Optimization of pulsed electric field energy delivery timing

Abstract

Devices, systems, and methods are provided for treating target tissue using pulsed electric field energy in a manner that does not induce cardiac arrhythmias such as cardiac fibrillation, and therefore eliminates any need for cardiac synchronization of energy delivery. Cardiac synchronization is typically employed to avoid delivering energy during portions of the cardiac cycle that are prone to inducing fibrillation. Accordingly, parameters are manipulated herein to reduce the probability of inducing arrhythmias. Typically, high voltage energy can induce early action potentials in the myocardium as the delivered energy increases myocardial cell membrane permeability, enabling ion transport, which can induce cardiac arrhythmias, particularly ventricular fibrillation. However, both shorter pulse durations (i.e., higher frequencies such as 100–600 kHz) and biphasic waveform shapes theoretically and practically reduce the probability of inducing arrhythmias.

Description

Technical Field

[0001] (Cross - reference to Related Applications) This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 491,025, filed on 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 Art

[0002] Pulsed electric field (PEF) therapy uses the short - time application of electrical energy to the body for the treatment of diseases and pain. In some cases, such delivery is to tissues that are within or accessible within a body lumen, passageway, or similar anatomical structure, or through such a passageway. Such devices typically include a flexible elongate shaft and an energy delivery element mounted thereon for delivering such energy to a remote or enclosed location such as a body lumen. Such devices have been developed, for example, to treat the passages of the lungs or the blood vessels of the vasculature, or to treat various organs such as the heart, stomach, intestine, etc. In other cases, the delivery is directed through an invasive surgery or through a percutaneous approach. Different diseases, such as those affecting different environments and surface tissues like the airway - to - blood - filled environment, versus those affecting deeper layers or tissues, lead to various purposes for these devices.

[0003] PEF energy disrupts the integrity of target tissue cells, initiating a series of biochemical processes that induce different forms of cell death, including necrosis, apoptosis, aponecrosis, necroptosis, and / or pyroptosis. Because PEF therapy is independent of thermal processes, cells die within their volume in vivo without altering interstitial proteins and extracellular matrix within the volume, thus promoting the preserved function of their important and sensitive anatomical structures, such as tubular systems including major blood vessels and common bile ducts, and tissue structures such as the pleura. Consequently, PEF therapy offers a superior safety profile compared to other localized resection modalities. As a result of their properties, PEF is being applied in a variety of different disease states with increasing regularity, including cancer, heart disease, and lung disease.

[0004] Variations exist among clinical PEF systems, including differences in waveform parameters and delivery polarity (i.e., bipolar or unipolar). In a bipolar electrode configuration, energy is delivered between effector devices placed within or adjacent to the targeting environment. Conversely, a unipolar system uses a single end-effector to deliver energy to the targeting location, with a remote distributed electrode acting as electrical feedback. The distributed electrode has sufficient surface area to distribute the PEF energy over a sufficiently wide area so that no therapeutic effect occurs at its remote location.

[0005] A key consideration regarding the clinical use of PEF energy is its potential to stimulate cardiac tissue and interfere with the normal cardiac cycle. This is especially true for unipolar delivery arrays, which penetrate deeper into the body than delivery using bipolar electrode arrays. In addition, several other variables, including the location, range, and timing of the stimulation, influence the potential for proarrhythmic activity of any given PEF therapy. Many PEF techniques reduce proarrhythmic activity by synchronizing PEF delivery with the cardiac refractory period (i.e., ST interval). However, such synchronization involves additional equipment such as an external cardiac monitor and a mechanism for obtaining an electrocardiogram (ECG). In some cases, the cardiac monitor is used to continuously obtain ECG signals via an external electrode positioned on the patient's chest. The PEF generator provides the ability to analyze one or more cardiac cycles and identify the beginning of periods during which it is safe to apply energy to the patient, and thus synchronize energy delivery with the cardiac cycle. In some embodiments, this period is within a few milliseconds of the R wave (of the ECG QRS complex) to avoid inducing arrhythmias that may occur when the energy pulse is delivered on the T wave. Such synchronization also complicates energy delivery in that energy delivery is limited to the period made possible by the synchronization.

[0006] Improved delivery of PEF energy is desired for reasons such as efficiency, simplicity, reduced cost, and improved patient outcomes, to name a few. At least some of these objectives will be satisfied by the systems, devices, and methods described herein. [Overview of the project] [Means for solving the problem]

[0007] The embodiments described herein are devices, systems, and methods for treating target tissues within the body. Similarly, the present invention relates to the following numbered appendices.

[0008] 1. A system for delivering energy to target tissues within the torso of a patient with a cardiac cycle, At least one energy delivery device configured to deliver energy to a target tissue, A generator electrically communicating with at least one energy delivery electrode, comprising an algorithm for delivering a dose of energy to at least one energy delivery electrode such that the dose is delivered to a target tissue, wherein the energy has a waveform comprising multiple pulses, each pulse having a voltage of at least 1,000V and each below a threshold for inducing arrhythmia, A system that includes these features.

[0009] 2. The system described in Appendix 1, wherein the multiple pulses consist of biphasic pulses.

[0010] 3. The voltage is within the range of 1,000 to 10,000V, as specified in any of the appendices above.

[0011] 4. The pulses are spaced apart so that at least one of the pulses is delivered to target tissue during at least a portion of the T wave of the cardiac cycle, as described in any of the appendices above.

[0012] 5. The pulses are spaced apart so that at least one of the pulses is delivered to target tissue during the intermediate and / or terminal phases of the T wave of the cardiac cycle, as described in Appendix 4.

[0013] 6. The pulses are spaced apart so that at least one of the pulses is delivered to a target tissue during atrial contraction of the cardiac cycle, as described in any of the Appendices 1-3.

[0014] 7. The pulses are spaced apart so that at least one of the pulses is delivered to the target tissue during the peak of maximal contraction of the atrial or ventricular systole of the cardiac cycle, as described in any of the Appendices 1-3.

[0015] 8. Multiple pulses are systems as described in any of the above appendices, comprising at least one packet of pulses.

[0016] 9. The system as described in Appendix 8, wherein at least one packet of pulses comprises at least six packets of pulses, each packet containing 40 biphasic pulses with an inter-pulse delay of 1,000 microseconds.

[0017] 10. A system as described in any of the above appendices, in which each pulse has a pulse duration of less than 10 microseconds or equal to 10 microseconds.

[0018] 11. The system as described in Appendix 10, wherein each pulse has a pulse duration in the range of 0.5 μs to 5 μs.

[0019] 12. The system described in Appendix 10, wherein each pulse has a voltage in the range of 1,000 to 10,000V.

[0020] 13. The system described in Appendix 12, wherein each pulse has a voltage in the range of 1,000 to 5,000V.

[0021] 14. A system as described in any of the appendices 1-9, wherein each pulse has a voltage in the range of 1,000 to 3,000 V, and each pulse has a pulse duration in the range of less than 25 μs or equal to 25 μs.

[0022] 15. A system as described in any of the appendices 1-9, wherein each pulse has a voltage in the range of 1,000 to 1,500 V, and each pulse has a pulse duration in the range of less than 50 μs or equal to 50 μs.

[0023] 16. The dose is administered by a system described in any of the above appendices, having a delivery time of at least one cardiac cycle.

[0024] 17. The target tissue is any of the systems described in the appendix above, located within the patient's lungs.

[0025] 18. The target tissue is the system according to any one of Appendices 1-16, including being present within the patient's gastrointestinal tract, urinary system, or genital system.

[0026] 19. The energy is delivered at a constant delivery rate, the target tissue includes cardiac tissue, and the system further comprises a robotic device programmed to pull the energy delivery body along the cardiac tissue during energy delivery. The system is according to any one of Appendices 1-16.

[0027] 20. The target tissue includes a tumor, and the energy delivery body comprises a probe. The system is according to any one of Appendices 1-18.

[0028] 21. The energy is delivered at a constant delivery rate. The system is according to any one of the above Appendices.

[0029] 22. The system further comprises a robotic device for operating the energy delivery body within the patient. The system is according to any one of the above Appendices.

[0030] 23. The energy delivery is synchronized with the patient's respiration without cardiac synchronization. The system is according to any one of the above Appendices.

[0031] 24. The energy delivery is actuated when the lungs are not in motion. The system is according to the system described in Appendix 23.

[0032] 25. The energy delivery is decoupled from synchronization with the cardiac cycle and is actuated by feedback control. The system is according to any one of Appendices 1-22.

[0033] 26. The feedback control comprises temperature monitoring, impedance monitoring, pH monitoring, contact detection, and / or contact force. The system is according to the system described in Appendix 25.

[0034] 27. The system according to Appendix 25, further comprising one or more sensors configured to detect active substances within the body, wherein energy delivery is actuated by feedback from one or more sensors.

[0035] 28. The active substance is a system as described in Appendix 27, comprising a drug, molecule, gene, or chemotherapeutic agent.

[0036] 29. The system according to any one of the appendices 27-28, wherein the energy delivery body comprises at least one tine extending from the catheter, and the system further comprises one or more impedance sensors configured to measure the impedance between one of the at least one tine and another of the at least one tine or a portion of the catheter.

[0037] 30. The system according to Appendix 29, comprising one or more impedance sensors, a pH sensor, an optical fiber sensor, or a bipolar impedance sensor.

[0038] 31. A system for delivering energy to target tissues within the torso of a patient with a cardiac cycle, At least one energy delivery device configured to deliver energy to a target tissue, A generator electrically communicating with at least one energy delivery electrode, comprising an algorithm for delivering a dose of energy to at least one energy delivery electrode such that the dose is delivered to a target tissue, wherein the dose consists of a plurality of pulses, at least one of which is arranged within the dose so as to be received by the target tissue during the T wave of the cardiac cycle, and the dose does not induce arrhythmias, and the generator and A system that includes these features.

[0039] 32. The system described in Appendix 31, wherein the multiple pulses comprise two-phase pulses.

[0040] 33. The voltage is within the range of 1,000 to 10,000V, as specified in either of the appendices 31-32.

[0041] 34. The system as described in Appendix 31, wherein the pulses are spaced apart so that at least one of the pulses is delivered to target tissue during the intermediate and / or terminal phases of the T wave of the cardiac cycle.

[0042] 35. Multiple pulses are systems as described in any of the appendices 31-34, comprising at least one packet of pulses.

[0043] 36. The system as described in Appendix 35, wherein at least one packet of pulses comprises at least six packets of pulses, each packet containing 40 biphasic pulses with an inter-pulse delay of 1,000 microseconds.

[0044] 37. A system as described in any of the appendices 31-36, wherein each pulse has a pulse duration of less than 10 microseconds or equal to 10 microseconds.

[0045] 38. The system as described in Appendix 37, wherein each pulse has a pulse duration in the range of 0.5 μs to 5 μs.

[0046] 39. The system described in Appendix 37, wherein each pulse has a voltage in the range of 1,000 to 10,000V.

[0047] 40. The system described in Appendix 39, wherein each pulse has a voltage in the range of 1,000 to 5,000V.

[0048] 41. A system as described in any of the appendices 31-36, wherein each pulse has a voltage in the range of 1,000 to 3,000 V, and each pulse has a pulse duration in the range of less than 25 μs or equal to 25 μs.

[0049] 42. A system as described in any of the appendices 31-36, wherein each pulse has a voltage in the range of 1,000 to 1,500 V, and each pulse has a pulse duration in the range of less than 50 μs or equal to 50 μs.

[0050] 43. The dosage is administered by a system described in any of the appendices 31-42, having a delivery time of at least one cardiac cycle.

[0051] 44. The target tissue is a system located in the patient's lungs, as described in any of the appendices 31-43.

[0052] 45. The target tissue is one of the systems described in any of Appendix 31-43, including being located within the patient's gastrointestinal tract, urinary tract, or reproductive tract.

[0053] 46. ​​The system according to any of the appendices 31-45, wherein energy is delivered at a constant delivery rate, the target tissue includes cardiac tissue, and the system further comprises a robotic device programmed to pull an energy delivery body along the cardiac tissue during energy delivery.

[0054] 47. The target tissue includes a tumor, and the energy delivery body comprises a probe, as described in any of the appendices 31-46.

[0055] 48. A system described in any of the appendices 31-47, in which energy is delivered at a constant delivery rate.

[0056] 49. The system according to any of the appendices 31-48, further comprising a robotic device for manipulating an energy delivery body within a patient.

[0057] 50. Energy delivery is synchronized with the patient's respiration, without cardiac synchronization, as described in any of the appendices 31-49.

[0058] 51. Energy delivery is performed by the system described in Appendix 50, which is activated when the lungs are not exercising.

[0059] 52. A system for delivering energy to target tissue within the torso of a patient with a cardiac cycle, At least one energy delivery device configured to deliver energy to a target tissue, A generator electrically communicating with at least one energy delivery electrode, comprising an algorithm for delivering a dose of energy to at least one energy delivery electrode such that the dose is delivered to a target tissue, wherein the dose consists of a plurality of pulses and the dose has a delivery time of at least one cardiac cycle. A system that includes these features.

[0060] 53. Multiple pulses, comprising at least one packet of pulses, as described in Appendix 52.

[0061] 54. The system as described in Appendix 53, wherein at least one packet of pulses comprises at least six packets of pulses, each packet containing 40 biphasic pulses with an inter-pulse delay of 1,000 microseconds.

[0062] 55. A system as described in any of the appendices 52-54, wherein each pulse has a pulse duration of less than 10 microseconds or equal to 10 microseconds.

[0063] 56. The system as described in Appendix 55, wherein each pulse has a pulse duration in the range of 0.5 μs to 5 μs.

