Devices, systems and methods for pulsed electric field treatment of tissue

Abstract

Described herein are devices, systems, and methods for applying pulsed or modulated electric fields to tissue. In some variations, a method of treatment may include advancing a pulsed electric field device into a body cavity of a patient. The pulsed electric field device may include an elongate body and an expandable member coupled to the elongate body. The expandable member may include an electrode array. A pulse waveform may be delivered to the electrode array to generate a pulsed or modulated electric field to treat tissue.

Description

[Technical Field]

[0001] The devices, systems, and methods herein relate to applying pulsed electric fields to tissue to treat chronic diseases, including, but not limited to, diabetes.

[0002] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 177,290, filed April 20, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Diabetes is a widespread condition affecting millions of people worldwide. In the United States alone, it is estimated that over 20 million people have the condition. Diabetes accounts for hundreds of billions of dollars annually in direct and indirect medical costs. Depending on the type (e.g., type 1, type 2), diabetes can be associated with one or more symptoms such as fatigue, blurred vision, and unexplained weight loss, and can be further associated with one or more complications such as hypoglycemia, hyperglycemia, ketoacidosis, neuropathy, and nephropathy.

[0004] Duodenal resurfacing has been proposed as a treatment for chronic diseases such as obesity and diabetes. For example, removing a large proportion of mucosal cells from the portion of the large intestine closest to the stomach may regenerate a rejuvenated mucosal layer, thereby restoring healthy (non-diabetic) signaling. Conventional treatments that apply thermal energy to the duodenum risk excessive heating and therefore damage to more layers of the duodenum (e.g., the muscularis fascia) and / or require compensation for this excessive heating. Conversely, conventional solutions may result in incomplete and / or uneven treatment. Therefore, additional systems, devices, and methods for treating duodenal tissue may be desirable. Summary of the Invention [Means for solving the problem]

[0005] Described herein are devices, systems, and methods for applying pulsed or modulated electric fields to tissue. These systems, devices, and methods can treat a patient's duodenal tissue, for example, to treat diabetes. In some variations, a method for treating diabetes can include advancing a pulsed electric field device into the patient's duodenum, the pulsed electric field device comprising an elongate body and an expandable member coupled to the elongate body. The expandable member can comprise an electrode array. A pulsed waveform can be delivered to the electrode array to generate a pulsed or modulated electric field, thereby treating the duodenum. The pulsed waveform can include a frequency of about 50 kHz to about 950 kHz, a driving voltage of about 400 V to about 600 V at the electrode array, and a current of about 36 A to about 48 A per square centimeter of tissue from the electrode array through the tissue.

[0006] In some variations, the frequency can be about 300 kHz to about 400 kHz. In some variations, the pulsed or modulated electric field in the tissue can be about 2,000 V / cm to about 3,000 V / cm. In some variations, the driving voltage (e.g., the voltage measured at the electrode array) can be about 440 V to about 550 V. In some variations, the pulse waveform can include a set of about 50 pulses in about 8 to about 13 groups, with a delay of about 4 seconds to about 10 seconds between each group.

[0007] In some variations, the method may include measuring the temperature of the tissue using a temperature sensor at about 37° C. to about 45° C. during delivery of the pulse waveform. In some variations, the method may include raising the temperature of the tissue to about 41° C. before delivering the pulse waveform.

[0008] In some variations, the pulsed or modulated electric field can be a therapeutic electric field at a first compressed tissue depth of about 0.25 mm to about 0.75 mm, hi some variations, the pulsed or modulated electric field can be a therapeutic electric field at a first non-compressed tissue depth of about 0.50 mm to about 1.5 mm.

[0009] In some variations, the method may include adjusting the delivery of the pulse waveform based on the measured temperature, hi some variations, adjusting the delivery of the pulse waveform may include preventing the delivery of the pulse waveform.

[0010] In some variations, the method can include aspirating the tissue against the expandable member at a pressure of about 10 mmHg to about 200 mmHg. In some variations, the pulsed or modulated electric field can be a therapeutic electric field that treats the cells but leaves the tissue scaffold intact. In some variations, the pulse waveform can include a pulse width of about 0.5 μs to about 4 μs.

[0011] In some variations, the method may include generating a visual marker on the tissue using a fiducial generator. In some variations, the method may include visualizing the visual marker. In some variations, the treated duodenum may be histologically indistinguishable from native tissue after about 30 days.

[0012] Also described herein is a method of treating diabetes comprising advancing a pulsed electric field device into a patient's stomach, the pulsed electric field device comprising an elongate body and an expandable member coupled to the elongate body, the expandable member comprising an electrode array; and delivering a pulse waveform to the electrode array to generate a pulsed or modulated electric field, thereby treating the stomach, the pulse waveform comprising a frequency of about 50 kHz to about 950 kHz and a driving voltage of about 400 V to about 600 V at the electrode array, generating a current through the tissue from the electrode array of about 36 A to about 48 A per square centimeter of tissue. The present invention provides, for example, the following items. (Item 1) 1. A method of treating diabetes, comprising: advancing a pulsed electric field device into the patient's duodenum, the pulsed electric field device comprising an elongate body and an expandable member coupled to the elongate body, the expandable member comprising an electrode array; delivering a pulse waveform to the electrode array to generate a pulsed or modulated electric field, thereby treating the duodenum, wherein the pulse waveform comprises a frequency of about 50 kHz to about 950 kHz and a driving voltage of about 400 V to about 600 V at the electrode array, generating a current through tissue from the electrode array of about 36 A to about 48 A per square centimeter of tissue. (Item 2) Item 2. The method according to item 1, wherein the frequency is about 300 kHz to about 400 kHz. (Item 3) Item 2. The method according to item 1, wherein the pulsed or modulated electric field in the tissue is about 2,000 V / cm to about 3,000 V / cm. (Item 4) Item 2. The method according to item 1, wherein the driving voltage is about 440V to about 550V. (Item 5) Item 10. The method of item 1, wherein the pulse waveform comprises a set of about 50 pulses in about 8 to about 13 groups with a delay of about 4 seconds to about 10 seconds between each group. (Item 6) 2. The method of claim 1, further comprising measuring the temperature of the tissue using a temperature sensor during delivery of the pulse waveform, wherein the measured temperature is between about 37°C and about 45°C. (Item 7) 10. The method of claim 1, further comprising increasing the temperature of the tissue to about 41° C. prior to delivering the pulse waveform. (Item 8) Item 10. The method of claim 1, wherein the pulsed or modulated electric field is a therapeutic electric field at a compressed tissue depth of about 0.25 mm to about 0.75 mm. (Item 9) Item 10. The method of claim 1, wherein the pulsed or modulated electric field is a therapeutic electric field at a non-compressed tissue depth of about 0.50 mm to about 1.5 mm. (Item 10) measuring the temperature of the tissue using a temperature sensor; adjusting the delivery of the pulse waveform based on the measured temperature; Item 1, the method further comprising: (Item 11) 11. The method of claim 10, wherein modulating delivery of the pulse waveform comprises inhibiting delivery of the pulse waveform. (Item 12) Item 10. The method of claim 1, further comprising aspirating the tissue into the expandable member at a pressure of about 10 mmHg to about 200 mmHg. (Item 13) 2. The method of claim 1, wherein the pulsed or modulated electric field is a therapeutic electric field that treats cells but leaves the tissue scaffold intact. (Item 14) Item 10. The method according to item 1, wherein the pulse waveform comprises a pulse width of about 0.5 μs to about 4 μs. (Item 15) Item 10. The method of item 1, further comprising generating a visual marker on the tissue using a reference generator. (Item 16) Item 16. The method of item 15, further comprising visualizing the visual marker. (Item 17) 2. The method of claim 1, wherein the treated duodenum is histologically indistinguishable from native tissue after about 30 days. (Item 18) 10. The method of claim 1, wherein the pulse waveforms include a first pulse waveform, and wherein at least a second pulse waveform is delivered to the electrode array to generate a second pulsed or modulated electric field, thereby treating at least a portion of the duodenum that was previously treated. (Item 19) 1. A method of treating diabetes, comprising: advancing a pulsed electric field device into the patient's stomach, the pulsed electric field device comprising an elongate body and an expandable member coupled to the elongate body, the expandable member comprising an electrode array; delivering a pulse waveform to the electrode array to generate a pulsed or modulated electric field, thereby treating the stomach, the pulse waveform comprising a frequency of about 50 kHz to about 950 kHz and a driving voltage of about 400 V to about 600 V at the electrode array, generating a current through tissue from the electrode array of about 36 A to about 48 A per square centimeter of tissue. (Item 20) 20. The method of claim 19, wherein the pulse waveforms include a first pulse waveform, and wherein at least a second pulse waveform is delivered to the electrode array to generate a second pulsed or modulated electric field, thereby treating at least a portion of the stomach that was previously treated. [Brief explanation of the drawings]

[0013] The patent or application file contains at least one drawing executed in color. Copies of this patent and patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0014] [Figure 1A] 1 is a cross-sectional view of the digestive tract showing various anatomical structures.

[0015] [Figure 1B] FIG. 1 is a cross-sectional view of the duodenum.

[0016] [Figure 2A] 1 is a cross-sectional schematic view of a portion of the small intestine. [Figure 2B] 1 is a cross-sectional schematic view of a portion of the small intestine. [Figure 2C] 1 is a cross-sectional schematic view of a portion of the small intestine.

[0017] [Figure 3A] This is a cross-sectional image of the duodenum. [Figure 3B] Detailed cross-sectional images of various duodenal tissues. [Figure 3C] Detailed cross-sectional images of various duodenal tissues. [Figure 3D] Detailed cross-sectional images of various duodenal tissues. [Figure 3E] Detailed cross-sectional images of various duodenal tissues. [Figure 3F] Detailed cross-sectional images of various duodenal tissues.

[0018] [Figure 4] FIG. 10 is a block diagram of an illustrative variation of a pulsed electric field system.

[0019] [Figure 5A] 10A-10C are perspective views of illustrative variations of pulsed electric field devices in a compressed configuration. [Figure 5B] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices in expanded configurations. [Figure 5C] FIG. 5B is a detailed perspective view of the pulsed electric field device shown in FIG. 5A. [Figure 5D] FIG. 5C is a detailed perspective view of the pulsed electric field device shown in FIG. 5B.

[0020] [Figure 6A] 10A-10C are perspective views of illustrative variations of expandable members in a rolled configuration. [Figure 6B] 10A-10C are perspective views of illustrative variations of expandable members in deployed configurations.

[0021] [Figure 7A] 10A-10C are cross-sectional perspective views of illustrative variations of expandable members in deployed configurations. [Figure 7B] FIG. 7B is a detailed cross-sectional perspective view of the expandable member shown in FIG. 7A.

[0022] [Figure 8A] 10A-10C are perspective views of illustrative variations of pulsed electric field devices in a wound configuration. [Figure 8B] 8B is a perspective view of an illustrative variation of the visualization device and pulsed electric field device shown in FIG. 8A in a partially deployed configuration. [Figure 8C] FIG. 8C is a perspective view of the visualization device and pulsed electric field device shown in FIG. 8B in an expanded configuration.

[0023] [Figure 9A] 10A-10C are perspective views of illustrative variations of pulsed electric field devices in a wound configuration. [Figure 9B] 9B is a perspective view of an illustrative variation of the visualization device and pulsed electric field device shown in FIG. 9A in an expanded configuration.

[0024] [Figure 10A] 10A-10C are perspective views of illustrative variations of pulsed electric field devices in a wound configuration. [Figure 10B] FIG. 10B is a detailed perspective view of the pulsed electric field device shown in FIG. 10A. [Figure 10C] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices in deployed configurations. [Figure 10D] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices in deployed configurations. [Figure 10E] FIG. 10E is a detailed perspective view of the pulsed electric field device shown in FIG. 10D.

[0025] [Figure 11] 10 is a perspective view of an illustrative variation of a visualization device and pulsed electric field device in a partially deployed configuration.

[0026] [Figure 12A] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices. [Figure 12B] FIG. 12B is a cross-sectional side view of the pulsed electric field device shown in FIG. 12A. [Figure 12C] FIG. 12B is a detailed cutaway perspective view of the pulsed electric field device shown in FIG. 12A.

[0027] [Figure 13A] 10A-10C are perspective views of illustrative variations of expandable members. [Figure 13B] FIG. 13B is a plan view of the expandable member shown in FIG. 13A in a deployed configuration. [Figure 13C] 10A-10C are cross-sectional views of illustrative variations of expandable members with winding configurations and gears.

[0028] [Figure 14A] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device. [Figure 14B] FIG. 14B is a cutaway perspective view of the pulsed electric field device and visualization device shown in FIG. 14A.

[0029] [Figure 15A] 1 is a cutaway perspective view of an illustrative variation of a pulsed electric field device and visualization device. FIG. [Figure 15B] 1 is a cutaway perspective view of an illustrative variation of a pulsed electric field device and visualization device. FIG.

[0030] [Figure 16] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0031] [Figure 17] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0032] [Figure 18] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0033] [Figure 19] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0034] [Figure 20] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0035] [Figure 21] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0036] [Figure 22] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0037] [Figure 23] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0038] [Figure 24] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0039] [Figure 25] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0040] [Figure 26] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0041] [Figure 27] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device.

[0042] [Figure 28A] 10A-10C are perspective views of illustrative variations of the expandable members of the pulsed electric field device and visualization device. [Figure 28B] FIG. 28B is a perspective view of the pulsed electric field device and visualization device shown in FIG. 28A. [Figure 28C] FIG. 28B is a perspective view of the pulsed electric field device and visualization device shown in FIG. 28A. [Figure 28D] FIG. 28B is a perspective view of the pulsed electric field device and visualization device shown in FIG. 28A. [Figure 28E] FIG. 28B is a perspective view of the pulsed electric field device and visualization device shown in FIG. 28A.

[0043] [Figure 29A] 1 is a perspective view of an illustrative variation of a pulsed electric field device and visualization device. [Figure 29B] FIG. 29B is a perspective view of the pulsed electric field device removed from the visualization device shown in FIG. 29A.

[0044] [Figure 30A] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices. [Figure 30B] FIG. 30B is a perspective view of the pulsed electric field device shown in FIG. 30A within a tissue lumen.

[0045] [Figure 31] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices.

[0046] [Figure 32] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices. [Figure 33A] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices. [Figure 33B] FIG. 33B is a perspective view of the pulsed electric field device shown in FIG. 33A.

[0047] [Figure 34A] 10A and 10B are perspective views of illustrative variations of electrode arrays. [Figure 34B] FIG. 34B is a cross-sectional side view of the electrode array shown in FIG. 34A. [Figure 34C] 10A and 10B are perspective views of illustrative variations of electrode arrays in deployed configurations.

[0048] [Figure 35] 10 is a plot of electric field strength for an illustrative variation of an electrode array.

[0049] [Figure 36] 1 is a plot of the electric field strength of a conventional electrode array.

[0050] [Figure 37] 10A-10C are schematic cross-sectional views of illustrative variations of electrode arrays and embossing dies.

[0051] [Figure 38] 10A-10C are schematic cross-sectional views of illustrative variations of electrode arrays with tissue contacting layers.

[0052] [Figure 39] 10A-10C are schematic cross-sectional views of illustrative variations of electrode arrays with tissue contacting layers.

[0053] [Figure 40] 10A-10C are schematic cross-sectional side views of illustrative variations of electrode arrays.

[0054] [Figure 41A]1 is an electric field strength plot of an illustrative electrode array configuration. [Figure 41B] 1 is an electric field strength plot of an illustrative electrode array configuration. [Figure 41C] 1 is an electric field strength plot of an illustrative electrode array configuration. [Figure 41D] 1 is an electric field strength plot of an illustrative electrode array configuration.

[0055] [Figure 42] 10 is a plot of electric field strength for an illustrative variation of an electrode array.

[0056] [Figure 43] 10A and 10B are perspective views of illustrative variations of expandable members comprising electrode arrays.

[0057] [Figure 44] 10A and 10B are perspective views of illustrative variations of expandable members comprising electrode arrays.

[0058] [Figure 45A] 10A-10C are schematic diagrams of illustrative variations of electrode arrays. [Figure 45B] 10A-10C are schematic diagrams of illustrative variations of electrode arrays. [Figure 45C] 10A-10C are schematic diagrams of illustrative variations of electrode arrays. [Figure 45D] 10A-10C are plan views of electric field strength plots of illustrative variations of electrode arrays. [Figure 45E] FIG. 45D is a cross-sectional view of the electric field intensity plot of the electrode array depicted in FIG. 45D.

[0059] [Figure 46A] 10A and 10B are schematic perspective views of illustrative variations of the coordinate system of the electrode array; [Figure 46B] 46B is an electric field intensity plot corresponding to the electrode array shown in FIG. 46A.

[0060] [Figure 47A] 10A-10C are schematic plan views of illustrative variations of polarity configurations of electrode arrays. [Figure 47B] 47B is an electric field intensity plot corresponding to the electrode array shown in FIG. 47A.

[0061] [Figure 48] 10A-10C are schematic plan views of illustrative variations of electrode arrays.

[0062] [Figure 49] 10A-10C are perspective views of illustrative variations of electrode arrays of pulsed electric field devices.

[0063] [Figure 50] 10A-10C are perspective views of illustrative variations of electrode arrays of pulsed electric field devices.

[0064] [Figure 51A] 10A-10C are schematic circuit diagrams of illustrative variations of the electrode array, temperature sensor array, and reference generator; [Figure 51B] 10A-10C are schematic circuit diagrams of illustrative variations of the electrode array, temperature sensor array, and reference generator; [Figure 51C] 1 is an image of a visual marker generated by a reference generator. [Figure 51D] 10A-10C are schematic circuit diagrams of illustrative variations of the electrode array, temperature sensor array, and reference generator;

[0065] [Figure 52A] 10A-10C are schematic circuit diagrams of illustrative variations of the electrode array, temperature sensor array, and reference generator; [Figure 52B] FIG. 52B is a detailed diagram of the schematic circuit diagram of the electrode array, temperature sensor, and reference generator shown in FIG. 52A.

[0066] [Figure 53] FIG. 10 is a schematic circuit block diagram of an illustrative variation of a signal generator.

[0067] [Figure 54] 1 is a flowchart illustrating an illustrative variation of a method for treating diabetes.

[0068] [Figure 55A] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Figure 55B] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Figure 55C] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Figure 55D] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Figure 55E] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Figure 55F] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes.

[0069] [Figure 56A] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 56B] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 56C] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 56D] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 56E] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 56F] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 56G] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 56H] FIG. 10 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device.

[0070] [Figure 57] 10 is an image of an illustrative variation of thermal marking of tissue.

[0071] [Figure 58A] 10 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Figure 58B] 10 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Figure 58C] 10 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Figure 58D] 10 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Figure 58E] 10 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device.

[0072] [Figure 59] 10 is an image of an illustrative variation of an electrode array.

[0073] [Figure 60] 1 is an image of an illustrative variation of a pulsed electric field device.

[0074] [Figure 61A] 10A-10C are perspective views of images of illustrative variations of pulsed electric field devices and visualization devices. [Figure 61B] 61B is a detailed image of the pulsed electric field device and visualization device shown in FIG. 61A.

[0075] [Figure 62A] 1 is an image of an illustrative variation of a pulsed electric field device. [Figure 62B] 10 is an image of an illustrative variation of a pulsed electric field device comprising a balloon. [Figure 62C] FIG. 62B is a perspective view of the pulsed electric field device shown in FIG. 62A.

[0076] [Figure 63A] 10 is an image of an illustrative variation of a pulsed electric field device in a wound configuration. [Figure 63B] 1 is an image of an illustrative variation of a pulsed electric field device in a deployed configuration. [Figure 63C] FIG. 63C is a perspective view of the pulsed electric field device shown in FIG. 63B.

[0077] [Figure 64A] 10 is an image of an illustrative variation of a pulsed electric field device and visualization device. [Figure 64B] 10 is an image of an illustrative variation of a pulsed electric field device in a deployed configuration within a tissue lumen.

[0078] [Figure 65] 1 is an image of an illustrative variation of a pulsed electric field device.

[0079] [Figure 66] FIG. 10 is a schematic circuit diagram of an illustrative variation of an electrode array.

[0080] [Figure 67] 10 is an image of an illustrative variation of an electrode array.

[0081] [Figure 68] 10 is an image of an illustrative variation of an electrode array.

[0082] [Figure 69A] FIG. 10 is a plan view of an illustrative variation of an electrode array. [Figure 69B] FIG. 69B is a perspective view of the electrode array shown in FIG. 69A. [Figure 69C] FIG. 69B is a perspective view of the electrode array shown in FIG. 69A. [Figure 69D] FIG. 69B is a perspective cross-sectional view of the electrode array shown in FIG. 69A.

[0083] [Figure 70]10 is an illustrative variation of a voltage plot comparing the voltage output of pulsed electric field treatment with the voltage output of radiofrequency treatment over time.

[0084] [Figure 71A] 1 is a cross-sectional image of a pulsed electric field device in an expanded configuration expanding the duodenum. [Figure 71B] 1 is a cross-sectional image of an undilated duodenum. [Figure 71C] 1 is a cross-sectional image of an undilated duodenum. [Figure 71D] FIG. 71C is a detailed cross-sectional image of the undilated duodenum. [Figure 71E] This is a cross-sectional image of a dilated duodenum. [Figure 71F] FIG. 71E depicts a detailed cross-sectional image of a dilated duodenum.

[0085] [Figure 72A] This is a detailed cross-sectional image of duodenal tissue approximately one day after treatment. [Figure 72B] This is a detailed cross-sectional image of duodenal tissue approximately one day after treatment.

[0086] [Figure 73] This is a detailed cross-sectional image of duodenal tissue approximately three days after treatment.

[0087] [Figure 74A] Detailed cross-sectional images of duodenal tissue approximately 7 days after treatment. [Figure 74B] Detailed cross-sectional images of duodenal tissue approximately 7 days after treatment.

[0088] [Figure 75] This is a detailed cross-sectional image of duodenal tissue approximately 14 days after treatment.

[0089] [Figure 76] 10A and 10B are perspective views of illustrative variations of electrode arrays in deployed configurations.

[0090] [Figure 77] 10A and 10B are perspective views of illustrative variations of pulsed electric field devices in expanded configurations.

[0091] [Figure 78A] 10 is an image of an illustrative variation of a pulsed electric field device in a contracted or compressed configuration. [Figure 78B] FIG. 78C is a detailed image of the deployed or expanded electrode array of the pulsed electric field device depicted in FIG. 78B.

[0092] [Figure 79A] 10 is an image of an illustrative variation of a pulsed electric field device in a compressed configuration. [Figure 79B] 10 is an image of an illustrative variation of a pulsed electric field device in an expanded configuration. [Figure 79C] FIG. 79C is a detailed image of the deployed electrode array of the pulsed electric field device depicted in FIGS. 79A and 79B.

[0093] [Figure 80A] 10 is a plot of electric field strength for an illustrative variation of an electrode array. [Figure 80B] 10 is a plot of electric field strength for an illustrative variation of an electrode array.

[0094] [Figure 81A] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Figure 81B] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Figure 81C] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes.

[0095] [Figure 82A] 10 is an image of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 82B] 10 is an image of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 82C]10 is an image of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Figure 82D] 10 is an image of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device.

[0096] [Figure 83A] 10 is a plot of tissue temperature, voltage, and current over time for an illustrative variation of a method of treating tissue. [Figure 83B] 10 is a plot of tissue temperature, voltage, and current over time for an illustrative variation of a method of treating tissue.

[0097] [Figure 84] FIG. 1 is a cross-sectional perspective view of a set of twisted pair lead wires.

[0098] [Figure 85] 10A-10C are perspective views of illustrative variations of electrode arrays of pulsed electric field devices.

[0099] [Figure 86] 10 is a plot of temperature over time for an illustrative variation of a method for treating tissue.

[0100] [Figure 87] 10 is a plot of impedance and temperature distributions for an illustrative variation of a method for treating tissue. DETAILED DESCRIPTION OF THE INVENTION

[0101] Described herein are devices, systems, and methods for treating tissue to address chronic diseases. For example, the devices, systems, and methods may include those for treating diabetes by treating a patient's duodenal tissue. In some variations, treating the duodenum may include treating at least about 30% of the mucosal lining of the duodenum with minimal trauma, damage, or scarring to the submucosa, vasculature, and muscle. For example, the mucosal layer of the duodenum may be treated using a pulsed electric field (PEF) system.

[0102] It may be useful to briefly identify and describe relevant small intestinal anatomical structures. Figure 1A is a cross-sectional view of the gastrointestinal tract of a patient (100). A visualization device (150) (e.g., an endoscope) is shown advanced through the esophagus (110) into the stomach (120). The stomach (120) connects to the duodenum (130). Figure 1B is a detailed cross-sectional view of the duodenum (130), which surrounds the upper portion of the pancreas (140). The duodenum is a "C"-shaped, hollow, jointed tubular structure, typically about 20 cm to about 35 cm in length and about 20 mm to about 45 mm in diameter. Figures 2A-2C are cross-sectional schematic diagrams of the layers of the small intestine (200), including the mucosa (210), submucosa (220), muscularis externa (230), and serosa (240). Treatment of the duodenum may include resurfacing the mucosa (210) as described herein. Access to the duodenum may be achieved by advancing the systems and devices described herein through one or more of the esophagus, stomach, pylorus, lower esophageal junction, cranio-pharyngeal junction, and several sharp, small radius bends throughout the length of the digestive tract.

[0103] A brief discussion of electroporation and the role of ohmic heating may be further useful. Electroporation is the application of an electric field to living cells, causing ions of opposite charge to accumulate on opposite sides of the cell membrane. Generally, electroporation requires a potential difference across the cell membrane on the order of about 0.5 to about 1 volt, with an accumulation duration on the order of about 1 to about 2 milliseconds. Electroporation inevitably generates ohmic heating, but there is considerable confusion in the literature regarding this, including a significant number of references that erroneously claim the existence of non-thermal electroporation. For example, the ionic conductivity σ ic An external uniform electric field of magnitude E applied to the intracellular fluid of ic generates a thermal power density E 2 σ ic The medium dissipates heat. p and density p, the resulting rate of temperature rise is given by equation (1).

number

[0104] For example, a 1 kV / cm electric field acting on tissue with a conductivity of approximately 0.3 S / m, a heat capacity of approximately 3.7 Joules / (gm°C), and a density of approximately 1 gm / cc will heat the tissue at a rate of approximately 800°C / sec. Note that because tissue is an ionic conductor, there is no electric field within the tissue when no current flows through it. The initial time after an external electric field is suddenly applied to a membrane to accumulate charge can be on the order of approximately 30 nanoseconds, suggesting that the average temperature rise during the initial membrane charging phase can be tens of microdegrees. When an external electric field is applied and ionic currents charge the membrane surface, disrupting the electric field in the lipid bilayer, heating may be confined to the membrane on a timescale of less than a microsecond, although leakage currents may still flow. For example, if the conductivity of the lipid layer is σ ii Using a ρ = 0.002 S / m, a potential of 1 volt across an 8 nm layer can be locally heated at an instantaneous rate of about 8 °C / microsecond. This heating rate decreases with time from the application of the external electric field, as heat can further diffuse out of the film.

