Manipulation and use of pulsed electric field waveforms

Abstract

Providing devices, systems, and methods for treating target tissue SOLUTION: Devices, systems, and methods for delivering pulsed electric field (PEF) energy to tissue through one or more energy delivery bodies each having one or more electrodes are provided. PEF energy is generated from waveforms having various characteristics. Waveform delays, such as pulse-to-pulse delays, cycle-to-cycle delays, phase-to-phase delays, packet-to-packet delays, bundle-to-bundle delays, etc., may be utilized within a treatment to achieve a desired result. In particular, these delays may be specifically manipulated to achieve certain desired results. For example, one, some, or all of these delays may be manipulated to control various aspects of PEF therapy to mitigate any associated risks, such as gas formation, electrical discharge, cavitation, muscle contraction, and temperature rise, to name a few.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 007,233, entitled "PULSED ELECTRIC FIELD WAVEFORM MANIPULATION AND USE," filed April 8, 2020, and U.S. Provisional Patent Application No. 63 / 078,784, entitled "PULSED ELECTRIC FIELD WAVEFORM MANIPULATION AND USE," filed September 15, 2020. The disclosures of the above-referenced applications are incorporated herein by reference in their entireties for all purposes. [Background technology]

[0002] Background of the Invention

[0002] Various devices and methods have been developed for delivering therapeutic energy to the body for the treatment of disease and affliction. In some cases, such delivery is to tissue within a body lumen, passageway, or similar anatomical structure to treat diseased tissue along or within the wall of the passageway, or to affect disease associated with or accessible through the passageway. Such devices generally include a flexible, elongated shaft for traversing tortuous luminal anatomical structures and an energy delivery element mounted on the flexible, elongated shaft for delivering such energy to remote or confined locations, such as a body lumen. Such devices have been developed, for example, to treat pulmonary passageways or blood vessels of the vasculature.

[0003]

[0003] For therapeutic treatments, a variety of different types of energy are used, including radiofrequency energy, microwave energy, high-intensity focused ultrasound (HIFU) energy, and pulsed electric field (PEF) energy, to name a few. PEF energy generally delivers high-energy discharges over very short periods of time. Thus, low-voltage energy from a DC power source is converted into a high-intensity pulsed electric field. The high-intensity energy is stored in a capacitor to be discharged into the target tissue at different electrical intensities (20-80 kV cm-1) and for different times (<1 s).

[0004] PEF energy is delivered in a non-thermal manner (i.e., below the threshold for causing thermal cell death). As a result, if an extracellular matrix is ​​present, it is preserved, and the target tissue maintains its structural architecture, including blood and lymphatic vessels. Therefore, delicate structures, such as biological lumens, blood vessels, and nerves, essential for maintaining tissue integrity and functionality, can be preserved. This offers several advantages. First, it enables the treatment of tissues often considered untreatable by conventional methods. Target tissues near delicate structures generally cannot be surgically removed because it is impossible to completely and effectively surgically separate the tissue from the delicate structures. Similarly, many conventional non-surgical therapies are contraindicated due to the potential for damage to the delicate structures by the therapy or because the therapy is deemed ineffective due to the proximity of the delicate structures. Additionally, the ability to treat tissues near delicate structures also provides a more comprehensive treatment that does not leave a margin of malignancy near the delicate structures. Once the tissue is treated, the remaining structural architecture also allows for the natural influx of biological elements, such as components of the immune system, or the introduction of various drugs to promote therapeutic treatment.

[0005]

[0005] However, the use of PEF energy carries various risks, some of which are described herein below.

[0006] bubble formation

[0006] Generally, delivering PEF in an ionic solution (such as saline, blood, or interstitial fluid) results in electrolytic reactions that affect compounds in the solution, specifically the separation of water molecules to produce hydrogen gas components (at the active cathode) and chlorine gas components (at the active anode). These gases are therefore considered electrochemically produced gases. Alternating the polarity of the PEF during energy delivery reduces the degree of bubble formation by alternating the components produced. However, this alone does not completely eliminate gas generation, as active periods during each polarity phase continue to contribute to gas formation.

[0007]

[0007] Gas bubble formation has various effects in clinical cases, which vary depending on the targeted location and application. In tissue ablation applications, where one or more electrodes are placed within a targeted area of ​​tissue to deliver PEF between the electrodes or in communication with a remote external dispersion pad, gas formation is clearly visualized with ultrasound. It is mechanistically considered a minor side effect of treatment delivery and not a confounding factor that alters treatment delivery. However, gas formation contributes to several effects that may be desirable or undesirable depending on the application. In one consideration, gas formation may apply pressure to adjacent tissue areas, distort tissue geometry, disrupt tissue architecture, or displace other material within the tissue. In another consideration, gas formation may enter the bloodstream before dissolving. Circulating gaseous "bubbles" may then travel through arterial pathways or subsequent veins, causing embolism that causes ischemia in downstream tissues, resulting in downstream cell and tissue death, pain, and other risks to the patient. The bubbles may travel back through the systemic circulation before dissolving, causing pulmonary embolism, which can cause pain, morbidity, or death to the patient.

[0008] In addition to gases generated by induced electrochemical reactions, gases can also be generated by vaporization. Electric current increases the temperature of the ionic solution through Joule heating. When the induced temperature exceeds the phase change value, water vaporization occurs. Both vaporized and electrochemically generated gases exhibit much lower electrical conductivity than ionic solutions. Therefore, in tissue areas being treated with high-voltage, high-energy electrical pulses, the resulting electric field within the gas can exceed electrical breakdown, manifesting as sparking electric arcs or larger combustion events depending on the size, quantity, type, and distribution of the bubbles being generated. This is a particular risk when the PEF protocol and tissue type result in the generation of large amounts of gas that cannot be easily removed from the local tissue environment. Such spark generation, promotion, and potential combustion events caused by bubble formation can result in high-current events that affect generator performance (or destroy the generator) and distortions of the energy deposition pattern that affect treatment outcomes, thereby creating risks including burned tissue, over-treated tissue, under-treated tissue, or a combination of these effects. All of these effects can seriously impact the efficacy, morbidity, and potentially mortality of PEF therapy.

[0009] Another consideration regarding gas formation is that the presence of a gas:liquid:tissue mixture results in a non-uniformly altered electrical conductivity environment (essentially, current may preferentially flow around or through the gas, thereby altering its flow through the target tissue). This can result in higher energy concentration in some areas and a lack or reduced energy concentration in other areas. This essentially distorts the delivery and application of energy, thereby potentially impacting the effectiveness of the treatment, morbidity, and mortality of the procedure.

[0010]

[0010] Risks beyond the effects of gas formation in solid tissue regions are presented and potentially enhanced when delivering PEF therapy to fluid targets, such as blood in the vascular or cardiopulmonary systems. Of particular concern, gas bubbles generated in the left atrium and left ventricle of the heart are readily released by the heart into the aorta. These bubbles can enter the coronary circulation, carotid canal, or other blood vessels. If the bubbles do not dissolve and return to fluid, they can become lodged in narrowed sections of arteries, thereby restricting or eliminating blood flow through these vessels and causing ischemia in downstream tissues. Bubble formation has been identified as a risk in cardiac treatment for conditions such as atrial fibrillation with various energy modalities, including cryoablation, radiofrequency ablation, and PEF therapy. There is a significant risk of symptomatic and silent cerebral ischemic events. Additionally, the tendency of bubbles to float or rise increases the likelihood of bubbles entering the coronary arteries of patients in the supine position. Due to the potential and severity of problems that can be induced by gas formation during conventional procedures, such as atrial fibrillation electrical isolation procedures, clinicians and researchers have taken special care to quantify and reduce the risk of these events in patients, including efforts to reduce or capture bubble formation. However, gas formation from PEF treatment remains a common side effect and patient risk.

[0011] electrical discharge

[0011] When delivering PEF between electrodes, the generally high voltages used can cause dielectric breakdown in the delivery device, the solid components of the tissue, or the fluid within the tissue. This can cause an electrical discharge within this medium from the excitation area of ​​the electrode. The electrical discharge can occur on a microscale, where it is invisible to the eye, or it can occur on a visible scale, where it generally appears as a visible "arc" or spark. The discharge is often accompanied by a pressure wave and an audible sound that increase with the intensity of the discharge.

[0012]

[0012] Discharges from electrodes can distort the quantity and distribution of items affected by PEF therapy. They can concentrate currents in focal areas, causing stronger therapeutic effects (overtreatment) or Joule heating burnout in the area near the discharge. This can also reduce the induced current and subsequent electric field in the rest of the tissue (undertreatment). Electrical breakdown of the current path can also result in spikes in current flowing through the system, which can increase the total current that must be generated by the PEF generator. Such spikes can exceed the generator's PEF generation capacity or cause high currents within the generator that damage its internal circuitry. In addition, electrical discharges across ionic media can generate reactive species (primarily nitrogen and oxygen) that alter the composition of the media, which has a significant impact on the solution's pH and normal biomolecular interactions.

[0013]

[0013] Electrical discharges can generally occur in PEF therapies due to the voltages used in these therapies. Bipolar electrode configurations, due to the close proximity of the cathode and anode to one another, are particularly susceptible to large electrical arcing events, which can cause electrical discharges between the electrodes, also known as full discharges. This can lead to complete short circuits if the voltage-to-distance ratio is not properly determined. Allowing electrical discharges introduces a degree of uncertainty and risk into treatment. Avoiding them can reduce the effectiveness of the therapy by reducing the intensity of the therapy that can be delivered.

[0014] cavity formation

[0014] As a result of both visible and invisible electrical discharges, pressure waves are produced that are evident as an audible "popping" sound. This sound is common in many PEF therapies and is recognized as a side effect of treatment delivery. However, if the discharge and pressure waves are of sufficient intensity and repeated a sufficient number of times, the energy transferred and imparted into tissue from these pressure waves can severely disrupt tissue architecture and cells. The resulting effect is the repeated creation of defects or cavities in the tissue in areas near the electrodes that experience the greatest intensity of these effects.

[0015]

[0015] Cavity formation poses significant risks to treatment delivery within or near solid tissues and ductal systems. The resulting tissue "fragmentation" and destruction can damage delicate structures such as blood vessels, nerves, or other ductal systems, such as the bile duct, urethra, ureter, or lymphatic vessels. These fragmentation effects can result in bleeding, the formation of thrombi or emboli, or disruption of tissue function. PEF therapy is generally utilized in place of other therapies due to its ability to spare these delicate structures. The formation of voids by therapy negates this advantage of most PEF therapies for tissue regions in close proximity (0.1-5 mm) to the electrode.

[0016]

[0016] In other instances, cavity formation and destruction by the generated pressure waves may be desirable. For example, the destruction or removal of gallstones or kidney stones may be the goal of this type of effect. Furthermore, the fluid-filled cavities created by these effects are generally more conductive than the existing tissue. Therefore, continuing to deliver PEF (or other energy-based modalities) into this generated tissue cavity helps expand the applicable effect of the electrode, which functions as a "virtual electrode." Furthermore, the conductive fluid has a more homogeneous electrical conductivity, providing a more evenly distributed conduit for electrical flow, thereby reducing the likelihood of electrical discharge into the tissue, which can occur when electrical conductivity is non-uniform. Therefore, it is sometimes desirable to control the cavity formation resulting from PEF therapy.

[0017] Muscle contraction PEF therapy can induce desirable clinical effects by altering target tissues, which can also result in the generation of action potentials in nerves, particularly motor neurons and skeletal muscle cells. The generation of action potentials in motor neurons can result in muscle contractions during energy delivery. Muscle contractions and the generation of nerve action potentials can be uncomfortable or painful when performed in conscious or semi-conscious patients. Additionally, the electrodes delivering the therapy can move or become dislodged, potentially altering the location of the therapeutic effect. Electrode movement can also perforate or damage delicate tissues that were adjacent to the electrode location at the start of treatment. These factors, combined, pose safety concerns for patients and users when delivering PEF therapy. In general, contractions worsen as the waveform of a particular polarity becomes longer, with DC being the worst and fully symmetrical biphasic being the least contractile across a particular pulse length, and with a strong correlation to asymmetrical waveforms across the spectrum as they move from fully symmetrical to fully DC (weaker to stronger).

[0018]

[0018] In other instances, the induction of muscle contraction may be a desirable secondary (or primary) effect of PEF therapy. For example, it may be used to re-stimulate tissue that has atrophied due to nerve fibers temporarily severed by injury or clinical treatment. In such instances, PEF may be delivered in close proximity to the proximal or peripheral side of motor neurons, thereby inducing action potentials that stimulate downstream skeletal muscles, keeping them active and preventing atrophy, and promoting the regeneration and recovery of muscle and nerve tissue. Therefore, it is sometimes desirable to control and promote muscle contraction resulting from PEF therapy.

[0019] Temperature rise

[0019] The delivery of energy to tissue results in Joule heating depending on the length of time the energy is applied, among other factors. When packets or pulses of energy are delivered sequentially, the individual portions of the energy are applied simultaneously, resulting in a gradual temperature increase. This results in PEF therapy with very high to extreme and rapid temperature increases, particularly in the tissue-electrode interface and in the region within the first few millimeters of distance from the electrode. Unless appropriate mitigation measures are taken, the cumulative temperature increase can result in a thermal effect range that can destroy extracellular matrix structural proteins (e.g., collagen), resulting in disruption of tissue function and potential danger to the patient. Summary of the Invention [Problem to be solved by the invention]

[0020]

[0020] Consequently, improved therapies are desirable to control these aspects of PEF and mitigate any associated risks. Such improvements should be safe, reliable, effective, simple to implement, and cost-effective. At least some of these objectives are met by the present invention. [Means for solving the problem]

[0021] Summary of the Invention

[0021] Described herein are embodiments of devices, systems and methods for treating target tissue. Similarly, the present invention relates to the following numbered clauses:

[0022] 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with at least one electrode, the generator including at least one energy delivery algorithm that provides energy to the electrode such that pulsed electric field energy provides therapy to tissue, the energy being generated from a waveform including one or more packets of pulses to provide therapy and including one or more delay periods to manipulate, reduce, or avoid one or more secondary effects; A system including:

[0023] 2. The system of claim 1, wherein the one or more secondary effects include bubble formation.

[0024]

[0024] 3. The system of claim 2, wherein the bubble formation includes the formation of bubbles having a diameter of 0.1 mm or more.

[0025] 4. A system as claimed in any one of the preceding claims, wherein each of the pulses in the one or more packets of pulses has an on-time in the range of 0.5 to 20 microseconds.

[0026] 5. A system as claimed in any one of claims 1 to 3, wherein each of the pulses in one or more packets of pulses has a continuous on-time of up to 5 microseconds.

[0027] 6. A system as claimed in any one of the preceding claims, wherein each of the pulses has a duty cycle of 2.5 percent or less.

[0028] 7. A system as claimed in any preceding claim, wherein the delay period is 1 microsecond or greater.

[0029] 8. The system of claim 7, wherein the delay period is in the range of 1 to 250 microseconds.

[0030] 9. The system of claim 7, wherein the delay period is in the range of 10 to 100 microseconds.

[0031] 10. The system of claim 7, wherein the delay period is 100 microseconds or greater.

[0032] 11. The system of claim 7, wherein the delay period is 250 microseconds or greater.

[0033] 12. The system of claim 7, wherein the delay period is 500 microseconds or greater.

[0034] 13. The system of claim 7, wherein the delay period is 1000 microseconds or greater.

[0035]

[0035] 14. The system of claim 7, wherein at least one electrode is configured to be positioned in the ionic solution near the tissue and the delay period is in the range of 100 microseconds to 10 milliseconds.

[0036] 15. The system of claim 14, wherein the delay period is in the range of 250 microseconds to 1000 microseconds.

[0037] 16. The system of claim 7, wherein at least one electrode is configured to be positioned within tissue and the delay period is in the range of 10 microseconds to 1 millisecond.

[0038] 17. The system of claim 16, wherein the delay period is in the range of 25 microseconds to 100 microseconds.

[0039]

[0039] 18. A system as described in any one of the preceding claims, wherein the one or more packets of pulses include 100 packets, each packet including 40 biphasic pulses.

[0040]

[0040] 19. The system of claim 1, wherein the one or more secondary effects include an electrical discharge event.

[0041]

[0041] 20. The system of claim 19, wherein the electrical discharge event includes an electrical arc discharge from at least one of the at least one electrodes.

[0042] 21. A system as described in claim 19 or 20, wherein each of the pulses in the one or more packets of pulses has an on-time in the range of 1 to 50 microseconds.

[0043]

[0043] 22. A system as claimed in any one of claims 18 to 20, wherein each of the pulses in the one or more packets of pulses has a continuous on-time in the range of up to 20 microseconds.

[0044]

[0044] 23. A system as claimed in any one of claims 18 to 22, wherein each of at least one packet of pulses has a duty cycle of 20 percent or less.

[0045]

[0045] 24. The system of claim 20, wherein the electrical discharge event includes the generation of a pressure wave against the tissue.

[0046]

[0046] 25. The system of claim 24, wherein the pressure waves are sufficient to create a cavity in the tissue.

[0047] 26. The system of claim 25, wherein each of the at least one packet of pulses has a duty cycle of 50 percent or less.

[0048]

[0048] 27. A system as described in claim 25 or 26, wherein each of the pulses in the one or more packets of pulses has an on-time in the range of 10 to 100 microseconds.

[0049]

[0049] 28. A system as described in claim 25 or 26, wherein each of the pulses in the one or more packets of pulses has a continuous on-time of up to 50 microseconds.

[0050] 29. A system according to any one of claims 18 to 28, wherein the delay period is 1 microsecond or greater.

[0051] 30. The system of claim 29, wherein the delay period is in the range of 1 to 500 microseconds.

[0052] 31. The system of claim 29, wherein the delay period is in the range of 10 to 250 microseconds.

[0053] 32. The system of claim 29, wherein the delay period is 50 microseconds or greater.

[0054] 33. The system of claim 29, wherein the delay period is 250 microseconds or greater.

[0055] 34. The system of claim 29, wherein the delay period is 500 microseconds or greater.

