Devices, systems and methods for pulsed electric field treatment of tissue - Patents.com

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 the application of 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 (type 1, type 2, etc.), 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] Treatment of chronic diseases such as obesity and diabetes by resurfacing the duodenum has been proposed. For example, removing a large portion 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 overheating and therefore risk damaging more layers of the duodenum (e.g., the muscularis fascia) and / or must compensate for this excessive thermal heating. Conversely, conventional solutions may result in incomplete and / or uneven treatment. As such, 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 a pulsed or modulated electric field to tissue. These systems, devices, and methods can treat duodenal tissue of a patient, for example, to treat diabetes. In some variations, a method for treating diabetes can include advancing a pulsed electric field device into the duodenum of a patient, the pulsed electric field device comprising an elongated body and an expandable member coupled to the elongated body. The expandable member can comprise an electrode array. A pulse waveform can be delivered to the electrode array to generate a pulsed or modulated electric field, thereby treating the duodenum. The pulse waveform can include a frequency of about 50 kHz to about 950 kHz, a driving voltage at the electrode array of about 400 V to about 600 V, and a current from the electrode array through the tissue of about 36 A to about 48 A per square centimeter of tissue.

[0006] In some variations, the frequency may be about 300 kHz to about 400 kHz. In some variations, 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 driving voltage (e.g., the voltage measured at the electrode array) may be about 440 V to about 550 V. 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.

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

[0010] In some variations, the method may 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 may be a treatment field that treats the cells but leaves the tissue scaffold intact. In some variations, the pulse waveform may 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 at the electrode array of about 400 V to about 600 V, generating a current through the tissue from the electrode array of about 36 A to about 48 A per square centimeter of tissue. [Brief description 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 diagram of a portion of the small intestine. [Figure 2B] 1 is a cross-sectional schematic diagram of a portion of the small intestine. [Figure 2C] FIG. 1 is a cross-sectional schematic diagram of a portion of the small intestine.

[0017] [Figure 3A] This is a cross-sectional image of the duodenum. [Figure 3B] 1A-1D are detailed cross-sectional images of various duodenal tissues. [Figure 3C] 1A-1D are detailed cross-sectional images of various duodenal tissues. [Figure 3D] 1A-1D are detailed cross-sectional images of various duodenal tissues. [Figure 3E] 1A-1D are detailed cross-sectional images of various duodenal tissues. [Figure 3F] 1A-1D are detailed cross-sectional images of various duodenal tissues.

[0018] [Figure 4] FIG. 1 is a block diagram of an illustrative variation of a pulsed electric field system.

[0019] [Figure 5A] 13A-13C are perspective views of illustrative variations of pulsed electric field devices in a compressed configuration. [Figure 5B] 13A-13C are perspective views of illustrative variations of pulsed electric field devices in an expanded configuration. [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] 13A-13C are perspective views of illustrative variations of expandable members in a rolled configuration. [Figure 6B] 13A-13C are perspective views of illustrative variations of expandable members in deployed configurations.

[0021] [Figure 7A] 13A-13C 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] 1A-1C 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] 1A-1C 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] 1A-1C 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] 13A-13C are perspective views of illustrative variations of pulsed electric field devices in a deployed configuration. [Figure 10D] 13A-13C are perspective views of illustrative variations of pulsed electric field devices in a deployed configuration. [Figure 10E] FIG. 10E is a detailed perspective view of the pulsed electric field device shown in FIG. 10D.

[0025] [Figure 11] 13A-13C are perspective views of illustrative variations of visualization devices and pulsed electric field devices in a partially deployed configuration.

[0026] [Figure 12A] 1 is a perspective view of an illustrative variation of a pulsed electric field device. [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] 13A-13C 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] 13A-13C 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 a 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. [Figure 15B] 1 is a cutaway perspective view of an illustrative variation of a pulsed electric field device and visualization device.

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

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

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

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

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

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

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

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

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

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

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

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

[0042] [Figure 28A] 13A-13C are perspective views of illustrative variations of expandable members of pulsed electric field devices and visualization devices. [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 a 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] 1 is a perspective view of an illustrative variation of a pulsed electric field device. [Figure 30B] FIG. 30B is a perspective view of the pulsed electric field device shown in FIG. 30A within a tissue lumen.

[0045] [Diagram 31] 1 is a perspective view of an illustrative variation of a pulsed electric field device.

[0046] [Diagram 32] 1 is a perspective view of an illustrative variation of a pulsed electric field device. [Figure 33A]1 is a perspective view of an illustrative variation of a pulsed electric field device. [Figure 33B] FIG. 33B is a perspective view of the pulsed electric field device shown in FIG. 33A.

[0047] [Figure 34A] 13A-13C 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] 13A-13C are perspective views of illustrative variations of electrode arrays in deployed configurations.

[0048] [Diagram 35] 11 is an electric field strength plot of an illustrative variation of an electrode array.

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

[0050] [Figure 37] 13A-13C are schematic cross-sectional views of illustrative variations of electrode arrays and embossing dies.

[0051] [Figure 38] 1 is a schematic cross-sectional view of an illustrative variation of an electrode array with a tissue contacting layer.

[0052] [Figure 39] 1 is a schematic cross-sectional view of an illustrative variation of an electrode array with a tissue contacting layer.

[0053] [Diagram 40] 1A-1C 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] [Diagram 42] 11 is an electric field strength plot of an illustrative variation of an electrode array.

[0056] [Diagram 43] 13A-13C are perspective views of illustrative variations of expandable members comprising electrode arrays.

[0057] [Diagram 44] 13A-13C are perspective views of illustrative variations of expandable members comprising electrode arrays.

[0058] [Figure 45A] 1A-1C are schematic diagrams of illustrative variations of electrode arrays. [Figure 45B] 1A-1C are schematic diagrams of illustrative variations of electrode arrays. [Figure 45C] 1A-1C are schematic diagrams of illustrative variations of electrode arrays. [Figure 45D] 1A-1C are plan views of electric field strength plots of illustrative variations of electrode arrays. [Figure 45E] FIG. 45E is a cross-sectional view of the electric field intensity plot of the electrode array depicted in FIG. 45D.

[0059] [Figure 46A] FIG. 13 is a schematic perspective view of an illustrative variation of a coordinate system of an electrode array. [Figure 46B] 46B is an electric field intensity plot corresponding to the electrode array shown in FIG. 46A.

[0060] [Figure 47A] 13A-13C 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] 1A-1C are schematic plan views of illustrative variations of electrode arrays.

[0062] [Figure 49] 1A-1C are perspective views of illustrative variations of electrode arrays of pulsed electric field devices.

[0063] [Figure 50] 1A-1C are perspective views of illustrative variations of electrode arrays of pulsed electric field devices.

[0064] [Figure 51A] FIG. 13 is a schematic circuit diagram of an illustrative variation of the electrode array, temperature sensor array, and reference generator. [Figure 51B] FIG. 13 is a schematic circuit diagram of an illustrative variation 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. [Fig. 51D] FIG. 13 is a schematic circuit diagram of an illustrative variation of the electrode array, temperature sensor array, and reference generator.

[0065] [Figure 52A] FIG. 13 is a schematic circuit diagram of an illustrative variation 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. 13 is a schematic circuit block diagram of an illustrative variation of a signal generator.

[0067] [Figure 54] 1 is a flow chart 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. [Fig. 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. [Fig. 55F] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes.

[0069] [Figure 56A] 1 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] 1 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] 1 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] 1 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] 1 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Fig. 56F] 1 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] 1 is a perspective view of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Fig. 56H] 1 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] 1 is an image of an illustrative variation of thermal marking of tissue.

[0071] [Figure 58A] 1 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Figure 58B] 1 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Figure 58C] 1 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Fig. 58D] 1 is an image of an illustrative variation of a patient treatment procedure using a pulsed electric field device and a visualization device. [Figure 58E] 1 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] 1 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] 1 is a perspective view of an image of an illustrative variation of a pulsed electric field device and visualization device. [Figure 61B] FIG. 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] 13 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] 1 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] [Fig. 64A] 1 is an image of an illustrative variation of a pulsed electric field device and a visualization device. [Fig. 64B] 1 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. 13 is a circuit schematic diagram of an illustrative variation of an electrode array.

[0080] [Figure 67] 1 is an image of an illustrative variation of an electrode array.

[0081] [Figure 68] 1 is an image of an illustrative variation of an electrode array.

[0082] [Figure 69A] FIG. 13 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] 13 is an illustrative variation of a voltage plot comparing the voltage output of a pulsed electric field treatment with the voltage output of a 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 the undilated duodenum. [Figure 71C] 1 is a cross-sectional image of the undilated duodenum. [Fig. 71D] FIG. 71D is a detailed cross-sectional image of the undilated duodenum shown in FIG. [Figure 71E] This is a cross-sectional image of a dilated duodenum. [Fig. 71F] FIG. 71E is a detailed cross-sectional image of the dilated duodenum.

[0085] [Figure 72A] This is a detailed cross-sectional image of duodenal tissue approximately 1 day after treatment. [Fig. 72B] This is a detailed cross-sectional image of duodenal tissue approximately 1 day after treatment.

[0086] [Figure 73] FIG. 1 is a detailed cross-sectional image of duodenal tissue approximately three days after treatment.

[0087] [Fig. 74A] FIG. 1 is a detailed cross-sectional image of duodenal tissue approximately 7 days after treatment. [Fig. 74B] FIG. 1 is a detailed cross-sectional image of duodenal tissue approximately 7 days after treatment.

[0088] [Figure 75] 1 is a detailed cross-sectional image of duodenal tissue approximately 14 days after treatment.

[0089] [Figure 76] 13A-13C are perspective views of illustrative variations of electrode arrays in deployed configurations.

