Optimization of energy delivery for various applications

Abstract

To achieve optimization 1 of energy delivery.SOLUTION: Methods, systems and devices are provided which transmit energy to a body lumen or passageway in the form of pulsed electric fields (PEFs) and in a manner which provides focal therapy. In some embodiments, PEFs are delivered through independent electrically active electrodes of an energy delivery body, typically in a monopolar fashion. Such delivery concentrates the electrical energy over a smaller surface area, resulting in stronger effects than delivery through an electrode extending circumferentially around the lumen or passageway. It also forces the electrical energy to be delivered in a staged regional approach, mitigating the effect of preferential current pathways through the surrounding tissue. Focal delivery of PEFs can provide increased tissue lethality by employing precise timing and sequencing of energy delivery to the electrodes.SELECTED DRAWING: Figure 6

Description

[Technical field]

[0001] cross reference

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 610,430, filed December 26, 2017, and entitled "Methods, Apparatuses, and Systems for the Treatment of Pulmonary Disorders," and to U.S. Provisional Patent Application No. 62 / 693,622, filed July 3, 2018, and entitled "Optimization of Energy Delivery for Various Applications," the entire contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background

[0002] Various devices and methods have been developed to deliver therapeutic energy to the body to treat diseases and afflictions. In some instances, such delivery is to tissue within a body cavity, passageway, or similar anatomical structure to treat diseased tissue along or within the passageway wall, or to affect diseases associated with or accessible through the passageway. Such devices typically include a flexible, elongated shaft that traverses the tortuous luminal anatomical structure, and an energy delivery element disposed thereon that delivers such energy to a remote location or to an enclosed location, such as a body cavity. Such devices have been developed, for example, to treat vascular passageways in the lungs or vasculature. Different environments, such as airways versus blood-filled environments, and different diseases, such as diseases affecting surface tissue versus diseases affecting deeper layers or tissues, have different purposes for these devices. The embodiments of the present disclosure will meet at least some of these purposes. Summary of the Invention [Means for solving the problem]

[0003] overview

[0003] In a first aspect, there is provided a method of treating a passageway within a body, the passageway having an inner periphery, the method comprising: positioning a plurality of electrodes within the passageway such that the plurality of electrodes span the inner periphery of the passageway; creating a first treatment zone along a first portion of the inner periphery of the passageway by supplying pulsed electric field energy to at least one of the plurality of electrodes so as to prioritize energy delivery to the first treatment zone through at least one of the plurality of electrodes; and creating at least one additional treatment zone along at least one additional portion of the inner periphery of the passageway by supplying pulsed electric field energy to at least one of the plurality of electrodes so as to prioritize energy delivery to the at least one additional treatment zone through at least one of the plurality of electrodes, wherein the first portion and the at least one additional portion extend along the inner periphery so as to create a functionally continuous treatment zone across the inner periphery.

[0004]

[0004] In some embodiments, a passageway is provided in the heart to treat arrhythmia, and the functionally continuous treatment zone includes an electrical disconnection between a pulmonary vein and the left atrium. Optionally, the passageway includes a pulmonary vein. In some embodiments, the functionally continuous treatment zone includes a transmural lesion. In other embodiments, the passageway includes an airway in the lung, and the functionally continuous treatment zone creates pores for cell types while maintaining the cartilage layer of the airway. In some embodiments, the cell types include epithelial cells, goblet cells, and / or submucosal gland cells. In some embodiments, the functionally continuous treatment zone has a depth of up to and not exceeding 2.5 cm.

[0005] In some embodiments, the pulsed electric field energy is biphasic.

[0006] In some embodiments, creating a first treatment zone along a first portion of the inner circumference of the passageway is accomplished by providing pulsed electric field energy to at least one of the plurality of electrodes for 10,000 μs or less. Optionally, creating a first treatment zone along a first portion of the inner circumference of the passageway is accomplished by providing pulsed electric field energy to at least one of the plurality of electrodes for 500 μs or less. Still further, in some embodiments, creating a first treatment zone along a first portion of the inner circumference of the passageway is accomplished by providing pulsed electric field energy to at least one of the plurality of electrodes for 5 μs to 50 μs.

[0007] In some embodiments, the pulsed electric field energy is comprised of up to 1000 packets, 40-500 packets, or up to 10 packets. In some embodiments, the pulsed electric field energy is delivered in a monopolar configuration.

[0008] In some embodiments, the at least one additional portion comprises 2 to 7 additional portions. In some embodiments, the pulsed electric field energy is delivered to the multiple electrodes in a manner such that the first treatment zone and the at least one additional treatment zone are created in succession. In some embodiments, the first treatment zone and the at least one additional treatment zone overlap.

[0009]

[0009] In some embodiments, creating the first treatment zone includes supplying pulsed electric field energy to the first treatment zone in multiple stages. Optionally, creating the at least one additional treatment zone includes supplying pulsed electric field energy to the at least one additional treatment zone in multiple different stages, the multiple stages and the multiple different stages not occurring simultaneously. In some embodiments, creating the at least one additional treatment zone includes supplying pulsed electric field energy to the at least one additional treatment zone in multiple different stages, the multiple stages and the multiple different stages forming a repeating pattern. In some embodiments, the method further includes supplying maintenance pulsed electric field energy to the first treatment zone and / or the at least one additional treatment zone between stages, the maintenance pulsed electric field energy having a lower voltage than the pulsed electric field energy. Optionally, the maintenance pulsed electric field energy has a voltage less than half the voltage of the pulsed electric field energy.

[0010] In some embodiments, the plurality of electrodes comprises a plurality of electrodes disposed on or embedded within an expandable member, and positioning the plurality of electrodes comprises expanding the expandable member. In some embodiments, the plurality of electrodes comprises a plurality of wires or ribbons forming an electrode delivery body having an expandable basket shape, a portion of the basket shape is insulated, and positioning the plurality of electrodes comprises expanding the electrode delivery body.

[0011]

[0011] In a second aspect, there is provided a method for treating a passageway within a body, the passageway having an inner periphery, the method comprising: positioning an electrode within the passageway such that the electrode spans a portion of the inner periphery of the passageway; creating a first treatment zone along a first portion of the inner periphery of the passageway by supplying pulsed electric field energy to the electrode; repositioning the electrode one or more times within the passageway so that the electrode spans additional portions of the inner periphery each time the electrode is repositioned; and creating additional treatment zones along each additional portion of the inner periphery of the passage by supplying pulsed electric field energy to the repositioned electrode each time the electrode is repositioned, wherein the first portion and each additional portion extend along the inner periphery to create a functionally continuous treatment zone along the inner periphery.

[0012]

[0012] In a third aspect, there is provided a system for treating a passageway within a body, comprising: a catheter including a first electrode and at least one additional electrode disposed near a distal end thereof, the catheter configured such that a distal end of the catheter is positioned within the passageway such that the first electrode and the at least one additional electrode can transmit pulsed electric field energy to an inner periphery of the passageway; and a generator in electrical communication with the first electrode and the at least one additional electrode, the generator including at least one energy delivery algorithm: a) supplying an electrical signal of pulsed electric field energy to the first electrode to prioritize energy delivery through the first electrode to create a first treatment zone, and b) switching, when the electrical signal is supplied, to supply the electrical signal of pulsed electric field energy to each of the at least one additional electrode individually to prioritize energy delivery through each of the at least one additional electrode to create additional treatment zones corresponding to each of the at least one additional electrode, wherein the first treatment zone and the additional treatment zones extend along an inner periphery of the passageway to create a functionally continuous treatment zone across the inner periphery.

[0013] In some embodiments, the passageway is provided within the heart, the distal end of the catheter is configured to be positioned within the heart, and the at least one energy delivery algorithm includes signal parameters that cause the functionally continuous treatment zone to include an electrical disconnection between a pulmonary vein and the left atrium to treat the arrhythmia. Optionally, the passageway includes a pulmonary vein, and the distal end of the catheter is configured to be positioned within the pulmonary vein. In some embodiments, the signal parameters cause the functionally continuous treatment zone to include a transmural lesion.

[0014] In some embodiments, the passageway includes an airway in the lung, the distal end of the catheter is configured to be positioned within the airway, and the at least one energy delivery algorithm includes signal parameters that cause the functionally continuous treatment zone to include voids of cell types while maintaining the cartilage layer of the airway. In some embodiments, the cell types include epithelial cells, goblet cells, and / or submucosal gland cells. In some embodiments, the functionally continuous treatment zone has a depth of up to and not exceeding 2.5 cm.

[0015]

[0015] In some embodiments, the pulsed electric field energy is biphasic. In some embodiments, the at least one energy delivery algorithm delivers the pulsed electric field energy to at least one of the plurality of electrodes for 10,000 μs or less to create each of the first treatment zone and / or at least one additional treatment zone. In some embodiments, the at least one energy delivery algorithm delivers the pulsed electric field energy to at least one of the plurality of electrodes for 500 μs or less to create each of the first treatment zone and / or at least one additional treatment zone. In some embodiments, the at least one energy delivery algorithm delivers the pulsed electric field energy to at least one of the plurality of electrodes for 5 μs-50 μs to create each of the first treatment zone and / or at least one additional treatment zone.

[0016] In some embodiments, the pulsed electric field energy is comprised of 1000 packets or less, 40-500 packets, or 10 packets or less.

[0017]

[0017] In some embodiments, the pulsed electric field energy is delivered in a monopolar configuration.

[0018] In some embodiments, the at least one additional electrode comprises 2-7 additional electrodes. In some embodiments, the at least one energy delivery algorithm sequentially delivers an electrical signal of pulsed electric field energy to each of the first electrode and the at least one additional electrode. In some embodiments, the first treatment zone and the at least one additional treatment zone overlap.

[0019]

[0019] In some embodiments, at least one energy delivery algorithm is configured to provide an electrical signal of pulsed electric field energy to the first electrode in multiple stages. In some embodiments, at least one energy delivery algorithm is configured to provide an electrical signal of pulsed electric field energy to the at least one additional electrode in multiple different stages, the multiple stages and the multiple different stages not occurring simultaneously. In some embodiments, the multiple stages and the multiple different stages form a repeating pattern. In some embodiments, at least one energy delivery algorithm provides a maintenance pulsed electric field energy to the first electrode and / or the at least one additional electrode between stages, the maintenance pulsed electric field energy having a lower voltage than the pulsed electric field energy. In some embodiments, the maintenance pulsed electric field energy has a voltage less than half the voltage of the pulsed electric field energy.

[0020] In some embodiments, at least a first electrode and at least one additional electrode are disposed on or embedded within the expandable member. In some embodiments, the at least a first electrode and at least one additional electrode include a plurality of wires or ribbons that form an electrode delivery body having an expandable basket shape, with a portion of the basket shape being insulated.

[0021]

[0021] In a fourth aspect, there is provided a system for treating a passageway within a body, comprising: a catheter including at least one electrode disposed near its distal end, the distal end of the catheter configured to be positioned within the passageway such that the at least one electrode can transmit pulsed electric field energy to an inner surface of the passageway; and a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm providing an electrical signal to the at least one electrode such that the pulsed electric field energy is delivered to cells on the inner surface of the passageway, the electrical signal comprising a plurality of packets, each packet comprising a plurality of biphasic cycles, and each packet being separated in time by 0.0001 to 10 seconds.

[0022] In some embodiments, the plurality of packets produces pulsed electric field energy for 10,000 μs or less, for 500 μs or less, or for 5 μs to 50 μs or less. In some embodiments, the pulsed electric field energy is comprised of 1000 packets or less, 40 to 500 packets, or 10 packets or less. In some embodiments, the pulsed electric field energy is delivered in a monopolar configuration.

[0023]

[0023] In some embodiments, the at least one electrode includes at least a first electrode and at least one additional electrode arranged to deliver pulsed electric field energy to a circumferential surface of the inner surface of the passageway. In some embodiments, the at least one energy delivery algorithm delivers a plurality of packets to the first electrode prior to delivering another plurality of packets to each of the at least one additional electrode. In some embodiments, the at least one energy delivery algorithm delivers another plurality of packets to each of the at least one additional electrode prior to finishing delivering the plurality of packets to the first electrode. In some embodiments, the at least one energy delivery algorithm delivers maintenance pulsed electric field energy to the first electrode and / or the at least one additional electrode between packets, the maintenance pulsed electric field energy having a lower voltage than the pulsed electric field energy. In some embodiments, the maintenance pulsed electric field energy has a voltage less than half the voltage of the pulsed electric field energy.

[0024]

[0024] In some embodiments, the system further includes a cardiac monitor configured to acquire a cardiac signal of the patient, and the generator delivers the maintenance pulse electric field energy in synchronization with the cardiac signal.

[0025]

[0025] In some embodiments, the at least first electrode and the at least one additional electrode are placed on or embedded in the expandable member. In some embodiments, the at least first electrode and the at least one additional electrode include a plurality of wires or ribbons forming an electrode delivery body having an expandable basket shape, a portion of the basket shape being insulated. In some embodiments, the pulsed electric field energy is delivered to cells on the inner surface of the passage to disrupt cellular homeostasis at a depth of up to and not exceeding 2.5 cm. In some embodiments, the system further includes a cardiac monitor configured to acquire a cardiac signal of the patient, and the generator provides the electrical signal in synchronization with the cardiac signal.

[0026]

[0026] In a fifth aspect, there is provided a method of treating a passage within a body, the passage having an inner periphery, the method comprising: positioning a plurality of electrodes within the passage such that the plurality of electrodes span at least a portion of the inner periphery of the passage; creating a first treatment zone along a first portion of the inner periphery of the passage by supplying pulsed electric field energy to at least one of the plurality of electrodes, thereby prioritizing energy delivery to the first treatment zone through at least one of the plurality of electrodes; and creating at least one additional treatment zone along at least one additional portion of the inner periphery of the passage by supplying pulsed electric field energy to at least one of the plurality of electrodes, thereby prioritizing energy delivery to the at least one additional treatment zone through at least one of the plurality of electrodes, wherein the first portion and the at least one additional portion extend along the inner periphery so as to create balanced treatment zones.

[0027]

[0027] In a sixth aspect, there is provided a system for treating a passageway within a body, comprising: a catheter including a first electrode and at least one additional electrode disposed near a distal end thereof, the catheter configured such that a distal end of the catheter is positioned within the passageway such that the first electrode and the at least one additional electrode can transmit pulsed electric field energy to an inner periphery of the passageway; and a generator in electrical communication with the first electrode and the at least one additional electrode, the generator including at least one energy delivery algorithm: a) supplying an electrical signal of pulsed electric field energy to the first electrode to prioritize energy delivery through the first electrode to create a first treatment zone, and b) switching, when the electrical signal is supplied, to supply the electrical signal of pulsed electric field energy to each of the at least one additional electrode individually to prioritize energy delivery through each of the at least one additional electrode to create additional treatment zones corresponding to each of the at least one additional electrode, wherein the first treatment zone and the additional treatment zones extend along the inner periphery of the passageway to create balanced treatment zones.

[0028]