[0105] When ionic currents are confined to pores in the cell membrane, current crowding results in correspondingly high heating rates within the pores. Because the pore area can be 1% or less of the membrane area, the current density within the pores can be 100 times higher than in the bulk tissue. This increases the heating rate by a factor of 10,000, leading to local heating rates on the order of 10 °C / microsecond.

[0106] Local temperature increase is a mechanism that contributes to the transition from electroporation to irreversible electroporation. Thermal diffusion reduces the local temperature change. For example, if the thermal diffusivity of tissue, κ, is 0.13 mmHg, 2 / sec, the thermal diffusion length at 10 μsec is

number

[0107] Bulk tissue remains a good ionic conductor during the electroporation process and heats at a rate on the order of about 800°C / sec while the external electric field is applied. When the external electric field is removed, cell membranes can discharge in the order of about 30 nanoseconds, necessitating the continued application of an external voltage and current to induce pore formation and growth. Because the maximum allowable temperature rise in bulk tissue can be on the order of about 13°C, the maximum duration for which the external electric field can be applied, even in a bipolar configuration, can be in the range on the order of about 10 milliseconds. Because this heat is generated to a treatment depth of about several millimeters within the tissue, the time required to cool the tissue by conduction can be on the order of about 70 seconds (e.g., 3 mm). 2 ) / (0.13mm 2 / sec). Blood convection may dominate the observed cooling time, which is on the order of about 10 seconds. Electroporation may also increase with bulk tissue temperature due to a phase transition of lipid cell membranes, which is 41°C for some cells on the duodenum. The phase transition temperature may be the temperature required to induce a change in the physical state of lipids from an ordered gel phase to a liquid crystalline phase.

[0108] Electroporation parameters can be varied to produce different effects on the tissue. Figure 3A is a cross-sectional image of an untreated duodenum (300A), including the muscularis (310A) and villi (320A). Figure 3D is an image of an illustrative variation of duodenal tissue in its original, untreated state, including the muscularis (310D), submucosa (330D), villous crypts (340D), and villi (320D). As described in more detail herein, Figure 3E depicts duodenal tissue that has undergone a majority heat treatment, and Figure 3F depicts duodenal tissue that has undergone a majority pulsed or modulated electric field treatment. The treatments described herein (e.g., Figure 3F), which primarily treat the mucosal layer while preserving tissue architecture that appears similar to native tissue, reduce trauma to the tissue compared to the heat treatment shown in Figure 3E.

[0109] Application of pulsed electric fields to duodenal tissue results in non-thermal tissue changes. For example, Figure 3D is an image of normal, untreated (e.g., native) porcine duodenal mucosa. Figure 3F is an image of the initial mucosal histological appearance, with progressive epithelial loss and preservation of the lamina propria structure / architecture. For example, Figure 3F depicts the histological progression with complete native epithelial loss and early crypt regeneration within the preserved lamina propria. The glandular layers across Figures 3A-3D and 3F clearly demonstrate the structural preservation of the lamina propria after treatment. For example, histopathology confirms that the PEF treatment described herein, applied at a depth of approximately 1 mm in duodenal tissue, treats the mucosal layer without pulsed electric field energy affecting the lamina propria at the therapeutic level.

[0110] In some variations, pulsed electric field (PEF) treatment can be combined with localized thermal treatment. For example, thermal treatment can be applied to superficial or near-surface tissue, while PEF treatment can be applied to deeper tissue. As described in more detail herein, the depth of tissue treatment received by one or more layers can be adjusted based on one or more of the electrode design, applied voltage, time or duration of energy delivery, frequency of applied energy, and tissue composition. An example of such control is thermal treatment applied to a tissue depth of approximately 0.1 mm and PEF treatment applied to a tissue depth of up to approximately 1 mm. The ratio and depth of thermal treatment relative to PEF treatment can be based on the desired clinical outcome (e.g., efficacy). In some variations, thermal treatment can be applied to a tissue depth of approximately 3 mm, and PEF treatment can be applied to a tissue depth of approximately 5 mm. Thus, in some variations, more thermal treatment than PEF treatment can be applied to the tissue. Depending on the depth and type of tissue, different healing cascades may be optimal. In some variations, up to about 1 mm of the villous mucosa can be heat treated to replace essentially the entire tissue structure, and the submucosa can be PEF treated to preserve the tissue structure and promote rapid healing of that layer. Furthermore, neither heat nor PEF treatment can affect the deeper muscularis propria.

[0111] FIG. 3B shows images of illustrative variations of duodenal tissue subjected to different treatments. Specifically, the tissue (360) was treated with pulsed or modulated electric field energy, and the first mucosal region (362) was additionally exposed to radiofrequency energy. The excised villi in the first mucosal region (362) disrupted cell membranes and destroyed cellular structure, such that these cells are no longer viable or functional. In contrast, the second mucosal region (360) has cells that have undergone cytolysis, in which the cell membranes remain intact but the cells are no longer viable or functional. That is, cytolysis corresponds to functional cell death with intact cellular structure, while ablation represents the loss of both cellular structure and function. The submucosa (370) and muscularis mucosae (380) remain healthy (e.g., viable and fully functional with cellular integrity). In Figure 3B, villi in a first mucosal region (362) are thermally ablated, while cell lysis in a second mucosal region (360) is induced by a pulsed or modulated electric field. A third mucosal region (363), adjacent to the thermal lesion in the first mucosal region (362), is completely untreated and contains viable tissue.

[0112] Figure 3C illustrates a histological slide of duodenum from tissue approximately 24 hours after treatment with heat and pulsed electric fields, showing partial healing of the mucosa down to the crypt layer, with damaged cells. The fourth mucosal region (391) corresponds to the heat / heat-fixed tissue of the villi, including villus-associated enteroendocrine cells. The fourth mucosal region (391) shows structural and cytological preservation, with cellular details characterized by hyperchromatic nuclear and hypereosinophilic cytoplasmic staining. Overall, no interstitial hemorrhage or infiltrating post-treatment-associated inflammatory cells were identified. Sloughing of the heat-fixed tissue, followed by villous structural healing with surface re-epithelialization and crypt cell repopulation, can be expected. The crypt tissue is partially affected by the combined heat and pulsed electric field effects. The tissue healing timeline is expected to be longer than that of pulsed electric field treatment without the heat effect. The submucosa (370) and muscularis mucosae (380) are histologically unaffected. Figure 3E shows an illustrative variation of a porcine duodenal tissue image 24 hours after isolated thermal tissue treatment (i.e., without pulsed electric field exposure) that disrupted the lamina propria, in that the tissue scaffold was burned and destroyed, sloughing off and being removed during healing. This shows histological characteristics of thermal tissue dose consistent with thermal / thermal-induced coagulation necrosis without heat / thermal fixation. In this area, glandular epithelial and neuroendocrine cells (321) show a loss of cytological detail, consistent with cellular "ghost images." Interstitial hemorrhage in the mucosal layer (341) and reactive inflammatory cells are present at the edges of the area. The submucosa (331) and muscularis mucosae (311) also show injury-related changes. This area can be expected to heal similarly to ischemic-type coagulation necrosis, with resorption and remodeling accompanied by mucosal regeneration. The thermal lesion destroyed the lamina propria. The scaffold was burned and destroyed, sloughing off and being removed during healing. The tissue healing time frame in this area needs to be longer than that expected with pulsed electric field treatment.

[0113] Figure 3F shows images of exemplary variations of duodenal tissue treated with pulsed or modulated electric field energy to a controlled depth, including the muscularis, untreated muscularis propria (310), submucosa (330), treated submucosa (332), treated villous crypts (342) with partial cell lysis and maintained tissue scaffolding, and treated villi (322) with detached villi. The treated submucosa (332) also maintains tissue scaffolding. These treated tissues exhibit cells that have undergone cell death, with cell membranes remaining intact but the cells no longer viable and functional. The healing cascade replaces these cells without the infiltration of numerous inflammatory cells, resulting in surface re-epithelialization, structural healing of the villus, and crypt cell repopulation. The muscularis (310) remains healthy (e.g., viable and fully functional with cellular integrity) even without the therapeutic effects of pulsed electric field energy. That is, with pulsed or modulated electric field energy, cell death corresponds to functional cell death with intact cellular structure, while ablation implies loss of both cellular structure and function, as well as an active necroinflammatory response healing cascade.

[0114] In some variations, the target depth of treatment includes the mucosal layer but excludes the muscularis propria. Human tissue data evaluated through histopathology support a target depth of approximately 1 mm for PEF tissue treatment, where the pulsed electric field does not penetrate the muscularis propria at the treatment level. As a result, the mucosa exhibits a healing progression with the initiation of crypt and glandular epithelial regeneration on day 1 (e.g., Figures 72A and 72B), continued epithelial development with surface re-epithelialization on day 3 (e.g., Figure 73), early cobblestone-like blunted villus development on day 7 (e.g., Figures 74A and 74B), and continued villus elongation and narrowing on day 14 (Figure 75). Based on the methods described herein, the healing response can be essentially complete in approximately 30 days. Furthermore, the systems, devices, and methods described herein can provide uniform treatment coverage throughout the circumference and length of the duodenum.

[0115] Some methods for treating diabetes may involve treating the submucosa of the duodenum without treating the muscularis mucosa. Conventional solutions do not consistently treat the submucosa without adversely affecting the muscularis mucosa. Instead, conventional solutions may add complex palliative steps, such as saline injection lifts, to protect the muscularis mucosa. For reference, the mucosal layer is typically about 0.5 mm to about 1 mm thick, the submucosa is typically about 0.5 mm to about 1 mm thick, and the muscularis mucosa is typically about 0.5 mm thick. Inducing injury to the muscularis mucosa can have adverse clinical consequences. Furthermore, the anatomical structure along the circumference of the duodenum is not uniform, complicating efforts to treat only the submucosa and not the muscularis mucosa.

[0116] The methods described herein can selectively alter tissue viability in the duodenum by applying a predetermined pulsed or modulated electric field without losing the integrity of the majority of the treated tissue, and optionally without other treatment of the tissue to mitigate the pulsed or modulated electric field on a portion of the tissue. In contrast, RF-based energy treatments can primarily cause thermally induced cell lysis (e.g., cell death) or ablation, which indiscriminately damages tissue and can disrupt cellular structure, which can be difficult to regulate and therefore adversely affect treatment outcomes. In some variations, the methods described herein can include applying a pulsed or modulated electric field to thermally induce localized necrotic cell death (e.g., local ablation) and cell lysis (e.g., functional cell death) in duodenal tissue directly adjacent to the electrode array within a predetermined depth range of the duodenal tissue (e.g., up to about 1 mm, about 0.5 mm to 0.9 mm), while minimizing physiological effects on tissue greater than the selected depth.

[0117] FIG. 3F is an image of an illustrative variation of duodenal tissue treated with pulsed or modulated electric field energy to a controlled depth. In FIG. 3F, portions of the muscularis (310) and submucosa (330) are untreated (i.e., the energy delivered to the tissue does not affect the tissue), while different portions of the villous crypts (342), villi (322), and submucosa (332) are treated. Thus, treatment applied to the duodenal tissue shown in FIG. 3F results in a more superficial (e.g., closer to the tissue surface) treated submucosa (332) and a deeper, untreated muscularis (310). The treated tissue contains cells that have undergone cell lysis; the tissue scaffold remains intact, but the cells are no longer viable and functional. A gentle healing cascade replaces these cells. The muscularis mucosae (310) adjacent to the treated submucosa (332) remains healthy (eg, viable and fully functional with cellular integrity).

[0118] Pulsed or modulated electric fields near the electrode array generate some thermal heating of the tissue, which can lead to tissue ablation that destroys both cellular structure and function. However, cell lysis in tissue caused by the pulsed or modulated electric fields applied herein is at least 50% pore-induced and less than 50% thermally induced, resulting in the majority of cell death being functional cell death with intact cellular structure. For example, the thermal heating generated by pulsed or modulated electric fields is generally localized to a relatively small radius from each electrode of the electrode array and does not affect deeper layers of tissue, such as the muscularis.

[0119] The systems, devices, and methods described herein deliver energy to provide optimized treatment characteristics for each tissue layer, improving treatment outcomes. Near the tissue surface (e.g., less than about 0.5 mm, about 0.1 mm to about 0.5 mm), thermal heating can cause localized necrotic cell death in the tissue, which may slough off after treatment. At tissue depths of about 0.5 mm to about 1.3 mm (e.g., the duodenal mucosa), thermal heating is limited (e.g., less than about a 13°C increase or a 6°C increase), while pulsed or modulated electric fields can cause cell lysis. For example, the electric field strength at about 1.0 mm can be about 2.5 kV / cm. At tissue depths greater than 1.0 mm, energy delivered to the tissue can cause reversible electroporation with even less thermal heating, leaving deeper tissues substantially untreated. Thus, while still delivering pulsed or modulated electric field energy for mucosal cell lysis, thermal heating can be limited to the superficial tissue layer (e.g., less than about 0.5 mm, about 0.1 mm to about 0.5 mm).

[0120] For example, Figure 3C is an image of an illustrative variation of duodenal tissue that has undergone the methods of treating duodenal tissue described herein, in which the villi (391) are treated by a combination of thermal heating (e.g., greater than 50%) and pore-induced cell death (e.g., less than 50%). A pulsed or modulated electric field applied to the villous crypts and submucosal tissue (370) treated the tissue to a large extent (e.g., greater than 50%) of pore-induced cell death, with a smaller contribution (e.g., less than 50%) from thermal heating. The muscularis (380) is substantially untreated by the pulsed or modulated electric field or other methods. For example, the submucosal tissue in Figure 3C has not received a saline injection. The depth of treatment can be controlled so that certain portions of the mucosal layer, such as the villous crypts, remain untreated as desired. The configurations and shapes of the electrode arrays described herein may enable the tissue treatment characteristics described herein.

[0121] In contrast, conventional solutions that apply other forms of thermal energy (e.g., steam, radiofrequency, laser, heated liquid) to the duodenum thermally ablate through multiple layers of tissue (e.g., inducing greater than 50% heat-induced necrotic cell death and less than 50% pore-induced cell death), thereby disrupting mucosal cellular structure at similar depths and potentially causing harmful thermal damage to the mucosa. In an attempt to mitigate the risk of unintended thermal damage when applying thermal energy to deeper layers of the duodenum (e.g., the muscularis), saline can be injected into a portion of the duodenal tissue (e.g., the submucosa (330)). This additional step further complicates the procedure and is not always sufficient to prevent unwanted thermal tissue damage. The pulsed or modulated electric field-based methods described herein eliminate this additional step and enhance protection against unwanted tissue damage by improving the energy delivery characteristics generated by pulsed electric field devices.

[0122] In some variations, pulsed electric field therapy can be applied while monitoring and / or minimizing tissue temperature rise. For example, a predetermined increase in tissue temperature (e.g., about 1°C, about 2°C, about 3°C) can be followed by a pause in energy delivery (e.g., a predetermined time interval) to allow the tissue to cool. In this manner, the total energy delivered can raise the tissue temperature below a predetermined threshold (e.g., below a safety limit). In some variations, the predetermined threshold can be up to about 3°C, about 6°C, about 10°C, or about 13°C, including all ranges and subvalues ​​therebetween.

[0123] Furthermore, the difficulties encountered with conventional solutions in controlling unwanted thermal tissue damage would steer one of ordinary skill away from using the pulsed or modulated electric field energy levels and methods described herein. In some variations, the tissue power density generated by pulsed or modulated electric fields can be several orders of magnitude higher than the tissue power density generated by radiofrequency ablation. For example, the power density ratio of similar designs for radiofrequency ablation is about 25 V for radiofrequency devices. rms The device is driven by a pulsed electric field of approximately 600V. rmsWhen driven by a PEF pulse, the peak power can be approximately 576. Thus, it is unexpected that the pulsed or modulated electric field methods described herein not only treat tissue, but also do so without excessive thermal tissue damage that would require mitigation procedures. Furthermore, increased power density may require additional insulation and protection for the pulsed electric field device, as well as a signal generator capable of generating such peak power levels. Generally, the duty cycle of PEF treatment can be several orders of magnitude lower than radiofrequency ablation to keep bulk tissue temperature rise below approximately 10°C. For example, radiofrequency ablation energy can generally be delivered continuously for several seconds. In some variations, PEF treatment can collectively accumulate an on-time of approximately 15 milliseconds over approximately 10 seconds for a net duty cycle of approximately 0.0015.

[0124] Figure 70 is a plot (7000) comparing the voltage output of pulsed electric field treatment (7010) with the voltage output of radio frequency treatment (7020) over time. During RF treatment (7020), energy can be delivered continuously within the time scale of Figure 70, while during PEF treatment (7010), energy is intermittently pulsed at a voltage output that is orders of magnitude higher than the voltage output for RF treatment (7020).

[0125] Generally, the devices described herein may include an elongate body coupled to an electrode array positionable in the lumen of the duodenum. In some variations, the devices may further include an expandable member configured to releasably engage a portion of the duodenum. The expandable member may include or be coupled to an electrode array configured to generate a pulsed or modulated electric field. The electrodes of the electrode array may have predetermined dimensions and spacing configured to generate a pulsed or modulated electric field with a predetermined uniformity to treat desired tissue while limiting damage to other tissue. In some variations, the expandable member may expand and compress as needed to engage the inner diameter of the duodenum. In some variations, a system including the devices described herein may further include a signal generator configured to generate a pulse waveform for delivery to the electrode array to thereby treat the engaged tissue.

[0126] Also described herein are methods. In some variations, a method of treating duodenal tissue, for example, to treat diabetes, can include advancing a pulsed electric field device toward a first portion of a patient's duodenum. The pulsed electric field device can include an expandable member including an electrode array. The expandable member can transition from a compressed configuration to an expanded configuration to bring the expandable member (and electrode array) close to or into contact with the inner surface of the duodenum. The expandable member can have flexibility to apply force against and match the inner circumference of the duodenum, which itself can have a range of diameters. A first pulse waveform can be delivered to the electrode array to generate a first pulsed electric field or a first modulated electric field to treat tissue in the first portion. The pulsed electric field device can be moved (e.g., advanced or retracted) toward a second portion of the duodenum (which can be distal or proximal to the first portion), and a second pulse waveform can be delivered to the electrode array to generate a second pulsed electric field or a second modulated electric field, thereby treating tissue in the second portion. For example, in some variations, the signal generator may generate a driving voltage (e.g., voltage measured at the electrode array) of about 400 V to about 1500 V, which may correspond to electric field strengths of about 400 V / cm and about 7000 V / cm in the treatment portion of the duodenum. The expandable member may be in a compressed configuration, a semi-expanded configuration, and an expanded configuration during movement of the pulsed electric field device. In some variations, the visualization device may be configured to visualize one or more of the pulsed electric field device and tissue. In some variations, temperature sensor measurements may be used to monitor and / or control the delivery of the pulsed waveform. In some variations, current and voltage measurements may be used to monitor and / or control the delivery of the pulsed waveform.

[0127] I. System overview The systems described herein may include one or more components used to treat tissue, such as, for example, a pulsed electric field device and a visualization device. Suitable examples of such systems and devices are described in International Application No. PCT / US2020 / 056720, filed October 21, 2020, the disclosure of which is incorporated herein by reference in its entirety. Figure 4 is a block diagram of a variation of a pulsed electric field system (400) including one or more of a pulsed electric field device (410), a signal generator (430), a multiplexer (470), a visualization device (450), and a display (460).

[0128] In some variations, the pulsed electric field device (410) may comprise one or more (e.g., first and second) elongate bodies (412) sized and shaped to be placed in one or more body cavities of a patient, such as the esophagus, stomach, large intestine, small intestine, and any portion of the digestive tract. In some variations, the pulsed electric field device (410) may further comprise one or more expandable members (414), one or more electrode arrays (416), one or more dilators (418), a handle (420), one or more sensors (422), a guidewire (424), and a delivery catheter (426). The distal end of the pulsed electric field device (410) may comprise the dilator (418), and the guidewire (424) may extend from the lumen of the dilator (418). The expandable member (414) may comprise the electrode array (416). For example, as described in more detail herein, in some variations, the electrode array (416) can be coupled to a surface (e.g., an outer surface) of the expandable member (416), while in other variations, the electrode array itself can form the expandable member and / or the electrode array can be integral with the expandable member. In some variations, the expandable member (414) and / or the electrode array (416) can be disposed adjacent to one or more expanders, for example, between at least one pair of expanders (418). In some variations, the pulsed electric field system (400) can optionally include a delivery catheter (426) configured to advance over the pulsed electric field device (410). Additionally or alternatively, the pulsed electric field device (410) can include one or more sensors (422) configured to measure one or more predetermined properties, such as temperature, pressure, impedance, etc.

[0129] As described above, the pulsed electric field system (400) may include a visualization device (450). In some variations, the visualization device (450) may be configured to visualize one or more steps of a treatment procedure. The visualization device (450) may assist in one or more of advancing the pulsed electric field device (410), positioning the pulsed electric field device and / or its components (e.g., the electrode array (416)), and verifying the treatment procedure. For example, the visualization device (450) may be configured to generate image signals that are transmitted to a display (460) or output device. In some variations, the visualization device (450) may be advanced separately from and concurrently with the pulsed electric field device (410) during the treatment procedure. For example, the expandable member (414) of the pulsed electric field device (410) may be configured to retain the visualization device (450), such that the pulsed electric field device (410) translates with the visualization device (450) as it moves through the body. The expandable member (414) can expand to release the visualization device (450), thereby allowing freedom of movement of the visualization device (450). In other variations, the visualization device (450) can be integrated with the pulsed electric field device (450). For example, the expander (418) can include the visualization device (450).

[0130] The visualization device (450) may be any device (intracorporeal or extracorporeal) that assists a user in visualizing a treatment procedure. In some variations, the visualization device (450) may comprise one or more of an endoscope (e.g., a chip-on-chip camera endoscope, a three-camera endoscope), an image sensor (e.g., a CMOS or CCD array with or without a color filter array and associated processing circuitry), a camera, an endoscope, an external light source, and an ultrasound catheter. In some variations, an external light source (e.g., a laser, LED, lamp, etc.) may generate light that may be carried by a fiber optic cable. Additionally or alternatively, the visualization device (450) may comprise one or more LEDs to provide illumination. For example, the visualization device (450) may comprise a bundle of flexible optical fibers (e.g., a fiberscope). The fiber optic cable or fiberscope bundle may be configured to receive and transmit light from the external light source. The endoscope may comprise an image sensor configured to receive reflected light from tissue and a pulsed electric field device. It should be understood that visualization device (450) may comprise any device that allows or facilitates visualization of any portion of the pulsed electric field device and / or internal structures of the body. For example, the visualization device may comprise a capacitance sensor array for real-time x-ray imaging and / or fluoroscopy technology.

[0131] In some variations, the signal generator (430) can be configured to provide energy (e.g., energy waveform, pulse waveform) to the pulsed electric field device (410) to treat a predetermined portion of tissue, such as duodenal tissue. In some variations, the PEF systems described herein can include a signal generator comprising an energy source and a processor. The signal generator can be configured to deliver a bipolar waveform to the electrode array, thereby delivering energy to the tissue (e.g., duodenal tissue). The delivered energy can assist in resurfacing the duodenal mucosa while minimizing damage to surrounding tissue. In some variations, the signal generator can generate one or more bipolar waveforms. In some variations, the signal generator can be configured to control the generation and delivery of waveforms in response to received sensor data. For example, energy delivery can be modulated (e.g., inhibited) unless the measured temperature falls within a predetermined range.

[0132] In some variations, to limit neural stimulation, the pulse waveform may comprise, on average, about zero net current (e.g., generally balanced positive and negative current) and may have a non-zero duration of less than about 2 μsec or less than about 5 μsec. In some variations, the pulse waveform may comprise a square wave. For example, the pulse waveform may comprise a square in voltage drive and current drive, or a square in voltage drive and a sawtooth in current drive. In some variations, one or more pulses may comprise half-sine waves for both current and voltage. In some variations, one or more pulses may comprise two exponential functions with different rise and fall times. In some variations, one or more pulses may comprise a bipolar pulse at a first potential followed by a pulse pair at a second potential lower than the first potential.

[0133] In some variations, a multiplexer 470 can be coupled to the pulsed electric field device 410. For example, the multiplexer 470 can be coupled between the signal generator 430 and the pulsed electric field device 410, or the signal generator 430 can include the multiplexer 470. The multiplexer 470 can be configured to select a subset of electrodes in the electrode array 416 to receive a pulse waveform generated by the signal generator 430 according to a predetermined sequence. Additionally or alternatively, the multiplexer 470 can be coupled to multiple signal generators and configured to select between waveforms generated by one of the multiple signal generators 430 for a selected subset of electrodes.

[0134] Pulsed Electric Field Device Generally, the pulsed electric field devices described herein may include an elongate body and an expandable member comprising an electrode array. The pulsed electric field device may be configured to facilitate deployment in and treatment of the duodenum. In some variations, the pulsed electric field device may be configured to apply pulsed or modulated electric field energy to the inner circumference of the duodenum. The devices described herein may be used to treat only a specific, pre-designated portion of the duodenum and / or the entire length of the duodenum. In some variations, the electrode array of the pulsed electric field device may generate an electric field strength of about 400 V / cm to about 1500 V / cm, about 1500 V / cm to about 4500 V / cm, at a treatment depth of about 0.5 mm to about 1.5 mm from the inner surface of the duodenum, e.g., about 1 mm, including all values ​​and subranges therebetween. In some variations, the electric field may decay such that the electric field strength is less than about 400 V / cm at about 3 mm from the inner surface of the duodenum. In some variations, a predetermined bipolar current and voltage sequence can be applied to the electrode array of a pulsed electric field device to generate a pulsed or modulated electric field. The generated pulsed or modulated electric field can be substantially uniform to reliably induce cell lysis in a predetermined portion of duodenal tissue. For example, the generated pulsed or modulated electric field can vary spatially up to about 20%, between about 5% and about 20%, between about 10% and 20%, and between about 5% and about 15% at a predetermined depth in the tissue, including all ranges and subvalues ​​therebetween. Furthermore, the pulsed electric field device can be biocompatible and resistant to gastric acid and intestinal fluids.

[0135] Expandable Member Generally, the expandable members described herein can be configured to change configurations to assist in positioning the electrode array relative to the duodenum during a treatment procedure. For example, the expandable member can expand to contact tissue and hold the pulsed electric field device (e.g., elongate body, electrode array, sensor) in place relative to the tissue. The expandable member can also partially expand to hold a visualization device in place relative to the pulsed electric field device. The expandable member can have a compressed configuration and an expanded configuration. As discussed in more detail herein, in some cases, the compressed configuration can be a rolled configuration, and the expanded configuration can be an expanded configuration. Furthermore, in some variations, the expandable member can have a semi-expanded (or partially expanded) configuration between the compressed and expanded configurations. Placing the expandable member in the compressed configuration can compact the size of the pulsed electric field device, which may enable it to be more easily advanced through one or more body cavities. Once properly positioned, the expandable member can transition to the expanded configuration, which allows the electrode array of the expandable member to contact all or a portion of the inner circumference of the duodenum. In some variations, the semi-expanded configuration can allow the expandable member to hold another device (e.g., a visualization device) within the lumen of the expandable member. Additionally or alternatively, a lumen can refer to a tubular or non-tubular structure having one or more openings, apertures, holes, slots, combinations thereof, etc.