[0064] 57. The system described in Appendix 55, wherein each pulse has a voltage in the range of 1,000 to 10,000V.

[0065] 58. The system described in Appendix 57, wherein each pulse has a voltage in the range of 1,000 to 5,000V.

[0066] 59. A system as described in any of the appendices 52-58, wherein each pulse has a voltage in the range of 1,000 to 3,000 V, and each pulse has a pulse duration in the range of less than 25 μs or equal to 25 μs.

[0067] 60. A system as described in any of the appendices 52-58, wherein each pulse has a voltage in the range of 1,000 to 1,500 V, and each pulse has a pulse duration in the range of less than 50 μs or equal to 50 μs.

[0068] 61. The dosage is provided by any of the systems described in Appendix 52-60, having a delivery time of at least one cardiac cycle.

[0069] 62. The target tissue is a system located in the patient's lungs, as described in any of the appendices 52-61.

[0070] 63. The target tissue is one of the systems described in any of Appendix 52-61, including being located within the patient's gastrointestinal tract, urinary tract, or reproductive tract.

[0071] 64. The system according to any of the appendices 52-61, wherein energy is delivered at a constant delivery rate, the target tissue includes cardiac tissue, and the system further comprises a robotic device programmed to pull an energy delivery body along the cardiac tissue during energy delivery.

[0072] 65. The target tissue includes a tumor, and the energy delivery body comprises a probe, as described in any of the appendices 52-63.

[0073] 66. A system described in any of the appendices 52-65, in which energy is delivered at a constant delivery rate.

[0074] 67. A system according to any of the appendices 52-66, further comprising a robotic device for manipulating an energy delivery body within a patient.

[0075] 68. A system for delivering energy to target tissue within the torso of a patient with a cardiac cycle, At least one energy delivery device configured to deliver energy to a target tissue, A generator electrically communicating with at least one energy delivery electrode, comprising an algorithm for delivering a dose of energy to at least one energy delivery electrode so that the dose is delivered to target tissue, wherein the energy delivery is decoupled from synchronization to the cardiac cycle and is operated by feedback control, A system that includes these features.

[0076] 69. The feedback control system, as described in Appendix 68, includes temperature monitoring, impedance monitoring, pH monitoring, contact detection, and / or contact force.

[0077] 70. The system as described in Appendix 68, further comprising one or more sensors configured to detect active substances within the body, wherein energy delivery is actuated by feedback from one or more sensors.

[0078] 71. The system described in Appendix 70, wherein the active substance comprises a drug, molecule, gene, or chemotherapeutic agent.

[0079] 72. The system according to any one of the appendices 70-71, wherein the energy delivery body comprises at least one tine extending from the catheter, and the system further comprises one or more impedance sensors configured to measure the impedance between one of the at least one tine and another of the at least one tine or a portion of the catheter.

[0080] 73. The system according to Appendix 72, comprising one or more impedance sensors, a pH sensor, an optical fiber sensor, or a bipolar impedance sensor.

[0081] 74. A system for delivering energy to treat target tissue within a patient that is sufficiently close to the patient's heart to cause arrhythmia, At least one energy delivery device configured to deliver energy to a target tissue, A generator that electrically communicates with at least one energy delivery electrode, and includes an algorithm for delivering a dose of energy to at least one energy delivery electrode in a manner that is not synchronized with the cardiac cycle and does not induce arrhythmias, such that the dose is delivered to target tissue. A system that includes these features.

[0082] 75. Multiple pulses comprising biphasic pulses, as described in Appendix 74.

[0083] 76. The voltage is within the range of 1,000 to 10,000V, as specified in any of the appendices 74-75.

[0084] 77. A system according to any one of the appendices 74-76, wherein the pulses are spaced apart so that at least one of the pulses is delivered to target tissue during at least a portion of the T wave of the cardiac cycle.

[0085] 78. The system as described in Appendix 77, wherein the pulses are spaced apart so that at least one of the pulses is delivered to target tissue during the intermediate and / or terminal phases of the T wave of the cardiac cycle.

[0086] 79. A system according to any one of the appendices 74-76, wherein the pulses are spaced apart so that at least one of the pulses is delivered to a target tissue during atrial contraction of the cardiac cycle.

[0087] 80. A system according to any one of the appendices 74-76, wherein the pulses are spaced apart so that at least one of the pulses is delivered to target tissue during the peak of maximal contraction of the atrial or ventricular systole of the cardiac cycle.

[0088] 81. Multiple pulses are systems as described in any of the appendices 74-80, comprising at least one packet of pulses.

[0089] 82. The system as described in Appendix 81, wherein at least one packet of pulses comprises at least six packets of pulses, each packet containing 40 biphasic pulses with an inter-pulse delay of 1,000 microseconds.

[0090] 83. A system as described in any of the appendices 74-82, in which each pulse has a pulse duration of less than 10 microseconds or equal to 10 microseconds.

[0091] 84. The system as described in Appendix 83, wherein each pulse has a pulse duration in the range of 0.5 μs to 5 μs.

[0092] 85. The system described in Appendix 83, wherein each pulse has a voltage in the range of 1,000 to 10,000V.

[0093] 86. The system described in Appendix 85, wherein each pulse has a voltage in the range of 1,000 to 5,000V.

[0094] 87. A system as described in any of the appendices 74-82, wherein each pulse has a voltage in the range of 1,000 to 3,000 V, and each pulse has a pulse duration in the range of less than 25 μs or equal to 25 μs.

[0095] 88. A system as described in any of the appendices 74-82, wherein each pulse has a voltage in the range of 1,000 to 1,500 V, and each pulse has a pulse duration in the range of less than 50 μs or equal to 50 μs.

[0096] 89. The dosage is provided by any of the systems described in Appendix 74-88, having a delivery time of at least one cardiac cycle.

[0097] 90. The target tissue is a system located in the patient's lungs, as described in any of the appendices 74-89.

[0098] 91. The target tissue is one of the systems described in any of Appendix 74-89, including being located within the patient's gastrointestinal tract, urinary tract, or reproductive tract.

[0099] 92. The system according to any of the appendices 74-89, wherein energy is delivered at a constant delivery rate, the target tissue includes cardiac tissue, and the system further comprises a robotic device programmed to pull an energy delivery body along the cardiac tissue during energy delivery.

[0100] 93. The target tissue includes a tumor, and the energy delivery body comprises a probe, as described in any of the appendices 74-91.

[0101] 94. Energy is delivered at a constant delivery rate in any of the systems described in Appendix 74-93.

[0102] 95. A system according to any of the appendices 74-94, further comprising a robotic device for manipulating an energy delivery device within a patient.

[0103] 96. Energy delivery systems as described in any of Appendix 74-95, which are synchronized with the patient's respiration without cardiac synchronization.

[0104] 97. Energy delivery is performed by the system described in Appendix 96, which is activated when the lungs are not exercising.

[0105] 98. Energy delivery is operated by feedback control in any of the systems described in Appendix 74-95.

[0106] 99. Feedback control is a system as described in Appendix 98, comprising temperature monitoring, impedance monitoring, pH monitoring, contact detection, and / or contact force.

[0107] 100. The system as described in Appendix 98, further comprising one or more sensors configured to detect active substances within the body, wherein energy delivery is actuated by feedback from one or more sensors.

[0108] 101. The active substance is a system as described in Appendix 100, comprising a drug, molecule, gene, or chemotherapeutic agent.

[0109] 102. The system according to any of Appendix 100-101, wherein the energy delivery body comprises at least one tine extending from the catheter, and the system further comprises one or more impedance sensors configured to measure the impedance between one of the at least one tine and another of the at least one tine or a portion of the catheter.

[0110] 103. The system according to Appendix 102, comprising one or more impedance sensors, a pH sensor, an optical fiber sensor, or a bipolar impedance sensor.

[0111] These and other embodiments will be described in further detail in the following description relating to the figures in the attached drawings. (Integrated by reference)

[0112] All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is incorporated by specific and individual reference. [Brief explanation of the drawing]

[0113] In drawings that are not necessarily drawn to scale, the same numbering may describe similar components in different drawings. The same numbering with different subscripts may represent different instances of similar components. Generally, the drawings illustrate various embodiments discussed herein as examples, not as limitations.

[0114] [Figure 1] Figure 1 illustrates an embodiment of the organizational restructuring system.

[0115] [Figure 2] Figures 2A-2B illustrate another embodiment of the organizational restructuring system.

[0116] [Figure 3] Figure 3 illustrates an embodiment of the signal waveform defined by the energy delivery algorithm.

[0117] [Figure 4] Figure 4 provides a table illustrating various exemplary effects of parameter changes.

[0118] [Figure 5] Figure 5A illustrates the simulated structural conductivity as a function of electric field exposure. Figure 5B illustrates the simulated current and impedance as a function of the simulated applied voltage over a range of 500 to 5,000 V.

[0119] [Figure 6] Figures 6A-6C illustrate A) the baseline data, B) the power-law curve fitting for the "stimulation (coil)" curve from (A), and C) the power-law curve fitting for the "evoked" curve from (A). Note: "Stimulation (coil)" was used for stimulation because it reflects the same electrode relationship used to generate the "evoked" data.

[0120] [Figure 7] Figure 7 illustrates an embodiment of a unipolar system used in the evaluation of specialized PEF energy.

[0121] [Figure 8]Figures 8A-8D illustrate representative results of the numerical simulation, namely (Figure 8A) the geometric shape of the numerical simulation and (Figures 8B-8D) cross-sectional views of the conductivity, electric field, and voltage distribution within the simulated lung parenchyma tissue. The grid size is 5 mm.

[0122] [Figure 9] Figures 9A-9B illustrate the sensitivity of the PEF cardiac effect related to basic treatment.

[0123] [Figure 10] Figures 10A-10D illustrate fluorescence fluoroscopy images of a basket unfolded from a pig's chest, accompanied by CT images.

[0124] [Figure 11] Figures 11A–11D illustrate examples of cardiac effects from asynchronous PEF delivery, namely, cases where no changes may occur (Figure 11A), immediate cardiac ECG artifact changes due to signal interference (Figure 11B), PAC without ventricular conduction that temporarily delays subsequent heartbeats (Figure 11C), or PAC that conducts to the ventricles resulting in premature heartbeats (Figure 11D). [Modes for carrying out the invention]

[0125] Detailed explanation Devices, systems, and methods for treating body tissues using pulsed electric field (PEF) energy are provided. PEF energy is typically characterized as high-voltage pulsed energy configured to be delivered in one or more doses. Each energy dose delivered to the target tissue is configured to maintain a temperature in or within the target tissue below a threshold for thermal ablation. Instead of inducing thermal damage from thermal ablation, which is described as extracellular protein coagulation, the effect is considered non-thermal, and such energy corrects or destroys cells within the tissue but preserves the underlying extracellular protein matrix of the tissue, which provides the tissue's interstitial architectural structure and structure-related functions. In some cases, this allows for tissue regeneration, such as by regrowth of the extracellular matrix. In addition, nearby sensitive tissues are spared from damage. It should be understood that the dose may be gradually increased or decreased over time to further reduce or eliminate heat buildup during the treatment procedure. It should be understood that in some embodiments, energy delivery is actuated by various mechanisms, such as the use of a foot switch operationally connected to an actuator or generator on the device. Such actions typically provide a single energy dose or activation.

[0126] Target tissue cells include, to name a few, cells of the gastrointestinal tract or digestive system (e.g., mouth, 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 and larynx, trachea, bronchi, lungs, etc.), cells of the urinary system (e.g., kidneys, ureters, bladder, urethra, etc.), cells of the reproductive system (e.g., genitals, ovaries, fallopian tubes, uterus, cervix, vagina, testes, epididymis, vas deferens, seminal vesicles, prostate, glands, penis, scrotum, etc.), and cells of the endocrine system (e.g., pituitary gland). Treatment may be administered at any location throughout the body, including cells of the pineal gland, thyroid gland, parathyroid gland, and adrenal gland; cells of the circulatory system (e.g., heart, arteries, veins, etc.); cells of the lymphatic system (e.g., lymph nodes, bone marrow, thymus, spleen, etc.); cells of the nervous system (e.g., brain, spinal cord, nerves, ganglia, etc.); cells of the eye (e.g., retina, macula, cone layers, retinal pigment epithelium, optic nerve, choroid, sclera, etc.); cells of the muscular system (e.g., muscle cells, etc.); and cells of the skin (e.g., epidermis, dermis, subcutaneous tissue, etc.).

[0127] The conditions treated include arrhythmias, particularly atrial fibrillation. When treating atrial fibrillation, a lesion ring, such as around the lateral ostium of the pulmonary veins, is typically generated by the delivery of PEF energy using either a focused catheter or a one-shot catheter. In addition, focused catheters can be used to generate lines along many other types of lesions, particularly various surfaces of cardiac tissue. In one embodiment, an inferior vena cava-annulus tricuspid isthmus line is generated for the treatment of typical atrial flutter in the right atrium. In another embodiment, a roof line and / or base line is generated for a box lesion along the posterior wall of the left atrium, particularly for patients with atrial fibrillation, with respect to persistent atrial fibrillation. In yet another embodiment, a mitral isthmus line is generated along the anterior or lateral wall of the left atrium for atypical atrial flutter. In yet another embodiment, a ventricular line is generated, typically in patients with ventricular tachycardia resulting from ischemic heart disease, connecting two non-excitatory boundaries that are important for the initiation or maintenance of reentrant ventricular arrhythmias.

[0128] Other medical conditions treated include, to name a few, lung disorders such as chronic obstructive pulmonary disease, chronic bronchitis, hypermucositis, asthma, and cystic fibrosis.