[0090] [Figure 77] 13A-13C are perspective views of illustrative variations of pulsed electric field devices in an expanded configuration.

[0091] [Fig. 78A] 1 is an image of an illustrative variation of a pulsed electric field device in a contracted or compressed configuration. [Fig. 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] 1 is an image of an illustrative variation of a pulsed electric field device in a compressed configuration. [Figure 79B] 1 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] 11 is an electric field strength plot of an illustrative variation of an electrode array. [Figure 80B] 11 is an electric field strength plot of 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. [Fig. 81B] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes. [Fig. 81C] FIG. 1 is a schematic diagram of an illustrative variation of a method for treating diabetes.

[0095] [Figure 82A] 1 is an image of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Fig. 82B] 1 is an image of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Fig. 82C] 1 is an image of an illustrative variation of a method for treating diabetes using a pulsed electric field device and a visualization device. [Fig. 82D]1 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] 11 is a plot of tissue temperature, voltage, and current over time for an illustrative variation of a method of treating tissue. [Figure 83B] 11 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. 2 is a cross-sectional perspective view of a set of twisted pair lead wires.

[0098] [Figure 85] 1A-1C are perspective views of illustrative variations of electrode arrays of pulsed electric field devices.

[0099] [Figure 86] 11 is a plot of temperature over time for an illustrative variation of a method of treating tissue.

[0100] [Figure 87] 11 is a plot of impedance and temperature distributions for an illustrative variation of a method for treating tissue. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 the relevant small intestinal anatomy. FIG. 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) is connected to the duodenum (130). FIG. 1B is a detailed cross-sectional view of the duodenum (130) surrounding 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. FIGS. 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, crackle-pharyngeal junction, and several sharp small radius bends throughout the length of the digestive tract.

[0103] A brief review 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. In general, electroporation requires a potential difference across the cell membrane on the order of about 0.5 to about 1 volt, and an accumulation duration on the order of about 1 to about 2 milliseconds. Electroporation inevitably produces ohmic heating, but there is considerable confusion in the literature on this, including a significant number of references which erroneously claim the existence of non-thermal electroporation. For example, the ionic conductivity σ ic The external uniform electric field of magnitude E applied to the intracellular fluid of ic Generates heat with a density of 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, an electric field of 1 KV / cm acting on tissue with a conductivity of about 0.3 S / m, a heat capacity of about 3.7 Joules / (gm °C), and a density of about 1 gm / cc will heat the tissue at a rate of about 800 °C / sec. Note that because tissue is an ionic conductor, if no current flows through the tissue, there is no electric field in the tissue. The initial time after an external electric field is suddenly applied to the membrane to accumulate charge may be on the order of about 30 nanoseconds, suggesting that the average temperature rise during the initial membrane charging phase may be on the order of tens of microdegrees. If an external electric field is applied and ionic currents charge the membrane surface to collapse the electric field into 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, the conductivity of the lipid layer, σ ii = 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 following application of the external electric field as heat can further diffuse out of the film.

[0105] If the ionic current is confined to the pores of the cell membrane, current crowding will result in a correspondingly high heating rate 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 results in a 10,000-fold increase in the heating rate, 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 mm 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 up 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, the 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. The maximum allowable temperature rise of bulk tissue can be on the order of about 13°C, so that even in a bipolar configuration, the maximum duration for which the external electric field can be applied can be in the range on the order of about 10 milliseconds. This heat is generated to a treatment depth of about several millimeters within the tissue, so the time required to cool the tissue by conduction can be on the order of 70 seconds (e.g., 3 mm 2 ) / (0.13mm 2 / sec). Blood convection may dominate the observed cooling times, which are on the order of about 10 seconds. Electroporation may also increase with bulk tissue temperature due to a phase transition of the lipid cell membrane, 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 the lipids from an ordered gel phase to a liquid crystalline phase.

[0108] Electroporation parameters can be varied to produce different effects on the tissue. FIG. 3A is a cross-sectional image of an untreated duodenum (300A) including the muscularis (310A) and villi (320A). FIG. 3D is an image of an illustrative modification 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, FIG. 3E depicts a duodenal tissue that has undergone a majority of thermal treatment, and FIG. 3F depicts a duodenal tissue that has undergone a majority of pulsed or modulated electric field treatment. The treatments described herein (e.g., FIG. 3F), which primarily treat the mucosal layer with tissue architecture that appears similar to native tissue, reduce trauma to the tissue compared to the thermal treatment shown in FIG. 3E.

[0109] Application of a pulsed electric field to duodenal tissue results in non-thermal tissue changes. For example, FIG. 3D is an image of normal untreated (e.g., native tissue) porcine duodenal mucosa. FIG. 3F is an image of early mucosal histological appearance with progressive epithelial loss and preservation of lamina propria structure / architecture. For example, FIG. 3F depicts histological progression with complete native epithelial loss and early crypt regeneration within preserved lamina propria. The glandular layers across FIGS. 3A-3D and 3F demonstrate 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, the pulsed electric field (PEF) treatment can be combined with a localized thermal treatment. For example, the thermal treatment can be applied to superficial or near-surface tissue, while the PEF treatment can be applied to deeper tissue. As described in more detail herein, the depth of tissue treatment that one or more layers receive can be adjusted based on one or more of the electrode design, the applied voltage, the time or duration of energy delivery, the frequency of the applied energy, and the tissue composition. An example of such control is a thermal treatment applied to a tissue depth of about 0.1 mm, and a PEF treatment applied to a tissue depth of about 1 mm. The ratio and depth of thermal treatment to PEF treatment can be based on the desired clinical outcome (e.g., efficacy). In some variations, the thermal treatment can be applied to a tissue depth of about 3 mm, and the PEF treatment can be applied to a tissue depth of about 5 mm. Thus, in some variations, more thermal treatment than PEF treatment can be applied to the tissue. Based on the depth and type of tissue, different healing cascades can 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. Additionally, neither heat nor PEF treatments may affect the deeper muscularis propria.

[0111] FIG. 3B is an image of an illustrative variation of duodenal tissue subjected to different treatments. In particular, the tissue (360) was treated with pulsed or modulated electric field energy, and the first mucosal region (362) was further exposed to radiofrequency energy. The excised villi of the first mucosal region (362) have disrupted cell membranes and destroyed cellular structures such that these cells are no longer viable or functional. In contrast, the second mucosal region (360) has cells that have undergone cytolysis, where the cell membranes remain intact but the cells are no longer viable and functional. That is, cytolysis corresponds to functional cell death with intact cellular structures, whereas ablation refers to the loss of both cellular structures and functions. The submucosa (370) and muscularis mucosae (380) remain healthy (e.g., viable and fully functional with cellular integrity). In Figure 3B, villi in the first mucosal region (362) are thermally ablated while cell lysis in the second mucosal region (360) occurs via 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 comprises viable tissue.

[0112] FIG. 3C illustrates a histological slide of the 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 heat / heat-fixed tissue of the villi, including villi-associated enteroendocrine cells. The fourth mucosal region (391) shows architectural and cytological preservation with cellular details with hyperchromatic nuclear and hypereosinophilic cytoplasmic staining. Overall, no interstitial hemorrhage and infiltrative post-treatment associated inflammatory cells have been identified. Sloughing of the heat-fixed tissue followed by villous architectural 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 timeline of tissue healing is expected to be longer than that of pulsed electric field treatment without heat effects. The submucosa (370) and muscularis mucosa (380) are histologically unaffected. FIG. 3E is an illustrative variation of a 24-hour porcine duodenal tissue image after isolated thermal tissue treatment (i.e., no pulsed electric field exposure) that destroys the lamina propria in that the tissue scaffold is burned and destroyed, sloughing off and being removed during healing. This shows histological features of thermal tissue dose consistent with thermal / thermal-induced coagulation necrosis without heat / thermal fixation. In this area, glandular epithelium and neuroendocrine cells (321) show loss of cytological detail consistent with cellular "ghost images." Interstitial hemorrhage and reactive inflammatory cells in the mucosal layer (341) are present at the edge of the area. The submucosa (331) and muscularis mucosa (311) also show injury-related changes. This area can be expected to heal similarly to ischemic-type coagulation necrosis with resorption and remodeling with mucosal regeneration. The thermal lesion has destroyed the lamina propria. The scaffold is burned and destroyed, sloughing off and being removed during healing. The tissue healing time frame in this area must be longer than that expected with pulsed electric field treatment.

[0113] FIG. 3F is an image of an illustrative variation of duodenal tissue treated with pulsed or modulated electric field energy to a controlled depth, including the muscularis, untreated lamina 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. Treated submucosa (332) also maintains tissue scaffolding. These treated tissues show cells that have undergone cell death where the cell membrane remains intact but the cells are no longer viable and functional. The healing cascade replaces these cells without infiltration of large numbers of inflammatory cells, the surface re-epithelializes, and structural healing of the villus and repopulation of crypt cells. The lamina muscularis (310) remains healthy (e.g., viable and fully functional with cellular integrity) 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, whereas 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 proper treatment. Human tissue data evaluated through histopathology supports a target depth of approximately 1 mm for PEF tissue treatment where the pulsed electric field does not penetrate the muscularis proper at the treatment level. As a result, the mucosa exhibits a healing progression with the initiation of crypt and glandular epithelial regeneration at day 1 (e.g., Figures 72A, 72B), continued epithelial development with surface re-epithelialization at day 3 (e.g., Figure 73), early cobblestone-like blunted villus development at day 7 (e.g., Figures 74A, 74B), and continues until villus elongation and stenosis at day 14 (Figure 75). Based on the methods described herein, the healing response can be essentially complete in about 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 include 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 mitigation steps, such as saline injection lifts, to protect the muscularis mucosa. For reference, the mucosa layer typically has a thickness of about 0.5 mm to about 1 mm, the submucosa layer typically has a thickness of about 0.5 mm to about 1 mm, and the muscularis layer typically has a thickness of about 0.5 mm. Inducing injury to the muscularis layer may result in adverse clinical outcomes. Furthermore, the anatomy along the circumference of the duodenum is not uniform, complicating the approach of treating only the submucosa and not the muscularis mucosa.