[0056] 35. The system of claim 29, wherein the delay period is 1000 microseconds or greater.

[0057]

[0057] 36. A system described in any one of claims 18 to 29, wherein at least one electrode is configured to be positioned in the ionic solution near tissue and the delay period is in the range of 50 microseconds to 10 milliseconds.

[0058]

[0058] 37. The system of claim 36, wherein the delay period is in the range of 250 to 1000 microseconds.

[0059]

[0059] 38. A system as described in any one of claims 18 to 29, wherein at least one electrode is configured to be positioned within tissue and the delay period is in the range of 100 microseconds to 10 milliseconds.

[0060] 39. The system of claim 38, wherein the delay period is in the range of 250 to 2000 microseconds.

[0061]

[0061] 40. A system described in any one of claims 18 to 29, wherein at least one electrode is configured to be positioned within a lumen, tissue is present within the lumen wall, and the delay period is in the range of 10 microseconds to 10 milliseconds.

[0062]

[0062] 41. The system of claim 40, wherein the delay period is in the range of 50 to 500 microseconds.

[0063]

[0063] 42. A system as claimed in any one of claims 18 to 41, wherein the one or more packets of pulses comprise 100 packets, each packet comprising 40 biphasic pulses.

[0064]

[0064] 43. The system of claim 1, wherein the one or more secondary effects include muscle contraction.

[0065]

[0065] 44. The system described in claim 43, wherein at least one electrode is configured to cause a lesion having a width, and reducing or avoiding muscle contraction causes the at least one electrode to maintain a position that does not move more than 25% of the width.

[0066]

[0066] 45. The system of claim 44, wherein the tissue comprises cardiac tissue and the injury comprises focal injury.

[0067]

[0067] 46. A system as claimed in any one of claims 43 to 45, wherein the delay period is 5 milliseconds or longer.

[0068]

[0068] 47. The system of claim 46, wherein the delay period is 10 milliseconds or more.

[0069]

[0069] 48. The system of claim 46, wherein the delay period is in the range of 5 milliseconds to 1 second.

[0070]

[0070] 49. The system of claim 46, wherein the delay period is in the range of 5 to 100 milliseconds.

[0071]

[0071] 50. The system of claim 46, wherein the delay period is in the range of 5 to 10 milliseconds.

[0072]

[0072] 51. The system of claim 46, wherein the delay period is in the range of 10 to 30 milliseconds.

[0073]

[0073] 52. The system of claim 46, wherein the delay period is 1000 microseconds or greater.

[0074]

[0074] 53. A system according to any one of claims 43 to 52, wherein the one or more packets of pulses comprise 100 packets, each packet comprising 40 biphasic pulses.

[0075]

[0075] 54. A system as described in any one of claims 43 to 53, wherein the one or more packets of pulses include at least two packets separated by a packet delay period of at least 30 milliseconds.

[0076]

[0076] 55. The system of claim 54, wherein each of the packets is separated by a packet delay period of at least 30 milliseconds.

[0077]

[0077] 56. A system as described in any one of the preceding claims, wherein the pulse comprises a biphasic pulse and the delay period comprises an interphase delay between a positive phase and a negative phase of the biphasic pulse.

[0078]

[0078] 57. The system of claim 56, wherein each biphasic pulse includes an interphase delay.

[0079]

[0079] 58. A system as claimed in any preceding claim, wherein the delay period includes an inter-packet delay.

[0080]

[0080] 59. The system of claim 58, wherein the inter-packet delay is in the range of 30 to 5000 milliseconds.

[0081]

[0081] 60. The system of claim 59, wherein the inter-packet delay is between 30 and 40 milliseconds.

[0082]

[0082] 61. The system of claim 59, wherein the inter-packet delay is between 3000 and 5000 milliseconds.

[0083]

[0083] 62. A system as claimed in any preceding claim, wherein the delay period includes an inter-pulse delay.

[0084]

[0084] 63. A system according to any preceding claim, wherein the waveform comprises one or more bundles, each bundle comprising two or more packets.

[0085]

[0085] 64. The system of claim 63, wherein each bundle includes three packets, and each bundle is spaced to be delivered within the ST interval of the patient's cardiac rhythm.

[0086]

[0086] 65. The system of claim 63, wherein the delay period includes an inter-bundle delay.

[0087]

[0087] 66. A system as claimed in any one of the preceding claims, wherein the waveform has a voltage amplitude of 500 to 4,000 volts.

[0088]

[0088] 67. A system according to any preceding claim, wherein the waveform has a frequency of 300 to 800 kHz.

[0089]

[0089] 68. A system as described in any one of the preceding claims, wherein each of the one or more packets has between 10 and 200 biphasic pulses.

[0090]

[0090] 69. A system as described in any one of the preceding claims, wherein each of the one or more packets has 20 to 50 biphasic pulses.

[0091]

[0091] 70. A system according to any preceding claim, wherein the treatment comprises between 5 and 100 packets.

[0092]

[0092] 71. A system according to any preceding claim, wherein the treatment comprises 10 to 60 packets.

[0093]

[0093] 72. A system as described in any one of the preceding claims, further comprising remotely distributed electrodes positionable so that energy is delivered in a monopolar manner.

[0094] 73. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides energy to the electrode such that pulsed electric field energy provides therapy to the tissue, the energy being generated from a waveform including one or more packets of pulses to provide therapy and including one or more delay periods that avoid a peak tissue temperature that would otherwise be reached by the delivery of energy; A system including:

[0095]

[0095] 74. The system of claim 73, wherein the peak temperature causes bubble formation.

[0096]

[0096] 75. A system as described in claim 73 or 74, wherein the peak temperature is 100 degrees Celsius.

[0097]

[0097] 76. A system as described in any one of claims 73 to 75, wherein the peak temperature causes an electrical discharge.

[0098]

[0098] 77. A system as claimed in any one of claims 73 to 76, wherein the delay period is 5 milliseconds or longer.

[0099]

[0099] 78. The system of claim 77, wherein the delay period is 10 milliseconds or more.

[0100]

[0100] 79. The system of claim 77, wherein the delay period is in the range of 5 milliseconds to 1 second.

[0101]

[0101] 80. The system of claim 77, wherein the delay period is in the range of 5 milliseconds to 100 milliseconds.

[0102]

[0102] 81. The system of claim 77, wherein the delay period is in the range of 5 milliseconds to 10 milliseconds.

[0103]

[0103] 82. The system of claim 77, wherein the delay period is in the range of 10 to 30 milliseconds.

[0104]

[0104] 83. A system as claimed in any one of claims 73-82, wherein the waveform comprises one or more bundles, each bundle comprising two or more packets.

[0105]

[0105] 84. The system of claim 83, wherein each bundle includes three packets, and each bundle is spaced to be delivered within the ST interval of the patient's cardiac rhythm.

[0106]

[0106] 85. The system of any one of claims 73-84, wherein the one or more packets of pulses include 100 packets, each packet including 40 biphasic pulses.

[0107]

[0107] 86. The system of any one of claims 73-85, wherein the pulse comprises a biphasic pulse and the delay period comprises an interphase delay between a positive phase and a negative phase of the biphasic pulse.

[0108]

[0108] 87. The system of claim 86, wherein each biphasic pulse includes an interphase delay.

[0109]

[0109] 88. A system as claimed in any one of claims 73 to 85, wherein the delay period includes an inter-packet delay.

[0110]

[0110] 89. The system of claim 88, wherein the inter-packet delay is in the range of 30 to 5000 milliseconds.

[0111]

[0111] 90. The system of claim 88, wherein the inter-packet delay is in the range of 30 to 40 milliseconds.

[0112]

[0112] 91. The system of claim 88, wherein the inter-packet delay is in the range of 3000 to 5000 milliseconds.

[0113]

[0113] 92. A system as claimed in any one of claims 73 to 85, wherein the delay period includes an inter-pulse delay.

[0114]

[0114] 93. A system as claimed in any one of claims 73-92, wherein the waveform comprises one or more bundles, each bundle comprising two or more packets.

[0115]

[0115] 94. The system of claim 93, wherein each bundle includes three packets, and each bundle is spaced to be delivered within the ST interval of the patient's cardiac rhythm.

[0116]

[0116] 95. The system of claim 93, wherein the delay period includes an inter-bundle delay.

[0117]

[0117] 96. A system as claimed in any one of claims 73 to 95, wherein the waveform has a voltage amplitude of 500 to 4,000 volts.

[0118]

[0118] 97. A system as claimed in any one of claims 73 to 96, wherein the waveform has a frequency of 300 to 800 kHz.

[0119]

[0119] 98. A system as described in any one of claims 73 to 97, wherein each of the one or more packets has between 10 and 200 biphasic pulses.

[0120]

[0120] 99. A system as described in any one of claims 73 to 97, wherein each of the one or more packets has between 20 and 50 biphasic pulses.

[0121]

[0121] 100. A system as claimed in any one of claims 73 to 99, wherein the treatment comprises between 5 and 100 packets.

[0122]

[0122] 101. A system according to any one of claims 73 to 99, wherein the treatment comprises 10 to 60 packets.

[0123]

[0123] 102. The system of any one of claims 73-101, further comprising remotely distributed electrodes positionable so that energy is delivered in a monopolar manner.

[0124] 103. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides energy to the electrode such that pulsed electric field energy provides therapy to tissue, the energy being generated from a waveform including at least one packet of pulses for providing therapy, each pulse having a pulse length, and at least one of the at least one packet including a delay having a delay period at least twice the pulse length; A system including:

[0125]

[0125] 104. The system of claim 103, wherein the delay period is at least 10 times the pulse length.

[0126]

[0126] 105. A system as described in claim 103 or 104, wherein at least one packet has a packet length at least 50 times the delay period.

[0127]

[0127] 106. The system of claim 105, wherein at least one packet has a packet length at least 100 times the delay period.

[0128]

[0128] 107. A system as claimed in any one of claims 103 to 106, wherein the delay includes an inter-pulse delay.

[0129]

[0129] 108. The system of claim 107, wherein the pulses are biphasic pulses and the inter-pulse delay is an inter-cycle delay.

[0130]

[0130] 109. A system according to any one of claims 103 to 106, wherein the pulse is a biphasic pulse and the delay includes an interphase delay.

[0131]

[0131] 110. A system as claimed in any one of claims 103 to 109, wherein the delay period is between 250 and 1000 microseconds.

[0132]

[0132] 111. A system as described in any one of claims 103 to 110, wherein at least one packet includes at least 25 pulses.

[0133]

[0133] 112. The system of claim 111, wherein at least one packet includes at least 40 pulses.

[0134]

[0134] 113. The system of any one of claims 103-112, wherein at least one packet is separated from an adjacent packet by an inter-packet delay of at least 30 microseconds.

[0135]

[0135] 114. The system of claim 113, wherein at least one packet is separated from an adjacent packet by an inter-packet delay of between 100 and 5000 microseconds.

[0136]

[0136] 115. A system according to any one of claims 103 to 114, wherein the treatment comprises between 5 and 100 packets.

[0137]

[0137] 116. The system of claim 115, wherein the treatment includes 10 to 60 packets.

[0138]

[0138] 117. A system as described in any one of claims 103 to 116, wherein the waveform has a voltage amplitude of 500 to 10,000 volts.

[0139]

[0139] 118. A system as claimed in any one of claims 103 to 117, wherein each pulse has a pulse length of 1.66 microseconds.

[0140]

[0140] 119. The system of any one of claims 103-117, wherein each pulse has a pulse length of 2.5 microseconds.

[0141]

[0141] 120. The system of any one of claims 103-117, wherein each pulse has a pulse length of 20 microseconds.

[0142]

[0142] 121. The system of any one of claims 103-120, further comprising remotely distributed electrodes positionable so that energy is delivered in a monopolar manner.

[0143]

[0143] 122. A system described in any one of claims 103 to 121, wherein the delay period is long enough to reduce or avoid bubble formation near at least one electrode.

[0144]

[0144] 123. A system described in any one of claims 103 to 122, wherein the delay period is sufficiently long to reduce or avoid an electrical discharge event near at least one electrode.

[0145]

[0145] 124. A system according to any one of claims 103 to 123, wherein the delay period is long enough to reduce or avoid cavitation in the tissue.

[0146]

[0146] 125. A system as described in any one of claims 103-124, wherein the delay period is of sufficient length to reduce or avoid contraction of the patient's muscles.

[0147]

[0147] 126. A system according to any one of claims 103-125, wherein the delay period is long enough for:

[0148]

[0148] Avoiding peak tissue temperatures that would have been reached by the delivery of energy but for one or more delay periods.

[0149]

[0149] 127. The system of claim 126, wherein the peak temperature causes bubble formation.

[0150]

[0150] 128. The system of claim 126 or 127, wherein the peak temperature is 100 degrees Celsius.

[0151]

[0151] 129. A system as described in any one of claims 126-128, wherein the peak temperature causes an electrical discharge.

[0152] 130. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm for providing energy to the electrode such that pulsed electric field energy provides treatment to tissue, the energy being generated from a waveform including at least one packet of biphasic pulses for providing treatment, each biphasic pulse including an interphase delay in the range of 250 to 1000 microseconds; A system including:

[0153]

[0153] 131. The system of claim 130, wherein the waveform has a voltage amplitude of 500 to 10,000 volts.

[0154]

[0154] 132. The system of claim 130 or 131, wherein each pulse has a pulse length of 1.66 microseconds.

[0155]

[0155] 133. The system of claim 130 or 131, wherein each pulse has a pulse length of 2.5 microseconds.

[0156]

[0156] 134. The system of claim 130 or 131, wherein each pulse has a pulse length of 20 microseconds.

[0157]

[0157] 135. A system described in any one of claims 130-134, wherein the delay period is long enough to reduce or avoid bubble formation near at least one electrode.

[0158]

[0158] 136. A system described in any one of claims 130-135, wherein the delay period is sufficiently long to reduce or avoid an electrical discharge event near at least one electrode.

[0159]

[0159] 137. A system described in any one of claims 130-136, wherein the delay period is long enough to reduce or avoid cavitation in the tissue.

[0160]

[0160] 138. A system described in any one of claims 130-137, wherein the delay period is of sufficient length to reduce or avoid contraction of the patient's muscles.

[0161]

[0161] 139. A system according to any one of claims 130-138, wherein the delay period is long enough for:

[0162]

[0162] Avoiding peak tissue temperatures that would have been reached by the delivery of energy but for one or more delay periods.

[0163]

[0163] 140. The system of claim 139, wherein the peak temperature causes bubble formation.

[0164]

[0164] 141. The system of claim 139 or 140, wherein the peak temperature is 100 degrees Celsius.

[0165]

[0165] 142. A system as described in any one of claims 139-141, wherein the peak temperature causes an electrical discharge.

[0166]

[0166] 143. The system of any one of claims 130-142, further comprising remotely distributed electrodes positionable so that energy is delivered in a monopolar manner.

[0167] 144. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides energy to the electrode such that pulsed electric field energy provides treatment to tissue, the energy being generated from a waveform including 2 to 60 packets of pulses for providing treatment, each packet including at least one delay period within a range of 250 to 1000 microseconds; A system including:

[0168]

[0168] 145. The system of claim 144, wherein the waveform has a voltage amplitude of 500 to 10,000 volts.

[0169]

[0169] 146. The system of claim 144 or 145, wherein each pulse has a pulse length of 1.66 microseconds.

[0170]

[0170] 147. The system of claim 144 or 145, wherein each pulse has a pulse length of 2.5 microseconds.

[0171]

[0171] 148. The system of claim 144 or 145, wherein each pulse has a pulse length of 20 microseconds.

[0172]

[0172] 149. A system described in any one of claims 144-148, wherein the delay period is sufficiently long to reduce or avoid bubble formation near at least one electrode.

[0173]

[0173] 150. A system described in any one of claims 144-149, wherein the delay period is sufficiently long to reduce or avoid an electrical discharge event near at least one electrode.

[0174]

[0174] 151. A system described in any one of claims 144-150, wherein the delay period is long enough to reduce or avoid cavity formation in the tissue.

[0175]

[0175] 152. A system as described in any one of claims 144-151, wherein the delay period is of sufficient length to reduce or avoid contraction of the patient's muscles.

[0176]

[0176] 153. A system as claimed in any one of claims 144-152, wherein the delay period is long enough for:

[0177]

[0177] Avoiding peak tissue temperatures that would have been reached by delivery of energy but for one or more delay periods.

[0178]

[0178] 154. The system of claim 153, wherein the peak temperature causes bubble formation.

[0179]

[0179] 155. The system of claim 153 or 154, wherein the peak temperature is 100 degrees Celsius.

[0180]

[0180] 156. A system as described in any one of claims 153-155, wherein the peak temperature causes an electrical discharge.

[0181]

[0181] 157. The system of any one of claims 144-156, further comprising remotely distributed electrodes positionable so that energy is delivered in a monopolar manner.

[0182] 158. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides energy to the electrode such that pulsed electric field energy provides treatment to tissue, the energy being generated from a waveform including at least one packet of pulses having a delay period, the at least one packet having a packet length at least 50 times the delay period; A system including:

[0183]

[0183] 159. The system of claim 158, wherein at least one packet has a packet length at least 100 times the delay period.

[0184]

[0184] 160. The system of claim 158 or 159, wherein each pulse has a pulse length of 1.66 microseconds.

[0185]

[0185] 161. The system of claim 158 or 159, wherein each pulse has a pulse length of 2.5 microseconds.

[0186]

[0186] 162. The system of claim 158 or 159, wherein each pulse has a pulse length of 20 microseconds.

[0187]

[0187] 163. A system described in any one of claims 158-162, wherein the delay period is sufficiently long to reduce or avoid bubble formation near at least one electrode.

[0188]

[0188] 164. A system described in any one of claims 158-163, wherein the delay period is sufficiently long to reduce or avoid an electrical discharge event near at least one electrode.

[0189]

[0189] 165. A system described in any one of claims 158-164, wherein the delay period is of sufficient length to reduce or avoid cavitation in the tissue.

