This reduction in muscle contraction can be used to facilitate treatment doses with lower frequencies, longer dose durations, or higher voltages to achieve a greater therapeutic effect while maintaining acceptable levels of safe muscle contraction.

[0160] Understandably, parameters can be manipulated to reduce the probability of inducing arrhythmias. Typically, high voltage energy can trigger premature action potentials (PEPs) in the myocardium because the delivered energy increases myocardial cell membrane permeability, allowing ion transport, which can induce arrhythmias, particularly ventricular fibrillation. However, shorter pulse durations (i.e., higher frequencies, such as 100 kHz to 600 kHz) and biphasic waveform shapes theoretically and practically reduce the probability of inducing arrhythmias. Stimulation of excitable tissue follows an intensity-duration curve. For example, not only does the stimulation threshold increase with shortening pulse duration, but the ventricular fibrillation induction threshold also increases significantly with decreasing pulse width. Since the duration of stimulation is more than an order of magnitude smaller than that of fibrillation, shorter pulses are much less likely to induce ventricular fibrillation. The exponential increase in the amplitude of stimulation of tissue with decreasing pulse width results in 1 to 5 microsecond PEFs being much safer for the heart than 70 to 100 microsecond PEFs. It is noteworthy that the 70 to 100 microsecond pulses commonly seen in conventional 3kV IRE ablation fall within the ventricular fibrillation induction range of these intensity-duration curves, while for the same amplitude, shorter microsecond pulses will fall above the stimulation threshold but below the ventricular fibrillation induction threshold. Furthermore, two other factors contribute to biphasic waveforms being less arrhythmic than monophasic waveforms: 1) biphasic waveforms have higher stimulation and ventricular fibrillation induction thresholds than monophasic waveforms, and 2) biphasic waveforms result in more uniform tissue polarization, which reduces the likelihood of voltage gradient-induced arrhythmias after shock.

[0161] However, the provocation of arrhythmias is highly dependent on the three-dimensional cardiac base (including cardiac fiber anisotropy), the non-uniform conductivity (including in the tissue plane between the power source and the myocardium), and the complex spatiotemporal interaction between the electric field generated by treatment and the intrinsic wavefront in the heart. Therefore, evaluating in vivo electrotherapy to determine its true arrhythmogenic potential is crucial. In this paper, the arrhythmogenic potential of specific PEF energy was assessed by testing it in a highly arrhythmogenic animal model and by purposefully applying treatment at the most susceptible therapeutic anatomy and intracardiac rhythm time.

[0162] Materials and Methods Theoretical assessment of the probability of arrhythmia Numerical simulations provide a valuable tool for representing tissue electrical changes in response to PEF treatment. The cardiac safety of PEF treatment depends on several factors, including the duration of the electrical pulse, the applied voltage, and the distance from the heart. This analysis investigated these factors and their effects on two cardiac phenomena: cardiac activation and the induction of fibrillation. Comsol Multiphysics 5.4 (Comsol, Sweden) was used to model the voltage distribution and electric field for various applied voltages.

[0163] Geometric shapes The electrodes were modeled as a series of five rings extending within an airway with a diameter of 1 cm. Each ring was a 1 mm wide boundary contacting the circumference of the airway and spaced 1 mm apart along the length of the airway. The epithelial and submucosa layers were assumed to be 0.35 mm thick, and the cartilage layer 0.7 mm thick, consistent with the approximate dimensions of the porcine airway tissue layers. The airway region was placed within a lung parenchyma region with a diameter of 20 cm and a length of 40 cm, with a 5 cm diameter dispersion plate electrode placed at the distal end.

[0164] Tissue electrical properties The airway interior is modeled as air with a conductivity of 1.10. -7 The conductivity is S / m, while the epithelial and cartilaginous layers each have a conductivity of 0.362 S / m. As previously mentioned, lung parenchyma is considered to exhibit dynamic conductivity that varies with the electric field. This results in the following conductivity function:

[0165] in, The baseline conductivity of the inflated lung at a frequency consistent with the 1µs pulse duration (0.126 S / m) increases with electric field exposure, approaching the conductivity of the inflated lung at β-dispersion domain frequencies (200 MHz, 0.335 S / m). The 1µs pulse duration was chosen because it is within the typical range of biphasic PEF waveforms. The values ​​of B and C provide the center of the curve and the ± distance to the inflection point along the curve, respectively: 400 V / cm and 125 V / cm, which yields a function of conductivity that increases with electric field exposure from approximately 250 V / cm to approximately 1000 V / cm. Figures 5A to 5B The range and curve shape are consistent with experimental data. Only electrical effects were modeled in the simulation because they have the greatest impact on the risk of arrhythmias.

[0166] Numerical simulation conditions The geometry was meshed to 1.24·10. 6 Each element (ultra-fine physical control mesh) is considered an element. The outer boundary is assumed to be electrically insulating, while the inner boundary follows current conservation. The dispersion pad boundary is set to ground. The electrode ring is evaluated parametrically, with the applied voltage assessed in 1000V increments from 1000V to 3000V. The function of voltage versus distance from the electrode ring in the tissue is determined.

[0167] Theoretical assessment of arrhythmogenicity Cardiac stimulation (i.e., pacing) and arrhythmia induction are both voltage- and pulse duration-related processes, and these intensity-duration relationships are extracted from reference data describing them for monophasic pulses ranging from approximately 90 µs to 50 ms. Notably, the thresholds for pacing the heart and inducing arrhythmias diverge sharply below a pulse width of approximately 1 ms. Data from monophasic pulses are extrapolated because the most robust literature on PEF-related arrhythmias was conducted with monophasic pulses, and biphasic waveforms have previously been shown to have higher stimulation and VF induction thresholds, implying that monophasic pulses represent the worst-case scenario. Figure 6 A to Figure 6 As shown in Figure C, reference data were extrapolated by fitting the VF evoked and stimulated curves with a power-law relationship. These data were used to infer the probability of inducing any cardiac effect over various pulse durations between 1 µs and 100 µs, depending on the applied voltage and distance from the heart.

[0168] In vivo experiments in pigs In this IACUC-approved study, four pigs (44.3 kg to 63.3 kg) received PEF energy. Electrocardiograms (ECGs) were recorded from a data acquisition module (DAQ) connected to an Ivy 7600 cardiac monitor (Ivy Biomedical, CT, USA) and a PEF generator. The cardiac monitor output the ECG waveform and a trigger pulse (R-trigger) corresponding in time to the R wave of ventricular depolarization, allowing for precise control of the PEF delivery timing relative to cardiac depolarization. The cardiac monitor was connected to the subjects via a 4-lead cable. The DAQ simultaneously recorded the ECG signal, the R-trigger, and the delivery of PEF energy, enabling review of the PEF energy delivery relative to the pig's heart rhythm.

[0169] ECGs were continuously recorded throughout all experiments and reviewed by certified electrophysiologists to interpret any changes in heart rhythm or ECG waveform caused by PEF delivery. ECGs were screened for the following: signal saturation, effect on RR timing interval (heart rate), atrial activation or atrial arrhythmias, and ventricular activation or ventricular arrhythmias (including tachycardia, bradycardia, and fibrillation). Any other incidental ECG findings were also documented.

[0170] C-arm fluorescence fluoroscopy visualization of duct location. Computed tomography (CT) images of the pig's chest to determine airway-heart proximity.