[0028] These and other embodiments are described in further detail in the following description in conjunction with the accompanying drawings. The present invention provides, for example, the following items. (Item 1) 1. A method for treating a passageway in a body, the passageway having an inner periphery, comprising: positioning a plurality of electrodes within the passageway such that the electrodes span the inner periphery of the passageway; creating a first treatment zone along a first portion of the inner periphery of the passageway by supplying pulsed electric field energy to at least one of the plurality of electrodes, and prioritizing energy delivery to the first treatment zone through the at least one of the plurality of electrodes; creating at least one additional treatment zone along at least one additional portion of the inner periphery of the passageway by supplying pulsed electric field energy to at least one of the plurality of electrodes and prioritizing energy delivery to the at least one additional treatment zone through the at least one of the plurality of electrodes; Including, The method, wherein the first portion and the at least one additional portion extend along the inner periphery to create a functionally continuous treatment area across the inner periphery. (Item 2) 2. The method of claim 1, wherein the passageway is provided within the heart and the functionally continuous treatment area includes an electrical disconnection between a pulmonary vein and the left atrium for treating arrhythmia. (Item 3) 3. The method of claim 2, wherein the passageway includes the pulmonary vein. (Item 4) 4. The method of claim 2 or 3, wherein the functionally continuous treatment zone comprises a transmural lesion. (Item 5) 2. The method of claim 1, wherein the passageway comprises an airway within a lung, and the functionally continuous treatment area creates voids for cell types while maintaining a cartilage layer of the airway. (Item 6) 6. The method of claim 5, wherein the cell types include epithelial cells, goblet cells and / or submucosal gland cells. (Item 7) 7. The method according to item 5 or 6, wherein the functionally continuous treatment zone has a depth of up to and not exceeding 2.5 cm. (Item 8) 8. The method of any one of items 1 to 7, wherein the pulsed electric field energy is biphasic. (Item 9) 9. The method of any one of claims 1 to 8, wherein creating the first treatment zone along the first portion of the inner periphery of the passageway is accomplished by supplying pulsed electric field energy to at least one of the plurality of electrodes for 10,000 μs or less. . (Item 10) 10. The method of claim 9, wherein creating the first treatment zone along the first portion of the inner circumference of the passageway is accomplished by supplying pulsed electric field energy to at least one of the plurality of electrodes for 500 μs or less. (Item 11) 10. The method of claim 9, wherein creating the first treatment zone along the first portion of the inner circumference of the passageway is accomplished by delivering pulsed electric field energy to at least one of the plurality of electrodes for a duration of between 5 μs and 50 μs. (Item 12) 12. The method of any one of claims 1 to 11, wherein the pulsed electric field energy is comprised of 1000 or less packets. (Item 13) Item 13. The method of item 12, wherein the pulsed electric field energy is comprised of 40 to 500 packets. (Item 14) 13. The method of claim 12, wherein the pulsed electric field energy is comprised of up to 10 packets. (Item 15) 15. The method of any one of the preceding claims, wherein the pulsed electric field energy is delivered in a monopolar configuration. (Item 16) 16. The method according to any one of items 1 to 15, wherein the at least one additional moiety comprises 2 to 7 additional moieties. (Item 17) 17. The method of any one of claims 1 to 16, wherein the pulsed electric field energy is delivered to the plurality of electrodes in a manner such that the first treatment area and the at least one additional treatment area are created in succession. (Item 18) 18. The method of any one of items 1 to 17, wherein the first treatment zone and the at least one additional treatment zone overlap. (Item 19) 19. The method of any one of claims 1 to 18, wherein creating the first treatment area comprises delivering the pulsed electric field energy to the first treatment area. (Item 20) 20. The method of claim 19, wherein creating the at least one additional treatment area comprises delivering the pulsed electric field energy to the at least one additional treatment area in a plurality of distinct phases, the plurality of phases and the plurality of distinct phases not occurring simultaneously. (Item 21) 21. The method of claim 20, wherein creating the at least one additional treatment area comprises delivering the pulsed electric field energy to the at least one additional treatment area in a plurality of distinct phases, the plurality of phases and the plurality of distinct phases forming a repeating pattern. (Item 22) 21. The method of claim 20, further comprising delivering a maintenance pulsed electric field energy to the first treatment area and / or the at least one additional treatment area between stages, the maintenance pulsed electric field energy having a lower voltage than the pulsed electric field energy. (Item 23) 23. The method of claim 22, wherein the maintenance pulsed electric field energy has a voltage that is less than half the voltage of the pulsed electric field energy. (Item 24) 24. The method of any one of claims 1 to 23, wherein the plurality of electrodes comprises a plurality of electrodes disposed on or embedded within an expandable member, and positioning the plurality of electrodes comprises expanding the expandable member. (Item 25) 24. The method of any one of items 1 to 23, wherein the plurality of electrodes comprises a plurality of wires or ribbons forming an electrode delivery body having an expandable basket shape, a portion of the basket shape being insulated, and positioning the plurality of electrodes comprises expanding the electrode delivery body. (Item 26) 1. A method for treating a passageway in a body, the passageway having an inner periphery, comprising: positioning an electrode within the passageway such that the electrode spans a portion of the inner periphery of the passageway; creating a first treatment zone along a first portion of the inner periphery of the passageway by applying pulsed electric field energy to the electrode; repositioning the electrode within the passage one or more times such that the electrode spans an additional portion of the inner periphery each time the electrode is repositioned; creating additional treatment zones along each additional portion of the inner periphery of the passageway by supplying pulsed electric field energy to the repositioned electrode each time the electrode is repositioned; Including, The method, wherein the first portion and each additional portion extend along the inner periphery to create a functionally continuous treatment area across the inner periphery. (Item 27) 1. A system for treating a passageway within a body, comprising: a catheter including a first electrode and at least one additional electrode disposed near a distal end thereof, the distal end of the catheter configured to be positioned within the passageway such that the first electrode and the at least one additional electrode can transmit pulsed electric field energy to an inner periphery of the passageway; a generator in electrical communication with the first electrode and the at least one additional electrode, a) providing an electrical signal of the pulsed electric field energy to the first electrode to prioritize energy delivery through the first electrode to create a first treatment zone; b) switching to deliver the electrical signal of the pulsed electric field energy to each of the at least one additional electrode individually to prioritize energy delivery through each of the at least one additional electrode when an electrical signal is delivered to create an additional treatment zone corresponding to each of the at least one additional electrode. said generator including at least one energy delivery algorithm; Including, The system, wherein the first treatment zone and the additional treatment zone extend along the inner circumference of the passageway to create a functionally continuous treatment zone across the inner circumference. (Item 28) 28. The system of claim 27, wherein the passage is provided within the heart and the distal end of the catheter is configured to be positioned within the heart, and the at least one energy delivery algorithm includes signal parameters that cause the functionally continuous treatment zone to include an electrical disconnection between a pulmonary vein and the left atrium to treat arrhythmia. (Item 29) 30. The system of claim 28, wherein the passageway includes the pulmonary vein, and the distal end of the catheter is configured to be positioned within the pulmonary vein. (Item 30) 30. The system of claim 29, wherein the signal parameters cause the functionally continuous treatment zone to include a transmural lesion. (Item 31) 28. The system of claim 27, wherein the passage includes an airway in a lung, and the distal end of the catheter is configured to be positioned within the airway, and the at least one energy delivery algorithm includes signal parameters that cause the functionally continuous treatment zone to include voids for cell types while maintaining a cartilage layer of the airway. (Item 32) 32. The system of claim 31 , wherein the cell types include epithelial cells, goblet cells, and / or submucosal gland cells. (Item 33) 32. The system of claim 31, wherein the functionally continuous treatment zone has a depth of up to and not exceeding 2.5 cm. (Item 34) 34. The system of any one of claims 27 to 33, wherein the pulsed electric field energy is biphasic. (Item 35) 35. The system of any one of claims 27-34, wherein the at least one energy delivery algorithm delivers pulsed electric field energy to at least one of the plurality of electrodes for 10,000 μs or less to create the first treatment zone and / or each of the at least one additional treatment zone. (Item 36) 36. The system of claim 35, wherein the at least one energy delivery algorithm delivers pulsed electric field energy to at least one of the plurality of electrodes for 500 μs or less to create the first treatment zone and / or each of the at least one additional treatment zone. (Item 37) 37. The system of claim 36, wherein the at least one energy delivery algorithm delivers pulsed electric field energy to at least one of the plurality of electrodes for between 5 μs and 50 μs to create each of the first treatment zone and / or the at least one additional treatment zone. (Item 38) 38. The system of any one of claims 27 to 37, wherein the pulsed electric field energy is composed of 1000 or less packets. (Item 39) Item 39. The system of item 38, wherein the pulsed electric field energy is comprised of 40 to 500 packets. (Item 40) 40. The system of claim 38, wherein the pulsed electric field energy is comprised of 10 or fewer packets. (Item 41) 41. The system of any one of claims 27 to 40, wherein the pulsed electric field energy is delivered in a monopolar configuration. (Item 42) 42. The system of any one of claims 27 to 41, wherein the at least one additional electrode comprises 2 to 7 additional electrodes. (Item 43) 43. The system of any one of claims 27 to 42, wherein the at least one energy delivery algorithm delivers the electrical signal of the pulsed electric field energy sequentially to each of the first electrode and at least one additional electrode. (Item 44) 44. The system of any one of claims 27 to 43, wherein the first treatment zone and the at least one additional treatment zone overlap. (Item 45) 45. The system of any one of claims 27 to 44, wherein the at least one energy delivery algorithm is configured to deliver the electrical signal of the pulsed electric field energy to the first electrode in multiple stages. (Item 46) 46. ​​The system of claim 45, wherein the at least one energy delivery algorithm is configured to deliver the electrical signal of the pulsed electric field energy to the at least one additional electrode in a plurality of distinct phases, the plurality of phases and the plurality of distinct phases not occurring simultaneously. (Item 47) Item 47. The system of item 46, wherein the plurality of stages and the plurality of different stages form a repeating pattern. (Item 48) 47. The system of claim 46, wherein the at least one energy delivery algorithm provides maintenance pulsed electric field energy to the first electrode and / or the at least one additional electrode between stages, the maintenance pulsed electric field energy having a lower voltage than the pulsed electric field energy. (Item 49) Item 49. The system of item 48, wherein the maintenance pulsed electric field energy has a voltage less than half the voltage of the pulsed electric field energy. (Item 50) 50. The system of any one of items 27 to 49, wherein the at least first electrode and the at least one additional electrode are disposed on or embedded within an expandable member. (Item 51) 50. The system of any one of claims 27 to 49, wherein the at least first electrode and the at least one additional electrode comprise a plurality of wires or ribbons forming an electrode delivery body having an expandable basket shape, a portion of the basket shape being insulated. (Item 52) 1. A system for treating a passageway within a body, comprising: a catheter including at least one electrode disposed near a distal end thereof, the distal end of the catheter configured to be positioned within the passageway such that the at least one electrode can transmit pulsed electric field energy to an inner surface of the passageway; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm that provides an electrical signal to the at least one electrode such that pulsed electric field energy is delivered to cells on the interior surface of the passageway; Including, the electrical signal includes a plurality of packets; Each packet includes a number of two-phase cycles, and Each packet is separated in time by 0.0001 to 10 seconds in the system. (Item 53) 53. The system of claim 52, wherein the plurality of packets generate the pulsed electric field energy for 10,000 μs or less. (Item 54) 54. The system of claim 53, wherein the plurality of packets produces the pulsed electric field energy for 500 μs or less. (Item 55) 55. The system of claim 54, wherein the plurality of packets generate the pulsed electric field energy for a duration of 5 μs to 50 μs or less. (Item 56) 56. The system of any one of claims 52 to 55, wherein the pulsed electric field energy is composed of 1000 or less packets. (Item 57) Item 57. The system of item 56, wherein the pulsed electric field energy is comprised of 40 to 500 packets. (Item 58) Item 57. The system of item 56, wherein the plurality of packets includes 10 or fewer packets. (Item 59) 59. The system of any one of items 52-58, wherein the pulsed electric field energy is delivered in a monopolar configuration. (Item 60) 60. The system of any one of claims 52 to 59, wherein the at least one electrode comprises at least a first electrode and at least one additional electrode arranged to deliver the pulsed electric field energy circumferentially around the inner surface of the passageway. (Item 61) 61. The system of claim 60, wherein the at least one energy delivery algorithm delivers the plurality of packets to the first electrode prior to delivering another plurality of packets to each of the at least one additional electrode. (Item 62) 61. The system of claim 60, wherein the at least one energy delivery algorithm provides another of the plurality of packets to each of the at least one additional electrode before finishing delivering the plurality of packets to the first electrode. (Item 63) Item 61. The system of item 60, wherein the at least one energy delivery algorithm supplies maintenance pulsed electric field energy to the first electrode and / or the at least one additional electrode between packets, the maintenance pulsed electric field energy having a lower voltage than the pulsed electric field energy. (Item 64) Item 64. The system of item 63, wherein the maintenance pulsed electric field energy has a voltage less than half the voltage of the pulsed electric field energy. (Item 65) Item 64. The system of item 63, further comprising a cardiac monitor configured to acquire a cardiac signal of a patient, the generator delivering the maintenance pulse electric field energy in synchronization with the cardiac signal. (Item 66) 66. The system of any one of items 60 to 65, wherein the at least first electrode and the at least one additional electrode are mounted on or embedded within an expandable member. (Item 67) 66. The system of any one of items 60 to 65, wherein the at least first electrode and the at least one additional electrode comprise a plurality of wires or ribbons forming an electrode delivery body having an expandable basket shape, a portion of the basket shape being insulated. (Item 68) 68. The system of any one of claims 52-67, wherein the pulsed electric field energy is delivered to the cells on the inner surface of the passageway to disrupt cellular homeostasis at a depth of up to but not exceeding 2.5 cm. (Item 69) 69. The system of any one of items 52 to 68, further comprising a cardiac monitor configured to acquire a cardiac signal of the patient, the generator providing the electrical signal in synchronization with the cardiac signal. (Item 70) 1. A method for treating a passageway in a body, the passageway having an inner periphery, comprising: positioning a plurality of electrodes within the passageway such that the plurality of electrodes spans at least a portion of the inner periphery of the passageway; creating a first treatment zone along a first portion of the inner periphery of the passageway by supplying pulsed electric field energy to at least one of the plurality of electrodes and prioritizing energy delivery to the first treatment zone through the at least one of the plurality of electrodes; creating at least one additional treatment zone along at least one additional portion of the inner periphery of the passageway by supplying pulsed electric field energy to at least one of the plurality of electrodes and prioritizing energy delivery to the at least one additional treatment zone through the at least one of the plurality of electrodes; Including, The first portion and the at least one additional portion extend along the inner periphery to create a balanced treatment zone. (Item 71) 1. A system for treating a passageway within a body, comprising: a catheter including a first electrode and at least one additional electrode disposed near a distal end thereof, the distal end of the catheter configured to be positioned within the passageway such that the first electrode and the at least one additional electrode can transmit pulsed electric field energy to an inner periphery of the passageway; a generator in electrical communication with the first electrode and the at least one additional electrode, a) providing an electrical signal of the pulsed electric field energy to the first electrode to prioritize energy delivery through the first electrode to create a first treatment zone; b) switching to deliver the pulsed electric field energy electrical signal individually to each of the at least one additional electrode when the electrical signal is delivered to prioritize energy delivery through each of the at least one additional electrode to create additional treatment zones corresponding to each of the at least one additional electrode. said generator including at least one energy delivery algorithm; Including, The system, wherein the first treatment zone and the additional treatment zone extend along the inner periphery of the passageway to create balanced treatment zones.

[0029] Incorporation by Reference

[0029] 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.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Examples of features and advantages of the present disclosure are described with reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Brief description of the drawings]

[0031] [Figure 1]

[0031] An embodiment of an existing known lung tissue modification system suitable for use in treating a patient is illustrated. [Diagram 2]

[0032] FIG. 2 is an enlarged view of the therapeutic energy delivery catheter of FIG. 1. [Figure 3A]

[0033] 1 illustrates one embodiment of a waveform of a signal provided by an energy delivery algorithm. [Figure 3B]

[0034] 1 illustrates various examples of biphasic pulses (including a positive peak and a negative peak) with a switching time in between. [Figure 3C]

[0035] 1 illustrates the relationship between effective electric field threshold and switching time. [Figure 3D]

[0036] 13 illustrates an example waveform for another energy delivery algorithm. [Figure 3E]

[0037] 4 illustrates further examples of unequal voltage waveforms. [Figure 3F] Further examples of unequal voltage waveforms are illustrated. [Figure 3G]

[0038] 13 illustrates an example waveform for another energy delivery algorithm. [Figure 3H]

[0039] 1 illustrates a further example of a waveform having monophasic pulses. [Figure 3I]

[0040] 1 illustrates an example of a waveform with phase imbalance achieved by delivering two or more pulses of one polarity before reversing to an unequal number of pulses of opposite polarity. [Figure 3J]

[0041] 13 illustrates an example waveform for another energy delivery algorithm. [Figure 4]

[0042] 1 illustrates one embodiment of a therapeutic energy delivery catheter that includes an elongate shaft having at least one energy delivery entity near a distal end. [Figure 4A]

[0043] 1 illustrates a method of delivering energy in a circumferential ring along a body lumen using one embodiment of a therapeutic energy delivery catheter in a series of steps. [Figure 4B]

[0043] A method for delivering energy in a circumferential ring along a body lumen using one embodiment of a therapeutic energy delivery catheter in a series of steps is illustrated. [Figure 4C]

[0043] A method for delivering energy in a circumferential ring along a body lumen using one embodiment of a therapeutic energy delivery catheter in a series of steps is illustrated. [Figure 4D]

[0043] A method for delivering energy in a circumferential ring along a body lumen using one embodiment of a therapeutic energy delivery catheter in a series of steps is illustrated. [Figure 5A]

[0044] 4B illustrates treatment results corresponding to the method of FIG. 4A. [Figure 5B]

[0044] FIG. 4B illustrates treatment results corresponding to the method of FIG. [Figure 5C]

[0044] FIG. 4C illustrates treatment results corresponding to the method. [Figure 5D]

[0044] FIG. 4D illustrates treatment results corresponding to the method. [Figure 6]

[0045] 1 illustrates one embodiment of an electrode assembly having four electrodes configured to facilitate circumferential energy delivery to a body lumen without rotating the catheter. [Figure 7]

[0046] 7 is an illustrative example of the electrode assembly of FIG. 6 used in a monopolar configuration. [Figure 8A]

[0047] 3 illustrates an example of electric field distribution through various tissue layers of an airway wall when energy is delivered circumferentially using an energy delivery body such as that of FIG. 2. [Figure 8B]

[0048] 7 illustrates an example of electric field distribution through various tissue layers of an airway wall under focal delivery, where an electrode, such as the first electrode in FIG. 6, is energized alone. [Figure 9]

[0049] 1 illustrates a cross-sectional view of an example of a body cavity in which an embodiment of an energy delivery body is positioned. [Figure 10]

[0050] 1 is an example plot showing pore or defect formation over time in response to pulsed electric field (PEF) energy delivery. [Figure 11]

[0051] 1 is an example plot showing the formation of pores or defects when PEF energy is delivered at a typical interval that is not optimized for lethality. [Figure 12]

[0052] FIG. 11 is an example plot showing the formation of pores or defects when PEF energy packets are delivered at intervals such that the rest period between each packet is close enough to maintain a broken membrane, but far enough away that subsequent PEF is delivered to increase the cumulative amount of cell content leakage. [Figure 13]

[0053] 1 illustrates a cross-sectional view of an example of a body cavity having a wall in which an energy delivery entity is positioned. [Figure 14]

[0054] 1 is an example plot showing the effect of delivering multiple PEF packets (5 packets) to each electrode in sequence. [Figure 15]

[0055] FIG. 13 is an example plot showing the effect of delivering multiple PEF packets in sequence, involving delivering spaced packets to an electrode in an overlapping pattern rather than a sequential pattern. [Figure 16]

[0056] 1 is a plot showing an example of a sequence of PEFs including a primary PEF and a maintenance PEF in between. [Figure 17]

[0057] 17 is a plot showing an example of the effect of the delivery sequence of FIG. 16 on the number of pores in a target membrane. [Figure 18A]

[0058] 1 illustrates one embodiment of a unipolar energy delivery sequence using a maintenance PEF during various portions of the cardiac cycle. [Figure 18B]

[0058] One embodiment of a unipolar energy delivery sequence using a maintenance PEF during various portions of the cardiac cycle is illustrated. [Figure 18C]

[0058] One embodiment of a unipolar energy delivery sequence using a maintenance PEF during various portions of the cardiac cycle is illustrated. [Figure 18D]

[0058] One embodiment of a unipolar energy delivery sequence using a maintenance PEF during various portions of the cardiac cycle is illustrated. [Figure 19A]

[0059] 1 illustrates the potential effect of delivering a maintenance PEF to various electrodes simultaneously with a primary PEF to another electrode. [Figure 19B]

[0059] Illustrates the potential effect of delivering a maintenance PEF to various electrodes simultaneously with a primary PEF to another electrode. [Figure 20A]

[0060] 1 illustrates an example of bipolar delivery of a maintenance PEF while a primary PEF is delivered monopolarly. [Figure 20B]

[0060] An example of bipolar delivery of a maintenance PEF while a primary PEF is delivered monopolarly is illustrated. [Figure 20C]

[0060] An example of bipolar delivery of a maintenance PEF while a primary PEF is delivered monopolarly is illustrated. [Figure 20D]

[0060] An example of bipolar delivery of a maintenance PEF while a primary PEF is delivered monopolarly is illustrated. [Figure 21A]

[0061] Illustrated is an embodiment in which the effect of localized delivery can be achieved by delivering energy to two or more electrodes. [Figure 21B]

[0061] An embodiment is illustrated in which the effect of localized delivery can be achieved by delivering energy to two or more electrodes. [Figure 22]

[0062] An example of an insulating material is illustrated that covers a portion of the energy delivery body and leaves another portion exposed, which is considered an electrode. [Diagram 23]

[0063] 1 illustrates an example of an insulating material that covers a portion of the energy delivery body and leaves two portions exposed, thereby creating a first electrode and a second electrode. [Figure 24]

[0064] 1 illustrates an example of an electrode that includes a ring, where energy delivered through the ring is focused and restricted to the area of ​​the ring by an expandable member that expands through and around the ring. [Diagram 25]

[0065] 1 illustrates an example of an electrode that includes a disk configured such that energy delivered through the disk is focused and confined by expandable members on either side of the disk. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Detailed Description

[0066] Therapeutic energy may be applied to the pulmonary passageways in the treatment of various pulmonary diseases and disorders, such as chronic obstructive pulmonary disease (COPD) (e.g., chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, primary ciliary dyskinesia (PCD), acute bronchitis, or related pulmonary diseases and disorders, and / or other pulmonary diseases or disorders. Examples of pulmonary tissues accessible through the pulmonary passageways include, but are not limited to, epithelium (goblet cells, pseudostratified ciliated columnar epithelial cells, and basal cells), lamina propria, submucosa, submucosal glands, basement membrane, smooth muscle, cartilage, nerves, pathogens present near or within the tissue, or any or all combinations of the foregoing.