[0190]

[0190] 166. A system as described in any one of claims 158-165, wherein the delay period is of sufficient length to reduce or avoid contraction of the patient's muscles.

[0191]

[0191] 167. A system described in any one of claims 158 to 166, wherein the delay period is sufficiently long to avoid peak tissue temperatures that would have been reached by delivery of energy in the absence of one or more delay periods.

[0192]

[0192] 168. The system of claim 167, wherein the peak temperature causes bubble formation.

[0193]

[0193] 169. The system of claim 167 or 168, wherein the peak temperature is 100 degrees Celsius.

[0194]

[0194] 170. A system described in any one of claims 167-169, wherein the peak temperature causes an electrical discharge.

[0195]

[0195] 171. The system of any one of claims 167-170, further comprising remotely distributed electrodes positionable so that energy is delivered in a monopolar manner.

[0196] 172. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with at least one electrode, the generator including at least one energy delivery algorithm that provides energy to the electrode such that pulsed electric field energy provides treatment to tissue, the energy being generated from a waveform including at least one packet of pulses, each pulse having a duty cycle of 50 percent or less to reduce or avoid one or more secondary effects; A system including:

[0197]

[0197] 173. The system of claim 172, wherein the one or more secondary effects include cavity formation in the tissue.

[0198]

[0198] 174. The system of claim 172, wherein each pulse has a duty cycle of 20 percent or less.

[0199]

[0199] 175. The system of claim 174, wherein the one or more secondary effects include an electrical discharge event.

[0200]

[0200] 176. The system of claim 172, wherein each pulse has a duty cycle of 2.5 percent or less.

[0201]

[0201] 177. The system of claim 176, wherein the one or more secondary effects include bubble formation.

[0202]

[0202] 178. The system of claim 177, wherein forming bubbles includes forming bubbles having a diameter of 0.1 mm or more.

[0203]

[0203] 179. A system for treating tissue, comprising: an electrode positionable near the tissue; a generator in electrical communication with the electrode, the generator including at least one energy delivery algorithm providing energy to the electrode such that pulsed electric field energy treats tissue, the energy being generated from a waveform having a specific delay period between pulses selected to affect gas formation, external electrical discharge, muscle contraction, cavitation, and / or temperature increase; A system including:

[0204] 180. A method of affecting at least one secondary effect of pulsed electric field therapy, comprising: A method comprising selecting a particular delay period between portions of a pulsed electric field waveform to affect at least one secondary effect.

[0205]

[0205] 181. The method of claim 1, wherein at least one secondary effect includes gas formation.

[0206]

[0206] 182. The method of claim 1, wherein at least one secondary effect includes an electrical discharge.

[0207]

[0207] 183. The method of claim 1, wherein at least one secondary effect includes cavitation.

[0208]

[0208] 184. The method of claim 1, wherein at least one secondary effect includes muscle contraction.

[0209]

[0209] 185. The method of claim 1, wherein at least one secondary effect includes an increase in temperature.

[0210]

[0210] These and other embodiments are described in further detail in the following description in conjunction with the accompanying drawings.

[0211] Incorporation by Reference

[0211] All publications, patents, and patent applications mentioned in this specification are incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0212] BRIEF DESCRIPTION OF THE DRAWINGS

[0212] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

[0213] [Figure 1]

[0213] An embodiment of a pulsed electric field waveform is shown that is monophasic and has pulses separated by an inter-pulse delay measured from a pulse of one polarity to the next pulse of the same polarity. [Figure 2]

[0214] 1 illustrates one embodiment of a pulsed electric field waveform having pulses that are biphasic, with each cycle consisting of a pulse of one polarity followed by a pulse of the opposite polarity. [Figure 3]

[0215] FIG. 2 shows one embodiment of a pulsed electric field waveform having pulses that are biphasic, but in this embodiment, pulses of opposite polarity are separated by an interphase delay. [Figure 4]

[0216] 1 shows exemplary pulses grouped into bursts or packets. [Figure 5]

[0217] 1 shows exemplary packets grouped into batches or bundles. [Figures 6A-6C]

[0218] 10 provides ultrasound images showing bubble formation under various conditions when an energy delivery body is submerged in saline solution. [Figure 7A]

[0219] 10 shows a comparison example between the effect of different magnitudes of cycle delay on electrical discharge. [Figure 7B]

[0219] An example of a comparison between the effect of different magnitudes of cycle delay on electrical discharge is shown. [Figure 8A]

[0220] Figure 8 shows the effect of identical pulsed electric field treatment protocols, but with different cycle delays, delivered to liver tissue. Figure 8A shows the results using a waveform with a cycle delay of approximately 50 ns, which resulted in significant tissue cavitation. [Figure 8B]

[0220] Figure 8B shows the effect of identical pulsed electric field treatment protocols, but with different cycle delays, delivered to liver tissue. Figure 8B shows the results using the same waveform but with a cycle delay of approximately 1000 μs. [Figure 9]

[0221] Shown are nodes of Ranvier that occur along myelinated axons where the axolemma (axon membrane) is exposed to the extracellular space. [Figure 10]

[0222] We show that the modeling of myelinated axonal regions is modeled as electrical components. [Figure 11A]

[0223] 1 shows a pulsed electric field waveform with no or little cycle delay. [Figure 11B]

[0223] Figure 1 shows the charging and discharging behavior of motor neurons in response to pulsed electric field waveforms with no or little cycle delay. [Figure 11C]

[0223] A pulsed field waveform with a larger cycle delay is shown. [Figure 11D]

[0223] Figure 1 shows the charging and discharging behavior of motor neurons in response to pulsed electric field waveforms with larger cycle delays. [Figure 12]

[0224] 1 shows the effect of cycle delay on muscle stimulation threshold. [Figure 13]

[0225] 1 shows the amplitude and distribution of temperature rise due to a pulsed electric field protocol generated by numerical simulation. [Figure 14A]

[0226] The temperature distribution at the time of maximum temperature rise related to FIG. [Figure 14B]

[0226] The temperature distribution at the time of maximum temperature rise related to FIG. [Figure 15]

[0227] 1 provides a schematic diagram of an exemplary treatment system for use in delivering specialized pulsed electric field energy. [Figure 16]

[0228] 1 illustrates another embodiment of a treatment device configured for use in delivering specialized pulsed electric field energy, particularly configured to deliver focal therapy. [Figure 17]

[0229] A portion of the heart showing cutaway views of the right and left atria is shown with the treatment device of FIG. 16 positioned therein. [Figure 18]

[0230] 17 illustrates point-by-point treatment of tissue surrounding the opening of the left inferior pulmonary vein using the treatment device of FIG. 16. [Figure 19A]

[0231] 1 illustrates another embodiment of a therapeutic energy delivery catheter or device. [Figure 19B]

[0231] Another embodiment of a therapeutic energy delivery catheter or device is shown. [Figure 20]

[0232] 1 illustrates another embodiment of a treatment system. [Figure 21A]

[0233] 1 illustrates one embodiment of a waveform of a signal defined by an energy delivery algorithm. [Figure 21B]

[0234] 1 shows various examples of biphasic pulses with interphase time between them. [Figure 21C]

[0235] Further examples of waveforms with unequal voltages are shown. [Figure 21D]

[0236] Further examples of waveforms with unequal pulse widths are shown. [Figure 21E]

[0237] 10 shows an exemplary waveform defined by another energy delivery algorithm, in which the waveform is monophasic. [Figure 21F]

[0238] 10 shows a further example of a waveform having a monophasic pulse. [Figure 21G]

[0239] Further examples of waveforms with such phase imbalance are shown below. [Figure 21H]

[0240] 1 shows an example of a waveform that is unbalanced in both positive and negative voltages. [Figure 22]

[0241] 1 is a graph showing a portion of a sample electrocardiogram (ECG) recording of a human heart highlighting periods during which it is desirable to deliver energy pulses to the pulmonary passageways using an energy delivery body. DETAILED DESCRIPTION OF THE INVENTION

[0214] Detailed Description of the Invention

[0242] Specific embodiments of the disclosed devices, systems, and methods will now be described with reference to the drawings. Nothing in this detailed description is intended to imply that any particular component, feature, or step is essential to the invention.

[0215]

[0243] A variety of different types of energy are used for therapeutic treatment of patients, including radiofrequency (RF) energy, microwave (MW) energy, high intensity focused ultrasound (HIFU) energy, and pulsed electric field (PEF) energy, to name a few. These energy modalities differ according to the waveform of the electronic signal provided by the generator. Where possible, they are classified according to the electromagnetic spectrum. The electromagnetic spectrum ranges from less than 1 hertz to 10 Hz, corresponding to wavelengths ranging from thousands of kilometers to a fraction of the size of an atomic nucleus. 25Covers electromagnetic waves with frequencies in the range above hertz. This frequency range is divided into distinct bands, and electromagnetic waves within each frequency band are called by different names. Starting at the low-frequency (long-wavelength) end of the spectrum, these are radio waves, microwaves, terahertz waves, infrared, visible light, ultraviolet, X-rays, and gamma rays at the high-frequency (short-wavelength) end. Electromagnetic waves in each of these bands have different characteristics, such as how they are generated, how they interact with matter, and their practical uses.

[0216]

[0244] RF energy is the lowest part of the electromagnetic spectrum, commonly used as a medium for analog and modern digital wireless communication systems. It spans the range of 3 kHz to 300 GHz and is a continuous waveform. Waveforms with frequencies within the RF range can be engineered to vary from continuous to pulsed waveforms. Thus, energy is applied intermittently in pulses or short pulse bursts. Pulsed RF or pulsed electric fields (PEF) have different effects on tissue than continuously delivered RF because cells respond differently over the time the energy is applied. For example, RF ablation causes cell death due to thermal damage to cells, while PEF causes cell death through non-thermal effects (i.e., below the threshold for thermal ablation). Such cell death preserves the extracellular matrix so that target tissues maintain their structural architecture, including blood and lymphatic vessels. This preserves delicate structures, such as biological lumen, blood vessels, and nerves, essential for maintaining tissue integrity and functionality.

[0217]

[0245] FIG. 1 illustrates an embodiment of a PEF waveform 10 having pulses 12 that are monophasic and separated by an inter-pulse delay 14 measured from one polarity pulse to the next of the same polarity. Therefore, the inter-pulse delay 14 can be considered a DC pulse delay. FIG. 2 illustrates an embodiment of a PEF waveform 10 having two pulses 12, each biphasic, with each cycle consisting of a phase 12a of one polarity followed by a phase 12b of the opposite polarity. In this embodiment, there is no delay between these two opposite polarity phases 12a, 12b, but there is an inter-cycle delay 16 between cycles (i.e., biphasic pulses). The inter-cycle delay can be understood to be a form of inter-pulse delay where the pulses are biphasic pulses. FIG. 3 illustrates an embodiment of a PEF waveform 10 having pulses 12 that are biphasic as in FIG. 2, but in this embodiment, the opposite polarity phases 12a, 12b are separated by a switching delay or inter-phase delay 18.

[0218]

[0246] Optionally, pulses 12 are grouped into bursts or packets 20, as shown in FIG. 4. Here, five packets 20 are shown, with each packet 20 consisting of multiple cycles or biphasic pulses. Packets 20 are separated by inter-packet delays 22. It will be appreciated that packets 20 may be composed of a variety of different types of pulses (e.g., monophasic, biphasic, etc.) and of the same or different polarities. For example, in some embodiments, a packet 20 may consist of a train of pulses 12 of the same polarity followed by a polarity switch for one or more pulses 12, which may or may not be followed by a subsequent polarity switch for one or more additional pulses 12.

[0219]

[0247] Optionally, packets 20 are grouped into batches or bundles 24, as shown in FIG. 5 . Here, two bundles 24 are shown, each consisting of three packets 20. The bundles 24 are separated by an inter-bundle delay 26. Typically, energy is applied to the patient such that the inter-bundle delay 26 is synchronized with the heartbeat, and the inter-bundle delay 26 occurs during a sensitive portion of the heartbeat. Therefore, to avoid inducing arrhythmias, energy is applied outside of the sensitive portion of the heartbeat. In some embodiments, energy is delivered during the RT interval of the patient's ECG rhythm. In other embodiments, PEF energy is delivered regardless of its location within the ECG waveform. Biphasic waveforms, in particular, can be safely delivered in this manner without disrupting the heart's normal electrophysiological behavior. Therefore, bundles with different inter-bundle delays 26 established for reasons such as rapid treatment or other reasons, such as thermal relaxation, may be used. Alternatively, packets 20 can be delivered consecutively without bundling the packets. These packets can be delivered synchronously or asynchronously with respect to the ECG rhythm.

[0220]

[0248] Generally, a treatment is considered a period of energy delivery to a target area before moving on to the next target area. For example, when treating a pulmonary passageway, the energy delivery device may include an electrode that circumferentially contacts the interior surface of a portion of the pulmonary passageway. Energy from a waveform may be applied continuously, or the user may start and stop activating / application of energy. In either case, energy is delivered to the electrode until the portion of the target tissue receiving the energy is desirably treated. Energy delivery is then stopped, and the electrode is repositioned within the pulmonary passageway to treat a new portion of the target tissue (which may or may not overlap with the first portion of the target tissue). Each period of energy delivery to a target area before moving on to the next target area is considered a treatment. Thus, a patient typically receives multiple treatments within their lungs during a procedure.

[0221]

[0249] When treating a portion of the heart, such as when ablating a portion of the heart to treat atrial fibrillation, the energy delivery device may include an electrode with a rounded tip that contacts the surface of the atrium or pulmonary vein. In such instances, energy is delivered from the tip to the cardiac tissue, causing ablation at the contact area. This is repeated as the tip is moved to various locations to create circular or linear ablations that block electrical conduction through the cardiac tissue. Again, a treatment is considered a period of energy delivery to one target area before moving to the next target area. Thus, a complete conduction block typically involves multiple treatments, each consisting of one or more activations.

[0222]

[0250] In summary, for purposes described herein, a treatment generally includes the entire period of PEF delivery to affect a target section of tissue, delivered from one electrode (or set of electrodes) to another electrode (or set of electrodes) prior to moving one of the electrodes. Similarly, an activation generally includes PEF treatment delivery for a single "start" sequence initiated by the user. Multiple activations may be delivered in a single treatment. The time between activations is determined by the user and secondary constraints on PEF delivery (such as synchronization with cardiac rhythm, time for temperature to return to baseline, or due to accidental incomplete treatment delivery of the first activation).

[0223]

[0251] The PEF waveform is delivered to tissue through one or more energy delivery bodies, each having one or more electrodes. Ultimately, the physical arrangement of the electrodes forms a circuit. An electrode can act as a cathode or an anode, or both, at any particular time within a packet, pulse train, cycle, activation, or other period separating two pulses. When electrodes that partially or completely create an electrical circuit are in the same regional proximity, particularly within or near the target tissue, the system is called a bipolar or multipolar electrode arrangement. Multipolar arrangements apply when three or more polarity orientations are used, for example, one electrode is set to 1000 V, a second electrode is set to 500 V, and a third electrode is set to 0 V, where the second electrode is negative relative to the first electrode but positive relative to the third electrode. When one or more of the electrodes in the circuit are placed remotely in a remote, non-target region of the tissue (e.g., a dispersive pad), this arrangement is called a unipolar electrode arrangement. These descriptions are for convenience only, and descriptions of the use of the concepts described herein with respect to one of these configurations may be construed as applicable to other configurations of electrodes.

[0224]

[0252] Energy delivery can be activated by a variety of mechanisms, such as using the actuator 132 on the device 102 or a footswitch operably connected to the generator 104. Such activation typically provides a single energy dose or activation. The energy dose is generally defined by the number of packets delivered and the voltage of the packets. Each energy dose delivered to the target tissue is configured to maintain the temperature at or within the target tissue below the threshold for thermal ablation (particularly thermal ablation or denaturation of interstitial proteins in the basement membrane or deeper submucosal extracellular protein matrix). Additionally, the dose can be titrated or moderated over time to further reduce or eliminate heat accumulation during the treatment procedure. Instead of inducing thermal damage, defined as extracellular protein coagulation, at sites at risk for therapy, the energy dose provides energy at a level that induces treatment of the disease without damaging delicate tissue.

[0225]

[0253] It will be appreciated that the delays described herein (e.g., inter-pulse delay 14, inter-cycle delay 16, inter-phase delay 18, inter-packet delay 22, inter-bundle delay 26, etc.) may be consistent or variable throughout a packet 20, bundle 26, and / or treatment, depending on the type of waveform. Similarly, some delays may not be present because they are zero or because they are irrelevant to the waveform (e.g., if there is no bundle 24, there is no inter-bundle delay 26 because it is not relevant). The inter-pulse delays 14 may be consistent throughout a packet 20 of pulses 12, or they may vary throughout the packet 20. For example, the first inter-pulse delay may be 50 ns, followed by a second inter-pulse delay of 1 ms, and then the sequence is repeated. There may be sub-patterns within a packet 20 where a predetermined sequence of similar pulses 12 with varying polarity is repeated (e.g., up, up, down, delay, up, up, down...; up, up, down, down, up, delay, down, up, up, down, down..., etc.), and these sub-patterns are referred to as pulse trains. Each pulse train has the same pattern, defined as a train. However, each train may have different characteristics, such as having pulses of different polarity, different pulse widths, different amplitudes, and different interphase and / or interpulse delays in different patterns. In some embodiments, the different trains are arranged in a repeating sequence. Thus, in some embodiments, there is a quadratic range of associated intra-train delays and inter-train delays between particular trains from a particular pulse to a subsequent pulse.

[0226]

[0254] In some embodiments, the inter-pulse delay 14 is consistent across packets 20, while in other embodiments, the inter-pulse delay 14 varies within a packet 20. In some embodiments, the duty cycle of the pulses comprising a packet ranges from <0.01% to 100%. In some embodiments, a therapy includes identical packets 20, with each packet 20 having a consistent inter-pulse delay 14 or an inconsistent inter-pulse delay 14. In other embodiments, a therapy includes at least two different types of packets 20, with each of the at least two different types of packets 20 having a consistent inter-pulse delay 14, but the inter-pulse delay 14 differing between the at least two different types of packets 20. Or, in other embodiments, at least one of the at least two different types of packets 20 has an inconsistent inter-pulse delay 14 that differs from the other of the at least two different types of packets 20. Generally, when bundles 24 are present, the inter-bundle delay 26 is consistent when synchronized with the cardiac rhythm, but it can be understood that the inter-bundle delay 26 may vary with changes in the patient's cardiac rhythm or due to other therapy delivery protocol constraints.