[0171] PEF System Background The system evaluated in this study used a variety of PEF waveforms, including a specific PEF used to treat chronic bronchitis. Figure 7An embodiment of a tissue modification system 100 is shown, which is used to deliver specialized PEF energy to target tissue in the lungs, such as for the treatment of chronic bronchitis. As shown, the monopolar system includes a PEF generator 104, a foot switch, an energy delivery body 108 (e.g., an expandable basket electrode), and a large dispersion electrode 106 placed at a distal position on the body. The generator delivers a series of specialized PEF energy packets, each consisting of multiple biphasic pulses. The basket electrode-tissue interface has a distance of approximately 100 cm from the dispersion electrode. 2 Significantly smaller surface area (0.67 cm²) 2 Up to 1.30cm 2 (This depends on the airway diameter).

[0172] In the targeted attempts to intentionally induce arrhythmias, three experiments were conducted to test the worst-case timing of dedicated PEFs: single-pack dedicated PEFs delivered at timed points throughout the cardiac cycle (whole ECG scan), single-pack deliveries delivered at close intervals in the most vulnerable T-wave portion of the cardiac cycle (high-resolution T-wave delivery), and multiple packs organized and delivered together throughout the cardiac cycle (multiple packs). All studies used generators with custom software to allow precise timing of energy delivery relative to R triggers and delivery of dedicated PEF energy at different locations in the airway tree (including distal and proximal to the left and right lungs) to account for locational and anatomical variability around the heart.

[0173] Full ECG scan In both pigs, a dedicated PEF is delivered in single groups. Generator 104 sequentially extends the R-trigger delay interval in 25ms increments before the dedicated PEF delivery. This results in dedicated PEF delivery throughout all periods of the cardiac cycle. One group is delivered every five heartbeats to allow observation of the cardiac response before the next group is delivered.

[0174] High-resolution T-wave transmission In the third pig, single groups were delivered at a higher resolution (10 ms increments) to cover the entire duration of the T-wave region expected to be affected. The T-wave is considered the most arrhythmia-prone part of the ECG because the tissue at this point exhibits varying degrees of ventricular repolarization, which can lead to unidirectional block and arrhythmia induction upon stimulation. One group was delivered every five heartbeats to facilitate the interpretation of ECG and rhythm changes induced by PEF treatment. The entire T-wave scan was repeated at the clinical PEF dose and at a dose delivering 44% more energy than the clinical dose.

[0175] Multiple groups Most specialized PEF therapies deliver large numbers of packets to accumulate cell damage and increase cell death beyond what would result from delivering a single packet. To assess cardiac safety in the case of multiple packet delivery, a fourth pig was used to investigate whether asynchronously delivered composite PEF packets would induce arrhythmias when a single PEF packet failed to induce them.

[0176] The generator was set to deliver a sequence of 5 or 10 groups in a single bundle. The PEF bundle delivery began at different times throughout the ECG waveform, with a resolution of 40 ms, to ensure thorough detection of all potentially vulnerable areas. The resolution for both experiments was 80 ms. The rhythm of the groups within each bundle was also varied, delivered at a rate that was fast (5 Hz / 300 ppm), slow (0.66 Hz / 40 ppm), or at a rate close to the animal's intrinsic heart rate (approximately 1.2 Hz / 70 ppm). As in previous experiments, five ECG beats were recorded after the bundle delivery to determine the presence of induced arrhythmias.

[0177] result Theoretical evaluation exist Figure 8 A to Figure 8 Figure D shows the geometry used in the numerical simulation and the representative distributions of conductivity, electric field, and voltage for a 3000V pulse.

[0178] Because larger volumes of tissue experience an increase in conductivity induced by PEF, the dynamic conductivity causes a slight decrease in tissue impedance under higher applied voltages. Figures 5A to 5B ).

[0179] Figure 9A The extrapolated voltage thresholds for cardiac stimulation and fibrillation induction are shown to separate by approximately two orders of magnitude and decrease logarithmically with increasing monophasic pulse duration. Although the activation energy for pulses longer than 1 µs is less than 250 V, the voltages required to induce fibrillation for durations of 0.5 µs, 1 µs, 10 µs, 50 µs, and 100 µs are significantly higher, decreasing from 62.6 kV to 35.6 kV, 5.48 kV, 1.48 kV, and 0.843 kV, respectively. This highlights the high sensitivity of arrhythmias to pulse duration.

[0180] Combining data from numerical simulation with extrapolated threshold curves to generate Figure 9B .exist Figure 9B In this study, voltage decay at a depth of 3 cm in tissue under different applied voltages overlapped with the activation and tremor thresholds at different monophasic pulse durations. Figure 9BIn all cases, the applied voltage exposed the tissue to the activation energy up to a depth of 3 cm. Furthermore, when the applied voltage was higher than 2 kV, within 1 cm, the voltage required to induce fibrillation for pulses with durations of 50 µs and 100 µs exceeded this threshold for all pulses. Conversely, for pulse durations ≤10 µs, the applied voltage did not induce fibrillation in the exposed tissue at any distance. These data suggest that PEF therapy has a significant safety margin for arrhythmia induction when the monophasic pulse duration is 10 µs or shorter.

[0181] Experimental evaluation The minimum distance between the heart and the main bronchus where the basket electrode was placed was measured by combining images of a basket-deployed fluorescence microscope with CT images of the pig's chest; the distance indicated was approximately 2 mm. Figure 10 A to Figure 10 D). Figure 10 A shows a fluorescence microscopic image of a bronchoscope in the left main bronchus of a pig with a basket electrode deployed. A representative CT scan of the pig is provided, showing the axial ( Figure 10 B, 1.96mm), coronal ( Figure 10 C, 5.97 mm and 4.74 mm) and sagittal ( Figure 10 The proximity to the epicardial surface was measured in the plane (D, 7.06 mm).

[0182] In the three studies, a total of 3125 PEF groups were delivered to four pigs. No sustained changes in heart rhythm or ECG waveforms were observed, particularly no atrial or ventricular fibrillation, ST-segment elevation, or ventricular tachycardia. Overall, the cardiac response to specialized PEF energy delivery fell into one of four categories, such as… Figure 11 A to Figure 11 As shown in D: 1) No change ( Figure 11 A): Group delivery did not have any effect or change on ECG.

[0183] 2) Signal interference Figure 11 B): Dedicated PEF delivery causes ECG artifacts. When these artifacts coincide with ECG characteristics (e.g., QRS complexes), the appearance of the characteristics is altered. Artifacts exist related to experimental setup and data recording devices, but have no effect on cardiac activation or timing.

[0184] 3) Premature atrial contractions (PACs) without ventricular conduction Figure 11C): The delivered beat stimulates atrial contraction before the natural conduction of the beat from the sinoatrial (SA) node. The atrioventricular (AV) node is in a refractory period during this premature beat, and therefore the electrical signal cannot conduct to capture the ventricle. However, the SA node has been reset, so the subsequent normal heartbeat does not occur until a period aligned with the baseline heart rate following the atrial premature beat. This appears on the ECG as a “non-conducting” or missed beat, with a cycle length approximately twice the baseline cycle length. After the subsequent heartbeat, the rhythm returns to the baseline heart rate.

[0185] 4) Premature atrial contractions (PACs) accompanied by ventricular conduction ( Figure 11 D): The premature beats stimulate atrial contraction before the natural conduction from the SA node. The AV node is not in its refractory period and allows premature beats to conduct and activate the ventricles, resulting in normal ventricular conduction. This manifests as premature beats occurring before the baseline heartbeat is encountered. After the premature beat, the heart rhythm returns to its baseline rate, sometimes with sinus reactivation or sustained sinus timing.

[0186] Both PAC conditions are considered as altering a specific RR interval, but without any residual effect extending to subsequent heartbeats. Arrows and numbers indicate the time interval from QRS complex to PEF delivery. Bars and numbers indicate the time when the PEF packet was delivered and the PEF packet number.