[0033]

[0067] In some instances, the therapeutic energy is generally characterized by high voltage pulses that allow removal of target tissue with little or no destruction of tissue-level architectural proteins in the extracellular matrix. This prevents dangerous side effects such as vascular stenosis or esophageal fistulas, and also allows for regeneration of healthy new target tissue within a few days of treatment. Examples of systems that provide this type of treatment include lung tissue modification systems (e.g., energy delivery catheter systems) described in commonly-owned patent applications, including International Patent Application No. PCT / US2017 / 039527, entitled "GENERATOR AND A CATHETER WITH AN ELECTRODE AND A METHOD FOR TREATING A LUNG PASSAGEWAY," which claims priority to U.S. Provisional Patent Application Nos. 62 / 355,164 and 62 / 489,753, each of which is incorporated herein by reference for all purposes. Although such treatments have been successful, improvements may be desirable. For example, it may be desirable to increase the regularity of the therapeutic effect over the circumference of the airway lumen.

[0034]

[0068] Therapeutic energy can also be applied to blood vessels for the treatment of various conditions, including atherosclerosis (particularly in the prevention of restenosis after angioplasty) and atrial fibrillation. Atrial fibrillation is the most common sustained cardiac arrhythmia and significantly increases the risk of death in affected individuals, especially by causing stroke. This phenomenon causes the heart to deviate from normal sinus rhythm due to the generation of erroneous electrical impulses. Atrial fibrillation is thought to arise in the myocardial sleeve of the pulmonary veins (PV) due to the presence of automaticity in cells within the myocardial tissue of the PV. Pacemaker activity from these cells is thought to generate the ectopic beats that cause atrial fibrillation. The PVs are also thought to be important in the maintenance of atrial fibrillation, as the chaotic architecture and electrophysiological properties of these vessels provide an environment in which atrial fibrillation can persist. Thus, the destruction or ablation of these abnormal pacemaker cells in the myocardial sleeve of the PV is the goal, and atrial fibrillation is often treated by delivering therapeutic energy to the pulmonary veins. However, due to reports of PV stenosis, this approach has traditionally been modified to target the PV sinuses to achieve a continuity block between the PVs and the left atrium. In addition to the pulmonary veins, the PV sinuses surround the left atrial roof and posterior wall, and in the case of the right-sided pulmonary vein sinuses, a portion of the interatrial septum. In some instances, this technique results in higher success rates and lower complication rates compared to isolation of the pulmonary vein ostium.

[0035]

[0069] Thermal ablation therapy, particularly radiofrequency (RF) ablation, is currently the "gold standard" for the treatment of symptomatic atrial fibrillation due to localized tissue necrosis. Despite improvements in the restoration of sinus rhythm using available methods, both success rates and safety are limited by the thermal nature of these procedures. Thus, while keeping the technique in clinical practice, safer and more versatile methods of removing abnormal tissue have been used, including irreversible electroporation (IRE), a treatment based on the irreversible permeabilization of cell membranes caused by brief pulses of high-voltage energy. IRE has been found to be tissue specific, trigger apoptosis rather than necrosis, and safer for structures adjacent to the myocardium. However, so far, the success of these IRE methodologies has been heterogeneous.

[0036]

[0070] In some instances, delivery of IRE energy results in incomplete interruption of the abnormal electrical rhythm. This may be due to irregularities in the circumferential treatment around the pulmonary veins and / or insufficient transmural delivery of wall energy. In either case, atrial fibrillation is not adequately treated or atrial fibrillation subsequently recurs. Thus, improvements in atrial fibrillation treatment are desirable.

[0037]

[0071] It will be appreciated that therapeutic energy may be applied to a wide variety of body cavities to treat many specific diseases and conditions. In some instances, the characteristics of the environment or disease are such that improved delivery of energy from current devices and / or improved devices and methods are desired. As discussed above, improved depth of energy delivery may be desired, improved circumferential delivery to the lumen wall, or some combination of the two. Similarly, in other instances, improved control of delivery is desired, such as reduced spatial or cumulative distortion of energy delivery, or unexpected changes in delivery direction due to various inhomogeneous or other environmental factors. Typically, such improvements are desired while maintaining or reducing the total energy delivered and while maintaining or shortening treatment time. This may, for example, aid in managing costs and side effects. At least some of the aforementioned objectives may be achieved by embodiments of the present disclosure.

[0038]

[0072] Specific embodiments of the disclosed devices, delivery 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 any embodiment.

[0039] I. Big picture

[0073] Methods, devices and systems are provided for optimized delivery of therapeutic energy to parts of the body, particularly body cavities, to improve outcomes under a variety of conditions, particularly providing dedicated catheter designs and / or distinct energy delivery algorithms for use with tissue modification systems. Examples of such tissue modification systems include the lung tissue modification systems described in commonly-owned International Patent Application No. PCT / US2017 / 039527, entitled "GENERATOR AND A CATHETER WITH AN ELECTRODE AND A METHOD FOR TREATING A LUNG PASSAGEWAY," which claims priority to U.S. Provisional Patent Application Nos. 62 / 355,164 and 62 / 489,753, and commonly-owned International Patent Application No. PCT / __________, entitled "METHODS, APPARATUSES, AND SYSTEMS FOR THE TREATMENT OF DISEASE STATES AND DISORDERS," which claims priority to U.S. Provisional Patent Application Nos. 62 / 610,430, all of which are incorporated herein by reference for all purposes. These catheter designs and energy delivery algorithms provide energy delivery to the pulmonary passageways to improve outcomes for certain conditions. Similarly, these catheter designs and energy delivery algorithms enable aspects of the pulmonary tissue modification system to be utilized in the treatment of other body cavities such as blood vessels, and in particular for the treatment of atrial fibrillation.

[0040]

[0074] 1 and 2 illustrate one embodiment of a lung tissue modification system 100 for use in treating a body cavity or passageway of a patient P. In this embodiment, the system 100 includes a therapeutic energy delivery catheter 102 connectable to a generator 104. In this embodiment, the catheter 102 has an elongate shaft 106 having at least one energy delivery body 108 near its distal end and a handle 110 at its proximal end. The connection of the catheter 102 to the generator 104 provides, among other functions, electrical energy to the energy delivery body 108. As illustrated in FIG. 1, the catheter 102 can be inserted into the bronchial passageway of the patient P in a variety of ways, such as through the lumen of a bronchoscope 112.

[0041]

[0075] FIG. 2 shows an expanded view of an embodiment of the therapeutic energy delivery catheter 102 of FIG. 1. In this embodiment, the energy delivery body 108 includes only one monopolar delivery electrode. The energy delivery body 108 includes multiple wires or ribbons 120 that are constrained by a proximal end constraint 122 and a distal end constraint 124 to form a helical shaped basket that functions as an electrode. In an alternative embodiment, the wires or ribbons are straight rather than helically shaped (i.e., configured to form a straight shaped basket). In yet another embodiment, the energy delivery body 108 is laser cut to form a tube. In some embodiments, the energy delivery body 108 is self-expandable and is delivered to the target area in a folded configuration. This folded configuration can be achieved, for example, by placing a sheath 126 over the energy delivery body 108. 2, the catheter shaft 106 (within the sheath 126) terminates in the proximal end constraint 122, while the distal end constraint 124 remains substantially unconstrained and free to move relative to the shaft 106 of the catheter 102. Advancing the sheath 126 over the energy delivery body 108 causes the distal end constraint 124 to move forward, thereby allowing the energy delivery body 108 to expand / collapse and be constrained.

[0042]

[0076] As shown in this example, the catheter 102 includes a handle 110 at its proximal end. In some embodiments, the handle 110 can be removed, such as by pressing a handle removal button 130. In this embodiment, the handle 110 includes an energy delivery device control knob 132, movement of which causes the basket-shaped electrodes to expand or contract / collapse. In this example, the handle 110 also includes a bronchoscope working port snap 134 for connecting to a bronchoscope 112 and a cable plug-in port 136 for connecting to the generator 104.

[0043]

[0077] Referring back to FIG. 1 , in this embodiment, the therapeutic energy delivery catheter 102 is connectable to a generator 104 with a distributive (return) electrode 140 applied externally to the skin of the patient P. Thus, in this embodiment, monopolar energy delivery is achieved by providing energy between an energy delivery body 108 located near the distal end of the catheter 102 and the return electrode 140. However, it will be understood that bipolar energy delivery and other configurations may alternatively be used. When using bipolar energy delivery, the therapeutic energy delivery catheter 102 may have a different overall design, such as including multiple energy delivery bodies 108, or may have a similar overall design, such as including only one energy delivery body 108 configured to function in a bipolar manner. In some instances, bipolar energy delivery may achieve a therapeutic effect using a lower voltage than monopolar energy delivery. In a bipolar configuration, the positive and negative poles are close enough to each other to provide a therapeutic effect both at the poles and between the poles. This allows the therapeutic effect to be spread over a larger surface area, and therefore requires a lower voltage to achieve the therapeutic effect, as compared to monopolar. Similarly, the lower voltage can be used to reduce the depth of penetration. Additionally, the reduced voltage requirements may obviate the use of cardiac synchronization if the delivered voltage is low enough to avoid stimulation of the myocardial cells.

[0044]

[0078] 1 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / retrieval unit 156 (such as a memory and / or database), and an energy storage subsystem 158 that generates and stores the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery, although any other suitable energy storage elements may be used. Additionally, one or more communication ports are included.

[0045]

[0079] In some embodiments, the generator 104 includes three subsystems: 1) a high energy storage system; 2) a high voltage, mid-frequency switching amplifier; and 3) a system controller, firmware, and user interface. The system controller includes a cardiac synchronization trigger monitor that allows the pulse energy output to be synchronized to the patient's cardiac rhythm. The generator takes alternating current (AC) mains and powers multiple direct current (DC) power supplies. The generator controller can cause the DC power supplies to charge a high energy capacitor storage bank before initiating energy delivery. When initiating therapeutic energy delivery, the generator controller, high energy storage bank, and biphasic pulse amplifier can operate simultaneously to produce a high voltage, mid-frequency output.

[0046]

[0080] It will be appreciated that numerous generator electrical architectures may be used to implement the energy delivery algorithm. In particular, some embodiments use advanced switching systems capable of directing the pulsed electric field circuitry to the energy delivery electrodes separately from the same energy storage and high voltage delivery systems. Additionally, generators used in advanced energy delivery algorithms that employ rapidly changing pulse parameters (e.g., voltage, frequency, etc.) or multiple energy delivery electrodes may utilize modular energy storage and / or high voltage systems that facilitate highly customizable waveform and geographic pulse delivery paradigms. It should be further appreciated that the electrical architectures described herein above are merely examples, and that systems that deliver pulsed electric fields may or may not include additional switching amplifier components.

[0047]

[0081] The user interface 150 may include a touch screen and / or conventional buttons that enable an operator to input patient data, select a treatment algorithm (e.g., the energy delivery algorithm 152), initiate energy delivery, view records stored in the memory / retrieval unit 156, and / or otherwise communicate with the generator 104.

[0048]

[0082] In some embodiments, the user interface 150 is configured to receive operator-defined input. The operator-defined input may include duration of energy delivery, one or more other temporal aspects of the energy delivery pulse, power, and / or mode of operation, or a combination thereof. Examples of modes of operation may include (but are not limited to) system start-up and self-test, operator input, algorithm selection, pre-treatment system status and feedback, energy delivery, post-energy delivery display or feedback, treatment data viewing and / or download, software updates, or any combination or subcombination thereof.

[0049]

[0083] In some embodiments, the system 100 also includes a mechanism for acquiring an electrocardiogram (ECG), such as an external cardiac monitor 170. An example cardiac monitor is available from AccuSync Medical Research Corporation. In some embodiments, the external cardiac monitor 170 is operatively connected to the generator 104. The cardiac monitor 170 may be used to continuously acquire an ECG signal. External electrodes 172 may be attached to the patient P to acquire the ECG. The generator 104 provides the ability to synchronize energy delivery with the cardiac cycle by analyzing one or more cardiac cycles and identifying the beginning of a period when it is safe to apply energy to the patient P. In some embodiments, this period is within milliseconds of the R wave (of the ECG QRS complex) to avoid induction of arrhythmias that may occur if the energy pulse is delivered at the T wave. It will be appreciated that such cardiac synchronization is typically utilized when using unipolar energy delivery, although it may also be utilized as part of other energy delivery methods.

[0050]

[0084] In some embodiments, the processor 154 performs, among other tasks, modifying and / or switching between energy delivery algorithms, monitoring energy delivery and any sensor data, and responding to the monitoring data via a feedback loop. In some embodiments, the processor 154 is configured to execute one or more algorithms for implementing a feedback control loop based on one or more measured system parameters (e.g., current), one or more measured tissue parameters (e.g., impedance), and / or a combination thereof.

[0051]

[0085] The data storage / retrieval unit 156 stores data related to the delivered treatment, which can be optionally downloaded by connecting a device (e.g., a laptop or thumb drive) to the communication port. In some embodiments, the device has local software used to direct the download of information, such as instructions executable by the processor 154 stored in the data storage / retrieval unit 156. In some embodiments, the user interface 150 allows the operator to select the download of data to a device and / or system, such as, but not limited to, a computing device, tablet, mobile device, server, workstation, cloud computing device / system, etc. A communication port capable of wired and / or wireless connection allows for the download of data as described above, but also allows for the upload of data or the provision of software updates, such as uploading custom algorithms.

[0052]

[0086] As described herein, a wide variety of energy delivery algorithms 152 may be programmed or preprogrammed into the generator 104, such as stored in the memory or data storage / retrieval unit 156. Alternatively, the energy delivery algorithms may be added to the data storage / retrieval unit and executed by the processor 154. Each of these algorithms 152 may be executable by the processor 154. In some embodiments, the catheter 102 includes one or more sensors 160 that can be used to determine temperature, impedance, resistance, capacitance, conductivity, permittivity, and / or conductance, to name a few. The sensor data can be used to plan therapy, monitor therapy, and / or provide direct feedback by the processor 154, which can subsequently modify the energy delivery algorithm 152. For example, impedance measurements can be used to determine the initial dose to apply, as well as to determine whether further therapy is required.

[0053]

[0087] It will be appreciated that the system 100 may include automatic therapy delivery algorithms that are capable of dynamically adapting and adjusting and / or terminating therapy in response to inputs such as temperature, impedance at various voltages or AC frequencies, treatment duration or other temporal aspects of the energy delivery pulse, treatment power and / or system status.

[0054]

[0088] In some embodiments, imaging can be performed using a commercially available system, such as a bronchoscope 112 in connection with a separate imaging screen 180, as shown in Figure 1. It will be appreciated that the imaging device can be incorporated into the catheter 102 or can be used alongside or in conjunction with the catheter 102. The imaging device can be mechanically, operatively, and / or communicatively coupled to the catheter 102 using any suitable mechanism.