[0227]

[0255] Regardless, it will be appreciated that any combination of delays (e.g., inter-pulse delay 14, inter-cycle delay 16, inter-phase delay 18, inter-packet delay 22, inter-bundle delay 26, etc.) may be utilized within a therapy to achieve a desired result. In particular, these delays may be specifically manipulated to achieve a particular desired result. For example, one, several, or all of these delays may be manipulated to control various aspects of PEF therapy to mitigate any associated risks such as gas formation, electrical discharge, cavitation, muscle contraction, and temperature rise, to name a few. In some embodiments, the delays distribute the period over which (high) voltage PEF energy is delivered, resulting in significant variation and optimization of the therapy delivery outcome. In some embodiments, the delays described herein range from 0 s to 100 ms.

[0228]

[0256] In some embodiments, the delay period is manipulated to distribute the pace of energy delivery and allow certain effects to resolve and decay before triggering their cumulative effects. When applying PEF for the manipulation of biological cells and tissues (where charge buildup and decay are on a different timescale than other effects), multiple cycles or trains of pulses are used to allow the therapeutic effect to accumulate in cells without triggering various secondary therapeutic effects, such as gas formation, electrical discharge, cavitation, muscle contraction, and temperature increase, to name a few. In other instances, these secondary cumulative therapeutic effects may be desired to produce or enhance a therapeutic outcome; thus, a delay is selected to facilitate these effects, again in a manner that does not alter the primary goal of inducing a cellular and tissue response to PEF. These examples of secondary effects are not an exhaustive list; other secondary effects desired to be manipulated may also be controlled by selecting an appropriate delay.

[0229] Gas formation

[0257] In some embodiments, the delay is manipulated to prevent gas formation resulting from PEF therapy. As previously mentioned, energy must be delivered for a sufficient period of time to break molecular bonds and thereby generate gas. Furthermore, as gas is generated, it collects over time, collectively consolidating into larger areas and forming progressively larger bubbles. The larger the bubbles, the longer it takes for them to be reabsorbed into the fluid. By appropriately introducing a delay into the waveform, these processes can be reduced or avoided. Such a delay provides energy for a period of time that is insufficient to generate any gas or any significant amount of gas and / or to allow the generated bubbles to grow large enough to avoid dissolution. The total energy delivered is not altered by such delay manipulation, thereby maintaining the overall therapeutic effect. Thus, appropriate selection of the delay can avoid gas generation or allow the bubbles to completely redissolve or reform other molecules.

[0230]

[0258] Even if the delay is insufficient to completely eliminate gas reabsorption into the fluid, it may be sufficient to prevent significant aggregation of the gas into larger bubbles. In such instances, smaller bubbles migrate and begin reabsorption before the next energy initiation and further gas formation. In this way, the bubbles do not aggregate into larger bubbles. Importantly, bubble size also relates to their effect within the body. Small bubbles (less than 0.1 mm in diameter) are generally reabsorbed within seconds and are generally too small to induce significant ischemic events. Therefore, bubbles generated at this size generally do not pose a significant threat to patient safety. Conversely, larger bubbles (greater than 0.1 mm) may take several minutes or longer to reabsorb and may disrupt or occlude blood vessels. Therefore, even if bubble generation cannot be completely eliminated, simply limiting the size and quantity of bubbles generated to a size and quantity that is clinically insignificant and / or quickly reabsorbed can be similarly effective.

[0231]

[0259] In some embodiments, when delivering PEF therapy in blood (electrolyte fluid) in a monopolar manner (i.e., using a remotely placed return electrode) using a 7F tip cardiac ablation focal electrode catheter, suppression of the amount and size of gas formation that occurs can begin to occur when there is a 1 μs cycle delay in a waveform with pulses 12 that are biphasic (1 μs duration) and have a voltage of 3000 V. In other embodiments, equivalent energy delivery begins to show a significant reduction in gas formation when the cycle delay is 10 or 20 μs, with complete elimination of hyperechoic bubbles when the cycle delay is 150 μs or greater.

[0232]

[0260] 6A-6C provide ultrasound images showing bubble formation under various conditions when an energy delivery body 108 (e.g., an electrode) is submerged in saline solution. FIG. 6A shows a baseline image of the energy delivery body 108, indicated by the arrow, with no energy delivered. This image therefore serves as a control. The arrowheads highlight the shading artifact. FIG. 6B shows energy delivery by an energy delivery body 108 with a waveform having a 50 ns cycle delay. This shows a wide range of hyperechoic bubbles being generated and visualized on the screen. FIG. 6D shows energy delivery by an energy delivery body 108 with a waveform having the same parameters as FIG. 6B, but with a 1 ms cycle delay. As shown, no visible bubbles are present anywhere within the imaging window.

[0233]

[0261] Thus, in some embodiments, when delivering PEF therapy in blood or any electrolyte fluid adjacent to a target tissue, such as in cardiac or vascular clinical applications, a delay such as a cyclic delay or other delay in the range of 100 μs to 10,000 μs, preferably 100 μs to 1000 μs (e.g., 250 μs to 1000 μs) can be used to eliminate gas production. In some embodiments, the delay may be understood to be 100 μs, 150 μs, 200 μs, 250 μs, 300 μs, 400 μs, 500 μs, 600 μs, 700 μs, 800 μs, 900 μs, 1000 μs, in the range of 100-250 μs, in the range of 250-500 μs, in the range of 500-1000 μs, greater than 250 μs, greater than 500 μs, greater than 1000 μs, in the range of 1000-5,000 μs, or in the range of 1000-10,000 μs, to name a few. In some embodiments, when delivering PEF to solid tissue, such as when positioning the energy delivery body 108 within the target tissue, a delay such as a cyclic delay or other delay in the range of 10 μs-1000 μs, preferably 25 μs-100 μs, may be used to eliminate gas formation. In some embodiments, the delay may be understood to be 10 μs, 20 μs, 25 μs, 30 μs, 40 μs, 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, in the range of 10-100 μs, in the range of 25-500 μs, in the range of 500-1000 μs, greater than 25 μs, greater than 50 μs, or greater than 100 μs, to name a few.

[0234] electrical discharge

[0262] In some cases, as energy is delivered from the energy delivery body 108 to the patient, current concentrates and accumulates in a focal region around the energy delivery body 108. At some point, the cumulative energy delivery exceeds the breakdown voltage of the material of the energy delivery body 108 or the surrounding tissue or fluid. This causes an electrical discharge event (e.g., a sudden flow of electricity, such as an arc) from the energy delivery body 108 to the nearby tissue, fluid, or cells. However, the introduction of an appropriate waveform delay allows for relaxation of charge buildup in the fluid and tissue material. Thus, by introducing a delay, energy delivery is not constant, thereby allowing for relaxation of charge buildup at various times before resuming energy delivery. Delays of sufficient number and duration can prevent discharge events. The number and duration of delays sufficient to prevent discharge are related to the energy and intensity of the treatment protocol, with higher voltages associated with longer delays.

[0235]

[0263] Electrical arc events are highly likely in PEF therapy with waveforms having voltages in the range of 500-5000 V to produce a therapeutic effect, especially when using bipolar electrode configurations. It is understood that electrical arc events may occur outside this range depending on the specific conditions, especially when energy is delivered via bipolar electrodes. With respect to these parameter ranges, a delay (e.g., cycle delay) of 50, 250, 500, or 1000 μs or more may be optimal to maintain the most significant degree of therapeutic effect while also preventing electrical arcing.

[0236]

[0264] Figures 7A-7B show a comparative example between the effects of different cycle delays on electrical discharge. Here, the energy delivery body 108 was submerged in saline solution and delivered PEF therapy until a visible electrical discharge was encountered. The waveform consisted of multiple pulses 12 forming packets 20 with an on-time of 300 μs. These 300 μs on-time packets were delivered at progressively higher voltages until a visible electrical discharge event was encountered. The on-time was then decreased, and the voltage continued to increase until the electrical discharge was again visible. Figure 7A shows a waveform with a very small cycle delay (50 ns). Figure 7B shows a waveform with a moderate cycle delay (50 μs). Notably, the 50 μs cycle delay test set showed a 78% increase in the current that could be delivered before an electrical discharge was recognized compared to a very small cycle delay of approximately 50 ns. Therefore, this moderate cycle delay was shown to significantly increase the amount of energy that could be delivered by the electrode before an electrical discharge. This cycle delay is well below the range where we might encounter a decline in therapeutic efficacy (most likely beginning at cycle delays of 5-10 ms, depending on cell size and characteristics). This greater resilience to electrical arcing was demonstrated to persist for all packet on-times tested in this series.

[0237]

[0265] It may be appreciated that the design of the energy delivery body 108 or the physical placement of the energy delivery body 108 also plays a role. If the design or placement of the energy delivery body 108, such as a smaller contact area or region of distinct boundaries on the energy delivery body 108, promotes current concentration, a longer delay is utilized to mitigate the electrical discharge event.

[0238]

[0266] Thus, in some embodiments, when delivering PEF therapy in blood or any electrolyte fluid adjacent to a target tissue, such as in cardiac or vascular clinical applications, a delay such as a cycle delay or other delay in the range of 50 μs to 10,000 μs, preferably 250 μs to 1000 μs, can be used to eliminate electrical discharge. In some embodiments, the delay may be understood to be 50 μs, 100 μs, 150 μs, 200 μs, 250 μs, 300 μs, 400 μs, 500 μs, 600 μs, 700 μs, 800 μs, 900 μs, 1000 μs, in the range of 50-250 μs, in the range of 250-500 μs, in the range of 500-1000 μs, greater than 250 μs, greater than 500 μs, greater than 1000 μs, in the range of 1000-5,000 μs, or in the range of 1000-10,000 μs, to name a few. In some embodiments, when delivering PEF to solid tissue, such as when the energy delivery body 108 is positioned within the target tissue, a delay can be used to eliminate the electrical discharge, such as a cycle delay or other delay in the range of 100 μs to 10,000 μs, preferably 250 μs to 2000 μs. In some embodiments, the delay can be understood to be 100 μs, 200 μs, 250 μs, 300 μs, 400 μs, 500 μs, 600 μs, 700 μs, 800 μs, 900 μs, 1000 μs, 1500 μs, 2000 μs, in the range of 250 to 500 μs, in the range of 250 to 1000 μs, in the range of 500 to 1000 μs, in the range of 1000 to 2000 μs, greater than 250 μs, greater than 500 μs, or greater than 1000 μs, to name a few. In some embodiments, when delivering PEF to a luminal target (e.g., an airway), such as when the energy delivery body 108 is placed within a lumen of target tissue that does not have a conductive fluid, a delay such as a cycle delay or other delay in the range of 10 μs to 10,000 μs, preferably 50 μs to 500 μs, can be used to eliminate the electrical discharge.In some embodiments, the delay may be understood to be 10 μs, 20 μs, 30 μs, 40 μs, 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 200 μs, 300 μs, 400 μs, 500 μs, in the range of 50-100 μs, in the range of 100-250 μs, in the range of 250-500 μs, in the range of 1000-10,000 μs, greater than 50 μs, greater than 250 μs, greater than 500 μs, or greater than 1000 μs, to name a few.

[0239] cavity formation

[0267] As mentioned above, when an electrical discharge occurs, a pressure wave is produced that is evident as an audible "popping" sound. If the discharge and pressure wave are of sufficient intensity and are repeated a sufficient number of times, the energy transferred and imparted into tissue from this pressure wave can severely disrupt the tissue architecture and cells. The resulting effect is the repeated creation of defects or cavities in the tissue in areas near the electrode that experience the greatest intensity of these effects.

[0240]

[0268] Incorporating delays between excitation portions of a waveform, such as within a PEF packet, allows time for physical effects at the molecular level to resolve before accumulating into pressure waves that can create tissue cavitations. This results in a more dispersed energy deposition within the tissue, thereby reducing or eliminating the pressure waves that result from PEF therapy. Therefore, introducing cycle delays and other delays into a waveform can be used to mitigate or eliminate cavitation. This can be used to improve the predictability of therapeutic outcomes and can also be used to eliminate the risks associated with cavitation, such as disruption of the integrity of the vasculature, fistula formation, or damage to other delicate tissues.

[0241]

[0269] 8A-8B show the effects of identical PEF treatment protocols delivered to liver tissue T, but with different cycle delays. FIG. 8A shows the results using a waveform with a cycle delay of approximately 50 ns, which resulted in the formation of significant tissue cavities C. FIG. 8B shows the results using the same waveform but with a cycle delay of approximately 1000 μs, thus delivering the same amount of energy. As shown, such a longer cycle delay can completely eliminate the large cavities that form in liver tissue T.

[0242]

[0270] One of the side benefits of cavity elimination is more efficient energy deposition into the tissue by potentially eliminating gaps at the tissue-electrode interface, which may result in greater therapeutic efficacy.

[0243]

[0271] In some embodiments, when delivering PEF to solid tissue, such as when the energy delivery body 108 is positioned within the target tissue, a delay such as a cycle delay or other delay in the range of 100 μs to 10,000 μs, preferably 250 μs to 2000 μs, can be used to eliminate cavitation. In some embodiments, the delay can be understood to be 100 μs, 200 μs, 250 μs, 300 μs, 400 μs, 500 μs, 600 μs, 700 μs, 800 μs, 900 μs, 1000 μs, 1500 μs, 2000 μs, in the range of 250 to 500 μs, in the range of 250 to 1000 μs, in the range of 500 to 1000 μs, in the range of 1000 to 2000 μs, greater than 250 μs, greater than 500 μs, or greater than 1000 μs, to name a few.

[0244] Muscle contraction

[0272] Cells and tissues closest to the energy delivery body 108 are those most strongly affected by PEF therapy. It is possible to subject these cells and tissues to repeated production of therapeutic effects while avoiding or preventing the generation of action potentials in distant motor neurons and skeletal muscle (as well as cardiac and smooth muscle). This is achieved using biphasic pulses and further achieved using delays within the waveform. It has been found that the charging and relaxation properties of these distant motor neurons require cycle delays of longer duration to prevent their generation. For example, cycle delays of 10 ms, 20 ms, 30 ms, 40 ms, or 50 ms may be used.

[0245]

[0273] In some cases, the desired cycle delay is determined, at least in part, by numerical simulation of action potential generation. In some embodiments, a model based on the arrangement of nodes of Ranvier between myelinated axon regions is utilized. Referring to FIG. 9 , nodes of Ranvier NR, also known as myelin sheath gaps, occur along myelinated axons MA, where the axoplasmic membrane AA (axonal membrane) is exposed to the extracellular space. The nodes of Ranvier NR are not insulated and are highly enriched in ion channels, allowing them to participate in the ion exchange required for action potential regeneration. Nerve conduction in myelinated axons MA occurs in a manner that the action potential appears to "jump" from one node NR to the next along the axon MA. This results in faster conduction of the action potential.

[0246]

[0274] Referring to Figure 10, the myelinated axon MA region is modeled as a resistor for the intracellular environment. Each node NR, consisting of a membrane for the cell that separates the intracellular environment from the extracellular environment, is modeled as a capacitor in parallel with a leakage resistor and a voltage source. When exposed to an electric field, the myelinated axon MA begins to charge along with the capacitor. When the electric field is removed (e.g., the pulse is stopped for a delay period), the charge accumulation on the myelinated axon MA begins to discharge. Therefore, the ability of PEF therapy to induce action potentials in motor neurons is related to the effective duty cycle of the PEF waveform.

[0247]

[0275] This concept is conveyed in Figures 11A-11D. Figure 11A shows an exemplary PEF waveform 10 with no or reduced cycle delay 16, and Figure 11B provides a schematic diagram of the charging 62 and discharging 64 behavior of a motor neuron. Two packets 20 of waveform 10 are shown separated by an inter-packet delay 22. As packets 20 are delivered, the motor neuron becomes increasingly charged throughout the delivery. After a time, the accumulated membrane potential induces an action potential (indicated by dashed line 66). The motor neuron then begins discharging at the beginning of the inter-packet delay 22. This is repeated for each subsequent packet 20.

[0248]

[0276] FIG. 11C shows an exemplary PEF waveform 10 with a longer cycle delay 16 than the waveform of FIG. 11A. FIG. 11D provides a schematic diagram of the charging 62 and discharging 64 behavior of a motor neuron. When waveform 10 is delivered, the motor neuron incrementally charges throughout the delivery but begins discharging at the beginning of cycle delay 16. It is therefore clear that the inclusion of a larger cycle delay 16 results in suppressing the accumulated membrane potential below that which induces an action potential (below dashed line 66). During a particular active period of energy delivery, there is a characteristic delay for that waveform and field strength that prevents the accumulated axonal charge from reaching the threshold for inducing an action potential.

[0249]

[0277] The characteristics of the mathematical model are selected to mimic the properties of motor neuron axons. Using this model, we can see that the benefit of cycle delay 16 in relaxing muscle contractions begins at a cycle delay of 10 ms and levels off at a cycle delay of 1 second, as shown in FIG. 12. Thus, this is the modeled effective range for limiting muscle contractions. Note that these ranges vary with respect to the proximity of a particular motor neuron to the PEF electrode, including its strength, phase behavior (monophasic or biphasic, or biphasic with varying levels of asymmetry), other parameters of the PEF waveform (such as total packet on-time), the geometry of the electrode placement (bipolar, multipolar, or unipolar), and whether an action potential is ultimately induced in the neuron. Muscle cells (skeletal, cardiac, and smooth muscle cells) also have similar effects and characteristics that affect their susceptibility to contraction, although with different intrinsic sensitivities based on the unique characteristics and specific properties of these cells.