[0116] The methods described herein can selectively alter tissue viability by applying a predetermined pulsed or modulated electric field without losing the integrity of the majority of the treated tissue in the duodenum, 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 that can indiscriminately damage tissue and disrupt cellular structures, 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 local necrotic cell death (e.g., local ablation) and induce 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 tissues greater than the selected depth.

[0117] FIG. 3F is an image of an illustrative variation of duodenal tissue that has been treated with pulsed or modulated electric field energy to a controlled depth. In FIG. 3F, a portion of the muscularis (310) and submucosa (330) is untreated (i.e., the energy delivered to the tissue has no effect on the tissue), and different portions of the villous crypts (342), villi (322), and submucosa (332) are treated. Thus, the 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, and although the tissue scaffold remains intact, 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] The pulsed or modulated electric field near the electrode array generates some thermal heating of the tissue, which may lead to tissue ablation that destroys both cellular structure and function. However, the cell lysis in tissue caused by the pulsed or modulated electric field applied herein is at least 50% pore-induced and less than 50% thermally induced, so that the majority of cell death comprises functional cell death with intact cellular structure. For example, the thermal heating generated by the pulsed or modulated electric field 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 therapeutic characteristics to each tissue layer, improving treatment outcomes. Near the surface of the tissue (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 that may fall off after treatment. At tissue depths of about 0.5 mm to about 1.3 mm (e.g., the mucosa of the duodenum), thermal heating is limited (e.g., less than about 13° C. increase or 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, the energy delivered to the tissue causes reversible electroporation with even less thermal heating, so the deeper tissue can remain 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 layers (e.g., less than about 0.5 mm, about 0.1 mm to about 0.5 mm).

[0120] For example, FIG. 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%). The pulsed or modulated electric field applied to the villous crypts and submucosal tissue (370) has treated the tissue to a large extent (e.g., greater than 50%) of pore-induced cell death, with lesser contribution of cell death from thermal heating (e.g., less than 50%). The muscularis (380) is substantially untreated by the pulsed or modulated electric field or other methods. For example, the submucosal tissue in FIG. 3C has not received a saline injection. The depth of treatment can be controlled so that a given portion of the mucosal layer, such as the villous crypts, remains untreated as desired. The configurations and shapes of the electrode arrays described herein may enable the tissue treatment properties described herein.

[0121] In contrast, conventional solutions that apply other forms of thermal energy (e.g., steam, radio frequency, laser, heated liquids) to the duodenum thermally ablate through multiple layers of tissue (e.g., inducing more than 50% heat-induced necrotic cell death and less than 50% pore-induced cell death), thereby destroying the mucosal cellular structure at similar depths and potentially causing detrimental 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., muscle), saline can be injected into a portion of the duodenal tissue (e.g., submucosa (330)). This additional step further complicates the procedure and is not always sufficient to prevent undesired thermal tissue damage. The pulsed or modulated electric field based methods described herein eliminate this additional step and provide enhanced 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, about 13°C, including all ranges and subvalues ​​therebetween.

[0123] Moreover, the difficulties faced by 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 approximately 25 V for radiofrequency devices. rms The pulsed electric field device is driven at approximately 600V rmsWhen driven at 1000 Hz, the peak power of the PEF treatment can be approximately 576. Thus, it is unexpected that the pulsed or modulated electric field methods described herein not only treat tissue, but do so without excessive thermal tissue damage that would require mitigation procedures. Furthermore, the increased power density may require additional insulation and protection of the pulsed electric field device, as well as a signal generator capable of generating such peak power levels. In general, the duty cycle of PEF treatment can be several orders of magnitude lower than radiofrequency ablation to keep the bulk tissue temperature rise below about 10°C. For example, radiofrequency ablation energy can generally be delivered continuously for several seconds. In some variations, the PEF treatment can collectively accumulate an on-time of about 15 milliseconds over about 10 seconds for a net duty cycle of about 0.0015.

[0124] Figure 70 is a plot (7000) comparing the voltage output of a pulsed electric field treatment (7010) with the voltage output of a 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 disposable 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 a predetermined size and spacing configured to generate a pulsed or modulated electric field having a predetermined uniformity to treat a 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, thereby treating the engaged tissue.

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

[0127] I. System overview The systems described herein may include one or more of the 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 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, for example, 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 a dilator (418), and the guidewire (424) may extend from a lumen of the dilator (418). The expandable member (414) may comprise an 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 aid in one or more of the following: advancement of the pulsed electric field device (410), positioning of the pulsed electric field device and / or its components (e.g., the electrode array (416)), and confirmation of 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 in parallel with the pulsed electric field device (410) during a 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), thus 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 aids 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, an LED, a 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 propagate light from an external light source. The endoscope may comprise an image sensor configured to receive reflected light from the tissue and a pulsed electric field device. It should be appreciated that the 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 capacitive 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 mucosa of the duodenum while minimizing damage to the 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 the 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 currents) and may have a non-zero time 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 the voltage drive and current drive, or the pulse waveform may comprise a square in the voltage drive and a sawtooth shape in the current drive. In some variations, the one or more pulses may comprise a half-sine wave for both the current and voltage. In some variations, the one or more pulses may comprise two exponential functions with different rise and fall times. In some variations, the 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 the electrodes of the electrode array (416) to receive a pulsed 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 comprise an elongated 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 certain pre-specified portions 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 the 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 the duodenal tissue. For example, the generated pulsed or modulated electric field can vary spatially up to about 20%, about 5% to about 20%, about 10% to 20%, and about 5% to about 15% at a predetermined depth of the tissue, including all ranges and subvalues ​​therebetween. Additionally, the pulsed electric field device can be biocompatible and resistant to gastric acid and intestinal fluids.

[0135] Expandable Members In general, the expandable members described herein can be configured to change configuration 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 to hold the pulsed electric field device (e.g., elongated 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 comprise 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 unfolded configuration. Additionally, in some variations, the expandable member can comprise a semi-expanded (or partially unfolded) configuration between the compressed and expanded configurations. Placing the expandable member in a compressed configuration can compact the size of the pulsed electric field device, which can allow it to be more easily advanced through one or more body cavities. Once properly positioned, the expandable member can transition to an 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, and the like.

[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 exterior surface of the expandable member (530). In some variations, the 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 rolled configuration configured for advancement through one or more body cavities. When in the compressed or rolled 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 for engaging 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 a second inner diameter and a second outer diameter having a predetermined size that is greater than the first inner diameter and the first outer diameter, 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) can transition 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 aid in visualization. It should be understood that the pulsed electric field device (500) can be advanced next to the visualization device and / or over a guidewire. In some variations, a 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 a compressed configuration and an expanded configuration) to allow a visualization device (e.g., an endoscope) to be disposed within a lumen of the expandable member (530). In some variations, an inner surface of the expandable member can engage and retain a 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., an innermost portion of a roll) and an outer end (534) (e.g., an outermost portion of a 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 an outer surface of) the second elongate body (520), and the outer end (534) can be coupled to (e.g., an outer surface of) the first elongate body (510). In this manner, by coupling the ends of the expandable member (530) to the first and second elongate bodies (510, 520), the size and shape of the expandable member (530) can be better controlled. 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 an 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 Figures 5C and 5D facilitates advancement of the device (500) in a 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 of the first elongate body (510) and a lumen of the connector (540). Additionally or alternatively, one or more leads can be coupled to the electrode array through a lumen of the second elongate body (520). In some variations, the connector (540) can be constructed of a rigid or semi-rigid material or combinations 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, the expansion and compression of the expandable member (600) may be caused by the 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, including all ranges and subvalues ​​therebetween, hi some variations, the expandable member (600) in the expanded configuration can have a diameter of about 10 mm to about 50 mm, including 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 allow 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 allow 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 may 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, and the like.

[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 proximal electrodes to width of the electrodes 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 includes 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 recess relative to a 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 wrapped configuration. The device (800) in the wrapped configuration can be configured to be advanced 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 wrapped around or about 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 exterior 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, the system including the device (800) may further include a third elongate body (850) disposed within the lumen of the expandable member (830). In some of these variations, the third elongate body (850) comprises a visualization device (e.g., an endoscope). FIG. 8B is a perspective view of a variation of a visualization device (850) (e.g., an endoscope) and a pulsed electric field device (800). In FIG. 8B, the expandable member (830) may transition to a partially deployed configuration (e.g., semi-expanded) sufficient for the visualization device (850) to be disposed within the lumen of the expandable member (830). For example, the device (800) may be configured to hold the visualization device (850) in a predetermined position relative to the device (800). In this manner, the pulsed electric field device (800) and the 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 attachment, 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, a 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 a roll) and an opposing outer end (e.g., an outermost portion of a 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 an outer end of the expandable member (830). In some variations, the 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 combinations 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 rolled configuration. The device (900) in the rolled 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 of the multiple outer elongate bodies (910) comprising a lumen and a second elongate body (920) positioned at least partially within each lumen of the outer elongate body (910). The multiple expandable members (930) can be disposed along a 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 an exterior surface of each of the expandable members (930). In some variations, each expandable member (930) may be coupled to a 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) with multiple expandable members (930) may allow 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) may be the same or different. Energy may be delivered to multiple electrode arrays of the device (900) in any predetermined order. For example, the electrode arrays may 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, the 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 visualization device (950) (e.g., an endoscope) and a variation of 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 depict 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), the inner end being coupled to the inner elongate body (920) and the outer end being 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 combinations 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. FIG. 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 elongated body (1010) having a lumen therethrough and a second elongated body (1020) positioned at least partially within the lumen of the first elongated body (1010). The expandable member (1030) may be wound around the second elongated body (1020) as described in more detail herein. For example, the expandable member (1030) may include multiple turns around the second elongated body (1020). The expandable member (1030) may be coupled to distal portions 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 comprise an electrode array (not shown for clarity), which may comprise any of the electrode arrays described herein. For example, the electrode array may be disposed on an exterior surface of the expandable member (1030). In some variations, the pulsed electric field device (1000) may further comprise one or more dilators. For example, the pulsed electric field device (1000) may comprise 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) may aid in smoothly advancing and / or retracting the pulsed electric field device (1000) through one or more body cavities and may help prevent the expandable member from catching 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 the 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 elongated 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 length and taper 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] FIG. 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 comprise a connector (1040) that may 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) may couple the first elongate body (1010) to an outer end of the expandable member (1030). In some variations, the electrode array may be electrically coupled to the first elongate body (1010) through the connector (1040). For example, one or more leads may 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 combinations thereof, such that the position of the 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, including 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, including 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 a rolled configuration and a deployed configuration. For example, the second elongate body (1020) can be rotatably positioned within a 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, including all ranges and subvalues ​​therebetween.