[0136] 5A is a perspective view of a variation of a pulsed electric field device (500). As shown therein, the pulsed electric field device (500) may comprise a first elongate body (510) having a lumen therethrough and a second elongate body (520) positioned at least partially within the lumen of the first elongate body (510). The pulsed electric field device (500) may further comprise an expandable member (530), which may be wrapped around (e.g., in mechanical contact with) the second elongate body (520) about its longitudinal axis. For example, as shown in FIGS. 5A-5D, the expandable member (530) may include multiple turns around the second elongate body (520), such that the expandable member (530) forms multiple (e.g., two, three, four, five, or more) layers wrapped or wound around the second elongate body (520). That is, the expandable member (530) may be in mechanical contact with the second elongate body (520). In some variations, the expandable member (530) (e.g., a circuit board, a flex circuit) may include an electrode array (not shown for clarity), which may include any of the electrode arrays described herein. For example, in some variations, the expandable member may be a flex circuit, while in other variations, the expandable member may include a base layer, and the flex circuit may be coupled to the base layer. The electrode array may be disposed on an outer surface of the expandable member (530). In some variations, a connector (540) can couple the first elongate body (510) to the expandable member (530). For example, the connector (540) can be configured to provide structural support to the expandable member (530) such that at least a portion of the expandable member (530) can be substantially fixed relative to the first elongate body (510).

[0137] FIG. 5A depicts a pulsed electric field device (500) having an expandable member (530) in a compressed or coiled configuration configured for advancement through one or more body cavities. When in the compressed or coiled configuration, the expandable member (530) may have a generally cylindrical shape with a first inner diameter (e.g., luminal diameter) and a first outer diameter. FIG. 5B depicts a pulsed electric field device (500) having an expandable member (530) in an expanded or deployed configuration configured to engage tissue, such as the inner surface of the duodenum (not shown for clarity). When in the expanded or deployed configuration, the expandable member (530) may have a generally elliptical or cylindrical shape, with second inner and outer diameters having predetermined dimensions that are greater than the first inner and outer diameters, respectively. The expandable member in the expanded configuration may have a predetermined flexibility configured to conform to the shape of the tissue it engages.

[0138] In some variations, the first and second elongate bodies (510, 520) can be configured to rotate axially relative to one another to transition the expandable member (530) between a compressed configuration, an expanded configuration, and a semi-expanded configuration therebetween. For example, the second elongate body (520) (e.g., an internal torsion member, rotatable member) can be rotatably positioned within the lumen of the first elongate body (510), such that rotation of the second elongate body (520) relative to the first elongate body (510) transitions the expandable member (530) between a rolled configuration and a deployed configuration. In some of these variations, the inner diameter of the lumen (550) of the expandable member (530) can be at least about 8 mm, at least about 10 mm, or between about 8 mm and about 10 mm in the deployed configuration, including all values ​​and subranges therebetween. As described in more detail herein, a visualization device (not shown) can be disposed within the lumen (550) of the expandable member (530) to assist in visualization. It should be understood that the pulsed electric field device (500) can be advanced adjacent to the visualization device and / or over a guidewire. In some variations, the visualization device can be used to guide advancement and visualize the treatment procedure such that a guidewire and / or other visualization modalities (e.g., fluoroscopy) are not required.

[0139] In some variations, the expandable member 530 can be configured to transition between a compressed configuration and an expanded configuration. For example, the expandable member 530 can transition to a partially expanded or semi-expanded configuration (between the compressed and expanded configurations) to allow a visualization device (e.g., an endoscope) to be disposed within the lumen of the expandable member 530. In some variations, the inner surface of the expandable member can engage and retain the visualization device in the semi-expanded configuration.

[0140] As shown in the detailed perspective views of FIGS. 5C and 5D, the expandable member 530 can have an inner end 532 (e.g., the innermost portion of the roll) and an outer end 534 (e.g., the outermost portion of the roll). FIG. 5C depicts the expandable member 530 in a compressed configuration, and FIG. 5D depicts the expandable member 530 in an expanded configuration. In some variations, the inner end 532 can be coupled to (e.g., attached to) the second elongate body 520, and the outer end 534 can be coupled to (e.g., attached to) the first elongate body 510. In this manner, coupling the ends of the expandable member 530 to the first and second elongate bodies 510, 520 can provide greater control over the size and shape of the expandable member 530. For example, an edge of the inner end 532 substantially parallel to the longitudinal axis of the second elongate body 520 can be attached to the outer surface of the second elongate body 520, such that the inner end 532 rotates with the rotation of the second elongate body 520. The direction of rotation (e.g., clockwise, counterclockwise) of the second elongate body 520 can determine the configuration (e.g., expansion or compression) of the expandable member 530. For example, rotating the second elongate body 520 in a clockwise direction relative to the first elongate body 510 can expand or deploy the expandable member 530, while rotating the second elongate body 520 in a counterclockwise direction relative to the first elongate body 510 can compress or rotate the expandable member, or vice versa.

[0141] In some variations, the connector 540 can couple the first elongate body 510 to the outer end 534 of the expandable member 530, allowing the expandable member 530 to expand and compress while maintaining its position relative to the first elongate body 510. In some variations, the connector can act as a torsional control arm between the expandable member 530 and the first elongate body 510. In some variations, the connector 540 can have a curved shape, such as an "S" shape, or can be straight (linear). The configuration shown in FIGS. 5C and 5D facilitates advancement of the device 500 in the compressed configuration by minimizing the size of the connector 540 and reducing the diameter of the compressed device 500.

[0142] In some variations, the electrode array can be electrically coupled to the first elongate body 510 through the connector 540. For example, one or more leads can be coupled to the electrode array through a lumen in the first elongate body 510 and a lumen in the connector 540. Additionally or alternatively, one or more leads can be coupled to the electrode array through a lumen in the second elongate body 520. In some variations, the connector 540 can be constructed of a rigid or semi-rigid material or a combination thereof, such that the position of the outer end 534 relative to the first elongate body 510 remains substantially the same between the compressed and expanded configurations. Additionally or alternatively, the expandable members described herein can include a bimetallic strip configured to expand and compress through ohmic heating.

[0143] FIG. 6A is a perspective view of a variation of the expandable member 600 in a rolled configuration, and FIG. 6B is a perspective view of the expandable member 600 in a deployed configuration. In some variations, the expandable member 600 may comprise a substrate 610, such as a flex circuit. Additionally, the expandable member 600 may comprise or be coupled to an electrode array (not shown). In some variations, the expandable member 600 may be comprised of a self-expanding material biased to expand to a predetermined shape and / or diameter. For example, the expandable member 600 may comprise one or more of flexible polymeric materials (e.g., polyamide, PET), nitinol, stainless steel, copper, gold, other metals, adhesives, combinations thereof, and the like. In some variations, expansion and compression of the expandable member 600 may be caused by contraction and advancement, respectively, of a sheath (e.g., a delivery catheter) over the expandable member 600. The expandable member in a rolled configuration may include one or more turns. In some variations, the expandable member (600) in the rolled configuration can have a diameter of about 6 mm to about 15 mm, inclusive of all ranges and subvalues ​​therebetween. In some variations, the expandable member (600) in the expanded configuration can have a diameter of about 10 mm to about 50 mm, inclusive of all ranges and subvalues ​​therebetween.

[0144] FIG. 7A is a cross-sectional perspective view of a portion of the expandable member (700) in a deployed configuration. In some variations, the expandable member (700) may comprise a substrate (710), such as a flex circuit and a support (720). In these variations, the support (720) may provide structural reinforcement to enable the expandable member (700) to expand and adhere to the inner surface of the duodenum. That is, the support (720) may help apply an apposition force against tissue to enable engagement with the expandable member (700) during a procedure. In some variations, the support (720) may comprise a stiffness greater than that of the substrate (710) and / or comprise one or more components (e.g., a sensor, a reference generator). In some cases, the support (720) may extend circumferentially along the radial edge of the expandable member (700). In some variations, the support (720) may be configured to add stiffness to the substrate (710) coupled to the electrode array. In some variations, the support 720 can be disposed along a surface of the substrate 710 opposite the electrode array 730. In some variations, the support 720 can be composed of a rigid or semi-rigid material or combinations thereof configured to facilitate expansion and compression of the expandable member 700, and can include one or more of nitinol, stainless steel, carbon, polymers, etc.

[0145] 7B is a detailed cross-sectional perspective view of an expandable member 700 comprising a substrate 710, a support 720, and an electrode array 730. As depicted in FIG. 7B, the electrode array 730 may comprise a plurality of substantially parallel elongated electrodes disposed on an outer surface of the substrate 710. Additionally or alternatively, the plurality of elongated electrodes may comprise an interdigitated configuration. For example, the plurality of elongated electrodes may comprise a curved shape (e.g., S-shaped, W-shaped).

[0146] The electrode array 730 can be configured to modify the bending stiffness of the expandable member 700 to facilitate consistent expansion and compression of the expandable member 700. In some variations, the electrode array 730 can include a plurality of electrodes with a ratio of center-to-center distance between adjacent electrodes to electrode width of about 2.3:1 to about 3.3:1 and about 2.8:1 to about 3.0:1. In some variations, the plurality of elongated electrodes can include a center-to-center distance between proximal electrodes of less than about 5 mm. In some cases, the electrode array can include a plurality of semi-elliptical electrodes. In some variations, the electrode array 730 can include a plurality of electrodes configured to protrude and / or be recessed relative to the surface of the substrate 710. In some variations, one or more electrodes of the electrode array 730 can vary in height relative to the substrate 710 by about -0.25 mm to about 0.765 mm.

[0147] 8A-33B illustrate additional pulsed electric field device variations. FIG. 8A is a perspective view of a variation of a pulsed electric field device (800) in a wound configuration. The device (800) in the wound configuration can be configured for advancement through one or more body cavities. In some variations, the pulsed electric field device (800) can include a first elongate body (810) having a lumen therethrough and a second elongate body (820) positioned at least partially within the lumen of the first elongate body (810). The expandable member (830) can be wound around or around the second elongate body (820). For example, the expandable member (830) can include multiple turns around the second elongate body (820). The expandable member (830) can be coupled to distal portions of the first elongate body (810) and the second elongate body (820). In some variations, the expandable member (830) (e.g., a circuit board, a flex circuit) can include an electrode array (not shown for clarity), which can include any of the electrode arrays described herein. For example, the electrode array can be disposed on an outer surface of the expandable member (830). In some variations, a connector (840) can couple the first elongate body (810) to the expandable member (830).

[0148] In some variations, a system including device (800) may further include a third elongate body (850) disposed within the lumen of expandable member (830). In some of these variations, third elongate body (850) comprises a visualization device (e.g., an endoscope). FIG. 8B is a perspective view of a variation of visualization device (850) (e.g., an endoscope) and pulsed electric field device (800). In FIG. 8B, expandable member (830) may transition to a partially deployed configuration (e.g., semi-expanded) sufficient for visualization device (850) to be disposed within the lumen of expandable member (830). For example, device (800) may be configured to hold visualization device (850) in a predetermined position relative to device (800). In this manner, pulsed electric field device (800) and visualization device (850) may be advanced together through one or more body cavities to facilitate navigation and delivery to the duodenum. Once delivered to the target tissue region, the visualization device 850 can be detached from the pulsed electric field device 800 such that the visualization device 850 can be moved independently of the pulsed electric field device 800. Additionally or alternatively, the device 800 can include a coupling mechanism configured to releasably couple the device 800 to the visualization device 850. For example, the coupling mechanism can include one or more of a snare, a snap fitting, a wire loop, a grabber, forceps, combinations thereof, and the like.

[0149] FIG. 8C is a perspective view of the visualization device (850) and pulsed electric field device (800) in a deployed (i.e., fully deployed) configuration. For example, the third elongate body (850) can be configured to translate relative to the first elongate body (810) in the deployed configuration. The pulsed electric field device (800) and expandable member (830) in FIG. 8C depict a deployed configuration configured to engage tissue, such as the inner surface of the duodenum (not shown for clarity). In some variations, the second elongate body (820) (e.g., an internal torsion member, rotatable member) can be configured to rotate relative to the first elongate body (810) to transition the expandable member (830) between a rolled configuration and a deployed configuration. In some of these variations, the expandable member (830) can comprise a lumen (860) having a diameter of at least 10 mm in the deployed configuration.

[0150] Similar to the pulsed electric field device (500) of Figures 5A-5D, the expandable member (830) can have an inner end (e.g., an innermost portion of the roll) and an opposing outer end (e.g., an outermost portion of the roll), where the inner end can be coupled to the second elongate body (820) and the outer end can be coupled to the first elongate body (810). As described in more detail above with respect to Figures 5A-5D, the direction of rotation (e.g., clockwise, counterclockwise) of the second elongate body (820) can determine the expansion or compression of the expandable member (830).

[0151] In some variations, a connector 840 can couple the first elongate body 810 to the outer end of the expandable member 830. In some variations, an electrode array can be electrically coupled to the first elongate body 810 through the connector 840. For example, one or more leads can be coupled to the electrode array through the first elongate body 810 and the connector 840. Additionally or alternatively, one or more leads can be coupled to the electrode array through the second elongate body 820. In some variations, the connector 840 can be constructed of a rigid or semi-rigid material or a combination thereof, such that the position of the outer end relative to the first elongate body 810 remains substantially the same between the rolled and deployed configurations.

[0152] FIG. 9A is a perspective view of a variation of a pulsed electric field device (900) comprising multiple expandable members in a wound configuration. The device (900) in the wound configuration can be configured for advancement through one or more body cavities. In some variations, the pulsed electric field device (900) can comprise multiple outer elongate bodies (910), each comprising a lumen and a second elongate body (920) positioned at least partially within each lumen of the outer elongate body (910). Multiple expandable members (930) can be disposed along the length of the device (900) and rolled around the second elongate body (920). For example, each expandable member (930) can include multiple turns around the second elongate body (920). The multiple expandable members (930) can be coupled to a distal portion of the second elongate body (920). In some variations, each of the expandable members 930 (e.g., circuit board, flex circuit) may include an electrode array (not shown for clarity), which may include any of the electrode arrays described herein. The expandable members 930 may include the same electrode array or different electrode arrays. The electrode arrays may be disposed on the exterior surface of each of the expandable members 930. In some variations, each expandable member 930 may be coupled to its respective outer elongate body 910 by a respective connector 940. Thus, in some variations, the pulsed electric field device 900 may include two, three, or more connectors 940, one or more for each expandable member 930. A pulsed electric field device 900 including multiple expandable members 930 may allow for a longer length of tissue to be treated at one time, thereby reducing the need to reposition the device 900 multiple times for different portions of tissue. The length of each expandable member 930 and the spacing between each expandable member 930 can be the same or different. Energy can be delivered to multiple electrode arrays of the device 900 in any predetermined order. For example, the electrode arrays can generate pulsed or modulated electric fields simultaneously or in series with the same or different pulse waveforms.That is, the electrode arrays can be operated independently.

[0153] In some variations, a system including the pulsed electric field device (900) may further include a third elongate body (950) disposed within the lumen of the expandable member (930). In some of these variations, the third elongate body (950) may include a visualization device (e.g., an endoscope). FIG. 9B is a perspective view of a variation of a visualization device (950) (e.g., an endoscope) and the pulsed electric field device (900). For example, the third elongate body (950) may be configured to translate relative to the first elongate body (910) in the deployed configuration. The pulsed electric field device (900) and expandable member (30) in FIG. 9B are depicted in a deployed configuration configured to engage tissue, such as the inner surface of the duodenum (not shown for clarity). In some variations, the inner elongate body (920) (e.g., an inner torsion member, rotatable member) can be configured to rotate relative to the outer elongate body (910) to transition the plurality of expandable members (930) between a rolled configuration and a deployed configuration. In some of these variations, the plurality of expandable members (930) can each include a lumen (960) having a diameter of at least 10 mm in the deployed configuration. In some variations, a visualization device (950) can be disposed within the lumen (960) of each of the plurality of expandable members (930).

[0154] Similar to the pulsed electric field device (500) of Figures 5A-5D, each of the expandable members (930) can have an inner end (e.g., an innermost portion of a roll) and an outer end (e.g., an outermost portion of a roll), where the inner end is coupled to the inner elongate body (920) and the outer end is coupled to at least one of the outer elongate bodies (910) and the electrode array. As described in more detail above with respect to Figures 5A-5D, the direction of rotation (e.g., clockwise, counterclockwise) of the inner elongate body (920) can determine the expansion or compression of each of the plurality of expandable members (930).

[0155] In some variations, a connector 940 can couple the outer elongate body 910 to the outer end of each expandable member 930. In some variations, the electrode array of each expandable member can be electrically coupled to the outer elongate body 910 through a connector 940. For example, one or more leads can be coupled to each electrode array through the outer elongate body 910 and the connector 940. Additionally or alternatively, one or more leads can be coupled to the electrode array through the inner elongate body 920. In some variations, each connector 940 can be constructed of a rigid or semi-rigid material or a combination thereof, such that the position of the outer end relative to the outer elongate body 910 remains substantially the same between the rolled and deployed configurations. In some variations, each electrode can include an independent lead.

[0156] In some variations, the pulsed electric field device may include one or more dilators configured to assist in advancing the device through one or more body cavities. Figure 10A is a perspective view of a variation of a pulsed electric field device (1000) in a wound configuration. As shown therein, the pulsed electric field device (1000) may include a first elongate body (1010) having a lumen therethrough and a second elongate body (1020) positioned at least partially within the lumen of the first elongate body (1010). The expandable member (1030) may be wound around the second elongate body (1020), as described in more detail herein. For example, the expandable member (1030) may include multiple turns around the second elongate body (1020). The expandable member (1030) may be coupled to a distal portion of the first elongate body (1010) and the second elongate body (1020).

[0157] In some variations, the expandable member (1030) (e.g., circuit board, flex circuit) may include an electrode array (not shown for clarity), which may include any of the electrode arrays described herein. For example, the electrode array may be disposed on an outer surface of the expandable member (1030). In some variations, the pulsed electric field device (1000) may further include one or more dilators. For example, the pulsed electric field device (1000) may include a distal dilator (1060) and a proximal dilator (1062), each of which is coupled to one of the first elongate body (1010) and the second elongate body (1020). The dilators (1060, 1062) can aid in smoothly advancing and / or retracting the pulsed electric field device (1000) through one or more body cavities and can help prevent the expandable member from getting caught on tissue. For example, the dilators (1060, 1062) can be configured to protect the edges of the expandable member (1030) from contacting tissue as the expandable member (1030) advances through a body cavity. One or more of the dilators can include a recess (1064). In some variations, the recess (1064) can have a shape configured to facilitate mating or coupling with another elongate member, such as a visualization device (e.g., an endoscope). The expandable member (1030) can be disposed between the distal dilator (1060) and the proximal dilator (1062). The lengths and tapers of the dilators of the device can be the same or different. For example, the distal dilator (1060) can have a steeper taper than the proximal dilator (1062). In some variations, the pulsed electric field device (1000) can include only a single distal dilator (1060).

[0158] 10B is a detailed perspective view of a pulsed electric field device 1000 having an expandable member 1030 in a coiled configuration. In some variations, the pulsed electric field device 1000 may further include a connector 1040 that can couple one or more of the first elongate body 1010, the distal dilator 1060, and the proximal dilator 1062 to the expandable member 1030. For example, the connector 1040 can couple the first elongate body 1010 to an outer end of the expandable member 1030. In some variations, an electrode array can be electrically coupled to the first elongate body 1010 through the connector 1040. For example, one or more leads can be coupled to the electrode array through the first elongate body 1010 and the connector 1040. Additionally or alternatively, one or more leads may be coupled to the electrode array through the second elongate body 1020. In some variations, the connector 1040 may be constructed of a rigid or semi-rigid material, or a combination thereof, such that the position of its outer end relative to the first elongate body 1010 remains substantially the same between the rolled and deployed configurations. In some variations, the distal dilator 1060 and the proximal dilator 1062 are attached to the first elongate body 1010. In some variations, the maximum diameter of the dilators 1060, 1062 may be approximately the same as the diameter of the expandable member in the rolled configuration. For example, the dilators 1060, 1062 may have a maximum diameter of about 10 mm to about 15 mm, inclusive of all ranges and subvalues ​​therebetween, in which case the expandable member 1030 in the rolled configuration may have a diameter of about 8 mm to about 15 mm, inclusive of all ranges and subvalues ​​therebetween.

[0159] 10C, 10D, and 10E are perspective views of a pulsed electric field device (1000) having an expandable member (1030) in a deployed configuration. In the deployed configuration, the expandable member (1030) can be configured to engage tissue, such as the inner surface of the duodenum (not shown for clarity). In some variations, the second elongate body (1020) (e.g., an internal torsion member, a rotatable member) can be configured to rotate relative to the first elongate body (1010) to transition the expandable member (1030) between the rolled configuration and the deployed configuration. For example, the second elongate body (1020) can be rotatably positioned within the lumen of the first elongate body (1010). In some of these variations, the expandable member (1030) can include a lumen (1080), the diameter of which can increase between the rolled configuration and the deployed configuration. In some variations, the diameter of the lumen of the expandable member can be at least 8 mm in the deployed configuration. In some variations, the expandable member (1030) in the deployed configuration can have a diameter of about 10 mm to about 50 mm, and about 15 mm to about 50 mm, inclusive of all ranges and subvalues ​​therebetween.

[0160] In some variations, a system including the device may further include a third elongate body disposed within the lumen of the expandable member. In some of these variations, the third elongate body comprises a visualization device (e.g., an endoscope). FIG. 11 is a perspective view of a visualization device (1150) (e.g., an endoscope) and a variation of a pulsed electric field device (1100). The pulsed electric field device (1100) may include a first elongate body (1110) having a lumen therethrough and a second elongate body (1120) positioned at least partially within the lumen of the first elongate body (1110). The expandable member (1130) may be wrapped around the second elongate body (1120). In some variations, the pulsed electric field device (1100) may further include one or more dilators. For example, the pulsed electric field device 1100 may include a distal dilator 1160 and a proximal dilator 1162, each coupled to one of the first elongate body 1110 and the second elongate body 1120. In FIG. 11 , the expandable member 1130 may transition to a partially deployed configuration sufficient for the visualization device 1150 to be disposed within the lumen of the expandable member 1130. For example, the device 1100 may be configured to hold the visualization device 1150 in a predetermined position relative to the device 1100. In this manner, the pulsed electric field device 1100 and the visualization device 1150 may be advanced together through one or more body cavities.

[0161] In some variations, the rolled expandable member of a pulsed electric field device can transition configurations using an actuator, which allows for improved control over the expansion and / or compression of the expandable member. For example, the actuator may comprise a set of gears and / or friction rollers (e.g., knurled friction rollers) and a track configured for consistent transmission of rotational torque from the rotating elongate body to the expandable member. FIG. 12A is a perspective view, and FIG. 12B is a cross-sectional side view, of a variation of a pulsed electric field device (1200) comprising an actuator (1270). As shown therein, the pulsed electric field device (1200) may comprise a first elongate body (1210) comprising a lumen therethrough, a second elongate body (1212) positioned at least partially within the lumen of the first elongate body (1210), and the actuator (1270). The pulsed electric field device (1200) may further comprise an expandable member (1230) wrapped around the second elongate body (1212) and operably coupled to an actuator (1270), as described in more detail herein. In some variations, the pulsed electric field device (1200) may further comprise one or more dilators, such as a distal dilator (1250) and a proximal dilator (1252) coupled to one of the first elongate body (1210) and the second elongate body (1212). In some variations, one or more of the dilators (1250, 1252) may have a sigmoid shape. The actuator (1270) may be disposed between the distal dilator (1250) and the proximal dilator (1252). The expandable member (1230) may be disposed between a distal dilator (1250) and a proximal dilator (1252). The dilators (1250, 1252) may allow the pulsed electric field device (1200) to smoothly translate through one or more body cavities, as described in more detail herein.

[0162] As described above, the pulsed electric field device 1200 may include an actuator operably coupled to the expandable member 1230 and configured to assist in the expansion (e.g., deployment) and compression (e.g., rolling) of the expandable member 1230. In some variations, the actuator may include one or more gears, which may interface with one or more tracks formed in the expandable member 1230. For example, in the variation depicted in FIGS. 12A-12C, the actuator 1270 may include a first gear 1220 and a second gear 1222, each of which may be coupled to the second elongate body 1212. The expandable member 1230 may further include a first track 1232 on a first side thereof and a second track 1234 on a second side thereof. The first track 1232 can be operably coupled to the first gear 1220, and the second track 1234 can be operably coupled to the second gear 1222. In some of these variations, the first and / or second tracks 1232, 1234 can include a plurality of spaced-apart openings in the expandable member 1230 configured to receive the teeth of the respective gears 1220, 1222. The expandable member 1230 can be coupled to the second elongate body 1212 via the gears 1220, 1222. Figure 12C is a detailed cutaway perspective view of the pulsed electric field device 1200 depicting the engagement of the teeth of the gears 1220, 1222 with the respective tracks 1232, 1234 of the expandable member 1230. Additionally or alternatively, the actuator may comprise a metal roller with a multi-tooth texture configured to press directly against the expandable member 1230. The metal roller may be configured to operate with a drum plotter or film canister type mechanism. Similar to the pulsed electric field device 500 of FIGS. 5A-5D, the expandable member 1230 may have an inner end (e.g., an innermost portion of the roll) and an outer end (e.g., an outermost portion of the roll), the inner end coupled to the second elongate body 1212 and the outer end coupled to the first elongate body 1210.The direction of rotation (e.g., clockwise, counterclockwise) of the second elongate body 1212 can determine the expansion or compression of the expandable member 1230. In some variations, a connector 1240 can couple the second elongate body 1212 to the inner end of the expandable member 1230. The outer end of the expandable member 1230 can be coupled to one or more of the dilators 1220, 1222 and the first elongate body 1210. However, FIG. 12A shows the unattached outer end of the expandable member 1230 for purposes of illustration. In some variations, the expandable member 1230 in the rolled configuration can have a diameter of about 6 mm to about 15 mm, including all ranges and subvalues ​​therebetween. The expandable member 1230 in the rolled configuration can include one or more turns. In some variations, the expandable member (1230) in the expanded configuration can have a diameter of about 10 mm to about 50 mm, including all ranges and subvalues ​​therebetween.

[0163] In some variations, the electrode array can be electrically coupled to the second elongate body 1212 through a connector 1240. For example, one or more leads can be coupled to the electrode array via the second elongate body 1212 and the connector 1240. Additionally or alternatively, one or more leads can be coupled to the electrode array through the first elongate body 1210.

[0164] 13A is a perspective view of a variation of the expandable member 1330 of the pulsed electric field device 1300, depicting the expandable member 1330 in a compressed configuration and the corresponding alignment of the openings in the tracks 1332, 1334. The openings in the tracks 1332, 1334 can be sized and positioned to substantially overlap one another when the expandable member 1330 is in the compressed configuration, such that the teeth of the gears (e.g., gears 1220, 1222) can pass through and be positioned within multiple openings in the tracks 1332, 1334, as described in more detail herein. In some variations, the size and spacing of the tracks 1332, 1334 can be varied along the length of the expandable member 1330 to aid in smooth rolling and deployment.