[0250]

[0278] Depending on the details of the PEF waveform, as cycle delay 16 is increased from approximately 5 ms to 10 ms and beyond, the total volume of tissue treated by PEF may begin to decrease. However, cells closest to the excitation electrode remain affected and therefore treated by the tissue. Thus, as cycle delay 16 begins to extend into tens of milliseconds, the therapeutic effect varies, but it is still possible to produce significant therapeutic results using cycle delays that reduce or eliminate muscle contraction. Conversely, shorter to eliminated delays can be used to promote further muscle contraction as needed.

[0251]

[0279] In some embodiments, when delivering PEF to solid tissue, such as when the energy delivery body 108 is positioned within the target tissue, a delay, such as a cycle delay or other delay in the range of 5 ms to 100 ms, preferably 10 to 30 ms, can be used to reduce or eliminate muscle contraction. In some embodiments, when delivering PEF to a luminal target (e.g., the airway), such as when the energy delivery body 108 is positioned within a lumen of the target tissue that does not have a conductive fluid, a cycle delay in the range of 5 ms to 100 ms, preferably 10 to 30 ms, can be used to reduce or eliminate muscle contraction. In any event, in some embodiments, the delay can be understood to be 5 ms, 10 ms, 25 ms, 30 ms, 40 ms, 50 ms, 60 ms, 70 ms, 80 ms, 90 ms, 100 ms, in the range of 5 to 10 ms, in the range of 10 to 20 ms, in the range of 20 to 30 ms, greater than 5 ms, greater than 10 ms, greater than 15 ms, or greater than 30 ms, to name a few.

[0252] Temperature rise

[0280] As described herein, introducing and manipulating a delay period between active periods of a PEF waveform distributes energy deposition into tissue over a longer period. This significantly affects the shape and amplitude of the temperature spikes characteristic of PEF therapy during pulse delivery, particularly in the region very close to the electrode (the tissue-electrode interface). This improves treatment safety, reduces the potential for tissue side effects, and reduces the likelihood of electrical discharge events, including sparking or arcing, by eliminating the potential for hot spots in the tissue or fluid that promote arcing. Therefore, introducing a cycle delay can be used to significantly improve treatment results by attenuating the resulting peak temperatures.

[0253]

[0281] Referring to FIG. 13 , calculations of the amplitude and distribution of temperature rise due to PEF protocols can be performed through numerical simulations. In this example, three PEF protocols are compared, each including a waveform 10 with a single packet 20 of biphasic pulses 12. The first PEF protocol includes no cycle delay, the second PEF protocol includes a 1 ms cycle delay 16, and the third PEF protocol includes a 10 ms cycle delay 16. As shown in FIG. 13 , the general mm-scale distribution of temperatures above 50°C was comparable between the protocol with no cycle delay and the protocol with a 1 ms cycle delay. However, the instantaneous spike in maximum temperature at the tissue-electrode interface was dramatically different. The protocol with no cycle delay produced a maximum temperature of approximately 175°C, while the protocol with a 1 ms cycle delay reached a peak temperature of approximately 80°C, and the protocol with a 10 ms cycle delay limited the maximum temperature rise to approximately 55°C. The temperature distribution at maximum temperature rise is shown in Figures 14A-14B, thus reflecting the different durations within the packet for a 0 ms delay (Figure 14A) versus a 1 ms delay (Figure 14B). Thus, the introduction and manipulation of the cycle delay 16 induces a significant and measurable effect on the thermal effect produced on the tissue.

[0254]

[0282] Note that these values ​​are at the immediate tissue-electrode interface, where a maximum temperature is encountered, followed by a very rapid drop in temperature. Once the packet is complete, there is a similarly rapid drop in temperature. Thus, while these values ​​indicate very high temperatures, they do not indicate that a significant degree of thermal damage results from the modeled PEF therapy at millimeter-scale distances from the electrode into the tissue. However, the mitigated temperature peak significantly reduces the potential for harmful thermal damage and protein denaturation in close proximity to the electrode, reducing the likelihood of an electrical discharge event. These are two of the primary benefits of utilizing cycle delays in these procedures.

[0255]

[0283] Thus, in some embodiments, when delivering PEF therapy in blood or any electrolyte fluid adjacent to a target tissue, such as in cardiac or vascular clinical applications, a delay, such as a cycling delay or other delay in the range of 200 μs to 20,000 μs, preferably 500 μs to 10,000 μs, can be used to reduce peak temperatures. In some embodiments, when delivering PEF to solid tissue, such as when the energy delivery body 108 is positioned within the target tissue, a delay, such as a cycling delay or other delay in the range of 200 μs to 20,000 μs, preferably 500 μs to 10,000 μs, can be used to reduce peak temperatures. In any event, in some embodiments, the delay may be understood to be 500 μs, 1000 μs, 2000 μs, 3000 μs, 4000 μs, 5000 μs, 6000 μs, 7000 μs, 8000 μs, 9000 μs, 10,000 μs, in the range of 200-500 μs, in the range of 500-1000 μs, in the range of 500-1000 μs, in the range of 1000-10,000 μs, in the range of 10,000-20,000 μs, in the range of more than 200 μs, in the range of more than 500 μs, or in the range of more than 1000 μs, to name a few.

[0256]

[0284] In some embodiments, when delivering PEF to a luminal target (e.g., the airway), such as when the energy delivery body 108 is placed within the lumen of the target tissue that does not have a conductive fluid, a delay such as a cycle delay or other delay in the range of 100 μs to 10,000 μs, preferably 200 μs to 1000 μs, can be used to reduce the peak temperature. In any event, in some embodiments, the delay may be understood to be 100 μs, 200 μs, 300 μs, 400 μs, 500 μs, 600 μs, 700 μs, 800 μs, 900 μs, 1000 μs, in the range of 100-200 μs, in the range of 100-500 μs, in the range of 500-1000 μs, in the range of 500-1000 μs, in the range of 1000-10,000 μs, greater than 200 μs, greater than 500 μs, or greater than 1000 μs, to name a few.

[0257] Comparison of delay ranges to control for effects

[0285] Overall, the susceptibility and sensitivity of a particular therapy to each secondary therapeutic effect, such as gas formation, electrical discharge, cavitation, muscle contraction, and temperature increase, varies. Table 1 below summarizes the most potentially applicable ranges of delays that can be used to mitigate these effects for various target tissue types. In particular, this table focuses on applications for mitigating secondary effects, although it may be desirable to accelerate these effects, and therefore different delay ranges may be applicable for specific therapeutic targets.

[0258] [Table 1]

[0259]

[0286] Thus, the inclusion and manipulation of various delays (particularly phase delay, cycle delay 16, and / or inter-packet delay 20) within a PEF waveform provides a powerful tool for dramatically improving therapeutic outcomes. This is achieved by eliminating or reducing the risks associated with secondary effects inherent in the nature of delivering high-voltage electrical pulses with PEF therapy. These effects and benefits apply regardless of the range of energies delivered in the waveform.

[0260]

[0287] Thus, methods have been provided for controlling the above-mentioned secondary effects (e.g., gas formation, electrical discharge, muscle contraction, cavitation, and temperature rise) by controlling the duration and / or sequence of component delays comprising PEF therapeutic waveforms contained within cycles, trains, packets, bundles, and / or activations, including those collectively referred to as PEF waveforms. While the examples and embodiments described herein focus on cycle delays 16, it can be understood that such information (e.g., exemplary ranges for delay values, delay positions, number of delays, delay types, etc.) applies to any delay or combination of delays in a PEF waveform. Different types of delays, alone or in combination, can have the same effect by enabling a particular therapeutic effect while distributing energy delivery to mitigate various secondary effects. Thus, in some cases, manipulation of the timing of energy delivery can be achieved in various ways with the same or similar results. Such effects can be influenced by electrode placement.

[0261]

[0288] Table 2 is provided below to provide ample examples of various parameter combinations and resulting effects. Table 2 provides various combinations of treatment scenarios including electrode geometry, circuit type, various parameter values, and treatment effects. Given specific scenarios, exemplary minimum values ​​for cycle delay 16 are provided to avoid various secondary effects (e.g., bubble formation, arcing, cavitation). Thus, while it will be apparent that delay values ​​will depend on various factors related to the treatment protocol, a unifying concept is demonstrated as described throughout this specification.

[0262] [Table 2]

[0263]

[0290] The main principle underlying the use of these methods to reduce secondary effects is that the delay is too short for the complete discharge of accumulated electrical charge distortions and / or recovery of cells and organelles from the effects induced by the pulsed electric field (e.g., cell polarization, ATP depletion, etc.). Thus, repeated exposure of target cells and tissues to a subsequent pulse, multiple pulses, or pulse trains following the initial pulse or pulse train results in the accumulation of damage to the cells, which ultimately increases their susceptibility to macromolecular transport (drugs, genetic materials, etc.) or leads to their death (phagocytosis, programmed cell death (e.g., perthanatosis, pyroptosis, apoptosis), necrosis, etc.). Therefore, the effectiveness of PEF therapy remains consistent or altered while secondary effects are controlled.

[0264]

[0291] With these methods, secondary effects can be reduced when delays of sufficient duration are selected to attenuate or completely prevent the induction of one or more of these behaviors. Effects can also be selectively enhanced, such as by using delays that are sufficiently short to favor their occurrence, particularly when subsequent pulses within a portion of the waveform have similar polarity configurations. For example, gas formation can sometimes be used to the clinician's advantage, using mechanisms such as physically disrupting the treatment environment. This can be used for purposes such as promoting cell death, enhancing cell sensitivity to cell-activating agents, increasing mixing efficiency for infusions, and other potential uses. Therefore, it is sometimes desirable to control and enhance the formation of gases resulting from PEF therapy. However, for convenience, this specification primarily describes methods for reducing secondary (non-cellular) effects that can result from PEF therapy.

[0265] Wave Length

[0292] When introducing and / or manipulating delays in a PEF waveform, various characteristics of the waveform may be changed. For example, when introducing or increasing cycle delay 16 in a packet 20 of a PEF waveform 10, the time to complete the packet increases. It can be understood that such an increase in packet duration or completion time does not increase packet on-time if the only change is an increase in delay. If a treatment is determined by delivering a specific number of packets 20, treatment time increases with increasing packet duration. Similarly, when inter-packet delay 26 is introduced or increased, treatment time also increases if the treatment includes two or more packets.

[0266]

[0293] In some cases, a PEF waveform without delay is delivered in pulses or packets that are 100 μs long. When using a waveform with a fundamental frequency of 400 kHz, the waveform has 400,000 cycles per second, or one cycle is 2.5 μs long. Thus, in this example, a packet contains 40 cycles. If a 250 μs cycle delay is introduced into such a packet (e.g., after each cycle within the packet), the packet length or packet duration increases by 10,000 μs, resulting in a total packet duration of 10,100 μs. Table 3 below shows the total packet time for various introduced cycle delays (e.g., 250 μs, 500 μs, 1000 μs) compared to the packet duration of a conventional PEF waveform. In this table, a cycle delay is introduced after each cycle within the packet. This behavior is the same for a phase delay instead of a cycle delay.

[0267] [Table 3]

[0268]

[0295] In some embodiments, the inclusion of delays may be 2,000 μs, 5,000 μs, 10,000 μs, 20,000 μs, 25,000 μs, 30,000 μs, 40,000 μs, 50,000 μs, 60,000 μs, 70,000 μs, 80,000 μs, 90,000 μs, 100,000 μs, 110,000 μs, 120,000 μs, 130,000 μs, 140,000 μs, 150,000 μs, 160,000 μs, 170,000 μs, 180,000 μs, 190,000 μs, 200,000 μs, 1000-2000 μs, 1 The packet duration may be increased to a range of approximately 1000 to 200,000 microseconds, such as 000 to 3000 μs, 1000 to 4000 μs, 1000 to 5000 μs, 1000 to 10,000 μs, 10,000 to 20,000 μs, 10,000 to 30,000 μs, 10,000 to 40,000 μs, 10,000 to 50,000 μs, 50,000 to 100,000 μs, 50,000 to 150,000 μs, 50,000 to 200,000 μs, greater than 10,000 μs, greater than 25,000 μs, greater than 50,000 μs, greater than 100,000 μs, and greater than 200,000 μs.

[0269]

[0296] It will be appreciated that Table 3 shows a small sample of combinations. A waveform may include delays of any length, any number of delays, and any type of delay (i.e., not limited to cycle delays). The delays may be consistent (e.g., the same length, the same location, etc.) throughout the waveform, or may be inconsistent (e.g., at least one of different lengths, at least one in a different or interleaved location, different between packets, different between batches, etc.). Similarly, different fundamental frequencies may be used. Furthermore, there may be any number of packets in a waveform, and any number of batches, including none. In any case, the introduction of these types of delays significantly increases packet time, as noted above. However, such an increase has minimal impact on overall treatment time, given the relatively small timescale of such an increase. That is, the allowable limit on treatment time during a procedure far exceeds such an increase due to the inclusion of delays.

[0270] Delivery Devices and Systems

[0297] Generally, energy is delivered using systems and devices designed for specific clinical applications. With sufficient access, energy can be delivered to any target within a patient's body. In some embodiments, systems and devices are designed for endoluminal access to target tissue throughout the body, particularly in locations previously deemed unavailable via percutaneous approaches. Endoluminal access allows treatment of target tissue from within various lumens in the body. A lumen is the interior space of a tubular or hollow structure within the body, including passageways, tubes, ducts, and cavities, to name a few. Exemplary luminal structures include blood vessels, the esophagus, the stomach, the small and large intestines, the colon, the bladder, the urethra, the collecting ducts, the uterus, the vagina, the fallopian tubes, the ureters, the kidneys, the renal tubules, the spinal canal, the spinal cord, and other luminal structures throughout the body, as well as structures within and including organs such as the lungs, heart, and kidneys, to name a few. In some embodiments, the target tissue is accessed through a nearby luminal structure. In some cases, the treatment device 102 is advanced through various luminal structures or branches of the luminal system to reach the target tissue location. For example, when accessing a target tissue site via a blood vessel, the treatment device 102 may be inserted remotely and advanced through various branches of the vascular system to reach the target site. Similarly, when 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 treatment device 102 is then advanced through branches of the luminal system to reach the target tissue location. Alternatively, a cutdown or other method can be used to enter a luminal structure near the target tissue. This may be the case when accessing a luminal structure that is not part of a larger system or is otherwise difficult to access.

[0271]

[0298] Target tissues include the luminal structures themselves, tissues near these luminal structures, and tissues accessible either by endoluminal approaches or other approaches, such as percutaneous, laparoscopic, or open surgical approaches. These include cells, tissues, and / or organs in the integumentary, skeletal, muscular, nervous, endocrine, cardiovascular, lymphatic, respiratory, digestive, urinary, and reproductive systems, to name a few. Exemplary cells, tissues, and / or organs include the luminal structures themselves, soft tissues throughout the body located near the luminal structures, and solid organs accessible from the luminal structures, including, but not limited to, the liver, pancreas, gallbladder, kidneys, prostate, ovaries, lymph nodes and lymphatic drainage ducts, underlying muscle tissue, bone tissue, brain, eye, thyroid, etc.

[0272]

[0299] Examples of systems that may utilize waveform manipulation as described herein are described in International Patent Application No. PCT / US2017 / 039527, entitled "GENERATOR AND A CATHETER WITH AN ELECTRODE AND A METHOD FOR TREATING A LUNG PASSAGEWAY," International Patent Application No. PCT / US2018 / 067501, entitled "METHODS, APPARATUSES, AND SYSTEMS FOR THE TREATMENT OF DISORDERS," International Patent Application No. PCT / US2018 / 067504, entitled "OPTIMIZATION OF ENERGY DELIVERY FOR VARIOUS APPLICATIONS," International Patent Application No. PCT / US2020 / 028844, entitled "DEVICES, SYSTEMS AND METHODS FOR THE TREATMENT OF ABNORMAL TISSUE," and International Patent Application No. PCT / US2020 / 028844, entitled "DEVICES, SYSTEMS AND METHODS FOR THE TREATMENT OF ... and International Patent Application No. PCT / US2020 / 042260, entitled "TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRIC FIELDS," and International Patent Application No. PCT / US2020 / 066205, entitled "TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRIC FIELDS," all of which are incorporated herein by reference for all purposes.

[0273]

[0300] FIG. 15 provides a schematic diagram of an exemplary treatment system 100 for use in delivering specialized PEF energy. In this embodiment, the system 100 includes an elongated device 102 including a shaft 106 having a distal end 103 and a proximal end 107. The device 102 includes an energy delivery body 108, generally shown as a dashed circle near the distal end 103 of the shaft 106. The energy delivery body 108 may take a variety of forms with structural differences that prevent a single representational illustration, but it can be understood that individual exemplary embodiments are described and illustrated herein. The energy delivery body 108 may be mounted on or integral with the outer surface of the shaft 106 so as to be externally visible. Alternatively, the energy delivery body 108 may be internally housed within the shaft 106 and exposed by advancing or retracting the shaft 106 itself. Similarly, there may be more than one energy delivery body 108, which may be external, internal, or both. In some embodiments, the shaft 106 is constructed from a polymer, such as an extruded polymer. In some embodiments, the shaft 106 may be constructed from multiple layers of material with different durometers to control flexibility and / or stiffness. In some embodiments, the shaft 106 is reinforced with various elements, such as individual wires or wire braids. In either case, such wires may be flat or round wires. The wire braids have a braid pattern, and in some embodiments, the braid pattern is tailored to a desired flexibility and / or stiffness. In other embodiments, the wire braid reinforcing the shaft 106 may be advantageously combined with multiple layers of material with different durometers to provide further control of flexibility and / or stiffness along the length of the shaft.