[0187] Table 2 provides a summary of the delivered treatments and a review of the heart rhythm and ECG waveforms. For any PEF delivery, there were no persistent changes in ECG waveforms (e.g., ST-segment elevation) or heart rhythm, including no bradycardia, tachycardia, atrial fibrillation, or ventricular fibrillation. Furthermore, the results are limited to a single PAC. This data is further clarified in Table 2 by lung and location.

[0188] Table 2 Summary of PEF delivery

[0189] *When a full ECG scan is performed, the R-wave trigger delay ranges from the shortest resolution time point to the appearance of the next R-wave. This varies based on the pig's heart rate.

[0190] The following is a brief description of the results of each experiment.

[0191] Full ECG scan A total of 1180 groups were transported from the two pigs. Each section (distal and proximal) of the left and right lungs underwent a full-cycle PEF scan, for a total of 16 full-cycle PEF scans. As previously stated, PAC occurred only in the presence of a basket electrode in the proximal main bronchus. When PAC occurred, its effect was only in the timing of the immediately following heartbeat, and in all cases, regardless of whether it was conducted to the ventricle, it resolved spontaneously immediately. Overall, there were no defined safety risks associated with group transport, such as any arrhythmias, any abnormal ventricular conduction outside the normal conduction system, or any ST-segment changes.

[0192] High-resolution T-wave transmission During high-resolution T-wave delivery, individual pigs were grouped into 160 clinical PEF doses. Despite high-resolution delivery of PEF in the most vulnerable parts of the ECG, no persistent (>1 heartbeat) changes in heart rhythm were observed, and no significant safety risks associated with biphasic PEF group delivery were documented in any region.

[0193] Multiple groups In total, 1945 groups were delivered to individual pigs via 341 PEF activations. PAC was again recorded only when the treatment had been adequately delivered beyond the refractory period, with the basket electrode positioned in the proximal left main bronchus. A summary of observations is provided in Table 2. Consistent with the previous two experiments, no persistent changes in heart rhythm, including fibrillation or other dangerous arrhythmias, were observed. These findings were consistent regardless of the PEF group delivery rate, whether 5 or 10 groups were delivered, and regardless of the initial timing of the first group delivery. Experimental conditions and discrete decomposition of PAC-induced arrhythmias are shown in Table 3.

[0194] Table 3 summarizes the experimental results of delivering multiple groups of PEF to the heart.

[0195]

[0196] In these studies, all treated animals had normal heart rhythms immediately after treatment and maintained them until their pre-specified survival time. Therefore, these data demonstrate that no clinically significant arrhythmias exist regardless of electrode placement, the testing conditions of PEF delivery relative to heart rhythm, or the number of subsequent groups.

[0197] discuss The arrhythmogenic potential of an embodiment of a biphasic monopolar PEF system in the airway was systematically explored. Numerical simulations assessed the likelihood of arrhythmia induction with variations in pulse duration, applied voltage, and distance from the heart. Experimentally, for both single-group and multi-group treatments, individual group doses and waveform characteristics were matched to clinical airway treatment parameters.

[0198] Despite increasingly vigorous attempts to induce arrhythmias with short-duration (≤10µs) biphasic pulses tested in this experimental setup, no sustained changes in ECG waveforms or heart rhythm were observed. These data contrast sharply with previous reports by Deodhar et al. regarding different PEF techniques (i.e., irreversible electroporation). In this study, 90 nanoknife (AngioDynamics, NY, USA) pulses, each lasting 70µs, were delivered over a range of voltages relative to the heart. They observed that a significant portion of the test conditions induced a range of arrhythmias, including ventricular tachycardia and ventricular fibrillation, when energy was delivered asynchronously. ST-segment elevation and T-wave inversion were still observed when R-triggered cardiac synchronization was incorporated as they suggested. These differences highlight that not all PEF techniques are created equal, and key distinctions exist regarding the safety and effectiveness of various electric field platforms and delivery systems. Besides pulse duration, other differences exist between this study and Deodhar's research, including electrode placement (monopolar in this case) and biphasic waveforms.

[0199] In this study, the end effector was intentionally placed in the airway as close to the heart as possible (approximately 2 mm from the myocardium). Documentation shows that pigs are more prone to arrhythmias than humans. Despite these worst-case scenarios, the only alteration on the ECG was PAC occurring when energy was delivered with the basket electrode positioned in the proximal main bronchus. For biphasic waveforms, such as the waveform of the PEF therapy used in this study, the arrhythmogenicity of specific PEF energy was significantly reduced.

[0200] Theoretical checks of cardiac activation and fibrillation thresholds indicate that even at low PEF applied voltages (≤1 kV), short (<10 µs) single monophasic pulses can induce activation. However, the fibrillation threshold is approximately two orders of magnitude higher, so arrhythmia induction is only noted with pulse durations of 50 µs or longer, and a 100 µs pulse was able to induce fibrillation for all tested voltages. Notably, regarding the biphasic PEF waveforms described herein, the pulse duration for each phase ranges from 0.5 µs to 5 µs, falling well within this “safe zone” for monopolar electrodes and applied voltages well above 3.0 kV. This is consistent with the experimental evaluation of commercially available dedicated PEF systems used to induce arrhythmias in pigs. These systems employ a PEF scheme that includes voltage and frequency characteristics consistent with those evaluated in simulations and demonstrates induced cardiac activation without fibrillation under any test conditions.

[0201] One limitation of the theoretical portion of this study is that it assesses the risk of arrhythmia with respect to a single monophasic pulse. While consistent with some commercially available PEF systems that use a series of long monophasic pulses (durations ranging from 50 µs to 100 µs), it cannot fully reproduce the cardiac effects that a biphasic waveform composed of rapidly alternating short pulses (0.5 µs to 5 µs) can induce. This limitation is a consequence of previous explorations of the activation and fibrillation risk of cardiac tissue as pulse waveform characteristics vary. Additional theoretical work can better characterize the likelihood of activation and fibrillation induction under typical PEF ablation waveforms that incorporate these additional variables (biphasic pulse width, the number of biphasic cycles including complete groups, and the delivery rate of multiple biphasic groups).

[0202] The experimentally evaluated specific PEF treatment regimen was able to treat cell death. The tested regimen was optimized to produce significant epithelial (43±27%) and submucosal gland (3±4%) cell death without altering airway integrity or function. The clinical applicability of the system's regimen was evaluated in a multicenter clinical trial for the treatment of patients with chronic bronchitis (CB). No device-related adverse events were observed, while patient-reported symptom improvements were observed on the Chronic Obstructive Lung Disease Assessment Trial (CAT) and the St. George's Respiratory Questionnaire (SGRQ) by -8.0 (p<0.001) and -14.7 (p<0.001), respectively. These changes were significantly greater than the minimum clinically important differences in each test (-2 and -4 points, respectively). When comparing airway tissue samples before and after treatment, the histological measurement of goblet cell proliferation was reduced by approximately 39% (p<0.001).

[0203] In these studies, occasional PAC induction was the only significant effect of delivering specialized PEF on the heart, consistent with simulated cardiac stimulation predictions, but not associated with arrhythmia induction. PAC is a common clinical phenomenon, occurring at least once every 24 hours in >99% of the general adult population. The effect of the delivered energy is limited to a single beat and never extends to any subsequent beats. Therefore, these findings do not demonstrate a measurable risk to patient health.

[0204] One consideration is that, although relatively healthy pig hearts may be more resilient compared to human hearts with underlying disease conditions such as myocardial ischemia, it should be noted that pigs are nearly three times more sensitive to electrically induced arrhythmias than humans, thus serving as a highly sensitive model for cardiac safety. This study also relies on historical literature to demonstrate the potential for arrhythmias induced by prolonged monophasic waveforms, rather than on positive controls. While humans and pigs may respond differently to monophasic versus biphasic waveforms, this is unlikely, as both show the same preferential response to biphasic cardioversion relative to monophasic cardioversion.