[0129] Other conditions may include coagulation disorders such as hemophilia (e.g., hemophilia A or hemophilia B), von Willebrand disease, factor XI deficiency, fibrinogen disorder, or vitamin K deficiency. Coagulation disorders may be characterized by mutations in genes encoding fibrinogen, prothrombin, factor V, factor VII, factor VIII, factor X, factor XI, factor XIII, or enzymes involved in their post-translational modification, 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.

[0130] In some embodiments, the disorder comprises a neurological disorder, such as a neurodegenerative disease. In some embodiments, the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, or multiple sclerosis. In some embodiments, the neurodegenerative disease comprises autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis, encephalomyelitis, paraneoplastic syndromes, autoimmune inner ear diseases, or opsoclonus myoclonus syndrome. The neurological disorder may be a stroke, spinal cord injury, central nervous system disorder, neuropsychiatric disorder, or channel disease (e.g., epilepsy or migraine). The neurological disorder may be an anxiety disorder, mood disorder, childhood disorder, cognitive impairment, schizophrenia, substance-related disorder, or eating disorder. In some embodiments, the neurological disorder is a symptom of a stroke, cerebral infarction, traumatic brain injury, or spinal cord injury.

[0131] In some embodiments, the disorder comprises lysosomal storage disorders such as Tay-Sachs disease, Gaucher disease, Fabry disease, Pompe disease, Niemann-Pick disease, or mucopolysaccharidosis (MPS).

[0132] In some embodiments, the disorder comprises cardiovascular disorders such as degenerative heart disease, coronary artery disease, ischemia, angina pectoris, acute coronary syndrome, peripheral vascular disease, cerebrovascular disease, or atherosclerosis. The cardiovascular disorder may be a degenerative heart disease selected from the group consisting of ischemic cardiomyopathy, conduction disorders, and congenital defects.

[0133] In some embodiments, the disorder comprises an immune disorder, such as an autoimmune disorder. An autoimmune disorder may be type 1 diabetes, multiple sclerosis, rheumatoid arthritis, lupus, encephalomyelitis, paraneoplastic syndrome, autoimmune inner ear disease, or opsoclonus 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.

[0134] In some embodiments, the disorder comprises liver diseases such as hepatitis, Alagille syndrome, biliary atresia, liver cancer, cirrhosis, cystic disease, Calori syndrome, congenital hepatic fibrosis, fatty liver, galactosemia, primary sclerosing cholangitis, tyrosinemia, glycogen storage disease, Wilson's disease, or endocrine deficiency. The liver disease may be liver cancer such as hepatocellular hyperplasia, hepatocellular adenoma, focal nodular hyperplasia, or hepatocellular carcinoma.

[0135] In some embodiments, the disorder comprises tumors or cancers such as blood cancers (e.g., acute lymphoblastic leukemia, acute myeloblastic leukemia, chronic myeloid leukemia, Hodgkin's disease, multiple myeloma, and non-Hodgkin lymphoma) or solid tissue cancers (e.g., to name a few, 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).

[0136] In some embodiments, the disorder comprises a recessive genetic disorder. In some embodiments, the disorder is a Mendelian genetic disorder.

[0137] In some embodiments, the disorder comprises an ocular disorder such as retinal dystrophy (e.g., Mendelian retinal dystrophy). Retinal dystrophy may consist of Leber congenital amaurosis (LCA), Stargardt disease, pseudoxanthoma elasticum, rod-cone dystrophy, exudative vitreoretinopathy, Joubert syndrome, CSNB-1C, age-related macular degeneration, retinitis pigmentosa, Stickler syndrome, microcephaly and chorioretinopathy, retinitis pigmentosa, CSNB-2, Usher syndrome, or Wagner syndrome.

[0138] Figure 1 illustrates an exemplary tissue modification system 100 used to deliver PEF energy to target tissue within the heart. In this embodiment, the tissue modification system 100 includes a specialized catheter 102, a high-voltage waveform generator 104, and at least one distinctly 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 / read unit 156 (memory and / or database, etc.), and an energy storage subsystem 158 that generates and stores the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery, however, any other suitable energy storage element may be used. In addition, one or more communication ports are included. In this embodiment, the therapeutic catheter 102 is designed to be unipolar, and the distal end of the catheter 102 has at least one energy delivery device (e.g., an electrode), and the return electrode 106 is positioned on the skin outside the body, typically on the thigh, lower back, or on the back. In this embodiment, the heart H is accessed via the right femoral vein FV by a preferred access technique such as the Seldinger method. Typically, an introducer sheath 112, acting as a conduit, is inserted into the femoral vein FV, through which various catheters and / or tools, including the therapeutic catheter 102, can be advanced. The distal end of the catheter 102 is advanced into the left atrium, through the inferior vena cava, through the right atrium, through the transseptal puncture site, to access an entrance to the pulmonary vein. In this embodiment, the catheter 102 is used to perform cardiac mapping, which refers to the process of identifying the temporal and spatial distribution of myocardial potentials during a particular cardiac rhythm. Cardiac mapping during abnormal cardiac rhythms aims to elucidate the mechanisms of cardiac rhythms, explain the propagation of activation from its initiation to completion within the region of interest, and identify key sites of emergence or conduction to serve as targets for treatment. Once the desired treatment site is identified, catheter 102 is utilized to deliver therapeutic energy.

[0139] Additional exemplary embodiments of an energy delivery catheter 102 configured to deliver focused therapy to various parts of the body are provided in International Patent Application PCT / US2018 / 067504, titled “OPTIMIZATION OF ENERGY DELIVERY FOR VARIOUS APPLICATIONS,” claiming 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 any purpose). In other embodiments, in some embodiments, the energy delivery catheter 102 may have various end effectors, such as Provisional Patent Application No. 63 / 159,331, filed on March 10, 2021, entitled “DEVICES FOR THE DELIVERY OF PULSED ELECTRIC FIELDS IN THE TREATMENT OF CARDIAC TISSUE” (all of which are incorporated herein by reference for all purposes). Similarly, therapeutic energy may be delivered using various catheter designs, including, at the discretion of the use of various accessories, as provided for Provisional Patent Application No. 62 / 949,633, filed on 18 December 2019, Provisional Patent Application No. 63 / 000,275, filed on 26 March 2020, and International Patent Application No. PCT / US2020 / 066205, filed on 18 December 2020, titled "TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRIC FIELDS" (all of which are incorporated by reference for any purpose), claiming priority to Provisional Patent Application No. 63 / 083,644, filed on 25 September 2020.

[0140] Figures 2A-2B illustrate another embodiment of the tissue repair system 100, which includes an energy delivery catheter 102 connectable to a generator 104. As shown, the catheter 102 comprises a shaft 106 having a distal end 103, a proximal end 107, and at least one lumen 105 extending at least partially through it. Similarly, the catheter 102 also includes at least one energy delivery body 108. In this embodiment, the energy delivery body 108 has the form of a probe 700 positioned within the lumen 105 of the shaft 106. The probe 700 has a probe tip 702 that is advancing through the lumen 105 and extending from the distal end 103 of the shaft 106 (enlarged in detail in Figure 2A). In this embodiment, the tip 702 has a pointed shape configured to penetrate tissue, such as being needle-like. Therefore, in this embodiment, the probe tip 702 is used to penetrate the lumen wall W and surrounding tissue so that it can be inserted into target tissue outside the body lumen. Thus, the probe 700 has sufficient flexibility to be delivered 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 advanced to ensure the desired placement.

[0141] In some embodiments, the probe extends 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 from the distal end 103 of the shaft 106. In some embodiments, the probe extends 1–3 cm or 2–3 cm from the distal end of the shaft 106. 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 made of a conductive material so as to serve as an electrode. Thus, the electrode will have the size of the exposed probe. Exemplary materials include stainless steel, nitinol, cobalt-chromium alloy, copper, and gold. In some embodiments, the conductive material of the exposed probe is coated with different materials, and examples include platinum-iridium, gold, platinum black, palladium, or other materials. Conductive materials or conductive material coatings may be designed, among other purposes, to reduce biological interactions of tissue, reduce the occurrence of electrochemical effects from PEF treatment, or distribute PEF energy more efficiently within the tissue. The material may be smooth, electropolished, sandblasted with various sands, or treated with other mechanical or chemical preparations to modify surface roughness, which may be done, among other purposes, to reduce biological interactions of tissue, facilitate easier deployment and withdrawal of electrodes, reduce the occurrence of electrochemical effects from PEF treatment, or distribute PEF energy more efficiently within the tissue. Thus, in these embodiments, PEF energy is transmittable through the probe 700 to the probe tip 702. Consequently, the shaft 106 is made of an insulating material or covered by an insulating sheath. Exemplary insulating materials include polyimide, silicone, polytetrafluoroethylene, and polyether block amide. The insulating material may be consistent or varied along the length of the shaft 106 or sheath. Similarly, in either case, the insulating material typically provides complete electrical insulation.However, in some embodiments, the insulating material allows a certain amount of leakage current to pass through.

[0142] When the probe 700 is energized, the insulating shaft 106 protects the surrounding tissue from therapeutic energy and directs the energy to the probe tip 702 (and any exposed portion of the probe 700), which allows the therapeutic energy to be delivered to the surrounding tissue. Thus, the tip 702 acts as a delivery electrode, and its size can be selected based on the amount of exposed probe 700. 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. In some embodiments, the exposed tip 702 during energy delivery (measured from its distal end to the distal edge of the insulating shaft) has lengths of 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, 0.2–0.3 cm, 0.1–0.5 cm, 0.1–1 cm, and all and partial ranges in between. In addition to changing the size of the electrode, the tip 702 is retractable into the shaft 106 to enable non-traumatic endoscopic delivery and then, if desired, can be advanced to reach target tissue. In this embodiment, forward and backward movement is controlled by an actuator 732 (e.g., a knob, button, lever, slide, or other mechanism) on a handle 110 attached to the proximal end 107 of the shaft 106. It should be understood that the shaft 106 itself may be advanced toward the target tissue with or without advancing the probe from the distal end 103 of the shaft 106. In some embodiments, the distal end of the shaft 106 is advanced up to 20 cm into the tissue, such as from the external surface of a tubular structure or from the external surface of the patient's body.

[0143] The handle 110 is connected to the generator 104 by the use of a specialized energy plug 510. The energy plug 510 has a first end 512 that connects to the handle 110 and a second end 514 that connects to the generator 104. The connection between the first end 512 and the handle 110 is enlarged for detail in Figure 2B. In this embodiment, the first end 712 has an adapter 716 which includes a connecting wire 718 extending therefrom. The connecting wire 718 is insertable into the proximal end of the probe 700 in the handle 110. This allows energy to be transferred from the generator 104 to the probe 700 through the connecting wire 718. Thus, the probe 700 can be charged throughout its entire length, however, only the exposed tip 702 delivers energy to the tissue due to the presence of the insulating shaft 106.

[0144] In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / read unit 156 (memory and / or database, etc.), and an energy storage subsystem 158 that generates and stores the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery; however, any other suitable energy storage element may be used. In addition, one or more communication ports are included.

[0145] In some embodiments, the generator 104 includes three subsystems: 1) a high-energy storage system, 2) a high-voltage medium-frequency switching amplifier, and 3) a system controller, firmware, and a user interface. In some embodiments, the system controller includes a synchronous trigger monitor that enables the pulsed energy output to be synchronized to a desired trigger. The generator draws on an alternating current (AC) mains power supply to power multiple direct current (DC) power sources. The generator's controller can cause the DC power sources 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 produce a high-voltage medium-frequency output.

[0146] It should be understood that numerous generator electrical architectures can be employed to implement energy delivery algorithms. In particular, in some embodiments, advanced switching systems are used that allow pulsed electric field circuits to be directed to energy delivery electrodes, separate from the same energy storage and high-voltage delivery system. Furthermore, generators employed in advanced energy delivery algorithms employing rapidly fluctuating pulse parameters (e.g., voltage, frequency, etc.) or multiple energy delivery electrodes can utilize modular energy storage and / or high-voltage systems to facilitate highly customizable waveform and geographic pulse delivery paradigms. It should be further understood that the electrical architectures described herein are merely examples, and that the system delivering the pulsed electric field may or may not include additional switching amplifier components.

[0147] The user interface 150 may include a touchscreen and / or more conventional buttons to enable the operator to input patient data, select a treatment algorithm (e.g., energy delivery algorithm 152), initiate energy delivery, view records stored on the memory / read unit 156, and / or otherwise communicate with the generator 104. The user interface 150 may include a voice activation mechanism for inputting patient data, or may be able to communicate with additional devices in the suite, such that control of the generator 104 is through a secondary, separate user interface.

[0148] In some embodiments, the user interface 150 is configured to receive operator-defined inputs. Operator-defined inputs may include the duration of energy delivery, energy delivery pulses, power, and / or one or more other timing aspects of the operating mode, or a combination thereof. Exemplary operating modes may include (but are not limited to) system startup and self-testing, operator input, algorithm selection, pre-treatment system status and feedback, energy delivery, post-energy delivery display or feedback, treatment data review and / or download, software updates, or any combination or secondary combination thereof.

[0149] In some embodiments, the processor 154 modifies and / or switches between energy delivery algorithms, among other activities, monitors energy delivery and any sensor data, and responds to the monitored data via a feedback loop. In some embodiments, the processor 154 is configured to execute one or more algorithms for initiating a feedback control loop based on one or more measured system parameters (e.g., current), one or more measured tissue parameters (e.g., impedance), and / or a combination thereof.