[0160] In some variations, the 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 includes 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 of which is 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 a 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 the pulsed electric field device can transition configurations by using an actuator that allows for improved control over the expansion and / or compression of the expandable member. For example, the actuator can include 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 elongated 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) including an actuator (1270). As shown therein, the pulsed electric field device (1200) can include a first elongated body (1210) with a lumen therethrough, a second elongated body (1212) positioned at least partially within the lumen of the first elongated 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 sigmoidal 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., unfolding) 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). FIG. 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 comprise 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 being coupled to the second elongate body (1212) and the outer end being coupled to the first elongate body (1210).The direction of rotation (e.g., clockwise, counterclockwise) of the second elongate body (1212) may determine the expansion or compression of the expandable member (1230). In some variations, a connector (1240) may couple the second elongate body (1212) to an inner end of the expandable member (1230). The outer end of the expandable member (1230) may 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 illustration purposes. In some variations, in the rolled configuration, the expandable member (1230) may 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 may 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] FIG. 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) at a first portion of the expandable member (1330) adjacent or near the first end (1302) or at the first end (first end) can be less than dimension B (1362) at a second portion of the expandable member (1330) adjacent or near the second end (1304) or at the second end (second end). Conversely, the length of each opening (1360, 1364) may decrease from the first end (1302) to the second end (1304) along the longitudinal axis of the expandable member (1330). For example, the length of dimension C (1364) adjacent or near the first end (1302) or at the first end may be longer than the length of dimension A (1360) adjacent or near the second end (1304). This spacing and opening geometry may allow the expandable member to form a more precise and compact shape around the gear in a wrapped configuration, as shown in FIG. 13C, which is described in more detail below.

[0166] 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 expandable member (1330) (such as the expandable member shown in FIG. 13B) in a wound configuration. Expandable member (1330) is depicted wound around gear (1310) with one or more teeth (1312). Although depicted in FIG. 13C as a cylindrical gear (e.g., having a cylindrical body), gear (1310) need not be, and gear body (1342) may have any suitable cross-sectional shape, such as, for example, elliptical, 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 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 the 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 the layers.Thus, the openings of the tracks (1332, 1334) may fit smoothly over and / or around the gear teeth (1312), while the portions of the expandable member (1330) between the tracks (1332, 1334) may fit smoothly around the body of the gear between the gear teeth (1312), which may reduce interference, binding, and bunching of the expandable member (1330) in the wrapped 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 exterior surface of the expandable member (1330).

[0168] In some variations, the distance (1341, 1343) between the openings (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) may 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) may 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 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). A plurality of 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 in shape. 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 comprise 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 may be configured to expand tissue and / or improve visualization of tissue within the body cavity. For example, the second expandable member (1440) may be concentrically coupled to a distal end of the second elongate body (1420). That is, a central longitudinal axis of the second expandable member (1440) may be coupled to a 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, including 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). A plurality of expandable members (1560) may be coupled to the first elongate body (1510). For example, a plurality of 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 comprise an electrode array (not shown for clarity), which may comprise 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 a distal end of the second elongate body (1520). That is, a central longitudinal axis of the second expandable member (1540) may be coupled to a 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 a 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) can be transparent, thereby allowing a visualization device (1550) to image through the second expandable member (1540).

[0175] FIG. 16 is a perspective view of a variation of a pulsed electric field device (1600) and a visualization device (1650). In some variations, the pulsed electric field device (1600) may comprise 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 comprise an electrode array (not shown for clarity), which may comprise any of the electrode arrays described herein. For example, the electrode array may be disposed on or coupled to an exterior surface of the expandable member (1630). The expandable member (1630) may comprise a lumen formed by longitudinally coupling 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) comprising 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) may be coupled to the second elongate body (1620). For example, the second expandable member (1640) is offset relative to a longitudinal axis of the second elongate body (1620). For example, a sidewall of the second expandable member (1640) may be coupled to a distal end of the second elongate body (1620). In some variations, the second expandable member (1640) may be an inflatable member, such as a balloon. The visualization device (1640) may be disposed within a 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 a lumen of the expandable member (1630). In some variations, at least a proximal end and a distal end 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 comprise an interdigitated configuration, for example, the plurality of elongate electrodes may comprise a curved shape (e.g., S-shaped, W-shaped).

[0178] In some variations, the pulsed electric field device may include a length of expandable member and / or an electrode array for ablating a 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 end of the device (1700, 1800) will bend. For example, the device (1700) may have more flexibility than the 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) comprising 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) 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. At least proximal and distal portions of the expandable members (1740, 1840) can be transparent.

[0180] In some variations, the pulsed electric field device may comprise an expandable member comprising a transparent inflatable member. FIG. 19 is a perspective view of a variation of a pulsed electric field device (1900) and a visualization device (1940). In some variations, the pulsed electric field device (1900) may comprise an elongated body (1910), and an expandable member (1920) may be coupled to the elongated body (1910). In some variations, the expandable member (1920) may comprise an electrode array (1930), which may comprise 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 a distal end of the elongated 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 expand 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 a proximal and distal portion 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 a plurality of expandable members (2130) proximal to a distal second expandable member (2140) (e.g., inflatable member). The spacing between the plurality of expandable members (2130) may determine the degree to which the distal end of the device (2130) may bend. In some variations, the pulsed electric field device (2100) may comprise an elongate body (2110), and the plurality of expandable members (2130) may be coupled to the elongate body (2110). In some variations, the plurality of expandable members (2120) may comprise an electrode array (2130), which may comprise any of the electrode arrays described herein. At least the proximal and distal portions of the expandable member (2120) may be transparent.

[0183] 22 is a perspective view of a variation of a pulsed electric field device (2200) and visualization device (2250) similar to FIG. 19, but with an expandable member (2220) and a sidewall of a second expandable member (2240) 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 to the center of the expandable member (2220). In some variations, the expandable member (2220) may comprise an electrode array (2230), which may comprise any of the electrode arrays described herein. At least the proximal and distal portions of the expandable member (2220) may be transparent.

[0184] 23 is a perspective view of a variation of a pulsed electric field device (2300) and visualization device (2340) similar to FIG. 19, but with an expandable member (2320) and a sidewall of a second expandable member (2330) 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 to the center of the expandable member (2320). In some variations, the expandable member (2320) may comprise an electrode array (not shown), which may comprise 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 with an expandable member (2420) and a sidewall of a second expandable member (2440) (e.g., inflatable member) attached to an elongated body (2410). In some variations, the pulsed electric field device (2400) may comprise an elongated body (2410) and a plurality of expandable members (2420) may be coupled to the elongated 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 a proximal and distal portion 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 visualization device (2540) similar to FIG. 23, but with an expandable member (2530) concentrically coupled to the distal end of the first elongate body (2520). That is, the central longitudinal axis of the expandable member (2530) may be aligned with and may be 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 comprise an electrode array (not shown), which may comprise 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 visualization device (2650) similar to FIG. 21 but bent to show the flexibility of the device (2600). The spacing between the expandable members (2620) may determine the degree to which the distal end of the device (2600) may bend. In some variations, the pulsed electric field device (2600) may comprise an elongate body (2610) and the expandable members (2620) may be coupled to the elongate body (2610). In some variations, the expandable members (2620) may comprise an electrode array (2630) that may comprise any of the electrode arrays described herein. At least the proximal and distal portions of the expandable members (2620) may be transparent. A second expandable member (2610) may be attached to the elongate body (2610) proximal to the expandable members (2620).

[0188] FIG. 27 is a perspective view of a variation of a pulsed electric field device (2700) and visualization device (2750) similar to FIG. 24. For example, the side walls 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 an expandable member (2810) of a pulsed electric field device (2800) and a visualization device (2830). FIGS. 28B-E are perspective views of a pulsed electric field device (2800) and a 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 an 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 a 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 image, for example, a proximal portion of the expandable member (2810) and to be steered independently of the expandable member (2830). After energy delivery is completed, 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) may bend. In some variations, as shown in Figure 28E, the visualization device (2830) may bend within the lumen of the expandable member (2810).

