Ferritin directed duodenal mucosal recellurization

Abstract

Described here are methods that may help predict a positive response of a patient to pulsed electric field treatment of intestinal tissue. The methods may include selecting a patient for treatment based on their baseline ferritin level. When the patient has a metabolic condition such as diabetes (e.g., Type 1 or Type 2 diabetes), the positive response may include a decrease in HbA1c level. The degree of the positive response may be dependent on the baseline ferritin level, with higher baseline ferritin levels being associated with a greater positive response.

Description

FERRITIN DIRECTED DUODENAL MUCOSAL RECELLURIZATIONRELATED APPLICATIONSThis application claims priority to provisional application number 63 / 661,884, filed June 19, 2024 and titled FERRITIN DIRECTED DUODENAL MUCOSAL RECELLULARIZATION, the entire content of which is incorporated herein by reference.TECHNICAL FIELD

[0001] This application generally relates to methods that may help predict a positive response of a patient to pulsed electric field treatment of intestinal tissue. The methods may include selecting a patient for treatment based on their baseline ferritin level. For patients with diabetes, the positive response may include a decrease in HbAlc level.BACKGROUND

[0002] Diabetes is a widespread condition, affecting millions worldwide. In the United States alone, over 20 million people are estimated to 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, and the like), diabetes may be associated with one or more symptoms such as fatigue, blurred vision, and unexplained weight loss, and may further be associated with one or more complications such as hypoglycemia, hyperglycemia, ketoacidosis, neuropathy, and nephropathy.

[0003] The treatment of chronic diseases such as obesity and diabetes through duodenal resurfacing using pulsed electric field energy has been proposed. For example, removing the majority of the mucosal cells from the section of the large intestine nearest the stomach may allow a rejuvenated mucosal layer to be regenerated, thereby restoring healthy (non-diabetic) signaling.However, there are currently no established criteria that may help determine the responsiveness of a diabetic patient to an intestinal procedure, including but not limited to a duodenal resurfacingprocedure. Accordingly, it may be beneficial to have methods that may more reliably predict a patient’s response to pulsed electric field treatment of duodenal and / or other intestinal tissue.SUMMARY

[0004] Described herein are methods of predicting the response of a patient to an intestinal procedure, e.g., a duodenal recellularization procedure. The methods may generally include obtaining a baseline level of a first biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition, where the first biomarker is ferritin, and predicting a positive response to the intestinal procedure based on the baseline level of ferritin. An exemplary intestinal procedure may include delivery of a pulsed electric field to a target tissue in an intestine. When the patient has a metabolic condition such as diabetes (e.g., Type 1 or Type 2 diabetes), the positive response may correspond to a reduction in a level of a second biomarker (e.g., a HbAlc level) of the patient.

[0005] The metabolic disorder of the patient may be one or more of obesity, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Type 1 diabetes, and Type 2 diabetes. In one variation, the metabolic disorder of the patient may be Type 2 diabetes. In other variations, for example, when the patient has an inflammatory disorder, the inflammatory disorder may be one or more of rheumatoid arthritis, a thyroid disorder, and a viral infection.

[0006] The reduction in the level of the second biomarker may be predicted when the baseline level of ferritin is at least about 100 pg / L to at least about 400 pg / L, including all values and subranges therein. For example, the reduction in the level of the second biomarker may be predicted when the baseline level of ferritin is at least about 100 pg / L, at least about 150 pg / L, at least about 200 pg / L, at least about 250 pg / L, at least about 300 pg / L, at least about 350 pg / L, or at least about 400 pg / L. The second biomarker may be a biomarker indicative of glycemic control. For example, the second biomarker may be HbAlc. When HbAlc is the second biomarker, the positive response may be based on a baseline HbAlc level of the patient in addition to the patient’s baseline ferritin level. In this instance, the positive response may be predicted when the baseline HbAlc level of the patient is at least about 8%. The positive response may correspond to a reduction in the HbAlc level by at least about 0.5%.

[0007] The intestinal procedure used in the predictive methods may include delivery of a pulsed electric field from a device comprising an expandable member and a plurality of electrodes to a target tissue comprising one or more portions of the duodenum or the jejunum. For example, the target tissue may include one or more of a proximal portion of the duodenum, a proximal and a middle portion of the duodenum, and a portion of the duodenum and the jejunum. The intestinal procedure may recellularize at least a portion of a duodenum of the patient. In some variations, the intestinal procedure may further include administering a drug therapy to the patient. The drug therapy may be administered concurrently with the intestinal procedure, before the intestinal procedure, or after the intestinal procedure.

[0008] Also described herein are methods for treating patients that may include obtaining a baseline level of a first biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition, where the first biomarker is ferritin, selecting the patient for treatment with an intestinal procedure based on the baseline level of ferritin, and performing the intestinal procedure to achieve a reduction in a level of a second biomarker of the patient. The intestinal procedure may include the delivery of energy, e.g., pulsed electric field energy, to a target tissue in an intestine.

[0009] As previously mentioned, the metabolic disorder of the patient may be one or more of obesity, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Type 1 diabetes, and Type 2 diabetes. In one variation, the metabolic disorder may be Type 2 diabetes. In other variations, for example, when the patient has an inflammatory disorder, the inflammatory disorder may be one or more of rheumatoid arthritis, a thyroid disorder, and a viral infection.

[0010] Selection of a patient for treatment with the intestinal procedure may be based on the baseline level of ferritin being at least about 100 pg / L to at least about 400 pg / L, including all values and sub-ranges therein. For example, the baseline level of ferritin may be at least about 100 pg / L, at least about 150 pg / L, at least about 200 pg / L, at least about 250 pg / L, at least about 300 pg / L, at least about 350 pg / L, or at least about 400 pg / L. Performing the intestinal procedure may result in a reduced level of a second biomarker indicative of glycemic control. For example, the second biomarker may be HbAlc, and after an intestinal procedure is performed, the HbAlc levelof the patient may be reduced by at least about 0.5%. In other variations, selecting a patient for treatment with the intestinal procedure may be based on a baseline HbAlc level and the patient’s baseline ferritin level. In this variation, the patient may have a HbAlc level of at least about 8%.

[0011] The methods for treating patients may include an intestinal procedure that delivers energy from a device comprising an expandable member and a plurality of electrodes to a target tissue such as one or more portions of the duodenum or the jejunum. For example, the target tissue may include one or more of a proximal portion of the duodenum, a proximal and a middle portion of the duodenum, and a portion of the duodenum and the jejunum. The intestinal procedure may recellularize at least a portion of a duodenum of the patient. In some variations, the intestinal procedure may further include administering a drug therapy to the patient. The drug therapy may be administered concurrently with the intestinal procedure, before the intestinal procedure, or after the intestinal procedure.

[0012] Some variations of the methods for treating patients may further include one or more of obtaining a second ferritin level after performing the intestinal procedure, repeating the intestinal procedure based on the second ferritin level exceeding a predetermined threshold for the patient, and adjusting one or more parameters of the energy delivery based on the baseline ferritin level or the second ferritin level. The one or more parameters may include one or more of a voltage, an amplitude, a pulse number, and a pulse duration of the energy delivery. Other variations of the method may further include adjusting one or more components of a device configured to perform the intestinal procedure based on the second ferritin level. For example, one or more of an electrode spacing and an electrode length may be adjusted.

[0013] In other variations, selecting the patient for treatment with the intestinal procedure may be further based on one or more patient characteristics. For example, the one or more patient characteristics may include an age of the patient, a duration of the metabolic disorder, a duration of the inflammatory condition, presence of a comorbid condition, a body mass index (BMI), concurrent use of a drug therapy, and an amount of liver fat.

[0014] Further described herein are methods of predicting a response to an intestinal procedure including obtaining a baseline level of an inflammatory biomarker of a patient having one or moreof a metabolic disorder and an inflammatory condition and predicting a positive response to the intestinal procedure based on the baseline level of the inflammatory biomarker. The intestinal procedure may include delivery of a pulsed electric field to a target tissue in an intestine and the positive response may correspond to a reduction in a level of a second biomarker of the patient. In some variations, the inflammatory biomarker may be ferritin and the second biomarker may be HbAlc. The patient may have a metabolic disorder such as but not limited to Type 2 diabetes.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A is a cross-sectional representation of a gastrointestinal tract showing various anatomical structures.

[0016] FIG. IB is a cross-sectional representation of a duodenum.

[0017] FIG. 2A is a cross-sectional schematic view of a portion of the small intestine.

[0018] FIG. 2B is a cross-sectional schematic view of a portion of the small intestine.

[0019] FIG. 2C is a cross-sectional schematic view of a portion of the small intestine.

[0020] FIG. 3A is a cross-sectional image of a duodenum.

[0021] FIG. 3B is a detailed cross-sectional image of various duodenal tissue.

[0022] FIG. 3C is a detailed cross-sectional image of various duodenal tissue.

[0023] FIG. 3D is a detailed cross-sectional image of various duodenal tissue.

[0024] FIG. 3E is a detailed cross-sectional image of various duodenal tissue.

[0025] FIG. 3F is a detailed cross-sectional image of various duodenal tissue.

[0026] FIG. 4 is a block diagram of an illustrative variation of a pulsed electric field system.

[0027] FIG. 5A is a plan view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0028] FIG. 5B is a plan view of an illustrative variation of a pulsed electric field device in an unrolled or expanded configuration.

[0029] FIG. 5C is a bottom view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0030] FIG. 5D is a bottom view of an illustrative variation of a pulsed electric field device in an unrolled or expanded configuration.

[0031] FIG. 5E is a left side view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0032] FIG. 5F is a left side view of an illustrative variation of a pulsed electric field device in an unrolled or expanded configuration.

[0033] FIG. 5G is a right side view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0034] FIG. 5H is a right side view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0035] FIG. 51 is a right side view of an illustrative variation of a pulsed electric field device in an unrolled or expanded configuration.

[0036] FIGS. 5 J is a right side view of an illustrative variation of a pulsed electric field device in an unrolled or expanded configuration.

[0037] 5K is a right side view of an illustrative variation of a pulsed electric field device in an unrolled or expanded configuration.

[0038] FIG. 5L is a perspective view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0039] FIG. 5M is a bottom view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0040] FIGS. 5N is a perspective view of an illustrative variation of a pulsed electric field device in an expanded configuration.

[0041] FIG. 50 is a perspective view of an illustrative variation of a pulsed electric field device in an expanded configuration.

[0042] FIG. 5P is a perspective view of an illustrative variation of a pulsed electric field device in an expanded configuration.

[0043] FIG. 5Q is a cross-sectional view of an illustrative variation of a pulsed electric field device in a rolled or unexpanded configuration.

[0044] FIG. 5R is a cross-sectional view of an illustrative variation of a pulsed electric field device in an unrolled or expanded configuration.

[0045] FIG. 6A is a graph illustrating the correlation between baseline HbAlc levels, ferritin levels, and changes in HbAlc levels 24 weeks after an intestinal procedure.

[0046] FIG. 6B is a graph illustrating the correlation between baseline HbAlc levels, ferritin levels, and changes in HbAlc levels 24 weeks after an intestinal procedure.

[0047]

[0048] FIGS. 7A is a graph illustrating changes in HbAlc level based on baseline ferritin levels.

[0049] FIG. 7B is a graph illustrating changes in HbAlc level based on baseline ferritin levels.

[0050] FIG. 7C is a graph illustrating changes in HbAlc level based on baseline ferritin levels.

[0051] FIG. 8 is a perspective view of an illustrative variation of an expandable member comprising an electrode array in an unrolled configuration.