[0150] The data storage / reading unit 156 stores data related to the treatment being delivered, etc., and can optionally be downloaded by connecting a device (e.g., a laptop or thumb drive) to the communication port. In some embodiments, the device has local software used to instruct the download of information such as instructions stored on the data storage / reading unit 156 and executable by the processor 154. In some embodiments, the user interface 150 allows the operator to choose to download data to devices and / or systems such as, but not limited to, computer devices, tablets, mobile devices, servers, workstations, cloud computing devices / systems, and / or equivalents. The communication port, which may enable wired and / or wireless connectivity, enables data downloads as described herein, but may also enable data uploads such as uploading custom algorithms or providing software updates.

[0151] The data storage / read unit 156 may be, for example, random access memory (RAM), a memory buffer, a hard drive, a database, erasable programmable read-only memory (EPROM), electrically erasable read-only memory (EEPROM), read-only memory (ROM), flash memory, and / or others. The data storage / read unit 156 can store instructions for the processor 154 to execute modules, processes, and / or functions associated with the system 100.

[0152] In some embodiments, the data storage / reading unit 156 includes a computer storage product with a non-transient computer-readable medium (which may also be called a non-transient processor-readable medium) having instructions or computer code in order to perform various computer implementation operations. The computer-readable medium (or processor-readable medium) is non-transient in the sense that it does not contain transient propagation signals themselves (e.g., propagation electromagnetic waves that carry information on a transmission medium such as space or a cable). The medium and computer code (which may also be called code) may be designed and constructed for a specific purpose or for multiple purposes. Examples of non-transient 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 compact disks / digital video discs (CDs / DVDs), compact disk read-only memory (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; and hardware devices specifically configured to store and execute program code, such as carrier signal processing modules, and ASICs, programmable logic devices (PLDs), read-only memory (ROMs), and random access memory (RAM) devices. Other embodiments described herein relate to computer program products, which may include instructions and / or computer code discussed herein.

[0153] Examples of computer code include, but are not limited to, microcode or microinstructions, machine instructions generated by compilers, etc., code used to generate web services, and files containing higher-level instructions executed by a computer using an interpreter. For example, embodiments can be implemented using imperative programming languages ​​(e.g., C, Fortran, etc.), functional programming languages ​​(e.g., 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. Additional examples of computer code include, but are not limited to, control signals, encryption code, and compression code.

[0154] In some embodiments, system 100 can be communicably coupled to a network, which may be any type of network, such as a wired network and / or a wireless network, 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 secured using any preferred type and / or method of secure communication (e.g., Secure Sockets Layer (SSL)) and / or encryption. In other embodiments, any or all communications may not be secured.

[0155] As described herein, various energy delivery algorithms 152 can be programmable or pre-programmed within the generator 104, such as being stored in memory or a data storage / read unit 156. Alternatively, energy delivery algorithms can be added within a data storage / read unit to be executed by a processor 154. The processor 154 may be, for example, a general-purpose processor, a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), a digital signal processor (DSP), and / or equivalents. The processor 154 may be configured to start and / or run application processes and / or other modules, processes and / or functions, and / or networks associated with the system 100. As used herein, the term “module” means any assembly and / or set of operationally coupled electrical components, which may include, for example, memory, processors, electrical traces, optical connectors, software (executed in hardware), and / or equivalents. For example, a module executed in a processor may be any combination of hardware-based modules (e.g., FPGAs, ASICs, DSPs) and / or software-based modules (e.g., modules of computer code stored in memory and / or executed in the processor) that are capable of performing one or more specific functions associated with that module.

[0156] Each of these algorithms 152 may be executed by a processor 154. In some embodiments, the apparatus 102 includes one or more sensors 160 which may be used to determine, to some examples, temperature, impedance, resistance, capacitance, conductivity, pH, optical properties (coherence, echo brightness, fluorescence), electrical or photoelectric dielectric constant, and / or conductance. In some embodiments, one or more of the electrodes act as one or more sensors. In other embodiments, one or more sensors are separate from the electrodes. It should be understood that one or more sensors 160 may be located in various places, in particular, depending on the parameter being sensed. For example, sensors may be located along the energy delivery body 108, along the interior of the apparatus, along the shaft 106, along elements protruding from the apparatus, etc. Multiple sensors 160 may exist to sense the same parameter at multiple locations, to sense different parameters at different locations, or to sample parameters at different locations and aggregate a single metric value measurement (e.g., average temperature, average voltage exposure, average conductivity, etc.). One or more sensors 160 may be located on separate devices, either as an alternative or in addition. Sensor data can be used to plan and monitor therapy and / or provide direct feedback via processor 154, which can then modify the energy delivery algorithm 152. For example, impedance measurements can be used not only to determine the initial dose to be applied, but also to determine whether there is a need for further treatment.

[0157] It should be understood that system 100 may include an automated treatment delivery algorithm that can dynamically respond to, adjust, and / or terminate treatment in response to inputs such as temperature, impedance at various voltages or AC frequencies, treatment duration, or energy delivery pulses, treatment power, and / or other timing aspects of system status.

[0158] Figure 3 illustrates an embodiment of the signal waveform 400 as defined by the energy delivery algorithm 152. Here, two packets, namely a first packet 402 and a second packet 404, are shown, separated by a pause period or inter-packet delay 406. In this embodiment, each packet 402, 404 consists of a first biphasic cycle (having a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic cycle (having a second positive pulse peak 408' and a second negative pulse peak 410'). The first and second biphasic pulses are separated by a dead time or inter-cycle delay 412 (i.e., interruption) between each pulse. In this embodiment, the biphasic pulses are symmetrical such that the set voltage 416 is identical with respect to the positive and negative peaks. Here, the biphasic symmetrical wave is also a square wave such that the magnitude and time of the positive voltage wave are approximately equal to the magnitude and time of the negative voltage wave.

[0159] It is important to understand that manipulating various parameters (e.g., voltage, fundamental frequency, number of pulses per packet, number of packets, and various delays) can have various effects on the resulting lesions and the body itself. In some cases, parameter changes can balance each other, and the effect of changing one or more parameters can be balanced by changing one or more different parameter values, leading to the same or similar results. In other cases, parameter values ​​can be adjusted to produce or cause different effects, such as different lesion characteristics (e.g., presence, size, and / or nature of different areas) and / or different effects on the body. These effects on the body can be immediate, such as muscle stimulation, or delayed, such as the occurrence of a specific immune response.

[0160] Figure 4 provides a table (Table 1) illustrating various exemplary effects of parameter changes. Typically, the electrode configuration is unipolar, in contrast to bipolar. In a unipolar array, one or more delivery electrodes are positioned near the target tissue site, and at least one remote feedback electrode is positioned relative to the patient's skin. By utilizing a unipolar electrode configuration, muscle contraction intensity increases. To counteract this effect, a waveform consisting of sufficiently short individual pulse durations with a biphasic waveform or packets with appropriate delays between pulses generally offsets the degree of muscle contraction. This waveform variability results in a reduced therapeutic effect, but the reduction is less significant than the reduction in muscle contraction, and therefore still leads to effective PEF therapy application. The unipolar configuration also reduces the risk of electric arc discharge compared to bipolar or multipolar configurations, where all effector electrodes are placed within similar regions, potentially allowing for electric arc discharge between them. Typically, the waveform utilizes biphasic pulses, in contrast to monophasic pulses. The use of biphasic pulses reduces treatment size, decreases muscle contraction, and reduces the risk of arc discharge. Therefore, the use of biphasic pulses counteracts the increased muscle contraction caused by unipolar electrode systems. Since both unipolar electrode systems and biphasic pulses reduce treatment size, treatment size can be increased by changing other variables. For example, increasing voltage, packet duration, and the number of packets increases treatment size. However, increasing these parameters has various other effects. For instance, increasing voltage and increasing packet duration increases the risk of muscle contraction, temperature rise, and electrical arc discharge, respectively. Increasing the fundamental frequency can reduce muscle contraction, but this also reduces treatment size. Similarly, increasing the number of packets increases treatment size, but also increases temperature rise and treatment delivery time. Treatment delivery time can be reduced by increasing the packet delivery rate, but this increases temperature rise. Therefore, managing the effects of various parameter changes is a complex undertaking. This is further complicated by the increments in which these changes are made.Once considering the number of parameters related to the PEF waveform and the dosage itself, and the increments in which they can be changed, the set of combinations becomes enormous. This is further amplified by the influence of electrode geometry, such as the fact that larger electrodes delivering a particular voltage will have different properties than smaller electrodes, or by the influence of unipolar vs. bipolar and multipolar arrays (and the separation distance between electrodes in these arrays). These properties also include temperature rise, therapeutic effect size, current delivered, muscle contraction, risk of electric arc discharge, and the time required to achieve coverage of the targeted therapeutic effect size. Furthermore, certain conditioning solutions provided to the patient may be used specifically to target and reduce the induced muscle contraction. For example, neuromuscular blocking agents with pancuronium bromide, vecuronium, succinylcholine, and other blocking agents may be used. This reduction of muscle contraction may be used to facilitate therapeutic doses with lower frequencies, longer packet durations, or higher voltages in order to achieve a greater therapeutic effect while maintaining acceptable and safe muscle contraction.

[0161] It should be understood that parameters can be manipulated to reduce the probability of inducing arrhythmias. Typically, high voltage energy can induce early action potentials in the myocardium as the delivered energy increases myocardial cell membrane permeability, enabling ion transport, which can induce cardiac arrhythmias, particularly ventricular fibrillation. However, both shorter pulse durations (i.e., higher frequencies such as 100–600 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 shorter pulse durations, but the ventricular fibrillation induction threshold also increases significantly as the pulse width decreases. Shorter pulses are far less likely to induce ventricular fibrillation because the clonaxi to stimulation is more than an order of magnitude lower than that of fibrillation. The exponential increase in amplitude for stimulating tissue as pulse width decreases results in a 1–5 microsecond PEF, which is far safer with respect to the heart than those of 70–100 microseconds. In particular, pulses of 70-100 microseconds, which are common in conventional IRE-type ablation at 3kV, would fall within the ventricular fibrillation induction range of these intensity duration curves, while shorter microsecond pulses would exceed the stimulation threshold but fall below the ventricular fibrillation induction threshold for the same amplitude. In addition, two other factors contribute to the lower proarrhythmic potential of biphasic waveforms compared to monophasic waveforms: 1) biphasic waveforms have higher stimulation and ventricular fibrillation induction thresholds than monophasic waveforms, and 2) biphasic waveforms result in more homogeneous tissue polarization, which reduces the likelihood of the post-shock voltage gradient initiating arrhythmias.

[0162] However, because the induction of cardiac arrhythmias depends heavily on the three-dimensional cardiac matrix (including myocardial fiber anisotropy), heterogeneity (including within the tissue plane between the electrical source and the myocardium), and the complex spatiotemporal interactions between the therapeutically generated electric field and the intrinsic electrical wavefront within the heart, electrotherapy is evaluated in vivo to determine its true proarrhythmic potential. Herein, the proarrhythmic potential of specialized PEF energies is assessed by testing it in highly proarrhythmic animal models and by intentionally applying the therapy at the most susceptible therapeutic anatomical locations and times within the cardiac rhythm. material and method Theoretical evaluation of the possibility of proarrhythmics

[0163] Numerical simulations provide a valuable tool for representing the electrical tissue changes in response to PEF therapy. Cardiac safety of PEF therapy depends on several factors, including electrical pulse duration, applied voltage, and distance to the heart. This analysis investigated these factors and their effects on the induction of two cardiac phenomena: cardiac activation and fibrillation. Comsol Multiphysics 5.4 (Comsol, Sweden) was used to model the voltage distribution and electric field from various applied voltages. geometric shapes

[0164] The electrodes were modeled as a series of five rings expanded within a 1 cm diameter airway. Each ring was a 1 mm wide boundary in contact with the airway circumference and separated by 1 mm along the length of the airway. Consistent with the approximate dimensions of the porcine airway tissue layers, the epithelium and submucosa were considered to be 0.35 mm thick, and the cartilage 0.7 mm thick. The airway region was placed within a lung parenchyma region 20 cm in diameter and 40 cm in length, with 5 cm diameter dispersed plate electrodes placed at the ends. Electrical properties of tissues

[0165] The inside of the airway is 1.10 -7Air was modeled as having a conductivity of S / m, while the epithelial and cartilage layers had conductivity of 0.362 S / m, respectively. The lung parenchyma was considered to exhibit dynamic conductivity as a function of the electric field, as described above. This resulted in the following conductivity function: [ka]

[0166] In the equation, σ0 is the baseline conductivity of the inflated lung at a frequency consistent with a pulse duration of 1 μs (0.126 S / m), which increases with electric field exposure and approaches the conductivity of the inflated lung at frequencies within the β-dispersion region (200 MHz, 0.335 S / m). The pulse duration of 1 μs was chosen because it falls within the typical range of a biphasic PEF waveform. The values ​​for B and C provide the centers and ± distances for the inflection points along the curves at 400 and 125 V / cm, respectively, resulting in a conductivity function that increases as electric field exposure increases from approximately 250 to approximately 1,000 V / cm (Figures 5A-5B). This range and curve shape are consistent with experimental data. Only electrical effects were modeled in the simulation because they have the greatest impact on arrhythmia risk. Numerical simulation conditions

[0167] Geometric shapes are 1.24·10 6 The elements were meshed (extremely fine physical control mesh). The external boundary was considered electrically insulated, while the internal boundary followed current conservation. The dispersed pad boundary was set to ground. The electrode ring was evaluated in a parametric study, and the applied voltage was evaluated from 1,000 to 3,000 V in 1,000 V increments. The voltage as a function of distance from the electrode ring in the tissue was determined. Theoretical evaluation of proarrhythmics

[0168] Both cardiac stimulation (i.e., pacing) and arrhythmia induction are voltage and pulse duration-dependent processes, and their intensity-duration relationships were extracted from reference data describing them for monophasic pulses of approximately 90 μs–50 milliseconds. In particular, the thresholds for pacing the heart and inducing arrhythmias diverge sharply below a pulse width of approximately 1 millisecond. The most reliable PEF-related arrhythmia literature is performed using monophasic pulses, and biphasic waveforms have previously been shown to have higher stimulation and VF induction thresholds; therefore, data from monophasic pulses were extrapolated, meaning that monophasic pulses represent the worst-case scenario. Reference data were extrapolated by fitting VF induction and stimulation curves to power law relationships, as depicted in Figures 6A–6C. These data were used to infer the likelihood of inducing any cardiac effect as a function of applied voltage and distance from the heart over various pulse durations from 1–100 μs. In vivo pig experiments

[0169] In this IACUC-approved study, four pigs (44.3–63.3 kg) received PEF energy. Electrocardiograms (ECGs) were recorded from an Ivy 7600 cardiac monitor (Ivy Biomedical, CT, USA) and a data acquisition module (DAQ) connected to the PEF generator. The cardiac monitor outputs the ECG waveform and a trigger pulse (R trigger) that corresponds in time to the R wave of ventricular depolarization, allowing for precise control of the PEF delivery timing in response to cardiac depolarization. The cardiac monitor was connected to the subjects using a 4-core cable. The DAQ recorded the ECG signal, R trigger, and PEF energy delivery in parallel, enabling detailed examination of PEF energy delivery in response to the pig cardiac rhythm.