[0205] This study theoretically evaluated several relevant variables that could cause arrhythmias, including applied voltage, pulse duration, and proximity to the heart. The safety of asynchronous PEF delivery in various regions of the ECG waveform was determined experimentally using a biphasic, monopolar PEF technique for airway management. Despite delivering thousands of packets, including many directly on the susceptible T wave, only occasional PACs occurred, and no arrhythmias or ECG waveform changes were observed. This study suggests that specialized PEF does not appear to require cardiac synchronization of energy delivery to prevent associated arrhythmias.

[0206] By using waveforms that significantly reduce the chance of inducing arrhythmias (i.e., specialized PEF), energy can be delivered without cardiac synchronization. Therefore, energy can be delivered using methods and procedures previously considered contraindicated.

[0207] In some embodiments, specific PEF energy is delivered to the target tissue throughout the patient's entire heartbeat. In other embodiments, energy is delivered during specific periods of the heartbeat. A typical ECG trace includes a P wave representing atrial depolarization, a QRS complex representing ventricular depolarization and atrial repolarization, and a repetitive cycle of a T wave representing ventricular repolarization. Generally, a portion of the heartbeat is considered a "vulnerable period" for the myocardium. Within a cardiac cycle (heartbeat), the vulnerable period of the ventricular myocardium is represented on the ECG by the entire T wave. The T wave is considered the most arrhythmia-prone part of the ECG because the tissue exhibits varying degrees of ventricular repolarization at this time, which can lead to unidirectional block and arrhythmia induction upon stimulation. Typically, for the ventricular myocardium, the vulnerable period coincides with the middle and terminal phases of the T wave. However, when a high-energy pulse is delivered immediately adjacent to the ventricle, the vulnerable period may occur milliseconds earlier in the heartbeat. Therefore, the entire T wave can be considered within the vulnerable period of the ventricle. In some embodiments, energy (such as a single or multiple packets) is delivered throughout the entire vulnerable period of the ventricular myocardium, the entire T wave, at least a portion of the T wave, at least a phase of the T wave, at least a middle phase of the T wave, at least a terminal phase of the T wave, at least a portion of the middle phase of the T wave, and / or at least a portion of the terminal phase of the T wave.

[0208] In some embodiments, specialized PEF energy is delivered to the target tissue via a generator, wherein the generator sequentially extends the R trigger delay interval in 25 ms increments prior to PEF delivery. This results in PEF being delivered throughout all phases of the cardiac cycle. In other embodiments, single bundles are delivered at a higher resolution (in 10 ms increments) to cover the entire duration of the intended vulnerable area of ​​the T wave. In some cases, PEF therapy delivers a bundle of bundles to accumulate cell damage and increase cell death beyond the cell death induced by delivering a single bundle. Thus, in some embodiments, a sequence such as 5 or 10 bundles is delivered in a bundle during the vulnerable period. In some embodiments, PEF bundle delivery begins at different times throughout the ECG waveform, with a resolution of 40 ms to 80 ms. In some cases, the cadence of the bundle delivery within each bundle is varied, delivering the bundles at a rate that is fast (5 Hz / 300 ppm), slow (0.66 Hz / 40 ppm), or close to the natural heart rate (approximately 1.2 Hz / 70 ppm).

[0209] In some embodiments, a specialized PEF is delivered during atrial contraction. Delivery during atrial contraction is generally contraindicated due to the increased risk of inducing arrhythmias, but this delivery can be achieved using a specialized PEF. Delivery during atrial contraction ensures that the heart is in the same physical state when energy is delivered during each dose period. At the start of the cardiac cycle, both the atria and ventricles are in diastole (the relaxation phase). Blood flows into the right atrium from the superior and inferior vena cava and the coronary sinus. Blood flows into the left atrium from the four pulmonary veins. Both atrioventricular valves, the tricuspid and mitral valves, are open, allowing blood to flow unimpeded from the atria into the ventricles. Approximately 70% to 80% of ventricular filling occurs in this manner. The pulmonary and aortic valves, the two semilunar valves, are closed, preventing blood from flowing back from the right pulmonary trunk and the left aorta into the left and right ventricles. Atrial contraction is accompanied by depolarization, represented by the P wave on the ECG. As the atrial myocardium contracts from the upper part of the atrium towards the atrioventricular septum, the pressure inside the atrium increases, and blood is pumped into the ventricles through the open atrioventricular valves (tricuspid and mitral valves, or bicuspid valves). At the beginning of an atrial contraction, the ventricles are typically about 70% to 80% full due to the influx during diastole. The atrial contraction, also known as the "atrial kick," contributes the remaining 20% ​​to 30% of the filling. An atrial contraction lasts about 100 ms and ends before ventricular contraction as the atrial myocardium resumes relaxation.

[0210] In some embodiments, a specialized PEF is delivered during the peak of atrial or ventricular contraction. This is helpful in treating cardiac tissue, where such delivery overcomes contact variability during heartbeat. In another embodiment, a specialized PEF is delivered as the myocardium begins its diastolic process after maximal contraction. In such embodiments, the ratio of the contact force electrode to the tissue is maintained in a high range, which can be achieved by continuously monitoring the contact force or sensing the presence of contact. During this period, the diastolic myocardium presents a thinner configuration but delivers the same energy. Due to the higher energy ratio per tissue thickness, this favors the generation of transmural damage.

[0211] Atrial or ventricular contraction can be determined by contact force measurement, pressure monitoring (e.g., synchronizing pulse delivery with pressure as an alternative to anticipated tissue contraction), and / or blood flow monitoring (e.g., using Doppler ultrasound imaging to synchronize pulse delivery with flow as an alternative to anticipated contraction).

[0212] In some embodiments, energy delivery is timed to provide artifact-free or artifact-reduced visualization of specific electrical features. It is understood that intracardiac electrical monitoring systems typically exhibit large electrical artifacts across all surfaces of cardiac tissue when energy is delivered. These artifacts can make readings of surface ECGs or intracardiac EGMs difficult for short periods. The duration depends on how quickly the recording amplifier recovers from saturation. Therefore, having limited delivery periods can restrict a user's ability to visualize specific electrical features. However, dedicated PEFs can be delivered without restriction, allowing for the selection of delivery periods that do not overlap with specific ECG and / or EGM features. This allows for improved or artifact-free visualization of these features. For example, energy delivery can be selected to avoid atrial depolarization, which would allow for clearer visualization of atrial P waves.

[0213] In some embodiments, this control over the timing of energy delivery also improves compatibility with accessories and other systems. Some accessories or device systems, particularly those connected to a patient, offer functionality that benefits operation during periods without energy delivery. One such example is the electroanatomical mapping system used when treating cardiac tissue, such as in the treatment of arrhythmias. Preferably, energy is avoided when performing electrical measurements on cardiac tissue. Therefore, energy delivery can be timed to these preferred periods without the complexity of the additional requirement to synchronize with the heartbeat. This eliminates or reduces artifacts and mitigates the possibility of system damage.