[0052] FIG. 9A is a perspective view of an illustrative variation of an expandable member in a rolled or unexpanded configuration.

[0053] FIG. 9B is a perspective view of an illustrative variation of an expandable member in an unrolled or expanded configuration.

[0054] FIG. 10A is a perspective view of an illustrative variation of a distal portion of a pulsed electric field device.

[0055] FIG. 10B is a cross-sectional side view of the pulsed electric field device shown in FIG. 10A.

[0056] FIG. 10C is a detailed cutaway perspective view of the pulsed electric field device shown in FIG. 10A.

[0057] FIG. 10D is a detailed side view of an illustrative variation of a dilator of a pulsed electric field device.DETAILED DESCRIPTION

[0058] Described herein are methods of predicting a positive response of a patient to an intestinal procedure and treatment methods including selection of patients for an intestinal procedure, both of which may be based on a baseline ferritin level of the patient. The intestinal procedure may be performed using a system and / or device having a plurality of electrodes on an expandable member. The electrodes of the system and / or device may deliver a pulsed electric field to a part of the duodenum and / or jejunum to recellularize at least a portion thereof. When a metabolic condition such as Type 2 diabetes is treated with an intestinal procedure including but not limited to duodenal recellularization, the positive response may correspond to a reduction in the HbAlc level of the patient.METHODSDelivery of Pulsed Electric Fields and Relevant Anatomy

[0059] Given that the methods relate to a procedure performed on one or more portions of the intestines, it may be helpful 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). Shown there is a visualization device (150) (e.g., endoscope) advanced into the stomach (120) through the esophagus (110). The stomach (120) is connected to the duodenum (130). FIG. IB is a detailed cross-sectional view of the duodenum (130), which surrounds the head of the pancreas (140). The duodenum is a “C” shaped hollow jointed tube structure that is typically between about 20 cm and about 35 cm in length and between about 20 mm and about 45 mm in diameter. FIGS. 2A-2C are cross-sectional schematic views 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 comprise resurfacing the mucosa (210) as described herein. Access to the gastrointestinal tract (e.g., duodenum, stomach, large intestine) may be performed 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 acute small radius bends throughout the length of the digestive tract.

[0060] It may further be helpful to briefly discuss treatment using pulsed electric fields (PEFs), e.g., electroporation, and the role of ohmic heating. Electroporation is the application of an electric field to living cells to cause ions of opposite charge to accumulate on opposite sides of cell membranes. Generally, electroporation requires a potential difference across the cell membrane on the order of about 0.5 to about 1 volt and for a cumulative duration on the order of about 1 to about 2 milliseconds. Electroporation necessarily generates ohmic heating but there is considerable confusion in the literature about this, including a significant number of references that incorrectly assert the existence of non-thermal electroporation. For example, an external uniform electric field of magnitude E applied to an intracellular fluid with ionic conductivity aicwill generate a current density Eaicand dissipate a thermal power density E2aic. If the medium has a heat capacity Cpand density p. the resulting rate of temperature rise is given by equation (1): eqn. (1)

[0061] For example, a 1 KV / cm electric field acting on tissue with a conductivity of about 0.3 S / m, a heat capacity of about 3.7 joule / (gm°C), and a density of about Igm / cc will heat the tissue at a rate of about 800 °C / second. Note that, without current passing through the tissue, there is no electric field in the tissue since the tissue is an ionic conductor. The initial time after an external field is abruptly applied to the membrane to accumulate charge may be on the order of about 30 nanoseconds, which suggests that, during an initial membrane-charging phase, the average temperature rise may be in the tens of microdegrees. When an external electric field is applied, and ionic currents have charged the membrane surfaces to collapse the field into the lipid bilayers, leakage current may still flow, though the heating may be confined to the membranes for submicrosecond timescales. For example, using a lipid layer conductivity of cr;i=0.002 S / m, a 1 volt potential across an 8 nm layer may locally heat at an instantaneous rate of about 8 °C / microsecond. This heating rate drops with time from the application of the external electric field, as the heat may diffuse further from the membrane.

[0062] If the ionic currents are confined to pores in the cell membranes, current crowding will cause the heating rate in the pores to be correspondingly higher. Since the pore area might be 1% or less of the membrane area, the current density in the pores may be one hundred times higher than in the bulk tissue. This gives a ten thousand times increase in heating rate, leading to local heating rates on the order of 10 °C / microsecond.

[0063] Local temperature rise is a contributing mechanism to the transition from electroporation to irreversible electroporation. Thermal diffusion lowers the local temperature excursions. For example, assuming a tissue thermal diffusivity K of 0.13 mnr / s, the thermal diffusion length at 10 psec is (10 ps)(0.13 mm2I s) or 1.1 micron, which is much larger than a typical pore. At 1 millisecond, the thermal diffusion length is on the order of the cell size, so the localized heating effects may be ignored.

[0064] The bulk tissue remains a good ionic conductor during the electroporation treatment, heating at a rate on an order of magnitude of about 800 °C / s while the external field is being applied. If the external field is removed, the cell membranes may discharge on the order of about 30 nanoseconds, obliging the continued application of external voltage and current to induce poreformation and growth. As the maximum tolerable temperature rise of the bulk tissue may be on the order of about 13 °C, the maximum duration that the external field may be applied, even in a bipolar configuration, may be within an order of magnitude of about 10 milliseconds. As this heat is generated to a treatment depth in the tissue of about several millimeters, the required time to cool the tissue by conduction may be about 70 seconds (e.g., (3 mm2) / (0.13mm2 / sec)). Blood convection likely dominates the observed cooling times that are on the order of about 10 seconds.Electroporation may also increase with the temperature of the bulk tissue due to the phase transition of the lipid cell membrane, which for some cells on the duodenum is 41 °C. The phase transition temperature may be the temperature required to induce a change in the lipid physical state from the ordered gel phase to the liquid crystalline phase.

[0065] Electroporation parameters may be varied to produce different effects on tissue. FIG. 3A is a cross-sectional image of an untreated duodenum (300A) including a muscular layer (310A) and villi (320A). FIG. 3D is an image of an illustrative variation of duodenal tissue in its native untreated state including a muscularis layer (310D), submucosa (330D), villus crypts (340D) and villi (320D). As described in more detail herein, FIG. 3E depicts duodenal tissue that has undergone majority thermal heat treatment and FIG. 3F depicts duodenal tissue that has undergone majority pulsed or modulated electric field treatment. The treatments described herein (e.g., FIG. 3F), which primarily treat the mucosa layer with preserved tissue architecture appearing similar to the native tissue, reduces trauma to tissue relative to the thermal treatment shown in FIG. 3E.

[0066] The application of a pulsed electric field to 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 the initial mucosal histologic appearance with evolving epithelial loss and lamina propria structural / architcctural preservation. For example, FIG. 3F depicts the histologic evolution with complete native epithelial loss and early crypt regeneration within the preserved lamina propria. The glandular layer across FIGS. 3A-3D and 3F demonstrates the structural preservation of the lamina propria following treatment. For example, histopathology confirms that the PEF treatment as described herein applied at a depth of about 1 mm in duodenal tissue will treat the mucosal layer without the pulsed electric field energy affecting the muscularous propria at a therapeutic level.

[0067] FIG. 3B is an image of an illustrative variation of duodenal tissue that has undergone different treatments. In particular, the tissue (360) was treated with pulsed or modulated electric field energy and first mucosa region (362) was further subjected to radiofrequency (RF) ablation energy. The ablated villi of the first mucosa region (362) have broken cellular membranes and destroyed cell structures such that those cells are no longer viable or functioning. By contrast, a second mucosa region (360) has cells that have undergone cell lysis where the cellular membranes remain intact but the cells are no longer viable and functioning. That is, cell lysis corresponds to functional cell death with intact cellular structures while ablation refers to loss of both cell structure and function. The submucosa (370) and muscularis (380) remain healthy (e.g., viable and fully functioning with cell integrity). In FIG. 3B, villi in the first mucosa region (362) are thermally ablated while the cell lysis in the second mucosa region (360) is generated by a pulsed or modulated electric field. A third mucosa region (363) adjacent to the thermal lesion of the first mucosa region (362) is not treated at all and comprises viable tissue.

[0068] FIG. 3C illustrates a histological slide of the duodenum from tissue about 24 hours after treatment with heat and pulsed electric field, showing a partial treatment of the mucosa down to the crypt layer, with injured cells. A fourth mucosa region (391) corresponds to thermal / heat fixed tissue of the villi, including the villi-associated enteroendocrine cells. The fourth mucosa region (391) demonstrates architectural and cytological preservation with cellular detail with hyperchromatic nuclear and hypereosinophilic cytoplasmic staining. Overall, interstitial hemorrhage and infiltrating post-treatment-associated inflammatory cells are not identified. The heat fixed tissue may be expected to slough off, followed by surface re-epithelialization and villous structural healing with crypt cell repopulation. The crypt tissues are partially affected by a combination of heat and pulsed electric field effects. The tissue healing timeline is expected to be longer than that of a pulsed electric field treatment without thermal effect. The submucosa (370) and muscularis (380) arc histologically unaffected. FIG. 3E is an image of an illustrative variation of 24 hour porcine duodenal histology following an isolated hyperthermic tissue treatment (i.e., no concomitant pulsed electrical field exposure) which destroys the lamina propria in that tissue scaffolding is burned and destroyed, and will be sloughed off and removed during healing. This demonstrates the histologic features of a thermal tissue dose, consistent with thermal / heat-induced coagulative necrosis withoutthermal / heat fixation. In this region, the glandular epithelium and neuroendocrine cells (321) show a loss of cytologic detail, consistent with cellular “ghost images.” Interstitial hemorrhage and reactive inflammatory cells of the mucosal layer (341) are present at the region’s edge. The submucosa (331) and muscularis (311) also show injury related changes. This region may be anticipated to heal similar to an ischemic type coagulative necrosis with resorption and remodeling with mucosal regeneration. The thermal lesion destroyed the lamina propria. Scaffolding is burned and destroyed and will be sloughed off and removed during healing. The tissue healing time frame for this region should be longer than that expected for a pulsed electric field treatment.

[0069] FIG. 3F is an image of an illustrative variation of duodenal tissue that has undergone treatment with pulsed or modulated electric field energy to a controlled depth not including the muscularis, untreated muscularis propria layer (310), submucosa (330), treated submucosa (332), treated villus crypts, with partial cell lysis and maintained tissue scaffolding (342), and treated villi with villas sloughing (322). The treated submucosa (332) also maintains tissue scaffolding. These treated tissues illustrate cells that have undergone a cell death where the cellular membranes remain intact but the cells are no longer viable and functioning. The healing cascade will replace these cells without infiltration of large number of inflammatory cells, and the surface will re-epithelialize and with villous structural healing and crypt cell repopulation. The muscularis (310) remains healthy (e.g., viable and fully functioning with cell integrity) without therapeutic effect from the pulsed electric field energy. That is, with pulsed or modulated electric field energy cell death corresponds to functional cell death with intact cellular structures while ablation refers to loss of both cell structure and function and an aggressive necrotic inflammatory response healing cascade.

[0070] In some variations, a target depth of treatment includes the mucosal layer but excludes treatment of the muscularous propria. Human tissue data assessed through histopathology supports about a 1 mm target depth for PEF tissue treatment where the pulsed electric field does not penetrate through to the muscularous propria at a therapeutic level. Based on the methods described herein, the healing response may be essentially completed in about thirty days. Moreover, the systems, devices, and methods described herein may provide uniform treatment coverage throughout a circumference and length of the duodenum.