[0170] ECGs were recorded continuously throughout all experiments and examined by a qualified electrophysiologist to interpret any changes in cardiac rhythm or ECG waveform resulting from PEF delivery. ECGs were screened for signal saturation, effects on RR timing intervals (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 observed.

[0171] C-arm fluoroscopy visualized the catheter position. Computed tomography (CT) images of the pig's chest were performed to determine the airway-cardiac proximity. PEF System Background

[0172] The system evaluated in this study uses various PEF waveforms, including specialized PEFs used in the treatment of chronic bronchitis. Figure 7 illustrates an embodiment of a tissue modification system 100 used to deliver specialized PEF energy to target tissue in the lungs to treat chronic bronchitis, etc. As shown, the unipolar system comprises a PEF generator 104, a foot switch, an energy delivery body 108 (e.g., an expandable basket electrode), and a large dispersed electrode 106 placed at a distant location on the body. The generator delivers a series of packets of specialized PEF energy, each packet consisting of multiple biphasic pulses. The basket electrode-tissue interface is the dispersed electrode (approximately 100 cm²). 2 ) is significantly smaller in surface area (0.67-1.30 cm², depending on the airway diameter) 2 ) has.

[0173] In directed attempts to intentionally induce cardiac arrhythmias, three experiments were conducted to test the worst-case timing of specialized PEFs: a single packet of specialized PEF delivered at a timed point across the entire cardiac cycle (full ECG sweep), a single packet delivered at a precisely timed interval across the most sensitive T-wave portion of the cardiac cycle (high-resolution T-wave delivery), and multiple packets (multiple packets) arranged together and delivered across the entire cardiac cycle. All studies used generators with custom software to allow for precise timing of energy delivery to R triggers, and specialized PEF energy was delivered at various locations within the airway tree, including the distal and proximal sides of both the left and right lungs, to account for positional and anatomical variability around the heart. complete ECG sweep

[0174] In two pigs, a single packet of specialized PEF was delivered. Generator 104 sequentially extended the R trigger delay interval in 25-millisecond increments prior to the delivery of the specialized PEF. This resulted in the delivery of the specialized PEF across all phases of the cardiac cycle. One packet was delivered every five heartbeats to allow observation of the cardiac response before the delivery of the next packet. High-resolution T-wave delivery

[0175] In the third pig, a single packet was delivered at a higher resolution (10-millisecond increments) to cover the entire duration of the expected susceptible region of the T wave. The T wave is recognized as the most arrhythmia-prone portion of the ECG because the tissue at that point in time has varying degrees of ventricular repolarization, which, when stimulated, can lead to unidirectional block and arrhythmia induction. One packet was delivered every five heartbeats to facilitate the interpretation of the occurrence of ECG and cardiac rhythm changes from PEF treatment. Overall T-wave sweeps were repeated at clinical PEF doses, as well as doses delivering 44% more energy than the clinical doses. Multiple packets

[0176] Most specialized PEF therapies deliver bundles of packets to accumulate cytotoxicity and increase cell death beyond what would be caused by the delivery of a single packet. To evaluate cardiac safety in the context of multiple packet delivery, a fourth pig was used to investigate whether asynchronously delivered composite PEF packets could induce arrhythmias that a single PEF packet could not.

[0177] The generator was configured to deliver sequences of 5 or 10 packets in bundles. PEF bundle delivery was initiated at different points throughout the entire ECG waveform with a 40-millisecond resolution to ensure proper probing of all potentially sensitive areas. Two trials had an 80-millisecond resolution. The cadence of packets within each bundle was also varied, delivering packets either rapidly (5 Hz / 300 ppm), slowly (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, the ECG was recorded for five beats following the delivery of the packet bundles to determine the presence of induced arrhythmias. result Theoretical evaluation

[0178] The geometric shapes used in the numerical simulation, as well as the typical distributions of conductivity, electric field, and voltage for a 3,000V pulse, are shown in Figures 8A-8D.

[0179] Dynamic conductivity induced a slight decrease in tissue impedance with increasing applied voltage, due to the PEF-induced increase in conductivity of a larger volume of tissue (Figures 5A-5B).

[0180] Figure 9A shows that the extrapolated voltage thresholds for cardiac stimulation and fibrillation induction are separated by approximately two orders of magnitude and decrease logarithmically with increasing monophasic pulse duration. While the activation energy for pulses longer than 1 μs is less than 250 V, the voltages required to induce fibrillation over durations of 0.5, 1, 10, 50, and 100 μs are much higher, decreasing from 62.6 to 35.6, 5.48, 1.48, and 0.843 kV, respectively. This highlights the high sensitivity of cardiac arrhythmias to pulse duration.

[0181] Data from numerical simulations were combined with extrapolated threshold curves to produce Figure 9B. In Figure 9B, the voltage decay of tissue over 3 cm at various applied voltages is overlaid with the thresholds for activation and fibrillation at different monophasic pulse durations. From Figure 9B, all applied voltages exposed the tissue to activation energy to a depth of 3 cm. Furthermore, the voltage required to induce fibrillation over pulses with durations of 50–100 μs was exceeded within 1 cm for all pulses when the applied voltage exceeded 2 kV. Conversely, for pulse durations ≤ 10 μs, no applied voltage resulted in the tissue being exposed to a voltage capable of inducing fibrillation at any distance. These data demonstrate a substantial safety margin against cardiac arrhythmia induction in PEF treatment when the monophasic pulse duration is 10 μs or less. Experimental evaluation

[0182] The minimum distance between the heart and the main bronchus where the basket electrode was placed was measured by combining a fluoroscopic image of the basket deployment with a CT image of the pig's chest, and showed a proximity of approximately 2 mm (Figures 10A-10D). Figure 10A illustrates a fluoroscopic image of a bronchoscope in the left main bronchus of a pig with the basket electrode deployed. Representative pig CT scans are provided, and the proximity to the epicardial surface is measured in the axial plane (Figure 10B, 1.96 mm), coronal plane (Figure 10C, 5.97 mm and 4.74 mm), and sagittal plane (Figure 10D, 7.06 mm).

[0183] A total of 3,125 PEF packets were delivered to four pigs across three studies. No sustained changes in cardiac rhythm or ECG waveform, particularly any atrial or ventricular fibrillation, any ST elevation, or any ventricular tachycardia, were observed. Overall, cardiac responses to specialized PEF energy delivery fell into one of four categories, as shown in Figures 11A–11D.

[0184] 1) None (Figure 11A): No impact or change on the ECG results from packet delivery.

[0185] 2) Signal interference (Figure 11B): Specialized PEF delivery resulted in ECG artifacts. When these artifacts coincided with ECG features (e.g., QRS complex), the feature appearance was altered. No effect on cardiac activation or timing was present; these were artifacts of the experimental setup and data recording device.

[0186] 3) Premature atrial contraction without ventricular conduction (PAC) (Figure 11C): The delivery packet stimulates atrial contraction prior to the innate conduction beat from the sinoatrial (SA) node. The atrioventricular (AV) node is unresponsive during this premature beat, and therefore the electrical signal does not conduct to capture the ventricles. However, the SA node is reset, and therefore the subsequent normal heartbeat does not occur until the period following the premature atrial contraction that matches the basal heart rate. This appears on the ECG as a “non-conducted” or skipped beat, with a cycle length of approximately twice the basal cycle length. The cardiac rhythm returns to the basal heart rate following the subsequent beat.

[0187] 4) Premature atrial contraction with ventricular conduction (PAC) (Figure 11D): The delivery packet stimulates atrial contraction prior to the innate conduction beat from the SA node. The AV node is refractory, allowing the premature beat to conduct to the ventricles and activate them, resulting in normal ventricular conduction. This manifests as a premature beat, occurring before the basal beat would occur. Following the premature beat, the cardiac cycle returns to its basal rate, which occurs with either voluntary sinus reset or continued sinus timing.

[0188] The two PAC conditions modify the specific RR interval but are considered to have no residual effect beyond subsequent heartbeats. The arrows and numbers represent the time interval from the QRS complex to PEF delivery. The bars and numbers represent when the PEF packet was delivered and the PEF packet number.

[0189] Table 2 provides an overview of the treatments delivered and a detailed examination of cardiac rhythm and ECG waveforms. There were no instances of sustained changes in ECG waveforms (e.g., ST elevation) or cardiac rhythm related to any PEF delivery, including the absence of episodes of bradycardia, tachycardia, atrial fibrillation, or ventricular fibrillation. Furthermore, findings were limited to a single PAC. These data are further detailed in Table 2 by lung and location.

[0190] [Table 1]

[0191] *When a complete ECG sweep was performed, the R-wave trigger delay was the range from the shortest resolution time point to the occurrence of the subsequent R-wave. This varied based on the pig's heart rate.

[0192] A brief explanation of each experimental result is provided below. complete ECG sweep

[0193] A total of 1,180 packets were delivered across two pigs. Each segment (distal and proximal) of both the left and right lungs underwent a complete cyclic PEF sweep, resulting in a total of 16 complete cyclic PEF sweeps. PACs occurred as described above and only with a basket electrode in the proximal main bronchus. When a PAC occurred, its effect was limited to the timing of the immediate following heartbeat, which resolved immediately and spontaneously in all cases, regardless of whether it was conducted to the ventricle. Overall, there were no safety risks associated with packet delivery, such as any arrhythmias, any abnormal ventricular conduction outside the normal conduction system, or any changes in the ST compartment. High-resolution T-wave delivery

[0194] During high-resolution T-wave delivery, a single pig received 160 packets at a clinical PEF dose. Overall, despite high-resolution PEF delivery across the most sensitive portion of the ECG, no sustained (>1 heartbeat) changes in cardiac rhythm were observed, and no significant safety risks associated with biphasic PEF packet delivery in any region were identified. Multiple packets

[0195] In total, 1,945 packets were delivered to a single pig over 341 PEF activations. PACs were again observed only in the proximal left main bronchus with a basket electrode when the treatment was delivered well beyond the refractory period. A summary of the observations is provided in Table 2. Consistent with two previous experiments, there were no observed occurrences of any sustained changes in cardiac rhythm, including the appearance of fibrillation or other dangerous arrhythmias. These findings were consistent regardless of the PEF packet delivery rate, whether 5 or 10 packets were delivered, and the initial timing of the first packet delivered. A breakdown of the experimental conditions and individual PAC inductions is shown in Table 3.

[0196] [Table 2]

[0197] All animals treated in these studies had a normal cardiac rhythm immediately after treatment, which persisted until their pre-specified time of survival. Therefore, these data demonstrate the absence of any clinically significant cardiac arrhythmias, regardless of the test conditions regarding electrode placement, PEF delivery to the cardiac rhythm, or the number of subsequent packets. Discussion

[0198] A systematic exploration of the potential proarrhythmic effects of a biphasic unipolar PEF system embodiment in the airway was conducted. Numerical simulations evaluated the likelihood of arrhythmia induction as a function of pulse duration, applied voltage, and distance to the heart. Experimentally, individual packet administrations and waveform characteristics were matched to those of therapeutic parameters for clinical airway therapy for both single and multiple packet therapies.

[0199] Despite increasing intensity of various attempts to induce arrhythmias with respect to short-duration (≤10 μs) biphasic pulses tested in this experimental setup, no sustained changes in ECG waveform or cardiac rhythm were observed. These data are in stark contrast to results previously reported by Deodhar et al. regarding a different PEF technique (i.e., irreversible electroporation). In that study, 90 NanoKnife (AngioDynamics, NY, USA) pulses, each with a pulse duration of 70 μs, were delivered to the heart across a series of voltages and locations. They observed that most of the test conditions induced a series of cardiac arrhythmias, including ventricular tachycardia and ventricular fibrillation, when energy was delivered asynchronously. ST elevation and T-wave inversion were still observed when R-triggered cardiac synchronization was included as recommended. These differences highlight that not all PEF techniques are the same, and there are significant differences in terms of safety and efficacy regarding various electric field platforms and delivery systems. Other differences exist between this study and Deodhar's study, besides pulse duration, including electrode arrangement (unipolar in this case) and biphasic waveform.