[0214] In some embodiments, a specific PEF energy is delivered at a dose-related rate. In some embodiments, the dose is a predetermined energy delivery that results in the desired therapeutic effect (e.g., lesion formation). In this case, one dose produces one lesion. Because the dose is based on the energy delivered, the dose can be delivered over a variety of time periods. When not hindered by cardiac synchronization, the delivery of specific PEF energy can be regulated to the desired energy dose. In this case, energy is delivered within the shortest amount of time required to provide the desired effect. It is understood that the dose may include delays to allow heat dissipation, thereby reducing or eliminating any thermal effects. However, the dose is variable and may exceed the clinically desired treatment time when adapting to thermal effects and cardiac synchronization. In some cases, even if the outcome is not the most optimal therapeutic result, delays may be manipulated to adapt the dose to the desired clinical treatment time. For example, to adapt to patients with a variety of potential heart rates (e.g., 40 bpm to 140 bpm), the dose is designed to deliver energy quickly enough that adapting to 40 bpm does not take too long clinically, but also slowly enough that adapting to 140 bpm does not cause excessive temperature rise. However, delivering specialized PEF energy as needed, without synchronization with the cardiac cycle, allows energy delivery to be entirely dependent on dose optimization, thus delivering at a dose-dependent rate. This typically results in a faster overall treatment time while still allowing for delays to minimize any thermal damage. This can be particularly useful for lower voltage doses that can be delivered more quickly without causing a widespread temperature rise.

[0215] In some embodiments, specialized PEF energy is delivered at a constant rate, which provides a constant time for injury to form. When energy delivery is not constant, for example, depending on the cardiac cycle, the delivery time depends on the heart rate. However, average resting heart rate varies with age, sex, body mass index (BMI), and sleep patterns. In some cases, the daily resting heart rate varies by up to 70 beats per minute (bpm) between individuals. Daily resting heart rates are typically between 50 and 80 bpm for men and between 53 and 82 bpm for women. Men with a moderate BMI tend to have the lowest resting heart rates, while those with very low or very high BMIs tend to have higher resting heart rates. Variability also exists within individual patients. Women of reproductive age exhibit greater variability in their individual resting heart rate compared to men. However, even small seasonal variations exist for all patients. Average daily resting heart rates for both men and women peak in early January and then drop to a yearly low by the end of July. When energy delivery is synchronized with the heartbeat, all of this introduces unpredictability into the time it takes for damage to form in any given patient. However, if this synchronization is eliminated by using a specialized PEF (penetrating electrode delivery system), a constant delivery rate can be used, which translates into a constant time for damage formation. This is particularly advantageous for electrophysiologists using a "drag" technique to deliver energy, in the treatment of cardiac tissue. In this technique, the delivery electrode is dragged across the cardiac tissue at a constant rate to deliver energy, rather than being placed in one position while delivering energy. By delivering energy at a constant rate, the energy is delivered uniformly to the cardiac tissue. This is also advantageous for automated systems, such as robotic surgery, which are often predetermined or have limited capacity to provide variation or adaptation.

[0216] Once energy delivery is no longer correlated with synchronization to the heartbeat, it can be associated with other anatomically based features. For example, energy delivery can be synchronized with breathing. Respiratory expansion can be detected using, for example, a chest band, corrugated tube, or padding. For “chest-breathing” patients, the band should be placed around the lower chest, while for “abdominal-breathing” patients, it should be placed around the mid-abdomen. Alternatively, impedance plethysmography devices that measure the change in resistance throughout the chest during breathing can be used. This can be particularly useful in treating lung tissue or ablating tumors within or around the lungs. Thus, energy delivery can be actuated when the lungs are not moving, which can allow for more consistent and / or predictable energy delivery. This also allows for avoiding energy delivery during particularly disruptive events such as coughing or sneezing. Similarly, when delivering energy near the coronary vascular system or other parts of the vascular system, delivery can be modulated to reduce the risk of vasospasm. For example, when delivering energy to tissue near coronary vessels, the delivery rate can be reduced to avoid or minimize smooth muscle contraction of the vessels.

[0217] Once energy delivery is no longer correlated with synchronization to the heartbeat, it can be actuated by feedback control instead, unaffected by synchronization with the heartbeat. Examples of feedback control include temperature monitoring, impedance monitoring, pH monitoring, contact detection and / or contact force, and so on. Temperature monitoring can be used to more easily and effectively keep thermal damage at a level that is minimal or nonexistent. PEF energy is considered “non-thermal” because the tissue receiving the energy does not suffer thermal injury or damage. This is typically achieved by incorporating a predetermined timing delay into the waveform that mitigates the temperature rise. These delays essentially slow down the procedure. Similarly, the built-in safety margin causes the procedure to be longer than necessary. Real-time temperature monitoring allows temperature mitigation to be diverted from the predetermined delay, making energy delivery more efficient. This results in faster treatment while maintaining reduced or eliminated thermal damage.

[0218] In some embodiments, energy delivery is actuated via impedance-based feedback control. It is understood that the measured impedance can vary depending on the location of the energy delivery electrode. The impedance when the delivery electrode is embedded in the tissue (i.e., “encapsulated”) will be higher than the impedance when only in contact with the tissue, which in turn is higher than the impedance in the blood when not in contact with the tissue. Excessive encapsulation can lead to greater thermal damage relative to PEF treatment. Insufficient impedance can result in delivery primarily into the bloodstream rather than the tissue, leading to insufficient or absent damage formation. Therefore, in some embodiments, energy delivery is actuated when the impedance is within a desired range reflecting the desired encapsulation in the tissue.

[0219] In some embodiments, energy delivery is actuated by feedback from one or more sensors configured to detect the distribution of the agent within the body, such as in a specific region or tissue. This can be useful when the procedure involves gene therapy, electrochemical therapy, or the delivery of an agent to cells within the body. In some embodiments, the agent comprises molecules, and a key characteristic of in vivo molecular transfer involves the biodistribution of the molecules. Example molecules include plasmids, DNA plasmids, RNA (e.g., messenger RNA (mRNA), small interfering RNA (siRNA), microRNA), oligonucleotides, antisense oligonucleotides (ASO), proteins, and / or substances that cause genetic or epigenetic changes in cellular behavior, etc. For a molecule to be successfully transferred to a cell, for the energy used for the transfer to be delivered, the molecule must be in a desired location within the body at a desired time and concentration. Therefore, when these key factors coincide, energy can be delivered regardless of the cardiac cycle. This provides increased effectiveness and efficiency.

[0220] In one embodiment, one or more impedance sensors can be used to measure, for example, the impedance between two tines or between a tine and a central axis on the delivery device, through which the drug is delivered. If the injected drug has a different conductivity than the surrounding tissue, the sensors can provide information about the drug distribution. In another embodiment, pH, fiber optics, bipolar impedance, or other types of sensors can be used to detect when the drug diffuses, for example, from the central injection site to the lateral tines. In some embodiments, the drug is a drug loaded with a radiopaque dye. In this case, imaging, rather than sensors, is used to provide feedback control for PEF energy delivery.

[0221] These optional delivery options provide better results and also speed up the procedure. Since the time portion typically excluded from energy delivery is now available, including constant energy delivery for any given time period, more energy can be delivered in a shorter time. Typically, only 20% of the available time (e.g., the entire cardiac cycle) is available for energy delivery when cardiac synchronization is taken into account. By eliminating these limitations using a specialized PEF, the remaining 80% is now available. This is a five-fold increase or a 500% increase. Similarly, when multi-spline or multi-tined devices are used for energy delivery, individual energy delivery elements (e.g., splines, tines, etc.) can be used sequentially or in any desired order, regardless of the cardiac state at any given time. This allows for a more temporally denser sequence or pattern of activation, resulting in increased energy delivery rates and reduced procedure time.

[0222] Further example embodiments of energy delivery systems configured to provide PEF therapy to various parts of the body are provided in the following documents: International Patent Application No. PCT / US2021 / 044469, filed August 3, 2021, entitled “PULSED ELECTRIC FIELD TRANSFER OF MOLECULES TO CELLS WHILE IN THE BODY”; International Patent Application No. PCT / US2022 / 019719, filed March 10, 2022, entitled “DEVICES FOR THE DELIVERY OF PULSED ELECTRIC FIELD IN THE TREATMENT OF CARDIAC TISSUE”; and International Patent Application No. PCT / US2022 / 019719, filed September 19, 2022, entitled “CONTROLLED LESION AND IMMUNE RESPONSE TOPULSED ELECTRIC FIELD”. The international patent application “THERAPY” with application number PCT / US2022 / 044021, all of which are incorporated herein by reference for all purposes. Similarly, various forms of PEF energy may be used, such as those described in the references incorporated herein and pursuant to the international patent application filed April 8, 2021, entitled “PULSED ELECTRIC FIELDWAVEFORM MANIPULATION AND USE” with application number PCT / US2021 / 026221, all of which are incorporated herein by reference for all purposes.