[0165] 13B is a plan view of the expandable member 1330 and tracks 1332, 1334 in a deployed configuration. In some variations, the distance between adjacent openings (e.g., tracks) 1362, 1366 can vary along the length of the expandable member 1330. In particular, the distance between adjacent openings 1362, 1366 can increase along the longitudinal axis of the expandable member 1330 from the first end 1302 of the expandable member to the second end 1304 of the expandable member. For example, dimension D 1366 of a first portion of the expandable member 1330 adjacent to or near the first end 1302 or at the first end (first end) can be smaller than dimension B 1362 of a second portion of the expandable member 1330 adjacent to or near the second end 1304 or at the second end (second end). Conversely, the length of each opening 1360, 1364 can decrease along the longitudinal axis of the expandable member 1330 from the first end 1302 to the second end 1304. For example, the length of dimension C 1364 adjacent to or near the first end 1302 or at the first end can be longer than the length of dimension A 1360 adjacent to or near the second end 1304 or at the second end. This spacing and opening geometry can allow the expandable member to form a more precise and compact shape around the gear in a wound configuration, as shown in FIG. 13C, which is described in more detail below.

[0166] An expandable member 1330 with variable length openings and distances between openings may allow for a more compact winding configuration around a gear with a gear body 1342 and curved or angled teeth extending therefrom, as shown in FIG. 13C. FIG. 13C is an illustrative variation of an expandable member 1330 (such as the expandable member shown in FIG. 13B) in a wound configuration. The expandable member 1330 is depicted wound around a gear 1310 with one or more teeth 1312. While depicted in FIG. 13C as a cylindrical gear (e.g., having a cylindrical body), the gear 1310 need not be, and the gear body 1342 may have any suitable cross-sectional shape, such as, for example, oval, square, rectangular, etc. Each tooth 1312 may have a predetermined tapered (e.g., angled, curved) shape configured to facilitate even load transfer between the openings of the tracks 1332, 1334. The variable spacing and aperture geometry of the expandable member 1330 can facilitate precise winding of the expandable member around the gear 1310. In the wound configuration shown in FIG. 13C, the expandable member 1330 can include one or more overlapping layers (e.g., turns). For example, in a radially outward direction from the radial center of the wound expandable member 1330, the expandable member 1330 can include a first layer 1345 (the innermost layer), a second layer 1347, a third layer 1349, and a fourth layer 1351 (the outermost layer). The number of layers of the expandable member 1330 in a wound configuration can be based on at least the length and thickness of the expandable member, the diameter of the gear, the number of teeth, etc. The distance (1341, 1343) (e.g., spiral pitch) between adjacent openings (e.g., tracks) may increase (e.g., radially outward) from the first layer (1345) to the fourth layer (1351). The length (1341) of the openings (1332) may decrease (e.g., radially outward) from the first layer (1345) to the fourth layer (1351). This may allow the expandable member (1330) to be wrapped around the gear (1310) with minimal spacing between layers.Thus, the openings in the tracks (1332, 1334) can fit smoothly over and / or around the gear teeth (1312), while the portions of the expandable member (1330) between the tracks (1332, 1334) can fit smoothly around the body of the gear between the gear teeth (1312), which can reduce interference, binding, and bunching of the expandable member (1330) in the wound configuration.

[0167] In some variations, the expandable member (1330) (e.g., a circuit board, a flex circuit) can include an electrode array (not shown for clarity), which can include any of the electrode arrays described herein. For example, the electrode array can be disposed on an outer surface of the expandable member (1330).

[0168] In some variations, the distance 1341, 1343 between the openings of the tracks 1332, 1334 (e.g., spiral pitch) can be a function of the thickness of the expandable member 1330 and the number of turns (e.g., layers) of the expandable member 1330. For example, the expandable member 1330 can include one or more electrodes (e.g., electrode pads) of an electrode array (not shown in FIGS. 13A-13C ) that can increase the thickness of those portions of the expandable member 1330. The length of the openings 1332, 1334 and / or the distance between adjacent openings can increase with increasing thickness of the expandable member 1330.

[0169] In some variations, the second elongate body (1312) (e.g., an internal torsion member, a rotatable member) can be configured to rotate relative to the first elongate body (1310) to transition the expandable member (1330) between a rolled configuration and a deployed configuration. In some of these variations, the expandable member (1330) can comprise a lumen having a diameter of at least 10 mm in the deployed configuration.

[0170] 14-29B illustrate additional pulsed electric field device variations including an expandable member comprising an inflatable member (e.g., a balloon). FIG. 14A is a perspective view of a variation of a pulsed electric field device (1400) and a visualization device (1450). FIG. 14B is a cutaway perspective view of the pulsed electric field device (1400) and the visualization device (1450) without the base layer (1430) and electrode array. In some variations, the pulsed electric field device (1400) may comprise a first elongate body (1410) comprising a lumen and a second elongate body (1420) positioned at least partially within the lumen of the first elongate body (1410). Multiple expandable members (1460) may be coupled to the first elongate body (1410). For example, multiple torus-shaped or spiral tube-shaped expandable members 1460 may be coupled in parallel to the first elongate body 1410. In some variations, the expandable members 1460 may be helical, spiral, and / or serpentine. For example, one or more of the expandable members 1460 may comprise one or more helices or coils. In these variations, the expandable members need not have inner or outer ends coupled to their respective elongate bodies. In some variations, the expandable members 1460 may comprise inflatable members.

[0171] In some variations, the expandable member (1460) may comprise a base layer (1430) (e.g., a circuit board, a flex circuit) that may be coupled to any of the electrode arrays described herein. For example, the electrode array (1430) may be disposed on an outer surface of the expandable member (1460). The second expandable member (1440) may optionally be coupled to the second elongate body (1420) and configured to dilate tissue and / or improve visualization of tissue within the body cavity. For example, the second expandable member (1440) may be concentrically coupled to the distal end of the second elongate body (1420). That is, the central longitudinal axis of the second expandable member (1440) may be coupled to the longitudinal axis of the second elongate body (1420). In some variations, the second expandable member (1440) may be an inflatable member, such as a balloon.

[0172] 14A and 14B depict a pulsed electric field device 1400 and a plurality of expandable members 1460 in an expanded or inflated configuration, where the expandable members 1460 are configured to engage tissue, such as the inner surface of the duodenum (not shown for clarity). In some variations, the expandable members 1460 may comprise a lumen having a diameter of at least 10 mm in the expanded configuration. In some variations, the plurality of expandable members 1460 may be configured to transition between a compressed configuration and an expanded configuration, such as a partially or semi-expanded configuration. In some variations, the expandable members 1600 in the expanded configuration may have a diameter of about 10 mm to about 50 mm, and about 15 mm to about 50 mm, inclusive of all ranges and subvalues ​​therebetween. A visualization device 1440 may be disposed within the lumen of the expandable members 1460 in the expanded configuration. In some variations, at least the proximal and distal ends of the second expandable member (1440) may be transparent, thereby allowing a visualization device (1450) to image through the second expandable member (1440).

[0173] 15A and 15B are cutaway perspective views of a variation of a pulsed electric field device (1500) and visualization device (1550) similar to those described in FIGS. 14A and 14B. As shown therein, the pulsed electric field device (1500) may include a first elongate body (1510) having a lumen therethrough and a second elongate body (1520) positioned at least partially within the lumen of the first elongate body (1510). Multiple expandable members (1560) may be coupled to the first elongate body (1510). For example, multiple torus-shaped expandable members (1560) may be coupled to the first elongate body (1510) in parallel.

[0174] In some variations, the expandable member (1560) may include an electrode array (not shown for clarity), which may include any of the electrode arrays described herein. For example, the electrode array may be disposed on or coupled to an outer surface of the expandable member (1560). The second expandable member (1540) may be coupled to the second elongate body (1520). For example, the second expandable member (1540) may be concentrically coupled to the distal end of the second elongate body (1520). That is, the central longitudinal axis of the second expandable member (1540) may be coupled to the longitudinal axis of the second elongate body (1520). In some variations, the second expandable member (1540) may be an inflatable member, such as a balloon. The visualization device (1540) may be disposed within the lumen of the expandable member (1560) in the expanded configuration. In some variations, at least the proximal and distal ends of the second expandable member (1540) may be transparent, thereby allowing a visualization device (1550) to image through the second expandable member (1540).

[0175] 16 is a perspective view of variations of a pulsed electric field device (1600) and a visualization device (1650). In some variations, the pulsed electric field device (1600) may include a first elongate body (1610) having a lumen therethrough and a second elongate body (1620) positioned at least partially within the lumen of the first elongate body (1610). An expandable member (1630) may be coupled to the first elongate body (1610). In some variations, the expandable member (1630) may include an electrode array (not shown for clarity), which may include any of the electrode arrays described herein. For example, the electrode array may be disposed on or coupled to an outer surface of the expandable member (1630). The expandable member 1630 may include a lumen formed by longitudinally joining an outer wall of the expandable member 1630 to an inner wall of the expandable member 1630 and a plurality of elongated recesses 1632. For example, the elongated recesses 1632 may be pleated to control the inner and outer diameters of the expandable member 1630. This configuration may aid in the expansion of the expandable member 1630 including an electrode array (not shown for clarity). For example, one or more electrodes may be disposed on the expandable member 1630 between the elongated recesses 1632.

[0176] The second expandable member (1640) can be coupled to the second elongate body (1620). For example, the second expandable member (1640) can be offset relative to the longitudinal axis of the second elongate body (1620). For example, a sidewall of the second expandable member (1640) can be coupled to the distal end of the second elongate body (1620). In some variations, the second expandable member (1640) can be an inflatable member such as a balloon. The visualization device (1640) can be disposed within the lumen of the expandable member (1640) in the expanded configuration.

[0177] In some variations, the expandable member (1630) can be concentrically coupled to the first elongate body (1610). In some variations, the first elongate body (1610) can be coupled to a sidewall of the expandable member (1630). In some variations, the second expandable member (1640) can be coupled to the second elongate body (1620) and disposed distally of the expandable member (1630). In some variations, the visualization device (1650) can be disposed within the lumen of the expandable member (1630). In some variations, at least the proximal and distal ends of the second expandable member (1640) can be transparent, thereby allowing the visualization device (1650) to image through the second expandable member (1640). In some variations, the multiple electrodes can comprise multiple parallel elongate electrodes, as described in more detail herein. Additionally or alternatively, the plurality of elongate electrodes may have an interdigitated configuration, for example, the plurality of elongate electrodes may have a curved shape (e.g., S-shaped, W-shaped).

[0178] In some variations, the pulsed electric field device may include a predetermined length of expandable member and / or electrode array for ablating a predetermined length of tissue. Figures 17 and 18 are perspective views of variations of pulsed electric field devices (1700, 1800) and visualization devices (1750, 1850) similar to Figures 16A and 16B but having multiple expandable members (1730, 1830). The spacing between the multiple expandable members (1730, 1830) may determine the degree to which the distal ends of the devices (1700, 1800) bend. For example, device (1700) may have greater flexibility than device (1800) due to the greater distance between the expandable members (1730).

[0179] In some variations, the pulsed electric field device (1700, 1800) may comprise a first elongate body (1710, 1810) having a lumen therethrough and a second elongate body (1720, 1820) positioned at least partially within the lumen of the first elongate body (1710, 1810). A plurality of expandable members (1730, 1830) may be coupled to the first elongate body (1710, 1810). In some variations, the expandable members (1730, 1830) may comprise an electrode array (not shown for clarity), which may comprise any of the electrode arrays described herein. A second expandable member (1740, 1840) may be coupled to the second elongate body (1720, 1820). For example, the second expandable member (1740, 1840) is offset relative to the longitudinal axis of the second elongate body (1620). In some variations, the second expandable member (1740) may be an inflatable member such as a balloon. The visualization device (1640) may be disposed within the lumen of the expandable member (1640) in the expanded configuration. At least proximal and distal portions of the expandable members (1740, 1840) may be transparent.

[0180] In some variations, the pulsed electric field device may include an expandable member comprising a transparent inflatable member. FIG. 19 is a perspective view of variations of a pulsed electric field device (1900) and a visualization device (1940). In some variations, the pulsed electric field device (1900) may include an elongate body (1910), and an expandable member (1920) may be coupled to the elongate body (1910). In some variations, the expandable member (1920) may include an electrode array (1930), which may include any of the electrode arrays described herein. For example, the electrode array may be disposed on or coupled to an outer surface of the expandable member (1920). At least a proximal and distal portion of the expandable member (1920) may be transparent to allow a visualization device (1940) to visualize through the expandable member (1920). In some variations, the expandable member (1920) may be concentrically coupled to the distal end of the elongate body (1920). That is, the central longitudinal axis of the expandable member (1920) may be aligned with and may be the same as the longitudinal axis of the elongate body (1910).

[0181] FIG. 20 is a perspective view of a variation of a pulsed electric field device (2000) and visualization device (2040) similar to FIG. 19 , further comprising a second expandable member (2050) disposed distal to the expandable member (2020). The second expandable member (2050) can be configured to dilate tissue. The second expandable member (2050) can be an expandable member such as a balloon. In some variations, the pulsed electric field device (2000) can comprise an elongate body (2010), and the expandable member (2020) can be coupled to the elongate body (2010). In some variations, the expandable member (2020) can comprise an electrode array (2030), which can comprise any of the electrode arrays described herein. At least the proximal and distal portions of the expandable member (2020) can be transparent.

[0182] FIG. 21 is a perspective view of a variation of a pulsed electric field device 2100 and visualization device 2150 similar to FIG. 20 but having multiple expandable members 2130 proximal to a distal second expandable member 2140 (e.g., inflatable member). The spacing between the multiple expandable members 2130 can determine the degree to which the distal end of the device 2130 can bend. In some variations, the pulsed electric field device 2100 can include an elongate body 2110, and the multiple expandable members 2130 can be coupled to the elongate body 2110. In some variations, the multiple expandable members 2120 can include an electrode array 2130, which can include any of the electrode arrays described herein. At least the proximal and distal portions of the expandable member 2120 can be transparent.

[0183] Figure 22 is a perspective view of a variation of a pulsed electric field device 2200 and visualization device 2250 similar to Figure 19, but in which the side walls of an expandable member 2220 and a second expandable member 2240 are attached to an elongate body 2210. This may aid in visualization through the device 2200 by the visualization device 2250, as the visualization device 2250 may be aligned with the center of the expandable member 2220. In some variations, the expandable member 2220 may include an electrode array 2230, which may include any of the electrode arrays described herein. At least the proximal and distal portions of the expandable member 2220 may be transparent.

[0184] Figure 23 is a perspective view of a variation of a pulsed electric field device 2300 and visualization device 2340 similar to Figure 19, but in which the sidewalls of an expandable member 2320 and a second expandable member 2330 are attached to an elongate body 2310. This may aid in visualization through the device 2300 by the visualization device 2340, as the visualization device 2340 may be aligned with the center of the expandable member 2320. In some variations, the expandable member 2320 may include an electrode array (not shown), which may include any of the electrode arrays described herein. At least the proximal and distal portions of the expandable member 2320 may be transparent.

[0185] FIG. 24 is a perspective view of a variation of a pulsed electric field device 2400 and visualization device 2450 similar to FIG. 21 , but in which an expandable member 2420 and a sidewall of a second expandable member 2440 (e.g., an inflatable member) are attached to an elongate body 2410. In some variations, the pulsed electric field device 2400 may comprise an elongate body 2410, and a plurality of expandable members 2420 may be coupled to the elongate body 2410. In some variations, the plurality of expandable members 2420 may comprise an electrode array 2430, which may comprise any of the electrode arrays described herein. At least the proximal and distal portions of the plurality of expandable members 2420 may be transparent. The spacing between the plurality of expandable members 2420 may determine the degree to which the distal end of the device 2400 bends.

[0186] FIG. 25 is a perspective view of a variation of a pulsed electric field device 2500 and a visualization device 2540 similar to FIG. 23, but in which an expandable member 2530 is concentrically coupled to the distal end of a first elongate body 2520. That is, the central longitudinal axis of the expandable member 2530 may be aligned with and the same as the longitudinal axis of the elongate body 2520. Similarly, a second expandable member 2330 (e.g., an inflatable member) is concentrically coupled to the distal end of a second elongate body 2510 that is at least partially disposed within the lumen of the first elongate body 2520. In some variations, the expandable member 2530 may include an electrode array (not shown), which may include any of the electrode arrays described herein. At least the proximal and distal portions of the expandable member 2530 may be transparent.

[0187] FIG. 26 is a perspective view of a variation of a pulsed electric field device 2600 and a visualization device 2650, similar to FIG. 21, but bent to demonstrate the flexibility of the device 2600. The spacing between the expandable members 2620 can determine the degree to which the distal end of the device 2600 can bend. In some variations, the pulsed electric field device 2600 can include an elongate body 2610, and the expandable members 2620 can be coupled to the elongate body 2610. In some variations, the expandable members 2620 can include an electrode array 2630, which can include any of the electrode arrays described herein. At least the proximal and distal portions of the expandable members 2620 can be transparent. A second expandable member 2610 can be attached to the elongate body 2610 proximal to the expandable members 2620.

[0188] Figure 27 is a perspective view of a variation of a pulsed electric field device 2700 and visualization device 2750 similar to that of Figure 24. For example, the sidewalls of each expandable member 2720 and second expandable member 2740 can be attached to an elongate body 2710. In some variations, the plurality of expandable members 2720 can comprise an electrode array 2730, which can comprise any of the electrode arrays described herein. At least the proximal and distal portions of the plurality of expandable members 2720 can be transparent. The spacing between the plurality of expandable members 2720 can determine the degree to which the distal end of the device 2700 can bend.

[0189] FIG. 28A is a perspective view of a variation of the expandable member 2810 of the pulsed electric field device 2800 and visualization device 2830. FIGS. 28B-28E are perspective views of the pulsed electric field device 2800 and visualization device 2830. As shown therein, in some variations, the pulsed electric field device 2800 may comprise a releasable elongate body 2840 and an expandable member 2810 coupled to the elongate body 2840. The expandable member 2810 may comprise a lumen, a compressed configuration, a semi-expanded configuration, and an expanded configuration. The expandable member 2810 may further comprise an electrode array 2820. The lumen of the expandable member may be configured to releasably couple to the visualization device 2830. In some variations, the lumen defines a central longitudinal axis of the expandable member 2830. The elongate body 2840 can be configured to provide one or more of power to the electrode array 2820 and fluid to the expandable member 2810 for expansion and compression. As used herein, fluid refers to a liquid, a gas, or a combination thereof. For example, in some variations, gases commonly used in interventional procedures, such as CO2 and / or air, can be used.

[0190] In Figures 28A and 28C, the visualization device 2830 is disposed within a lumen of the expandable member 2810, allowing the visualization device 2830 to translate the expandable member 2810 through one or more body cavities. Figure 28B depicts the visualization device 2830 decoupled (e.g., disconnected, separated) from the expandable member 2830. This may allow the visualization device 2830 to, for example, image a proximal portion of the expandable member 2810 and to be manipulated independently of the expandable member 2830. After energy delivery is complete, the visualization device 2830 can be recoupled to the expandable member 2830 and withdrawn from the patient. In Figure 28D, the visualization device (2830) has been advanced further relative to the expandable member (2810) such that the distal end of the visualization device (2830) can bend. In some variations, the visualization device (2830) can bend within the lumen of the expandable member (2810), as shown in Figure 28E.

[0191] FIG. 29A is a perspective view similar to FIGS. 28A-28E, but of a variation of a pulsed electric field device 2900 and visualization device 2930 having multiple expandable members 2910. The spacing between the multiple expandable members 2910 can determine the degree to which the distal end of the device 2900 can bend. In some variations, the multiple expandable members 2910 can include an electrode array 2920, which can include any of the electrode arrays described herein. FIG. 29B is a perspective view of the pulsed electric field device 2900 and visualization device 2930 detached (e.g., disconnected, separated) from the multiple expandable members 2910 shown in FIG. 29A.

[0192] FIG. 30A is a perspective view of a variation of a pulsed electric field device (3000) comprising an expandable member (3010) (e.g., inflatable member) comprising an electrode array (3020). In some variations, the expandable member (3010) may comprise a base layer (e.g., circuit board, flex circuit) that can be coupled to any of the electrode arrays described herein. For example, the electrode array (3020) may be disposed on an outer surface of the expandable member (3010). The electrode array (3020) may comprise a plurality of substantially parallel elongated electrodes arranged circumferentially about the longitudinal axis of the expandable member. The expandable member (3010) of FIG. 30A is shown in an expanded configuration. FIG. 30B is a perspective view of the pulsed electric field device (3000) of FIG. 30A positioned within a tissue lumen (3030). The expandable member (3010) in Figure 30A is shown in an expanded configuration such that the electrode array (3020) contacts the tissue lumen (3030).

[0193] 31 is a perspective view of a variation of a pulsed electric field device (3100) comprising an expandable member (3110) (e.g., inflatable member) comprising an electrode array (3122). The electrode array (3122) may comprise a helical shape including predetermined turns. In some variations, the expandable member (3110) may comprise a base layer (e.g., circuit board, flex circuit) that may be coupled to any of the electrode arrays described herein. For example, the electrode array (3122) may be disposed on an outer surface of the expandable member (3110).

[0194] FIG. 32 is a perspective view of a variation of a pulsed electric field device 3200 comprising a visualization device 3230 coupled to an expandable member 3210 comprising an electrode array 3220. The expandable member 3210 may comprise a stent-like structure that can be configured to transition between a compressed configuration and an expanded configuration. For example, the expandable member 3210 may change configuration by one or more of a change in length and a helical rotation. In some variations, the expandable member 3210 may comprise a base layer (e.g., a circuit board, a flex circuit) that may be coupled to any of the electrode arrays described herein. For example, the electrode array 3220 may be disposed on an outer surface of the expandable member 3210. The electrode array 3220 may comprise a plurality of substantially parallel elongated electrodes arranged circumferentially about the longitudinal axis of the expandable member. Additionally or alternatively, the plurality of elongated electrodes may comprise an interdigitated configuration. The expandable member 3210 of Figure 32 is shown in an expanded configuration. The expandable member 3210 may include a lumen configured to receive a visualization device 3230. Figures 33A and 33B are side and perspective views, respectively, of an expandable member 3310 similar to the pulsed electric field device 3200 of Figure 32.

[0195] Electrode array Generally, the electrodes and electrode arrays described herein can be configured to treat tissue, such as duodenal tissue, of a patient. In some variations, the electrode array can engage the duodenum and be energized to treat a predetermined portion of the tissue to resurface the duodenum. For example, the tissue may undergo cell lysis using PEF energy during a treatment procedure. PEF energy tissue treatment can be delivered uniformly at a predetermined depth (e.g., about 1 mm) to quickly and precisely treat the tissue without significant damage to surrounding (e.g., deeper) tissue.

[0196] In some variations, tissue treatment properties can be controlled by the size, shape, spacing, composition, and / or geometry of the electrode array. For example, the electrode array can be flexible to conform to a non-planar tissue surface. In some variations, the electrode array can be embossed or reflowed to form a non-planar electrode surface. In some variations, the electrode array can include a tissue contacting layer. In some variations, the tissue contacting layer can function as a salt bridge between the electrode and the tissue. In some variations, the electrode array can include a hydrophilic coating. In some variations, the electrode array can be divided into subarrays to reduce drive current requirements.

[0197] In some variations, raised and / or rounded (e.g., semi-ellipsoidal) electrodes may generally promote more reliable contact with tissue than flat electrodes, thus promoting a more uniform electric field and improved treatment results. For example, tissue contact (e.g., apposition) with the electrode completes the electrical circuit during energy delivery, thus providing resistance within the circuit for uniform electric field distribution. Raised and / or rounded (e.g., semi-ellipsoidal) electrodes may reduce sharp edges and arcing. Spacing electrodes in an electrode array may further reduce ion concentration and associated electrolysis. The electrode array configurations (e.g., arrangement, spacing, shape, size) shown and described herein provide uniformly spaced electrodes that allow the corresponding expandable member to repeatedly expand and compress.

[0198] In some variations, one or more of the electrodes (e.g., a plurality of electrodes, a portion of the electrodes in an array, all of the electrodes in an array) may comprise one or more biocompatible metals, such as gold, titanium, stainless steel, nitinol, palladium, silver, platinum, combinations thereof, etc. In some variations, one or more of the electrodes (e.g., a plurality of electrodes, a portion of the electrodes in an array, all of the electrodes in an array) may comprise an atraumatic (e.g., blunt, rounded) shape so that the electrodes do not puncture tissue when pressed against it. For example, the electrode array may engage the inner circumference of the duodenum.

[0199] In some variations, the electrode array can be connected to the signal generator by one or more leads (e.g., conductors). For example, the leads can extend through an elongate body (e.g., an outer catheter, an outer elongate body) to the electrode array. One or more portions of the leads can be insulated (e.g., PTFE, ePTFE, PET, polyolefin, parylene, FEP, silicone, nylon, PEEK, polyimide). The leads can be configured to maintain a predetermined electrical potential without breakdown of the corresponding insulator.

[0200] In some variations, the electrode array may comprise multiple elongated electrodes in a substantially parallel or interdigitated configuration. The electrode array shapes and configurations described herein may generate electric fields of a predetermined strength (e.g., about 400 V / cm to about 7,500 V / cm) at a predetermined tissue depth (e.g., about 0.7 mm, about 1 mm) without excessive heat, breakdown, steam generation, etc. In contrast, some electrode configurations have shapes (e.g., radii of curvature) that allow the generated electric field to rapidly decrease without the application of very high voltages (e.g., thousands of volts) that can lead to the aforementioned excessive heat, breakdown, and steam generation.

[0201] FIG. 34A is a perspective view of a variation of an electrode array (3400) comprising multiple elongated electrodes (3410) on a substrate (3420). In some variations, at least one of the electrodes (3410) may have a semi-elliptical cross-sectional shape. In some cases, all of the electrodes (3410) in the electrode array (3400) may have a semi-elliptical cross-sectional shape. Generally, the electric field is strong near the points and edges of the electrodes due to concentrated surface charge on the electrodes. Sharp-edged electrodes and high electric fields can generate one or more of the following effects: electrical discharge (e.g., arcing), high heat (e.g., boiling), high current density (e.g., electrolysis), and gas bubbles. The semi-elliptical cross-sectional shape described herein can reduce one or more of these effects compared to sharp-edged electrodes. In some variations, the major axis of the electrode (3410) is twice the electrode width, and the minor axis of the electrode is equal to the electrode height at the center of the electrode.

[0202] The electrode arrays described herein can be formed using any suitable manufacturing technique. For example, as shown in Figure 37, in some variations, the electrode array (3700) can be formed by pressing the electrode array (3700) between a pair of embossing dies (3750) to form a plurality of spaced-apart round electrodes. The electrode arrays described herein can be fabricated using any suitable technique, including, but not limited to, deposition of solder or other metals, dimples on a substrate, plating of metals (e.g., gold), and lamination.

[0203] In some variations, additional layers and / or coatings may be applied to the electrodes. For example, the electrode array (3800) depicted in Figure 38 may depict a tissue-contacting layer (3810), as further described herein.

[0204] If the edges of a flat electrode are 2d apart (the width of the electrode), then the equivalent electric field is provided by an elliptical conductor with height h (minor axis) and width 2w (where w is the major axis), with the foci of the ellipse d from the center. The eccentricity can be obtained by equation (2): ε=(1+(h / d) 2 ) -1 / 2 Formula (2)

[0205] The footprint of a raised electrode is 2w=2d / ε, which increases from a flat electrode by a factor of ½ε. When raised or solder-reflowed electrodes are used, they will generally have some mechanical resistance to bending around a centerline other than one parallel to the electrode.