[0055] II. Energy Delivery Algorithm

[0089] As previously described, one or more energy delivery algorithms 152 can be programmable or preprogrammed 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 airway wall W that is non-thermal (e.g., below the threshold for thermal ablation; below the threshold for inducing coagulative thermal damage), reduces or avoids inflammation, and prevents denaturation of matrix proteins. Generally, the algorithms 152 are individually tailored to affect tissue to a predetermined depth and / or target specific types of cellular responses to the delivered energy. It can be appreciated that the depth and / or targeting may be influenced by the parameters of the energy signal defined by the one or more energy delivery algorithms 152, the design of the catheter 102 (particularly the one or more energy deliverers 108), and / or the selection of monopolar or bipolar energy delivery. In particular, when treating the inner walls of airways or lung passageways, depths of up to 0.01 mm, up to 0.02 mm, 0.01-0.02 mm, up to 0.03 mm, 0.03-0.05 mm, up to 0.05 mm, up to 0.08 mm, up to 0.09 mm, up to 0.1 mm, up to 0.2 mm, up to 0.5 mm, up to 0.7 mm, up to 1.0 mm, up to 1.5 mm, up to 2.0 mm, or up to 2.3 mm, or less than 2.3 mm, may be targeted. In some instances, such as when targeting airway epithelium and submucosal glands, the predetermined depth targeted is 0.5 mm, with a significant safety margin to prevent cartilage effects related morbidity at a depth of 2.3 mm. In another example, the targeted depth of effect was increased to treat all airway epithelial cells and submucosal glands up to a depth of 1.36 mm, while still preventing safety-related effects on cartilage at a depth of 2.3 mm.In other embodiments, such as when applying such treatments to other clinical applications, such as cardiac applications, the algorithms 152 are individually tuned to affect tissue to a greater predetermined depth, for example, up to 0.1 cm, up to 0.2 cm, up to 0.3 cm, up to 0.5 cm, up to 0.8 cm, up to 0.9 cm, up to 1 cm, or from 0.5 cm to 1 cm. In yet other embodiments, such as when applying such treatments to clinical applications involving deeper targets, the algorithms 152 are individually tuned to affect tissue to a greater predetermined depth, for example, up to 2 cm, or up to 2.5 cm.

[0056]

[0090] In some instances, bipolar energy delivery can achieve a therapeutic effect using lower voltages compared to monopolar energy delivery. In a bipolar configuration, the positive and negative poles are close enough together to provide a therapeutic effect both at the poles and between the poles. This allows the therapeutic effect to be focused to a specific tissue area, and therefore requires lower voltages to achieve the therapeutic effect compared to monopolar. Similarly, this localized ability to use lower voltages can be used to reduce the penetration depth, such as affecting epithelial cells rather than submucosal cells. In other instances, this reduced penetration depth of effect can be used to focus energy while sparing deeper cartilage tissue, such as to target epithelial and submucosal layers. Additionally, the reduced voltage requirements may obviate the use of cardiac synchronization if the delivered voltage is low enough to avoid stimulation of myocardial cells.

[0057]

[0091] It can be appreciated that a wide variety of energy delivery algorithms 152 may be used. In some embodiments, the algorithm 152 defines a signal having a waveform that includes a series of energy packets, each energy packet including a series of high voltage pulses. In such embodiments, the algorithm 152 specifies parameters of the signal such as the energy amplitude (e.g., voltage), consisting of the number of packets, the number of pulses in the packet, and the fundamental frequency of the pulse sequence, as well as the duration of the applied energy, to name a few. Additional parameters may include the switching time between polarities in a biphasic pulse, the dead time between biphasic cycles, and the rest time between packets, which are described in more detail below. There may be a fixed rest period between packets, or the packets may be gated to the cardiac cycle, and thus the packets are variable depending on the patient's heart rate. There may be an intentional, variable rest period algorithm, or no rest period may be applied between packets. There may be a feedback loop based on sensor information, an automatic shutoff specification, and the like.

[0058]

[0092] 3A illustrates one embodiment of a waveform 400 of a signal defined by the energy delivery algorithm 152. 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 composed of a first biphasic cycle (including a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic cycle (including a second positive pulse peak 408' and a second negative pulse peak 410'). The first biphasic pulse and the second biphasic pulse are separated by a dead time 412 (i.e., a pause) between each pulse. In this embodiment, the biphasic pulses are symmetric, such that the set voltage 416 is the same for the positive and negative peaks. Here, the biphasic, symmetrical wave is also a square wave, so that the magnitude and duration of the positive voltage wave is approximately equal to the magnitude and duration of the negative voltage wave. When using a bipolar configuration, the portions of the cells of the airway wall W facing the negative voltage wave will have the cells depolarized in these regions, causing the normally negatively charged cell membrane regions to become temporarily positive. Conversely, the portions of the cells of the airway wall W facing the positive voltage wave will become hyperpolarized, causing the potential of the cell membrane regions to become extremely negative. It can be seen that with each positive phase or negative inverse phase of the biphasic pulse, the portions of the cells of the airway wall W will experience the opposite effect. For example, the portions of the cell membrane facing the negative voltage will be depolarized, while the portions 180° to this portion will be hyperpolarized. In some embodiments, the hyperpolarized portions face the dispersive or return electrode 140.

[0059] A. Voltage

[0093] The voltages used and considered can be the crest of a square wave, the peak of a sine or sawtooth waveform, or the RMS voltage of a sine or sawtooth waveform. In some embodiments, the energy is delivered in a monopolar manner, and the high voltage pulse voltage or set voltage 416 is between about 500V and 10,000V, in particular about 500V to 5000V, about 500V to 4000V, about 1000V to 4000V, about 2500V to 4000V, about 2000V to 3500V, about 2000V to 2500V, about 2500V to 3500V, including all values ​​and subranges therebetween, inclusive of about 500V, 1000V, 1500V, 2000V, 2500V, 3000V, 3500V, 4000V. In some embodiments, each of the high voltage pulses is in the range of approximately 1000V to 2500V and can penetrate the airway wall W with a particular combination of parameters to treat or affect certain cells more shallowly, such as epithelial cells. In some embodiments, each of the high voltage pulses is in the range of approximately 2500V to 4000V and can penetrate the airway W with a particular combination of parameters to treat or affect certain cells more deeply, such as submucosal or smooth muscle cells.

[0060]

[0094] It can be appreciated that the set voltage 416 may vary depending on whether the energy is delivered bipolarly or bipolarly. Lower voltages may be used with bipolar delivery due to the smaller and more directed electric field. In some embodiments, the energy is delivered bipolarly and each pulse is in the range of approximately 100V to 1900V, specifically 100V to 999V, more specifically approximately 500V to 800V, e.g., 500V, 550V, 600V, 650V, 700V, 750V, 800V. In other embodiments, the energy is delivered bipolarly and each pulse is between approximately 50 and 5000 volts, including 250 to 1500 volts.

[0061]

[0095] The bipolar voltage selected for use in treatment is determined by the electrode separation, whereas a monopolar electrode configuration using a remote dispersive pad electrode can be delivered without much consideration of the exact placement of the catheter electrode and dispersive electrode on the body. In monopolar electrode embodiments, larger voltages are typically used due to the dispersive behavior of the energy delivered through the body until it reaches the dispersive electrode, which is on the order of 10 cm to 100 cm effective separation distance. Conversely, in a bipolar electrode configuration, the active area of ​​the electrode is on the order of 0.5 mm to 10 cm, including 1 mm to 1 cm, and the relatively close distance increases the impact of the separation distance on the electrical energy concentration and effective dose delivered to the tissue. For example, if the targeted distance-to-voltage ratio is 3000 V / cm to induce the desired clinical effect at the appropriate tissue depth (1.3 mm), if the separation distance is changed from 1 mm to 1.2 mm, this requires an increase in the treatment voltage from 300 to about 360 V, a change of 20%.

[0062] B.Frequency

[0096] The number of biphasic cycles per second of time is the frequency. In some embodiments, biphasic pulses are utilized to reduce undesired muscle stimulation, particularly myocardial stimulation. In other embodiments, the pulse waveform is monophasic and has no apparent inherent frequency, instead the frequency is derived by doubling the monophasic pulse length and can be considered as the fundamental frequency. In some embodiments, the signal has a frequency in the range of 100 kHz to 1 MHz, more specifically 100 kHz to 1000 kHz. In some embodiments, the signal has a frequency in the range of approximately 100 to 600 kHz, and penetrates the airway W to treat or affect specific cells that are typically somewhat deeper, such as submucosal or smooth muscle cells. In some embodiments, the signal has a frequency in the range of approximately 600 kHz to 1000 kHz or 600 kHz to 1 MHz, and penetrates the airway wall W to treat or affect specific cells that are typically somewhat shallower, such as epithelial cells. It can be appreciated that at some voltages, frequencies below 300 kHz may cause undesired muscle stimulation. Thus, in some embodiments, the signal has a frequency in the range of 400-800 kHz or 500-800 kHz, for example, 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz. In particular, in some embodiments, the signal has a frequency of 600 kHz. In addition, cardiac synchronization is typically utilized to reduce or avoid undesirable myocardial stimulation during sensitive rhythmic periods. It can be appreciated that even higher frequencies may be used, provided that the component minimizes signal artifacts.

[0063] C. Voltage-Frequency Balancing

[0097] The frequency of the delivered waveform may be varied synchronously with respect to the treatment voltage to maintain adequate therapeutic effect. Such synergistic changes include a decrease in frequency that produces a stronger effect, which, when combined with a decrease in voltage, produces a weaker effect. For example, in one case, treatment may be delivered using 3000V in a monopolar fashion with a waveform frequency of 800kHz, while in another case, treatment may be delivered using 2000V with a waveform frequency of 400kHz.

[0064]

[0098] When used in the opposite direction, the treatment parameters may be manipulated to be too effective, which may increase the likelihood of muscle contraction or risk effects to unwanted tissues such as cartilage in the case of airway treatment. If the frequency is increased and the voltage is decreased, for example using 2000V at 800kHz, the treatment may not have sufficient clinical therapeutic benefit. Conversely, if the voltage is increased to 3000V and the frequency is decreased to 400kHz, there may be an undesirable degree of therapeutic effect on cartilage or other collateral sensitive tissues. In some cases, over-treating these unwanted tissues may result in patient morbidity or safety concerns.

[0065] D. Packet

[0099] As described above, the algorithm 152 defines a signal having a waveform that includes a series of energy packets, each of which includes a series of high voltage pulses. The number of cycles 420 is half the number of pulses in each biphasic packet. With reference to FIG. 3A, the first packet 402 has a number of cycles 420 that is 2 (i.e., 4 biphasic pulses). In some embodiments, the number of cycles 420 is set between 1 and 100 per packet, including all values ​​and subranges therebetween. In some embodiments, the number of cycles 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 1000 pulses, or up to 2000 pulses, including all values ​​and subranges therebetween.

[0066]

[0100] The packet duration depends on the number of cycles. The more cycles, the longer the packet duration and the greater the amount of energy delivered. In some embodiments, the packet duration is in the range of approximately 50 to 100 microseconds, such as 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, or 100 μs. In other embodiments, the packet duration is in the range of approximately 100 to 1000 microseconds, such as 150 μs, 200 μs, 250 μs, 500 μs, or 1000 μs.

[0067]

[0101] The number of packets, i.e., the number of packets, delivered during treatment can include 1 packet, 2 packets, 3 packets, 4 packets, 5 packets, 10 packets, 15 packets, 20 packets, 50 packets, 100 packets, 1000 packets, up to 5 packets, up to 10 packets, up to 15 packets, up to 20 packets, up to 100 packets, or up to 1,000 packets, including all values ​​and subranges therebetween. In some embodiments, 5 packets are delivered, each with a packet duration of 100 microseconds and a set voltage of 2500V. In some embodiments, 5 to 10 packets are delivered, each with a packet duration of 100 microseconds and a set voltage of 2500V, thereby improving the efficacy and uniformity of the treatment effect. In some embodiments, less than 20 packets are delivered, each with a packet duration of 100 microseconds and a set voltage of 2500V, to avoid impacting the cartilage layer CL. In some embodiments, a total energy delivery period of 0.5 to 100 milliseconds with a set voltage of 2500V may be optimal for therapeutic effect.

[0068] E. Break Period

[0102] In some embodiments, the time between packets, referred to as the pause period 406, is set between about 0.1 seconds and about 5 seconds, including all values ​​and subranges therebetween. In other embodiments, the pause period 406 is in the range of about 0.001 seconds to about 10 seconds, including all values ​​and subranges therebetween. In some embodiments, the pause period 406 is approximately 1 second. Notably, in some embodiments, the pause period is aligned with the heartbeat by synchronizing the signal to the cardiac rhythm such that each packet is delivered synchronously within a specified period relative to the heartbeat. In other embodiments that utilize cardiac synchronization, the pause period between packets may be affected by cardiac synchronization, as described below, and therefore the pause period 406 may vary.

[0069] F. Switching Times and Dead Times

[0103] As illustrated in Figures 3B and 3C, the switching time is the delay or period during which no energy is delivered between the positive and negative peaks of a biphasic pulse. Figure 3B illustrates various examples of biphasic pulses (including a positive peak 408 and a negative peak 410) with a switching time 403 in between (however, if the switching time 403 is zero, it does not appear). In some embodiments, the switching time is in the range between about 0 and about 1 microseconds, including all values ​​and subranges therebetween. In other embodiments, the switching time is in the range between 1 and 20 microseconds, including all values ​​and subranges therebetween. Figure 3C illustrates the relationship between the effective electric field threshold and the switching time.

[0070]

[0104] A delay, referred to as a "dead time," may also be interposed between each cycle of the biphasic pulses. Dead times occur within a packet, but between biphasic pulses. This is in contrast to a quiescent period that occurs between packets. In some embodiments, the dead time 412 is set between about 0 and about 500 nanoseconds, including 0 to 20 microseconds, including all values ​​and subranges therebetween. In other embodiments, the dead time 412 is in the range of approximately 0 to 10 microseconds, or about 0 to about 100 microseconds, or about 0 to about 100 milliseconds, including all values ​​and subranges therebetween. In some embodiments, the dead time 412 is in the range of 0.2 to 0.3 microseconds. Dead times may also be used to define the period between separate monophasic pulses within a packet.

[0071]

[0105] Delays such as switching and dead times are introduced into the packets to reduce the effect of biphasic offset in the waveform. Biphasic offset or bipolar offset is a term used to refer to the reduced induction of cellular conditioning in response to biphasic waveforms versus monophasic waveforms, especially when the switching and dead times are short, such as less than 10 μs. Here, one explanation of this phenomenon is given, but it can be understood that there are likely other biological, physical, or electrical properties or changes that result in reduced conditioning from biphasic waveforms. When cells are exposed to electromotive forces induced by the presence of an electric field, there is electrokinetic movement of ions and solutes within the intracellular and extracellular fluids. These charges accumulate at dielectric boundaries such as cell and organelle membranes, changing the resting transmembrane potential (TMP). When the electric field is removed, the driving force that generated the engineered TMP is also removed, initiating the restoration of normal biological transport and ion dynamics, normative distribution of solutes operating with concentration gradients. This induces a logarithmic decay of the engineered TMP on the membrane. However, rather than removing the electric field, the electric field polarity is maintained, but if the polarity is reversed, a new electromotive force is present that actively removes the induced existing TMP, and then TMP is accumulated with the opposite polarity. This active excretion of the initially manipulated TMP significantly limits the downstream effect cascade that can occur in the cell, weakening the therapeutic effect of the initial electric field exposure. Furthermore, if a subsequent electric field with the opposite polarity must first "cancel" the original TMP manipulation that was generated and then start accumulating its own TMP with the opposite polarity, the final TMP reached by the second phase of the electric field will not be as strong as the original TMP, assuming the duration of each phase of the cycle is the same. This reduces the therapeutic effect produced from each phase of the waveform, and the therapeutic effect produced by either pulse in the cycle is lower than it would achieve alone. This phenomenon is called biphasic cancellation. For packets with many cycles, this pattern is repeated throughout the set of cycles and phase changes within the cycle of the packet. This dramatically limits the therapeutic effect.It can be appreciated that when cell behavior is modulated as a result of pulsed electric fields by mechanisms other than purely manipulating the transmembrane potential, the effects of biphasic cancellation are less pronounced and therefore the impact of switching and dead times on therapeutic outcome is reduced.

[0072]

[0106] Thus, in some embodiments, the effect of biphasic cancellation is reduced by introducing a switching time delay and a dead time. In some instances, both the switching time and the dead time are increased together to enhance the effect. In other instances, only the switching time or only the dead time is increased to induce this effect.

[0073]

[0107] It can be seen that proper timing is usually such that the relaxation of the TMP is complete after a constant τ, which is 5 times the charging time. For most cells, the time constant can be estimated as 1 μs. Thus, in some embodiments, both the switching time and the dead time are set to at least 5 μs to eliminate biphasic cancellation. In other embodiments, the reduction of biphasic cancellation may not require complete cell relaxation before reversing the polarity, and therefore both the switching time and the dead time are set to 0.5 μs to 2 μs. In other embodiments, the switching time and the dead time are set to the same length as the individual pulse lengths, since further increases in these delays may only provide diminishing returns in terms of increased therapeutic effect and concomitant increases in muscle contraction. Thus, the combination of longer scale pulse durations (>500 ns) and stacked pulse periods with substantial switching and dead time delays allows the use of biphasic waveforms without significantly reducing the therapeutic effect caused by biphasic cancellation. In some cases, fine-tuning of these parameters can be made to induce a stronger therapeutic effect without an equally proportional increase in muscle contraction. For example, a 600 kHz waveform with switching time = dead time = 1.66 μs (twice the duration as a pulse) can be used to retain the enhanced therapeutic effect while retaining the reduced muscle contraction relative to a monophasic pulse waveform.

[0074]

[0108] In some embodiments, the switching time period is adjusted so that the degree of therapeutic effect on the remote cell effect is optimized for the target of the treatment. In some embodiments, when the local therapeutic effect is reduced, the switching time period is minimized to reduce remote muscle cell contraction. In other embodiments, when additional remote muscle cell contraction is likely to occur, the switching time period is extended to increase the local therapeutic effect. In some embodiments, the switching time or dead time period is extended to increase the local therapeutic effect and the use of a neuromuscular paralyzer is employed to control the resulting increase in muscle contraction. In some embodiments, the switching time period is 10 ns to 2 μs, while in other embodiments, the switching time period is 2 μs to 20 μs. In some instances, when targeting cellular regulation in a manner where transmembrane potential manipulation is not the primary mechanism required to cause the targeted therapeutic effect, the switching time and dead time delays are minimized to less than 0.1 μs or to 0 μs. Removal of this delay minimizes non-targeted therapeutic effects, such as less important skeletal muscle contraction or cardiac action potentials and contractions, but does not alter the efficacy of the therapeutic effect at the target site.