[0191] FIG. 29A is a perspective view of a variation of a pulsed electric field device (2900) and visualization device (2930) similar to FIGS. 28A-28E, but 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 comprise an electrode array (2920), which can comprise any of the electrode arrays described herein. FIG. 29B is a perspective view of the pulsed electric field device (2900) and visualization device (2930) separated (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 may 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 disposed circumferentially about a 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 FIG. 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 may 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 turn. 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 disposed circumferentially around a 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. The PEF energy tissue treatment can be delivered uniformly at a predetermined depth (e.g., about 1 mm) to rapidly and precisely treat the tissue without significant damage to the 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 contact layer. In some variations, the tissue contact layer can act as a salt bridge between the electrodes 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 outcomes. For example, tissue contact (e.g., apposition) with the electrodes 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 reduce arcing. Spaced 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 members 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, round) shape such 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., outer catheter, 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 include shapes (e.g., radii of curvature) that allow the generated electric field to decrease rapidly without application of very high voltages (e.g., thousands of volts) that may 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 a plurality of elongated electrodes (3410) on a substrate (3420). In some variations, at least one of the electrodes (3410) may comprise a semi-elliptical cross-sectional shape. In some cases, all of the electrodes (3410) in the electrode array (3400) may comprise a semi-elliptical cross-sectional shape. Generally, the electric field is stronger near the points and edges of the electrodes due to the concentrated surface charge of the electrodes. Sharp-edged electrodes and high electric fields can generate one or more of the following effects: discharges (e.g., arcing), high heat (e.g., boiling), high current densities (e.g., electrolysis), and bubbles. The semi-elliptical cross-sectional shapes described herein may 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 FIG. 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 manufactured 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 described further 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 (w is major axis), with the foci of the ellipse d from the center. The eccentricity can be given by equation (2): ε = (1 + (h / d) 2 ) -1 / 2 Formula (2)

[0205] The footprint of a raised electrode is 2w=2d / ε, increasing by a factor of 1 / 2ε from a flat electrode. If 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 driving 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 effect 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 aid in energy delivery for a treatment procedure. For example, the electrode array may include multiple zones disposed 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 may comprise a plurality (e.g., 4, 8, 12, 16, 20, 24, 30, and any range therein) of elongated electrodes. For example, the electrode array may comprise more than about six electrodes. In some variations, the plurality of elongated electrodes may comprise a center-to-center ratio of adjacent (i.e., directly 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 include 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 a coordinate s(x,yi) (Equation 3), where x and y are parallel to a surface of the electrode array, a first distance (s+) is parallel to a nearest electrode of a first polarity (e.g., positive polarity), and a second distance (s.) is parallel to a nearest electrode of a second polarity (e.g., negative polarity) opposite to 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 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 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 about 36% conductors by area. In some variations, the surface area of ​​the 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 comprise multiple groups of electrodes (e.g., see zones A, B, C in FIG. 51), each group may be activated in a predetermined sequence. In some variations, more uniform treatment of tissue (e.g., areas where electrode groups intersect) may be obtained by decreasing the width of the most end electrodes of each group and decreasing the distance between those electrodes. In some variations, more uniform treatment of tissue (e.g., areas where electrode groups intersect) may be possible by interdigitating the most end electrodes of each group to overlap the treatment area.

[0211] As described in detail herein, the 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, e.g., multiple elongated parallel electrodes. The expandable member is depicted in an expanded cylindrical configuration in FIG. 34C.

[0212] FIG. 35 is a field strength plot of electrode arrays having 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 may vary spatially by up to about 20% at a given treatment distance from the electrode array. For example, the electric field (3520) generated by the electrode (3510) may 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 may improve consistency of energy delivery and treatment results.

[0213] FIG. 80A is 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) at a predetermined tissue treatment depth (8030) across its entire surface. For example, the predetermined tissue depth can be configured to receive a voltage field of about 2500 V / cm. A voltage of about 600 V can be applied to the electrodes at a current of about 50 A and a frequency of about 350 kHz. 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 about 600V and generate an electric field (8120) below the treatment threshold at a tissue depth of about 1.48mm.

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

[0216] 36 is a field strength plot of a conventional electrode array lacking field uniformity. The electrodes (3610) are shaped and spaced such that the generated electric field (3620) provides some portions of the submucosal tissue with a field strength of up to about 200 V / cm, 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 poor consistency of energy delivery has limited positive impact on treatment outcome.

[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 electrodes and tissue to improve conduction of matter 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) comprising a tissue contact layer (3920) and in contact with tissue (3910) (e.g., the duodenum). In some variations, the tissue contact layer (3920) can be disposed on a substrate of the electrodes and / or electrode array. The tissue contact layer (3920) can have a lower electrical conductivity than that of the electrodes. In some variations, the electrical conductivity of the tissue contact 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 contact layer can have a thickness of about 10% to about 20% of the width of the electrodes. In some variations, the tissue contact layer can be comprised of a porous material such as an open-cell sponge with an ohmic electrical conductor, such as carbon particle-loaded rubber, or an ionic conductor, such as sodium chloride or carbon.

[0219] In some variations, the portion of the tissue contact layer disposed between the electrodes and / or on the edges of the electrodes may comprise 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, including all ranges and subvalues ​​therebetween. The tissue contact layer disposed on the electrode edges may reduce heating by reducing current draw in the high electric field strength portions of the electrodes. For example, this portion of the tissue contact layer may comprise carbon black disposed in a polymer matrix (e.g., acrylic). For example, one or more electrode edges may comprise a tissue contact 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 away from the electrode (4000), z along the ) and above the space between the electrodes (e.g., E x It may be beneficial for the electric field strength along the axial direction (along the axial direction) to be as uniform as possible so that tissue can be treated with the same energy.

[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 between these is significantly larger than that in either of FIGS. 41B to 41C.

[0223] 42 is a histogram of the electric field strength of the electrode array at a treatment depth of about 0.7 mm and twice that treatment depth of about 1.4 mm. At the treatment depth, there is about a 5% spread at a dose of about 3,100 V / cm. At twice that treatment depth, there is less than a 2% spread at 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 system disclosed herein may include a return electrode for drawing PEF current from the patient. In some variations, the catheter (e.g., the third elongated 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., skin patch electrode, ground 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] 76 is a perspective view of a variation of an expandable member (e.g., 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 a 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). Use of suction or negative pressure applied through the openings may 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) may engage the duodenum via suction through one or more openings (7630), which may 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 outcome. Additionally, the applied suction may 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 (7610) to promote contact between the 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 (e.g., fluidically coupled) with a fluid source (not shown) for fluid irrigation. For example, fluid can be removed from the body cavity (e.g., aspirated from the body cavity) after application of 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 include a semi-elliptical cross-sectional shape. In some cases, all of the electrodes (7610) in the electrode array (7600) may include 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 a predetermined diameter 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, an electrode array (7600) depicted in FIG. 76.

[0230] In some variations, the first and second elongate bodies (7710, 7720) may 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) may 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) may transition 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) may 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 aid in visualization. It should be understood that the pulsed electric field device (7700) may be advanced next 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 a compressed configuration and an expanded configuration), which can allow for a visualization device (e.g., an endoscope) to be disposed within a lumen of the expandable member (7730). In some variations, an inner surface of the expandable member can engage and retain a 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 a deployed electrode array (7800) of the pulsed electric field device depicted in FIG. 77 and FIG. 78A. The electrodes shown in FIG. 76-FIG. 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, including all ranges and subvalues ​​therebetween. In some variations, the distance between adjacent (e.g., proximate) electrodes (7610) may be about 1.0 mm to about 1.4 mm to about 1.2 mm, including 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, including 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, to 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 a 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 an illustrative variation of another 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 couple 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 allow for the generation of a substantially uniform pulsed or modulated electric field. For example, electrode pair A (4510) and C (4530) may have opposite polarity, while electrode pair B (4540) and D (4520) may have opposite polarity. Other electrode array configuration types may be active in alternative combinations to provide uniform treatment within the 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 the electrode pairs will directly affect the magnitude of the electric field or 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 strength plot (4500) of an illustrative variation of an electrode array (4550). Figure 45E is a cross-sectional view of an electric field strength 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 an electrode array (4610) and a corresponding coordinate system for a set of planes. Figure 46B illustrates electric field intensity plots corresponding to the electrode array (4610) at positions defined relative to the primary 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] FIG. 47A is a schematic plan view of an illustrative variation of the polarity configuration of the electrode array (4700). FIG. 47B illustrates an electric field intensity plot corresponding to the electrode array (4700) shown in FIG. 47A at a position defined relative to the major plane depicted in FIG. 46A. The bottom two charts in FIG. 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 FIG. 47B and corresponding to the electrode array (4700) is denser than that depicted in FIG. 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 thermal bond 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, the first catheter (8510) advanced 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 heating. 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 an 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., conductive liquid, saline) while treating tissue as described herein. In some variations, the pulsed electric field device (8500) in a 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 a compressed configuration can have a diameter of about 1.5 mm to about 4 mm.

[0243] Washing 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 outcomes. Liquid irrigation of the tissue may further reduce the temperature of the tissue through forced convection and reduce arcing. Additionally, fluid delivery may reduce corrosion of electrical insulation and 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 may 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 an increase in 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 having a higher conductivity than tissue may be removed.