[0206] In some variations, the drive voltage applied to the electrode array may depend at least on the spacing between the electrodes of the electrode array as well as the dimensions of the electrodes. For example, relatively wide, elongated electrodes may reduce the effects of strong electric field strength at sharp, curved edges. In some variations, the electrode array may be configured in multiple sets (e.g., groups, zones) to assist in energy delivery for a treatment procedure. For example, the electrode array may include multiple zones arranged along the length of the expandable member. The multiple zones may be activated, for example, in a predetermined sequence.

[0207] 34B is a cross-sectional side view of an electrode array (3400). In some variations, the electrode array can include a plurality (e.g., 4, 8, 12, 16, 20, 24, 30, and any range therein) of elongated electrodes. For example, the electrode array can include more than about six electrodes. In some variations, the plurality of elongated electrodes can have a center-to-center ratio of adjacent (i.e., immediately adjacent) electrodes to electrode width (3414) of about 2.3:1 to about 3.3:1, and about 2.8:1 to about 3.0:1. For example, the distance (3412) between adjacent electrodes (3410) may be between about 1 mm and about 1.8 mm, the width (3414) of the electrodes (3410) may be between about 0.6 mm and about 1.8 mm, and the height (3416) of the electrodes (3410) may be between about 0.15 mm and about 0.5 mm, including all values ​​and subranges therebetween, such as about 0.3 mm. In some variations, the plurality of elongated electrodes may have a center-to-center distance between adjacent electrodes of less than about 10 mm, less than about 7 mm, and less than about 5 mm, including all values ​​and subranges therebetween. In some variations, the plurality of elongated electrodes may comprise a first electrode and a second electrode parallel to the first electrode. Additionally or alternatively, the plurality of electrodes may comprise an interdigitated configuration. In some variations, the center-to-center distance between adjacent electrodes and the width of the plurality of elongated electrodes may be substantially equal.

[0208] In some variations, adjacent electrodes may be spaced apart by a weighted average distance of about 0.3 mm to about 6 mm. The weighted average distance is defined as follows: Each electrode of the plurality of elongated electrodes may have coordinates s(x, yi) (Equation 3), where x and y are parallel to the surface of the electrode array, a first distance (s+) is parallel to the nearest electrode of a first polarity (e.g., positive polarity), and a second distance (s.) is parallel to the nearest electrode of a second polarity (e.g., negative polarity) opposite the first polarity. The weighted average distance (S) may be given by Equation (4):

number

[0209] In some variations, the ratio of electrode height to electrode width may be about 1:4 to about 1:8. In some variations, the surface area of ​​the plurality of electrodes may comprise about 20% to about 75% of the surface area of ​​the electrode array, including all ranges and subvalues ​​therebetween. In some variations, the surface area of ​​the plurality of electrodes may comprise about 20% to about 45% of the surface area of ​​the expandable member in a given configuration, including all ranges and subvalues ​​therebetween. In some variations, the electrode array may comprise conductors that are about 36% by area. In some variations, the surface area of ​​the plurality of electrodes may comprise about 4% to about 30% of the surface area of ​​the duodenum, including all ranges and subvalues ​​therebetween. A typical duodenum has a circumference of about 20 mm to about 45 mm, a length of about 25 mm to about 35 mm, and a diameter of about 700 mm. 2 ~approx. 1850mm 2 and a surface area of

[0210] In some variations, the electrode array may include multiple groups of electrodes (e.g., see zones A, B, and C in FIG. 51), each of which may be activated in a predetermined sequence. In some variations, more uniform treatment of tissue (e.g., in areas where electrode groups intersect) may be achieved by decreasing the width of the most peripheral electrodes of each group and decreasing the distance between those electrodes. In some variations, more uniform treatment of tissue (e.g., in areas where electrode groups intersect) may be achieved by interdigitating the most peripheral electrodes of each group to overlap the treatment area.

[0211] As described in detail herein, a pulsed electric field device may comprise an expandable member having a compressed (e.g., coiled) configuration and an expanded (e.g., deployed) configuration. In some variations, the expandable member may comprise or be otherwise formed from an electrode array (e.g., multiple electrodes). In some variations, the expandable member may comprise a flex circuit comprising multiple electrodes. FIG. 34C is a perspective view of an illustrative variation of an expandable member comprising an electrode array (3400). The electrode array (3400) may comprise multiple elongated electrodes (3410) on a substrate (3420). In some variations, the electrode array (3400) may be in the form of a flex circuit. As shown therein, the flex circuit may comprise the electrode array (3400) or multiple electrodes, for example, multiple elongated parallel electrodes. The expandable member is depicted in an expanded, cylindrical configuration in FIG. 34C.

[0212] Figure 35 is an electric field intensity plot for electrode arrays having the electrode spacing to electrode width ratios described herein. As can be seen, these electrode arrays generate a substantially uniform electric field. The pulsed or modulated electric field can vary spatially by up to about 20% at a given treatment distance from the electrode array. For example, the electric field (3520) generated by electrode (3510) can vary spatially by up to about 20% at a distance of about 0.7 mm from the electrode array (within the submucosal layer of tissue in contact with the electrode array). This can improve consistency in energy delivery and treatment results.

[0213] FIG. 80A shows an electric field intensity plot (8000) of a variation of an electrode array (8010). In some variations, the electrode array (8010) can be configured to generate a substantially uniform electric field (8020) across its entire surface at a predetermined tissue treatment depth (8030). For example, the predetermined tissue depth can be configured to receive a voltage field of approximately 2500 V / cm. A current of approximately 50 A and a voltage of approximately 600 V at a frequency of approximately 350 kHz can be applied to the electrodes. This can improve consistency of energy delivery and treatment results.

[0214] 80B is an electric field intensity plot (8100) of a variation of the electrode array (8110). In some variations, the electrode array (8110) can be configured to generate a substantially uniform electric field (8120) at a first predetermined tissue treatment depth (8130) with an electric field magnitude below the treatment threshold at a second predetermined tissue depth (8140). For example, the electrode array (8110) can receive a voltage of approximately 600 V and generate an electric field (8120) below the treatment threshold at a tissue depth of approximately 1.48 mm.

[0215] In some variations, the tissue treatment depth (e.g., mm) receiving a voltage field of approximately 2500 V / cm may depend on the electrode configuration and the voltage applied to the electrode array. For example, tissue treatment may require approximately 2,000 V / cm, in which case the table values ​​would be adjusted for deeper tissue treatment at the same applied voltage. Current may depend on tissue conductivity and electrode configuration. Assuming a constant voltage, the penetration of the electric field is also constant. Tissue treatment rate may depend on the state of the tissue during treatment (e.g., stretched, compressed, in contact with electrodes). Tissue treatment depth may depend on one or more of tissue treatment rate, current, effective voltage, and tissue type. Table 1 below provides exemplary variations of parameter sets (e.g., voltage, current, power) configured to provide a predetermined ratio of voltage field depth to tissue treatment depth. [Table 1]

[0216] Figure 36 shows a plot of electric field strength for a conventional electrode array lacking electric field uniformity. The electrodes (3610) are shaped and spaced such that the generated electric field (3620) provides a field strength of up to about 200 V / cm to some portions of the submucosal tissue, while other portions receive little, if any, of the electric field (3620). Similarly, a field strength of up to about 1000 V / cm is provided to some portions of the mucosa, while other portions receive little, if any, of the electric field (3620). Thus, with conventional electrodes, even if a given amount of energy is delivered to some portions of the tissue, the inconsistent energy delivery has limited positive impact on treatment outcomes.

[0217] In some variations, the electrode arrays described herein may further comprise a tissue contact layer. The tissue contact layer may be provided between the electrode and tissue to improve electrical conduction and reduce burning due to current crowding at the ends of the electrodes. Figure 38 is a schematic cross-sectional view of an illustrative variation of an electrode array (3800) comprising a tissue contact layer (3810). The electrode array (3800) may be formed by a pair of embossing dies (e.g., die (3750)) that form a plurality of spaced-apart round electrodes (e.g., embossed dimples).

[0218] FIG. 39 is a schematic cross-sectional view of an electrode array 3900 including a tissue-contacting layer 3920 and in contact with tissue 3910 (e.g., the duodenum). In some variations, the tissue-contacting layer 3920 can be disposed on the electrode and / or electrode array substrate. The tissue-contacting layer 3920 can have a lower conductivity than the electrode. In some variations, the conductivity of the tissue-contacting layer can be about 0.03 S / m to about 0.9 S / m, about 0.03 S / m to about 0.3 S / m, and about 0.01 S / m to about 0.7 S / m, including all ranges and subvalues ​​therebetween. In some variations, the tissue-contacting layer can have a thickness of about 10% to about 20% of the width of the electrode. In some variations, the tissue-contacting layer can be composed of an ohmic electrical conductor, such as carbon particle-loaded rubber, or a porous material, such as an open-cell sponge, with an ionic conductor, such as sodium chloride or carbon.

[0219] In some variations, the portion of the tissue-contacting layer disposed between the electrodes and / or on the edges of the electrodes may have a thickness of about 0.02 mm to about 0.08 mm and a conductivity of about 0.02 S / m to about 0.4 S / m, inclusive of all ranges and subvalues ​​therebetween. The tissue-contacting layer disposed on the electrode edges can reduce heating by reducing current draw in high field strength portions of the electrode. For example, this portion of the tissue-contacting layer may comprise carbon black disposed in a polymer matrix (e.g., acrylic). For example, one or more electrode edges may comprise a tissue-contacting layer (e.g., carbon black) having a thickness of about 0.02 mm to about 0.05 mm and a conductivity of about 0.02 S / m to about 0.4 S / m. Carbon black may improve the performance of the electrode array by absorbing ultraviolet energy and reducing sparkover.

[0220] In some variations, the electrode array may further comprise a hydrophilic layer disposed on the electrodes and / or substrate to improve the gliding of the pulsed electric field device over tissue. Similarly, the dilator or any component of the pulsed electric field device may comprise a hydrophilic layer to improve the gliding of the pulsed electric field device over tissue.

[0221] 40 is a schematic cross-sectional side view of an illustrative variation of an electrode array (4000). To uniformly treat tissue at a predetermined treatment distance from the electrode (4000), the electrode array (4000) may be configured to include a plurality of electrodes (e.g., E z along the electrodes) and above the space between the electrodes (e.g., E x It may be beneficial for the electric field strength (along the

[0222] 41A-41D are electric field strength plots of illustrative electrode array variations showing how the ratio of center-to-center electrode spacing to electrode width affects electric field strength uniformity. For treatment depths of 1 mm or less, a ratio of 2:1 (FIG. 41A) may produce a non-uniform electric field, while ratios of about 2.3:1 to about 3.3:1 and about 2.8:1 to about 3.0:1 (FIGS. 41B-41D) may produce a substantially uniform electric field. For example, at a treatment depth of about 0.7 mm, the E in FIG. x and E z The difference is significantly larger than that in either of FIGS. 41B and 41C.

[0223] Figure 42 shows a histogram of the total electric field strength of the electrode array at a treatment depth of about 0.7 mm and twice that, about 1.4 mm. At the treatment depth, there is a spread of about 5% for a dose of about 3,100 V / cm. At twice that treatment depth, there is a spread of less than 2% for a dose of about 1,550 V / cm. Thus, the pulsed electric field or modulated electric field energy is delivered substantially uniformly to a given tissue depth.

[0224] In some variations, the pulsed electric field systems disclosed herein may include a return electrode for drawing PEF current from the patient. In some variations, the catheter (e.g., the third elongate body) may include the return electrode. In some variations, the return electrode may be external to the patient and in contact with the patient (e.g., a skin patch electrode, a grounding pad). For example, a set of return electrodes may be disposed on the patient's back to allow current to flow from the electrode array through the patient and then to the return electrode. For example, one or more return electrodes may be disposed on the patient's skin. To improve contact, a conductive gel may be applied between the return electrode and the skin.

[0225] Figure 76 is a perspective view of a variation of an expandable member (e.g., an electrode array) 7600 in a partially deployed or expanded configuration. The electrode array 7600 may comprise a plurality of elongated electrodes 7610 on a substrate 7620. In some variations, the substrate 7620 may comprise a flex circuit comprising the plurality of electrodes. The electrode array 7600 may comprise a plurality of elongated electrodes 7610 on the substrate 7620. As shown therein, the flex circuit may comprise the electrode array 7600 or a plurality of electrodes, for example, a plurality of elongated parallel electrodes.

[0226] In some variations, the substrate (7620) of the electrode array (7600) may define one or more openings (7630) (e.g., fluid openings) between adjacent electrodes (7610) configured to generate suction (e.g., negative pressure) and / or output fluid (e.g., saline). The use of suction or negative pressure applied through the openings can draw tissue toward the electrode array (7600) and facilitate contact between the tissue and the electrode array (e.g., increase the contact area between the tissue surface and the electrode surface). For example, the electrode array (7600) can engage the duodenum via suction through one or more openings (7630), which can promote more reliable (e.g., consistent) electrical contact between the pulsed electric field device and the tissue, and thus a more uniform electric field and improved treatment results. Furthermore, the applied suction can be configured to uniformly secure the apposition of the tissue to the electrode array. In some variations, a plurality of openings 7630 (e.g., a row of openings 7630) can be disposed between each pair of adjacent electrodes 7610 at a predetermined interval. For example, the openings 7630 can be spaced along the length of the electrodes 6920. In some variations, the fluid openings 7630 can be disposed closer to one of the electrodes to promote contact between tissue and at least one of the electrodes 7610. Additionally or alternatively, the openings 7630 can be equally spaced between adjacent electrodes 7610.

[0227] Additionally or alternatively, the openings 7630 can be configured for fluid irrigation. The electrode array 7600 can be in fluid communication with (e.g., fluidly coupled to) a fluid source (not shown) for fluid irrigation. For example, fluid can be removed from (e.g., aspirated from) the body cavity after applying a pulsed or modulated electric field using the electrodes 7610. In some variations, removal of fluid can facilitate apposition and / or contact of tissue with the electrode array 7600.

[0228] In some variations, at least one of the electrodes (7610) may have a semi-elliptical cross-sectional shape. In some cases, all of the electrodes (7610) in the electrode array (7600) may have a semi-elliptical cross-sectional shape. In some variations, the major axis of the electrode (7610) may be approximately twice the electrode width, and the minor axis of the electrode may be approximately equal to the electrode height at the center of the electrode.

[0229] FIG. 77 is a perspective view of an illustrative variation of a pulsed electric field device (7700) in an expanded configuration configured to engage tissue, such as the inner surface of the duodenum (not shown). The pulsed electric field device (7700) may comprise a first elongate body (7710), a second elongate body (7720), an expandable member (7730), and dilators (7760, 7762). When in the expanded or deployed configuration, the expandable member (7730) may have a generally elliptical or cylindrical shape, with a second inner diameter and a second outer diameter having predetermined diameters greater than the first inner diameter and the first outer diameter, respectively. The expandable member (7730) in the expanded configuration may have a predetermined flexibility configured to conform to the shape of the tissue it engages. The expandable member (7730) may comprise, for example, the electrode array (7600) depicted in FIG. 76.

[0230] In some variations, the first and second elongate bodies 7710, 7720 can be configured to rotate axially relative to one another to transition the expandable member 7730 between a compressed configuration, an expanded configuration, and a semi-expanded configuration therebetween. For example, the second elongate body 7720 (e.g., an internal torsion member, rotatable member) can be rotatably positioned within the lumen of the first elongate body 7710, such that rotation of the second elongate body 7720 relative to the first elongate body 7710 transitions the expandable member 7730 between a rolled configuration and a deployed configuration. In some of these variations, the inner diameter of the lumen 7750 of the expandable member 7730 can be at least about 8 mm, at least about 10 mm, or between about 8 mm and about 10 mm in the deployed configuration, including all values ​​and subranges therebetween. As described in more detail herein, a visualization device (not shown) may be disposed within the lumen (7750) of the expandable member (7730) to assist in visualization. It should be understood that the pulsed electric field device (7700) may be advanced adjacent to the visualization device and / or over a guidewire. In some variations, a visualization device may be used to guide advancement and visualize the treatment procedure such that a guidewire and / or other visualization modalities (e.g., fluoroscopy) are not required.

[0231] In some variations, the expandable member (7730) can be configured to transition between a compressed configuration and an expanded configuration. For example, the expandable member (7730) can transition to a partially expanded or semi-expanded configuration (between the compressed and expanded configurations), which can allow a visualization device (e.g., an endoscope) to be disposed within the lumen of the expandable member (7730). In some variations, the inner surface of the expandable member can engage and retain the visualization device in the semi-expanded configuration.

[0232] FIG. 78A is an image of a pulsed electric field device (7800) in a compressed configuration, and FIG. 78B is a detailed image of the deployed electrode array (7800) of the pulsed electric field device depicted in FIGS. 77 and 78A. The electrodes shown in FIGS. 76-78B may have a generally hemispherical shape, as described herein. In some variations, one or more of the electrodes of the electrode array (7610) may have a height of about 0.07 mm to about 0.38 mm, to about 0.178 mm, inclusive of all ranges and subvalues ​​therebetween. In some variations, the distance between adjacent (e.g., nearby) electrodes (7610) may be about 1.0 mm to about 1.4 mm, to about 1.2 mm, inclusive of all ranges and subvalues ​​therebetween. In some variations, one or more of the electrodes of the electrode array (7610) may have a pad width of about 0.5 mm to about 0.7 mm, to about 0.6 mm, inclusive of all ranges and subvalues ​​therebetween. In some variations, the distance between the electrode (7610) and the temperature trace (not shown) can be about 1.0 mm to about 1.4 mm, about 1.2 mm, including all ranges and subvalues ​​therebetween.

[0233] 43 is a perspective view of an illustrative variation of an expandable member 4300 comprising an electrode array 4310 comprising a plurality of spaced-apart, semi-elliptical electrodes. The semi-elliptical electrodes may form a plurality (e.g., 4, 8, 12, 16, 20, or any value therebetween) of parallel or interdigitated lines. Additionally or alternatively, the semi-elliptical electrodes may be raised relative to the substrate of the electrode array and may comprise a rounded or hemispherical shape. In some variations, the electrode array may comprise a tissue-contacting layer disposed over one or more of the electrodes and the spaces between the electrodes, as described in detail herein.

[0234] 44 is a perspective view of another illustrative variation of an expandable member 4450 comprising an electrode array. As shown therein, the electrode array may comprise a plurality of semi-elliptical electrodes 4460 and a plurality of leads 4470 that connect two or more of the electrodes to one another in a zigzag pattern. The electrode array may comprise a flex circuit.

[0235] 45A-45C are schematic diagrams of illustrative variations of electrode array configurations, such as a pair of twisted pair wires driven 90 degrees out of phase with alternating polarity. This configuration may enable the generation of a substantially uniform pulsed or modulated electric field. For example, electrode pair A (4510) and C (4530) may have opposite polarities, while electrode pair B (4540) and D (4520) may have opposite polarities. Other electrode array configuration types may be activated in alternative combinations to provide uniform treatment within tissue (e.g., electrode pair A and B, electrode pair A and C, electrode pair A and D, electrode pair B and C, electrode pair B and D, electrode pair C and D). The distance between electrode pairs will directly affect the magnitude of the electric field or the tissue treatment distance into the tissue. Electrode pairs may be selected by the controller to treat tissue at one or more predetermined tissue treatment depths.

[0236] Figure 45D is a plan view of an electric field intensity plot 4500 of an illustrative variation of an electrode array 4550. Figure 45E is a cross-sectional view of an electric field intensity plot 4502 of the electrode array 4550 depicted in Figure 45D. The electrode array 4550 can be configured in a bipolar configuration to deliver non-thermal therapy primarily to duodenal tissue. For example, current flows from an anodal electrode, through tissue, to a cathodal electrode.

[0237] In some variations, the depth of electric field penetration into tissue may be based at least in part on the electrode spacing of the electrode array (e.g., 1.2 mm) and the voltage at the electrode array (e.g., 600 V). For example, the electrode array (4550) may be configured to generate a pulsed electric field that penetrates tissue to a depth of about 1 mm, while rapidly dissipating at the ends of the electrode array (4550) beyond a tissue depth of about 1.5 mm.

[0238] Figure 46A is a schematic perspective view of an illustrative variation of a coordinate system for an electrode array (4610) and a corresponding set of planes. Figure 46B depicts electric field intensity plots corresponding to the electrode array (4610) at positions defined relative to the major planes shown in Figure 46A. The bottom two charts in Figure 46B illustrate an equipotential plot at the target treatment depth (e.g., z=0.7 mm) and a histogram of the total electric field at the target treatment depth (e.g., z=0.7 mm).

[0239] Figure 47A is a schematic plan view of an illustrative variation of the polarity configuration of the electrode array (4700). Figure 47B depicts an electric field intensity plot corresponding to the electrode array (4700) shown in Figure 47A at a location defined relative to the major plane depicted in Figure 46A. The bottom two charts in Figure 47B illustrate an equipotential plot at the target treatment depth (e.g., z = 0.7 mm, 1.4 mm) and a histogram of the total electric field at the target treatment depth (e.g., z = 0.7 mm, 1.4 mm). The electric field density depicted in Figure 47B and corresponding to the electrode array (4700) is denser than that depicted in Figure 46B and corresponding to the electrode array (4600). The corresponding inactive electrode set may be at a floating potential while the other electrode set is active.

[0240] Figure 48 is a schematic plan view of an illustrative variation of an electrode array (4800) with illustrative dimensions and thermally bonded traces on the right side of the electrode array (4800). Figure 49 is a perspective view of a variation of an electrode array (4900) of a pulsed electric field device comprising multiple pairs of twisted pair wires. Figure 50 is a perspective view of another variation of an electrode array (5000) of a pulsed electric field device comprising multiple pairs of twisted pair wires. Twisted pair wires with exposed core locations can function similarly to a dot electrode configuration.

[0241] FIG. 85 is a perspective view of a variation of an electrode (8530) of a pulsed electric field device (8500). The pulsed electric field device (8500) may include a first catheter (8510) (e.g., an inner shaft) and a second catheter (8520) (e.g., an outer shaft). In some variations, the second catheter (8520) may be slidably advanced over the first catheter (8510) and the electrode (8530) to hold the electrode (8530) in a compressed configuration. As shown in FIG. 85, advancing the first catheter (8510) distally relative to the second catheter (8520) may transition the electrode (8530) to an expanded configuration. In some variations, the electrode (8530) may be coupled (e.g., attached) to the first catheter (8510) at one end and coupled to the second catheter (8520) at the other end. The second catheter (8520) can be slidably advanced and / or retracted over the first catheter (8510). The electrode (8530) can transition between an expanded configuration and a compressed configuration.

[0242] The electrode (8510) may comprise an expandable metal mesh and may be configured to have a first polarity. Another electrode having a second polarity opposite to the first polarity may be disposed, for example, on the patient's skin (e.g., a grounding pad). In some variations, the size of the grounding pad may have a surface area sufficient to minimize current crowding and heat generation. In some variations, the pulsed electric field device (8500) may be configured in a monopolar or bipolar configuration. In some variations, the expandable electrode (8510) may be configured to contact tissue in the expanded configuration. In some variations, negative suction may be applied through the lumen of the electrode (8510) to enhance the tissue-electrode interface. In some variations, the pulsed electric field device (8500) may be flushed using a liquid (e.g., a conductive liquid, saline) while treating tissue as described herein. In some variations, the pulsed electric field device (8500) in the compressed configuration may be configured to be slidably advanced through a lumen (e.g., a working lumen) of a visualization device (e.g., an endoscope). For example, the pulsed electric field device (8500) in the compressed configuration can have a diameter of about 1.5 mm to about 4 mm.

[0243] Cleaning In general, tissue treatment procedures using the pulsed electric field devices described herein may optionally include fluid delivery (e.g., fluid irrigation) during tissue treatment. In some variations, tissue treatment procedures may benefit from fluid irrigation, which may promote more reliable (e.g., consistent) electrical contact between the pulsed electric field device and the tissue, thus promoting a more uniform electric field and improved treatment results. Liquid irrigation of the tissue may further reduce tissue temperature through forced convection and reduce arcing. Additionally, fluid delivery may reduce corrosion of electrical insulation and the accumulation of electrolysis products. In some variations, the fluid may act as a salt bridge between the electrode and the tissue, allowing for control of resistivity. In variations in which a fluid is delivered, the fluid can be removed from the body cavity (e.g., aspirated from the body cavity) after application of the pulsed or modulated electric field. In some variations, the conductivity of the introduced or removed fluid may affect the delivered treatment. For example, adding a solution that is less conductive than the tissue may facilitate increasing the current introduced into the tissue. A conductivity similar to that of tissue may facilitate the transfer of electric field energy to tissue even in the absence of tissue contact between the electrode and the tissue. Finally, fluids with a higher conductivity than tissue can be removed.

[0244] In some variations, the pulsed electric field devices described herein can be configured to output fluid to irrigate tissue, such as duodenal tissue, of a patient. For example, an electrode array of a pulsed electric field device can engage the duodenum and be configured to output fluid (e.g., saline) where the electrodes contact the tissue. The electrode array, e.g., one or more electrodes of the electrode array, can output fluid between the electrode and the tissue, which can directly target the electrode and allow for a reduction in fluid volume. The electrode array can be energized to treat a predetermined portion of the tissue and resurface the duodenum. Utilizing an electrode array configured to deliver fluid can eliminate the need for a separate irrigation device and / or system. FIGS. 69A and 69B are respective plan and perspective views of an illustrative variation of an electrode array (6900) comprising a substrate (6910) (e.g., a flex circuit) and a plurality of electrodes (6920). For example, the plurality of electrodes (6920) can comprise a plurality of substantially elongated electrodes disposed on the substrate (6910). In some variations, one or more (e.g., all, half, one-third, two-thirds) of the electrodes (6920) may include one or more (e.g., one, two, three, four, or more) fluid openings (6930) configured to output a fluid, such as saline solution, for irrigation. For example, the openings (6930) may be spaced along the length of the electrode (6920). As shown in FIG. 69C, one or more openings (6930) may be disposed on the top of each electrode (6920), although openings (6930) may be disposed in any portion of the electrode (6920) (e.g., base, sidewall, edge). Additionally or alternatively, the substrate (6910) may include one or more fluid openings (not shown), such as between adjacent electrodes (6920). The electrode array (6900) may be in fluid communication (e.g., fluidly coupled) with a fluid source (not shown) for fluid irrigation.

[0245] FIG. 69D is a perspective cross-sectional view of an electrode array (6900) depicting an electrode (6920) with fluid paths (6940). The fluid paths (6940) of an electrode (6920) may be in fluid communication with the fluid openings (6930) of that electrode (6920). One or more of the fluid paths (6940) may be in fluid communication with a fluid source such that fluid flows through the electrode array (6900). In some variations, the electrode array (6900) has a flow rate of about 0.001 cc / (s cm 2 ) ~ approx. 1cc / (s cm 2 ) may output fluid at a predetermined rate. For example, the electrode array (6900) may be configured to drain water when in the expanded configuration. The fluid between the electrode array (6900) and the tissue may function in a manner similar to the tissue contact layer described herein.