[0274]

[0301] In any case, each energy delivery body 108 includes at least one electrode for delivery of PEF energy. Typically, the energy delivery bodies 108 include a single delivery electrode and operate in a monopolar configuration, achieved by supplying energy between the energy delivery body 108 located near the distal end 103 of the device 102 and a return electrode 140 positioned on the patient's skin. However, it will be understood that bipolar energy delivery and other configurations may alternatively be used. When using bipolar energy delivery, the device 102 may include multiple energy delivery bodies 108 configured to function in a bipolar manner, or may include a single energy delivery body 108 with multiple electrodes configured to function in a bipolar manner. The device 102 generally includes a handle 110 located near the proximal end 107. The handle 110 is used to manipulate the device 102 and typically includes an actuator 132 for manipulating the energy delivery bodies 108. In some embodiments, the energy delivery body 108 transitions from a closed or retracted position (during access) to an open or exposed position (for energy delivery), which is controlled by an actuator 132. As such, the actuator 132 generally has the form of a knob, button, lever, slide, or other mechanism. In some embodiments, the handle 110 can be seen to include a port 111 for the introduction of a liquid, agent, substance, tool, or other device for delivery through the device 102. Exemplary liquids include suspensions, mixtures, chemicals, fluids, chemotherapy agents, immunotherapy agents, micelles, liposomes, embolic agents, nanoparticles, drug-eluting particles, genes, plasmids, and proteins, to name a few.

[0275]

[0302] The device 102 is in electrical communication with a generator 104 configured to generate PEF energy. In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / retrieval unit 156 (e.g., a memory and / or database), and an energy storage subsystem 158 that generates and stores the delivered energy. In some embodiments, the desired treatment algorithm 152 is selected using the user interface 150 on the generator 104. In other embodiments, the algorithm 152 is automatically selected by the generator 104 based on information obtained by one or more sensors, which are described in more detail in a later section. A variety of energy delivery algorithms may be used. In some embodiments, one or more capacitors are used for energy storage / delivery, although other suitable energy storage elements may be used. Additionally, one or more communication ports are typically included.

[0276]

[0303] As shown in FIG. 15 , the distal end 103 of the device 102 is typically advanceable through a delivery device, such as an endoscope 10. The endoscope 10 typically includes a control body 12 attached to an elongated insertion tube 14 having a distal tip 16. The endoscope 10 has an internal lumen accessible by a port 18 through which the distal end 103 of the device 102 is threaded. The shaft 106 of the device 102 is advanceable through the internal lumen and exits the distal tip 16. Imaging is achieved by the endoscope 10 using a light guide 20 having an endoscope connector 22 connected to a light and energy source. The distal tip 16 of the endoscope may be equipped with visualization technologies, including, but not limited to, video, ultrasound, laser scanning, and the like. These visualization technologies collect signals consistent with their design and transmit the signals via wires down the length of the shaft or wirelessly to a video processing unit. The video processing unit then processes the video signal and displays the output on a screen. In general, endoscope 10 may be understood to be specific to the anatomical location in which it is being used, such as a gastroscope (upper GI endoscopy including the stomach, esophagus, and small intestine (duodenum)), colonoscope (large colon), bronchoscope (lungs), pharyngoscope (pharynx), cystoscope (urinary tract), duodenoscope (small intestine), enteroscope (digestive system), ureteroscope (ureter), hysteroscope (cervix, uterus), etc. In other embodiments, device 102 may be deliverable via a catheter, sheath, introducer, needle, or other delivery system.

[0277]

[0304] Upon approaching the target tissue area intraluminally, energy can be delivered to the target tissue in a variety of ways. In one arrangement, the energy delivery body 108 is positioned within a body lumen and energy is delivered to the target tissue (i.e., entering the body lumen and passing through at least a portion of the lumen wall to target tissue within and / or at least partially surrounding the lumen wall, or through the lumen wall to target tissue outside and near the lumen wall). In another arrangement, the energy delivery body 108 is advanced through the lumen wall and inserted into or near the target tissue outside the lumen wall. It can be understood that such arrangements can be combined to include at least two energy delivery bodies 108, one positioned within the body lumen and one extending through the wall of the body lumen. In some embodiments, each energy delivery body 108 functions in a monopolar manner (e.g., utilizing a remotely located return electrode). In other embodiments, at least some of the energy delivery bodies 108 function in a bipolar manner (e.g., utilizing an energy delivery body 108 as a return electrode). Optionally, two energy delivery bodies 108 may be positioned on opposite sides of a lumen wall and function in a bipolar manner to treat tissue therebetween (e.g., within the lumen wall). These delivery options are possible because the lumen itself is maintained throughout treatment, allowing for treatment of tissue within, on, or near the lumen itself. Delivery of such therapy allows access to previously inaccessible tissue, such as tumors or diseased tissue that have infiltrated the lumen wall or at least partially wrapped around the body lumen, which are too close to be surgically removed or treated using conventional focal therapy. Many conventional focal therapies, such as treatments using thermal energy, damage or destroy the structure of the lumen wall, such as by thermal protein coagulation.

[0278]

[0305] Endoscopic approaches are also suitable for monopolar energy delivery. As described above, monopolar delivery involves passing current from the energy delivery body 108 (near the distal end of the device 102) to the target tissue and through the patient to a return pad 140 positioned in contact with the patient's skin, thereby completing the current circuit. Thus, in some embodiments, the device 102 includes only one energy delivery body 108 or electrode. This allows the device 102 to have a thin profile so that it can be positioned within smaller body lumens. This also allows for deep penetration of the tissue surrounding the energy delivery body 108. Similarly, when penetrating a lumen wall with such a device, the use of only one energy delivery body 108 requires only one penetration per treatment. While various device designs or treatment protocols may result in additional penetrations, it can be appreciated that in some embodiments, a monopolar delivery design reduces the invasiveness of the procedure, simplifies device and treatment design, and provides a superior treatment zone at the target tissue.

[0279]

[0306] In contrast, bipolar delivery involves passing electrical current through the target tissue between two electrodes, either on the same energy delivery body 108, on different energy delivery bodies 108, or in other configurations. Most conventional energy therapies are bipolar and generally transcutaneous. Such therapies involve multiple penetrations of the skin, which can increase discomfort, prolong healing, and further complicate treatment. While the systems described herein can be utilized in a variety of formats, including bipolar and transcutaneous configurations, it can be understood that device features are generally combined in a manner that reduces overall invasiveness and provides better results.

[0280]

[0307] FIG. 16 illustrates another embodiment of a treatment device 102 configured for use in delivering specialized PEF energy, particularly for delivering focal therapy. In this embodiment, the device 102 includes an elongated shaft 106 having at least one energy delivery body 108 near its distal end 103 and a handle 110 near its proximal end 107. In this embodiment, the at least one energy delivery body 108 includes a "focal electrode" having a cylindrical shape. The cylindrical shape has a circular, substantially flat, or curved surface for positioning relative to tissue. In some embodiments, the device 102 has an overall length of 50-150 cm, preferably 100-125 cm, and more preferably 110-115 cm. Similarly, in some embodiments, it has an outer diameter of 7 Fr (3-15 Fr, preferably 4-12 Fr, and more preferably 7-8.5 Fr). In some embodiments, shaft 106 has a deflectable end 121, optionally having a length of 50-105 mm that results in a curve with a diameter ranging from approximately 15-55 mm. Deflection can be achieved by a variety of mechanisms, including pull wires extending to handle 110. Handle 110 is therefore used to manipulate device 102, particularly to manipulate the orientation of distal end 103 during delivery and treatment. Energy is provided to device 102, and thus at least one energy delivery body 108, via cable 13 that is connectable to generator 104.

[0281]

[0308] In some embodiments, the treatment device 102 of Figure 16 is utilized to treat cardiac tissue, particularly to treat arrhythmias such as atrial fibrillation. Figure 17 illustrates a portion of a heart H showing cutaway views of the right atrium RA and left atrium LA. The largest pulmonary veins are the four main pulmonary veins (the right superior pulmonary vein RSPV, the right inferior pulmonary vein RIPV, the left superior pulmonary vein LSPV, and the left inferior pulmonary vein LIPV), two from each lung that drain into the left atrium LA of the heart H. In some embodiments, treatment of atrial fibrillation involves placing the treatment device 102 deep within the pulmonary veins and gradually withdrawing it to the ostium proximal to the mapping catheter. Mapping and treatment then begin.

[0282]

[0309] In some embodiments, tissue surrounding the opening of the left inferior pulmonary vein LIPV is treated point-by-point (using mapping) with the treatment device 102 to form a circular treatment zone around the left inferior pulmonary vein LIPV, as shown in FIG. 18 . Optionally, dedicated navigation software can be used to facilitate proper positioning of the treatment catheter 120. A delivery electrode 122 is positioned near or in contact with the target tissue area, and energy is provided to the delivery electrode 122 to form a treatment area A. Because energy is delivered to a localized area (focal delivery), the electrical energy is concentrated over a smaller surface area, resulting in a stronger effect than delivery with electrodes that extend circumferentially around the lumen or ostium. It also forces the electrical energy to be delivered in a stepwise, localized approach, thereby mitigating the potential effects of preferential current paths through surrounding tissue. These preferential current paths are regions with electrical properties that induce a local increase in current flow through them rather than through adjacent regions. Such a path may result in an irregular current distribution around the circumference of the target lumen, which may distort the electric field and cause irregular increases in the therapeutic effect in some regions and decreases in the therapeutic effect in others. This can be mitigated or avoided using focal therapy, which stabilizes the therapeutic effect around the circumference of the target region. Therefore, by providing energy to a specific region at a time, the electrical energy is "forced" across multiple regions of the circumference, thereby ensuring a greater degree of circumferential regularity of the treatment. FIG. 18 illustrates repeated point-by-point energy application around the left inferior pulmonary vein LIPV using the treatment device 102 to form a circular treatment zone. As shown, in this embodiment, each treatment area A overlaps with adjacent treatment areas A to form a continuous treatment zone. The size and depth of each treatment area A may depend on various factors, such as parameter values, treatment time, and tissue characteristics. It may be understood that the number of treatment areas A may vary depending on various factors, particularly the unique conditions of each patient's anatomy and electrophysiology. In some embodiments, the number of treatment areas A includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or more.

[0283]

[0310] When all electrical connections between the atria and the veins are treated, there is an electrical pause in the pulmonary veins where only the far-field atrial signal is recorded. Occasionally, spikes of electrical activity are seen in the pulmonary veins with no conduction to the rest of the atrium; these clearly indicate electrical disconnection of the veins from the rest of the atrial myocardium.

[0284]

[0311] It can be appreciated that in various embodiments, the treatment device 102 includes various specialized features. For example, in some embodiments, the device 102 includes a mechanism for real-time measurement of the contact force applied by the tip of the catheter to the patient's heart wall during the ablation procedure. In some embodiments, this mechanism is contained within the shaft 120 and includes a three-axis optical force sensor that utilizes white light interferometry. By monitoring and modifying the applied force throughout the procedure, the user can better control the device 102 to produce more consistent and effective lesions.

[0285]

[0312] 16, in some embodiments, device 102 includes one or more additional electrodes 109 (e.g., ring electrodes) positioned along shaft 120 proximal to energy delivery body 108. In some embodiments, some or all of electrodes 109 can be used for stimulation and recording (for electrophysiological mapping), such that a separate cardiac mapping catheter is not required when using device 102 for ablation.

[0286]

[0313] In some embodiments, the device 102 includes a thermocouple temperature sensor, optionally embedded in the energy delivery body 108. Similarly, in some embodiments, the device 102 includes a lumen that can be used for irrigation and / or aspiration. In some embodiments, the device 102 includes one or more sensors that can be used to determine temperature, impedance, resistance, capacitance, conductivity, permittivity, and / or conductance, to name a few. In some embodiments, one or more of the electrodes serve as the one or more sensors. In other embodiments, the one or more sensors are separate from the electrodes. Sensor data can be used to plan therapy, monitor therapy, and / or provide direct feedback by the processor 154, which can then modify the energy delivery algorithm 152. For example, impedance measurements can be used to determine not only the initial dose to be applied, but also whether further treatment is needed.

[0287]

[0314] It may be appreciated that in some embodiments, the system 100 includes automated therapy delivery algorithms that dynamically respond to and adjust therapy and / or terminate therapy in response to inputs such as temperature, impedance at various voltages or AC frequencies, treatment duration or other timing aspects of energy delivery pulses, treatment power and / or system status.

[0288]

[0315] As described above, one or more energy delivery algorithms 152 may be programmable or pre-programmed into the generator 104 for delivery to the patient P. The one or more energy delivery algorithms 152 specify electrical signals that provide energy delivered to the cardiac wall that is non-thermal (e.g., below the threshold for thermal ablation, below the threshold for inducing coagulative thermal damage), thereby reducing or avoiding inflammation and / or preventing denaturation of interstitial proteins in luminal structures. Generally, the algorithms 152 are tailored to affect tissue to a predetermined depth and / or volume and / or to target specific types of cellular responses to the delivered energy.

[0289]

[0316] FIG. 19A shows another embodiment of a therapeutic energy delivery catheter or device 102. In this embodiment, the device 102 has an elongate shaft 106 with at least one energy delivery body 108 near its distal end and a handle 110 near its proximal end. The device 102 is connectable to a generator 104 as part of a treatment system 100. The connection of the device 102 to the generator 104 provides, among other features, electrical energy to the energy delivery body 108. In this embodiment, the energy delivery body 108 includes multiple wires or ribbons 120 constrained by a proximal end constraint 122 and a distal end constraint 124 to form a helical basket that functions as an electrode. In an alternative embodiment, the wires or ribbons are straight (i.e., configured to form a straight basket) instead of being helically formed. In yet another embodiment, the energy delivery body 108 is laser cut from a tube. It will be appreciated that various other designs may be used. For example, FIG. 19B shows an energy delivery body 108 having a paddle shape. In this embodiment, the energy delivery body 108 is composed of multiple wires or ribbons 120 arranged to form a flat pad or paddle. Such energy delivery body 108 is flexible so as to retract within the shaft 106. Referring again to FIG. 19A , in this embodiment, the energy delivery body 108 is self-expandable and is delivered to the target area in a collapsed configuration. This collapsed configuration may be achieved, for example, by placing a sheath 126 over the energy delivery body 108. The instrument shaft 106 (within the sheath 126) terminates at a proximal end constraint 122, while the distal end constraint 124 is essentially axially unconstrained and remains free to move relative to the shaft 106 of the device 102. Advancing the sheath 126 over the energy delivery body 108 allows the distal end constraint 124 to move forward, thereby lengthening / collapses and constraining the energy delivery body 108.

[0290]

[0317] As shown in this example, device 102 includes a handle 110 at its proximal end. In some embodiments, handle 110 is detachable, such as by pressing a handle removal button 130. In this embodiment, handle 110 includes an energy delivery body manipulation knob or actuator 132, movement of which causes the basket-shaped electrode to expand or retract / collapse. In this example, handle 110 also includes a working port snap 134 for optional connection to an endoscope or other type of visualization device and a cable plug-in port 136 for connection to generator 104. It can be appreciated that various types of visualization can be used, including angiography (optionally including markers), computed tomography, optical coherence tomography, ultrasound, and direct imaging visualization, to name a few.

[0291]

[0318] In this embodiment, the therapeutic energy delivery device 102 is connectable to the generator 104 along with a dispersive (return) electrode 140 applied externally to the skin of the patient P. Thus, in this embodiment, monopolar energy delivery is achieved by supplying energy between the energy delivery body 108 located near the distal end of the device 102 and the return electrode 140. However, it will be understood that bipolar energy delivery and other arrangements may alternatively be used. When using bipolar energy delivery, the therapeutic energy delivery device 102 may have a different overall design, such as including multiple energy delivery bodies 108, or may appear similar in overall design, such as including a single energy delivery body 108 configured to function in a bipolar manner. In some cases, bipolar energy delivery allows for a therapeutic effect to be achieved using lower voltages compared to monopolar energy delivery. In a bipolar configuration, the anode and cathode are close enough to provide a therapeutic effect both at and between the electrode poles. This allows for the therapeutic effect to be spread over a larger, shallower surface area, and therefore, a lower voltage may be required to achieve a therapeutic effect compared to monopolar. Likewise, this lower voltage can be used to reduce penetration depth.

[0292]

[0319] As previously mentioned, one or more energy delivery algorithms 152 may be programmable or pre-programmed into the generator 104 for delivery to the patient. The one or more energy delivery algorithms 152 specify electrical signals that provide energy delivered to tissue that is non-thermal (e.g., below the threshold for thermal ablation, below the threshold for inducing coagulative thermal damage), thereby reducing or avoiding inflammation and / or preventing denaturation of interstitial proteins in luminal structures. Generally, the algorithms 152 are tailored to affect tissue to a predetermined depth and / or target particular types of cellular responses to the delivered energy. It may be appreciated that depth and / or targeting may be influenced by parameters of the energy signal defined by the one or more energy delivery algorithms 152, the design of the device 102 (particularly the one or more energy delivery bodies 108), and / or the selection of monopolar or bipolar energy delivery. Typically, the depth is up to 0.01 cm, up to 0.02 cm, 0.01-0.02 cm, up to 0.03 cm, 0.03-0.05 cm, up to 0.05 cm, up to 0.08 cm, up to 0.09 cm, up to 0.1 cm, up to 0.2 cm, up to 0.5 cm, up to 0.7 cm, up to 1.0 cm, up to 1.5 cm, up to 2.0 cm, up to 2.5 cm, up to 3.0 cm, up to 3.5 cm, up to 4.0 cm, up to 4.5 cm, or up to 5.0 cm, to name a few. These depths may be greater for circumferential focal targets, or they may exist for full circumferential depths through the lumen and parenchyma.

[0293]

[0320] 20A-20B illustrate another embodiment of a treatment system 100. Here, the system 100 is configured to treat target tissue located at least partially outside a body lumen, where the treatment may benefit from initiating treatment energy away from the body lumen. In this embodiment, the system 100 includes an energy delivery device 102 connectable to a generator 104. It can be appreciated that many of the system components described above, such as certain aspects of the device 102, generator 104, and other accessories, are utilized in this embodiment of the system 100. Accordingly, such description provided above is applicable to the system 100 described below herein. The primary differences relate to the energy delivery body 108.