[0223] As previously described, one or more energy delivery algorithms 152 are programmable or can be pre-programmed into generator 104 to deliver energy to patient P. One or more energy delivery algorithms 152 specify an electrical signal that provides energy. It is understood that various energy delivery algorithms 152 can be used. In some embodiments, algorithm 152 specifies a signal having a waveform comprising a series of energy groups, where each energy group comprises a series of high-voltage pulses. In such embodiments, algorithm 152 specifies parameters of the signal, such as energy amplitude (e.g., voltage) and duration of the applied energy, including the number of groups, the number of pulses within a group, and the fundamental frequency of the pulse sequence, etc. Additional parameters may include the switching time between polarities in the biphasic pulses, the dead time between biphasic cycles, and the rest time between groups, which will be described in more detail later. There may be a fixed rest period between groups, or the groups may be selected for a specific metric. An intentional, varying rest period algorithm may exist between groups, or no rest period may be applied. Feedback loops based on sensor information and automatic shutdown specifications, etc., may be included.

[0224] A. Voltage The voltage used and considered can be the top of a square wave, the peak of a sine wave or sawtooth wave, or the RMS voltage of a sine wave or sawtooth wave. In some embodiments, energy is delivered in a unipolar manner, and each high-voltage pulse or set voltage 416 is between about 500V and 10000V, particularly about 3500V to 4000V, about 3500V to 5000V, about 3500V to 6000V, including all values ​​and sub-ranges therebetween, including about 250V, 500V, 1000V, 1500V, 2000V, 2500V, 3000V, 3500V, 4000V, 4500V, 5000V, 5500V, 6000V, etc. The voltage delivered to the tissue can be based on a set point on generator 104, taking into account electrical losses along the length of device 102 due to its inherent impedance, or without considering losses along the length. That is, the delivered voltage can be measured at the generator or at the tip of the instrument.

[0225] It is understood that, in various embodiments, the output can be controlled or modified to achieve a desired current rather than a voltage. In some embodiments, energy is delivered in a unipolar manner and has the following currents: 20 amps, 21 amps, 22 amps, 23 amps, 24 amps, 25 amps, 26 amps, 27 amps, 28 amps, 29 amps, 30 amps, 31 amps, 32 amps, 33 amps, 34 amps, or 35 amps, etc.

[0226] B. Frequency Understandably, the number of biphase cycles per second is the frequency of the signal when it is continuous. Typically, signals have frequencies in the range of 100kHz to 600kHz, such as 100kHz to 200kHz, 100kHz to 300kHz, 200kHz to 400kHz, 200kHz to 500kHz, 300kHz to 400kHz, 300kHz to 500kHz, 300kHz to 600kHz, 400kHz to 500kHz, 400kHz to 600kHz, 500kHz to 600kHz, 100kHz, 200kHz, 300kHz, 400kHz, 500kHz, or 600kHz, and so on.

[0227] C. Voltage-frequency balance The frequency of the delivered waveform can be varied synchronously with respect to the treatment voltage to maintain a sufficient therapeutic effect. This synchronous variation will include reducing the frequency that causes a stronger effect and reducing the voltage that causes a weaker effect. For example, in some cases, treatment can be delivered in a unipolar manner at 3000V with a waveform frequency of 600kHz, while in other cases, treatment can be delivered at 2000V with a waveform frequency of 400kHz.

[0228] D. Grouping As described above, Algorithm 152 typically specifies a signal having a waveform comprising a series of energy groups, where each energy group comprises a series of high-voltage pulses. The cycle count 420 is half the number of pulses within each biphase group. (Reference) Figure 4 The first group 402 has two (i.e., four biphase pulse) cycle counts 420. In some embodiments, the cycle count 420 is set between 2 and 1000 per group, including all values ​​and sub-ranges therebetween. In some embodiments, the cycle count 420 is 5 to 1000 per group, 2 to 10 per group, 2 to 20 per group, 2 to 25 per group, 10 to 20 per group, 20 per group, 20 to 30 per group, 25 per group, 20 to 40 per group, 30 per group, 30 to 45 per group, 45 per group, 20 to 50 per group, 30 to 60 per group, up to 60 per group, up to 80 per group, up to 100 per group, up to 1000 per group, or up to 2000 per group, including all values ​​and sub-ranges therebetween.

[0229] The packet duration is determined by the cycle count and other factors. For matched pulse durations (or a sequence of positive and negative pulse durations of a biphasic waveform), a higher cycle count results in a longer packet duration and a greater amount of energy delivered. In some embodiments, the packet duration is in the range of approximately 50 to 1000 microseconds, such as 50µs, 60µs, 70µs, 80µs, 90µs, 100µs, 125µs, 150µs, 175µs, 200µs, 250µs, 100µs to 250µs, 150µs to 250µs, 200µs to 250µs, 500µs to 1000µs, and so on. In other embodiments, the packet duration is in the range of approximately 100 to 1000 microseconds, such as 150µs, 200µs, 250µs, 500µs, or 1000µs.

[0230] The number of groups or group count delivered during treatment typically includes 1 to 250 groups, including all values ​​and subranges therebetween. In some embodiments, the number of groups delivered during treatment includes 2 to 5 groups, 3 groups, 5 groups, 5 to 10 groups, 10 groups, 12 groups, 10 to 15 groups, 15 groups, 20 groups, 15 to 20 groups, 25 groups, 30 groups, or more than 30 groups.

[0231] E. Rest period In some embodiments, the time between groups (referred to as rest period 406) is set between approximately 0.001 seconds and approximately 5 seconds, including all values ​​and sub-ranges therebetween. In other embodiments, rest period 406 ranges from approximately 0.01 seconds to 0.1 seconds, including all values ​​and sub-ranges therebetween. In some embodiments, rest period 406 is approximately 0.5 ms to 500 ms, 1 ms to 250 ms, or 10 ms to 100 ms, etc.

[0232] F. Batch In some embodiments, the signal is synchronized with physiological or other characteristics such that each group is delivered synchronously within a specified time period or in response to a specified trigger. It is understood that the groups delivered at such times can be considered a batch or a bundle. Thus, each batch has a desired number of groups such that by the end of the treatment period, the total desired number of groups has been delivered. Each batch may have the same number of groups; however, in some embodiments, batches may have different numbers of groups.

[0233] In some embodiments, only one packet is delivered upon triggering. In this case, the rest period can be considered the same as the period between batches. However, when more than one packet is delivered between batches, the rest time is typically different from the period between batches. In this case, the rest time is typically much shorter than the period between batches. In some embodiments, each batch includes 1 to 10 packets, 1 to 5 packets, 1 to 4 packets, 1 to 3 packets, 2 to 3 packets, 2 packets, 3 packets, 4 packets, 5 packets, 5 to 10 packets, and so on. In some embodiments, each batch has a period of 0.5ms to 1 sec, 1ms to 1 sec, 10ms to 1 sec, 10ms to 100ms, and so on. In some embodiments, the period between batches is variable. In some cases, the period between batches is 0.25 seconds to 5 seconds.