[0075]

[0109] Another benefit of utilizing switching and dead time delays to increase the therapeutic effect of biphasic waveforms is the reduced demands on the generator, which allows for the introduction of pauses to enhance the therapeutic effect without the need for asymmetric / unbalanced pulse waveforms. In this case, an unbalanced waveform is described as a waveform that is monophasic, has an unbalanced duration or voltage, or is a combination of one polarity with the other. In some cases, unbalanced means that the integral of the positive portion of the waveform is not equal to the integral of the negative portion of the waveform. Generators capable of delivering unbalanced waveforms have a separate set of design considerations, which increases the potential for generator complexity.

[0076] G. Waveform

[0110] FIG. 3A illustrates an embodiment of a waveform 400 with symmetric pulses, such that the voltage and duration of the pulse in one direction (i.e., positive or negative) is equal to the voltage and duration of the pulse in the other direction. FIG. 3D illustrates an example waveform 400 with voltage imbalance defined by another energy delivery algorithm 152. 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 composed of a first biphasic cycle (including a first positive pulse peak 408 with a first voltage V1 and a first negative pulse peak 410 with a second voltage V2) and a second biphasic cycle (including a second positive pulse peak 408' with a first voltage V1 and a second negative pulse peak 410' with a second voltage V2). Here, the first voltage V1 is greater than the second voltage V2. The first and second biphasic pulses 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 other direction such that the area under the positive part of the curve is not equal to the area under the negative part of the curve. This unbalanced waveform makes the therapeutic effect more obvious because the dominant positive or negative amplitude results in a longer period of potential of the cell membrane charge of the same charge. 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. FIG. 3E illustrates a further example of a waveform with unequal voltages. Here, four different types of packets are shown in a single figure for simple illustration. The first packet 402 is composed of pulses with unequal voltages but equal pulse widths, and there are no switching times and no dead times. Thus, the first packet 402 is comprised of four biphasic pulses, each including a positive peak 408 having a first voltage V1 and a negative peak 410 having a second voltage V2, where the first voltage V1 is greater than the second voltage V2.The second packet 404 is made up of pulses with unequal voltages (as in the first pulse 402) but symmetric pulse widths, with a switching time equal to the dead time. The third packet 405 is made up of pulses with unequal voltages (as in the first pulse 402) but symmetric pulse widths, with a switching time less than the dead time. The fourth packet 407 is made up of pulses with unequal voltages (as in the first pulse 402) but symmetric pulse widths, with a switching time greater than the dead time. It can be appreciated that in some embodiments, the positive and negative phases of a biphasic waveform are not identical but are balanced, with the voltage in one direction (i.e., positive or negative) being greater than the voltage in the other direction, but the pulse length is calculated such that the area under the curve for the positive phase is equal to the area under the curve for the negative phase.

[0077]

[0111] In some embodiments, the imbalance includes pulses whose pulse widths are not equal in duration. In some embodiments, a biphasic waveform is unbalanced such that the voltage in one direction is equal to the voltage in the other direction, but the duration of one direction (i.e., positive or negative) is greater than the duration of the other direction, such that the area under the curve of the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

[0078]

[0112] FIG. 3F illustrates a further example of a waveform with unequal pulse widths. Here, four different types of packets are shown in a single figure for simplicity of illustration. The first packet 402 is composed of pulses with equal voltages but unequal pulse widths, and has no switching time and dead time. 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 first pulse 402), and the switching time is equal to the dead time. The third packet 405 is composed of pulses with equal voltages but unequal pulse widths (as in the first pulse 402), and the switching time is shorter than the dead time. The fourth packet 407 consists of pulses of equal voltage (as in the first pulses 402) but unequal pulse widths, with switching times longer than the dead time.

[0079]

[0113] FIG. 3G illustrates an example waveform 400 defined by another energy delivery algorithm 152, where the waveform is monophasic, a special case of imbalance where there is only a positive or only a negative portion of the waveform. 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 composed of a first monophasic pulse 430 and a second monophasic pulse 432. The first monophasic pulse 430 and the second monophasic pulse 432 are separated by a dead time 412 between each pulse. This monophasic waveform may lead to a more desirable therapeutic effect since it maintains the cell membrane potential at the same charge for a longer period of time. However, adjacent muscle groups will be stimulated more with a monophasic waveform compared to a biphasic waveform.

[0080]

[0114] FIG. 3H illustrates a further example of a waveform with monophasic pulses. Here, four different types of packets are shown in a single figure for simplicity of illustration. The first packet 402 is composed of pulses with the same voltage and pulse width, with no switching time (as the pulses are monophasic) and with a dead time equal to the active time. In some cases, the duration of the dead time may be shorter than the active time of a given pulse. Thus, the first packet 402 is composed of three monophasic pulses 430, each including a positive peak. In an example where the dead time is equal to the active time, the waveform may be considered to be unbalanced with a fundamental frequency that represents a cycle with twice the period of 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 an increased dead time. 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 increased dead time. The fourth packet 407 consists of monophasic pulses 430 of equal voltage and pulse width (as in the first packet 402) with even longer dead times.

[0081]

[0115] In some embodiments, an unbalanced waveform is achieved by delivering two or more pulses at one polarity before reversing to an unequal number of pulses of the opposite polarity. FIG. 3I illustrates further examples of waveforms with such phase imbalance. Here, four different types of packets are shown in a single figure for simplicity of illustration. The first packet 402 is composed of four cycles with equal voltage and pulse width, but with pulses of opposite polarity 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 only positive pulses without a subsequent negative pulse 430. Then it repeats. The second packet 404 is composed of a mixture of biphasic and monophasic cycles (as in the first packet 402), except that the pulses are unequal in voltage. The third packet 405 is composed of a mixture of biphasic and monophasic cycles (as in the first packet 402), except that the pulses are unequal in pulse width. The fourth packet 407 consists of a mix of biphasic and monophasic pulses (as in the first packet 402), except that the pulses are of unequal voltage and unequal pulse width, so multiple combinations and permutations are possible.

[0082]

[0116] It should be noted that in each positive or negative phase of the biphasic cycle, the portions of the cells of the airway wall W facing either side of the energy will experience opposite effects. In some embodiments, the hyperpolarized portion faces the dispersive or return electrode 140. It can further be appreciated that cells have a natural negative resting electrical transmembrane potential (TMP). Thus, altering the natural TMP on the side of the cells that promotes a negative TMP will result in an exaggerated absolute TMP. Conversely, the side of the cells that induces a positive TMP will have a lower induced reaching absolute TMP. In either case, perturbing the natural cellular TMP and altering the behavior of the cells without regard to the final absolute TMP can produce the desired therapeutic outcome. Furthermore, this difference may change when considering the TMP induced in intracellular organelles.

[0083]

[0117] Regarding the usefulness of unequal waveforms, unbalanced TMP operation provides a reduction in the effects of biphasic cancellation. There is a correlation between the degree of imbalance that approximates a completely unbalanced unipolar waveform and the strength of the TMP operation. This results in a proportional relationship between the degree of muscle contraction as well as the degree of therapeutic effect. Thus, the approximation of the unbalanced waveform allows a stronger therapeutic effect than that resulting from a purely balanced biphasic waveform at the same voltage and frequency (if applicable) for the biphasic waveform. For example, the therapeutic effect caused by a sequence of 830ns-415ns-830ns-etc. pulse lengths in a packet will have pulses that make up the second half of the cycle that are half the duration of the original phase. This will limit the induction of TMP operation by the second phase of the cycle, but will also generate less inverted TMP, allowing a stronger effect from the original polarity of the subsequent cycle at the original length. In another example, the "positive" portion of the waveform can be 2500V and the "negative" portion 1500V (2500-1250-2500-etc.V), which will induce effects on the TMP polarization comparable to those described for pulse duration imbalance. In both of these cases, manipulating the intensity of the opposite polarity will result in a more powerful TMP manipulation being accumulated for the positive pulses in the cycle. This will therefore reduce the effect of biphasic cancellation and produce a stronger therapeutic effect than an 830-830-830ns or 2500-2500-2500V protocol, despite a lower total energy deposition delivered to the tissue. Thus, if TMP manipulation is essential to the mechanism of action of the therapy, it is possible to deliver less total energy to the tissue, yet still induce the desired therapeutic effect.

[0084]

[0118] By extension, a fully unbalanced waveform may contain no opposite polarity components, but still contain portions of short duration pulses that are delivered only in the positive phase. An example of this would be a packet containing 830ns of positive polarity, a pause of 830ns where no energy is delivered, followed by another 830ns of positive polarity, etc. Whether considering pulse length imbalance or voltage imbalance, the same approach applies, since the absence of a negative pulse is equivalent to setting either of these parameters to zero for the "negative" portion.

[0085]

[0119] However, delivery of adequate therapy takes into account that the benefits provided by biphasic waveforms, i.e., reduction in muscle contraction due to biphasic cancellation, are also reduced. Thus, the degree of adequate therapeutic effect is balanced against the acceptable degree of muscle contraction. For example, an ideal voltage imbalance could be 2500-1000-2500-...V, or 2500-2000-2500-...V, or 830-100-830-...ns, or 830-500-830-...ns.

[0086] H.Wave shape

[0120] 3J illustrates an example waveform 400 defined by another energy delivery algorithm 152, where the pulses are sinusoidal rather than square. Again, two packets are shown, a first packet 402 and a second packet 404, where the packets 402, 404 are separated by a rest period 406. In this embodiment, each packet 402, 404 is made up of three biphasic pulses 440, 442, 444. Also, rather than a square wave, the three pulses 440, 442, 444 are sinusoidal in shape. One benefit of the sinusoidal shape is that it is balanced, or symmetrical, so that the shape of each phase is equal. Being balanced helps reduce unwanted muscle stimulation.

[0087]

[0121] Energy delivery can be actuated by a wide variety of mechanisms, such as using a button 164 on the catheter 102 or a foot switch 168 operably connected to the generator 104. Such actuation typically delivers a single energy dose. The energy dose is defined by the number of packets delivered and the voltage of the packets. The energy dose delivered to the airway wall W maintains the temperature of or within the wall W below the threshold of thermal ablation, particularly of the basement membrane BM, including denaturation of matrix proteins within the basement membrane or deeper submucosal extracellular protein matrix. Additionally, the energy dose can be titrated or slowed down over time to further reduce or eliminate heat accumulation during the treatment procedure. Rather than inducing thermal damage defined as protein coagulation, the energy dose delivers energy at a level that induces biological mechanisms and cellular effects that ultimately lead to regeneration of healthy tissue.

[0088] III. Application to blood vessels

[0122] In some embodiments, the tissue modification system of Figs. 1 and 2 is adapted for use in the treatment of blood vessels and other cardiac tissue, particularly for the treatment of atrial fibrillation. In some embodiments, the tissue modification system utilizes an energy delivery algorithm specifically configured for cardiac application, and more specifically, to affect tissue in a manner that successfully treats atrial fibrillation. Potential cardiac targets for treatment include areas involved in the generation or conduction of abnormal electrical signals. These signals may induce uncoordinated activation of cardiac myocytes, particularly in the atrial region upstream of the atrioventricular node. Poor atrial surgery may reduce their functionality and increase the patient's risk of angina, stroke, or other cardiac events. In some embodiments, areas within the pulmonary veins (PVs), particularly the myocardial sleeves of the PVs, are targeted due to the presence of cellular automaticity within the myocardial tissue of the PVs. In some embodiments, the therapeutic energy delivery catheter 102 of Fig. 2 is utilized to treat the PVs. In other embodiments, a modified version of the therapeutic energy delivery catheter 102 of Fig. 2 is utilized to treat the PVs. For example, in some embodiments, the catheter 102 is modified so that the distal end is bent at an angle closer to the introducer sheath angle utilized to access the PV. In some embodiments, the catheter 102 is modified to reduce the contact length, such as by shortening the length of the electrode body 108. Similarly, in some embodiments, the catheter 102 is modified for femoral access. Typically, femoral access to the PV involves accessing the femoral vein and advancing the energy body 108 of the catheter 102 via the inferior vena cava into the right atrium and then via a transseptal puncture into the left atrium. This longer path is accommodated by modification of the catheter 102 of FIG. 2 to include an elongated shaft 206 with an increased length, such as 100 cm or 150 cm, to ensure it fits through the entire transseptal introducer sheath. Additional modifications include assisted deployment of the energy delivery body 108, such as by using an internal expansion member (e.g., a balloon) to improve the expansion characteristics and likelihood of achieving circumferential therapeutic contact within the PV.Such delivery is typically accomplished using ultrasound and angiography to guide the physical placement of the energy delivery body 108.

[0089]

[0123] Furthermore, in some embodiments, the catheter 102 and the energy delivery algorithm are customized to specifically treat cardiac tissue as opposed to other luminal targets. For example, in some embodiments, such customization is specifically aimed at treating atrial fibrillation, including killing superficial myocardial cells causing the abnormal rhythm or causing remodeling of transmural fibrotic tissue to provide appropriate electrical conduction interruption. When creating a transmural effect, the electrodes of the energy delivery body 108 have a sufficiently low and concentrated contact area to adequately focus the energy to achieve a highly focused therapeutic effect that fully penetrates the entire thickness of the target site, either in the pulmonary vein, its ostium, or atrium. Alternately, the electrical voltage delivered to other, more superficial luminal targets is increased to generally increase the intensity of the delivered energy while preserving the original electrode contact area. In addition, in some embodiments, secondary pulse parameters are further modified to reduce the lethal field threshold of the target cell layer (such as by increasing the individual pulse length, such as by decreasing the biphasic pulse field frequency), increase the number of cycles of pulses in a given packet (which increases the total packet duration), or increase the number of packets delivered. In addition, in some embodiments, the use of asymmetric (in length or voltage) or monophasic waveforms is used to significantly enhance the therapeutic effect, although the degree of asymmetric or monophasic pulses is balanced to ensure that the degree of muscle contraction of the patient remains within a tolerable range. If necessary, the use of muscle paralyzers can also be employed to further reduce muscle contraction and allow for enhanced pulse protocols or asymmetric biphasic or monophasic waveforms.

[0090]

[0124] As mentioned above, in some embodiments, the energy delivery body 108 includes a single monopolar delivery electrode, in which case the energy delivery body 108 is composed of multiple wires or ribbons 120 forming a helical shaped basket that functions as an electrode. The energy delivery body 108 is positioned within the PV, and a pulsed electric field is delivered to the PV via the energy delivery body 108 to induce cell death of cardiomyocytes and other nominal cell types in that region, which are replaced by fibrous tissue deposits as part of the tissue healing process. This fibrous tissue is a poor conduit for electrical conduction, and therefore circumferential transmural guidance of this tissue usually serves as an adequate electrical conduction block, preventing abnormal currents generated in the PV sinuses from propagating through the atrium. By stopping the abnormal currents, the atrial cardiomyocytes are able to eliminate fibrillation and better coordinate their activation.

[0091]

[0125] It will be appreciated that cardiac applications involve blood-filled regions. Numerical simulations of the vasculature have shown that blood is a conductive medium and to some extent acts as a virtual electrode, dissipating electrical energy longitudinally along the vessel and reducing the localized electric field strength at the electrode contact point. This can reduce the depth of therapeutic effect on the cardiac target compared to non-conductive air-filled pulmonary passages. In some embodiments, the catheter 102 is adapted to electrically insulate portions of the electrode body 108 to reduce current leakage into the blood. In some embodiments, this involves insulating the proximal and distal portions of the electrode body 108 that are in most contact with the blood flowing through the vessel. In some embodiments, this significantly reduces current leakage into the blood. Similarly, in some embodiments, the energy delivery algorithms of the present disclosure are configured to provide improved energy delivery under such conditions (i.e., in the presence of a conductive medium). In some embodiments, such algorithms use greater pulse strengths, thereby achieving deeper transmural thickness effects as well, such as increasing voltage, decreasing frequency, increasing cycles per packet, or increasing the total number of packets delivered per active site. However, another approach to overcoming the current leakage effect is to electrically insulate the circumferential electrode body 108 contact area to prevent conduction to the blood, significantly increasing the concentration of energy delivery to the target tissue itself and inducing a stronger therapeutic effect.

[0092]

[0126] During ideal conditions, the energy delivered by the energy delivery body 108 to the lumen wall is perfectly balanced around the entire lumen circumference. However, in some circumstances, the electrical properties of tissue and / or the environment induce preferential current flow through certain areas during monopolar delivery. Thus, there is often a natural distortion of the electric field towards these specific areas. This increases the therapeutic effect in these areas and decreases the therapeutic effect in non-preferential areas. While such irregularities may be inconsequential in some circumstances, in other circumstances such irregularities may affect the therapeutic outcome. Thus, increased regularity may make the treatment more predictable, shortening procedure times and reducing energy consumption while improving patient outcomes. The embodiments of the present disclosure's dedicated catheter designs, distinct energy delivery algorithms and methods of use provide such increased regularity. Such improvements may be useful for treating a wide variety of body cavities, including, but not limited to, vascular applications. Such improvements may be particularly useful when treating body cavities such as vascular and gastrointestinal lumens, and may be useful when treating pulmonary passageways.

[0093]

[0127] When treating blood vessels, environmental conditions, the natural tissue structure of the vessel wall, and the details of the treatment protocol can create a variety of situations in which adequate energy delivery is achieved. In addition to regularity of treatment effect across the entire luminal circumference, increased depth of penetration may also be desired. For example, when treating airways, a relatively shallow depth of penetration may be sufficient for adequate energy delivery in treating disease states. However, when treating blood vessels, particularly when treating conditions such as atrial fibrillation, a deeper depth of penetration may be desired for adequate energy delivery and tissue effect.

[0094]

[0128] Several known catheter and surgical ablation approaches in the treatment of atrial fibrillation electrically isolate the PVs from the left atrial (LA) wall. Complete electrical disconnection of the PVs from the left atrium is the electrophysiological endpoint that is responsible for achieving reliable control of arrhythmias. Although electrical disconnection is often achieved by the end of a conventional procedure, the long-term efficacy of catheter ablation is only moderate. Most patients require one to two procedures to achieve reasonable efficacy. The primary reason for repeating the procedure is to restore PV-to-LA conduction.