[0071] Some methods for treating diabetes may include treating the submucosa layer of the duodenum without treating the muscularis. Conventional solutions do not consistently treat the submucosa layer without negatively impacting the muscularis. Instead, conventional solutions may add complicated mitigating steps such as lifts with saline injection in an attempt to protect the muscularis. For reference, the mucosal layer typically has a thickness between about 0.5 mm to about 1 mm, the submucosa layer typically has a thickness of about 0.5 mm and about 1 mm, and the muscularis typically has a thickness of about 0.5 mm. Inducing injury to the muscularis may result in adverse clinical outcomes. Furthermore, the anatomical structure along a circumference of the duodenum is not uniform, thus complicating efforts to treat just the submucosa and not the muscularis.

[0072] The methods described herein may selectively change tissue viability without losing the integrity of the majority of the treated tissue by applying a predetermined pulsed or modulated electric field and, optionally, without other treatment of the tissue to mitigate the pulsed or modulated electric field to a portion of tissue. By contrast, RF based energy treatment may predominantly generate heat-induced cell lysis (e.g., cell death) or ablation that may indiscriminately damage tissue and destroy cellular structure, and which may be difficult to modulate, thus negatively impacting treatment outcomes. In some variations, the methods described here may comprise applying a pulsed or modulated electric field to thermally-induce local necrotic cell death (e.g., local ablation) for tissue immediately adjacent to an electrode array and to induce cell lysis (e.g., functional cell death) within a predetermined range of tissue depths of (e.g., up to about 1 mm, between about 0.5 mm and 0.9 mm) while minimizing the physiological impact to tissue greater than the selected depth.

[0073] FIG. 3F is an image of an illustrative variation of duodenal tissue that has undergone treatment with pulsed or modulated electric field energy to a controlled depth. In FIG. 3F, the muscularis layer (310) and a portion of the submucosa (330) are untreated (i.e., energy delivered to tissue does not affect the tissue) and the villus crypts (342), villi (322) and a different portion of the submucosa (332) have been treated. Thus, the treatment applied to the duodenal tissue shown inFIG. 3F results in a more superficial (e.g., closer to the tissue surface) treated submucosa (332) and a deeper, untreated muscularis layer (310). The treated tissues contain cells that have undergone celllysis where the tissue scaffolding remain intact but the cells are no longer viable and functioning. A mild healing cascade will replace these cells. The muscularis (310) adjacent to the treated submucosa (332) remains healthy (e.g., viable and fully functioning with cell integrity).

[0074] The pulsed or modulated electric fields near an electrode array may generate some thermal heating of tissue leading to tissue ablation that destroys both cell structure and function. However, cell lysis in tissue resulting from the pulsed or modulated electric fields applied herein are at least 50% pore-induced and less than 50% heat-induced such that a majority of cell death comprises functional cell death with intact cellular’ structures. For example, the thermal heating generated by a pulsed or modulated electric field is generally localized to a relatively small radius from each electrode of an electrode array and does not affect deeper layers of tissue such as the muscularis.

[0075] The systems, devices, and methods described herein may deliver energy to provide treatment characteristics optimized for each tissue layer to improve treatment outcomes. Near the surface of the tissue (e.g., less than about 0.5 mm, between about 0.1 mm and about 0.5 mm), thermal heating may generate local necrotic cell death of tissue that may slough off after treatment. At a tissue depth of between about 0.5 mm and about 1.3 mm (e.g., mucosa of duodenum), cell lysis may be generated by the pulsed or modulated electric field while thermal heating is limited (e.g., to less than about a 13 °C increase or 6 °C increase). For example, an electric field strength at about 1.0 mm may be about 2.5 kV / cm. At tissue depths beyond 1.0 mm, the energy delivered to tissue generates reversible electroporation with even less thermal heating such that deeper tissue may be substantially untreated. Thus, thermal heating may be limited to a surface tissue layer (e.g., less than about 0.5 mm, between about 0.1 mm and about 0.5 mm) while still delivering pulsed or modulated electric field energy for cell lysis of the mucosa.

[0076] For example, FIG. 3C is an image of an illustrative variation of duodenal tissue that has undergone a method of treating duodenal tissue described herein where villi (391) has been treated by a combination of thermal heating (e.g., more than 50%) and pore-induced cell death (e.g., less than 50%). The pulsed or modulated electric field applied to the villus crypts and submucosa (370) has treated the tissue to a majority (e.g., more than 50%) of pore-induced cell death with a lesser contribution (e.g., less than 50%) of cell death due to theimal heating. The muscularis (380) issubstantially untreated by the pulsed or modulated electric field or other methods. For example, the submucosa in FIG. 3C is not subject to saline injection. The depth of treatment may be controlled such that a predetermined portion of the mucosal layer such as the villus crypts may remain untreated if desired. The configuration and geometry of the electrode arrays as described herein may enable the tissue treatment characteristics described herein.Use of Baseline Ferritin Levels

[0077] Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, ferritin acts as a buffer against iron deficiency and iron overload. Ferritin is also an acute phase reactant protein, and thus serum levels are known to be increased in states of inflammation or tissue damage. Increased ferritin levels have been reported in various metabolic disorders such as Type 2 diabetes, obesity, metabolic syndrome, and non-alcoholic fatty liver disease. The methods described herein generally utilize baseline ferritin levels measured in a patient to help predict whether the patient may respond to an intestinal procedure positively by lowering their HbAlc level, and to help select patients for treatment with an intestinal procedure.

[0078] As previously described, the methods may generally include obtaining a baseline level of a first biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition, where the first biomarker is ferritin, and predicting a positive response to the intestinal procedure based on the baseline level of ferritin. An exemplary intestinal procedure may include delivery of a pulsed electric field to a target tissue in an intestine. When the patient has a metabolic condition such as diabetes (e.g., Type 1 or Type 2 diabetes), the positive response may correspond to a reduction in a level of a second biomarker (e.g., a HbAlc level) of the patient.

[0079] Some methods described herein may be methods of treatment that generally include obtaining a baseline level of a first biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition, where the first biomarker is ferritin, selecting the patient for treatment with an intestinal procedure based on the baseline level of ferritin, and performing the intestinal procedure to achieve a reduction in a level of a second biomarker of the patient. Theintestinal procedure may include the delivery of energy, e.g., pulsed electric field energy, to a target tissue in an intestine.

[0080] The metabolic disorder of the patient may be one or more of obesity, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Type 1 diabetes, and Type 2 diabetes. In one variation, the metabolic disorder of the patient may be Type 2 diabetes. In other variations, for example, when the patient has an inflammatory disorder, the inflammatory disorder may be one or more of rheumatoid arthritis, a thyroid disorder, and a viral infection.

[0081] The reduction in the level of the second biomarker may be predicted when the baseline level of ferritin is at least about 100 pg / L to at least about 400 pg / L, including all values and subranges therein. For example, the reduction in the level of the second biomarker may be predicted when the baseline level of ferritin is at least about 100 pg / L, at least about 150 pg / L, at least about 200 pg / L, at least about 250 pg / L, at least about 300 pg / L, at least about 350 pg / L, or at least about 400 pg / L. The second biomarker may be a biomarker indicative of glycemic control such as HbAlc, and the positive response may correspond to a reduction in HbAlc level by at least about 0.5% to about 2.5%, including all values and sub-ranges therein. For example, the positive response may correspond to a reduction in the HbAlc level by at least about 0.5%, at least about 0.75%, at least about 1.0%, at least about 1.25%, at least about 1.5%, at least about 1.75%, at least about 2.0%, at least about 2.25%, or at least about 2.5%. Referring to FIGS. 6A and 6B, a change in the level of HbAlc of at least about 0.5% to about 2.5% is illustrated when the baseline ferritin value of the patient ranges from about 100 pg / L to about 400 pg / L, with larger reductions in HbAlc resulting as baseline serum ferritin levels increase. When HbAlc is the second biomarker, the positive response may be based on a baseline HbAlc level of the patient in addition to the patient’s baseline ferritin level. In this instance, the positive response may be predicted when the baseline HbAlc level of the patient is at least about 8%.

[0082] The intestinal procedure used in the methods described herein may include delivery of a pulsed electric field from a device comprising an expandable member and a plurality of electrodes to a target tissue comprising one or more portions of the duodenum or the jejunum. For example, the target tissue may include one or more of a proximal portion of the duodenum, a proximal and amiddle portion of the duodenum, and a portion of the duodenum and the jejunum. The intestinal procedure may recellularize at least a portion of a duodenum of the patient. In some variations, the intestinal procedure may further include administering a drug therapy to the patient. The drug therapy may be administered concurrently with the intestinal procedure, before the intestinal procedure, or after the intestinal procedure.

[0083] In some variations, the intestinal procedure may include advancing a pulsed electric field device and a visualization device toward a target tissue. The pulsed electric field device may comprise an expandable member comprising an electrode array. The expandable member may be transitioned from a compressed (e.g., rolled, unexpanded) configuration into an uncompressed (e.g., unrolled, expanded) configuration bringing the expandable member (and the electrode array) closer to or in contact with the surface of the target tissue. The expandable member may comprise a flexibility to apply force against and conform to the target tissue, which, in some instances, may have a non-uniform surface and / or size. For example, the expandable member may comprise a flexibility to apply force against and conform to an inner circumference of the duodenum, which may itself comprise a range of diameters. In some variations, a visualization device may be configured to visualize one or more of the pulsed electric field device and all or a portion of the target tissue and / or surrounding tissue. A suction catheter may be advanced from a lumen of the visualization device toward a lumen of the expandable member in an expanded configuration. Suction may be applied to the target tissue through the expandable member using the suction catheter.

[0084] Additionally, the intestinal procedure may include delivery of a first pulsed electric field waveform to the electrode array to generate a first pulsed or modulated electric field, which may treat a first portion of target tissue. In some variations, the electrode array may have a plurality of sections. A first pulsed electric field waveform may be delivered to two or more non-proximate (e.g., non-adjacent, not immediately next to each other) sections of the plurality of sections in a predetermined sequence, which may increase safety and / or reduce unintended damage to the tissue by reducing a temperature increase in tissue. In some variations, the pulsed electric field device may be moved (e.g., advanced or retracted) toward a second portion of the target tissue (which may be distal or proximal to the first portion of the target tissue), and a second pulsed electric fieldwaveform may be delivered to the electrode array to generate a second pulsed or modulated electric field thereby treating the tissue in the second portion. For example, in some variations, a signal generator may generate a drive voltage (e.g., voltage measured at an electrode array) of between about 400 V and about 1500 V that may correspond to an electric field strength of about 400 V / cm and about 7000 V / cm at the treatment portions of the duodenum. The expandable member may be in a compressed configuration, semi-expanded configuration, or an expanded configuration during movement of the pulsed electric field device. In some variations, sensor measurements (e.g., temperature, impedance) may be used to monitor and / or control pulse waveform delivery. In some variations, current and voltage measurements may be used to monitor and / or control pulse waveform delivery.

[0085] Some variations of the methods for treating patients may further include one or more of obtaining a second ferritin level after performing the intestinal procedure, repeating the intestinal procedure based on the second ferritin level exceeding a predetermined threshold for the patient, and adjusting one or more parameters of the energy delivery based on the baseline ferritin level or the second ferritin level. The one or more parameters may include one or more of a voltage, an amplitude, a pulse number, and a pulse duration of the energy delivery. Other variations of the method may further include adjusting one or more components of a device configured to perform the intestinal procedure based on the second ferritin level. For example, one or more of an electrode spacing and an electrode length may be adjusted.