[0200] In this study, the end-effector was intentionally placed in the airway position closest to the heart (approximately 2 mm from the myocardium). Pigs have been documented to be significantly more proarrhythmic than humans. Despite these worst-case conditions, the only modification of the ECG was the occurrence of PAC when energy was delivered using a basket electrode in the proximal main bronchus. The proarrhythmic properties of specialized PEF energy are dramatically reduced with respect to biphasic waveforms, such as those used for PEF therapy evaluated here.

[0201] Theoretical validation of cardiac activation and fibrillation thresholds demonstrated that activation is likely for short (<10 μs) individual monophasic pulses, even at low PEF applied voltages (≤1 kV). However, the fibrillation threshold is approximately two orders of magnitude higher, and therefore, induction of arrhythmias is observed only when the pulse duration is 50 μs or longer, while pulses of 100 μs were capable of inducing fibrillation for all voltages tested. In particular, for the biphasic PEF waveforms described herein, the pulse duration for each phase is 0.5–5 μs, which clearly falls within this “safe zone” for monopolar electrodes and applied voltages clearly above 3.0 kV. This is consistent with the conditions of experimentally evaluated commercially available specialized PEF systems for inducing arrhythmias in pigs. These systems use a PEF protocol that encompasses voltage and frequency characteristics consistent with those evaluated in simulations and have been shown to induce cardiac activation but not fibrillation under any of the conditions tested.

[0202] One limitation of the theoretical part of this study is that it assessed the arrhythmia risk for a single monophasic pulse. This is consistent with some commercial PEF systems that use a series of long monophasic pulses (durations of 50–100 μs), but it does not fully summarize the cardiac effects potentially induced by biphasic waveforms, which consist of a collection of short pulses (0.5–5 μs) that rapidly and sequentially alter the phases. This limitation is a result of previous related explorations of activation and fibrillation risk in cardiac tissue as a function of pulse waveform characteristics. Additional theoretical studies incorporating these additional variables (biphasic pulse width, number of biphasic cycles with complete packets, and delivery rate of multiple biphasic packets) may better characterize the potential for activation and fibrillation induction under typical PEF ablation waveforms.

[0203] The experimentally evaluated specialized PEF therapy protocol enables therapeutic cell death. The tested protocol was optimized to induce significant epithelial (43±27%) and submucosal (3±4%) cell death without causing changes in airway integrity or function. The clinical utility of the protocol used with this system was evaluated in a multicenter clinical trial treating patients with chronic bronchitis (CB). No device-related adverse events were found, while patient-reported symptom improvements of -8.0 (p<0.001) and -14.7 (p<0.001) were observed in the Assessment Trial for Chronic Obstructive Pulmonary Disease (CAT) and St. George's Respiratory Questionnaire (SGRQ), respectively. These changes clearly exceeded the minimum clinically significant differences in each trial (-2 and -4 points, respectively). Histological measures of goblet cell hyperplasia were reduced by approximately 39% (p<0.001) when comparing pre- and post-treatment airway tissue samples.

[0204] In these studies, the occasional induction of PACs was the only observed cardiac effect from the delivery of specialized PEFs, consistent with simulated predictions of cardiac stimulation but inconsistent with simulated predictions of arrhythmia induction. PACs are a common clinical phenomenon, occurring at least once per 24-hour period in >99% of the general adult population. The effect of the delivery energy was limited to a single heartbeat and never extended to any subsequent heartbeats. Therefore, these findings do not demonstrate a measurable risk to patient health.

[0205] One consideration is that the hearts of relatively healthy pigs may be more resilient than those of human hearts with underlying conditions such as myocardial ischemia. However, it should be noted that pigs are approximately three times more sensitive to electrically induced arrhythmias than humans and therefore serve as a highly sensitive model for cardiac safety. This study also relied on past literature rather than positive controls to demonstrate the potential proarrhythmic activity of longer-duration monophasic waveforms. While it is possible that humans and pigs have different responses to monophasic versus biphasic waveforms, this is unlikely as both exhibit the same preferred response to biphasic versus monophasic cardioversion.

[0206] This study theoretically evaluated several relevant variables for inducing arrhythmias, including applied voltage, pulse duration, and proximity to the heart. It experimentally evaluated a biphasic unipolar PEF technique for treating the airway to determine the safety of asynchronous PEF delivery across various regions of the ECG waveform. Despite thousands of packets delivered, many of which were direct across the vulnerable T wave, only occasional PACs were observed, and no cardiac arrhythmias or ECG waveform changes were observed. This study demonstrates that specialized PEFs do not require cardiac synchronization of energy delivery to prevent problematic arrhythmias.

[0207] By using a waveform that significantly reduces the likelihood of initiating arrhythmias (i.e., a specialized PEF), energy can be delivered without cardiac synchronization. As a result, energy can be delivered according to methods and procedures that were previously contraindicated.

[0208] In some embodiments, specialized PEF energy is delivered to 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 repeating cycles of P waves representing atrial depolarization, QRS complexes representing ventricular depolarization and atrial repolarization, and T waves representing ventricular repolarization. Typically, there is a portion of the heartbeat that is considered the myocardium's "sensitive period." Within a single cardiac cycle (heartbeat), the sensitive period of the ventricular myocardium is represented on the ECG by the entire T wave. The T wave is recognized as the most arrhythmia-prone portion of the ECG because the tissue at that point in time has varying degrees of ventricular repolarization, which, when stimulated, can lead to unidirectional block and arrhythmia induction. Typically, with respect to ventricular myocardium, the sensitive period coincides with the middle and end of the T wave. However, when high-energy pulses are delivered in close proximity to the ventricles, the sensitive period may occur several milliseconds earlier in the heartbeat. Therefore, the entire T wave can be considered to be within the period when the ventricle is susceptible. In some embodiments, energy (a single packet or multiple packets, etc.) is delivered, to some examples, throughout the entire period when the ventricular muscle is susceptible, throughout the entire T wave, through at least a portion of the T wave, through at least a certain phase of the T wave, through at least the intermediate phase of the T wave, through at least the terminal phase of the T wave, or through at least a portion of the intermediate phase and / or terminal phase of the T wave.

[0209] In some embodiments, specialized PEF energy is delivered to the target tissue by a generator, which sequentially extends the R trigger delay interval in 25-millisecond increments before PEF delivery. This results in PEF delivery across all phases of the cardiac cycle. In other embodiments, a single packet is delivered at a higher resolution (10-millisecond increments) to cover the entire duration of the expected susceptible region of the T wave. In some cases, PEF therapy delivers bundles of packets to accumulate cytotoxicity and increase cell death beyond what would be caused by the delivery of a single packet. Thus, in some embodiments, a sequence of 5 or 10 packets in a bundle is delivered during the susceptible period. In some embodiments, PEF bundle delivery is initiated at different points throughout the entire ECG waveform with a resolution of 40–80 milliseconds. In some cases, the cadence of packet delivery within each bundle varies, delivering packets at either a rapid rate (5 Hz / 300 ppm), a slow rate (0.66 Hz / 40 ppm), or a rate close to the intrinsic heart rate (approximately 1.2 Hz / 70 ppm).

[0210] In some embodiments, the specialized PEF is delivered during atrial contraction. Typically, delivery during atrial contraction is contraindicated due to the increased risk of inducing arrhythmias, but such delivery can be achieved using the specialized PEF. Delivery during atrial contraction ensures that the heart is in the same physical state when energy is delivered between each dose. At the start of the cardiac cycle, both the atria and ventricles are relaxed (diastole). Blood flows into the right atrium from the superior and inferior vena cava and coronary sinuses. Blood flows into the left atrium from the four pulmonary veins. Both atrioventricular valves, namely the tricuspid and mitral valves, are open, and therefore blood flows unobstructed from the atria into the ventricles. Approximately 70–80 percent of ventricular filling is produced by this method. The two semilunar valves, namely the pulmonary valve and the aortic valve, close to prevent the backflow of blood from the right pulmonary trunk and the left aorta into the right and left ventricles. Atrial contraction is followed by depolarization, represented by the P wave on the ECG. As the atrial muscle contracts from the upper part of the atria toward the atrioventricular septum, pressure rises within the atria, and blood is pumped into the ventricles through the opening atrioventricular (tricuspid and mitral or bicuspid) valves. At the start of atrial systole, the ventricles are usually filled to about 70–80 percent of their volume, due to the inflow during diastole. Atrial contraction, also called "atrial stimulation," contributes to the remaining 20–30 percent of the filling. Atrial systole lasts about 100 milliseconds and ends prior to ventricular systole as the atrial muscle returns to diastole.

[0211] In some embodiments, the specialized PEF is delivered during the peak of maximal contraction in atrial or ventricular systole. This is useful when treating cardiac tissue, as such delivery overcomes contact variability while the heart is beating. In another embodiment, the specialized PEF is delivered when the myocardium begins the relaxation process after maximal contraction. In such embodiments, the ratio of electrode contact force to tissue is sustained over a high range, which can be achieved by continuously monitoring the contact force or contact presence. During this time, the relaxed myocardium presents a thinner morphology, but the same energy is delivered. This promotes the development of transmural lesions due to the higher energy-to-tissue ratio.

[0212] Determining atrial or ventricular systole can be done by, to name a few, contact force measurement, pressure monitoring (e.g., to synchronize pulse delivery with pressure as a surrogate indicator of expected tissue contraction), and / or blood flow monitoring (e.g., using Doppler ultrasound imaging to synchronize pulse delivery with flow as a surrogate indicator of expected contraction).

[0213] In some embodiments, energy delivery is timed to provide artifact-free or artifact-reduced visualization of specific electrical features. It should be understood that when energy is delivered, intracardiac electrical monitoring systems typically present significant electrical artifacts across all surfaces of cardiac tissue. These artifacts can make reading surface ECGs or intracardiac EGMs difficult for short periods. The length of time depends on how quickly the recording amplifier recovers from saturation. Therefore, having a limited delivery time can limit the user's ability to visualize specific electrical features. However, specialized PEFs can be delivered without limitation, and therefore, delivery can be selected over periods that do not overlap with specific ECG and / or EGM features. This would allow for improved or artifact-free visualization of these features. For example, energy delivery can be selected to avoid periods of atrial depolarization, which would allow for clearer visualization of atrial p waves.

[0214] In some embodiments, such control over the timing of energy delivery also improves compatibility with accessories and other systems. Some accessories or device systems, in particular patient connection devices, offer the ability to benefit from operating during periods without energy delivery. One such embodiment is an electroanatomical mapping system used when treating cardiac tissue, such as in the treatment of arrhythmias. It is preferable to avoid energy delivery to the tissue while the electrical measurements of the cardiac tissue are being taken. Thus, energy delivery can be timed to these preferred periods without the complexity of additional synchronization requirements with the heartbeat. This eliminates or reduces artifacts and mitigates the potential for system damage.

[0215] In some embodiments, specialized PEF energy is delivered at a dose-dependent rate. In some embodiments, the dose is a predetermined delivery of energy that produces a desired therapeutic effect, such as lesion formation. In such cases, one dose produces one lesion. Since the dose is based on the energy delivered, the dose can be delivered over various periods of time. When not constrained by cardiac synchronization, the delivery of specialized PEF energy can be adjusted to a desired dose of energy. In such cases, the energy is delivered in the shortest time amount that provides the desired effect. It should be understood that the dose may include delays to allow heat dissipation in order to reduce or eliminate any thermal effects. However, when accommodating both thermal effects and cardiac synchronization, the dose is variable and may exceed the clinically desirable treatment time. In some cases, delays are manipulated so that the dose falls within a desired clinical treatment time, even if the outcome is not entirely optimal for the therapeutic outcome. For example, to adapt to patients with various potential heart rates (e.g., 40–140 bpm), the dosage is designed so that adapting to 40 bpm delivers energy fast enough so that it does not take too long clinically, while adapting to 140 bpm delivers energy slowly enough so that it does not cause excessive temperature rise. However, delivering specialized PEF energy as desired, without synchronization with the cardiac cycle, allows the energy to be delivered at a dose-dependent rate, entirely dependent on dosage optimization. Typically, this results in a faster overall treatment time while still allowing for delays, such as reducing any thermal damage. This may be particularly useful for lower voltage dosages, which can be delivered faster without causing extensive temperature rise.

[0216] In some embodiments, specialized PEF energy is delivered at a constant delivery rate, which has the benefit of providing a certain amount of time to form a lesion. When energy delivery is not constant, depending on the cardiac cycle, etc., the delivery time depends on the heart rate. However, mean resting heart rate varies across age, sex, body mass index (BMI), and sleep habits. In some cases, daily resting heart rate can vary by as much as 70 beats per minute (bpm) between individuals. Men typically have a daily resting heart rate of 50–80 bpm, while women typically have a daily resting heart rate of 53–82 bpm. Men with a somewhat average BMI tended to have the lowest resting heart rates, while those with very low or very high BMI tended to have higher heart rates. Variability within a single patient also exists. Compared to men, women of childbearing age showed greater variability in their individual resting heart rates. However, even slight seasonal variations exist for all patients. The average daily resting heart rate in both men and women peaks in early January and then declines to its lowest point of the year at the end of July. All of this introduces unpredictability in the time required to form a lesion in any given patient when synchronizing energy delivery with the heartbeat. However, if such synchronization is eliminated by the use of specialized PEF, a constant delivery rate can be used, which would lead to a constant time for lesion formation. This is particularly advantageous in the treatment of cardiac tissue with respect to electrophysiologists delivering energy by the use of a "traction" technique. In such a technique, the delivery electrode is dragged across the cardiac tissue at a constant rate to deliver energy, rather than being placed in one location 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 often have a predetermined or limited ability to provide variability or adaptation.