[0244] In some variations, the pulsed electric field devices described herein can be configured to output fluid to cleanse tissue, such as the patient's duodenal tissue. For example, an electrode array of a pulsed electric field device can engage the duodenum and can 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 the amount of fluid. The electrode array can be energized to treat a predetermined portion of the tissue to resurface the duodenum. Utilizing an electrode array configured to deliver fluid can eliminate the need for a separate cleaning device and / or system. FIGS. 69A and 69B are respective plan and respective 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 (6920) of the electrodes (e.g., all, half, one third, two thirds) may include one or more (e.g., one, two, three, four or more) fluid openings (6930) configured to output a fluid, such as saline for irrigation. For example, the openings (6930) may be spaced along the length of the electrodes (6920). As shown in FIG. 69C, one or more openings (6930) may be disposed on the top of each electrode (6920), although the openings (6930) may be disposed on any portion of the electrodes (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 a fluid path (6940). The fluid path (6940) of the electrode (6920) may be in fluid communication with a fluid opening (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 fluid flow rate of about 0.001 cc / (s cm 2 ) ~ approx. 1cc / (s cm 2 ) at a predetermined rate. For example, the electrode array (6900) can be configured to drain when in the expanded configuration. The fluid between the electrode array (6900) and the tissue can 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 paths. In some variations, the fluid paths may be configured to facilitate the flow of fluid for conduction (e.g., ionic fluids) and heat transfer (e.g., temperature control during treatment). In some variations, the fluid paths 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 paths 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, the fluid openings may be disposed at the apex of one or more of the multiple electrodes (6920). In some of these variations, the 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] Sensors 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., CCD), a pressure sensor, an electrical sensor (e.g., impedance sensor, voltage sensor, a magnetic sensor (e.g., RF coil), an electromagnetic sensor (e.g., infrared photodiode, optical photodiode, RF antenna), a force sensor (e.g., strain gauge), a flow or velocity sensor (e.g., hot wire anemometer, vortex flowmeter), an acceleration sensor (e.g., accelerometer), a chemical sensor (e.g., pH sensor, protein sensor, glucose sensor), an oxygen sensor (e.g., 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 with the pulsed electric field device (e.g., full contact, partial contact, no contact) and successful energy delivery to the tissue. Thus, 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 that may otherwise result in insufficient or suboptimal treatment results. For example, energy delivery can be inhibited or delayed if the tissue temperature measurement exceeds a predetermined threshold.

[0249] As described herein, pulsed or modulated electric field treatment of tissue necessarily heats the tissue locally around the electrodes. 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 in an electrode array. For a four-point probe connection, a differential voltage developed through the sense lines can be sensed by a first pair of conductors, and a current drive that generates the differential voltage can be applied by a second pair of conductors. In some variations, the drive current or 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 a plurality of 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 may be disposed between adjacent electrodes in the array (5110). For example, the tissue temperature sensors may be configured to run parallel or interdigitated between adjacent elongated electrodes (5110). FIG. 51A illustrates multiple groups of electrodes (e.g., zones A, B, C) with corresponding temperature sensors. The tissue temperature sensor array may 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 may be provided per zone. For example, the trace (5140) is between the sense points of zone A and zone B, and the trace (5140) is in series with the trace (5130). The voltage difference of the sense current in each zone divided by the sense current flowing through the entire trace may provide the resistance of the 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 sensor can be configured to be thermally coupled and in contact with tissue such that the measured sensor temperature corresponds to the tissue temperature. The temperature sensor can be electrically isolated from the tissue so that the sense current passes only through the temperature sensor and high voltage driving of the electrodes does not damage the temperature sensor. In some variations, the electrode array can include one or more drive circuits for applying voltage or current pulses to the temperature sensor and a sense circuit for measuring the voltage or current across the temperature sensor.

[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 dielectric 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 a temperature of approximately

number

number

number

[0254] I s =0.5A and L s = 2cm and R s = 0.276 ohms gives 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 no tissue is in contact is given by equation (6).

number

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

[0256] s is the spacing of the temperature sensors. For temperature sensors spaced approximately 0.075 mm apart, the maximum pulse duration may be approximately 21 ms 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 of the temperature sensor carries current and voltage across a fine trace, in which 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 a plurality of temperature sensors (5120) and a reference generator (5160) (described in more detail with respect to FIG. 52 and FIG. 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 a plurality of 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 a gear and a friction roller. The track (5180) may include a plurality of spaced apart 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 about 2 mm and a width of about 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 identify 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 be absent after about three days. The visual markers may be configured to identify the treatment site and aid in repositioning the resection device. For example, the operator may advance the expandable member (5100) past the most distal visual marker of the duodenum during the resection procedure.

[0260] The duodenal tissue (5102) shown in FIG. 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. FIG. 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 sensor 5120 and the openings 5170 without the electrode array 5110 for clarity. As shown in FIG. 51D, the temperature sensor 5120 may include a serpentine shape that may meander back and forth along a predetermined path. For example, the temperature sensor 5120 may curve around each opening 5170 of 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 aspirated 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 about 60 mm and a width of about 20 mm. Thus, about 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 the signal generator requirements. For example, the electrode array (5110) may have a circumferential length of about 60 mm. An electrode array (5110) including two sections may have each section including a circumferential length of about 27 mm. In some variations, the configuration and placement of the electrode array (5110) on the expandable member may facilitate one or more of the manufacturing techniques and the temperature measurement of the tissue at a predetermined depth. In some variations, a set of reference generators may be disposed between the sections of the electrode array, for example, each reference generator may generate a visual marker having a length and width of about 2 mm. The expandable member (5100) depicted in FIG. 51B and as described herein may correspond to the expandable member (7600) depicted in FIG.

[0263] In some variations, one or more of the temperature sensors (5120) (e.g., temperature traces) may generally extend across the multiple electrodes of the electrode array (5110). For example, one or more of the temperature sensors (5120) may comprise a generally serpentine shape that may be continuous. In some variations, the temperature sensor (5120) may measure an average temperature across a given portion of the sensor (5120), which may be a better representation of the tissue temperature. In contrast, a temperature measurement taken very close to the end of the electrode may result in a misleadingly high temperature that is not representative of the temperature throughout the tissue. In some variations, the temperature trace lines may 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, the temperature measurements from one or more temperature sensors (5120) may correspond to the temperature of the tissue at a given depth.

[0264] In some variations, one or more of the temperature sensors (5120) may comprise 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 the other temperature sensors by about 0.10 mm to about 0.17 mm. In some variations, one or more of the temperature sensors (5120) may be disposed on the expandable member (5100) using button plating.

[0265] In some variations, visually marking the treated tissue can assist an operator in performing a tissue treatment procedure 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 the tissue to be visualized within the 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 circumference 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 helical 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., thus 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). FIG. 52B is a detailed view of the schematic circuit diagram of the electrode array (5210) and one helical reference generator (5220). FIG. 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) of 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 (e.g., the duodenum) being treated.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. In 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 an elongated shape 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 conical 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, and the like. In some variations, the dilator can comprise a solid construction. In some variations, the dilator can comprise multiple materials configured to provide a 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 may include a length of about 2 mm to about 10 cm. In some variations, the dilator may 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 may be atraumatic (e.g., rounded, blunt). In some variations, the pulsed electric field device may include multiple dilators (e.g., 2, 3, 4, 5, 6, or more). For example, each dilator may 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 length and taper of the multiple dilators of the 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 and slender body In general, 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 of a flexible polymeric material, such as Teflon, nylon, Pebax, urethane, combinations thereof, and 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, omni-directional). 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 bend radius of about 5 cm to about 23 cm and / or 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 and / or 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 comprise metal-based radiopaque markers comprising one or more of rings, bands, and inks (e.g., platinum, platinum iridium, gold, nitinol, palladium) configured to allow fluoroscopic visualization. In some variations, one or more of the first and second elongate bodies may comprise a magnetic member configured to attract and bond the bodies to one another. In this manner, the first elongate body need not comprise a lumen for the second elongate body. In some variations, the elongate body may comprise from about 2 layers to about 15 layers of material to achieve a predetermined set of properties.

[0272] handle In general, 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 generators, temperature sensors) 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 based on the frequency and current of the energy to be 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 the following: inductance between the wires, resistance of the wires, temperature rise of the wires, and skin effect of the wires. Additionally or alternatively, specially woven Litz wires and / or tubular conductors (e.g., coaxial cables) 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 transmission wire (8430) and the reference generating wire (8410).

[0274] Insulation In general, the insulators described herein can be configured to electrically insulate another portion of the electrode array, the expandable member, the expander, 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] Guidewires In some variations, the guidewire can be slidably disposed within the lumen of the elongated body of the pulsed electric field device. The guidewire can be configured to aid in advancement of the pulsed electric field device through the gastrointestinal tract. In some variations, the first and second elongated 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 comprise variable stiffness along its length. For example, the distal tip can be configured to be malleable (e.g., floppy) and the elongated body of the guidewire can be relatively stiff to aid pushability through the patient's anatomy. In some variations, the guidewire can comprise 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., PEF energy waveforms) 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 aid 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 to 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, a 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, to induce an electric field across the cell membrane in the duodenum of greater than about 0.5 V, about 1,000 V / cm to about 2,500 V / cm or more are required at the treatment depth of the tissue. In some variations, to induce an electric field across the cell membrane in the duodenum of greater than about 0.5 V, about 1,500 to about 4,500 V / cm or more are required at the treatment depth of the tissue, including all ranges and subvalues ​​therebetween. Even relatively low tissue conductivity (e.g., about 0.3 S / m) can generate bulk tissue heating rates of at least about 800° C. / sec. The maximum temperature rise to be generated can be about 8° C., so that the maximum continuous on-time (100% duty cycle of alternating polarity pulses) can be about 10 milliseconds. For example, the 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 longer and longer delays between the series. In some variations, a series of sequences may be applied with longer delays between sequences, hi some variations, a cumulative on-time of about 15 milliseconds may be spread out over about 10 seconds.

[0279] In some variations, the signal generator can be configured to generate currents, voltages, and powers in a pulsed or modulated electric field spectrum of about 250 kHz to about 950 MHz, pulse widths of about 0.5 μs to about 4 μs, voltages applied by the electrode array of about 100 V to about 2 kV, and current densities 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 into a tissue resistance of about 5 ohms to about 30 ohms of load. 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 comprise 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 comprise a group delay of about 10 μs to about 4000 μs and a replenishment rate of about 50 milliseconds to about 4000 milliseconds. For example, a balanced bipolar pulse waveform (e.g., within 10%) may reduce sympathetic excitation, which may reduce perceived pain and voluntary muscle contractions. Microsecond pulses of about 1 μs to about 10 μs may generate cell lysis while minimizing nerve stimulation. The electric field distribution produced by short bipolar pulses is less dependent on tissue homogeneity, especially in anisotropic regions.