[0086] In other variations, selecting the patient for treatment with the intestinal procedure may be further based on one or more patient characteristics. For example, the one or more patient characteristics may include an age of the patient, a duration of the metabolic disorder, a duration of the inflammatory condition, presence of a comorbid condition, a body mass index (BMI), concurrent use of a drug therapy, and an amount of liver fat.

[0087] Further described herein are methods of predicting a response to an intestinal procedure including obtaining a baseline level of an inflammatory biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition, and predicting a positive response to the intestinal procedure based on the baseline level of the inflammatory biomarker. The intestinalprocedure may include delivery of a pulsed electric field to a target tissue in an intestine and the positive response may correspond to a reduction in a level of a second biomarker of the patient. In some variations, the inflammatory biomarker may be ferritin and the second biomarker may be HbAlc. The patient may have a metabolic disorder such as but not limited to Type 2 diabetes.Other Exemplary Methods

[0088] In some variations, the methods of treatment may include delivery of pulsed or modulated electric field energy to remove native endothelial cell populations through non-thermal cell death that may address metabolic disorders such as, for example, obesity, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Type I diabetes, and Type II diabetes. Gastric mucosal devitalization (GMD) without thermal injury to muscularis propria may modify one or more of serum ghrelin levels, triglycerides, HDL, relative weight loss, visceral adiposity, organ lipid content, liver lipid / protcin ratio, gluconeogenesis, and liver lipid accumulation. Any of the methods described herein, such as energy delivery, may be performed using a monopolar or bipolar configuration in a body cavity or lumen of the patient such as, for example, an esophagus, a stomach, a large intestine (e.g., cecum, colon, rectum, anal canal), a small intestine, any portion of the gastrointestinal tract, vasculature (e.g., blood vessels), a thoracic cavity (e.g., lungs), an abdomino-pelvic cavity, a pelvic cavity (e.g., bladder), a vertebral cavity, a cranial cavity (e.g., nasal passageway), and the like. For example, energy delivery for treating 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.

[0089] In some variations, the suction may be applied at least radially and longitudinally by the suction catheter. In some variations, treating the target tissue treats one or more of a metabolic disorder, pre-cancer, cancer, proinflammatory processes, immunological processes. In some variations, the metabolic disorder may comprise one or more of obesity, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Type I diabetes, and Type II diabetes. In some variations, the target tissue may comprise one or more of a duodenum, a pylorus, an esophagus, a stomach, a small intestine, and a large intestine. Gastric mucosal devitalization (GMD) without thermal injury to muscularis propria may modify one or more of serum ghrelin levels,triglycerides, HDL, relative weight loss, visceral adiposity, organ lipid content, liver lipid / protein ratio, gluconeogenesis, and liver lipid accumulation. Energy delivery may be performed using a monopolar or bipolar configuration. For example, energy delivery for treating 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 in any portion of a body cavity or lumen of the patient such as, for example, an esophagus, a stomach, a large intestine (e.g., cecum, colon, rectum, anal canal), a small intestine, any portion of the gastrointestinal tract, vasculature (e.g., blood vessels), a thoracic cavity (e.g., lungs), an abdomino-pelvic cavity, a pelvic cavity (e.g., bladder), a vertebral cavity, a cranial cavity (e.g., nasal passageway), and the like.

[0090] 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 predetermined portion of tissue (e.g., mucosal layer of the duodenum) without significant energy delivery to deeper layers of the duodenum. Thus, the methods may improve the efficiency and effectiveness of energy delivery to duodenal tissue. Moreover, the methods described here may also avoid the excess thermal tissue heating necessarily generated by application of one or more other thermal energy modalities to tissue.

[0091] In some variations, methods may include applying suction to a pulsed electric field device in contact with tissue using a suction catheter. The suction catheter may, in some variations, be advanced from a lumen of a visualization device. For example, an expandable member having an electrode array may be in an expanded configuration for dilating tissue while the visualization device may be disposed proximal to expandable member to visualize the energy delivery. The suction catheter may be advanced into a lumen of the expandable member and may apply negative pressure to the tissue to further aid in a consistent tissue engagement with the expandable member and improved energy delivery. In some variations, energy delivery may include activating different sections of the electrode array in a predetermined order to minimize treatment time, an energy dose applied to tissue, and / or a temperature increase in the tissue. For example, non-proximate sections of the electrode array may be activated after an inter- section delay to generate a therapeutic electric field, minimize tissue temperature increase, and reduce electrical cross-talk.

[0092] In some variations, the methods of treatment may comprise generating a pulsed or modulated electric field to cause a change in tissue to treat one or more chronic condition, such as, for example, a metabolic disorder, pre-cancer, cancer, proinflammatory processes, immunological processes, and neurological disorders. For example, the metabolic disorder may comprise one or more of obesity, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Type I diabetes, and Type II diabetes. In some variations, the tissue may include tissue from any body lumen or cavity such as any portion of the gastrointestinal tract, vasculature (e.g., blood vessels), a thoracic cavity (e.g., lungs), an abdomino-pelvic cavity, a pelvic cavity (e.g., bladder), a vertebral cavity, a cranial cavity (e.g., nasal passageway), and the like.

[0093] Normally, the small intestine sends signals to the brain, pancreas, and liver to promote glycemic hemostasis. For example, enteroendocrine cells of the mucosal villa may generate these signals. Duodenal mucosal resurfacing using the systems, methods, and devices described herein may be used to treat, for example, type 2 diabetes. Clinical studies have demonstrated that duodenal mucosal resurfacing of the mucosal layer of the duodenum is a safe procedure that may have a positive impact on glycemic hemostasis in patients with type 2 diabetes.

[0094] In some variations, the pulsed or modulated electric field may cause cell lysis in tissue that is at least 50% pore-induced and less than 50% heat-induced. In some variations, a method of treating diabetes may include advancing a pulsed electric field device towards a target tissue of a patient. For example, a patient may be positioned on their left lateral side during the procedure, and the target tissue (e.g., duodenum) may optionally be insufflated (e.g., using CO2 or saline). The pulsed electric field device may comprise an elongate body and an expandable member comprising an electrode array. Once in the target tissue (e.g., duodenum), the expandable member may be transitioned into an expanded configuration. In some variations, one or more turns of the expandable member may be unrolled to contact the target tissue. In some variations, the expandable member may comprise an inflatable balloon surrounding a portion of the elongate body and configured to achieve a collapsed configuration and one or more inflated configurations when the inflatable balloon is at least partially filled with an inflating fluid. The inflatable balloon variation is described in provisional applications 63 / 638,851 entitled “Devices, Systems and Methods for Pulsed Electric Field Treatment of Tissue”; and 63 / 707,018, entitled “Devices, Systems and Methods forPulsed Electric Field Treatment of Tissue”, the contents of each of which are hereby incorporated by reference in their entirety.

[0095] In some variations, a visualization device (e.g., endoscope) may be advanced into the target tissue (e.g., duodenum) to visualize, inspect, and / or confirm a treatment area during a procedure. For example, one or more transparent portions of a pulsed electric field device may allow the visualization device to identify a location of the pulsed electric field device within patient anatomy (e.g., an ampulla of the duodenum, bulb of the duodenum). Once the device is located at a desired position within the target tissue, a pulse waveform may be delivered to the electrodes to generate a pulsed electric field to treat a portion of the target tissue. It should be appreciated that any of systems and devices described herein may be used in the methods described here.

[0096] In some variations, a method of treating diabetes may include one or more of application of a radially outward force to stretch (e.g., dilate) tissue and application of negative pressure (e.g., suction) to the tissue to facilitate a consistent (e.g., uniform) tissue-electrode interface. For example, tissue stretched or dilated by an expandable member of a pulsed electric field device in the expanded configuration, whether through the application of a radial force and / or negative pressure, may have a more uniform tissue thickness, which may aid in a consistent energy delivery and treatment. In some variations, tissue may be in contact with the expandable member in the expanded configuration within the target tissue. A visualization device (e.g., endoscope) may be positioned proximal to the expandable member in the expanded configuration. Then, a suction catheter may be advanced from a lumen of the visualization device into a lumen of the expandable member. The suction catheter may be configured to generate a negative pressure sufficient to pull 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 over the electrodes and ensure a consistent tissue-electrode interface tissue around an inner circumference of the target tissue. Furthermore, suction may enable 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 between about 50 mmHg and about 75 mmHg. In some variations, the negative pressure (e.g., suction) applied to the tissue may be applied intermittently or in relatively short time periods at a pressure of between about 100 mmHg andabout 250 mmHg. For example, higher negative pressure may be applied in spurts or feathered so as to ensure contact between the tissue and the electrodes without tissue pressure necrosis.

[0097] Stretched tissue dilated by the expandable member in the expanded configuration may reduce a wall thickness of the tissue, thereby allowing for a lower dose of energy to treat a predetermined depth of tissue. Stretched tissue may include realigning (e.g., reorienting) cellular structures that increase tissue circumference. Reducing total energy delivery may correspond to a lower overall temperature increase of the tissue, which may increases the safety profile of the treatment procedure as well as promote a faster and safer healing cascade.

[0098] In some variations, negative pressure may be applied to the tissue to ensure even contact between tissue and an electrode array during treatment. For example, negative pressure or suction may be applied by an expandable member to a tissue lumen (e.g., duodenum, duodenal tissue) to facilitate tissue apposition with an electrode array of the expandable member. Higher tissue apposition may further enable a reduction in total energy delivery and improved treatment outcomes.

[0099] In some variations, stretching the tissue by applying a radially outward force using the expandable member and / or application of negative pressure to the tissue from the expandable member may reduce a range of tissue thicknesses. For example, the expandable member may stretch tissue such that a ratio of manipulated (e.g., compressed / stretched / dilated) tissue thickness to unmanipulated tissue thickness is about 0.5. In some variations, the combination of tissue stretching and application of a pulsed electric field as described herein may synergistically treat a tissue of a patient.

[0100] In some variations, a pulsed electric field device as described herein may transition to an expanded configuration to dilate (e.g., stretch, extend) the tissue during a treatment procedure. In some variations, tissue may be treated within a predetermined range of dilation ratios. In some variations, a ratio of dilated to undilated mucosa tissue may be between about 0.40 and about 0.60, between about 0.45 and about 0.55, and about 0.50, including all ranges and sub-values in-between. In some variations, a ratio of dilated to undilated submucosa tissue may be between about 0.15 and about 0.35, between about 0.20 and about 0.30, and about 0.26, including all ranges and sub-valuesin-between. In some variations, a ratio of dilated duodenum diameter to undilated duodenum diameter may be between about 1.5 and about 2.3, between about 1.7 and about 2.1, and about 1.91, including all ranges and sub-values in-between. In some variations, a ratio of a dilated duodenum diameter to an undilated duodenum diameter may be between about 1.5 and about 2.3, between about 1.7 and about 2.1, and about 1.91, including all ranges and sub-values in-between.

[0101] In some variations, a signal generator may be configured to deliver a pulsed electric field waveform to two or more non-proximate sections of the plurality of sections in a predetermined sequence. For example, the signal generator may generate a waveform sequence (e.g., interleaving waveform) having an inter- section delay between sections of an electrode array. In particular, the predetermined sequence may comprise an inter-section delay between delivery of a first pulsed electric field waveform to a first section of the plurality of sections and a second pulsed electric field waveform to a second section of the plurality of sections. The first and second pulsed electric field waveforms may be the same or different. In some variations, the inter-section delay may be between about 10 ms and about 4000 ms. In some variations, the first and second sections are non- adjacent (e.g., not immediately next to each other) sections. In some variations, the predetermined sequence may further comprise an intra- section delay between delivery of the first pulsed electric field waveform to the first section and delivery of a second pulsed electric field waveform to the first section.