[0294]

[0321] Here, the device 102 includes a shaft 106 having a distal end 103, a proximal end 107, and at least one lumen 105 extending at least partially through the shaft 106. Similarly, the device 102 also includes at least one energy delivery body 108. In this embodiment, the energy delivery body 108 takes the form of a probe 500 disposed within the lumen 105 of the shaft 106. The probe 500 is advanceable through the lumen 105 and has a probe tip 502 extendable from the distal end 103 of the shaft 106 (enlarged in FIG. 20A to show detail). In this embodiment, the tip 502 has a pointed shape configured to penetrate tissue, similar to a needle. Thus, in this embodiment, the probe tip 502 is utilized 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 500 is flexible enough to be delivered intraluminally, yet has sufficient column strength to penetrate the lumen wall W and target tissue. In some embodiments, the device 102 has markings to indicate to the user the distance the probe tip 502 has been advanced to ensure desired placement.

[0295]

[0322] 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 500 is constructed from a conductive material to function as an electrode. Thus, the electrode has the size of the exposed probe. Exemplary materials include stainless steel, nitinol, cobalt-chromium alloy, copper, and gold. Thus, in these embodiments, PEF energy can be transmitted through the probe 500 to the probe tip 502. Consequently, the shaft 106 is constructed from an insulating material or is covered by an insulating sheath. Exemplary insulating materials include polyimide, silicone, polytetrafluoroethylene, and polyether block amide. The insulating material may be consistent or vary along the length of the shaft 106 or sheath. Likewise, in either case, the insulating material generally includes complete electrical insulation. However, in some embodiments, the insulating material allows some leakage current to penetrate.

[0296]

[0323] When the probe 500 is energized, the insulated shaft 106 protects the surrounding tissue from the treatment energy and directs the energy to the probe tip 502 (and any exposed portions of the probe 500), which can deliver the treatment energy to the surrounding tissue. The tip 502 thus functions as a delivery electrode, the size of which can be selected based on the amount of the probe 500 that is exposed. Larger electrodes can be formed by exposing a greater amount of the probe 500, and smaller electrodes can be formed by exposing less. In some embodiments, the exposed tip 502 (measured from its distal end to the distal end of the insulated shaft) during energy delivery has a length 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, more than 3 cm, up to 8 cm, 0.1 cm or less, 0.3 cm or less, 0.5 cm or less, 1 cm or less, 0.2-0.3 cm, 0.1-0.5 cm, 0.1-1 cm, and all ranges and subranges therebetween. In addition to varying the electrode size, the tip 502 is retractable within the shaft 106 to enable atraumatic endoscopic delivery and can then be advanced as needed to reach the target tissue. In this embodiment, advancement and retraction are controlled by an actuator 132 (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 may be appreciated that the shaft 106 itself may be advanced toward the target tissue with or without advancing a 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 outer surface of a luminal structure or the outer surface of a patient's body.

[0297]

[0324] The handle 110 connects to the generator 104 using 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 of the first end 512 to the handle 110 is enlarged for detail in FIG. 20B . In this embodiment, the first end 512 has an adapter 516 that includes a connecting wire 518 extending from the adapter 516. The connecting wire 518 is insertable into the proximal end of the probe 500 within the handle 110. This allows energy to be transferred from the generator 104 through the connecting wire 518 to the probe 500. Thus, the probe 500 can be energized throughout its entire length, but due to the presence of the insulated shaft 106, only the exposed tip 502 delivers energy to tissue.

[0298]

[0325] The devices, systems, and methods described herein can be used alone or in combination with other treatments. Such combination therapies may be particularly applicable to cancer treatments. For example, the PEF treatments described herein can be used in combination with various non-surgical therapies, including neoadjuvant and adjuvant therapies such as radiation therapy, chemotherapy, targeted therapy / immunotherapy, focal therapy, gene therapy, and plasmid therapy, to name a few. Exemplary focal therapies include microwave ablation, radiofrequency ablation, cryoablation, high-intensity focused ultrasound (HIFU), and other pulsed electric field ablation therapies. Such combinations may condition tissue for enhanced responsiveness and, in some cases, for a synergistic response greater than either therapy alone. Additionally, the PEF treatments described herein may provide long-range effects due to the nature of the therapies.

[0299] Energy Algorithm

[0326] The PEF energy is provided by one or more energy delivery algorithms 152. In some embodiments, the algorithm 152 defines a signal having a waveform including a train of energy packets, each of which includes a train of high-voltage pulses. In such embodiments, the algorithm 152 specifies parameters of the signal, such as the energy amplitude (e.g., voltage) and duration of applied energy, consisting of the number of packets, the number of pulses within a packet, and the fundamental frequency of the pulse sequence, to name a few. Further parameters may include the switching time or interphase delay between polarities in biphasic pulses, the dead time or cycle delay between biphasic cycles, and the pause time or interpacket delay between packets. In some embodiments, there is a fixed pause period between packets, while in other embodiments, the packets are gated to the cardiac cycle and therefore vary with the patient's heart rate. There may be an intentional variable pause period algorithm, or no pause period may be applied between packets. Feedback loops based on sensor information and automatic shutoff specifications and / or the like may be included.

[0300]

[0327] FIG. 21A illustrates one embodiment of a waveform 400 of a signal defined by the energy delivery algorithm 152. Two packets are shown: a first packet 402 and a second packet 404, separated by an inter-packet delay or rest period 406. In this embodiment, each packet 402, 404 is comprised of a first biphasic cycle (including a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic cycle (including a second positive pulse peak 408' and a second negative pulse peak 410'). The first and second biphasic pulses are separated by a cycle delay or dead time 412 (i.e., a pause) between each pulse. In this embodiment, the biphasic pulses are symmetrical such that the set voltage 416 is the same for the positive and negative peaks. Here, the biphasic symmetrical wave is also a square wave, such that the magnitude and duration of the positive voltage wave are approximately equal to the magnitude and duration of the negative voltage wave.

[0301] A. Voltage

[0328] The voltages used and considered can be the top of a square waveform, the peak of a sinusoidal or sawtooth waveform, or the RMS voltage of a sinusoidal or sawtooth waveform. In some embodiments, the energy is delivered in a unipolar manner and each high voltage pulse or set voltage 416 is between about 500V and 10,000V, particularly between about 3500V and 4000V, between about 3500V and 5000V, between about 3500V and 6000V, including all values ​​and subranges therebetween, including between about 250V, 500V, 1000V, 1500V, 2000V, 2500V, 3000V, 3500V, 4000V, 4500V, 5000V, 5500V, and 6000V, to name a few. The voltage delivered to the tissue may be based on the setting of the generator 104, with or without taking into account electrical losses along the length of the device 102 due to the inherent impedance of the device 102, i.e., the delivered voltage may be measured at the tip of the generator or instrument.

[0302]

[0329] It can be appreciated that the set voltage 416 may vary depending on whether the energy is delivered in a monopolar or bipolar manner. In bipolar delivery, a lower voltage may be used due to a smaller, more directional electric field. While the bipolar voltage selected for use in therapy depends on the electrode separation distance, a monopolar electrode configuration using one or more spaced dispersive pad electrodes may be delivered without much consideration for the precise placement of the catheter electrode and dispersive electrode on the body. In monopolar electrode embodiments, a higher voltage is typically used due to the dispersive behavior of the energy delivered through the body to reach the dispersive electrode at an effective separation distance of approximately 10 cm to 100 cm. Conversely, in a bipolar electrode configuration, the relatively close active area of ​​the electrodes, approximately 0.5 mm to 10 cm (including 1 mm to 1 cm), results in a greater effect from separation distance on the electrical energy concentration and effective dose delivered to the tissue. For example, if the target voltage-to-distance ratio to induce the desired clinical effect at the appropriate tissue depth (1.3 mm) is 3000 V / cm, then if the separation distance is changed from 1 mm to 1.2 mm, this would result in a required increase in treatment voltage from 300 V to approximately 360 V (a 20% change).

[0303] B.Frequency

[0330] The number of biphasic cycles per second of time can be understood to be the frequency of the signal as it continues. In some embodiments, biphasic pulses are utilized to reduce undesired muscle stimulation, particularly myocardial stimulation. In other embodiments, the pulse waveform is monophasic and does not have a distinct inherent frequency. Instead, the fundamental frequency can be considered by doubling the monophasic pulse length to derive the frequency. In some embodiments, the signal has a frequency in the range of 100 kHz to 1 MHz, particularly 100 kHz to 1000 kHz. In some embodiments, the signal has a frequency in the range of approximately 100 to 600 kHz, which generally penetrates the luminal wall to treat or affect certain cells located somewhat deeper, such as submucosal or smooth muscle cells. In some embodiments, the signal has a base or fundamental frequency in the range of approximately 600 kHz to 1000 kHz or 600 kHz to 1 MHz, which generally penetrates the luminal wall to treat or affect certain cells located somewhat shallower, such as epithelial or endothelial cells. It can be appreciated that, at some voltages, frequencies below 100-250 kHz can cause unwanted muscle stimulation. Thus, in some embodiments, the signal has a frequency in the range of 400-800 kHz or 500-800 kHz, such as 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, or 800 kHz. In particular, in some embodiments, the signal has a frequency of 600 kHz. Additionally, cardiac synchronization is commonly utilized to reduce or avoid unwanted myocardial stimulation during sensitive rhythmic periods. It can be appreciated that even higher frequencies can be used with components that minimize signal artifacts.

[0304] C. Voltage-Frequency Balancing

[0331] The frequency of the delivered waveform may be varied in synchrony with the treatment voltage to maintain adequate therapeutic effect. Such synergistic variations include a decrease in frequency causing a stronger effect combined with a decrease in voltage causing a decreased effect. For example, in some cases, treatment may be delivered using 3000V in a monopolar manner at an 800kHz waveform frequency, while in other cases, treatment may be delivered using 2000V at a 400kHz waveform frequency.

[0305]

[0332] When used in the opposite direction, treatment parameters may be manipulated in a way that makes it overly effective, which may increase the likelihood or risk of muscle contraction effects on undesirable tissues, such as cartilage, for treating the airway. For example, increasing the frequency and lowering the voltage, such as using 2000 V at 800 kHz, may result in treatment that does not have sufficient clinical therapeutic benefit. Conversely, increasing the voltage to 3000 V and decreasing the frequency to 400 kHz may result in undesirable therapeutic effects on adjacent delicate tissues. In some cases, overtreatment of these undesirable tissues may result in patient morbidity or safety concerns, such as destruction of cartilage tissue in the airway sufficient to cause airway collapse or destruction of smooth muscle in the gastrointestinal tract sufficient to cause disruption of normal peristalsis. In other cases, overtreatment of non-target or undesirable tissues may result in benign clinical outcomes and may not affect patient response or morbidity when overtreated.

[0306] D. Packet

[0333] As previously described, the algorithm 152 defines a signal having a waveform including a train of energy packets, each of which includes a train of high-voltage pulses. The cycle count 420 is half the number of pulses in each biphasic packet. Referring to FIG. 21A, 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 between 1 and 100 per packet, including all values ​​and subranges therebetween. In some embodiments, the cycle count 420 is up to 5 pulses, up to 10 pulses, up to 25 pulses, up to 40 pulses, up to 60 pulses, up to 80 pulses, up to 100 pulses, up to 1,000 pulses, or up to 2,000 pulses, including all values ​​and subranges therebetween.

[0307]

[0334] Packet duration is determined by cycle count, among other factors, such as insertion delay. In some embodiments, packet duration is in the range of approximately 50-1000 microseconds, such as 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 125 μs, 150 μs, 175 μs, 200 μs, 250 μs, 100-250 μs, 150-250 μs, 200-250 μs, or 500-1000 μs, to name a few. In other embodiments, packet duration is in the range of approximately 100-1000 microseconds, such as 150 μs, 200 μs, 250 μs, 500 μs, or 1000 μs. In some embodiments, the inclusion of delays may be 2,000 μs, 5,000 μs, 10,000 μs, 20,000 μs, 25,000 μs, 30,000 μs, 40,000 μs, 50,000 μs, 60,000 μs, 70,000 μs, 80,000 μs, 90,000 μs, 100,000 μs, 110,000 μs, 120,000 μs, 130,000 μs, 140,000 μs, 150,000 μs, 160,000 μs, 170,000 μs, 180,000 μs, 190,000 μs, 200,000 μs, 1000-2000 μs, 1 The packet duration may be increased to a range of approximately 1000 to 200,000 microseconds, such as 000 to 3000 μs, 1000 to 4000 μs, 1000 to 5000 μs, 1000 to 10,000 μs, 10,000 to 20,000 μs, 10,000 to 30,000 μs, 10,000 to 40,000 μs, 10,000 to 50,000 μs, 50,000 to 100,000 μs, 50,000 to 150,000 μs, 50,000 to 200,000 μs, greater than 10,000 μs, greater than 25,000 μs, greater than 50,000 μs, greater than 100,000 μs, and greater than 200,000 μs.

[0308] E. Waveform

[0335] FIG. 21A shows an embodiment of a waveform 400 having symmetric 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 opposite direction. FIG. 21B shows an exemplary waveform 400 defined by another energy delivery algorithm 152, where the waveform 400 has a voltage imbalance. Here, two packets are shown: a first packet 402 and a second packet 404, separated by a rest period 406. In this embodiment, each packet 402, 404 is comprised of a first biphasic cycle (including a first positive pulse peak 408 having a first voltage V1 and a first negative pulse peak 410 having a second voltage V2) and a second biphasic cycle (including a second positive pulse peak 408' having a first voltage V1 and a second negative pulse peak 410' having a second voltage V2). Here, the first voltage V1 is greater than the second voltage V2. The first and second biphasic cycles are separated by a dead time 412 between each pulse. Thus, the voltage in one direction (i.e., positive or negative) is greater than the voltage in the opposite direction, such that the area under the positive portion of the curve is not equal to the area under the negative portion of the curve. This unbalanced waveform may result in a more pronounced therapeutic effect because the predominant positive or negative amplitude results in a longer duration of the same charge cell membrane charge potential. In this embodiment, the first positive peak 408 has a set voltage 416 (V1) that is greater than the set voltage 416' (V2) of the first negative peak 410. Figure 21C shows another example of an unequal voltage waveform. For ease of illustration, four different types of packets are shown in one diagram. The first packet 402 consists of pulses of unequal voltage but equal pulse width, without interphase delay and dead time. Thus, the first packet 402 is comprised of four biphasic pulses, each including a positive peak 408 with a first voltage V1 and a negative peak 410 with a second voltage V2, where the first voltage V1 is greater than the second voltage V2. The second packet 404 is comprised of pulses with unequal voltages (as in the first pulses 402) but symmetric pulse widths, with an interphase delay equal to the cycle delay.The third packet 405 is comprised of pulses with unequal voltages (as in the first pulse 402) but symmetric pulse widths, with an interphase delay that is less than the cycle delay. The fourth packet 407 is comprised of pulses with unequal voltages (as in the first pulse 402) but symmetric pulse widths, with an interphase delay that is greater than the cycle delay. It can be appreciated that in some embodiments, the positive and negative phases of a biphasic waveform are not identical but are balanced, where the voltage in one direction (i.e., positive or negative) is greater than the voltage in the opposite direction, but the pulse lengths are calculated so that the area under the curve for the positive phase is equal to the area under the curve for the negative phase.

[0309]

[0336] In some embodiments, the imbalance includes pulses having pulse widths of unequal duration. In some embodiments, a biphasic waveform is unbalanced such that the voltage in one direction is equal to the voltage in the opposite direction, but the duration of one direction (i.e., positive or negative) is greater than the duration of the opposite direction, such that the area under the curve in the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

[0310]

[0337] FIG. 21D shows further examples of waveforms with unequal pulse widths. For brevity, four different types of packets are shown in one diagram. The first packet 402 is composed of pulses with equal voltages but unequal pulse widths, without interphase and cycle delays. Thus, the first packet 402 is composed of four biphasic pulses, each including a positive peak 408 with a first pulse width PW1 and a negative peak 410 with a second pulse width PW2. Here, the first pulse width PW1 is greater than the second pulse width PW2. The second packet 404 is composed of pulses with equal voltages but unequal pulse widths (as in the case of the first pulse 402), with an interphase delay equal to the cycle delay. The third packet 405 is composed of pulses with equal voltages but unequal pulse widths (as in the case of the first pulse 402), with an interphase delay shorter than the cycle delay. The fourth packet 407 is made up of pulses of equal voltage (as in the first pulses 402) but unequal pulse width, and has an interphase delay that is greater than the cycle delay.

[0311]

[0338] FIG. 21E shows an exemplary waveform 400 defined by another energy delivery algorithm 152, where the waveform is monophasic, illustrating the special case of imbalance where only the positive or negative portion of the waveform is present. Two packets are shown: a first packet 402 and a second packet 404, separated by an inter-packet delay or rest period 406. In this embodiment, each packet 402, 404 is composed of a first monophasic pulse 430 and a second monophasic pulse 432. The first and second monophasic pulses 430, 432 are separated by a cycle delay or dead time 412 between each cycle. This monophasic waveform may produce a more desirable therapeutic effect because the same charge cell membrane potential is maintained for a longer duration. However, adjacent muscle groups may be stimulated more with a monophasic waveform compared to a biphasic waveform.

[0312]

[0339] FIG. 21F shows a further example of a waveform with monophasic pulses. For clarity, four different types of packets are shown in one figure. The first packet 402 is composed of pulses with equal voltage and pulse width, with no switching time or interphase delay (because the pulses are monophasic), and a cycle delay equal to the active time. In some cases, there may be a cycle delay duration greater than the active time of a particular pulse. Thus, the first packet 402 is composed of three monophasic pulses 430, each with a positive peak. If the dead time is equal to the active time, the waveform may be considered unbalanced with a fundamental frequency representing a cycle period twice the active time and no dead time. The second packet 404 is composed of monophasic pulses 430 with equal voltage and pulse width (as in the first packet 402) and a larger cycle delay. The third packet 405 is composed of monophasic pulses 430 with equal voltage and pulse width (as in the first packet 402) and an even larger cycle delay. The fourth packet 407 is composed of monophasic pulses 430 with equal voltage and pulse width (as in the first packet 402) and an even larger cycle delay.