[0246] In some variations, the expandable member may include one or more fluid pathways. In some variations, the fluid pathways may be configured to facilitate fluid flow for conduction (e.g., ionic fluids) and heat transfer (e.g., temperature control during treatment). In some variations, the fluid pathways may be configured to remove (e.g., via suction or negative pressure), for example, fluid used for conduction. The use of suction or negative pressure applied through the fluid pathways may draw tissue toward the expandable member (e.g., electrodes) and facilitate uniform contact (e.g., apposition) of the tissue with the electrode array (e.g., increase the contact area between the tissue surface and the electrode surface). In some variations, fluid openings may be disposed at the peaks of one or more of the multiple electrodes (6920). In some of these variations, fluid openings may be disposed between the electrodes, for example, at the lowest point (e.g., depression, valley) between a pair of electrodes (6920). In some variations, a fluid source may be in fluid communication with the electrode array (6900). In some variations, removal of fluid may facilitate apposition and / or contact of the tissue with the electrode array (6900).

[0247] Sensor In some variations, the pulsed electric field devices and systems described herein may include one or more sensors. Generally, the sensors may be configured to receive and / or transmit signals corresponding to one or more parameters. In some variations, the sensors may include one or more of a temperature sensor, an imaging sensor (e.g., a CCD), a pressure sensor, an electrical sensor (e.g., an impedance sensor, a voltage sensor, a magnetic sensor (e.g., an RF coil), an electromagnetic sensor (e.g., an infrared photodiode, an optical photodiode, an RF antenna), a force sensor (e.g., a strain gauge), a flow or velocity sensor (e.g., a hot wire anemometer, a vortex flowmeter), an acceleration sensor (e.g., an accelerometer), a chemical sensor (e.g., a pH sensor, a protein sensor, a glucose sensor), an oxygen sensor (e.g., a pulse oximetry sensor), an audio sensor, a sensor for sensing other physiological parameters, combinations thereof, and the like. In some variations, the electrical characteristics of the cell may also be determined by applying an alternating current signal at a particular frequency to measure the voltage.

[0248] Temperature measurements performed during a tissue treatment procedure can be used to determine one or more of tissue contact (e.g., full contact, partial contact, no contact) with the pulsed electric field device and successful energy delivery to the tissue. Thus, the safety of the tissue treatment procedures described herein can be enhanced through temperature measurement and monitoring. In some variations, tissue temperature monitoring can be used to prevent excessive energy delivery to the tissue, which could otherwise result in insufficient or suboptimal treatment results. For example, if tissue temperature measurements exceed a predetermined threshold, energy delivery can be inhibited or delayed.

[0249] As described herein, pulsed or modulated electric field treatment of tissue inevitably heats the tissue around the electrodes locally. Temperature feedback allows for variations in electrical conductivity and contact resistance to be taken into account so as not to overheat the tissue to the point of necrotic cell death (e.g., heat-induced ablation). In some variations, a four-point probe can be configured as an invasive sensor element within the electrode array. In a four-point probe connection, a differential voltage developed across the sense lines can be sensed by a first pair of conductors, and a current drive generating the differential voltage can be applied by a second pair of conductors. In some variations, the drive current or drive voltage can be pulsed. For example, FIG. 51A is a schematic circuit diagram of an illustrative variation of an expandable member (5100) and a tissue temperature sensor array (5120). The electrode array (5110) can include multiple elongated electrodes parallel to and spaced apart from one another. The electrode array (5110) can further include a tissue temperature sensor array as described herein. For example, in some variations, one or more tissue temperature sensors can be disposed between adjacent electrodes in the array 5110. For example, the tissue temperature sensors can be configured to extend parallel or interdigitated between adjacent elongated electrodes 5110. FIG. 51A depicts multiple groups of electrodes (e.g., zones A, B, and C) with corresponding temperature sensors. The tissue temperature sensor array can include a common point 5120 where a four-point drive current (e.g., sense current) begins to pass through a temperature sense trace 5140. Multiple temperature sensors can be provided per zone. For example, trace 5140 is between the sense points of zone A and zone B, and trace 5140 is in series with trace 5130. The voltage difference between the sense current in each zone divided by the sense current flowing through the entire trace can provide the resistance of trace 5140. The measured change in resistance of the trace (5140) may correspond to a change in temperature given the known change in resistance of copper with temperature.

[0250] The temperature sensors can be configured to be thermally coupled and in contact with the tissue so that the measured sensor temperature corresponds to the tissue temperature. The temperature sensors can be electrically isolated from the tissue so that the sense current passes only through the temperature sensors and high voltage driving of the electrodes does not damage the temperature sensors. In some variations, the electrode array can include one or more drive circuits for applying voltage or current pulses to the temperature sensors and sense circuits for measuring the voltage or current across the temperature sensors.

[0251] In some variations, the temperature sensor (5120) may comprise an insulator configured to maintain a pulse waveform configured to generate a pulsed or modulated electric field to treat tissue without breakdown. In some variations, the insulator may include a thickness of at least about 0.02 mm. In some variations, the temperature sensor (5120) may include a width of up to about 0.07 mm and a length of at least about 2 cm. In some variations, the distance between the temperature sensor (5120) and the electrode (5110) may be at least about 0.2 mm. In some variations, the temperature sensor (5120) may extend substantially parallel to the elongated electrode (5110).

[0252] In some variations, each of the temperature sensors may include a temperature resolution of less than about 0.5° C. For example, a half-ounce copper electrode about 0.075 mm wide and about 2 cm long may include a resistance of about 0.267 ohms at 37° C. and about 0.273 ohms at 43° C., and may provide a resolution of about 0.5° C. for every 2 cm of electrode. Longer electrodes may provide proportionally greater sensitivity. In some variations, the temperature sensors may include a thermal diffusion time constant of less than about 5 milliseconds.

[0253] In some variations, the measured temperature can be used to determine whether the electrode array is in contact with tissue. For example, a current pulse of length t can be applied to the material surrounding the sense wires to approximately

number

number

number

[0254] I s =0.5A and L s = 2cm and R s Using a ΔT = 0.276 ohms results in ΔT = 1.6°C. This constant temperature difference is present in all measurements and is therefore removed from the temperature rise measurements. The temperature rise when there is no tissue contact is given by equation (6).

number

[0255] Z f is the thickness of the substrate. Z f = 0.135 mm and τ = 1 ms, resulting in ΔT = 0.65°C. Pulses longer than about 6 ms can cause a measured temperature rise corresponding to tissue temperature due to wire heating. The maximum pulse width is given by equation (7). τ=s 2 / κ Equation (7)

[0256] s is the spacing between the temperature sensors. For temperature sensors spaced approximately 0.075 mm apart, the maximum pulse duration may be approximately 21 milliseconds before the wire begins to heat linearly with time. By monitoring the rate of temperature rise, tissue contact can be determined. If the measured temperature exceeds a predetermined threshold, energy delivery may be modified (e.g., reduced, inhibited).

[0257] In some variations, the temperature sensor can be configured to operate in a second mode where one conductor in the temperature sensor carries current and voltage across a fine trace. In the second mode, the temperature can be calculated using V / I=R across the trace, assuming the temperature sensor has a rapidly changing resistance.

[0258] FIG. 51B is a schematic circuit diagram of an illustrative variation of an electrode array 5110 including multiple temperature sensors 5120 and a reference generator 5160 (described in more detail with respect to FIGS. 52 and 59). FIG. 51C is an image of a visual marker on duodenal tissue generated by the expandable member 5100 shown in FIG. 51B. The expandable member 5100 may define multiple openings 5170 (e.g., fluid openings, through-holes) configured for one or more of suction and / or fluid irrigation, as described in detail herein. Additionally, the expandable member 5100 may include one or more tracks 5180 configured to couple to one or more of gears and friction rollers. The track 5180 may include multiple spaced openings in the expandable member 5100 configured to assist in expansion and contraction of the expandable member between a compressed configuration and an expanded configuration. In some variations, the fiducial generators (5160) may include a length of approximately 2 mm and a width of approximately 2 mm. In some variations, one or more of the fiducial generators (5160) may include a shape having one or more vertices (e.g., corners, angle points, intersections), such as a square, rectangle, triangle, polygon, etc. Visual markers generated on tissue may be easier to identify and visualize if they are formed with sharp corners rather than rounded edges. For example, visual markers having a circular shape may be relatively difficult to distinguish from natural tissue.

[0259] In some variations, one or more of the reference generators (5160) may comprise a DC resistive heater configured to mark the tissue. The reference generators (5160) may be electrically isolated from the electrode array (5110). In some variations, one or more of the reference generators (5160) may be configured to raise the temperature of the top layer of mucosal tissue (e.g., less than 0.1 mm deep) to an average of about 49°C in less than about 2.5 seconds. In this manner, one or more of the visual markers may fade and become visually invisible after about one day. In some variations, histological evidence of the visual markers may disappear after about three days. The visual markers may be configured to identify the treatment site and aid in repositioning the ablation device. For example, an operator may advance the expandable member (5100) past the most distal visual marker in the duodenum during an ablation procedure.

[0260] The duodenal tissue (5102) shown in Figure 51C includes a pair of visual markers (5162) generated on the tissue (5102) by a fiducial generator (5160). In some variations, the visual markers can be identified based on one or more of the color, shape, number, and size of the markers left on the tissue. The visual markers can be visualized, for example, by using an endoscope. A set of repeating shapes may be easier to distinguish than a single visual marker. Figure 51B depicts a set of eight fiducial generators (5160).

[0261] FIG. 51D is a detailed schematic circuit diagram of the expandable member 5100, showing the temperature sensors 5120 and openings 5170 without the electrode array 5110 for clarity. As shown in FIG. 51D, the temperature sensors 5120 may include a serpentine shape that may snake back and forth along a predetermined path. For example, the temperature sensors 5120 may curve around each opening 5170 in the expandable member 5100. As described herein, one or more openings 5170 may extend through the expandable member 5100 such that tissue may contact the expandable member 5100 and be uniformly suctioned into and through the openings 5170. In some variations, the reference generator 5160 may be spaced between adjacent electrode array 5110 sections (e.g., between section 1 and section 2).

[0262] In some variations, the electrode array (5110) may include a length of approximately 60 mm and a width of approximately 20 mm. Thus, approximately 20 mm of the duodenum may be treated at one time. In some variations, the electrode array (5110) may be divided into two or more independently powered sections to reduce signal generator requirements. For example, the electrode array (5110) may have a circumferential length of approximately 60 mm. An electrode array (5110) including two sections may have each section including a circumferential length of approximately 27 mm. In some variations, the configuration and placement of the electrode array (5110) on the expandable member may facilitate one or more of manufacturing techniques and tissue temperature measurement at a predetermined depth. In some variations, a set of reference generators may be disposed between sections of the electrode array; for example, each reference generator may generate a visual marker having a length and width of approximately 2 mm. Expandable member (5100) as depicted in FIG. 51B and described herein may correspond to expandable member (7600) depicted in FIG.

[0263] In some variations, one or more of the temperature sensors (5120) (e.g., temperature traces) can generally extend across the multiple electrodes of the electrode array (5110). For example, one or more of the temperature sensors (5120) can comprise a generally serpentine shape, which may be continuous. In some variations, the temperature sensor (5120) can measure an average temperature across a predetermined portion of the sensor (5120), which may be a better representation of the tissue temperature. In contrast, temperature measurements taken very close to the ends of the electrodes can result in misleadingly high temperatures that are not representative of the temperature throughout the tissue. In some variations, the temperature trace lines can be disposed on the electrode side of the expandable member (5100) and / or along the opposite side of the expandable member (5100). In some variations, temperature measurements from one or more temperature sensors (5120) can correspond to the temperature of the tissue at a predetermined depth.

[0264] In some variations, one or more of the temperature sensors (5120) may have a thickness of about 0.030 mm to about 0.040 mm and a width of about 0.09 mm to about 0.12 mm. In some variations, a temperature sensor may be spaced apart from itself and / or other temperature sensors by about 0.10 mm to about 0.17 mm. In some variations, one or more temperature sensors (5120) may be disposed on the expandable member (5100) using button plating.

[0265] In some variations, visually marking treated tissue can assist an operator in performing tissue treatment procedures in which separate portions of tissue are treated sequentially. In some variations, the reference generator can be configured to generate a visual marker on the tissue, allowing the treated portion of tissue to be visualized within a body cavity (e.g., the duodenum). In some of these variations, the reference generator can be disposed on the substrate of the electrode array along the periphery of the elongated electrode. In some variations, the reference generator can include one or more temperature sensors as described herein. In some variations, the reference generator can include a spiral or serpentine shape. In some variations, the high-current pulse can be configured to heat one or more reference generators to greater than 80°C, thereby creating a visually discernible mark on the tissue in contact with the reference generator. FIG. 52A is a schematic circuit diagram (5200) of an illustrative variation of an electrode array (5210) and multiple (e.g., four) reference generators (5220). Figure 52B is a detailed view of the schematic circuit diagram of the electrode array 5210 and one spiral reference generator 5220. Figure 59 is an image of an illustrative variation of an electrode array 5900 comprising multiple electrodes grouped into different sections (5910, 5920, 5930, 5940), a connector pad 5950, and multiple reference generators 5960. For example, the electrode array 5900 can be grouped into a first section 5910, a second section 5920, a third section 5930, and a fourth section 5940. Each of the sections can be wired to a corresponding pad (S1, S2, S3, S4) on the connector pad 5950. In some variations, each section (5910, 5920, 5930, 5940) may include at least one reference generator (5960). The reference generators (5960) may be wired in series. In some variations, the electrode array (5210) within the tissue may be deployed at different diameters based on the local diameter of the tissue being treated (e.g., the duodenum).The electrode array (5210) can be configured such that only sections of the electrode array (5900) that are in at least partial contact with tissue can be energized by the signal generator, hi some variations, the signal generator can be configured to sequentially drive each section of the electrode array (5900).

[0266] In some variations, one or more reference generators can be disposed between electrodes of the electrode array, for example, the reference generators can have elongated shapes between adjacent electrodes and be disposed near the edges of the electrode array, which can reduce the length of one or more of the elongated electrodes.

[0267] expander Generally, the dilators described herein can be configured to aid in the advancement of one or more portions of a pulsed electric field device into and through a body cavity or lumen, such as the duodenum. In some variations, the dilator can be generally configured to dilate a body cavity or lumen, such as the lumen of the duodenum. The dilator can be atraumatic in shape to minimize inadvertent or unintended injury and can comprise any shape (e.g., conical) suitable for enlarging a tissue lumen. For example, in some variations, the dilator can comprise a cone shape with a taper of about 1 degree to about 45 degrees, which can facilitate the advancement of the PEF device through the gastrointestinal tract. In some variations, the dilator can comprise PET, PEBA, PEEK, PTFE, silicone, PS, PEI, latex, sulfate, barium sulfate, copolymers, combinations thereof, or the like. In some variations, the dilator can comprise a solid construction. In some variations, the dilator can comprise multiple materials configured to provide desired stiffness and compliance along the length of the dilator. In some variations, the dilator may include one or more components configured to facilitate advancement of the guidewire.

[0268] In some variations, the dilator can include a length of about 2 mm to about 10 cm. In some variations, the dilator can include a taper of about 5 degrees to about 30 degrees relative to the longitudinal axis of the dilator. In some variations, the distal end of the dilator can be atraumatic (e.g., rounded, blunt). In some variations, the pulsed electric field device can include multiple dilators (e.g., 2, 3, 4, 5, 6, or more). For example, each dilator can be disposed proximally and distally of the expandable member. This allows for smooth advancement of the pulsed electric field device proximally and distally.

[0269] In some variations, the dilator may include a recess configured to facilitate mating or coupling with another elongate member, such as a visualization device (e.g., an endoscope). For example, this may allow the dilator and expandable member to be removably coupled to a visualization device during a treatment procedure. The lengths and tapers of the dilators of a pulsed electric field device may be the same or different. For example, a distal dilator may have a steeper taper than a proximal dilator.

[0270] Long, slender body Generally, the elongate bodies (e.g., catheters) described herein can be configured to deliver an electrode array to the duodenum to treat tissue, such as duodenal tissue. In some variations, the elongate body can include a shaft constructed from a flexible polymeric material such as Teflon, nylon, Pebax, urethane, combinations thereof, or the like. In some variations, the pulsed electric field device can include one or more steerable or deflectable catheters (e.g., one-way, two-way, four-way, omnidirectional). In some variations, the elongate body can include one or more pull wires configured to steer or deflect a portion of the elongate body. In some variations, the elongate body can have a length of about 5 cm to about 23 cm and / or a bend radius of about 45 degrees to about 270 degrees. In some variations, the elongate bodies described herein can include a lumen through which another elongate body and / or a guidewire can slide. In some variations, the elongate body can include multiple lumens. For example, the elongate body may include one or more of an inflation lumen, a fluid lumen, a guidewire lumen, and a lead lumen.

[0271] In some variations, the elongate body may be woven, braided, and / or coiled and may be constructed from materials (e.g., nylon, stainless steel, nitinol, polymers) configured to enhance pushability, twistability, and flexibility. In some variations, one or more of the first and second elongate bodies may include a metal-based radiopaque marker comprising one or more of rings, bands, and inks (e.g., platinum, platinum-iridium, gold, nitinol, palladium) configured to enable fluoroscopic visualization. In some variations, one or more of the first and second elongate bodies may include a magnetic member configured to attract and bond the bodies to each other. In this manner, the first elongate body need not include a lumen for the second elongate body. In some variations, the elongate body may include from about 2 to about 15 layers of material to achieve a predetermined set of properties.

[0272] handle Generally, the handles described herein can be configured to allow an operator to grasp and control one or more of the position, orientation, and operation of the pulsed electric field device. In some variations, the handle can include actuators that allow translation and / or rotation of the first and second elongate bodies in addition to steering with an optional delivery catheter. In some variations, control of the expandable member can be performed by an expansion member of the handle (e.g., a screw / rotation actuator, an inflation actuator). In some variations, the handle can be configured to control PEF energy delivery to the electrode array of the expandable member using, for example, a handheld switch and / or a foot switch.

[0273] FIG. 84 is a cross-sectional perspective view of a set of lead wires (8400) (e.g., power transmission wires, wiring harness). In some variations, the set of lead wires (8400) can couple a signal generator and / or handle to one or more distal components (e.g., electrodes, reference generator, temperature sensor) of a pulsed electric field device (not shown for clarity). The lead wires (8400) can be configured for one or more of power delivery, temperature sensing, and reference generation. In some variations, the power transmission wires (8430) can comprise multiple twisted pair wires. In some variations, the set of twisted pair wires (8430) can comprise from about 1 to about 20 twisted pairs, depending on the frequency and current of the energy being delivered. In some variations, the set of twisted pair lead wires (8430) can facilitate high amperage and frequency transmission while minimizing losses. The set of twisted pair wires (8430) can be the same diameter or different diameters. For example, the wire size and insulation thickness can be configured to minimize one or more of inter-wire inductance, wire resistance, wire temperature rise, and wire skin effect. Additionally or alternatively, specially woven Litz wire and / or tubular conductors (e.g., coaxial cable) can be used to minimize these variations (e.g., inductance, resistance, temperature, skin effect) and reduce losses. In some variations, the reference generating wire (8410) can be configured to deliver energy to one or more reference generators as described herein. In some variations, the reference generating wire (8410) may be untwisted. In some variations, the temperature sense wire (8420) can be configured to measure temperature from one or more temperature sensors of the pulsed electric field device. In some variations, the reference generating wire (8410) can be untwisted and have a larger diameter than the power transmitting wire (8430) and the reference generating wire (8410).

[0274] insulator In general, the insulators described herein can be configured to electrically insulate another portion of the electrode array, the expandable member, the inflatable member, the dilator, and / or the elongate body of the pulsed electric field device from one another. In some variations, the insulator can include one or more of poly(p-xylylene) polymers (e.g., parylene C, parylene N), polyurethane (PU), polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyimide (PI), polyester, polyethylene terephthalate (PET), PEEK, polyolefins, silicones, copolymers, ceramics, combinations thereof, and the like.

[0275] Guidewire In some variations, a guidewire can be slidably disposed within the lumen of the elongate body of the pulsed electric field device. The guidewire can be configured to aid in the advancement of the pulsed electric field device through the gastrointestinal tract. In some variations, the first and second elongate bodies of the pulsed electric field device can translate along the guidewire, relative to each other, and / or relative to the duodenum. In some variations, the guidewire can comprise one or more of stainless steel, nitinol, platinum, and other suitable biocompatible materials. In some variations, the guidewire can have variable stiffness along its length. For example, the distal tip can be configured to be malleable (e.g., floppy), and the elongate body of the guidewire can be relatively stiff to aid in pushability through the patient's anatomy. In some variations, the guidewire can have a diameter of about 0.014 inches to about 0.060 inches and a length of about 180 cm to about 360 cm.

[0276] signal generator Generally, the signal generators described herein can be configured to provide energy (e.g., a PEF energy waveform) to a pulsed electric field device to treat a predetermined portion of tissue, such as duodenal tissue. In some variations, the PEF systems described herein can include a signal generator having an energy source and a processor configured to deliver a waveform for delivering energy to tissue. The waveforms disclosed herein can assist in the treatment of diabetes. In some variations, the signal generator can be configured to control the generation and delivery of the waveform in response to received sensor data. For example, if a temperature sensor measurement identifies that the tissue temperature exceeds a predetermined threshold or range (e.g., exceeds a predetermined maximum temperature), energy delivery can be inhibited.

[0277] The signal generator can generate and deliver several types of signals, including, but not limited to, AC current, square wave AC current, sinusoidal AC current, AC current interrupted at predetermined time intervals, multiple profile current pulse trains of various power intensities, direct current (DC) impulses, stimulation range impulses, and / or hybrid electric impulses. For example, the signal generator can generate monophasic (DC) pulses and biphasic (DC and AC) pulses. In some variations, the signal generator can be configured to generate a current of about 1 A to about 200 A delivered into a system resistance of about 1 V to about 3,000 V and about 2 Ω to about 30 Ω at a frequency of about 50 kHz to about 950 kHz. The signal generator can include a processor, memory, an energy source (e.g., a current source), and a user interface. The processor can incorporate data received from one or more of the memory, the energy source, the user interface, and the pulsed electric field device. The memory may further store instructions that cause the processor to execute modules, processes, and / or functions associated with the system, such as waveform generation and delivery. For example, the memory may be configured to store patient data, clinical data, treatment data, safety data, etc.

[0278] Generally, inducing an electric field across a cell membrane of greater than about 0.5 V in the duodenum requires about 1,000 V / cm to about 2,500 V / cm or more at the treatment depth of the tissue. In some variations, inducing an electric field across a cell membrane of greater than about 0.5 V in the duodenum requires about 1,500 to about 4,500 V / cm at the treatment depth of the tissue, including all ranges and subvalues ​​therebetween. Even with relatively low tissue conductivity (e.g., about 0.3 S / m), bulk tissue heating rates of at least about 800°C / sec can be generated. The maximum temperature rise to be generated can be about 8°C, and as a result, the maximum continuous on-time (100% duty cycle of alternating polarity pulses) can be about 10 milliseconds. For example, a pulse waveform can comprise pairs of about 1 μs unipolar pulses in about 5 to about 500 groups, with a delay between each group. In some variations, series of these groups can be applied repeatedly, with increasingly longer delays between series. In some variations, a series of sequences may be applied with a longer delay between sequences, hi some variations, a cumulative on-time of about 15 milliseconds may be distributed over about 10 seconds.

[0279] In some variations, the signal generator can be configured to generate current, voltage, and power in a pulsed or modulated electric field spectrum of about 250 kHz to about 950 MHz, a pulse width of about 0.5 μs to about 4 μs, a voltage applied by the electrode array of about 100 V to about 2 kV, and a current density from the electrode array of about 0.6 A to about 100 A per square centimeter of tissue. In some variations, the signal generator can be configured to drive a tissue resistance load of about 5 ohms to about 30 ohms. For example, the current density can be about 0.6 A to about 100 A per square centimeter of tissue from the electrode array. In some variations, the pulse waveform can include about 1 to about 50 pulse groups, with about 1 to about 100 pulses per group. In some of these variations, the pulse waveform can include a group delay of about 10 μs to about 4000 μs and an escaping rate of about 50 milliseconds to about 4000 milliseconds. For example, a balanced bipolar pulse waveform (e.g., within 10%) can reduce sympathetic excitation, thereby reducing perceived pain and voluntary muscle contractions. Microsecond pulses of approximately 1 μs to approximately 10 μs can generate cell lysis while minimizing nerve stimulation. The electric field distribution generated by short bipolar pulses is less dependent on tissue homogeneity, especially in anisotropic regions.

[0280] In some variations, a set of bipolar pulses can be divided into bursts of bipolar pairs with a time delay between bursts. This allows the heat generated at the cell membrane to dissipate, allowing for more treatment before cell lysis transitions to necrosis. The total time the pulsed or modulated electric field is applied to the tissue determines the density and size of the membrane pores and the extent to which ion flow has altered the cell contents. For example, if the thermal diffusivity κ of the tissue is 0.13 mm 2 / sec, cell diameter D cell When the temperature is 10 microns, the thermal diffusion time is approximately D 2 cell / κ=0.8 ms. Therefore, waiting milliseconds after applying the pulse burst allows the temperature to equilibrate throughout the cell.

[0281] Figure 53 is a circuit block diagram of a signal generator 5300 including a power supply 5310, a high-voltage DC power supply 5320, an output amplifier 5330, a controller 5340, a user interface 5350, and a display 5360. The controller 5340 may include a processor. Generally, a processor (e.g., a CPU) as described herein can process data and / or other signals to control one or more components of the system. The processor can be configured to receive, process, compile, calculate, store, access, read, write, and / or transmit data and / or other signals. In some variations, the processor can be configured to access or receive data and / or other signals from one or more of a sensor (e.g., a temperature sensor) and a storage medium (e.g., a memory, a flash drive, a memory card). In some variations, a processor may be any suitable processing device configured to operate and / or execute a set of instructions or code, and may comprise one or more data processors, image processors, graphics processing units (GPUs), physical processing units, digital signal processors (DSPs), analog signal processors, mixed signal processors, machine learning processors, deep learning processors, finite state machines (FSMs), compression processors (e.g., data compression to reduce data rates and / or memory requirements), encryption processors (e.g., for secure wireless data and / or power transfer), and / or central processing units (CPUs). A processor may be, for example, a general-purpose processor, a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), a processor board, etc.The processor may be configured to run and / or execute application processes and / or other modules, processes and / or functions associated with the system. The underlying device technology may be provided in a variety of component types (e.g., metal-oxide semiconductor field-effect transistor (MOSFET) technology such as complementary metal-oxide semiconductor (CMOS), bipolar technology such as emitter-coupled logic (ECL), polymer technology (e.g., silicone-conjugated polymers and metal-conjugated polymer-metal structures), mixed analog and digital technologies, etc.

[0282] The systems, devices, and / or methods described herein may be implemented by software (executed on hardware), hardware, or a combination thereof. Hardware modules may include, for example, general-purpose processors (or microprocessors or microcontrollers), field-programmable gate arrays (FPGAs), and / or application-specific integrated circuits (ASICs). Software modules (executed on hardware) may be expressed in various software languages ​​(e.g., computer code), including C, C++, Java, Python, Ruby, Visual Basic, and / or other object-oriented, procedural, or other programming languages ​​or development tools. Examples of computer code include, but are not limited to, microcode or microinstructions, machine instructions such as those produced by a compiler, code used to create web services, and files containing high-level instructions executed by a computer using an interpreter. Additional examples of computer code include, but are not limited to, control signals, encryption code, and compression code.