[0102] In some variations, the intra-section delay may be between about 1 seconds and about 10 seconds. In some variations, the first and second pulsed electric field waveforms may comprise a series of between about 10 bipolar pulses and about 500 bipolar pulses. In some variations, each of the bipolar pulses may comprise a pulse width between about 1 ps and about 3 ps.

[0103] In some variations, the first and second pulsed electric field waveforms may comprise the same number of bipolar pulses. In some variations, the first and second pulsed electric field waveforms may comprise a different number of bipolar' pulses. In some variations, between about 0.05 J per bipolar pulse and about 0.5 J per bipolar pulse may be delivered to the electrode array. In some variations, an instantaneous power between about 26,000 W per bipolar pulse and about 70,000 W per bipolar- pulse may be delivered by the electrode array. In some variations, thepredetermined sequence may be repeated between about 5 and about 15 times. In some variations, activation of the plurality of sections may have a cumulative activation time between about 0.1 ms and about 10 ms over a treatment time between about 30 seconds and about 35 seconds. In some variations, the predetermined sequence may comprise a duty cycle between about 0.003% and about 0.004%. In some variations, the plurality of sections may comprise between abut one section and about ten sections, between about two sections and eight sections, between about three sections and seven sections, and up to five sections, including all ranges and sub-values in-between. In some variations, the electrode array may comprise a surface area between about 4 square centimeters and about 42 square centimeters. In some variations, each section of the plurality of sections may comprise a plurality of electrodes. In some variations, each section of the plurality of sections may comprise between 10 and 18 electrodes.

[0104] In some variations, a pulsed electric field waveform (e.g., interleaving waveform) may be delivered in a predetermined sequence to each of a first section and a second section non-proximate to the first section. The predetermined sequence may have an inter-section delay between the first and second sections of an electrode array.

[0105] In some variations, the intra-section delay may be between about 10 ms and about 10,000 ms, between about 5000 ms and about 10,000 ms, between about 10 ms and about 5000 ms, and between about 2000 ms and about 8000 ms, including all ranges and sub-values in-between. In some variations, the first section may be re-activated after an intra-section delay relative to a previous activation of the first section. For example, the intra-section delay may be between about 3 seconds and about 5 seconds. In some variations, the pulsed electric field waveform may comprise a series of between about 40 bipolar pulses and about 60 bipolar pulses. In some variations, each of the bipolar pulses may comprise a pulse width between about 1 ps and about 3 ps. In some variations, activating each of the first and second sections may deliver between about 0.05 J per bipolar pulse and about 0.5 I per bipolar pulse. In some variations, activating each of the first and second sections may deliver an instantaneous power between about 38,800 W per bipolar pulse and about 41,250 W per bipolar pulse. In some valuations, each of the bipolar pulses may comprise a positively-charged portion and a negatively-charged portion each having a pulse width between about 1.3 ps and about 1.5 ps. In some variations, each of the bipolar pulses may comprise a timeinterval between the positively-charged and negatively-charged portions. In some variations, the time interval may be between about 0.05 ps and about 0.1 ps.

[0106] In some variations, the first and second sections are non-proximate. In some variations, the electrode array may further comprise one or more of a third section, a fourth section, and a fifth section. In some variations, the predetermined sequence may further comprise activating the one or more of the third section, fourth section, and fifth section with the inter- section delay between activation of successive sections. In some variations, the first and second sections may be activated for a cumulative activation time between about 0.1 ms and about 10 ms over a treatment time between about 30 and about 35 seconds. In some variations, the first wherein the predetermined sequence comprises a duty cycle between about 0.003% and about 0.004%. In some variations, the predetermined sequence may be repeated between about 5 and about 15 times.

[0107] The characteristics associated with the pulse waveform may correspond to an amount of energy generated by the electrode array, which in turn may be applied to tissue. The amount of energy may correspond to one or more electric fields generated by the electrode array.

[0108] In some variations, the same portion of tissue may be treated multiple times (e.g., double treated). Treating a same portion of tissue a plurality of times (e.g., two times, three times, four times) may increase the percentage of the tissue in the portion having been treated, thus yielding a more complete lesion leading to improved outcomes. The same pulse waveform energy parameters as first delivered in step 1310 or different pulse waveform energy parameters may be delivered to the same portion of tissue (e.g., gastrointestinal tract, including but not limited to, the duodenum, pylorus, esophagus, stomach, small intestine, and large intestine) when treating the same portion of tissue a plurality of times. In some variations, the pulsed waveform comprises a first pulsed waveform, and delivering at least a second pulsed waveform to the electrode array to generate a second pulsed or modulated electric field thereby treating at least a portion of the tissue previously treated. A plurality of treatments at the same portion of tissue improves the homogeneity of the treatment rather than a depth of penetration.SYSTEMS / DEVICESExemplary Systems and Devices

[0109] Generally, the systems and / or devices employed in the methods described herein may comprise an elongate body coupled to an electrode array, which may be disposed in a bodily lumen (e.g., a lumen of a duodenum). In some variations, the devices may further comprise an expandable member configured to releasably engage to a portion of the bodily lumen. The expandable member may comprise or be coupled to an electrode array configured to generate a pulsed or modulated electric field. The electrodes of the electrode array may have predetermined dimensions and spacing configured to generate a pulsed or modulated electric field having predetermined uniformity for treating desired tissue while limiting damage to other tissue. In some variations, the expandable member may expand and compress as necessary to engage an inner diameter of the bodily lumen. In some variations, a system comprising the devices described herein may further comprise a signal generator configured to generate a pulse waveform for delivery to the electrode array to thereby treat the engaged tissue.

[0110] Exemplary systems 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. FIG. 4 is a block diagram of a variation of a pulsed electric field system (400) comprising one or more of a pulsed electric field device (410), a signal generator (430), multiplexer (470), a visualization device (450), and a display (460).

[0111] In some variations, the pulsed electric field device (410) may comprise one or more (e.g., a first and a second) elongate bodies (412) sized and shaped to be placed in one or more body cavities or lumens of the patient such as, for example, an esophagus, a stomach, a large intestine (e.g., cecum, colon, rectum, anal canal), a small intestine, any portion of the gastrointestinal tract, vasculature (e.g., blood vessels), a thoracic cavity (e.g., lungs), an abdomino-pelvic cavity, a pelviccavity (e.g., bladder), a vertebral cavity, a cranial cavity (e.g., nasal passageway), and the like. In some variations, the pulsed electric field device (410) may further comprise one or more tissue barriers (413), one or more expandable members (414), one or more covers (415), 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). A distal end of the pulsed electric field device (410) may comprise the dilator (418), and the guidewire (424) may extend from a lumen of the dilator (418). The expandable member (414) may comprise the electrode array (416). For example, as will be described in more detail herein, in some variations the electrode array (416) may be coupled to a surface (e.g., outer surface) of the expandable member (416), while in other variations, the electrode array itself may form the expandable member and / or the electrode array may be integral with the expandable member. In some variations, the electrode array may have a plurality of sections that may be energized individually (e.g., concurrently, consecutively) to treat tissue in a predetermined sequence as described in more detail herein.

[0112] In some variations, the expandable member (414) and / or the electrode array (416) may be disposed adjacent to one or more dilators, for example, between at least a pair of dilators (418). In some variations, the tissue barrier (413) and the cover (415) may each be configured to reduce tissue catching with the pulsed electric field device (410) as further described herein. In some variations, the pulsed electric field system (400) may optionally comprise a delivery catheter (426) configured to advance over the pulsed electric field device (410). Additionally or alternatively, the pulsed electric field device (410) may comprise one or more sensors (422) configured to measure one or more predetermined characteristics such as temperature, pressure, impedance and the like.

[0113] As mentioned above, the pulsed electric field system (400) may comprise 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 one or more of advancement of the pulsed electric field device (410), positioning of the pulsed electric field device and / or components thereof (e.g., the electrode array (416)), and confirmation of the treatment procedure. For example, the visualization device (450) may be configured to generate an image signal that is transmitted to a display (460) or output device. In some variations, the visualization device (450) may be advanced separately from and alongside the pulsed electric field device (410)during the treatment procedure. For example, an expandable member (414) of the pulsed electric field device (410) may be configured to hold the visualization device (450) such that the pulsed electric field device (410) translates together with the visualization device (450) as they are moved through the body. The expandable member (414) may expand to release the visualization device (450), thus allowing freedom of movement for the visualization device (450). In other variations, the visualization device (450) may be integrated with the pulsed electric field device (450). For example, the dilator (418) may comprise the visualization device (450).

[0114] The visualization device (450) may be any device (internal or external to the body) that assists a user in visualizing a treatment procedure. In some variations, the visualization device (450) may comprise one or more of an endoscope (e.g., chip-on-the-tip camera endoscope, three camera endoscope), image sensor (e.g., CMOS or CCD array with or without a color filter array and associated processing circuitry), camera, fiberscope, external light source, and ultrasonic catheter. In some variations, an external light source (e.g., laser, LED, lamp, or the like) may generate light that may be carried by fiber optic cables. 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 bundle of fiber optic cables or fiberscope may be configured to receive and propagate light from an external light source. The fiberscope may comprise an image sensor configured to receive reflected light from the tissue and the pulsed electric field device. It should be appreciated that the visualization device (450) may comprise any device or devices that allows for or facilitates visualization of any portion of the pulsed electric field device and / or of the internal structures of the body. For example, the visualization device may comprise a capacitive sensor array and / or a fluoroscopic technique for real-time X-ray imaging.

[0115] In some variations, the system may comprise a suction catheter (452) configured to apply suction to the expandable member (414) and tissue. For example, the suction catheter (452) may be slidably positioning within, and advanced from, a lumen of the visualization device (450). In some variations, the suction catheter (452) may be advanced from the lumen of the visualization device (450) to or into a lumen of the expandable member (414) in an expanded configuration while thevisualization device (450) is positioned proximally of the expandable member (414). In some variations, the suction catheter (452) may be fluidically coupled to a negative pressure source (480).

[0116] Generally, a signal generator (430) may be configured to provide energy (e.g., energy waveforms, pulse waveforms) to the pulsed electric field device (410) to treat predetermined portions of tissue, such as, for example, duodenal tissue. In some variations, a PEF system as described herein may include a signal generator that comprises an energy source and a processor. The signal generator may be configured to deliver a bipolar waveform to an electrode array, which may deliver energy to the tissue (e.g., duodenal tissue). The delivered energy may aid in resurfacing or otherwise treating the desired tissue while minimizing damage to surrounding tissue. In variations in which the desired tissue is duodenal tissue, the delivered energy may aid in resurfacing the mucosa of the duodenum while minimizing damage to surrounding tissue (e.g., muscularis tissue). In some variations, the signal generator may generate one or more bipolar waveforms.

[0117] In some variations, in order to limit nerve stimulation, a pulse waveform may, on average, comprise a net current of about zero (e.g., generally balanced positive and negative current), and have a non-zero time of less than about 2 psec or less than about 5 psec. In some variations, the pulse waveform may comprise a square or rectangular waveform. For example, the pulse waveform may comprise a square or rectangular shape in voltage drive and in current drive, or the pulse waveform may comprise a square or rectangular shape in voltage drive and a sawtooth shape in current drive. In some variations, one or more pulses may comprise a half sine-wave for both current and voltage. In some variations, one or more pulses may comprise two exponentials with different rise and fall times. In some variations, one or more pulses may comprise bipolar pulse at a first potential followed by pulse pairs at a second potential less than the first potential.