[0095]

[0129] Several known studies have demonstrated the inevitability of time-dependent PV conduction recovery and its association with future atrial fibrillation recurrence. After initial PV isolation, up to 50%–64% of PVs reconnect during an intraprocedural waiting period of up to 60 minutes. Studies examining patients with recurrent AF at a second or subsequent procedure have shown that AF recurrence after catheter ablation is usually associated with resumption of PV-LA conduction.

[0096]

[0130] The presumed reasons for PV-LA conduction resumption are gaps in the ablation line and / or failure to create a transmural lesion. Gaps in the line allow resumption of electrical activity from PV to LA, causing PV triggers to reinitiate atrial fibrillation and may also act as triggers for other micro-reentrant atrial arrhythmias. Similarly, reversible atrial damage may result from incomplete lesion formation, resulting in temporary electrical decoupling but no cell death. Persistent conduction blockage across a linear lesion requires and / or uses a transmural lesion with associated cell death. As previously mentioned, the dedicated catheter design, distinct energy delivery algorithm, and method of use of the present disclosure provide improved circumferential ablation regularity, which reduces conduction gaps in the ablation line. In addition, the dedicated catheter design, distinct energy delivery algorithm, and method of use of the present disclosure can enhance the ability to create transmural lesions. Such improvements may be beneficial in treating atrial fibrillation, and may be useful in treating a wide variety of other conditions and / or other body cavities, including pulmonary passageways, gastrointestinal passageways, and other natural and artificial passageways within the body.

[0097] IV. Localized treatment

[0131] The above-mentioned algorithm provides energy in the form of a pulsed electric field (PEF) to a body cavity or passageway. Specific catheter designs and methods have been developed to deliver the PEF to provide localized treatment. In some embodiments, the PEF is delivered through a separate electroactive electrode of the energy delivery body, typically in a monopolar manner. Such delivery is more effective than delivery through electrodes that extend circumferentially around the lumen or passageway by concentrating the electrical energy over a smaller surface area. Such delivery also forces the electrical energy to be delivered in a stepwise localized approach, reducing the effect of preferential current paths through the surrounding tissue. These preferential current paths are regions that have electrical properties that induce a local increase in current through these preferential current paths rather than through adjacent regions. Such paths typically result in an irregular current distribution around the circumference of the targeted lumen, which distorts the electric field and causes irregular increases in the therapeutic effect in some regions and decreases in the therapeutic effect in others. This can be reduced or avoided using localized treatments that stabilize the therapeutic effect around the circumference of the target region. Thus, by "splitting" the PEF to certain areas at a time, the energy is electrically "pushed" throughout various areas of the circumference, ensuring an increased degree of circumferential regularity of the treatment.

[0098]

[0132] FIG. 4 illustrates one embodiment of a therapeutic energy delivery catheter 202 of the present disclosure configured to provide localized treatment. In this embodiment, the catheter 202 has an elongate shaft 206 with at least one energy delivery body 208 near its distal end. The catheter 202 includes a handle 211 (not shown) at its proximal end, such as a handle similar to the handle 110 of FIG. 2. The catheter 202 is connectable to a generator, such as the generator 104 of FIG. 1, to provide, among other functions, electrical energy to the energy delivery body 208. In this embodiment, the energy delivery body 208 includes an expandable member 210, such as an inflatable balloon, with electrodes 212 disposed thereon or incorporated therein. The energy delivery body 208 is delivered to the target area in a folded configuration. This folded configuration can be achieved, for example, by placing a sheath 226 over the energy delivery body 208, which maintains the folded configuration and allows for smooth delivery. When deployment is desired, the sheath 226 is retracted or the catheter 202 is advanced to allow the energy delivery entity 208 to expand.

[0099]

[0133] In this embodiment, the electrodes 212 have a pad configuration with a relatively large surface area and a thin cross section. This pad configuration provides a larger surface area than other configurations, such as wire configurations. The electrodes 212 are connected to a lead wire 214 that electrically connects the electrodes 212 to a generator. In this embodiment, the electrode body 208 has only one electrode 212, but it will be understood that the energy delivery body 208 may instead include a plurality of electrodes 212, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more electrodes 212, as described in more detail below. The electrodes 212 may be attached to or comprised of flexible circuit pads or other materials formed on the expandable member 210. The electrodes 212 may be distributed radially around the circumference of the expandable member 210 and / or they may be distributed longitudinally along the length of the expandable member 210. Such a design allows for improved deployment and retraction quality, ease of user manipulation, and compatibility with standard introducer needle lumens.

[0100]

[0134] In use, the catheter 202 is advanced into the body passageway or lumen L, such as over a guidewire, along the length of the lumen L to a target segment. The target segment has a length and typically extends circumferentially around the inner surface of the wall W of the body lumen L, thus forming a ring. In some embodiments, it is desired to deliver energy to the circumferential ring in a series of steps as illustrated in FIGS. 4A-4D, with corresponding treatment zone results illustrated in FIGS. 5A-5D. FIG. 4A illustrates a first step of extending the energy delivery body 208 into the target segment of the body lumen L such that the electrode 212 is positioned adjacent to, abutting, or pressing against a first portion of the wall W of the lumen L. Energy is then delivered from an electrically connected generator to the first portion of the wall W to create a first treatment zone A1. FIG. 5A provides a cross-sectional view of the body lumen L at the target segment, showing the first treatment zone A1 along the top quarter of the circumferential lumen wall. The energy delivery body 208 is then at least partially deflated or deflated, and the catheter 202 is rotated, for example, 90 degrees in a clockwise direction, as illustrated in FIG. 4B. The energy delivery body 208 is then expanded, and the electrode 212 is positioned adjacent to, abutting, or against a second portion of the wall W of the lumen L. Energy is delivered from an electrically connected generator to the second portion of the wall, creating a second treatment zone A2. FIG. 5B provides a cross-sectional view of the body lumen L at the target segment, showing the second treatment zone A2 along the right quarter of the circumferential lumen wall W. The catheter 202 is then rotated again, for example, another 90 degrees in a clockwise direction, as illustrated in FIG. 4C. The electrode 212 is positioned adjacent to, abutting, or against a third portion of the wall of the lumen L. Energy is delivered from an electrically connected generator to the third portion of the wall, creating a third treatment zone A3. 5C provides a cross-sectional view of body lumen L at the target segment, showing a third treatment zone A3 along the bottom quarter of the circumferential lumen wall W. The catheter 202 is then rotated again, e.g., another 90 degrees in a clockwise direction, as shown in FIG.The electrode 212 is positioned adjacent to, abutting, or against a fourth portion of the wall of the lumen L. Energy is delivered from an electrically connected generator to the fourth portion of the wall to create a fourth treatment zone A4. FIG. 5D provides a cross-sectional view of the body lumen L at the target segment, showing the fourth treatment zone A4 along the left quarter of the circumferential lumen wall W. In this manner, the treatment zones A1, A2, A3, A4 collectively cover a circumferential ring around the inner surface of the wall W of the body lumen L, forming a continuous treatment zone without gaps.

[0101]

[0135] It will be appreciated that in some embodiments, the catheter 202 includes one or more markings along its shaft 206, such as one or more markings around the circumference of the shaft 206, to aid the user in orienting the catheter 202 through rotation. In some embodiments, the one or more markings include multiple markings spaced apart by a fixed distance, each marking indicating a degree of rotation. For example, each marking may indicate a 15 degree rotation distance. In some embodiments, a particular marking indicates a known rotation distance, such as a larger marking indicating a 90 degree rotation and a smaller marking indicating a 45 degree rotation. In some embodiments, a particular marking indicates a known orientation, such as "up," and / or a particular marking indicates alignment with the electrode 212. It will be appreciated that in some embodiments, indicia are provided along the handle 211 and / or the sheath 226. Thus, a user can rotate both the delivery device (such as a bronchoscope or catheter) and the catheter 202, or can rotate only the catheter 202 independently.

[0102]

[0136] An alternative electrode body 208 design allows for circumferential energy delivery to the body lumen L without rotating the catheter 202. One embodiment of such an electrode body 208 is illustrated in FIG. 6. Here, the electrode body 208 includes four electrodes, a first electrode 212a, a second electrode 212b, a third electrode 212c, and a fourth electrode 212d. Here, the electrodes 212a, 212b, 212c, and 212d are evenly spaced apart from one another around the expandable member 210. Each of the electrodes 212a, 212b, 212c, and 212d has a corresponding lead wire 214a, 214b, 214c, and 214d that provides energy from the generator 104. In this embodiment, the electrodes 212a, 212b, 212c, 212d are independently energized via their respective lead wires 214a, 214b, 214c, 214d. When used in a monopolar configuration, as illustrated in Figure 7, the electrodes 212a, 212b, 212c, 212d each form an electrical path to the dispersive (return) electrode 140. As shown in Figure 7, the first electrode 212a forms a first electrical path 216a, the second electrode 212b forms a second electrical path 216b, the third electrode 212c forms a third electrical path 216c, and the fourth electrode 212d forms a fourth electrical path 216d. For example, when the first electrode 212a is energized and the remaining electrodes 212b, 212c, 212d are not energized, all of the energy flows along the first electrical pathway 216a to the dispersive electrode 140. This provides a predictable path in which any naturally occurring priority in current flow is overcome by the induced current flow through the electrical pathway 216a. This increases the therapeutic effect at the tissue section of the lumen wall through which the first electrical pathway 216a flows.

[0103]

[0137] Such increases in therapeutic effect include increased regularity and depth of penetration. Figures 8A and 8B illustrate such increased depth of penetration. Figure 8A illustrates an example of electric field distribution through various tissue layers of an airway wall when energy is delivered circumferentially in a monopolar configuration, such as with an energy delivery body 108 having basket-type electrodes (see, for example, Figure 2). As shown in Figure 8A, the tissue layers receive different levels of electric field along the electrodes. In contrast, Figure 8B illustrates an example of electric field distribution through various tissue layers of an airway wall under focal delivery, where an electrode pad, such as the first electrode 212a, is energized alone. As can be seen in Figure 8B, the tissue layers receive a much more consistent level of energy along the length of the electrode, and the reduction in the strength of the electric field occurs at deeper levels. This allows for improved transmural effects without increasing the overall voltage or current delivered. In addition, this reduces the likelihood of side effects, such as muscle contraction, pain, or thermal damage to the area.

[0104]

[0138] For example, it will be appreciated that if the second electrode 212b is energized and the remaining electrodes 212a, 212c, 212d are not energized, all of the energy will flow along the second electrical pathway 216b to the dispersive electrode 140. Similarly, this can be repeated for the third electrode 212c, with all of the energy flowing along the third electrical pathway 216c, and the fourth electrode 212d, with all of the energy flowing along the fourth electrical pathway 216d. This can be easily accomplished without rotating the catheter 202, as illustrated in FIG. 9. FIG. 9 illustrates a cross-sectional view of a body cavity having a wall W, with an energy delivery body 208 positioned therein. The expandable member 210 of the energy delivery body 208 expands such that the first electrode 212a, the second electrode 212b, the third electrode 212c, and the fourth electrode 212d lie against the wall W of the body cavity. The electrodes 212a, 212b, 212c, 212d are then energized individually in sequence. Energizing the first electrode 212a creates a first treatment zone A1, energizing the second electrode 212b creates a second treatment zone A2, energizing the third electrode 212c creates a third treatment zone A3, and energizing the fourth electrode 212d creates a fourth treatment zone A4. Using such an electrode configuration, an entire ring of wall tissue can be ablated without gaps and more accurately and quickly than by rotating the catheter 212.

[0105]

[0139] As shown in FIG. 8, the localized delivery of energy can be utilized in a variety of ways to enhance and / or maximize the effect on the tissue. In particular, precise timing and sequencing of energy delivery to the electrodes (e.g., 212a, 212b, 212c, 212d) can be utilized to ensure cell death in the tissue receiving the energy, as further described below. This may be particularly useful in the treatment of atrial fibrillation. As previously mentioned, permanent conduction block across a linear lesion uses and / or requires a transmural lesion with cell death, rather than a temporary reversible effect. In some embodiments, the PEF waveform uses bipolar offset with frequencies reflecting nanosecond to microsecond pulse durations to reduce the degree of generalized muscle contraction to an acceptable low level while retaining the ability to destabilize both cell and organelle membranes, with or without paralysis. This induces a variety of modalities of effects on cells that uniquely predispose to enhanced therapeutic outcomes beyond those reached using either nanosecond pulsed electric fields (nsPEF) or conventional millisecond irreversible electroporation (IRE) methods. Thus, the delivered energy can induce a sufficiently large and effective treatment zone in the target tissue, which is a challenge for nsPEF, while maintaining favorable safety and muscle contraction profiles is a challenge for conventional millisecond IRE, especially for monopolar pulse delivery configurations using external dispersive pads.

[0106]

[0140] When selecting an electrode type for a given therapeutic indication, it is important to consider the advantages and disadvantages of electrode configurations using monopolar electrical pulse delivery (e.g., the electrode circuit has the active portion of the electrode completing an electrical circuit with a remote secondary electrode) versus bipolar or multipolar electrical pulse delivery (e.g., both the delivery and return of the electrical pulse energy are contained within the electrode device itself). When delivering electrical pulses in a monopolar circuit configuration, the total impedance of the system is relatively constant and the possibility of electrical arcing is low to minimal. This allows for a very stable and controlled environment for delivering the pulsed electric field as well as the use of a greatly simplified electrode design. However, with a remote return electrode in the circuit, the electrical energy is distributed to a greater extent throughout the patient's body, which may limit some control of the affected area if very large lesions are desired. In addition, additional muscle activation may result, which can be adequately compensated for by carefully selecting the pulsed electric field parameters to retain the therapeutic effect without muscle contraction or by employing the use of paralytic subjects, but which would also require general anesthesia for the procedure.

[0107]

[0141] Conversely, bipolar and multipolar electrode designs face a unique set of advantages and challenges in practical use for therapeutic pulsed electric field delivery. Confinement of all active parts of the electrical circuit allows for highly concentrated electrical energy delivery, allowing for additional aspects of control of the electric field distribution and reduced likelihood of muscle contraction. However, because the current is so confined, the impedance of the system is often very low and the risk of electrical arcing for a given pulse protocol can be very high, which reduces the maximum pulsed electric field delivery voltage that can be used. These factors combine to severely limit the penetration depth of the therapeutic effect, especially in luminal applications. Furthermore, the therapeutic effect is highly sensitive to the electrode separation distance of bipolar and multipolar electrode configurations, so subtle variations or changes in contact area separation distance reduce the predictability of the therapeutic outcome in various target sites, especially in luminal applications, because electrodes are applied at target sites of various geometries, requiring electrodes with various deployment ranges, which can change the electrode contact separation distance. Overcoming such aspects can further complicate the therapeutic device design. Thus, while the embodiments described herein can be adapted to both monopolar and bipolar / multipolar electrode circuit systems, it should be understood that, depending on the application, a properly tuned monopolar treatment system can provide greater depth of penetration of effect, improved circumferential regularity of treatment, improved predictability of treatment zones, and / or significantly simplify the treatment delivery procedure for the operator.

[0108]

[0142] When delivered at the appropriate amplitude, waveform, frequency, repetition, and repetition rate, PEFs tend to destabilize cell and organelle membranes. This reduces the ability of cells to maintain the desired intracellular and extracellular environment and normal function, and may ultimately result in the destruction and / or removal of cells from their location in the tissue. In vivo, this may result in a complex cascade of tissue remodeling that is tissue specific, involving the regeneration of the affected area with new cells and / or the generation of fibrous scar formation. The cell- and tissue-scale response to pulsed electric fields may be partially related to the propensity to kill cells as well as the regenerative ability of the cells themselves. For example, if the liver is known to regenerate after partial surgical resection, it has likewise been shown to regenerate after being killed by pulsed electric fields. However, cardiomyocytes and tissues in the vestibular region and atrium do not show the same regenerative tendency, and thus, following their cell death, there is a high likelihood that fibroblast infiltration will deposit fibrin and other connective tissue components to replace the affected area with a non-conductive patch of scar tissue as a natural part of the tissue healing process. It should be noted that while the use of pulsed electric fields to initiate this process allows connective tissue deposition to occur as part of the natural healing process, heat-dependent ablation techniques induce coagulation necrosis and essentially alter protein structure, resulting in a different healing process and scar type formation, which may increase the incidence of necrosis or patient risk of unacceptable collateral damage to adjacent tissues, such as the esophagus or phrenic nerve.

[0109]

[0143] When used to treat atrial fibrillation, PEF offers several possibilities to function as an effective therapeutic tool in treatment. Since the PEF effect does not depend on a thermal mechanism, the blood perfusion heat sink effect can be considered irrelevant or even beneficial, for example, in reducing the risk of adverse events based on thermal damage. In addition, due to the improved safety of sensitive structures and tissues, it is possible to deliver PEF therapy in areas less suitable for thermal ablation.

[0110] V. Progressive Energy Delivery

[0144] The localized delivery of PEF can enhance tissue lethality by using precise timing and sequencing of energy delivery to the electrodes (e.g., 212a, 212b, 212c, 212d), as described above. To this end, embodiments of the present disclosure provide at least one energy delivery algorithm 252 designed according to advanced interval theory. Such an algorithm 252 may be utilized by a tissue modification system, such as the lung tissue modification system 100 illustrated in FIG. 1, or similar systems utilized to treat other body tissues and / or cavities. In either case, the at least one algorithm 252 controls the delivery of energy from the generator to the catheter 202 and energy delivery body 208.

[0111]

[0145] In some embodiments, the algorithm 252 delivers a single or limited amount of PEF energy to each electrode, which is then repeated multiple times to complete the delivery of the therapy. For example, as shown in FIG. 9, energy can be delivered to electrodes 212a, 212b, 212c, 212d in a clockwise configuration in sequence. This rotation may be repeated one or more times. However, it will be understood that other sequences may be used, including energizing the electrodes individually in any order. It will be understood that the entire sequence may be repeated, or a subset of the sequence may be repeated. Similarly, different sequences may be utilized for subsequent cycles.