[0283] In general, pulsed electric field devices described herein may comprise memory configured to store data and / or information. In some variations, the memory may comprise one or more of random access memory (RAM), static RAM (SRAM), dynamic RAM (DRAM), memory buffer, erasable programmable read-only memory (EPROM), electrically erasable read-only memory (EEPROM), read-only memory (ROM), flash memory, volatile memory, non-volatile memory, combinations thereof, etc. In some variations, the memory may store instructions that cause a processor to perform modules, processes, and / or functions associated with the pulsed electric field device, such as signal waveform generation, pulsed electric field device control, data and / or signal transmission, data and / or signal reception, and / or communications. Some variations described herein relate to computer storage products with non-transitory computer-readable media (which may also be referred to as non-transitory processor-readable media) having instructions or computer code for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include a transitory, propagating signal itself (e.g., a propagating electromagnetic wave that carries information over a transmission medium such as space or a cable). The medium and computer code (also called code or algorithms) may be designed and constructed for a specific purpose or for a variety of purposes.

[0284] In some variations, the pulsed electric field device may further include a communications device configured to allow an operator to control one or more of the devices of the PEF system. The communications device may include a network interface configured to connect the pulsed electric field device to another system (e.g., the Internet, a remote server, a database) via a wired or wireless connection. In some variations, the pulsed electric field device may communicate with other devices (e.g., a mobile phone, a tablet, a computer, a smartwatch, etc.) via one or more wired and / or wireless networks. In some variations, the network interface may include one or more of a radio frequency receiver / transmitter, an optical (e.g., infrared) receiver / transmitter, etc. configured to communicate with one or more devices and / or networks. The network interface may communicate with one or more of the pulsed electric field device, the network, the database, and the server via a wired and / or wireless connection.

[0285] The network interface may include RF circuitry configured to receive and / or transmit RF signals. This RF circuitry may convert electrical signals to and from electromagnetic signals and communicate with communication networks and other communication devices via electromagnetic signals. The RF circuitry may include known circuits for performing these functions, including, but not limited to, an antenna system, an RF transceiver, one or more amplifiers, a tuner, one or more oscillators, a mixer, a digital signal processor, a CODEC chipset, a subscriber identity module (SIM) card, memory, etc.

[0286] Wireless communication through any of the devices may be performed using any of the following technologies: Global System for Mobile Communications (GSM), Enhanced Data GSM Environment (EDGE), high-speed downlink packet access (HSDPA), high-speed downlink packet access (HSUPA), Evolution, Data-Only (EV-DO), HSPA, HSPA+, Dual-Cell HSPA (DC-HSPA), long term evolution (LTE), near field communication (NFC), wideband code division multiple access (W-CDMA), code division multiple access (CDMA), time division multiple access (TDMA), Bluetooth, Wireless Fidelity (WiFi) (e.g., IEEE 802.11a, IEEE 802.11b, IEEE 802.11g, IEEE 802.11n, IEEE 802.11nb, IEEE 802.11nc, IEEE 802.11nd, IEEE 802.11nf, IEEE 802.11ng, IEEE 802.11nh, IEEE 802.11nh, IEEE 802.11nh, IEEE 802.11nb, IEEE 802.11nh ...11n, and the like), voice over Internet Protocol (VoIP), Wi-MAX, protocols for email (e.g., Internet message access protocol (IMAP) and / or post office protocol (POP)), instant messaging (e.g., extensible messaging and presence protocol (XMPP), Session Initiation Protocol for Instant Messaging and Presence Leveraging Extensions (SIMPLE), Instant Messaging and Presence Service (IMPS)), and / or Short Message Service (SMS), or any other suitable communication protocol. In some variations, devices herein may communicate directly with each other without transmitting data over a network (e.g., via NFC, Bluetooth, WiFi, RFID, etc.).

[0287] In some variations, the user interface may include an input device (e.g., a touchscreen) and an output device (e.g., a display device) and may be configured to receive input data from one or more of the pulsed electric field device, a network, a database, and a server. For example, operator control of the input device (e.g., a keyboard, a button, a touchscreen) may be received by the user interface, which may then be processed by a processor and memory for the user interface to output a control signal to the pulsed electric field device. Some variations of the input device may include at least one switch configured to generate a control signal. For example, the input device may include a touch surface for an operator to provide input (e.g., a finger touch on the touch surface) corresponding to the control signal. Input devices with a touch surface may be configured to detect contact and movement on the touch surface using any of a number of touch sensitivity technologies, including capacitive, resistive, infrared, optical imaging, dispersive signal, acoustic pulse recognition, and surface acoustic wave technologies. In variations of input devices that include at least one switch, the switch may include, for example, at least one of a button (e.g., hard key, soft key), a touch surface, a keyboard, an analog stick (e.g., a joystick), a directional pad, a mouse, a trackball, a jog dial, a step switch, a rocker switch, a pointer device (e.g., a stylus), a motion sensor, an image sensor, and a microphone. The motion sensor may receive operator movement data from the optical sensor and classify the operator's gestures as control signals. The microphone may receive audio data and recognize the operator's voice as a control signal.

[0288] A haptic device can be incorporated into one or more of the input and output devices to provide additional sensory output (e.g., force feedback) to the operator. For example, the haptic device can generate a haptic response (e.g., vibration) to confirm an operator input to an input device (e.g., a touch surface). As another example, the haptic feedback may indicate that the operator input is overridden by a pulsed electric field device.

[0289] II. Method Also described herein are methods of treating tissue. In some variations, the methods can include treating diabetes in a patient using the systems and devices described herein. In particular, the systems, devices, and methods described herein can use pulsed or modulated (e.g., sinusoidal) electric fields to resurface a predetermined portion of tissue, e.g., duodenal tissue, for example, to treat diabetes.

[0290] Generally, methods of treating tissue can deliver pulsed or modulated electric field energy to ablate native endothelial cell populations through non-thermal cell death, which can address metabolic disorders such as obesity and type I and type II diabetes. Gastric mucosal devitalization (GMD) without thermal injury to the muscularis propria can alter one or more of serum ghrelin levels, relative weight loss, visceral adiposity, organ lipid content, liver lipid / protein ratio, gluconeogenesis, and liver lipid accumulation. Energy delivery can be performed using monopolar or bipolar configurations within the gastrointestinal tract (e.g., small intestine, large intestine, esophagus). For example, energy delivery to treat Barrett's esophagus can provide long-term symptom management and reduce complications such as cancer. In some variations, precancerous esophageal cells can be treated while preserving healthy esophageal tissue. Any of the methods described herein can be performed within any part of the gastrointestinal tract (e.g., small intestine, large intestine, and esophagus).

[0291] In some variations, the generated pulsed or modulated electric field can be substantially uniform so that pulsed or modulated electric field energy for tissue treatment can be delivered to a predetermined portion of the duodenum (e.g., the mucosal layer) without significant energy delivery to deeper layers of the duodenum. Thus, these methods can improve the efficiency and effectiveness of energy delivery to duodenal tissue. Furthermore, the methods described herein can also avoid excessive thermal tissue heating that inevitably occurs with the application of one or more other thermal energy modalities to tissue.

[0292] In some variations, the methods may include using a pulsed electric field system with a closed-loop temperature feedback system. The temperature feedback system may include a temperature sensor configured to monitor tissue temperature. In these variations, the methods may inhibit delivery of a pulse waveform by the signal generator based on the sensor measurement. In some variations, the temperature rise of the tissue may be limited to about 3°C ​​to about 10°C, about 2°C to about 5°C, or about 3°C ​​to about 8°C, including all subvalues ​​and ranges therebetween. In some of these variations, the reference generator may be configured to thermally generate visual markers (e.g., fiducials) on the tissue. The visual markers may assist in identifying the tissue treatment area during and after treatment.

[0293] How to Treat Diabetes Generally, methods for treating diabetes can include generating pulsed or modulated electric fields to induce changes in (e.g., treat) duodenal tissue. Normally, the small intestine sends signals to the brain, pancreas, and liver to promote glycemic hemostasis. For example, enteroendocrine cells in the mucosal villi can generate these signals. Duodenal mucosal resurfacing using the systems, methods, and devices described herein can be used, for example, to treat type 2 diabetes. Clinical studies have shown that duodenal mucosal resurfacing of the mucosal layer of the duodenum is a safe procedure that can positively impact glycemic hemostasis in patients with type 2 diabetes.

[0294] In some variations, the pulsed or modulated electric field can cause cell lysis in the tissue that is at least 50% pore-induced and less than 50% heat-induced. In some variations, a method of treating diabetes can include advancing a pulsed electric field device toward a patient's duodenum. In some of these variations, the patient can be positioned in a left lateral decubitus position during the procedure, and the duodenum can optionally be insufflated (e.g., using CO2 or saline). The pulsed electric field device can include an elongate body and an expandable member comprising an electrode array. Upon entering the duodenum, the expandable member can transition to an expanded configuration. In some variations, one or more turns of the expandable member can be deployed to contact the duodenum. In some variations, a visualization device (e.g., an endoscope) can be advanced into the duodenum to visualize, inspect, and / or confirm the treatment area during the procedure. For example, one or more transparent portions of the pulsed electric field device can enable the visualization device to identify the ampulla of the duodenum. Once the device is positioned at a desired location within the duodenum, a pulsed waveform can be delivered to the electrodes to generate a pulsed electric field to treat a portion of the duodenum. It should be understood that any of the systems and devices described herein can be used in the methods described herein.

[0295] In some variations, a method for treating diabetes may include one or more of applying a radially outward force to the tissue to stretch (e.g., expand) the tissue and applying a negative pressure (e.g., suction) to the tissue to facilitate a consistent (uniform) tissue-electrode interface. For example, tissue stretched or expanded by the expandable member of a pulsed electric field device in the expanded configuration, whether by application of a radial force and / or negative pressure, may have a more uniform tissue thickness, which may aid in consistent energy delivery and treatment. In some variations, tissue may contact the expandable member in the expanded configuration within the duodenum. A visualization device (e.g., an endoscope) may be advanced into and disposed within the lumen of the expandable member in the expanded configuration. The visualization device may then be configured to generate sufficient negative pressure to draw the tissue into and / or through one or more openings (e.g., fluid openings) in the expandable member. This may reduce tissue tenting and / or air pockets on the electrode and ensure a consistent tissue-electrode interface around the duodenum. Additionally, suction can allow for a reduction in the radial force exerted by the expandable member. In some variations, the negative pressure (e.g., suction) applied to the tissue can be between about 50 mmHg and about 75 mmHg. In some variations, the negative pressure (e.g., suction) applied to the tissue can be between about 100 mmHg and about 250 mmHg, applied intermittently or for relatively short periods of time. For example, higher negative pressures can be applied in bursts or quickly to ensure contact between the tissue and the electrodes without tissue pressure necrosis.

[0296] FIG. 71B is a cross-sectional image of an undistracted duodenum (7100), which has varying thickness around its circumference. As shown therein, in a natural state (e.g., no external force is applied, undistracted), duodenal tissue has variable thickness around the circumference of the duodenum. FIG. 71A is a cross-sectional image of a pulsed electric field device (7110) in an expanded configuration within the duodenum (7100). The pulsed electric field device (7110) comprises an expandable member (7120), an electrode array (7122), a dilator (7130), and an elongated body (7140). The expanded pulsed electric field device (7110) expands to apply a radial force to the duodenal tissue, distending the duodenum (7110), reducing the thickness of the duodenal tissue and / or creating a more uniform duodenal tissue thickness around the circumference of the duodenum compared to an undistracted duodenum. Stretched or expanded tissue may have a narrower range of tissue thickness than unstretched tissue. In some variations, approximately 1 inch to approximately 15 inches of water (inH2O) can be applied to expand but not damage the tissue through pressure necrosis. For example, the expandable member can be configured to generate approximately 2 inches to approximately 6 inches of water (inH2O) to slightly expand tissue, such as duodenal tissue. Expanded tissue stretched by the expandable member in the expanded configuration can reduce the tissue wall thickness, thereby allowing for a lower dose of energy to treat a given depth of tissue. Stretched tissue may have a realigned (e.g., reoriented) cellular structure that increases the tissue's perimeter. Reducing total energy delivery may correspond to a lower overall temperature rise in the tissue, which can promote a faster and safer healing cascade as well as improve the safety profile of the treatment procedure.

[0297] In some variations, negative pressure can be applied to the tissue to ensure uniform contact between the tissue and the electrode array during treatment. For example, negative pressure or suction can be applied by the expandable member to the tissue lumen (e.g., the duodenum, duodenal tissue) to facilitate tissue apposition with the expandable member's electrode array. Higher tissue apposition can further enable a reduction in total energy delivery and improved treatment results.

[0298] In some variations, stretching the tissue by applying a radially outward force using an expandable member and / or by applying negative pressure to the tissue from the expandable member may reduce the range of tissue thicknesses as shown in FIG. 71A. For example, the expandable member may stretch the tissue such that the ratio of the engineered (e.g., compressed / stretched / expanded) tissue thickness to the unengineered tissue thickness is about 0.5. In some variations, the combination of tissue stretching as described herein and application of a pulsed electric field may synergistically treat the patient's tissue.

[0299] 71C and 71D are cross-sectional images of an undistracted (e.g., unstretched) duodenum. 71E and 71F are cross-sectional images of a distended (e.g., stretched) duodenum. In some variations, the resection devices described herein can transition to an expanded configuration to expand (e.g., stretch, elongate) tissue during a treatment procedure. In some variations, tissue can be treated within a predetermined range of expansion ratios. In some variations, the ratio of expanded mucosal tissue to undistracted mucosal tissue can be about 0.40 to about 0.60, about 0.45 to about 0.55, and about 0.50, inclusive of all ranges and subvalues ​​therebetween. In some variations, the ratio of expanded submucosal tissue to undistracted submucosal tissue can be about 0.15 to about 0.35, about 0.20 to about 0.30, and about 0.26, inclusive of all ranges and subvalues ​​therebetween. In some variations, the ratio of distended duodenal diameter to undistended duodenal diameter can be about 1.5 to about 2.3, about 1.7 to about 2.1, and about 1.91, inclusive of all ranges and subvalues ​​therebetween. In some variations, the ratio of distended duodenal diameter to undistended duodenal diameter can be about 1.5 to about 2.3, about 1.7 to about 2.1, and about 1.91, inclusive of all ranges and subvalues ​​therebetween.

[0300] In some variations, the resection device can be configured to simultaneously expand tissue and suction it into the resection device. In some variations, the ratio of suctioned and expanded mucosal tissue to unexpanded mucosal tissue can be about 0.40 to about 0.60, about 0.45 to about 0.55, and about 0.47, inclusive of all ranges and subvalues ​​therebetween. In some variations, the ratio of suctioned and expanded submucosal tissue to unexpanded submucosal tissue can be about 0.20 to about 0.50, about 0.30 to about 0.40, and about 0.33, inclusive of all ranges and subvalues ​​therebetween.

[0301] In some variations, suction can be generated by the device itself while in the expanded configuration. Additionally or alternatively, suction can be generated by a visualization device such as an endoscope. The amount of suction can be configured to ensure uniform apposition of the tissue to the surface of the expandable member (e.g., the electrode surface), provided that the amount of suction does not exceed a predetermined threshold corresponding to pressure necrosis. In some variations, the negative pressure (e.g., suction) applied to the tissue can be about 50 mmHg to about 75 mmHg for less than about 1 minute. In some variations, the negative pressure (e.g., suction) applied to the tissue can be about 10 mmHg to about 200 mmHg. The amount of suction can be a function of one or more of the total surface area of ​​the expandable member, the number and size of the openings, the time the suction is applied, the condition of the opening edges, the compliance of the tissue, the vascularization of the tissue, and the fragility of the tissue.

[0302] In some variations, the amount of tissue compliance may correspond to the amount of expansion and suction necessary to ensure uniform electrode surface contact and desired tissue treatment. In some variations, tissue may respond better to less expansion and more suction (or vice versa), depending on compliance and structure. In some variations, apposition can be assessed visually and / or through impedance measurements. In some variations, apposition can be measured using one or more temperature and / or pressure sensors.

[0303] The introduction and advancement of various devices into the duodenum is illustrated in the schematic diagrams of FIGS. 55A-55F, in which the gastrointestinal tract (5500) comprises a stomach (5510), a pylorus (5520), and a duodenum (5530). FIG. 55B depicts a visualization device (e.g., an endoscope) (5540) being advanced through the stomach (5510) and into the duodenum (5530). The visualization device (5540) can be configured to image tissue, pulsed electric field devices, and visual markers (e.g., anatomical landmarks, thermal markers, fiducials) to aid in location determination. For example, the imaged tissue can be used to identify tissue as one or more of treated, marked, affected, untreated, etc. FIG. 55C shows a guidewire (5560) advanced through the stomach (5510) and into the duodenum (5530). In some variations, as shown in FIG. 55D, a visualization device 5540 may be advanced over a guidewire 5530 into the duodenum 5530. In some variations, as shown in FIG. 55D, a treatment device 5560 may be advanced over a guidewire 5560 positioned with the visualization device 5540 into the duodenum 5530. FIGS. 56A-56H are detailed perspective views of a pulsed electric field device 5650 and a visualization device 5640 within the duodenum 5630, as described in more detail herein with respect to methods for treating diabetes. FIGS. 81A-81C are schematic illustrations of another variation of a method for treating diabetes, as described in more detail herein. FIGS. 82A-82D are images corresponding to the method shown in FIGS. 81A-81C.

[0304] FIG. 54 is a flowchart generally illustrating a variation of a method (5400) for treating diabetes. The method (5400) may include advancing a pulsed electric field device comprising an expandable member comprising an electrode array toward a first portion of the duodenum (5402). For example, FIG. 55E depicts a pulsed electric field device (5550) advanced over a guidewire through the stomach (5510) and into the duodenum (5530). Similarly, a visualization device may be advanced into the duodenum. FIG. 55F depicts a visualization device (5540) (e.g., an endoscope) advanced into the duodenum (5530) alongside (e.g., substantially parallel to) the pulsed electric field device (5550). In FIG. 56A, a pulsed electric field device (5650) comprises an expandable member (5652) in a compressed configuration within the duodenum (5630). For example, the expandable member (5652) is in a wound configuration comprising multiple turns around the longitudinal axis of the pulsed electric field device (5650). In the compressed configuration, the expandable member (5652) may comprise a lumen having a first inner diameter. The visualization device (5640) may be operated independently of the pulsed electric field device (5650). Similarly, FIG. 81A depicts a method (8100) for treating diabetes including a pulsed electric field device (8120) comprising an expandable member (8130) and a visualization device (8140) advanced into the duodenum (8110) along a guidewire (8122). In some variations, one or more of the device (8120) and the visualization device (8140) may be disposed distal to the papilla. FIG. 82A is an image of the expandable member (8220) of a pulsed electric field device from the perspective of the distal end of a visualization device (e.g., an endoscope). The expandable member (8220) can be in a compressed configuration when advanced through the duodenum (8210).

[0305] In step 5404, the expandable member of the pulsed electric field device or modulated electric field device may transition from a compressed configuration to an expanded configuration, for example, to engage tissue and / or allow a visualization device to be advanced through the lumen of the expandable member. As shown in the expanded configuration in FIG. 56B , the expandable member (5652) may include a lumen having a second inner diameter larger than the first inner diameter. In some of these variations, a visualization device (5640) may be advanced through the lumen of the expandable member (5652) in the expanded configuration, allowing the visualization device (5640) to visualize, for example, the tissue (5600) and a distal portion of the pulsed electric field device (5650). Additionally or alternatively, the pulsed electric field device (5650) may include a second expandable member (e.g., an inflatable member, balloon) (not shown) disposed distal to the expandable member (5652). In some of these variations, the second expandable member can be expanded to assist in one or more of advancing, positioning, and visualizing the pulsed electric field device (5650) and tissue (5630). For example, one or more portions of the second expandable member can be transparent to allow a visualization device to see through the second expandable member.

[0306] As shown in FIG. 56B, the expandable member (5652) may be deployed through one or more turns to transition the expandable member (5652) to an expanded configuration (e.g., a deployed configuration). As shown in FIG. 56C, the pulsed electric field device (5650) may include a first elongate body (5654) and a second elongate body (5656) positioned within the first elongate body (5654). The expandable member (5652) may be wrapped around the second elongate body (5656) a predetermined number of turns. In some of these variations, the second elongate body (5656) may be rotated relative to the first elongate body (5654) to deploy the expandable member (5652) and bring the expandable member into contact with the duodenum (5630). Full circumferential contact between the expandable member 5652 and the duodenum 5630 can improve energy delivery and treatment outcomes. For example, FIG. 64B is an image of a variation of the pulsed electric field device 6400 in a deployed configuration within a tissue lumen 6430 as imaged with a visualization device retracted relative to the pulsed electric field device 6400 to allow visualization of the proximal end of the expandable member 6410 and the tissue 6430.

[0307] In some variations, as shown in FIG. 81B, the expandable member 8130 of the device 8120 can transition to an expanded configuration and contact tissue. In some variations, the distal end of the visualization device 8120 can be disposed within the lumen of the expandable member 8130, proximal to the proximal end of the expandable member 8130, or distal to the distal end of the expandable member 8130. As shown in FIG. 81B, the visualization device 8120 can be configured to generate negative pressure (e.g., suction) within the lumen of the expandable member 8130 that draws the tissue 8110 against the surface of the expandable member 8130. Additionally or alternatively, the device 8120 can be configured to generate negative pressure to draw the tissue 8110 against the surface of the expandable member 8130. In some variations, suction can be applied during delivery of the pulsed waveform and reduced during periods when pulsed electric field energy is not being delivered. For example, suction can be reduced (or stopped) when the tissue is cooling after energy delivery and when one or more of the device (8130) and visualization device (8110) are advancing within the tissue (8110). Thus, suction can be applied intermittently throughout the treatment process. The amount of suction applied to one or more portions of the tissue can be as described herein.

[0308] Figure 82B is an image of the expandable member (8220) in an expanded configuration, with the expandable member (8220) in contact with the duodenum (8210). Figure 82C is an image of tissue (8210) in contact with the expandable member (8220) after applying negative pressure as described herein. In Figure 82C, the tissue is pulled through multiple openings (8222) extending through the thickness of the expandable member (8220). Intimate contact between the tissue (8210) and the expandable member (8220) can improve energy delivery and treatment outcomes. One or more pulse waveforms can be delivered while suction is applied.

[0309] In step 5406, one or more pulse waveforms can be delivered to the electrode array of the expandable member to generate a pulsed or modulated electric field. For example, FIG. 56C depicts the expandable member (5652) in an expanded configuration with electrodes (not shown) configured to receive pulse waveforms to generate a pulsed or modulated electric field to treat the duodenum (5630). In some variations, one or more of the visualization member (5640) and the pulsed electric field device (5650) can be configured to apply suction or negative pressure to the tissue to increase apposition of the tissue (5630) to the electrode array of the expandable member (5652). In some variations, fluid can be drawn or aspirated between the pulsed electric field device and the duodenum from the expandable member. For example, suction or negative pressure can be applied by the visualization device.

[0310] In some variations, the pulse waveform comprises a frequency of about 250 kHz to about 950 kHz, about 250 kHz to about 950 kHz, or about 350 kHz, inclusive of all ranges and subvalues ​​therebetween, a pulse width of about 0.5 μs to about 4 μs, a voltage applied by the electrode array of about 100 V to about 2 kV, and a current density from the electrode array of about 0.6 A to about 100 A or about 0.6 A to about 65 A per square centimeter of tissue. For example, the current density can be about 0.6 A to about 100 A, or about 0.6 A to about 65 A per square centimeter of tissue from the electrode array.

[0311] In some variations, the pulse waveform may comprise about 1 to about 100 pulse groups, with about 1 to about 100 pulses per group. In some of these variations, the pulse waveform may comprise a group delay of about 10 μs to about 2000 μs, or about 10 μs to about 500 μs, and an evacuation rate of about 50 ms to about 4000 ms, or about 50 ms to about 500 ms. In some variations, the pulsed or modulated electric field generated by the pulsed electric field device (5650) varies spatially within the tissue (5360) by up to about 20% at a given treatment distance from the expandable member (5652). For example, at a 4 cm depth of the duodenum,2 Treatment of a treatment area of ​​approximately 81,000 watts or approximately 20,250 watts / cm 2 , or about 1,800 watts / cm 2 The voltage may include delivering about 900 V applied to 10 Ω or about 600 V applied to 50 Ω, respectively, for an instantaneous power of about 0.04 Joules / cm 2 for about 2 μs, or about 27 Joules / cm for a corresponding dose of 2 In some variations, the treatment pulse may be repeated about 1000 times to equal about 40.5 Joules of total energy. For example, about 400 cm 2 As another example, a treatment area of ​​about 100 cm of duodenum may be provided with a dose of about 16,200 J. 2 A treatment area of ​​the duodenum may provide a dose of approximately 27 kJ.

[0312] In some variations, the pulse waveform delivered to a portion (e.g., section) of tissue may comprise multiple pulse waveforms, i.e., the portion may be treated multiple times (e.g., two, three, four times).

[0313] In some variations, a temperature sensor may measure the temperature of the tissue and use that temperature to inhibit delivery of the pulse waveform, thereby adding a margin of safety to the procedure. In step 5408, the temperature of the tissue may be measured using a temperature sensor. For example, the temperature may be measured at least during delivery of the pulse waveform or immediately after each packet of energy. In step 5410, the delivery of the pulse waveform may be adjusted in response to the measured temperature. For example, if the measured temperature exceeds a predetermined threshold, the delivery of the pulse waveform may be inhibited. This may prevent unintended damage to the tissue due to thermal heating.

[0314] In some variations, a fiducial generator can be used to generate visual markers on the duodenal tissue. The visual markers can be visualized, for example, using a visualization device described herein, to identify treatment areas to aid in complete treatment coverage of the duodenum. In step 5412, one or more visual markers can be generated on the tissue using a fiducial generator (e.g., a temperature sensor). As shown in FIG. 57, one or more visual markers (5710) can be generated along the inner circumference of the duodenum (5700).

[0315] In step 5414, a treatment region can be identified based on one or more of the visual markers and the aspirated tissue. For example, a visualization device in the duodenum can image one or more visual markers. The region between the visual markers (5710) can correspond to the treatment region that underwent PEF-induced cell death. Figures 56D-56H illustrate visual markers (5634) generated on the tissue. Furthermore, retreatment of the duodenum in another procedure can be guided by one or more of the visual markers generated by the reference generator. Figure 82D depicts an image of tissue (8210) with aspirated tissue (8212) that can be visually identified by the visualization device. The visual markers can be used to identify the treated portion of the tissue and to align the pulsed electric field device to the untreated portion of the tissue to be treated.

[0316] In some variations, the pulsed electric field device can be retracted proximally through the duodenum to treat the entire duodenum with a pulsed or modulated electric field. Generally, the duodenum extends approximately 260 cm. 2In step 5416, the expandable member can be transitioned from the expanded configuration to a compressed configuration (or a partially expanded or semi-expanded configuration in which the expandable member collapses to the outer diameter of the visualization device) to assist in translation of the pulsed electric field device through the duodenum. FIG. 56D depicts the expandable member 5652 in a partially expanded configuration such that the expandable member 5652 disengages from the treated portion 5632 of the duodenum 5630 and engages the outer surface of the visualization device 5640. This allows the pulsed electric field device 5650 and visualization device 5640 to slidably translate together relative to the duodenum 5630.