[0118] In some variations, a multiplexer (470) may be coupled to the pulsed electric field device (410). For example, the multiplexer (470) may be coupled between the signal generator (430) and the pulsed electric field device (410), or the signal generator (430) may comprise the multiplexer (470). The multiplexer (470) may be configured to select a subset of electrodes of an electrode array (416) receiving a pulse waveform generated by the signal generator (430) according to a predetermined sequence. For example, in some variations, the electrode array (416) may compriseone or more sections that correspond to a subset of electrodes. The electrode array (416) may comprise between 1 and 10 sections, including 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 sections. Each section may comprise the same number of electrodes and / or the same surface area as every other section, but need not. The predetermined sequence may be optimized to treat tissue at a given treatment site. Additionally or alternatively, the multiplexer (470) may be coupled to a plurality of signal generators and may be configured to select between a waveform generated by one of the plurality of signal generators (430) for a selected subset of electrodes.

[0119] In some variations, the multiplexer (470) and the signal generator (430) may be configured to deliver a pulsed electric field waveform to two or more non-proximate sections (e.g., first section, second section) of the plurality of sections in a predetermined sequence. For example, the predetermined sequence may comprise activating a first section followed by a second section after an inter-section delay where activation of each of the first and second sections generates a therapeutic electric field, and where the first and second sections are not adjacent (i.e., directly next to) one another. Put differently, the predetermined sequence may comprise activating a first section followed by a second section, where at least a third section is positioned between the first and second sections. As another example, the signal generator may be configured to deliver a series of bipolar pulses to two or more non-proximate sections of the plurality of sections in a predetermined sequence for a cumulative activation time of between about 0.1 ms and about 10 ms over a treatment period between about 30 seconds and about 35 seconds. Each bipolar pulse may comprise a pulse width between about I ps and about 10 ps, and the electrode array may be configured to deliver between about 0.05 J per bipolar pulse and about 0.5 J per bipolar pulse and an instantaneous power between about 26,000 W per bipolar pulse and about 70,000 W per bipolar pulse. In some variations, the predetermined sequence may comprise a duty cycle between about 0.003% and about 0.004%, including all ranges and sub-values in-between. In some variations, the signal generator may be configured to control waveform generation and delivery in response to received sensor data. For example, energy delivery may be modulated (e.g., inhibited) based on one or more of a measured temperature and impedance.Pulsed Electric Field Devices

[0100] FIGS. 5A-5R are various schematic views of an illustrative variation of a pulsed electric field device (500) in respective unexpanded and expanded configurations. As depicted there, the pulsed electric field device (500) may comprise a first elongate body (510) comprising a lumen (511) therethrough and an expandable member (520). FIG. 5 A shows an exemplary expandable member (520) in an unexpanded (e.g., rolled, compressed) configuration and FIG. 5B shows the expandable member (520) in an expanded (e.g., unrolled, uncompressed) configuration. As noted above, the expandable member may comprise an inflatable balloon. In some variations, the first elongate body (510) may comprise a distal portion (512) and a proximal portion (514). The expandable member (520) may comprise an electrode array (520), and inner end (524) coupled to a second elongate body (560), and an outer end (522) coupled to the first elongate body (510). The expandable member (520) may be disposed between the proximal portion (514) and the distal portion (512). In some variations, the proximal portion (514) may comprise a proximal dilator and the distal portion (512) may comprise a distal dilator.

[0101] The pulsed electric field device (500) may further comprise a tissue barrier (540) configured to provide a smoother surface along a longitudinal axis of the device (500) to prevent undesirable tissue engagement (e.g., catching) with the device (500) that would pinch tissue and / or hold the device (500) in place relative to the tissue. For example, the tissue barrier (540) may be configured to prevent tissue from becoming trapped between the expandable member (520) and the first and second portions (540a, 540b) of the first elongate body (510). In some variations, the tissue barrier (540) may comprise a first portion (540a) (e.g., distal portion) and a second portion (540b) (e.g., proximal portion). In some variations, the first portion (540a) may be coupled to a distal edge of the expandable member (520) and to the distal portion (512) of the first elongate body (510). The second portion (540b) may be coupled to a proximal edge of the expandable member (520) and to the proximal portion (514) of the first elongate body (510).

[0102] The pulsed electric field device (500) may further comprise a cover (550) configured to reduce tissue catching between the expandable member (520) and the first elongate body (510). In some variations, the cover (550) may be coupled between the outer end 522 of the expandable member (520) and the first elongate body (510). The cover (550) may be configured to overlap a portion of the expandable member (520). For example, FIGS. 5Q and 5R illustrate an opening 512of the first elongate body (510) through which the expandable member (520) transitions between unexpanded and expanded configurations. When the expandable member (520) transitions from the expanded configuration to the unexpanded configuration, the expandable member (520) retracts into a lumen (511) of the first elongate body (510) and rolls about the second elongate body (560). Any tissue engaged with the expandable member (520) during this transition may also be drawn into the lumen (511) and may be caught between the expandable member (520) and the first elongate body (510). However, the cover (550) may be configured to separate tissue from the expandable member (520) before being caught between the expandable member (520) and the first elongate body (510), thereby facilitating transition of the expandable member (520) between rolled and unrolled configurations.Expandable Members

[0103] Generally, the expandable members described herein may be configured to change configurations to aid in positioning of the electrode array relative to target tissue during a treatment procedure. For example, the expandable member (e.g., circuit substrate, flex circuit) may expand to contact tissue to hold the pulsed electric field device in place (e.g., elongate body, electrode array, sensor) relative to the tissue. The expandable member may also partially expand to hold a visualization device in place relative to the pulsed electric field device. The expandable member may comprise a compressed configuration and an expanded configuration. As will be discussed in more detail herein, in some instances, the compressed configuration may be a rolled configuration and the expanded configuration may be an unrolled configuration. Moreover, in some variations, the expandable member may comprise a semi-expanded (or partially unrolled) configuration between the compressed configuration and the expanded configuration. Placing the expandable member in the compressed configuration may allow the pulsed electric field device to be compact in size, which may allow for easier advancement through one or more body cavities. Once appropriately positioned, the expandable member may be transitioned to the expanded configuration, which may allow an electrode array of the expandable member to contact or better contact a tissue surface, such as, for example, all or a portion of an inner circumference of the duodenum or other body lumen. In some variations, the semi-expanded configuration may allow the expandable member to hold another device (e.g., visualization device) within a lumen of the expandable member. Additionallyor alternatively, a lumen having one or more openings, apertures, holes, slots, combinations thereof, and the like.

[0104] In some variations, the expandable member (520) may be rolled around (e.g., wound about, spooled) and / or in contact with a second elongate body (560) about a longitudinal axis thereof. For example, as shown in the cross-sectional views of FIGS. 5Q and 5R, a second elongate body (560) may be at least partially positioned within a lumen (511) of the first elongate body (510). Furthermore, the expandable member (520) may comprise a plurality of turns such that the expandable member (520) may be rolled about the second elongate body (560) where the expandable member (520) forms a plurality (e.g., two, three, four, five, or more) layers wrapped around or rolled about the second elongate body (560). That is, the expandable member (520) may be in mechanical contact with the second elongate body (560). FIG. 5Q shows the expandable member (520) in an unexpanded or rolled configuration and FIG. 5R shows the expandable member (520) in an expanded or unrolled configuration.

[0105] In some variations, the expandable member (520) may comprise an electrode array (530), which may comprise any of the electrode arrays described herein. For example, in some variations, the expandable member (520) may be a flex circuit, while in other variations, the expandable member (520) may comprise a base layer and a flex circuit may be coupled to the base layer. The electrode array (530) may be disposed on an outer surface of the expandable member (520) facing away from the second elongate body (560).

[0106] FIGS. 5A, 5C, 5E, 5G, 5H, 5L, 5M, and 5Q depict a pulsed electric field device (500) with the expandable member (520) in an unexpanded or rolled configuration configured for advancement through one or more body cavities. When in the unexpanded or rolled configuration, the expandable member (520) may have a generally cylindrical shape (e.g., conforming to the shape of the first elongate body (510)) with a first inner diameter (e.g., lumen diameter) and a first outer diameter. FIGS. 5B, 5D, 5F, 5I-5K, 5N, 50, and 5R depict the pulsed electric field device (500) with the expandable member (520) in an expanded or unrolled configuration configured for engagement with tissue, such as an inner surface of a duodenum (not shown for the sake of clarity). In some variations, the first elongate body (510) may have a diameter of between about 5 mm and about 10mm, an inner diameter of up to about 1.3 mm, and a length between about 1500 and about 1900 mm, and between about 1800 and about 1900 mm, including all ranges and sub-values in-between. When in the expanded or unrolled configuration, the expandable member (520) may have a generally elliptic or cylindrical shape with a second inner diameter and a second outer diameter having a predetermined diameter larger than a respective first inner diameter and first outer diameter. The expandable member (520) in the expanded configuration may have a predetermined flexibility configured to conform to a shape of the tissue to which it is engaged.

[0107] In some variations, the first and second elongate bodies (510, 560) may be configured to axially rotate relative to one another to transition the expandable member (520) between the unexpanded configuration, the expanded configuration, and a semi-expanded configuration therebetween. For example, the second elongate body (560) (e.g., inner torsion member, rotatable member) may be rotatably positioned within a lumen of the first elongate body (510), such that rotation of the second elongate body (560) relative to the first elongate body (510) (or rotation of the first elongate body (510) relative to the second elongate body (560)) may transition the expandable member (520) between a rolled configuration and an unrolled configuration. As described in more detail herein, a suction catheter, such as a suction catheter advanced from a visualization device (not shown), may be disposed within the lumen (521) of the expandable member (520) to aid in tissue engagement. For example, the suction catheter may be configured to apply suction through the lumen (521) of the expandable member (520). It should be appreciated that the pulsed electric field device (500) may be advanced next to a visualization device and / or over a guidewire. In some variations, a visualization device may be used to guide advancement and to visualize a treatment procedure such that a guidewire and / or other visualization modalities (e.g., fluoroscopy) are not needed.

[0108] In some variations, the expandable member (520) may be configured to transition to a configuration between the unexpanded and expanded configurations. For example, the expandable member (520) may transition to a partially or semi-expanded configuration (between the compressed configuration and expanded configuration) that may allow a visualization device (e.g., endoscope) to be disposed within a lumen of the expandable member (520). In some variations, aninner surface of the expandable member (520) may engage and hold a visualization device in a semi-expanded configuration.

[0109] As shown in the cross-sectional views of FIGS. 5Q and 5R, the expandable member (520) may comprise an inner end (524) (e.g., innermost portion of roll) and an outer end (522) (e.g., outermost portion of roll). FIG. 5Q depicts the expandable member (520) in the unexpanded configuration where the expandable member (520) is rolled about both the first and second elongate bodies (510, 560). For example, the expandable member (520) rolls about the second elongate body (560) for a plurality of turns and at least an outer end (522) of the expandable member (520) engages with the outer surface of the first elongate body (510) so as to minimize a diameter of the pulsed electric field device (500) and facilitate translation of the device (500) through one or more body cavities of the patient. In some variations, the inner end (524) of the expandable member (520) may be coupled to the second elongate body (560) through the second connector (562). Optionally, one or more leads may be coupled to the electrode array (530) through the second elongate body (560) and second connector (562).