[0280] In some variations, the set of bipolar pulses can be split into bursts of bipolar pairs with a time delay between the bursts. This allows the heat generated at the cell membrane to disperse, allowing more treatment before the transition from cell lysis to necrosis. The total time that 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 is 10 microns, the thermal diffusion time is approximately D 2 cell / κ=0.8 ms. Thus, applying a pulse burst and then waiting a millisecond allows temperature equilibration throughout the cell.

[0281] FIG. 53 is a circuit block 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 may process data and / or other signals to control one or more components of the system. The processor may be configured to receive, process, compile, calculate, store, access, read, write, and / or transmit data and / or other signals. In some variations, the processor may 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, the 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 of a data processor, an image processor, a graphics processing unit (GPU), a physical processing unit, a digital signal processor (DSP), an analog signal processor, a mixed signal processor, a machine learning processor, a deep learning processor, a finite state machine (FSM), a compression processor (e.g., data compression to reduce data rates and / or memory requirements), an encryption processor (e.g., for secure wireless data and / or power transfer), and / or a central processing unit (CPU). The 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 technologies may be provided in a variety of component types (e.g., metal-oxide semiconductor field-effect transistor (MOSFET) technologies such as complementary metal-oxide semiconductor (CMOS), bipolar technologies such as emitter-coupled logic (ECL), polymer technologies (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 generate 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, the pulsed electric field devices described herein may comprise a 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, and the like. 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 communication. 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-transient in the sense that it does not include ephemeral propagating signals (e.g., propagating electromagnetic waves that carry information over a transmission medium such as space or a cable) themselves. 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 comprise a communication device configured to allow an operator to control one or more of the devices of the PEF system. The communication device may comprise a network interface configured to connect the pulsed electric field device to another system (e.g., the Internet, a remote server, a database) by 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 smart watch, etc.) via one or more wired and / or wireless networks. In some variations, the network interface may comprise 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, a network, a database, and a server via a wired and / or wireless connection.

[0285] The network interface may include RF circuitry configured to receive and / or transmit RF signals. The 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, antenna systems, RF transceivers, one or more amplifiers, tuners, one or more oscillators, mixers, digital signal processors, CODEC chipsets, subscriber identity module (SIM) cards, memory, etc.

[0286] Wireless communication through any of the devices may be implemented 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 uplink packet access (HSUPA), Evolution, Data-Only (EV-DO), HSPA, HSPA+, Dual-Cell HSPA (DC-HSPADA), 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, 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 touch screen) 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 touch screen) may be received by the user interface and then 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 an input (e.g., a finger contact on the touch surface) corresponding to the control signal. An input device 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., 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 voice 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 may generate a haptic response (e.g., vibration) to confirm operator input to the input device (e.g., touch surface). As another example, the haptic feedback may inform 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 given portion of tissue, e.g., duodenal tissue, for the treatment of diabetes, for example.

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

[0291] In some variations, the generated pulsed or modulated electric field may be substantially uniform such that pulsed or modulated electric field energy for tissue treatment may be delivered to a given portion of the duodenum (e.g., the mucosal layer) without significant energy delivery to deeper layers of the duodenum. Thus, these methods may improve the efficiency and effectiveness of energy delivery to duodenal tissue. Additionally, the methods described herein may 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 pulsed 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 aid in identifying tissue treatment areas during and after treatment.

[0293] How to Treat Diabetes In general, methods of treating diabetes may include generating pulsed or modulated electric fields to induce changes (e.g., treat) in 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 may generate these signals. Duodenal mucosal resurfacing using the systems, methods, and devices described herein may 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 may positively impact glycemic hemostasis in type 2 diabetes patients.

[0294] In some variations, the pulsed or modulated electric field may cause cell lysis in the tissue that is at least 50% pore-induced and less than 50% heat-induced. In some variations, the method of treating diabetes may include advancing a pulsed electric field device toward the patient's duodenum. In some of these variations, the patient may be positioned in a left lateral position during the procedure, and the duodenum may optionally be insufflated (e.g., using CO2 or saline). The pulsed electric field device may comprise an elongated body and an expandable member comprising an electrode array. Upon entering the duodenum, the expandable member may transition to an expanded configuration. In some variations, one or more turns of the expandable member may be deployed to contact the duodenum. In some variations, a visualization device (e.g., an endoscope) may 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 may 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 may be used in the methods described herein.

[0295] In some variations, the method of 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 an expanded configuration may have a more uniform tissue thickness, whether by application of a radial force and / or negative pressure, which may aid in consistent energy delivery and treatment. In some variations, the tissue may contact the expandable member in an 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) of the expandable member. This may reduce tissue tenting and / or air pockets on the electrode, ensuring a consistent tissue-electrode interface around the duodenum. Additionally, suction may allow for a reduction in the radial force applied by the expandable member. In some variations, the negative pressure (e.g., suction) applied to the tissue may be from about 50 mmHg to about 75 mmHg. In some variations, the negative pressure (e.g., suction) applied to the tissue may be applied intermittently or for relatively short periods of time, at pressures of from about 100 mmHg to about 250 mmHg. For example, higher negative pressures may 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 undistended duodenum (7100), which has a varying thickness around its circumference. As shown therein, in a natural state (e.g., no external force is applied, undistended), the duodenal tissue has a 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 to expand the duodenum (7110), reduce the thickness of the duodenal tissue, and / or create a more uniform duodenal tissue thickness around the circumference of the duodenum as compared to an undistended duodenum. Stretched or expanded tissue may comprise a narrower range of tissue thickness than unstretched tissue. In some variations, about 1 inch to about 15 inches of water (inH2O) may be applied to expand but not damage the tissue by pressure necrosis. For example, the expandable member may be configured to generate about 2 inches to about 6 inches of water (inH2O) to slightly expand tissue, such as duodenal tissue. Expanded tissue stretched by the expandable member in the expanded configuration may reduce the thickness of the tissue wall, thereby allowing for a lower dose of energy to treat a given depth of tissue. Stretched tissue may comprise a realigned (e.g., reoriented) cellular structure that increases the perimeter of the tissue. Reducing the total energy delivery may correspond to a reduction in the overall temperature rise of the tissue, which may 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 to the tissue lumen (e.g., duodenum, duodenal tissue) by the expandable member to facilitate apposition of the tissue with the electrode array of the expandable member. Higher tissue apposition can further allow for reduced total energy delivery and improved treatment outcomes.

[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 thickness as shown in FIG. 71A. For example, the expandable member may stretch the tissue such that the ratio of the manipulated (e.g., compressed / stretched / expanded) tissue thickness to the unmanipulated 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 unexpanded (e.g., unstretched) duodenum. FIG. 71E and 71F are cross-sectional images of an unexpanded (e.g., stretched) duodenum. In some variations, the resection devices described herein may transition to an expanded configuration to expand (e.g., stretch, elongate) tissue during a treatment procedure. In some variations, tissue may be treated within a range of expansion ratios. In some variations, the ratio of expanded mucosal tissue to unexpanded mucosal tissue may be about 0.40 to about 0.60, about 0.45 to about 0.55, and about 0.50, including all ranges and subvalues ​​therebetween. In some variations, the ratio of expanded submucosal tissue to unexpanded submucosal tissue may be about 0.15 to about 0.35, about 0.20 to about 0.30, and about 0.26, including all ranges and subvalues ​​therebetween. In some variations, the ratio of the dilated duodenal diameter to the undilated duodenal diameter can be about 1.5 to about 2.3, about 1.7 to about 2.1, and about 1.91, including all ranges and subvalues ​​therebetween. In some variations, the ratio of the dilated duodenal diameter to the undilated duodenal diameter can be about 1.5 to about 2.3, about 1.7 to about 2.1, and about 1.91, including all ranges and subvalues ​​therebetween.

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

[0301] In some variations, suction may be generated by the device itself while in the expanded configuration. Additionally or alternatively, suction may be generated by a visualization device such as an endoscope. The amount of suction may be configured to ensure uniform apposition of the tissue to the surface (e.g., electrode surface) of the expandable member. However, the amount of suction should not exceed a predetermined threshold corresponding to pressure necrosis. In some variations, the negative pressure (e.g., suction) applied to the tissue may be from 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 may be from about 10 mmHg to about 200 mmHg. The amount of suction may 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 edges of the openings, the compliance of the tissue, the vascularization of the tissue, and the friability 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 surface contact of the electrodes and the 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 may be assessed visually and / or through impedance measurements. In some variations, apposition may 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., endoscope) (5540) 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 into the duodenum (5530) over a guidewire (5530). In some variations, as shown in FIG. 55D, a treatment device (5560) may be advanced into the duodenum (5530) over a guidewire (5560) positioned with the visualization device (5540). FIGS. 56A-H 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 a method for treating diabetes. FIGS. 81A-C are schematic diagrams of another variation of a method for treating diabetes, as described in more detail herein. FIGS. 82A-D are images corresponding to the method shown in FIGS. 81A-C.