[0317] In step 5418, the pulsed electric field device can be translated to another portion of the duodenum. In some variations, the duodenum can be treated over about 2 to about 20 portions, about 6 to about 15 portions, or about 10 to about 12 portions, including all ranges and subvalues ​​therebetween. For example, FIG. 56E depicts the pulsed electric field device 5650 retracted proximally relative to the treated portion 5632. In some of these variations, the contraction can be guided by the location of a visual marker visualized by a visualization device. For example, the visualization device 5640 can be retracted to view the duodenal tissue 5630 proximal to the expandable member 5652 in FIG. 56F. Similarly, as shown in FIG. 81C, the device 8120 and / or visualization device 8140 can be advanced multiple times through the duodenum 8110 to repeat the energy delivery process described herein. In some variations, the total treated length of tissue may be from about 6 cm to about 20 cm. In some variations, the portion of tissue may have a circumference of from about 22 mm to an average of about 25 mm. In some variations, more than about 60 percent of the circumference of a portion of the duodenum may be treated.

[0318] As shown in FIG. 54, steps 5404-5418 may be repeated until a predetermined length of the duodenum has been treated. That is, the same portion of tissue may be treated multiple times (e.g., dual treatment). For example, after transitioning the expandable member from the expanded configuration to the compressed configuration in step 5416 and translating the device to the previously treated portion of the duodenum in step 5418, the expandable member may be transitioned to the expandable configuration in step 5404, and the previously treated portion of the duodenum may be treated with another pulsed electric field in step 5406. Treating the same portion of tissue multiple times (e.g., two, three, four times) may increase the proportion of tissue in the treated portion, thus resulting in a more complete lesion, leading to improved outcomes. The same pulse waveform energy parameters as initially delivered in step 5406, or different pulse waveform energy parameters, may be delivered to the same portion of tissue (e.g., the gastrointestinal tract, including but not limited to the duodenum, pylorus, esophagus, stomach, small intestine, and large intestine) multiple times. In some variations, the pulse waveforms include a first pulse waveform, and at least a second pulse waveform is delivered to the electrode array to generate a second pulsed or modulated electric field, thereby treating at least a portion of the previously treated tissue.

[0319] For example, Figure 56F depicts the expandable member 5652 transitioned to an expanded configuration just proximal to the treated portion 5632. The visualization device 5640 is retracted proximally relative to the expandable member 5652 so that the expandable member 5652 and treated portion 5632 may be visualized. The expandable member 5652 may be positioned proximal to the visual marker 5634. Figure 56G depicts the duodenum 5630 and pulsed electric field device 5650 after delivery of a second pulse waveform. Notably, the area of ​​the treated portion 5632 has increased and the expandable member 5652 has transitioned to a compressed configuration. For example, the second elongate body 5656 can be rotated relative to the first elongate body 5654 to rotate the expandable member 5652 about the longitudinal axis of the second elongate body 5656 and reduce the diameter of the expandable member 5652. In some variations, the pulse waveform and generated pulsed or modulated electric field can be the same or different for each portion of the duodenum.

[0320] In some variations, the electrode array can be configured so that the total surface area of ​​the electrodes in contact with the tissue can provide a system resistance or impedance that matches the voltage and current output of the signal generator. For example, the number of electrode arrays can be independently matched to the desired treatment area, thereby controlling the amount of voltage and current generated by the signal generator. This multiplexing technique can significantly reduce the cost and complexity of the signal generator.

[0321] In step 5420, the pulsed electric field device and visualization device may be withdrawn from the patient. The pulsed electric field device and visualization device may be withdrawn from the patient sequentially or simultaneously. Figure 56H depicts the pulsed electric field device 5650 being withdrawn from the duodenum 5630 after treating a predetermined area of ​​tissue (e.g., treated portion 5632). For example, Figure 64A is a planar image of a variation of a pulsed electric field device 6400 engaged with a visualization device 6410 and withdrawn from a patient. In Figure 64A, the expandable member of the pulsed electric field device 6400 is in a semi-extended configuration to hold the pulsed electric field device to the visualization device 6410.

[0322] An example of a treatment procedure on a patient using a pulsed electric field device is shown in the fluoroscopic images of Figures 58A-58E. Figure 58A depicts a pulsed electric field device 5810 and a visualization device 5820 (e.g., an endoscope) advanced into a distal portion of the duodenum 5800. Figure 58B depicts the pulsed electric field device 5810 in an expanded configuration with the endoscope 5820 proximal to the expandable member 5812. Figures 58C, 58D, and 58E depict the pulsed electric field device translating proximally through the duodenum 5800. Although depicted here as translating proximally through the duodenum (5800) during a treatment procedure, the pulsed electric field device (5810) may instead be advanced distally through the duodenum (5800) (e.g., a proximal portion of the duodenum (5800) may be treated before one or more portions distal to the proximal portion). In some variations, the treatment procedures performed herein may utilize fluoroscopic guidance without a visualization device.

[0323] In some variations, pulsed electric field energy can be delivered while safely controlling tissue temperature. For example, energy delivery can be pulsed, resulting in a sufficient delay for tissue temperature to decrease before another burst of energy is delivered. Furthermore, delivery can be inhibited once a predetermined tissue temperature (e.g., relative change in temperature, absolute temperature) is exceeded. For example, tissue temperature rise can be limited to about 6°C and / or about 43°C absolute. In the methods described herein, heat is a by-product of energy delivery and not the desired mechanism of action.

[0324] 83A and 83B are plots of tissue temperature, voltage, and current over time corresponding to the methods of treating tissue described herein. Figure 83A, for example, depicts a temperature rise of approximately 4°C when the temperature is measured at the expandable member of a pulsed electric field device.

[0325] Alternatively, one or more pulse waveforms can be delivered such that the tissue is initially heated to approximately 41° C., and then pulse waveforms can be delivered such that the tissue does not exceed a predetermined tissue temperature (e.g., 45° C.). For example, the initial heating of the tissue can be achieved with low-power energy application to control the time and depth at which the tissue reaches temperature. This method can reduce the tissue critical threshold of the pulsed electric field to affect cellular structure.

[0326] Energy Parameters A method of treating diabetes may generally include advancing a pulsed electric field device, such as any of the pulsed electric field devices described herein, into a patient's gastrointestinal tract, such as, for example, one or more of the patient's duodenum, pylorus, esophagus, stomach, small intestine, and / or large intestine. As described in more detail herein, the pulsed electric field device may include an elongate body and an expandable member coupled to the elongate body. The expandable member may include an electrode array configured to deliver an electric field to tissue of the patient to treat the tissue. For example, a pulsed waveform may be delivered to the electrode array to generate a pulsed or modulated electric field, thereby treating tissue, such as tissue in the duodenum. Any of the methods described herein may include delivering a pulsed waveform including any combination of the following energy parameters (e.g., any of a frequency range combined with any of a driving voltage, pulse width, current, etc.).

[0327] The tissue treated using any of the methods described herein may include one or more portions of the gastrointestinal tract, including, but not limited to, the duodenum, pylorus, esophagus, stomach, small intestine, and large intestine.

[0328] The pulse waveform may include frequencies from about 50 kHz to about 950 kHz, about 100 kHz to about 900 kHz, about 200 kHz to about 500 kHz, about 300 kHz to about 400 kHz, or about 350 kHz, about 0.1 Hz to about 10,000 Hz, about 1 Hz to about 1,000 Hz, about 1 Hz to about 100 Hz, about 100 Hz to about 1,000 Hz, about 1,000 Hz to about 5,000 Hz, about 5,000 Hz to about 10,000 Hz, about 2,000 Hz to about 8,000 Hz, about 4,000 Hz to about 6,000 Hz, including all values ​​and subranges between any of the foregoing ranges.

[0329] In some variations, the pulse waveform may comprise a driving voltage at the electrode array of about 400V to about 600V, about 400V to about 550V, about 440V to about 600V, or about 440V to about 550V, about 5kV to about 500kV, about 5kV to about 15kV, about 5kV to about 20kV, about 10kV to about 20kV, about 15kV to about 20kV, including all values ​​and subranges between any of the foregoing ranges.

[0330] In some variations, the pulse waveform may generate a current from the electrode array through tissue of about 0.6 A to about 100 A, about 1 A to about 75 A, about 20 A to about 60 A, about 30 A to about 50 A, or about 36 A to about 48 A per square centimeter of tissue, including all values ​​and subranges between any of the foregoing ranges.

[0331] In some variations, the pulse waveform may generate a pulsed or modulated electric field in the tissue of about 2,000 V / cm to about 3,000 V / cm, about 2,000 V / cm to about 2,500 V / cm, or about 2,500 V / cm, including all values ​​and subranges between any of the foregoing ranges.

[0332] In some variations, the pulse waveform may comprise a set of about 10 pulses to about 100 pulses in a group, a set of about 25 pulses to about 75 pulses in a group, a set of about 40 pulses to about 60 pulses in a group, or a set of about 50 pulses, including all values ​​and subranges between any of the foregoing ranges. In some variations, the pulse waveform may comprise about 5 groups to about 20 groups or about 8 groups to about 13 groups, including all values ​​and subranges between any of the foregoing ranges. In some variations, the pulse waveform may comprise a delay between groups of about 1 second to about 20 seconds, or about 4 seconds to about 10 seconds, including all values ​​and subranges between any of the foregoing ranges. In some variations, the pulse waveform may comprise a pulse width of about 0.5 μs to about 4 μs.

[0333] In some variations, the method may include measuring the temperature of the tissue during treatment using a temperature sensor as described herein, and the measured temperature may be about 37°C to about 45°C (e.g., an increase of about 3°C ​​to about 8°C) during delivery of the pulse waveform. Stated differently, delivery of a pulsed or modulated electric field produced by a pulse waveform described herein may produce an increase in tissue temperature of between about 3°C ​​and 8°C, and a resultant tissue temperature of between about 37°C and about 45°C. For example, the target temperature achieved by application of a pulsed or modulated electric field produced by a pulse waveform described herein may be about 41°C, which may correspond to a temperature increase in the tissue of about 4°C to about 5°C. In some variations, the method may include increasing the temperature of the tissue to about 41°C before delivering the pulse waveform.

[0334] In some variations, tissue may be compressed during treatment with a pulsed or modulated electric field, as described in more detail herein. In these variations, the pulsed or modulated electric field may be a treatment field that treats tissue at a compressed tissue depth of about 0.25 mm to about 0.75 mm and an uncompressed tissue depth of about 0.50 mm to about 1.5 mm.

[0335] In some variations, the pulse waveform may include a pulse width of about 0.5 μs to about 4 μs, about 0.1 ns to about 1000 ns, about 1 ns to about 100 ns, about 1 ns to about 500 ns, about 500 ns to about 1000 ns, about 200 ns to about 800 ns, about 400 ns to about 600 ns, including all values ​​and subranges between any of the foregoing ranges.

[0336] It should be understood that any combination of energy parameters as disclosed herein may be used. For example, in some variations, the pulse waveform may comprise a frequency of about 50 kHz to about 950 kHz or about 300 kHz to about 400 kHz and a drive voltage at the electrode array of about 400 V to about 600 V or about 440 V to about 550 V, generating a current of about 36 A to about 48 A per square centimeter of tissue from the electrode array through the tissue. The pulsed or modulated electric field in the tissue may be about 2,000 V / cm to about 3,000 V / cm. In some variations, the pulse waveform may include a set of about 50 pulses in about 8 to about 13 groups, with a delay of about 4 seconds to about 10 seconds between each group. In some variations, the pulsed or modulated electric field may be a treatment electric field at a compressed tissue depth of about 0.25 mm to about 0.75 mm and / or a non-compressed tissue depth of about 0.50 mm to about 1.5 mm. In some variations, the pulse waveform may include a pulse width of about 0.5 μs to about 4 μs.

[0337] As another example, the pulse waveform in some variations can include a drive voltage at the electrode array of between about 5 kV and about 500 kV, between about 5 kV and about 15 kV, between about 5 kV and about 20 kV, between about 10 kV and about 20 kV, or between about 15 kV and about 20 kV, including all values ​​and subranges between any of the foregoing ranges. In some variations, the pulse waveform can have a pulse width of between about 0.1 ns and about 1000 ns, between about 1 ns and about 100 ns, between about 1 ns and about 500 ns, between about 500 ns and about 1000 ns, between about 200 ns and about 800 ns, or between about 400 ns and about 600 ns, including all values ​​and subranges between any of the foregoing ranges. In some variations, the pulse waveform may comprise a frequency of about 0.1 Hz to about 10,000 Hz, about 1 Hz to about 1,000 Hz, about 1 Hz to about 100 Hz, about 100 Hz to about 1,000 Hz, about 1,000 Hz to about 5,000 Hz, about 5,000 Hz to about 10,000 Hz, about 2,000 Hz to about 8,000 Hz, or about 4,000 Hz to about 6,000 Hz, including all values ​​and subranges therebetween in any of the foregoing ranges. In some variations, the pulse waveform may comprise an amplitude of at least 10 kV / cm.

[0338] Tables 2 and 3 below provide illustrative variations of sets of parameters (eg, voltage, current, power) configured to provide a predetermined tissue treatment depth. [Table 2] [Table 3]

[0339] In some variations, the method may include adjusting the delivery of a pulse waveform based on the measured temperature. For example, adjusting the pulse waveform delivery may include inhibiting the delivery of a pulse waveform based on the measured temperature. In some variations, the pulsed or modulated electric field may be a therapeutic electric field that treats cells but leaves the tissue scaffold intact.

[0340] (Example) 72A-75 are images of healing (e.g., the healing cascade) of duodenal tissue after treatment using the systems, devices, and methods described herein. Advantageously, the healing process described herein can reduce necrotic responses (e.g., macrophage responses) that can cause widespread inflammation within the duodenal tissue.

[0341] Figures 72A and 72B are detailed cross-sectional images of duodenal tissue approximately one day after treatment. The tissue depicted in Figures 72A and 72B may include increased vascularization. Figure 73 is a detailed cross-sectional image of duodenal tissue approximately three days after treatment, showing increased blood supply to new cells and no significant macrophage response. Figures 74A and 74B are detailed cross-sectional images of duodenal tissue approximately seven days after treatment. Tissue viewed with an endoscope at approximately seven days may be indistinguishable from native tissue. For example, the blood supply in Figures 74A and 74B may be indistinguishable from native (e.g., untreated) tissue, and the dimensions of the new villi will be approximately the same as those of native villi. Figure 75 is a detailed cross-sectional image of duodenal tissue approximately 14 days after treatment, showing that the treated tissue may be histologically indistinguishable from native tissue.

[0342] FIG. 60 is an image of a variation of a pulsed electric field device (6000) comprising an expandable member (6030), a proximal dilator (6060), and a distal dilator (6062). The expandable member (6030) may include multiple turns about the longitudinal axis of the device (6000). The expandable member (6030) comprises an electrode array, as shown in FIG. 59. The dilators (6060, 6062) can aid in smoothly advancing and / or retracting the pulsed electric field device (6000) through one or more body cavities and can help prevent the expandable member (6030) from catching on tissue. For example, the dilators (6060, 6062) can be configured to protect tissue edges from contacting the tissue as the expandable member (6030) translates (e.g., advances, retracts) through the body cavity. The expandable member (6030) is disposed between the distal dilator (6062) and the proximal dilator (6060).

[0343] Figure 61A is an image showing a perspective view of the pulsed electric field device 6100 and visualization device 6150. Figure 61B is a detailed image of the pulsed electric field device 6100 and visualization device 6150. The pulsed electric field device 6100 shown in Figures 61A and 61B is similar to the pulsed electric field device 6000 shown in Figure 60 and includes an elongate body 6110, an expandable member 6030, a proximal dilator 6060, and a distal dilator 6062. The visualization device 6150 may have a diameter sufficient to be advanced through the lumen of the expandable member 6130 when in a semi-expanded or expanded configuration.

[0344] FIG. 62A is an image of an illustrative variation of the pulsed electric field device (6200, 6250). The pulsed electric field device (6200, 6250) shown in FIGS. 62A-62C is similar to the pulsed electric field device (6000) shown and described with respect to FIG. 60 and FIGS. 61A-61B. Additionally, the pulsed electric field device (6250) may include an expandable member (6232) (e.g., a balloon). As shown in FIG. 62A, an expansion actuator (6234) may be fluidly coupled to the balloon (6232) of the pulsed electric field device (6250). FIG. 62B is an image of an illustrative variation of the pulsed electric field device (6250) including the expandable member (6232) in a compressed configuration (e.g., uninflated, deflated). FIG. 62C is a perspective view of the pulsed electric field device (6200, 6250) shown in FIG. 62A.

[0345] 63A-63C illustrate additional variations of a pulsed electric field device 6300 comprising a first elongate body 6310, a second elongate body 6320, an expandable member 6330, a proximal dilator 6360, a distal dilator 6362, a lead 6332 coupled to the expandable member 6330, and a guidewire 6370. The expandable member 6330 may include multiple turns about the longitudinal axis of the device 6300. The expandable member 6330 may comprise an electrode array as shown in FIG. 66. The dilators 6360, 6362 may aid in smoothly advancing and / or retracting the pulsed electric field device 6300 through one or more body cavities and may help prevent the expandable member 6330 from getting caught on tissue. For example, the dilators (6360, 6362) can be configured to protect tissue edges from contacting the tissue as the expandable member (6330) translates (e.g., advances, retracts) through the body lumen. The expandable member (6330) is disposed between the distal dilator (6362) and the proximal dilator (6360). Figure 63A is an image of the pulsed electric field device (6300) having the expandable member (6330) in a rolled configuration. Figure 63B is an image of the pulsed electric field device (6300) having the expandable member (6330) in a deployed configuration. Figure 63C is a perspective view of the pulsed electric field device (6300) having the expandable member (6330) in a deployed configuration. The pulsed electric field device (6300) can be slidably translated along a guidewire (6370) extending through the second elongate body (6320).

[0346] FIG. 65 is an image of a variation of a pulsed electric field device (6500) comprising an elongate body (6510), a first expandable member (6520) comprising an electrode array (6530), and a second expandable member (6540) disposed distal to the first expandable member (6520). The first expandable member (6330) and the second expandable member (6540) may comprise inflatable members such as balloons. The first expandable member (6530) may comprise an electrode array as shown in FIG. 67. The second expandable member (6530) may aid in smoothly advancing and / or retracting the pulsed electric field device (6500) through one or more body cavities and may improve visualization of the tissue and the first expandable member (6530). In some variations, at least the proximal and distal portions of the first and second expandable members (6530, 6540) may be transparent. The elongate body (6510) may include one or more inflation lumens configured to transition the first and second expandable members (6530, 6540) between a compressed configuration and an expanded configuration.

[0347] Figure 66 is a schematic circuit diagram of a variation of the electrode array (6600) of a pulsed electric field device described herein. Figures 67 and 68 are images of variations of the electrode array (6700, 6800) of a pulsed electric field device described herein. Figure 67 depicts a flexible circuit with raised (e.g., dome-shaped) electrodes. Figure 68 depicts a rigid circuit board with raised (e.g., dome-shaped) electrodes.

[0348] Figure 79A is an image of a variation of a pulsed electric field device (7900) in a compressed configuration. The pulsed electric field device (7900) may include an expandable member (7930), a distal dilator (7960), and a proximal dilator (7962). Figure 79B is an image of the pulsed electric field device (7900) in an expanded configuration. The expandable member (7930) may include multiple turns about the longitudinal axis of the device (7900). The expandable member (7930) includes an electrode array as shown in Figure 79C. The dilators (7960, 7962) may aid in smoothly advancing and / or retracting the pulsed electric field device (7900) through one or more body cavities and may help prevent the expandable member (7930) from getting caught on tissue. For example, the dilators (7960, 7962) can be configured to protect tissue edges from contacting the tissue as the expandable member (7930) translates (e.g., advances, retracts) through the body cavity. The expandable member (7930) is disposed between the distal dilator (7962) and the proximal dilator (7960). Figure 79C is a detailed image of the deployed electrode array (7930) of the pulsed electric field device (7900) depicted in Figures 79A and 79B. The electrode array (7930) can include a plurality of electrodes (7932) defining one or more openings (7934), as described in more detail herein.

[0349] Figure 86 shows temperature plots over time for methods of treating tissue in simulations and animal experiments corresponding to the energy parameters described above. A set of 10 bursts of bipolar current pulses was applied to generate a corresponding rapid temperature increase followed by a temperature decrease as heat diffused from the duodenal surface. Figure 87 shows plots of the corresponding impedance and maximum temperature distributions, respectively, of the pulsed electric field device used to treat tissue, as well as a table of measured parameters (e.g., voltage, current impedance, maximum temperature increase).

[0350] Methods of treating diabetes may generally include advancing a pulsed electric field device, such as any of the pulsed electric field devices described herein, into a patient's gastrointestinal tract. As described in more detail herein, the pulsed electric field device may include an elongate body and an expandable member coupled to the elongate body. The expandable member may include an electrode array configured to deliver an electric field to tissue of the patient to treat the tissue. For example, a pulsed waveform may be delivered to the electrode array to generate a pulsed or modulated electric field, thereby treating tissue, such as tissue in the duodenum. Any of the methods described herein may include, for example, delivering a pulsed waveform including any of the following energy parameters to any portion of the patient's gastrointestinal tract, such as the duodenum, esophagus, stomach, and / or pylorus:

[0351] The pulse waveform may have a frequency of about 350 kHz, a driving voltage at the electrode array of about 440 V to about 550 V, generate a current from the electrode array through the tissue of about 36 A to about 48 A per square centimeter of tissue, and generate a pulsed or modulated electric field at the tissue of about 2,500 V / cm. The pulse waveform may include a set of about 50 pulses in a group and in about 8 to about 13 groups, with a delay between groups of about 4 seconds to about 10 seconds.

[0352] In some variations, the method may include measuring the temperature of the tissue during treatment using a temperature sensor as described herein, and the measured temperature may be a target temperature of about 41° C. For example, the target temperature achieved by application of a pulsed or modulated electric field produced by a pulse waveform described herein may be about 41° C., which may correspond to a temperature increase in the tissue of about 4° C. to about 5° C.

[0353] In some variations, tissue may be compressed during treatment with a pulsed or modulated electric field to treat a patient, as described in more detail herein. In these variations, the pulsed or modulated electric field may be a treatment electric field that treats tissue at a compressed tissue depth of about 0.25 mm to about 0.75 mm and an uncompressed tissue depth of about 0.50 mm to about 1.5 mm.

[0354] It will be understood that the examples and illustrations of the present disclosure are for illustrative purposes and that deviations and variations, such as the number of electrodes and devices, can be constructed and deployed in accordance with the teachings herein without departing from the scope of the present invention.

[0355] As used herein, the terms "about" and / or "approximately," when used in conjunction with a numerical value and / or range, generally refer to the numerical value and / or range that is near the recited numerical value and / or range. In some cases, the terms "about" and "approximately" can mean within ±10% of the stated value. For example, in some cases, "about 100 units" can mean within ±10% of 100 (e.g., 90 to 110). The terms "about" and "approximately" can be used interchangeably.

[0356] The specific examples and descriptions herein are exemplary in nature, and variations may be developed by those skilled in the art based on the material taught herein without departing from the scope of the present invention, which is limited only by the appended claims.

Claims

1. 1. A system for treating diabetes, comprising: a pulsed electric field device configured to be advanced into a patient's duodenum, the pulsed electric field device comprising: an elongate body; and an expandable member coupled to the elongate body, the expandable member comprising an electrode array; a signal generator configured to deliver a pulse waveform to the electrode array to generate a pulsed or modulated electric field, thereby treating the duodenum by ablating a native endothelial cell population through non-thermal cell death; Equipped with The system wherein the pulse waveform includes a frequency of 50 kHz to 950 kHz, and the pulse waveform generates a drive voltage of 400 V to 600 V at the electrode array and generates a current of 36 A to 48 A per square centimeter of tissue from the electrode array through tissue.

2. The system of claim 1 , wherein the frequency is between 300 kHz and 400 kHz.

3. 10. The system of claim 1, wherein the pulsed or modulated electric field in the tissue is between 2,000 V / cm and 3,000 V / cm.

4. The system described in claim 1, wherein the pulse waveform generates the drive voltage of 440V to 550V.

5. 10. The system of claim 1, wherein the pulse waveform comprises 5 to 20 groups of pulses, each group of pulses comprising a set of 50 pulses, with a delay of 4 to 10 seconds between pulses in each group.

6. 10. The system of claim 1, further comprising a temperature sensor configured to measure a temperature of the tissue during delivery of the pulse waveform, wherein delivery of the pulse waveform produces the measured temperature of between 37°C and 45°C.

7. The system described in claim 1, wherein the signal generator is configured to raise the temperature of the tissue to 41°C before the pulse waveform is delivered.

8. 10. The system of claim 1, wherein the pulsed or modulated electric field is a therapeutic electric field at a compressed tissue depth of 0.25 mm to 0.75 mm.

9. 10. The system of claim 1, wherein the pulsed or modulated electric field is a therapeutic electric field at a non-compressed tissue depth of 0.50 mm to 1.5 mm.

10. 10. The system of claim 1, wherein the system further comprises a temperature sensor configured to measure a temperature of the tissue, and the signal generator is further configured to adjust the delivery of the pulse waveform based on the measured temperature.

11. 11. The system of claim 10, wherein the signal generator regulates delivery of the pulsed waveform by pausing delivery of one or more pulses of the pulsed waveform when the measured temperature exceeds a predetermined threshold.

12. The system of claim 1 , further comprising: means for aspirating the tissue against the expandable member at a pressure between 10 mmHg and 200 mmHg.

13. 10. The system of claim 1, wherein the pulsed or modulated electric field is a therapeutic electric field that causes cell lysis in the tissue that is at least 50% pore-induced and less than 50% heat-induced while leaving the tissue scaffold intact.

14. The system of claim 1 , wherein the pulse waveform comprises a pulse width of 0.5 μs to 4 μs.

15. The system of claim 1 , further comprising a reference generator configured to generate a visual marker on the tissue.

16. The system of claim 15 , further comprising a visualization device used to visualize the visual marker.

17. 10. The system of claim 1, wherein the pulse waveform comprises a first pulse waveform, and the signal generator is further configured to deliver at least a second pulse waveform to the electrode array to generate a second pulsed or modulated electric field, thereby treating at least a portion of the previously treated duodenum by ablation of a native endothelial cell population through non-thermal cell death.

18. 1. A system for treating diabetes, comprising: a pulsed electric field device configured to be advanced into a patient's stomach, the pulsed electric field device comprising: an elongate body; and an expandable member coupled to the elongate body, the expandable member comprising an electrode array; a signal generator configured to deliver a pulse waveform to the electrode array to generate a pulsed or modulated electric field, thereby treating the stomach by devitalizing the gastric mucosa without thermal injury to the muscularis propria; Equipped with The system wherein the pulse waveform includes a frequency of 50 kHz to 950 kHz, and the pulse waveform generates a drive voltage of 400 V to 600 V at the electrode array and generates a current of 36 A to 48 A per square centimeter of tissue from the electrode array through tissue.

19. 20. The system of claim 18, wherein the pulse waveforms include a first pulse waveform, and the signal generator is further configured to deliver at least a second pulse waveform to the electrode array to generate a second pulsed or modulated electric field, thereby treating at least a portion of the previously treated stomach by devitalizing the gastric mucosa without thermal injury to the muscularis propria.

Images