[0110] FIG. 5R depicts the expandable member (520) in the expanded configuration where the expandable member (520) is unrolled from the second elongate body (560) such that the expandable member defines a lumen (521). The expandable member (520) in the expanded configuration may have a predetermined flexibility configured to conform to a shape of the tissue to which it is engaged.

[0111] In some variations, the inner end (524) may be coupled to the second elongate body (e.g., attached to an external surface thereof) (560) and the outer end (522) may be coupled to the first elongate body (510) (e.g., an external surface thereof). Coupling the ends of the expandable member (520) to the first and second elongate bodies (510, 560) in this way allows for better control over the size and shape of the expandable member (520). For example, the inner end (524) may be attached to an outer surface of the second elongate body (560) such that the inner end (524) rotates with the rotation of the second elongate body (560). A direction of the rotation (e.g., clockwise, counterclockwise) of the second elongate body (560) may determine the configuration (e.g., rolled, unrolled) of the expandable member (520). For example, rotating the second elongate body (560) ina clockwise direction relative to the first elongate body (510) may expand or unroll the expandable member (520), while rotating the second elongate body (560) in a counter-clockwise direction relative to the first elongate body (510) may compress or roll the expandable member, or vice versa. A portion of the first elongate body (510) may comprise an opening (e.g., slit) configured to facilitate transition of the expandable member (520) between unexpanded and expanded configurations.

[0112] FIG. 9A is a perspective view of a variation of an expandable member (900) in a rolled configuration and FIG. 9B is a perspective view of the expandable member (900) in an unrolled configuration. In some variations, the expandable member (900) may comprise a substrate (910) such as a flex circuit. Furthermore the expandable member (900) may comprise or be coupled to an electrode array (not shown). In some variations, the expandable member (900) may be composed of a self-expanding material biased to expand to a predetermined shape and / or diameter. For example, the expandable member (900) may comprise one or more of a flexible polymeric material (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 an expandable member (900) may be caused by respective retraction and advancement of a sheath (e.g., delivery catheter) over the expandable member (900). The expandable member in the rolled configuration may comprise one or more turns. In some variations, the expandable member (900) in the rolled configuration may have a diameter between about 6 mm and about 25 mm, between about 10 mm and about 25 mm, and between about 15 mm and about 20 mm, including all ranges and sub- values in-between. In some variations, the expandable member (900) in the expanded configuration may have a diameter between about 10 mm and about 60 mm, between about 20 mm and about 50 mm, between about 30 mm and about 50 mm, and between about 40 mm and about 50 mm, including all ranges and sub-values in-between. In some variations, the expandable member (900) may have a width of at least 10 mm, between about 10 mm and about 60 mm, between about 10 mm and about 50 mm, between about 10 mm and about 30 mm, and between about 20 mm and about 40 mm, including all ranges and sub-values in-between.

[0113] In some variations, the expandable member may comprise one or more sensors configured to determine a configuration of the expandable member. For example, the sensor may comprise oneor more inductive coils configured to measure proximity between the expandable member and the second elongate body such that a length of the unrolled expandable member may be determined. For example, one or more sensors may be disposed along a length of the expandable member. In some variations, a configuration of the expandable member may be confirmed via visual confirmation and via the sensor data.Electrode Arrays

[0114] Generally, the electrodes and electrode arrays described herein may be configured to treat tissue, such as the duodenal tissue, of a patient. In some variations, the electrode array may engage the tissue and be energized to treat a predetermined portion of tissue to resurface the or otherwise treat the tissue. For example, tissue may undergo cell lysis using PEF energy during a treatment procedure. PEF energy tissue treatment may be uniformly delivered at a predetermined depth (e.g., about 1 mm) to quickly and precisely treat tissue without significant damage to surrounding (e.g., deeper) tissue.

[0115] In some variations, tissue treatment characteristics may be controlled by the size, shape, spacing, composition, and / or geometry of the electrode array. For example, the electrode array may be flexible to conform to non-planar tissue surfaces. In some variations, the electrode array may be embossed or reflowed to form a non-planar electrode surface. In some variations, the electrode array may comprise a tissue contact layer. The tissue contact layer may function as a salt bridge between the electrodes and tissue. In some variations, the electrode array may comprise a hydrophilic coating. Additionally or alternatively, the electrode array may be electrically divided into sub-arrays to reduce drive current requirements. In some variations, the sub-arrays may correspond to the plurality of sections described herein.

[0116] In some variations, raised and / or rounded (e.g., semi-ellipsoid) electrodes may generally promote more reliable contact with tissue than flat electrodes and therefore a more uniform electrical field and improved treatment outcomes. For example, tissue contact (e.g., apposition) with the electrodes completes an electrical circuit during energy delivery and therefore provides the resistance in the circuit for a uniform electric field distribution. The raised and / or rounded (e.g., semi-ellipsoid) electrodes may reduce sharp edges to reduce arcing. The spaced-apart electrodes ofthe electrode array may further reduce ion concentration and associated electrolysis. The electrode array configurations (e.g., geometry, spacing, shape, size) shown and described herein provide uniform and spaced-apart electrodes that also allow a corresponding expandable member to repeatedly expand and compress.

[0117] In some variations, one or more of the electrodes (e.g., a plurality of the 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, ni tinol, palladium, silver, platinum, combinations thereof, and the like. In some variations, one or more electrodes (e.g., a plurality of the electrodes, a portion of the electrodes in an array, all of the electrodes in an array) may comprise an atraumatic (e.g., blunt, rounded) shape such that the electrode does not puncture tissue when pressed against tissue. For example, the electrode array may engage an inner circumference of the duodenum. In some variations, activation of one or more sections of an electrode array may provide partial or full circumferential treatment of tissue. For example, a predetermined sequence may treat a circumference of tissue of up to about 360°, of up to about 330°, of up to about 300°, of up to about 270°, of up to about 240°, of up to about 210°, of up to about 180°, of up to about 150°, of up to about 120°, of up to about 90°, of up to about 60°, and of up to about 30°, including all ranges and sub-values in-between.

[0118] In some variations, the electrode array may be connected by one or more leads (e.g., conductive wire) to a signal generator. For example, a lead may extend through an elongate body (e.g., outer catheter, outer elongate body) to the electrode array. One or more portions of the lead may be insulated (e.g., PTFE, ePTFE, PET, polyolefin, parylene, FEP, silicone, nylon, PEEK, polyimide). The lead may be configured to sustain a predetermined voltage potential without dielectric breakdown of its corresponding insulation.

[0119] In some variations, an electrode array may comprise a plurality of elongate electrodes in a substantially parallel or interdigitated configuration. The shape and configuration of the electrode arrays described herein may generate an electric field of predetermined strength (e.g., between about 400 V / cm and about 7,500 V / cm) at a predetermined tissue depth (e.g., about 0.7 mm, about 1 mm) without excess heat, breakdown, steam generation, and the like. By contrast, some electrodeconfigurations comprise a geometry (e.g., radius of curvature) where the electric fields generated decreases too quickly without application of very high voltages (e.g., thousands of volts) that may lead to the aforementioned excess heat, breakdown, and steam generation.

[0120] As described in detail herein, a pulsed electric field device may comprise an expandable member having a compressed (e.g., rolled) configuration and an expanded (e.g., unrolled) configuration. In some variations, the expandable member may comprise or may otherwise be formed from an electrode array (e.g., a plurality of electrodes). In some variations, the expandable member may comprise a flex circuit comprising a plurality of electrodes (e.g., electrode array). FIG. 8 is a perspective view of a variation of an electrode array (800) comprising a plurality of elongate electrodes (810) on a substrate (820) and a plurality of apertures (830). In some variations, the electrode array (800) may be in the form of a flex circuit. The flex circuit may comprise an electrode array (800) or a plurality of electrodes, for example, a plurality of elongate, parallel electrodes. In some variations, the substrate (820) of the electrode array (800) may define one or more apertures (830) (e.g., fluid openings) configured to generate suction (e.g., negative pressure) and / or output fluid (e.g., saline) between adjacent electrodes (810). The use of suction or negative pressure applied through the openings may draw tissue toward the electrode array (800) and may facilitate contact between the tissue and the electrode array (e.g., may increase a contact area between the surface of the tissue and the electrode surface). For example, the electrode array (800) may be engaged to the tissue via suction through the one or more apertures (830) that may promote more reliable (e.g., consistent) electrical contact between the pulsed electric field device and tissue, and therefore a more uniform electric field and an improvement to treatment outcomes.Furthermore, the applied suction may be configured to secure tissue apposition to the electrode array in a uniform manner. In some variations, a plurality of apertures (830) (e.g., row of openings) may be disposed between each pair of proximate (e.g., immediately adjacent) electrodes (810) with a predetermined spacing. For example, the apertures (830) may be spaced apart along a length of an electrode (820). In some variations, the aperture (830) may be disposed closer to one of the electrodes to promote contact between the tissue and at least one of the electrodes (810). Additionally or alternatively, the apertures (830) may be disposed equally between proximate electrodes (810) and / or through one or more electrodes (810).

[0121] In some variations, the electrode array may comprise a surface area between about 4 square centimeters and about 42 square centimeters, between about 6 square centimeters and about 10 square centimeters, between about 4 square centimeters and about 8 square centimeters, between about 20 square centimeters and about 42 square centimeters, between about 30 square centimeters and about 42 square centimeters, between about 10 square centimeters and about 30 square centimeters, and between about 8 square centimeters and about 42 square centimeters, including all ranges and sub-values in-between. In some variations, the expandable member in the unexpanded configuration may have an outer diameter between about 15 mm and about 20 mm, including all ranges and sub-values in-between.

[0122] Additionally or alternatively, the apertures (830) may be configured for fluid (e.g., gas, fluid) irrigation. The electrode array (800) may be in fluid communication with (e.g., fluidically coupled to) a fluid source (e.g., fluid source of saline, negative pressure source) for fluid irrigation and / or fluid cooling. For example, fluid may be removed from (e.g., suctioned out of) a body cavity or lumen after applying the pulsed or modulated electric field using the electrodes (810). In some variations, removal of the fluid may facilitate apposition and / or contact between the tissue and the electrode array (800).

[0123] In some variations, at least one of the electrodes (810) may comprise a semi-elliptical cross-sectional shape. In some instances, all of the electrodes (810) in the electrode array (800) may comprise a semi-elliptical cross-sectional shape. Generally, electric fields are intense near points and edges of electrodes due to the high concentration of surface charges there. Sharp-edged electrodes and high electric fields may generate one or more of electric discharge (e.g., arcing), high heat rates (e.g., boiling), high current density (e.g., electrolysis), and bubbles. The semi-elliptical cross-scctional shapes described herein may reduce one or more of these effects relative to sharp- edged electrodes. In some variations, a major axis of the electrode (810) is twice the electrode width and the minor axis of the electrode is equal to the electrode height in the middle of the electrode.

[0124] The electrode arrays described herein may be formed using any suitable manufacturing technique. The electrode arrays described herein may be manufactured using any suitable technique including, but not limited to, deposition of solder or other metal, dimpling of the substrate, platingof a metal (e.g., gold), and lamination. In some variations, additional layers and / or coatings may be applied to the electrode.

[0125] In some variations, a drive voltage applied to the electrode array may depend at least on the spacing between electrodes of the electrode array as well as electrode dimensions. For example, relatively wide elongate electrodes may reduce the effect of strong electric field intensities at sharply curved edges.