[0112]

[0146] The advanced delivery algorithm 252 of the present disclosure exploits the properties of membrane dynamics, including the creation and resolution of defects and pores, a capability unique to PEF delivery, especially in monopolar treatment systems. The creation of defects in membranes occurs rapidly, on the order of nanoseconds for organelles and hundreds of nanoseconds to microseconds for cell membranes. However, the resolution of the defects and restoration of normal membrane structure occurs on the order of seconds to tens of seconds. This time differential can be exploited to manipulate the bulk damage time. Thus, the advanced delivery algorithm 252 delivers energy in a time sequence that increases the rate of bulk damage over time and reduces the required voltage or total number of packets used to cause cell death circumferentially around the span around the lumen. This is in contrast to an approach that simply adjusts the number of PEFs delivered to modulate treatment efficacy. Increasing the number of PEFs not only extends the treatment time, but may also require the use of more powerful generators, especially if energy is delivered to all electrodes simultaneously for the entire duration of the procedure. Thus, advanced delivery algorithms 252 reduce the number of PEF exposures to a particular area and focus the effect on creating nanoscale defects in the membrane rather than on accumulated damage, where the treated cells are eventually killed rather than reverted. When an organelle or cell membrane is physically disrupted, the membrane may lose its ability to function as an environmental barrier for the organelle or cell. To maintain viability, cells must maintain homeostasis by retaining the basic building blocks for intracellular function and viability while preventing or impeding the influx of unwanted quantities or substances from the external environment into the cell. Thus, when the cell membrane is disrupted, diffusion gradients drive substances in and out of the cell against the needs of the cell. When the damage induced by this loss of homeostasis exceeds the cell's capacity and the residual intracellular adenosine triphosphate (ATP) stores recover from the effect and return to the appropriate concentration, the cell dies. This principle may also be applied to the leakage of organelle contents resulting from PEF, in particular the leakage of calcium and caspase 3 from certain organelles, both of which promote cellular apoptosis.The longer organelles remain disrupted, the more likely it is that leakage of these contents will continue and become more difficult to reverse.

[0113]

[0147] For both organelles and cellular targets for affecting cellular homeostasis, the longer defects are maintained in the cell, the more lethal they become. If these defects occur rapidly and resolve with a logarithmic decay on the order of seconds, it can be concluded that PEF only needs to be delivered once every few to tens of seconds to maintain continued damage to the cell. Figure 10 is a plot showing an example of pore or defect formation over time in response to PEF energy delivery. It can be seen that pores, defects, and openings are used interchangeably to describe inconsistencies in the walls of a cell or organelle that lead to a potential loss of homeostasis. As shown, the pore count rises on the microsecond scale. Thereafter, the pore count gradually decreases over time. In this example, using a pore count half-life of 4 seconds, approximately 25% of the pores are still open and continue to damage cellular homeostasis even 8 seconds after applying PEF.

[0114]

[0148] FIG. 11 illustrates the formation of pores or defects when PEF energy is delivered at intervals that are not optimized for lethality. In particular, FIG. 11 is a plot showing the effect of delivery of five packets (with rest periods between each packet) on pore number. Each of the five energy packets includes a series of biphasic high voltage pulses. Thus, five peaks 350a, 350b, 350c, 350d, 350e are illustrated in FIG. 11, each reaching a maximum value for pore number. In this example, after five packets are delivered, the pore number decreases over time, such that at 13 seconds (indicated by position 352 along the curve), approximately 25% of the pores are still open, damaging cellular homeostasis. FIG. 12 is a plot showing another example of delivery of five packets, each of which includes a series of biphasic high voltage pulses. Thus, five peaks 350a, 350b, 350c, 350d, 350e are illustrated, each reaching a maximum value for pore number. However, in this example, the resting period between each packet is such that subsequent PEFs are delivered close enough together to maintain the disrupted membrane, but far enough apart to increase the cumulative amount of leakage of cell contents. As a result, cell damage occurs over a longer period of time. In this example, the pores decrease over time such that roughly 25% of the pores are still open, damaging cell homeostasis at 25 seconds (indicated at position 354 along the curve). Thus, it is not only the number of PEFs that affect the lethality of a PEF regimen, but also the rhythm of the PEF delivery delivered. Another aspect of this prolonged disruption is that cells continually expend energy (ATP) to restore proper intracellular and extracellular, as well as organelle, material balance to maintain function, especially if the defect is provided time to resolve. As defects are repeatedly generated or continually maintained for extended periods of time, cells continue to use energy to restore homeostasis, depleting energy reserves for other functions essential for their continued viability, thus increasing the likelihood of necrotic or apoptotic cell death during prolonged disease periods.

[0115]

[0149] According to some embodiments of the present disclosure, such long-term disruption is accomplished by one or more algorithms that sequentially cause the delivery of PEF to one or more electrodes. The sequence of PEF is applied to the electrodes (e.g., 212a, 212b, 212c, 212d) individually while using unipolar delivery (i.e., each electrode is in electrical communication with the external dispersive electrode 140 in sequence). As described above, the one or more algorithms are typically controlled and automated by the generator, eliminating the need to rotate or manipulate the catheter 202.

[0116]

[0150] FIG. 13 illustrates a cross-sectional view of a body cavity having a wall W with an energy delivery body 208 positioned therein. Here, the energy delivery body 208 includes an expandable member 210 having a first electrode 212a, a second electrode 212b, and a third electrode 212c that are sized and oriented along the expandable body 210 to position and ablate a continuous ring along the inner surface of the wall W of the body cavity. Thus, each electrode delivers energy to approximately one-third of the circumferential lumen wall. The electrodes 212a, 212b, 212c are energized individually in sequence. Energizing the first electrode 212a creates a first treatment zone A1, energizing the second electrode 212b creates a second treatment zone A2, and energizing the third electrode 212c creates a third treatment zone A3. Not only are each treatment zones receiving electrical energy, but as the size of the electrode decreases, the amount of energy received by the tissue increases due to the boundary effect of the electrode. The current is concentrated at the sharp ends and boundaries of the electrode. Thus, the electric field is stronger at the ends than at the center of the electrode. Thus, with multiple small electrodes, more of the tissue gets the depth of the boundary effect, instead of the reduced field depth that would occur at the center of the electrode. This allows for greater coverage of the lumen, and an entire ring of wall tissue is ablated without leaving any gaps.

[0117]

[0151] 14 and 15 are plots illustrating the concepts of FIG. 11 and FIG. 12 when it comes to delivery to multiple electrodes (212a, 212b, 212c) rather than a single electrode. FIG. 14 is a plot illustrating the effect of delivering multiple PEFs (five packets) to each electrode 212a, 212b, 212c in sequence. It will be appreciated that each energy packet comprises a series of biphasic high voltage pulses. First, five packets are delivered to the first electrode 212a, while the second electrode 212b and the third electrode 212c are not energized. Next, five packets are delivered to the second electrode 212b, while the first electrode 212a and the third electrode 212c are not energized. Next, five packets are delivered to the third electrode 212c, while the first electrode 212a and the second electrode 212b are not energized. FIG. 14 illustrates the number of pores over time for each treatment zone (A1, A2, A3). As shown, each line graph decreases with time, such that at 13 seconds from the time the first packet was delivered to the corresponding electrode, approximately 25% of the pores are still open, damaging cellular homeostasis. Thus, FIG. 14 illustrates the concept of FIG. 11 repeated for each treatment zone. Thus, while effective in creating continuous lesions, PEF energy delivery is not optimized for cellular lethality.

[0118]

[0152] It will be appreciated that optimization of lethality can be achieved by delivering multiple PEFs (e.g., five packets) to each electrode 212a, 212b, 212c in sequence, with each packet spaced apart by a rest period that increases and / or maximizes the accumulation of factors that contribute to cell death. However, such a sequence results in a long treatment period. To shorten this, alternative sequences are provided that shorten and / or minimize treatment time while maintaining a desired amount and / or optimization of lethality. In one embodiment, the sequence involves delivering spaced packets to electrodes 212a, 212b, 212c in an overlapping pattern rather than a sequential pattern, the effect of which is illustrated in FIG. 15. For example, a first packet is delivered to electrode 212a, then a first packet is delivered to electrode 212b, and then a first packet is delivered to electrode 212c. This completes one round or rotation of the sequence pattern. Then a second packet is delivered to electrode 212a, a second packet is delivered to electrode 212b, and then a second packet is delivered to electrode 212c. This pattern is repeated until five packets have been delivered to each electrode 212a, 212b, 212c. Packets are delivered to each electrode with rest periods that allow cell damage to occur over a longer period of time. Recall that the number of pores decreases over time such that at 21 seconds, approximately 25% of the pores are still open, damaging cell homeostasis. Thus, shortly after 21 seconds, a continuous lesion has been created around the circumference of the cavity, increasing lethality and transmural penetration. This is in contrast to waiting three times as long (in this example, because there are three electrodes around the circumference) to achieve a similar result by delivering energy to the electrodes in sequence. Similarly, by overlapping cycles instead of fully delivering all PEFs to each contact area before proceeding to the next PEF, organelle and membrane defects are generated over a longer period of time across the entire circumference of the target area in the same number as the total number of PEFs delivered.

[0119]

[0153] The benefits of using a multi-electrode energy delivery body 208 that operates in a monopolar manner include the following: Increased mortality rate, b. Reduction of the effect of preferential current paths and therefore reduction of the energy requirements of the individual PEFs allowing for a reduction in the power demand of the generator; c. Reducing the risk of collateral damage to local tissue due to low voltages; d. A decrease in the total number of PEFs; e. Reduction of thermal effects, if any; f. reduced muscle contraction, if present; and g. Reduced risk of inducing cardiac arrhythmias (especially in non-cardiac applications of the present disclosure).

[0120]

[0154] Another approach that takes advantage of the advanced interval theory incorporates the use of maintenance PEFs. Energy requirements may be further reduced by replacing some of the PEFs in the delivery sequence with maintenance PEFs. Maintenance PEFs are of lower intensity compared to normal or primary PEFs. Initial membrane defect generation is accompanied by a relatively strong transmembrane potential generated in cells exposed to the electric field from the PEF. However, after the effect occurs, the impedance of the local area is reduced due to improved current flow through the cell (rather than the surroundings). Furthermore, a balance is generally created between the size, number, and distribution of cell defects, electric field strength, and defect generation that allows electrolyte movement throughout and through the cell. Thus, after the initial energy barrier threshold is exceeded to induce defects, the transmembrane potential is significantly reduced, as is its dielectric capacitance. This means that it may be possible to maintain defects for longer periods of time by later exposure to electric fields or PEFs at lower intensities than are required for defect generation. Therefore, rather than increasing the efficacy of PEF therapy by adding additional PEF, delivering a maintenance PEF to the target area in addition to the primary PEF can increase efficacy without significantly increasing energy requirements.

[0121]

[0155] FIG. 16 is a plot showing a sequence of PEFs, including a primary PEF and a maintenance PEF in between. It will be appreciated that the PEFs may be considered as pulses or packets. With reference to FIG. 16, a first primary PEF 400 is shown followed by three maintenance PEFs 402. Then, a second primary PEF 404 followed by three maintenance PEFs 402, and then a third primary PEF 406 followed by three maintenance PEFs 402, and so on. It will be appreciated that any number of maintenance pulses may be used, or may form a regular pattern (as shown in FIG. 16) or an irregular pattern, such as having a different number of maintenance pulses between primary pulses. Similarly, it will be appreciated that the strength of the maintenance pulses may be the same or may vary throughout the delivery sequence.

[0122]

[0156] FIG. 17 is a plot showing the effect of a delivery sequence such as in FIG. 16 on the number of pores in a target membrane. As shown, the number of pores reaches a maximum level upon receiving the first primary PEF 400. The number of pores then drops until receiving a maintenance PEF 402, after which the number of pores is restored toward the maximum level. This is repeated with each maintenance PEF 402, then with subsequent primary PEFs, followed by a maintenance PEF. It will be appreciated that in some instances, the maintenance PEFs are sufficient to restore (e.g., "top up") the number of pores such that subsequent primary PEFs are not needed as frequently, or at all.

[0123]

[0157] It will be appreciated that a sequence including a maintenance PEF 402 may be delivered to multiple electrodes in the same manner as a sequence including only a primary PEF. For example, with reference to FIG. 13, a first packet may be delivered to electrode 212a, then a first packet may be delivered to electrode 212b, and then a first packet may be delivered to electrode 212c. This completes one round or rotation of the sequence pattern. Then a first maintenance packet is delivered to electrode 212a, a first maintenance packet is delivered to electrode 212b, and then a first maintenance packet is delivered to electrode 212c. This pattern is repeated until four maintenance packets have been delivered to each of electrodes 212a, 212b, and 212c. This requires delivering a total of five packets (one primary packet and four subsequent maintenance packets) to each electrode 212a, 212b, and 212c with some overlap. In some instances, this will have the same effect as delivering five primary packets, with the added benefit of the time savings that come from overlapping some of the cycles.

[0124]

[0158] Typically, the subsequent PEF is delivered shortly after the delivery of the primary PEF (e.g., 1-100 ms after the completion of the primary PEF) so that all of the PEF is delivered within a safe period of the cardiac rhythm. As mentioned above, in some embodiments, the energy signal is synchronized with the patient's cardiac cycle to prevent the induction of cardiac arrhythmias. Thus, the patient's cardiac cycle is typically monitored using an electrocardiogram (ECG). A typical ECG tracing includes a repeating period of P waves representing atrial depolarization, QRS complexes representing ventricular depolarization and atrial repolarization, and T waves representing ventricular repolarization. To safely deliver energy in close proximity to the heart, synchronization between energy delivery and the patient's cardiac cycle is often used to reduce the risk of cardiac arrhythmias. High voltage energy may trigger premature action potentials in the myocardium, as the delivered energy increases the permeability of the myocardial cell membranes that allow ion transport, potentially inducing cardiac arrhythmias, particularly ventricular fibrillation. To avoid cardiac arrhythmias, electrical energy is delivered to the airway in a manner that avoids the "fibrillation vulnerable period" of the myocardium. Within a cardiac cycle (heartbeat), the fibrillation vulnerable period of the ventricular myocardium is represented on the ECG by the entire T wave. Normally, for ventricular myocardium, the fibrillation vulnerable period coincides with the middle and end phases of the T wave. However, when delivering high energy pulses very close to the ventricles, the fibrillation vulnerable period may occur several milliseconds earlier than the heartbeat. Therefore, the entire T wave can be considered to be within the fibrillation vulnerable period of the ventricles.

[0125]

[0159] The remaining portion of the cardiac cycle are the P wave and the QRS complex, both of which include periods during which the atrial or ventricular muscles are unresponsive to the stimulation of high voltage energy. If the pulse of high voltage energy is delivered during the muscle unresponsive period, the chance of arrhythmia can be minimized. The ST segment (the interval between ventricular depolarization and repolarization) of the first cardiac cycle and the TQ interval (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 myocardium being in a depolarized state (unresponsive period).

[0126]

[0160] However, because the maintenance PEF is delivered at a lower electrical energy (higher frequency, lower voltage, fewer cycles, etc.) than the primary PEF, in some instances it may be possible to deliver the maintenance PEF periodically (such as during a "fibrillation vulnerable period") between the primary PEFs without risk of inducing an abnormal cardiac rhythm in the patient. This latter aspect is particularly applicable to non-cardiac applications, such as intra-airway delivery, due to the reduced physical proximity to the heart and therefore inherently lower procedural risk of inducing arrhythmia. Delivered in this manner, it may be possible to provide any number of maintenance PEFs between the primary PEFs. FIGS. 18A-18D illustrate one embodiment of a unipolar focal energy delivery sequence using a maintenance PEF during various portions of the cardiac cycle. FIGS. 18A-18D provide a cross-sectional view of one embodiment of an energy delivery body 208 having three electrodes 212a, 212b, 212c spaced around the circumference of an inflatable member 210. When energy is delivered to one of the electrodes, an electrical path is formed to the external dispersive electrode 140. In particular, FIG. 18A illustrates a first primary PEF 400 delivered to the first electrode 212a. This occurs during a safe period of the cardiac rhythm. FIG. 18B illustrates a maintenance PEF 402 delivered to each of the electrodes 212a, 212b, 212c outside of the safe period. Such delivery may be simultaneous or staggered. FIG. 18C illustrates a second primary PEF 404 delivered to the second electrode 212b during a safe period of the cardiac rhythm. FIG. 18D illustrates a maintenance PEF 402 delivered to each of the electrodes 212a, 212b, 212c outside of the safe period. This pattern may be repeated any number of times.

[0127]

[0161] It will be appreciated that in some embodiments, the maintenance PEF 402 is delivered to the electrodes at the same time that the (primary or maintenance) PEF is delivered to the respective electrodes of the energy delivery body 208. When delivered synchronously with the primary PEF, some of the benefits of the localized delivery PEF may be somewhat diluted since the energy is not distributed purely localized. This utilizes an electrical generator capable of maintaining the targeted therapeutic PEF parameter characteristics to also simultaneously deliver a differential voltage to the respective electrode regions. This concept is illustrated in FIG. 19A and FIG. 19B. FIG. 19A illustrates a primary PEF delivered to the first electrode 212a of the four electrode energy delivery body 208, while no energy is delivered to the second electrode 212b, the third electrode 212c, and the fourth electrode 212d. The effect zone is illustrated by a dashed line indicating the effective area of ​​energy delivery. FIG. 19B illustrates a primary PEF delivered to the first electrode 212a, while a maintenance PEF is delivered to the second electrode 212b, the third electrode 212c, and the fourth electrode 212d. As shown, the zone of effect spreads more widely around the broad surface of the electrode 212a, as indicated by the dashed lines, and does not spread as deeply into the adjacent tissue (further from the electrode). This is because the maintenance PEF causes the focus of energy to be diluted around the circumference of the expandable member 140. In a further example, the energy delivery body 208 includes three electrodes distributed circumferentially around it, and the primary PEF can be delivered to the first electrode 212a at 3000V, while the other two electrodes 212b, 212c each receive a PEF of 500V of the same polarity. Again, this may somewhat dilute the benefit of using focal delivery due to a slight increase in electrical conductivity in the tissue receiving the maintenance PEF. This not only allows for the effect of several preferential current paths, but can also increase the power demands of the generator to generate multiple voltage signals for delivery.However, in some embodiments, delivering a maintenance PEF to some electrodes while simultaneously delivering a primary PEF to other electrodes allows all PEFs to be delivered in a window of safe cardiac rhythm, rather than delaying a time period for delivering a maintenance-only PEF set.