[0313]

[0340] In some embodiments, an unbalanced waveform is achieved by delivering two or more pulses in one polarity before reversing to an unequal number of pulses in the opposite polarity. FIG. 21G shows further examples of waveforms with such phase imbalance. Here, for brevity, four different types of packets are shown in one diagram. The first packet 402 consists of four cycles with equal voltage and pulse width, but opposite polarity pulses are mixed with monophasic pulses. Thus, the first cycle includes a positive peak 408 and a negative peak 410. The second cycle is monophasic and includes a single positive pulse without a subsequent negative pulse 430. This then repeats. The second packet 404 consists of mixed biphasic and monophasic cycles (as in the first packet 402), but the pulses have unequal voltages. The third packet 405 consists of mixed biphasic and monophasic cycles (as in the first packet 402), but the pulses have unequal pulse widths. The fourth packet 407 is comprised of mixed biphasic and monophasic pulses (as in the first packet 402), but the pulses have unequal voltages and unequal pulse widths. In this manner, multiple combinations and sequences are possible. FIG. 21H shows an example of a waveform that is unbalanced in both positive and negative voltage. Here, a packet is shown with a first positive pulse peak 408 and a first negative pulse peak 410 having a greater voltage than a second positive pulse peak 408' and a second negative pulse peak 410'. These different cycles are repeated throughout the packet.

[0314]

[0341] Regarding the usefulness of unequal waveforms, the achieved unbalanced TMP operation reduces the effects of biphasic cancellation. There is a correlation between the degree of imbalance approaching a fully unbalanced unipolar waveform and the intensity of TMP operation. This results in a proportional relationship between the extent of therapeutic effect and the degree of muscle contraction. Therefore, as the waveform approaches a more unbalanced waveform, a more powerful therapeutic effect can be achieved with the same voltage and frequency (if applicable) for a biphasic waveform than that resulting from a fully balanced biphasic waveform. For example, a therapeutic effect induced by a pulse length sequence such as 830 ns-415 ns-830 ns within a packet would have pulses comprising the second half of the cycle that are half the duration of the original phase. This limits the induction of TMP operation by the second phase of the cycle, but also reduces the generation of reverse TMP, thereby allowing a stronger effect from the original polarity in subsequent cycles of the original length. In another example, the "positive" portion of the waveform could be 2500 V and the "negative" portion 1500 V (e.g., 2500-1250-2500 V), which would induce an effect on TMP polarization equivalent to that described for pulse duration imbalance. In either case, the operation of opposite polarity intensities results in a cumulatively stronger TMP operation for the positive pulses within the cycle. This therefore reduces the effect of biphasic cancellation and produces a stronger therapeutic effect than 830-830-830 ns or 2500-2500-2500 V protocols, despite the deposition of less total energy delivered to the tissue. In this way, it is possible to deliver less total energy to the tissue but still produce the desired therapeutic effect if TMP operation is essential to the therapeutic mechanism of action.

[0315]

[0342] By extension, a fully unbalanced waveform may contain no opposite polarity components at all, but still contain short portions of pulses delivered only in the positive phase. An example of this would be a packet containing 830 ns of positive polarity, an 830 ns pause where no energy is delivered, followed by another 830 ns of positive polarity, etc. Whether considering pulse length imbalance or voltage imbalance, the same approach applies, as the absence of a negative pulse is equivalent to setting one of these parameters to zero for the "negative" portion.

[0316]

[0343] However, proper therapy delivery takes into account the benefits provided by biphasic waveforms, i.e., the reduction in muscle contraction due to biphasic cancellation. Therefore, the appropriate therapeutic range is balanced against the degree of tolerable muscle contraction. For example, the ideal voltage imbalance might be 2500-1000-2500...V, or 2500-2000-2500...V, or 830-100-830...ns, or 830-500-830...ns.

[0317]

[0344] In some embodiments, it can be understood that the pulses are sinusoidal rather than square. One advantage of a sinusoidal waveform is that it is balanced or symmetrical, so that the shape of each phase is equal. Balancing can help reduce unwanted muscle stimulation. In other embodiments, it can be understood that the pulses have a decaying waveform.

[0318] Alternative Delivery Approaches

[0345] As previously mentioned, in most embodiments, access relies on a minimally invasive, endoluminal approach, however, it can be appreciated that other approaches, such as percutaneous, laparoscopic, or open surgical approaches, may be used in some circumstances.

[0319]

[0346] In some embodiments, when accessing percutaneously, the shaft 106 of the device 102 is threaded through a delivery device that penetrates the skin layer into the underlying tissue. In some embodiments, the delivery device includes a needle that is inserted through the skin and directed toward the target tissue. The shaft 106 is then advanced through the needle. In some embodiments, the probe tip 502 is shaped, such as pointed, to facilitate penetration of the tissue. Thus, the shaft 106 can be advanced through the tissue to a desired location within the tissue. Once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue. It can be appreciated that the probe tip 502 can be advanced from the shaft 106 into the tissue and / or the conductive element 560 can be advanced into the tissue, where energy is delivered from the conductive element 560.

[0320]

[0347] In other embodiments, for percutaneous access, the shaft 106 of the device 102 is rigid so as to penetrate the skin layer without the use of a delivery device. In such embodiments, the probe tip 502 is generally shaped to facilitate penetration of tissue, such as by being pointed. Thus, the shaft 106 itself is advanced into the tissue to a desired location within the tissue. Once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue. It can be appreciated that the probe tip 502 can be advanced from the shaft 106 into the tissue, and / or the conductive element 560 can be advanced into the tissue, where energy is delivered from the conductive element 560.

[0321]

[0348] In a laparoscopic approach, the shaft 106 of the device 102 is threaded through a laparoscope inserted through a small incision. These small incisions result in less pain, less bleeding, and shorter recovery times compared to open surgery. In some embodiments, the probe tip 502 is shaped, such as pointed, to facilitate tissue penetration. Thus, the shaft 106 can be advanced through the tissue to a desired location within the tissue. Once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue.

[0322]

[0349] In an open surgical approach, the shaft 106 of the device 102 may be threaded through a delivery device, or the device 102 may penetrate tissue directly. In either case, once desirably positioned, energy is delivered through the probe tip 502 to treat the target tissue.

[0323] Heart Rate Synchronization

[0350] In some embodiments, the energy signal is synchronized with the patient's cardiac cycle to prevent the induction of cardiac arrhythmias. Therefore, the patient's cardiac cycle is typically monitored using an electrocardiogram (ECG). Referring to FIG. 22 , a typical ECG recording 600 includes a repeating cycle of a P wave 602 representing atrial depolarization, a QRS complex 604 representing ventricular depolarization and atrial repolarization, and a T wave 606 representing ventricular repolarization. Synchronization of energy delivery with the patient's cardiac cycle is used to safely deliver energy into the airways in close proximity to the heart, thereby reducing the risk of cardiac arrhythmias. High-voltage energy can trigger premature action potentials in the myocardium because the delivered energy increases myocardial cell membrane permeability, allowing ion transport, which can induce cardiac arrhythmias, particularly ventricular fibrillation. To avoid cardiac arrhythmias, electrical energy is delivered to the airways in a manner that is outside the "vulnerable period" of the myocardium. Within one cardiac cycle (heartbeat), the vulnerable period of the ventricular muscle is indicated by the entire T wave 606 on the ECG. Generally, for ventricular muscle, the vulnerable period coincides with the middle and terminal phases of the T wave 606. However, if a high-energy pulse is delivered in close proximity to the ventricle, the vulnerable period may occur several milliseconds earlier in the heartbeat. Thus, the entire T wave may be considered to be within the ventricular vulnerable period.

[0324]

[0351] The remaining portions of the cardiac cycle are the P wave 602 and QRS complex 604, both of which comprise periods during which the atrial or ventricular muscle is refractory to high-voltage energy stimulation. If a high-voltage energy pulse is delivered during the muscle's refractory period, proarrhythmic potentials can be minimized. The ST segment 608 of the first cardiac cycle (the interval between ventricular depolarization and repolarization) and the TQ interval 610 (the interval including the end of the first cardiac cycle and the midpoint of the second cardiac cycle) are periods during which high-voltage energy can be delivered without inducing cardiac arrhythmias due to the depolarized state (refractory period) of the myocardium. FIG. 22 includes shaded boxes showing exemplary portions of the cardiac cycle during which energy can be safely applied.

[0325]

[0352] It can be appreciated that in some embodiments, the components for acquiring the electrocardiogram 170 are integrally formed as part of the generator 104. If the cardiac monitor is limited to acquiring a maximum of five-lead ECGs, it may be beneficial to incorporate additional leads into the system. This would further eliminate the need to use the communications port 167 to receive cardiac synchronization pulses. Rather, the processor 154 can be configured to directly detect R waves and assess the completeness of the entire QRS complex.

[0326]

[0353] As used herein, the terms "about" and / or "approximately" when used in conjunction with a numerical value and / or range generally refer to a numerical value and / or range that is close to the stated numerical value and / or range. In some cases, the terms "about" and "approximately" may mean within ±10% of the stated value. For example, in some cases, "about 100 [units]" may mean within ±10% of 100 (e.g., 90 to 110). The terms "about" and "approximately" may be used interchangeably.

[0327]

[0354] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby. The present invention provides, for example, the following items. (Item 1) 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, the energy being generated from a waveform including one or more packets of pulses to provide the therapy and including one or more delay periods to manipulate, reduce, or avoid one or more secondary effects; A system including: (Item 2) Item 10. The system of item 1, wherein the one or more secondary effects include foam formation. (Item 3) 3. The system of claim 1, wherein each of the pulses in the one or more packets of pulses has an on-time in the range of 0.5 to 20 microseconds. (Item 4) 4. The system of any one of items 1 to 3, wherein each of the pulses in the one or more packets of pulses has a continuous on-time of up to 5 microseconds. (Item 5) 5. The system of any one of items 1 to 4, wherein each of the pulses has a duty cycle of 2.5 percent or less. (Item 6) 6. The system according to any one of items 1 to 5, wherein the delay period is 1 microsecond or longer. (Item 7) 7. The system of claim 6, wherein the delay period is in the range of 1 to 250 microseconds. (Item 8) Item 9. The system according to item 6, wherein the delay period is in the range of 10 to 100 microseconds. 7. The system of claim 6, wherein the delay period is 100 microseconds or greater. (Item 10) 7. The system of claim 6, wherein the delay period is 250 microseconds or greater. (Item 11) 7. The system of claim 6, wherein the delay period is 1000 microseconds or more. (Item 12) Item 10. The system of item 1, wherein the one or more secondary effects include an electrical discharge event. (Item 13) Item 13. The system of item 12, wherein the electrical discharge event comprises an electrical arc discharge from at least one of the at least one electrodes. (Item 14) 14. The system of claim 12 or 13, wherein each of the pulses in the one or more packets of pulses has an on-time in the range of 1 to 50 microseconds. (Item 15) 14. The system of claim 12 or 13, wherein each of the pulses in the one or more packets of pulses has a continuous on-time in the range of up to 20 microseconds. (Item 16) 16. The system of any one of items 12 to 15, wherein each of the at least one packet of pulses has a duty cycle of 20 percent or less. (Item 17) Item 13. The system of item 12, wherein the electrical discharge event includes the generation of a pressure wave to the tissue. (Item 18) Item 18. The system of item 17, wherein the pressure waves are sufficient to create a cavity in the tissue. (Item 19) 20. The system of claim 18, wherein each of the at least one packet of pulses has a duty cycle of 50 percent or less. (Item 20) 20. The system of claim 18 or 19, wherein each of the pulses in the one or more packets of pulses has an on-time in the range of 10 to 100 microseconds. (Item 21) 20. The system of claim 18 or 19, wherein each of the pulses in the one or more packets of pulses has a continuous on-time of up to 50 microseconds. (Item 22) 22. The system according to any one of items 12 to 21, wherein the delay period is 1 microsecond or more. (Item 23) Item 24. The system of item 22, wherein the delay period is in the range of 1 to 500 microseconds. 23. The system of claim 22, wherein the delay period is in the range of 10 to 250 microseconds. (Item 25) Item 10. The system of item 1, wherein the one or more secondary effects include muscle contraction. (Item 26) 26. The system of claim 25, wherein the at least one electrode is configured to create a lesion having a width, and wherein reducing or avoiding contraction of the muscle causes the at least one electrode to maintain a position that does not move more than 25% of the width. (Item 27) 27. The system of claim 25 or 26, wherein the delay period is 5 milliseconds or more. (Item 28) 28. The system of claim 27, wherein the delay period is 10 milliseconds or more. (Item 29) Item 28. The system of item 27, wherein the delay period is in the range of 5 milliseconds to 1 second. (Item 30) Item 28. The system of item 27, wherein the delay period is in the range of 5 to 10 milliseconds. (Item 31) 31. The system of any one of items 25 to 30, wherein the one or more packets of pulses include at least two packets separated by a packet delay period of at least 30 milliseconds. (Item 32) Item 32. The system of item 31, wherein each of the packets is separated by a packet delay period of at least 30 milliseconds. (Item 33) 33. The system of any one of items 1 to 32, wherein the pulse comprises a biphasic pulse and the delay period comprises an interphase delay between a positive phase and a negative phase of the biphasic pulse. (Item 34) Item 34. The system according to any one of items 1 to 33, wherein the delay period includes an inter-packet delay. (Item 35) Item 35. The system according to item 34, wherein the inter-packet delay is in the range of 30 to 5000 milliseconds. (Item 36) Item 36. The system according to item 35, wherein the inter-packet delay is 30 to 40 milliseconds. (Item 37) Item 36. The system according to item 35, wherein the inter-packet delay is 3000 to 5000 milliseconds. (Item 38) Item 39. The system of any one of items 1 to 37, wherein the delay period includes an inter-pulse delay. 39. The system of any one of items 1 to 38, wherein the waveform includes one or more bundles, each bundle including two or more packets. (Item 40) 40. The system of claim 39, wherein each bundle includes three packets, and each bundle is spaced apart to be delivered within the ST interval of the patient's cardiac rhythm. (Item 41) 40. The system of claim 39, wherein the delay period includes an inter-bundle delay. (Item 42) 42. The system of any one of items 1 to 41, wherein the waveform has a voltage amplitude of 500 to 4,000 volts. (Item 43) 43. The system of any one of items 1 to 42, wherein the waveform has a frequency of 300 to 800 kHz. (Item 44) 44. The system of any one of items 1 to 43, wherein each of the one or more packets has 10 to 200 biphasic pulses. (Item 45) 45. The system of any one of items 1 to 44, wherein each of the one or more packets has 20 to 50 biphasic pulses. (Item 46) 46. ​​The system of any one of items 1 to 45, wherein the treatment comprises 5 to 100 packets. (Item 47) 47. The system of any one of items 1 to 46, wherein the treatment comprises 10 to 60 packets. (Item 48) 48. The system of any one of items 1 to 47, further comprising remotely distributed electrodes positionable such that the energy is delivered in a monopolar manner. (Item 49) 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm for providing pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, the energy being and one or more delay periods that avoid a peak temperature of the tissue that would otherwise be reached by delivery of the energy; A system including: (Item 50) 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm for providing pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, the energy being generated from a waveform including at least one packet of pulses for providing the therapy, each pulse having a pulse length, and at least one of the at least one packet including a delay having a delay period at least twice the pulse length; A system including: (Item 51) Item 51. The system of item 50, wherein the delay period is at least 10 times the pulse length. (Item 52) 52. The system of claim 50 or 51, wherein the at least one packet has a packet length that is at least 50 times the delay period. (Item 53) Item 53. The system of item 52, wherein the at least one packet has a packet length at least 100 times the delay period. (Item 54) 54. The system of any one of items 50 to 53, wherein the delay includes an inter-pulse delay. (Item 55) 55. The system of claim 54, wherein the pulses are biphasic pulses and the inter-pulse delay is an inter-cycle delay. (Item 56) 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm for providing pulsed electric field energy to the electrode such that the energy provides treatment to the tissue, the energy being generated from a waveform including at least one packet of biphasic pulses for providing the treatment, each biphasic pulse including an interphase delay in the range of 250 to 1000 microseconds; A system including: (Item 57) 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm for providing pulsed electric field energy to the electrode such that the energy provides treatment to the tissue, the energy being generated from a waveform including 2 to 60 packets of pulses for providing the treatment, each packet including at least one delay period within a range of 250 to 1000 microseconds; A system including: (Item 58) 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides treatment to the tissue, the energy being generated from a waveform including at least one packet of pulses having a delay period, the at least one packet having a packet length at least 50 times the delay period; A system including: (Item 59) 1. A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides treatment to the tissue, the energy being generated from a waveform including at least one packet of pulses, each pulse having a duty cycle of 50 percent or less to reduce or avoid one or more secondary effects; A system including: (Item 60) 60. The system of claim 59, wherein the one or more secondary effects include cavity formation in the tissue. (Item 61) Item 59. The system of item 59, wherein each pulse has a duty cycle of 20 percent or less. (Item 62) Item 63. The system of item 61, wherein the one or more secondary effects include an electrical discharge event. Item 59. The system of item 59, wherein each pulse has a duty cycle of 2.5 percent or less. (Item 64) Item 64. The system of item 63, wherein the one or more secondary effects include foam formation. (Item 65) 1. A system for treating tissue, comprising: an electrode positionable near the tissue; a generator in electrical communication with the electrode, the generator including at least one energy delivery algorithm for providing pulsed electric field energy to the electrode such that the energy treats the tissue, the energy being generated from a waveform having a specific delay period between pulses selected to affect gas formation, external electrical discharge, muscle contraction, cavitation, and / or temperature increase; A system including:

Claims

[Claim 1] A system for treating tissue of a patient, comprising: at least one electrode positionable near the tissue; a generator in electrical communication with the at least one electrode, the generator comprising at least one energy delivery algorithm that provides pulsed electric field energy to the electrode such that the energy provides therapy to the tissue, the energy being generated from a waveform comprising one or more packets of pulses to provide the therapy and including one or more delay periods to manipulate, reduce, or avoid one or more secondary effects.

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