[0304] FIG. 54 is a flow chart generally illustrating a variation of a method (5400) of 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 about a longitudinal axis of the pulsed electric field device (5650). In a compressed configuration, the expandable member (5652) may comprise a lumen having a first inner diameter. The visualization device (5640) may be manipulated independently of the pulsed electric field device (5650). Similarly, FIG. 81A depicts a method (8100) of 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 the pulsed electric field device from the perspective of a 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 to 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 that is larger than the first inner diameter. In some of these variations, the 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., 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 visualization of 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 unfold 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 unfold 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) 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) may transition to an expanded configuration and contact tissue. In some variations, the distal end of the visualization device (8120) may be disposed either 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) may be configured to generate a negative pressure (e.g., suction) within the lumen of the expandable member (8130) that draws the tissue (8110) to the surface of the expandable member (8130). Additionally or alternatively, the device (8120) may be configured to generate a negative pressure to draw the tissue (8110) to 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 being advanced within the tissue. Thus, suction can occur intermittently throughout the treatment process. The amount of suction applied to one or more portions of the tissue can be as described herein.

[0308] FIG. 82B is an image of the expandable member (8220) in an expanded configuration where the expandable member (8220) is in contact with the duodenum (8210). FIG. 82C is an image of tissue (8210) in contact with the expandable member (8220) after application of negative pressure as described herein. In FIG. 82C, the tissue is pulled through multiple openings (8222) that extend through the thickness of the expandable member (8220). Intimate contact between the tissue (8210) and the expandable member (8220) may improve energy delivery and treatment outcomes. One or more pulse waveforms may 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 an expandable member (5652) in an expanded configuration with electrodes (not shown) configured to receive a pulse waveform 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, 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 a recruitment 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 4 cm 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 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 comprise 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, which may be used 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, the 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 has undergone PEF-induced cell death. FIGS. 56D-56H illustrate visual markers (5634) generated on the tissue. Additionally, retreatment of the duodenum in another procedure can be guided by one or more of the visual markers generated by the fiducial generator. FIG. 82D depicts an image of tissue (8210) with aspirated tissue (8212) that can be visually identified by a visualization device. The visual markers can be used to identify the treated portion of the tissue and 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 is approximately 260 cm long. 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 translating 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, 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 the visualization device. For example, the visualization device (5640) can be retracted to display the duodenal tissue (5630) proximal to the expandable member (5652) of 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 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 an expanded configuration to a compressed configuration in step 5416 and translating the device to a previously treated portion of the duodenum in step 5418, the expandable member may be transitioned to an 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 percentage 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 when treating the same portion of tissue multiple times (e.g., the gastrointestinal tract, including but not limited to the duodenum, pylorus, esophagus, stomach, small intestine, and large intestine). In some variations, the pulse waveform includes a first pulse waveform and delivers 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 tissue.

[0319] For example, FIG. 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). FIG. 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) to 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 arrays can be configured such that the total surface area of ​​the electrodes in contact with the tissue can provide a system resistance or impedance that is matched to 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] At 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. FIG. 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, FIG. 64A is a plan view image of a variation of a pulsed electric field device (6400) engaged with a visualization device (6410) and withdrawn from the patient. In FIG. 64A, the expandable member of the pulsed electric field device (6400) is in a semi-expanded 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-E. 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 an 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 to allow tissue temperature to drop before another burst of energy is delivered. Furthermore, delivery can be inhibited once a certain 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 is 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. FIG. 83A illustrates, for example, a temperature rise of about 4° C. as measured at the expandable member of a pulsed electric field device.

[0325] Alternatively, one or more pulse waveforms may be delivered such that the tissue is initially heated to about 41° C., and then pulse waveforms may 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 may be performed with application of low power energy to control the time and depth at which the tissue reaches temperature. This method may 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 digestive 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 elongated body and an expandable member coupled to the elongated 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 pulse waveform may be delivered to the electrode array to generate a pulsed or modulated electric field, thereby treating tissue, such as tissue of the duodenum. Any of the methods described herein may include delivering a pulse waveform including any combination of the following energy parameters (e.g., any of the frequency ranges combined with any of the driving voltages, pulse widths, currents, etc.).

[0327] The tissues 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 include a drive 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 aforementioned 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 aforementioned 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 aforementioned 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, the measured temperature being between about 37°C and 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 prior to delivery of 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 a non-compressed 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, the pulse waveform in some variations 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 may include a drive voltage at the electrode array 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, between about 15 kV and about 20 kV, including all values ​​and subranges between any of the aforementioned ranges. In some variations, the pulse waveform may have a pulse width 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, between about 400 ns and about 600 ns, including all values ​​and subranges between any of the aforementioned ranges. In some variations, the pulse waveform may include 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, about 4,000 Hz to about 6,000 Hz, including all values ​​and subranges between any of the foregoing ranges. In some variations, the pulse waveform may include 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 given 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 following treatment using the systems, devices, and methods described herein. Advantageously, the healing process described herein may reduce necrotic responses (e.g., macrophage responses) that can cause widespread inflammation within the duodenal tissue.

[0341] 72A and 72B are detailed cross-sectional images of duodenal tissue about 1 day after treatment. The tissue depicted in FIG. 72A and 72B may include increased vascularization. FIG. 73 is a detailed cross-sectional image of duodenal tissue about 3 days after treatment with increased blood supply to new cells and no significant macrophage response. FIG. 74A and 74B are detailed cross-sectional images of duodenal tissue about 7 days after treatment. Tissue viewed with an endoscope at about day 7 may be indistinguishable from native tissue. For example, the blood supply in FIG. 74A and 74B may be indistinguishable from native (e.g., untreated) tissue, and the dimensions of the new villi will have approximately the same dimensions as native villi. FIG. 75 is a detailed cross-sectional image of duodenal tissue about 14 days after treatment, where 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 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 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] FIG 61A is an image showing a perspective view of the pulsed electric field device (6100) and visualization device (6150). FIG 61B is a detailed image of the pulsed electric field device (6100) and visualization device (6150). The pulsed electric field device (6100) shown in FIG 61A and FIG 61B is similar to the pulsed electric field device (6000) shown in FIG 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 include 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 FIG. 62A-C is similar to the pulsed electric field device (6000) shown and described with respect to FIG. 60 and FIGS. 61A and 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 an 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 are 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 in tissue. For example, the dilators (6360, 6362) can be configured to protect the 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). FIG. 63A is an image of a pulsed electric field device (6300) having an expandable member (6330) in a rolled configuration. FIG. 63B is an image of a pulsed electric field device (6300) having an expandable member (6330) in a deployed configuration. FIG. 63C is a perspective view of a pulsed electric field device (6300) having an 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 an electrode array (6600) of a pulsed electric field device described herein. Figures 67 and 68 are images of variations of electrode arrays (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] FIG. 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). FIG. 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 FIG. 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 in tissue. For example, the dilators (7960, 7962) can be configured to protect the 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 is a temperature plot over time of a method of treating tissue in simulations and animal studies corresponding to the energy parameters listed above. A set of 10 bursts of bipolar current pulses was applied to generate a corresponding rapid temperature increase followed by a temperature decrease associated with diffusion of heat from the duodenal surface. Figure 87 is a plot 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 the measured parameters (e.g., voltage, current impedance, maximum temperature rise).

[0350] 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. As described in more detail herein, the pulsed electric field device may include an elongated body and an expandable member coupled to the elongated 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 to thereby treat tissue, such as tissue of the duodenum. Any of the methods described herein may include delivering a pulsed waveform including any of the following energy parameters to any of the portions of the gastrointestinal tract, such as the duodenum, esophagus, stomach, and / or pylorus, of the patient, for example:

[0351] The pulse waveform may have a frequency of about 350 kHz, a drive 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 groups 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 field that treats tissue at a compressed tissue depth of about 0.25 mm to about 0.75 mm and a non-compressed tissue depth of about 0.50 mm to about 1.5 mm.

[0354] It will be understood that the embodiments and illustrations of the present disclosure are for illustrative purposes only, and that deviations and modifications, 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 numerical values ​​and / or ranges, generally refer to those numerical values ​​and / or ranges that are close to the recited numerical values ​​and / or ranges. 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 modifications 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 scope of 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; and a signal generator configured to deliver a pulse waveform to the electrode array to generate a pulsed or modulated electric field to thereby treat the duodenum; wherein the pulse waveform comprises a frequency of about 50 kHz to about 950 kHz and a driving voltage at the electrode array of about 400 V to about 600 V to generate a current through tissue from the electrode array of about 36 A to about 48 A per square centimeter of tissue.

2. The system of claim 1 , wherein the frequency is from about 300 kHz to about 400 kHz.

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

4. The system of claim 1 , wherein the driving voltage is from about 440V to about 550V.

5. 10. The system of claim 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.

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

7. The system of claim 1 , wherein the temperature of the tissue is raised to approximately 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 about 0.25 mm to about 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 about 0.50 mm to about 1.5 mm.

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

11. The system described in claim 10, wherein the signal generator adjusts delivery of the pulse waveform by inhibiting delivery of the pulse waveform.

12. The system of claim 1, further comprising means for aspirating the tissue into the expandable member at a pressure of about 10 mmHg to about 200 mmHg.

13. 10. The system of claim 1, wherein the pulsed or modulated electric field is a therapeutic electric field that treats cells but leaves the tissue scaffold intact.

14. The system of claim 1 , wherein the pulse waveform comprises a pulse width of about 0.5 μs to about 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 treated duodenum becomes histologically indistinguishable from native tissue after about 30 days.

18. 2. The system of claim 1, 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 duodenum that was previously treated.

19. 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 elongated body and an expandable member coupled to the elongated body, the expandable member comprising an electrode array; and a signal generator configured to deliver a pulse waveform to the electrode array to generate a pulsed or modulated electric field to thereby treat the stomach; wherein the pulse waveform comprises a frequency of about 50 kHz to about 950 kHz and a driving voltage at the electrode array of about 400 V to about 600 V to generate a current through tissue from the electrode array of about 36 A to about 48 A per square centimeter of tissue.

20. 20. The system of claim 19, 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 stomach that was previously treated.