[0234] The tissue area is treated until the desired number of batches are delivered to the tissue area. In some embodiments, 2 to 50 batches are delivered per treatment, wherein the treatment is considered to be treatment of a specific tissue area. In other embodiments, the treatment includes 5 to 40 batches, 5 to 30 batches, 5 to 20 batches, 5 to 10 batches, 5 batches, 6 batches, 7 batches, 8 batches, 9 batches, 10 batches, 10 to 15 batches, etc.

[0235] G. Switching time and dead time Switching time, also known as inter-stage delay, such as Figure 4 As shown, this is a delay or period of time between the positive and negative peaks of the biphase pulse where no energy is delivered. 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 microsecond to 20 microseconds, including all values ​​and subranges therebetween. In other embodiments, the switching time ranges from about 2 microseconds to about 8 microseconds, including all values ​​and subranges therebetween.

[0236] A delay, referred to as a "dead time" or inter-pulse delay, can also be inserted between each biphase cycle. The dead time occurs within a group but between biphase pulses. This is the opposite of a rest period or inter-group delay that occurs between groups. In other embodiments, the dead time 412 is in the range of approximately 0 to 0.5 microseconds, 0 to 10 microseconds, 2 to 5 microseconds, 0 to 20 microseconds, approximately 0 to approximately 100 microseconds, or approximately 0 to approximately 100 milliseconds, including all values ​​and subranges therein. In some embodiments, the dead time 412 is in the range of 0.2 to 0.3 microseconds. The dead time can also be used to define the time interval between individual monophase pulses within a group.

[0237] Delays such as switching time and dead time are introduced into the grouping to reduce the effect of biphase cancellation within the waveform. In some cases, both switching time and dead time are increased together to enhance the effect. In other cases, only switching time or only dead time is increased to induce the effect.

[0238] G. Waveform It is understood that in some embodiments, waveform 400 has symmetrical pulses, such that the pulse voltage and duration in one direction (i.e., positive or negative) are equal to the pulse voltage and duration in the other direction. It is understood that in other embodiments, waveform 400 has voltage imbalance. For example, each group 402, 404 may include a first biphasic period (including a first positive pulse peak 408 with a first voltage V1 and a first negative pulse peak 410 with a second voltage V2) and a second biphasic period (including a second positive pulse peak 408' with a first voltage V1 and a second negative pulse peak 410' with a second voltage V2). Here, the first voltage V1 is greater than the second voltage V2. The first biphasic period and the second biphasic period 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, such that the area under the positive portion of the curve is not equal to the area under the negative portion of the curve. This imbalanced waveform can lead to a more pronounced therapeutic effect. It is understood that in some embodiments, the imbalance includes pulses with pulse widths having unequal durations. In some embodiments, the biphase 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, such that the area under the curve of the positive portion of the waveform is not equal to the area under the curve of the negative portion of the waveform.

[0239] It is understood that the apparatus, systems, and methods described herein utilize energy delivery systems to deliver energy to target tissue. Typically, energy delivery systems include a specialized energy delivery device, a waveform generator, and at least one different energy delivery algorithm. Additional accessories and instruments may be used. For example, in some embodiments, the energy delivery device is delivered via an endoscope, which is typically specific to the anatomical location it is used for, such as a gastroscopy (upper gastrointestinal endoscope, including the stomach, esophagus, and small intestine (duodenum)), a colonoscopy (large intestine), a bronchoscope (lung), a laryngoscope (larynx), a cystoscope (urinary tract), a duodenoscope (small intestine), an colonoscope (digestive system), a ureteroscope (ureter), a hysteroscope (cervix, uterus), etc. It is understood that in other embodiments, the energy delivery device may be delivered via a catheter, sheath, guide, needle, or other delivery system.

[0240] Intraluminal access allows treatment of target tissues from within various lumens of the body. A lumen is a space within a tubular or hollow structure in the body, including passageways, canals, ducts, and cavities, etc. Examples of luminal structures include blood vessels, esophagus, stomach, small and large intestine, colon, bladder, urethra, collecting ducts, uterus, vagina, fallopian tubes, ureters, kidneys, renal tubules, spinal canal, spinal cord, and other structures throughout the body, as well as structures within and including organs such as the lungs, heart, and kidneys, etc. In some embodiments, access to the target tissue is via a nearby luminal structure. In some cases, the energy delivery device is extended through various luminal structures or branches of the luminal system to reach the target tissue location. For example, when approaching the target tissue site via a blood vessel, the energy delivery device can be remotely inserted and extended through various branches of the vascular system to reach the target point. Similarly, if the lumen originates from a natural orifice, such as the nose, mouth, urethra, or rectum, access can be made through the natural orifice, and the energy delivery device can then be pushed through branches of the lumen system to reach the target tissue location. Alternatively, access to the lumen can be made near the target tissue by cutting or other methods. This may be the case when approaching a lumen that is not part of a larger system or that is difficult to access by other means.

[0241] It is understood that the systems and methods described herein can be used to treat various anatomical locations endovascularly. Examples include the luminal structures themselves, soft tissues throughout the body located near the luminal structures, and solid organs accessible from the luminal structures, including but not limited to the liver, pancreas, gallbladder, kidney, prostate, ovary, lymph nodes and lymphatic drainage vessels, deep muscle tissue, bone tissue, brain, eye, and thyroid gland. It is also understood that various tissue locations can be accessed percutaneously or through other methods.

[0242] The energy delivery device delivers energy supplied by a waveform generator according to at least one different energy delivery algorithm. It is understood that in some embodiments, the energy delivery device also delivers a drug. However, in other embodiments, the drug is delivered by a separate device, such as via IV, catheter, or needle injection. Optionally, the drug may be delivered by both the energy delivery device and a separate device. This document provides example embodiments of specialized energy delivery devices that primarily focus on unipolar energy delivery; however, it is understood that bipolar or multipolar arrangements may be used.

[0243] The above detailed description includes reference to the accompanying drawings, which form a part of the detailed description. The drawings illustrate, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are referred to herein as “examples.” These examples may include other elements besides those shown or described. However, the inventors also contemplate examples in which only those elements shown or described are provided. Furthermore, the inventors also contemplate examples using any combination or arrangement of those elements (or one or more aspects thereof) shown or described, either relative to a particular example (or one or more aspects thereof) or relative to other examples (or one or more aspects thereof) shown or described herein.

[0244] In the event of any inconsistency between the usage of this document and any other document thus incorporated by reference, the usage in this document shall prevail.

[0245] In this document, the terms “a” or “an”, as is common in patent documents, are used to include one or more, and are not related to any other instance or use of “at least one” or “one or more”. In this document, the term “or” is used to refer to a non-exclusive “or”, so unless otherwise stated, “A or B” includes “A but not B”, “B but not A”, and “A and B”. In this document, the terms “including” and “in which” are used as their plain English equivalents to the corresponding terms “comprising” and “wherein”. Furthermore, in the claims, the terms “including” and “comprising” are open-ended, meaning that a system, apparatus, article, composition, formulation, or process that includes elements other than those listed after such terms in the claims is still considered to fall within the scope of the claims. Additionally, in the claims, the terms “first,” “second,” and “third,” etc., are used merely as labels and are not intended to impose numerical requirements on their objects.

[0246] The above description is intended to be illustrative and 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 by those skilled in the art upon review of the above description. The abstract is provided in accordance with 37 CFR §1.72(b) to allow the reader to quickly determine the nature of the technical disclosure. It should be understood that it is not intended to interpret or limit the scope or meaning of the claims. Furthermore, in the above detailed description, various features may be combined together to simplify this disclosure. This should not be construed as making any unclaimed disclosed feature essential to any claim. Rather, the subject matter of the invention may lie in fewer than all features of a particular disclosed embodiment. Therefore, the claims are incorporated herein by way of example or embodiment, wherein each claim is an independent, separate embodiment, and these embodiments may be contemplated to be combined with each other in various combinations or arrangements. The scope of the invention should be determined with reference to the full scope of the claims together with the equivalents claimed by those claims.