[0217] Once energy delivery is decoupled from synchronization with the heartbeat, it can be associated with other anatomical structure-based features. For example, energy delivery can be synchronized with respiration. Respiratory expansion can be detected, for example, by the use of a chest belt, bellows, or cushion. The belt should be placed around the lower chest for "thoracic breathers" and around the mid-abdomen for "abdominal breathers." An impedance pleismysography device, which measures changes in electrical resistance across the chest with respiration, may be used as an alternative. This can be particularly useful when treating lung tissue or resecting tumors in or around the lungs. Thus, energy delivery can be activated when the lungs are not moving, which can allow for more consistent and / or predictable energy delivery. This also allows for the avoidance of energy delivery during particularly disruptive events, such as coughing or sneezing. Similarly, when delivering energy near coronary vasculature or other parts of the vasculature, delivery can be adjusted to reduce the risk of vasospasm. For example, when delivering energy to tissues near coronary arteries, the delivery rate may be reduced to avoid or reduce vascular smooth muscle contraction.

[0218] Once energy delivery is decoupled from synchronization with the heartbeat, it can, as an alternative, be operated by feedback control, without being constrained by synchronization with the heartbeat. Examples of feedback control include, to name a few, temperature monitoring, impedance monitoring, pH monitoring, contact detection, and / or contact force. Temperature monitoring can be used to more easily and effectively keep thermal damage at a minimum or non-existent level. 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 in the waveform that mitigates the temperature rise. These delays essentially slow down the procedure. Similarly, the built-in safety margin results in a longer procedure than necessary. Real-time temperature monitoring shifts the temperature reduction away from the predetermined delay, making energy delivery more efficient. This results in faster treatment while maintaining a state where thermal damage is reduced or eliminated.

[0219] In some embodiments, energy delivery is actuated by impedance-based feedback control. It should be understood that the measured impedance may vary depending on the location of the energy delivery electrode. When the delivery electrode is implanted in tissue (i.e., “encapsulated”), the impedance will be higher than when it is simply in contact with the tissue, and this will, in turn, be higher than in the blood which is not in contact with the tissue. Excessive encapsulation can lead to greater thermal damage for PEF treatment. Excessively low impedance can lead to delivery primarily into the blood rather than the tissue, potentially resulting in insufficient or absent lesion formation. Therefore, in some embodiments, energy delivery is actuated when the impedance is within a desired range that reflects the desired encapsulation within the tissue.

[0220] In some embodiments, energy delivery is actuated by feedback from one or more sensors configured to detect the distribution of an active substance within the body, such as within a specific region of the body or a particular tissue. This can be useful when the procedure involves gene therapy, electrochemotherapy, or the delivery of an active substance to cells within the body. In some embodiments, the active substance comprises a molecule, and a key feature of molecular transport within the body is the in vivo distribution of the molecule. Exemplary molecules, to name a few, include plasmids, DNA plasmids, RNA (e.g., messenger RNA (mRNA), small interfering RNA (siRNA), microRNA), oligonucleotides, antisense oligonucleotides (ASOs), proteins, and / or substances that induce genetic or epigenetic changes in cellular behavior. For a molecule to be successfully transported to a cell, the molecule should be at a desired location within the body at a desired time, at a desired concentration, in relation to the delivery of energy for transport. Thus, when these key factors coincide, energy can be delivered regardless of the cardiac cycle. This provides increased efficacy and efficiency.

[0221] In one embodiment, one or more impedance sensors may be used to measure the impedance, for example, between two tines, or between a tine and a central shaft on a delivery device, as the active substance is delivered through one or more tines. If the injected active substance has a different conductivity from the surrounding tissue, the sensors may provide information about the distribution of the active substance. In another embodiment, pH, optical fiber, bipolar impedance, or other types of sensors may be used to detect when the active substance diffuses, for example, from the central injection point to the lateral tines. In some embodiments, the active substance is a drug filled with a radiopaque dye. In such cases, imaging, rather than sensors, is used to provide feedback control over PEF energy delivery.

[0222] These alternative delivery options offer better outcomes but also increase the speed of the procedure. With constant energy delivery over any given period, typically, the portion of time excluded from energy delivery is available here, allowing more energy to be delivered in a shorter time. Typically, considering cardiac synchronization, only 20% of the available time (e.g., the entire cardiac cycle) may be available for energy delivery. By eliminating these limitations through the use of specialized PEFs, the remaining 80% is available here. This represents a 5-fold or 500-fold increase. Similarly, when multi-spline or multi-tine devices are used for energy delivery, the 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 the sequence or pattern of activation to be closer together over time, leading to an increased energy delivery rate and reduced procedure time.

[0223] Additional exemplary embodiments of energy delivery systems configured to deliver PEF therapy to various parts of the body are described in International Patent Application PCT / US2021 / 044469, filed on 3 August 2021 and titled "PULSED ELECTRIC FIELD TRANSFER OF MOLECULES TO CELLS WHILE IN THE BODY," International Patent Application PCT / US2022 / 019719, filed on 10 March 2022 and titled "DEVICES FOR THE DELIVERY OF PULSED ELECTRIC FIELDS IN THE TREATMENT OF CARDIAC TISSUE," and filed on 19 September 2022 and titled "CONTROLLED LESION AND IMMUNE RESPONSE TO PULSED ELECTRIC FIELD This is provided in International Patent Application No. PCT / US2022 / 044021, titled “THERAPY” (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, filed on April 8, 2021, and titled “PULSED ELECTRIC FIELD WAVEFORM MANIPULATION AND USE” (all of which are incorporated herein by reference for all purposes).

[0224] As mentioned above, one or more energy delivery algorithms 152 can be programmed or pre-programmed into the generator 104 for delivery to patient P. One or more energy delivery algorithms 152 define an electrical signal that delivers energy. It should be understood that various energy delivery algorithms 152 may be used. In some embodiments, algorithm 152 defines a signal having a waveform comprising a series of energy packets, each energy packet comprising a series of high-voltage pulses. In such embodiments, algorithm 152 defines signal parameters such as the energy amplitude (e.g., voltage) and duration of the applied energy, consisting of, to some extent, the number of packets, the number of pulses in the packets, and the fundamental frequency of the pulse sequence. Additional parameters may include, to some extent, the switching time between polarities in a biphasic pulse, the dead time between biphasic cycles, and the pause time between packets, which will be described in more detail in later sections. Fixed pause periods between packets may exist, or packets may be gated to a particular metric. Various intentional pause period algorithms may exist, or no pause period may be applied between packets. A feedback loop and / or equivalent based on sensor information and automatic shut-off specifications may be included. A. Voltage

[0225] The voltage used and considered may be the peak of a square waveform, the peak in a sinusoidal or sawtooth waveform, or the RMS voltage of a sinusoidal or sawtooth waveform. In some embodiments, energy is delivered in a unipolar manner, and each high-voltage pulse or set voltage 416 is approximately 500V to 10,000V, including, to some examples, approximately 250V, 500V, 1,000V, 1,500V, 2,000V, 2,500V, 3,000V, 3,500V, 4,000V, 4,500V, 5,000V, 5,500V, and 6,000V, in particular, approximately 3,500V to 4,000V, approximately 3,500V to 5,000V, and approximately 3,500V to 6,000V (including all values ​​and subranges in between). The voltage delivered to the tissue may be based on a setpoint on the generator 104, either taking into account the electrical loss along the length of the device 102 due to the inherent impedance of the device 102, or not taking into account the loss along the length; that is, the delivered voltage may be measured at the generator or at the tip of the instrument.

[0226] It should be understood that in various embodiments, the output is controlled or modified to achieve a desired current rather than voltage. In some embodiments, energy is delivered in a unipolar manner, with currents of 20 amperes, 21 amperes, 22 amperes, 23 amperes, 24 amperes, 25 amperes, 26 amperes, 27 amperes, 28 amperes, 29 amperes, 30 amperes, 31 amperes, 32 amperes, 33 amperes, 34 amperes, or 35 amperes, to name a few. B.Frequency

[0227] It should be understood that the number of biphasic cycles per second is the frequency when the signal is continuous. Typically, signals have frequencies in the range of 100-600kHz, such as 100-200kHz, 100-300kHz, 200-400kHz, 200-500kHz, 300-400kHz, 300-500kHz, 300-600kHz, 400-500kHz, 400-600kHz, 500-600kHz, 100kHz, 200kHz, 300kHz, 400kHz, 500kHz, or 600kHz, to name a few. C. Voltage-Frequency Balance

[0228] The frequency of the delivered waveform may vary in sync with the treatment voltage to ensure an appropriate therapeutic effect. Such synergistic changes may include a decrease in voltage that induces a weaker effect, combined with a decrease in frequency that induces a stronger effect. For example, in some cases the treatment may be delivered using 3,000V in a unipolar system with a waveform frequency of 600kHz, while in other cases the treatment may be delivered using 2,000V with a waveform frequency of 400kHz. D. Packet

[0229] As mentioned, algorithm 152 defines a signal having a waveform comprising a series of energy packets, each energy packet comprising a series of high-voltage pulses. The cycle count 420 is half the number of pulses in each biphasic packet. Referring to Figure 4, the first packet 402 has a cycle count 420 of 2 (i.e., four biphasic pulses). In some embodiments, the cycle count 420 is set to 2 to 1,000 per packet (including all values ​​and subranges in between). In some embodiments, the cycle count 420 is 5 to 1,000 per packet, 2 to 10 per packet, 2 to 20 per packet, 2 to 25 per packet, 10 to 20 per packet, 20 per packet, 20 to 30 per packet, 25 per packet, 20 to 40 per packet, 30 per packet, 30 to 45 per packet, 45 per packet, 20 to 50 per packet, 30 to 60 per packet, up to 60 per packet, up to 80 per packet, up to 100 per packet, up to 1,000 per packet, or up to 2,000 per packet (including all values ​​and subranges in between).

[0230] Packet duration is determined, among other factors, primarily by the cycle count. With respect to the matching pulse duration (or sequence of positive and negative pulse durations for a biphasic waveform), a higher cycle count results in a longer packet duration and a greater amount of energy delivered. In some embodiments, packet durations are in the range of approximately 50 to 1,000 microseconds, such as 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 125 μs, 150 μs, 175 μs, 200 μs, 250 μs, 100-250 μs, 150-250 μs, 200-250 μs, and 500-1,000 μs. In other embodiments, packet durations are in the range of approximately 100 to 1,000 microseconds, such as 150 μs, 200 μs, 250 μs, 500 μs, or 1,000 μs.

[0231] The number of packets or packet count delivered during treatment typically includes 1 to 250 packets (including all values ​​and subranges within that range). In some embodiments, the number of packets delivered during treatment includes 2 to 5 packets, 3 packets, 5 packets, 5 to 10 packets, 10 packets, 12 packets, 10 to 15 packets, 15 packets, 20 packets, 15 to 20 packets, 25 packets, 30 packets, or more than 30 packets. E. Suspension period

[0232] In some embodiments, the time between packets, referred to as the pause period 406, is set to approximately 0.001 seconds to approximately 5 seconds (including all values ​​and subranges within that period). In other embodiments, the pause period 406 extends to approximately 0.01 to 0.1 seconds (including all values ​​and subranges within that period). In some embodiments, the pause period 406 is approximately 0.5 milliseconds to 500 milliseconds, 1 to 250 milliseconds, or 10 to 100 milliseconds, to name a few. F. Batch

[0233] In some embodiments, the signal is synchronized with physiological or other characteristics so that each packet is delivered synchronously within a specified period or in response to a specified trigger. It should be understood that packets delivered in such a time can be considered a batch or bundle. Thus, each batch has a desired number of packets so that a desired total number of packets have been delivered by the end of the treatment period. Each batch may have the same number of packets, however, in some embodiments, batches may have varying numbers of packets.

[0234] In some embodiments, only one packet is delivered in response to a trigger. In such cases, the pause period may be considered the same as the period between batches. However, when more than one packet is delivered between batches, the pause period is typically different from the period between batches. In such cases, the pause period is typically much shorter than the period between batches. In some embodiments, each batch contains, to give a few examples, 1–10 packets, 1–5 packets, 1–4 packets, 1–3 packets, 2–3 packets, 2 packets, 3 packets, 4 packets, 5 packets, and 5–10 packets. In some embodiments, each batch has a period of, to give a few examples, 0.5 milliseconds–1 second, 1 milliseconds–1 second, 10 milliseconds–1 second, and 10 milliseconds–100 milliseconds. In some embodiments, the period between batches is variable. In some cases, the period between batches is 0.25–5 seconds.

[0235] Treatment of a tissue area continues until the desired number of batches are delivered to the tissue area. In some embodiments, 2 to 50 batches are delivered per treatment, and the treatment is considered to be the 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, and so on. G. Switching time and dead time

[0236] Also known as interphase delay, the switching time is an energy-free delay or period delivered between the positive and negative peaks of a biphasic pulse, as illustrated in Figure 4. In some embodiments, the switching time ranges from approximately 0 to approximately 1 microsecond (including all values ​​and subranges within that range). In other embodiments, the switching time ranges from 1 to 20 microseconds (including all values ​​and subranges within that range). In yet another embodiment, the switching time ranges from approximately 2 to approximately 8 microseconds (including all values ​​and subranges within that range).