[0128]

[0162] It will be understood that the above examples are illustrative and are not to be considered limiting in scope. The primary PEF and the maintenance PEF can be delivered to the various electrodes in any combination or pattern. For example, in some embodiments having three electrodes 212a, 212b, 212c, the primary PEF is delivered to the first electrode 212a, followed by a maintenance pulse applied simultaneously to all three electrodes 212a, 212b, 212c. The primary PEF is then applied to the second electrode 212b, followed by a maintenance pulse applied simultaneously to all three electrodes 212a, 212b, 212c. The primary PEF is then applied to the third electrode 212c, followed by a maintenance pulse applied simultaneously to all three electrodes 212a, 212b, 212c. This pattern may be repeated any number of times. Similarly, in some embodiments, the primary PEF is applied to the first electrode 212a, then the second electrode 212b, and then the third electrode 212c. This is followed by a maintenance pulse applied to all three electrodes 212a, 212b, 212c. This pattern may be repeated any number of times. In some embodiments, the primary PEF is applied to the first electrode 212a, and a maintenance PEF is applied to the second electrode 212b and the third electrode 212c. Then, the primary PEF is applied to the second electrode 212b, and a maintenance PEF is applied to the first electrode 212a and the third electrode 212c. Then, the primary PEF is applied to the third electrode 212c, and a maintenance pulse is applied to the first electrode 212a and the second electrode 212b. These examples are illustrative of only a few of the various combinations.

[0129]

[0163] In some embodiments, the maintenance PEF can be used to determine the treatment characteristics by measuring certain variables that are indicative of the treatment characteristics, such as impedance. Because the maintenance PEF is lower in energy than the primary PEF, the PEF has a smaller effect on the tissue (and therefore does not affect the treatment environment as much), which makes the data provided more useful. Thus, the reduced strength of the PEF reduces the primary effect at the tissue level and provides cleaner data that displays aspects such as accumulation / progression of the treatment effect, tissue temperature, cell density and composition, local cell viability, and other tissue aspects. Due to the localized nature of the electrical circuit system with bipolar and multipolar electrode delivery schemes, the application of this concept is particularly suitable for such electrode device designs.

[0130]

[0164] It will be appreciated that many of the concepts provided herein are applicable to bipolar delivery. For example, a maintenance PEF can be delivered in a bipolar manner even when the primary PEF is delivered monopolarly. FIGS. 20A-20D illustrate such a delivery sequence. FIGS. 20A-20D provide cross-sectional views of one embodiment of an energy delivery body 208 having four electrodes 212a, 212b, 212c, 212d spaced around the circumference of an inflatable member 210. When a first primary PEF 400 is delivered to the first electrode 212a in a monopolar configuration, an electrical path is formed to the outer dispersive electrode 140, as illustrated in FIG. 20A. This occurs during a safe period of the cardiac rhythm. FIG. 20B illustrates a maintenance PEF 402 delivered to each of the electrodes 212a, 212b, 212c, 212d in a bipolar manner outside of the safe period. Once another safe period in the cardiac rhythm is reached, a second primary PEF 404 is delivered in a unipolar manner to the second electrode 2l2b, as illustrated in Figure 20C. Again, an electrical path is formed to the external dispersive electrode 140. Figure 20D illustrates a maintenance PEF 402 delivered in a bipolar manner to each of the electrodes 212a, 2l2b, 212c, 2l2d outside of the safe period. This pattern may be repeated any number of times.

[0131]

[0165] In addition to keeping the pores open longer, maintenance pulses can also be used to gather system-level (unipolar) or local-level (bipolar) data on symptoms in the target area. This could include basic pulse metrics (Z', i', etc.) with lower parameter settings, or could use more advanced sensing and deductive techniques such as spectroscopic data or evaluation of multi-frequency data points that may indicate tissue characteristics such as tissue composition, depth / size / potency of effect, temperature, macromolecule uptake, etc.

[0132]

[0166] Although it has been described herein that the primary PEF can be applied to only one electrode at a time to achieve the effect of focal delivery, it will be understood that in certain circumstances the effect of focal delivery can also be achieved by delivering energy to more than one electrode. For example, FIG. 21A illustrates an embodiment of an energy delivery body 208 having eight electrodes 212a, 212b, 212c, 212d, 212e, 212f, 212g, 212h disposed around the circumference of an inflatable or expandable member 210. In this embodiment, the electrodes function in pairs. For example, electrodes 212a, 212b are disposed adjacent to each other, thus mimicking the action of a single electrode when energy is delivered to electrodes 212a, 212b simultaneously. Similarly, electrodes 212c, 212d can be paired together to act as a single electrode, as can electrodes 212e / 212f and 212g / 212h. Having pairs of electrodes rather than single electrodes allows for the use of smaller electrodes, which may be beneficial for the expansion and contraction of the expandable member 210 and / or other design features. It will be understood that any number of electrodes may be used, in which case the electrodes function in groups rather than pairs. For example, FIG. 21B illustrates one embodiment of an energy delivery body 208 having nine electrodes 212a, 212b, 212c, 212d, 212e, 212f, 212g, 212h, 212i disposed around the circumference of the inflatable member 210. In this embodiment, the electrodes function in triplets, i.e., 212a / 212b / 212c, 212d / 212e / 212f, and 212g / 212h / 212i. Thus, the electrodes 212a, 212b, 212c are provided adjacent to one another, thus mimicking the action of a single electrode when energy is delivered to the electrodes 212a, 212b, 212c simultaneously. Thus, the electrodes can function in groups of any size, including two, three, four, five, six or more. Similarly, the groupings can be varied throughout the sequence to maximize the therapeutic effect.For example, a grouping such as 212a / 212b / 212c, 212d / 212e / 212f, and 212g / 212h / 212i during one portion of the sequence can be changed to 212b / 212c / 212d, 212e / 212f / 212g, and 212h / 212i / 212a during another portion of the sequence.

[0133]

[0167] Similarly, it will be appreciated that different levels of energy may be delivered to adjacent electrodes. For example, rather than a pair of electrodes receiving energy and acting as a single electrode, a first electrode of the pair may receive a primary PEF and a second electrode of the pair may receive a maintenance PEF. In this instance, the second electrode receiving the maintenance PEF effectively extends the coverage of the first electrode by adding some "compensatory energy" to its boundary. This would improve the radial coverage of the first electrode.

[0134]

[0168] In some embodiments, a drug or therapeutic agent is delivered in combination with the PEF. The delivery of such an agent may precede, overlap, or follow the delivery of the PEF. In some embodiments, such a combination of therapies produces a stronger effect of a given PEF delivery algorithm. In some instances, this is preferable to increasing the delivery of the PEF to enhance the effect. It will be appreciated that in some instances, the enhanced effect of the combination of therapies may not be as great as adding additional PEF, which may be beneficial depending on the choice of therapeutic agent and the desired outcome. In some embodiments, adding a delay allows at least the large pores to remain open long enough to still receive additional therapeutic agent. In some embodiments, a monophasic, weaker (very low voltage), and optionally long duration (1 μs to 10 ms) maintenance PEF is utilized to facilitate electrokinetically driven uptake of adjuvant agents. In this situation, the cell would still maintain some pores open, but the PEF would now be designed to do more: move therapeutic agents around the cell and "push" them into the cell.

[0135]

[0169] A wide variety of therapeutic agents can be used, including chemotherapy drugs, gene therapy targeted to specific tissue types, and immunotherapy (such as CAR-T, which has the added benefit of reducing systemic toxicity (hydrabra), to name a few. When treating cardiac tissue, therapeutic agents can include antiarrhythmic drugs such as amiodarone to "calm down" ectopic lesions. When treating pulmonary tissue, therapeutic agents can include steroids and other anti-inflammatory drugs. When treating tissue of the gastrointestinal tract, therapeutic agents can include steroids and anti-TNF drugs used in patients with inflammatory bowel disease. Such examples are illustrative and not considered limiting.

[0136]

[0170] It will thus be appreciated that dedicated catheter designs (including various sized electrodes, multiple electrodes, therapeutic agent delivery mechanisms, etc.) and separate energy delivery algorithms in various combinations (including interval delivery, maintenance PEF, unipolar / bipolar coordination, etc.) can have many desired effects on effective contact area, including localization and depth. This serves as a powerful way to fine-tune the circumferential and depth of effect of the therapeutic energy delivery catheter 202 at a given generator capacity and PEF setting. This is also achieved without lengthening treatment time, increasing the risk of muscle contraction, increasing collateral damage, or increasing the risk of inducing cardiac arrhythmia during the procedure. In many instances, the desired combination of these techniques allows for faster treatment time, reduced muscle contraction, less collateral damage, and / or reduced risk of inducing cardiac arrhythmia.

[0137]

[0171] It will be understood that the catheter designs described herein are examples and are not intended to limit the scope of the present disclosure. Additional designs are provided to further illustrate exemplary embodiments. For example, in some embodiments, the energy delivery body 208 of the therapeutic energy delivery catheter 202 is designed for monopolar delivery, and the electrode 212 is comprised of multiple wires or ribbons 220 that are constrained by a proximal end constraint 222 and a distal end constraint 224 to form a helical shaped basket as illustrated in FIG. 22. Because the energy delivery body 208 is configured for monopolar energy delivery, the basket acts as a single electrode. Portions of the energy delivery body 208 are insulated to reduce the size and profile of the electrode 212 for focal delivery. FIG. 22 illustrates an insulating material 300 that covers a portion of the energy delivery body 208 (shown in shaded areas), leaving another portion exposed that is considered the electrode 212. Such insulation can be achieved by a variety of methods. For example, insulation can be achieved by either coating the spiral-shaped basket with an insulating material 300, such as silicone, and removing the insulating material 300 in the desired areas to expose the wire 220 in the shape of the electrode 212, or by masking the desired areas of the wire 220 before coating with the insulating material 300, and then removing the masking to expose the wire 220 in the shape of the electrode 212. Coating can be achieved by a wide variety of methods, such as dipping, spraying, or vapor deposition, to name a few. Alternatively, insulation could be achieved by masking a portion of the body 208, such as the spiral-shaped basket, as the energy delivery body 208 expands. This can be achieved by positioning the energy delivery body 208 within a balloon or other suitable masking material, with one or more portions of the material removed, such as creating one or more windows. The expansion of the energy delivery body 208 causes the body 208 to press against the material, optionally expanding the material. The portion of the energy delivery body 208 exposed through the window or windows will be capable of delivering energy, while the covered portion will be insulated.This would avoid coatings on the wires or braids, which depends on the distance between the individual braided wires to be movable.

[0138]

[0172] In other embodiments, the wires 220 or portions of the wires 220 are insulated before braiding into the helical basket. Portions of the insulating material 300 can then be removed after braiding to create the electrodes 212. In some embodiments, if some or all of the wires 220 of the energy delivery body 208 are capable of being activated independently, multiple electrodes may be created around or along the energy delivery body 208 in a similar manner. This is accomplished by strategically removing or masking the insulating material 300 to expose the wires 220 that are capable of being activated independently. For example, FIG. 23 illustrates the insulating material 300 covering a portion of the energy delivery body 208 (shown in cross-hatched form), leaving two portions exposed, creating the first and second electrodes 212a and 212b. These electrodes 212a, 212b can be activated independently due to the structure and orientation of the wires 220.

[0139]

[0173] It will be appreciated that there are implications to delivering a pulsed electric field to target a lumen or tissue that contains or is adjacent to a conductive medium, such as blood. If the electrodes are not properly insulated to force the pulse delivery into the tissue wall, thereby exposing the conductive medium to the pulse, some of the current will flow through the conductive medium rather than the targeted tissue wall. While this likely will not pose a risk of adverse events due to the low cumulative energy delivered with pulsed electric field therapy, it may dilute or weaken the electric field distribution, thereby reducing the electric field strength penetration depth into the tissue. This is an effect similar to the previously mentioned dependence of electric field strength on the electrode contact surface area, whereby the blood acts as a semi-conductive virtual electrode. Thus, some embodiments of electrode designs and energy delivery protocols are designed to overcome this effect, such as by appropriately fine-tuning the parameters of the pulse or designing an electrode device that can limit the amount of pulse exposure to the conductive medium. It will be appreciated that while a thin layer of conductive mucus lines the airways and other similar potential luminal targets, the volume available for attenuation of the electric field strength is often less, thus reducing the need to overcome this effect in these target indications. However, this effect becomes more significant in vascular targets and serves as one of the additional challenges to reach transmural circumferential lesions. It will be appreciated that in some embodiments, the energy delivery body 208 is mechanically expandable itself, and in other embodiments, the energy delivery body 208 is expandable using an expandable member 210. When an expandable member 210 is utilized, the expandable member 210 itself can act as an insulator. For example, in FIG. 24, the electrode 212 includes a ring 310. Energy delivered through the ring 310 is focused and restricted to the area of ​​the ring 310 by the expandable member 210 expanding through and around the ring 310 as shown. In this embodiment, the diameter of the expandable member 210 is restricted by the ring 310 within the area of ​​the ring 310 .However, the portion of the expandable member 210 that extends beyond the end of the ring 310 is allowed to expand further while slightly compressing the surrounding tissue of the body cavity L. This creates a complete or substantially complete energy blockage, limiting energy delivery to the area of ​​the ring 310. It will be appreciated that such a design may be particularly useful in environments having a conductive medium, such as blood, where energy is directed to the tissue without being delivered to the blood. It will also be appreciated that expansion of an expandable member within an energy delivery body having a basket shape, as illustrated in Figures 22 and 23, may also make it difficult to deliver energy to the blood in the vessel lumen.

[0140]

[0174] FIG. 25 provides a similar embodiment in which the expandable member 210 acts as an insulator. In this embodiment, the energy delivery body 208 includes a plurality of wires, or ribbons 220, that form a disk-like, helical-shaped basket. In this embodiment, the energy delivery body 208 is self-expanding. The expandable members 210 are provided on both sides of the energy delivery body 208. When expanded against the body cavity L, the expandable members 210 create a complete blockage of energy, limiting energy delivery to the area of ​​the energy delivery body 208. It will be appreciated that in some embodiments, the energy delivery body 208 is expandable by an internal expansion member rather than self-expanding. Optionally, the internal expansion member may be expandable in unison with the expandable members 210 on both sides of the energy delivery body 208, such as by interconnected inflation lumens.

[0141]

[0175] It will be appreciated that a wide variety of catheter designs having insulating regions may additionally provide a reduction in flow through a body lumen. When utilized in a blood vessel, blood flow is reduced, which may be beneficial in some procedures.

[0142]

[0176] It will be appreciated that many of the catheter designs and algorithms described herein are not limited to biphasic PEF delivery but may be utilized with the delivery of a wide variety of types of energy, including, but not limited to, electrochemotherapy, nanosecond pulsed electric fields, irreversible electroporation, electrochemical therapy, and electrogene therapy.

[0143]

[0177] While embodiments of the present disclosure 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 scope of the present disclosure. It should be understood that various alternatives to the embodiments described herein may be used in implementing the systems and methods of the present disclosure.

Claims

1. A system for providing localized treatment to a target tissue within a lumen of a patient, comprising: a plurality of independently energizable electrodes positionable within the lumen adjacent the target tissue; a generator comprising at least one energy delivery algorithm configured to provide pulsed electric field energy having a waveform that destabilizes both cells and cell organelle membranes of the target tissue by using bipolar cancellation having a frequency reflecting nanosecond to microsecond pulse durations, the at least one energy delivery algorithm delivering energy to each of the plurality of independently energizable electrodes in a repeating pattern to at least some of the plurality of independently energizable electrodes resulting in the eventual death of the cells having destabilized cell and organelle membranes; A system comprising:

2. The system of claim 1, further comprising a dispersive electrode positionable on the patient in a position that enables at least one of the independently energizable electrodes to function in a monopolar manner.

3. The system described in claim 1, wherein the frequency reflecting a nanosecond to microsecond pulse duration is in the range of approximately 100 to 600 kHz.

4. The system described in claim 1, wherein the multiple independently energizable electrodes are positioned around the inner circumference of the lumen when positioned near the target tissue.

5. The system of claim 1, wherein the pattern delivers the pulsed electric field energy to the multiple independently energizable electrodes in an overlapping pattern.

6. The system described in claim 5, wherein the pulsed electric field energy is composed of packets, each packet being spaced apart by a rest period such that the packets are delivered to the multiple independently energizable electrodes in the pattern.

7. The system described in claim 6, wherein the packets are spaced to increase and / or maximize death of said cells having destabilized cell and organelle membranes.

8. The system of claim 6, wherein at least one of the packets has a reduced strength compared to another of the packets.

9. The system of claim 8, wherein at least one of the packets having the reduced intensity comprises a plurality of maintenance pulses arranged in a regular pattern.

10. The system of claim 8, wherein at least one of the packets having the reduced intensity comprises a plurality of maintenance pulses arranged in an irregular pattern.

11. The system of claim 8, wherein at least one of the packets having the reduced intensity comprises a plurality of maintenance pulses having the same intensity as one another.

12. The system of claim 8, wherein at least one of the packets having the reduced intensity comprises a plurality of maintenance pulses, at least some of the plurality of maintenance pulses having different intensities compared to one another.

13. The system of claim 8, wherein the reduced intensity comprises a higher frequency, a lower voltage, and / or fewer cycles compared to others of the packets.

14. The system of claim 1, wherein the algorithm is configured to simultaneously deliver energy to at least two of the plurality of independently energizable electrodes, whereby the at least two of the plurality of independently energizable electrodes act as a single electrode.

15. The system of claim 14, wherein the algorithm is configured to simultaneously deliver energy to multiple different groupings of the multiple independently energizable electrodes, whereby each of the multiple different groupings acts as a single electrode.

Images