Claims

1. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject is configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the energy has a waveform comprising a plurality of pulses, each pulse having a voltage of at least 1000V and each pulse being below a threshold for inducing arrhythmia.

2. The system according to claim 1, wherein, The plurality of pulses includes biphasic pulses.

3. The system according to any one of the preceding claims, wherein, The voltage is in the range of 1000V to 10000V.

4. The system according to any one of the preceding claims, wherein, The pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during at least a portion of the T wave of the cardiac cycle.

5. The system according to claim 4, wherein, The pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the middle and / or terminal phases of the T wave of the cardiac cycle.

6. The system according to any one of claims 1 to 3, wherein, The pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during atrial contraction of the cardiac cycle.

7. The system according to any one of claims 1 to 3, wherein, The pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the peak contraction of atrial or ventricular contraction in the cardiac cycle.

8. The system according to any one of the preceding claims, wherein, The plurality of pulses includes at least one pulse group.

9. The system according to claim 8, wherein, The at least one pulse group comprises at least six pulse groups, wherein each group comprises 40 biphasic pulses with an inter-pulse delay of 1000 microseconds.

10. The system according to any one of the preceding claims, wherein, Each pulse has a pulse duration of less than or equal to 10µs.

11. The system according to claim 10, wherein, Each pulse has a duration ranging from 0.5µs to 5µs.

12. The system according to claim 10, wherein, The pulses all have a voltage in the range of 1000V to 10000V.

13. The system according to claim 12, wherein, The pulses all have a voltage in the range of 1000V to 5000V.

14. The system according to any one of claims 1 to 9, wherein, The pulses all have a voltage in the range of 1000V to 3000V, and each pulse has a pulse duration in the range of less than or equal to 25µs.

15. The system according to any one of claims 1 to 9, wherein, The pulses all have a voltage in the range of 1000V to 1500V, and each pulse has a pulse duration in the range of less than or equal to 50µs.

16. The system according to any one of the preceding claims, wherein, The dose has a delivery time of at least the cardiac cycle.

17. The system according to any one of the preceding claims, wherein, The target tissue is located in the patient's lungs.

18. The system according to any one of claims 1 to 16, wherein, The target tissue includes tissues located within the patient's gastrointestinal, urinary, or reproductive systems.

19. The system according to any one of claims 1 to 16, wherein, The energy is delivered at a constant delivery rate, and the target tissue includes heart tissue. The system also includes a robotic device programmed to drag the energy delivery body along the heart tissue during energy delivery.

20. The system according to any one of claims 1 to 18, wherein, The target tissue includes a tumor, and the energy delivery body includes a probe.

21. The system according to any one of the preceding claims, wherein, The energy is delivered at a constant delivery rate.

22. The system according to any one of the preceding claims further includes a robotic device for manipulating the energy delivery body within the patient.

23. The system according to any one of the preceding claims, wherein, Energy delivery is synchronized with the patient's breathing, but not with the heart.

24. The system according to claim 23, wherein, The energy transport is activated when the lungs are not moving.

25. The system according to any one of claims 1 to 22, wherein, Energy delivery is not associated with synchronization to the cardiac cycle and is actuated by feedback control.

26. The system according to claim 25, wherein, The feedback control includes temperature monitoring, impedance monitoring, pH monitoring, contact detection, and / or contact force.

27. The system of claim 25, further comprising one or more sensors configured to detect a drug within the body, wherein, Energy delivery is actuated by feedback from one or more of the sensors.

28. The system according to claim 27, wherein, The agents include drugs, molecules, genes, and chemotherapeutic agents.

29. The system according to any one of claims 27 to 28, wherein, The energy delivery body includes at least one tip extending from the conduit, and the system further includes one or more impedance sensors configured to measure the impedance between one of the at least one tips and another of the at least one tips, or between one of the at least one tips and a portion of the conduit.

30. The system according to claim 29, wherein, The one or more impedance sensors include pH sensors, fiber optic sensors, or bipolar impedance sensors.

31. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject is configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the dose consists of a plurality of pulses, wherein at least one of the pulses is arranged within the dose so as to be received by the target tissue during the T wave of the cardiac cycle, and wherein the dose does not induce arrhythmia.

32. The system according to claim 31, wherein, The plurality of pulses includes biphasic pulses.

33. The system according to any one of claims 31 to 32, wherein, The voltage is in the range of 1000V to 10000V.

34. The system according to claim 31, wherein, The pulses are spaced apart such that at least one of the pulses is delivered to the target tissue during the middle and / or terminal phases of the T wave of the cardiac cycle.

35. The system according to any one of claims 31 to 34, wherein, The plurality of pulses includes at least one pulse group.

36. The system according to claim 35, wherein, The at least one pulse group comprises at least six pulse groups, wherein each group comprises 40 biphasic pulses with an inter-pulse delay of 1000 microseconds.

37. The system according to any one of claims 31 to 36, wherein, Each pulse has a pulse duration of less than or equal to 10µs.

38. The system according to claim 37, wherein, Each pulse has a duration ranging from 0.5µs to 5µs.

39. The system according to claim 37, wherein, The pulses all have a voltage in the range of 1000V to 10000V.

40. The system according to claim 39, wherein, The pulses all have a voltage in the range of 1000V to 5000V.

41. The system according to any one of claims 31 to 36, wherein, The pulses all have a voltage in the range of 1000V to 3000V, and each pulse has a pulse duration in the range of less than or equal to 25µs.

42. The system according to any one of claims 31 to 36, wherein, The pulses all have a voltage in the range of 1000V to 1500V, and each pulse has a pulse duration in the range of less than or equal to 50µs.

43. The system according to any one of claims 31 to 42, wherein, The dose has a delivery time of at least the cardiac cycle.

44. The system according to any one of claims 31 to 43, wherein, The target tissue is located in the patient's lungs.

45. The system according to any one of claims 31 to 43, wherein, The target tissue includes tissues located within the patient's gastrointestinal, urinary, or reproductive systems.

46. ​​The system according to any one of claims 31 to 45, wherein, The energy is delivered at a constant delivery rate, and the target tissue includes heart tissue. The system also includes a robotic device programmed to drag the energy delivery body along the heart tissue during energy delivery.

47. The system according to any one of claims 31 to 46, wherein, The target tissue includes a tumor, and the energy delivery body includes a probe.

48. The system according to any one of claims 31 to 47, wherein, The energy is delivered at a constant delivery rate.

49. The system according to any one of claims 31 to 48, further comprising a robotic device for manipulating the energy delivery body within the patient.

50. The system according to any one of claims 31 to 49, wherein, Energy delivery is synchronized with the patient's breathing, but not with the heart.

51. The system according to claim 50, wherein, The energy transport is activated when the lungs are not moving.

52. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject is configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the dose consists of a plurality of pulses, and wherein the dose has a delivery time of at least the cardiac cycle.

53. A system for delivering energy to target tissue within the trunk of a patient with a cardiac cycle, comprising: At least one energy delivery subject is configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of the energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, wherein the energy delivery is not associated with synchronization to the cardiac cycle and is actuated by feedback control.

54. A system for delivering energy to treat a target tissue in a patient's body, the target tissue being sufficiently close to the patient's heart to induce arrhythmia, the system comprising: At least one energy delivery subject is configured to deliver energy to the target tissue; and A generator electrically connected to at least one energy delivery electrode, wherein the generator includes an algorithm for delivering a dose of energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue in a manner that is not synchronized with the cardiac cycle of the heart and does not induce arrhythmias.

Images