[0237] Delays may also be inserted between each biphasic cycle and are referred to as “dead time” or inter-pulse delay. Dead time occurs between biphasic pulses but within a packet. This is in contrast to pauses or inter-packet delays that occur between packets. In other embodiments, the dead time 412 is in the range of about 0–0.5 microseconds, 0–10 microseconds, 2–5 microseconds, 0–20 microseconds, about 0–about 100 microseconds, or about 0–about 100 milliseconds (including all values ​​and subranges within that range). In some embodiments, the dead time 412 is in the range of 0.2–0.3 microseconds. Dead time may also be used to define the period between separate monophasic pulses within a packet.

[0238] Delays such as switching time and dead time are introduced into packets to reduce the effect of biphasic cancellation within the waveform. In some cases, both switching time and dead time are increased together to enhance the effect. In other cases, only the switching time or only the dead time is increased to induce this effect. G. Waveform

[0239] In some embodiments, it should be understood that the waveform 400 has symmetrical pulses such that the voltage and duration of the pulse in one direction (i.e., positive or negative) are equal to the voltage and duration of the pulse in the other direction. In other embodiments, it should be understood that the waveform 400 has voltage imbalance. For example, each packet 402, 404 may consist of a first biphasic cycle (comprising a first positive pulse peak 408 having a first voltage V1 and a first negative pulse peak 410 having a second voltage V2) and a second biphasic cycle (comprising a second positive pulse peak 408' having a first voltage V1 and a second negative pulse peak 410' having a second voltage V2), where the first voltage V1 is greater than the second voltage V2. The first and second biphasic cycles are separated by a dead time 412 between each pulse. Therefore, the voltage in one direction (i.e., positive or negative) is greater than the voltage in the other direction, and thus the area under the positive portion of the curve is not equal to the area under the negative portion of the curve. This unbalanced waveform may produce a more pronounced therapeutic effect. It should be understood that in some embodiments, the unbalance includes pulses with pulse widths of unequal durations. In some embodiments, the biphasic waveform is unbalanced, and therefore the voltage in one direction is equal to the voltage in the other direction, but the duration in one direction (i.e., positive or negative) is greater than the duration in the other direction, and thus the area under the curve of the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

[0240] It should be understood that the devices, systems, and methods described herein deliver energy to target tissue using energy delivery systems. Generally, an energy delivery system includes a specialized energy delivery device, a waveform generator, and at least one distinctly different energy delivery algorithm. Additional accessories and instruments may be used. For example, in some embodiments, the energy delivery device is delivered through an endoscope, typically specific to the anatomical site in which it is used, such as a gastroscopy (upper GI endoscopy, including the stomach, esophagus, and small intestine (duodenum)), colonoscopy (large intestine), bronchoscope (lung), laryngoscope (larynx), cystoscope (urinary tract), duodenoscopy (small intestine), small intestinoscope (digestive system), ureteroscope (ureter), hysteroscope (cervix, uterus), etc. It should be understood that in other embodiments, the energy delivery device can be delivered through a catheter, sheath, introducer, needle, or other delivery system.

[0241] Intraluminal access allows for the treatment of target tissue from various lumens within the body. Lumens are the spaces inside tubular or hollow structures within the body, and some examples include passages, conduits, transport tubes, and cavities. Exemplary luminal structures include, to some extent, blood vessels, esophagus, stomach, small and large intestines, colon, bladder, urethra, urinary collecting duct, uterus, vagina, fallopian tubes, ureters, kidneys, renal tubules, spinal canal, spinal cord, and others throughout the body, as well as structures within and containing organs such as the lungs, heart, and kidneys. In some embodiments, target tissue is accessed via a nearby luminal structure. In some cases, energy delivery devices are advanced through various luminal structures or branches of luminal systems to reach the target tissue site. For example, when accessing a target tissue site via a blood vessel, the energy delivery device may be remotely inserted and advanced through various branches of the vascular system to reach the target site. Similarly, if the luminal structure originates from a natural orifice such as the nose, mouth, urethra, or rectum, entry may occur through the natural orifice, and the energy delivery device then advances through the bifurcation of the luminal system to reach the target tissue location. Alternatively, the luminal structure may be entered near the target tissue via incision or other means. This may be the case when accessing a luminal structure that is not part of a larger system or is otherwise difficult to access.

[0242] It should be understood that various anatomical sites can be treated within luminal structures using the systems and methods described herein. Examples include, but are not limited to, the liver, pancreas, gallbladder, kidneys, prostate, ovaries, lymph nodes and lymphatic drainage ducts, underlying muscle tissue, bone tissue, brain, eyes, thyroid gland, etc., including luminal structures themselves, soft tissues throughout the body located near luminal structures, and solid organs accessible from luminal structures. It should also be understood that various tissue sites can be accessed percutaneously or by other means.

[0243] The energy delivery device delivers the energy provided by the waveform generator according to at least one distinctly different energy delivery algorithm. In some embodiments, it should be understood that the energy delivery device also delivers an active substance. However, in other embodiments, the active substance is delivered by a separate device, such as an IV, catheter, or needle injection. Optionally, the active substance may be delivered by both the energy delivery device and the separate device. Exemplary embodiments of specialized energy delivery devices focusing primarily on unipolar energy delivery are provided herein, however, it should be understood that bipolar or multipolar arrays may also be used.

[0244] The above detailed description includes references to accompanying drawings, which form part of the detailed description. The drawings illustrate specific embodiments in which the invention may be put into practice. These embodiments are also referred to herein as “Examples.” Such embodiments may include elements in addition to those shown or described. However, the inventors also envision embodiments in which only those elements shown or described are provided. Furthermore, the inventors also envision embodiments that use any combination or arrangement of those elements shown or described, either relating to a particular embodiment (or one or more aspects thereof) shown or described herein, or to another embodiment (or one or more aspects thereof).

[0245] In the event of any conflict in usage between this book and any document incorporated in this manner, the usage in this book shall prevail.

[0246] In this text, the terms “a” or “an” are used to include “one or more than one,” independently of any other instance or use of “at least one” or “one or more,” as is common in patent documents. In this text, the term “or” is used to mean “non-exclusive or,” such that “A or B” includes “A but not B,” “B but not A,” and “A and B.” In this text, the terms “including” and “in which” are used as plain English equivalents of the individual terms “comprising” and “wherein.” Furthermore, in the following claims, the terms “including” and “comprising” are non-restrictive; that is, systems, devices, articles, compositions, formulations, or processes that include elements in addition to those enumerated after such terms in the claim are still considered to fall within the scope of that claim. Furthermore, in the following claims, the terms "first," "second," and "third," etc., are used merely as identifiers and are not intended to impose numerical requirements for their purpose.

[0247] The above description is intended to be illustrative, not restrictive. For example, the embodiments (or one or more aspects thereof) described above may be used in combination with one another. Other embodiments may also be used by those skilled in the art, subject to a closer examination of the above description. The abstract is provided in accordance with 37 C. FR § 1.72(b) to enable the reader to quickly confirm the nature of this technical disclosure. It should be considered with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above detailed description, various features may be grouped together for the sake of brevity of the disclosure. This should not be interpreted as meaning that any disclosed feature not claimed is essential to any claim. Rather, the subject matter of the invention may be less than all the features of a particular disclosed embodiment. Accordingly, the following claims are incorporated herein as examples or embodiments within the detailed description, and each claim stands independently as a separate embodiment, and it is assumed that such embodiments may be combined with one another in various combinations or rearrangements. The scope of the present invention should be determined by reference to the appended claims, along with the entire range of equivalents enjoyed by such claims.

Claims

1. A system for delivering energy to target tissues within the torso of a patient with a cardiac cycle, At least one energy delivery body configured to deliver energy to the target tissue, A generator electrically communicating with the at least one energy delivery electrode, the generator includes an algorithm for delivering the dose of energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, the energy having a waveform comprising a plurality of pulses, each of which has a voltage of at least 1,000 V and each below a threshold for inducing arrhythmias, and A system that includes these features.

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

3. The system according to any one of the claims, wherein the voltage is in the range of 1,000 to 10,000 V.

4. The system according to any one of the claims, wherein the pulses are spaced apart so 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 so that at least one of the pulses is delivered to the target tissue during the intermediate and / or terminal phase 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 so 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 so that at least one of the pulses is delivered to the target tissue during the peak of maximum contraction of the atrial or ventricular systole of the cardiac cycle.

8. The system according to any one of the claims, wherein the plurality of pulses comprises at least one packet of pulses.

9. The system according to claim 8, wherein the at least one packet of pulse comprises at least six packets of pulse, each packet comprising 40 biphasic pulses with an inter-pulse delay of 1,000 microseconds.

10. The system according to any one of the claims, wherein each pulse has a pulse duration of 10 microseconds or less.

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

12. The system according to claim 10, wherein each pulse has a voltage in the range of 1,000 to 10,000 V.

13. The system according to claim 12, wherein each pulse has a voltage in the range of 1,000 to 5,000 V.

14. The system according to any one of claims 1 to 9, wherein each pulse has a voltage in the range of 1,000 to 3,000 V, and each pulse has a pulse duration in the range of 25 μs or less.

15. The system according to any one of claims 1 to 9, wherein each pulse has a voltage in the range of 1,000 to 1,500 V, and each pulse has a pulse duration in the range of 50 μs or less.

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

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

18. The system according to any one of claims 1 to 16, wherein the target tissue is located within the gastrointestinal tract, urinary tract, or reproductive tract of the patient.

19. The system according to any one of claims 1 to 16, wherein the energy is delivered at a constant delivery rate, the target tissue includes cardiac tissue, and the system further comprises a robotic device programmed to pull the energy delivery body along the cardiac 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 comprises a probe.

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

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

23. The system according to any of the claims, wherein energy delivery is synchronized with the patient's respiration without cardiac synchronization.

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

25. The system according to any one of claims 1 to 22, wherein energy delivery is decoupled from synchronization with the cardiac cycle and is operated by feedback control.

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

27. The system according to claim 25, further comprising one or more sensors configured to detect the active substance in the body, wherein energy delivery is actuated by feedback from the one or more sensors.

28. The system according to claim 27, wherein the active substance comprises a drug, a molecule, a gene, or a chemotherapeutic agent.

29. The system according to any one of claims 27-28, wherein the energy delivery body comprises at least one tine extending from a catheter, and the system further comprises one or more impedance sensors configured to measure the impedance between one of the at least one tines and another of the at least one tine or a portion of the catheter.

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

31. A system for delivering energy to target tissues within the torso of a patient with a cardiac cycle, At least one energy delivery body configured to deliver energy to the target tissue, A generator electrically communicating with at least one energy delivery electrode, the generator includes an algorithm for delivering the dose of energy to the at least one energy delivery electrode so that the dose is delivered to the target tissue, the dose consists of a plurality of pulses, at least one of which is arranged within the dose so as to be received by the target tissue during the T wave of the cardiac cycle, and the dose does not induce arrhythmias, and the generator and A system that includes these features.

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

33. The system according to any one of claims 31 to 32, wherein the voltage is in the range of 1,000 to 10,000 V.

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

35. The system according to any one of claims 31-34, wherein the plurality of pulses comprises at least one packet of pulses.

36. The system according to claim 35, wherein the at least one packet of pulse comprises at least six packets of pulse, each packet comprising 40 biphasic pulses with an inter-pulse delay of 1,000 microseconds.

37. The system according to any one of claims 31-36, wherein each pulse has a pulse duration of 10 microseconds or less.

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

39. The system according to claim 37, wherein each pulse has a voltage in the range of 1,000 to 10,000 V.

40. The system according to claim 39, wherein each pulse has a voltage in the range of 1,000 to 5,000 V.

41. The system according to any one of claims 31 to 36, wherein each pulse has a voltage in the range of 1,000 to 3,000 V, and each pulse has a pulse duration in the range of 25 μs or less.

42. The system according to any one of claims 31 to 36, wherein each pulse has a voltage in the range of 1,000 to 1,500 V, and each pulse has a pulse duration in the range of 50 μs or less.

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

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

45. The system according to any one of claims 31-43, wherein the target tissue is located within the gastrointestinal tract, urinary tract, or reproductive tract of the patient.

46. The system according to any one of claims 31-45, wherein the energy is delivered at a constant delivery rate, the target tissue includes cardiac tissue, and the system further comprises a robotic device programmed to pull the energy delivery body along the cardiac tissue during energy delivery.

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

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

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

50. The system according to any one of claims 31-49, wherein energy delivery is synchronized with the patient's respiration without cardiac synchronization.

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

52. A system for delivering energy to target tissues within the torso of a patient with a cardiac cycle, At least one energy delivery body configured to deliver energy to the target tissue, A generator electrically communicating with the at least one energy delivery electrode, wherein the generator includes an algorithm for delivering the dose of energy to the at least one energy delivery electrode such that the dose is delivered to the target tissue, the dose consisting of a plurality of pulses, and the dose having a delivery time of at least the cardiac cycle. A system that includes these features.

53. A system for delivering energy to target tissues within the torso of a patient with a cardiac cycle, At least one energy delivery body configured to deliver energy to the target tissue, A generator electrically communicating with the at least one energy delivery electrode, the generator includes an algorithm for delivering the dose of energy to the at least one energy delivery electrode so that the dose is delivered to the target tissue, the energy delivery being decoupled from synchronization to the cardiac cycle and operated by feedback control, and A system that includes these features.

54. A system for delivering energy to treat target tissue within a patient that is close enough to the patient's heart to cause arrhythmia, At least one energy delivery body configured to deliver energy to the target tissue, A generator that electrically communicates with the at least one energy delivery electrode, wherein the generator includes an algorithm for delivering the 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. A system that includes these features.

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