[0126] 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-shape, W-shape). The electrode array (810) may be configured to modify a flexural stiffness of the expandable member (800) to facilitate consistent expansion and compression of the expandable member (800). In some variations, the electrode array (810) may comprise a plurality of electrodes configured to protrude and / or recess relative to a surface of the substrate (820).

[0127] In some variations, a more uniform treatment of tissue (e.g., in areas where the electrode groups intersect) may be obtained by reducing the widths of the end-most electrodes of each section and reducing the distance between those electrodes. In some variations, a more uniform treatment of tissue (e.g., in areas where the electrode sections intersect) may be enabled by interdigitating the end-most electrodes of each group to overlap the treatment areas.

[0128] In some variations, an electrode array may comprise a plurality of electrode sections (e.g., zones), including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 or more electrode sections. In some variations, each section of the plurality of sections may comprise a plurality of electrodes. For example, each section of the plurality of sections may comprises between 10 and 18 electrodes. In some variations, an electrode section of an electrode array may have a surface area of between about 250 mm2and about 1000 mm2, between about 250 mm2and about 750 mm2, between about 500 mm2and about 1000 mm2, between 400 mm2and about 500 mm2and between 400 mm2and about 600 mm2, including all ranges and sub-values in-between.Actuator

[0129] In some variations, an expandable member of a pulsed electric field device may transition configurations by using an actuator that allows improved control over the expansion and / or compression of the expandable member. For example, in variations in which a rolled expandable member is used, the actuator may comprise a set of gears and / or friction rollers (e.g., knurled friction rollers), and tracks configured for consistent transmission of rotational torque from the rotating elongate body to the expandable member. FIG. 10A is a perspective view and FIG. 10B is a cross-sectional side view of a variation of a pulsed electric field device (1000) comprising an actuator (1070). As shown there, the pulsed electric field device (1000) may comprise a first elongate body (1010) comprising a lumen therethrough and a second elongate body (1012) at least partially positioned within the lumen of the first elongate body (1010), and one or more actuators (1070). The pulsed electric field device (1000) may further comprise an expandable member (1030) rolled about the second elongate body (1012), as described in more detail herein, and operably coupled to the actuator (1070). In some variations, the pulsed electric field device (1000) may further comprise one or more dilators, for example, a distal dilator (1050) (e.g., corresponding to a distal portion (512) and a proximal dilator (1052) (e.g., corresponding to a proximal portion (514), coupled to one of the first elongate body (1010) and the second elongate body (1012). In some variations, one or more of the dilators (1050, 1052) may have a sigmoidal shape. The actuator (1070) may be disposed between the distal dilator (1050) and the proximal dilator (1052). The expandable member (1030) may be disposed between the distal dilator (1050) and the proximal dilator (1052).

[0130] As mentioned above, the pulsed electric field device (1000) may comprise an actuator operably coupled to the expandable member (1030) and configured to assist in expanding (e.g., unrolling) and compressing (e.g., rolling) the expandable member (1030). In some variations, the actuator may comprise one or more gears, which may interface with the expandable member (1030), such as, for example, via one or more tracks formed in the expandable member (1030). For example, in the variation depicted in FIGS. 10A-10C, the actuator (1070) may comprise a first gear (1020) and a second gear (1022), each of which may be coupled to the second elongate body (1012). The expandable member (1030) may further comprise a first track (1032) on a first side thereof and a second track (1034) on a second side thereof. The first track (1032) may be operably coupled tothe first gear- (1020) and the second track (1034) may be operably coupled to the second gear (1022). In some of these variations, the first and / or second tracks (1032, 1034) may comprise a plurality of spaced apart openings in the expandable member (1030) configured to receive the teeth of the respective gears (1020, 1022). The expandable member (1030) may be coupled to the second elongate body (1012) via the gears (1020, 1022). FIG. 10C is a detailed cutaway perspective view of the pulsed electric field device (1000) depicting engagement of the teeth of the gears (1020, 1022) with the respective tracks (1032, 1034) of the expandable member (1030). Additionally or alternatively, the actuator may comprise a metal roller comprising a plurality of teeth textures configured to directly press against the expandable member (1030). The metal roller may be configured to operate with a drum plotter or a film canister type of mechanism. Similar to the pulsed electric field device (500) of FIGS. 5A-5R, the expandable member (1030) may comprise an inner end (e.g., innermost portion of roll) and an outer end (e.g., outermost portion of roll) where the inner end is coupled to the second elongate body (1012) and the outer end is coupled to the first elongate body (1010). A direction of the rotation (e.g., clockwise, counter-clockwise) of the second elongate body (1012) may determine the expansion or compression of the expandable member (1030). In some variations, a connector (1040) may couple the second elongate body (1012) to the inner end of the expandable member (1030). An outer end of the expandable member (1030) may be coupled to one or more of the dilators (1020, 1022) and the first elongate body (1010). However, FIG. 10A shows an unattached outer end of the expandable member (1030) for the sake of illustration. In some variations, the expandable member (1030) in the rolled configuration may have a diameter between about 6 mm and about 15 mm, including all ranges and sub-values in-between. The expandable member (1030) in the rolled configuration may comprise one or more turns. In some variations, the expandable member (1030) in the expanded configuration may have a diameter between about 10 mm and about 50 mm, including all ranges and sub-values in-between.

[0131] In some variations, the electrode array may be electrically coupled to the second elongate body (1012) through the connector (1040). For example, one or more leads may couple to the electrode array through the second elongate body (1012) and connector (1040). Additionally or alternatively, one or more leads may couple to the electrode array through the first elongate body (1010).Elongate Body

[0132] Generally, the elongate bodies (e.g., catheters) of the pulsed electric field devices described herein may be configured to deliver an electrode array to a target tissue for treating the tissue. In some variations, an elongate body may comprise a shaft composed of a flexible polymeric material such as Teflon, Nylon, Pebax, urethane, combinations thereof, and the like. In some variations, the pulsed electric field device may comprise one or more steerable or deflectable catheters (e.g., unidirectional, bidirectional, 4-way, omnidirectional). In some variations, the elongate body may comprise one or more pull wires configured to steer or deflect a portion of the elongate body. In some variations, the elongate body may have a bend radius between about 5 cm and about 23 cm and / or between about 45 degrees and about 270 degrees. In some variations, the elongate bodies described herein may comprise a lumen through which another elongate body and / or a guidewire may slide. In some variations, the elongate bodies may comprise a plurality of lumens. For example, the elongate body may comprise one or more of an inflation lumen, fluid lumen, guidewire lumen, and lead lumen.

[0133] In some variations, a first elongate body may have a length of between about 150 cm and about 200 cm, between about 170 cm and about 200 cm, between about 180 cm and about 190 cm, and between about 150 cm and about 170 cm, including all ranges and sub-values in-between. In some variations, a first elongate body may decrease in stiffness proximally to facilitate navigation of the pulsed electric field device through one or more body cavities or lumens. For example, a distal portion of the first elongate body may comprise a stiffness of between about 45D and about 70D, between about 50D and about 60D, and about 55D, including all ranges and sub-values in-between. The distal portion of the first elongate body may have a length of between about 10 inches and about 30 inches, between about 15 inches and about 25 inches, between about 15 inches and about 20 inches, and about 17 inches, including all ranges and sub-values in-between. A proximal portion of the first elongate body may comprise a stiffness of between about 50D and about 100D, between about 60D and about 80D, between about 65D and about 75D, and about 70D including all ranges and sub-values in-between. The proximal portion of the first elongate body may have a length of between about 40 inches and about 70 inches, between about 50 inches and about 60 inches, and about 55 inches, including all ranges and sub-values in-between.

[0134] In some variations, a first elongate body may have a diameter of between about 1 mm and about 20 mm, between about 5 mm and about 15 mm, between about 5 mm and about 10 mm, and between about 10 mm and about 20 mm, including all ranges and sub-values in-between.

[0135] In some variations, a lumen of a first elongate body may have a diameter of up to about 2 mm, up to about 1.5 mm, up to about 1 mm, up to about 0.5 mm, between about 1 mm and about 2 mm, and between about 1 mm and about 1.5 mm, including all ranges and sub-values in-between.

[0136] In some variations, the elongate body may be woven and / or braided and / or coiled, and may be composed of a material (e.g., nylon, stainless steel, nitinol, polymer) configured to enhance pushability, torquabilty and flexibility. In some variations, one or more of the first and second elongate bodies may comprise a metal-based radiopaque marker comprising one or more of a ring, band, and ink (e.g. platinum, platinum-iridium, gold, nitinol, palladium) configured to permit fluoroscopic visualization. In some variations, one or more of the first and second elongate bodies may comprise magnetic members configured to attract and couple to the bodies to each other. 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 materials to achieve a predetermined set of characteristics.

[0137] In some variations, the first elongate body and visualization device may be coupled along a predetermined length using one or more of a coupling sleeve, a plurality of rings, and mechanical fasteners. For example, the coupling sleeve may comprise one or more of a polymer sleeve having a spine optionally including scalloped edges, a tubular braid (e.g., Nylon, PET), a balloon polymer sleeve (e.g., baleeve), and EPTFE biaxially oriented. The plurality of rings may include a chain of rings that may be FEP coated and / or formed of silicone and / or Viton.Dilator

[0138] Generally, the dilators of the pulsed electric field devices described here may be configured to assist advancement of one or more portions of a pulsed electric field device into and through a body cavity or lumen. In some variations, a dilator may generally be configured to dilate a body cavity or lumen, such as a lumen of a duodenum. The dilator may be atraumatic in shape tominimize any inadvertent or unintended damage and may comprise any shape suitable to enlarge a tissue lumen. For example, in some variations, a dilator may comprise a conical shape comprising a taper of between about 1 degree and about 45 degrees, which may facilitate PEF device advancement through a body lumen, such as a portion of the gastrointestinal tract. In some variations, the dilator may comprise PET, PEBA, PEEK, PTFE, silicone, elastomer, PS, PEI, latex, sulphate, barium sulfate, a copolymer, combinations thereof, and the like. In some variations, the dilator may comprise a solid configuration. In some variations, the dilator may comprise a plurality of materials configured to provide a desired stiffness and compliance along a length of the dilator. The dilator may comprise one or more components configured to facilitate advancement of a guide wire.

[0139] In some variations, the dilator may comprise a length of between about 2 mm and about 10 cm. In some variations, the dilator may comprise a taper of between about 5 degrees and about 30 degrees relative to a longitudinal axis of the dilator. Furthermore, a distal end of the dilator may be atraumatic (e.g., rounded, blunted). In some variations, a pulsed electric field device may comprise a plurality of dilators (e.g., 2, 3, 4, 5, 6, or more). For example, respective dilators may be disposed proximal and distal to an expandable member. This allows smooth proximal and distal advancement of the pulsed electric field device. In some variations, the dilator may comprise a shore A hardness of between about 30 Shore A and about 50 Shore A, and between about 40 Shore A and about 50 Shore A, including all ranges and sub-values in-between.

[0140] In some variations, a pulsed electric field device may comprise one or more dilators configured to aid advancement of the device through one or more tortuous body cavities without damaging tissue. FIG. 10A is a perspective view of a variation of a pulsed electric field device (1000) in a rolled configuration where the pulsed electric field device (1000) comprises one or more dilators (1010, 1050). For example, the pulsed electric field device (1000) may comprise a distal dilator (1050) and a proximal dilator (1052), each coupled to one of the first elongate body (1010) and the second elongate body (1020). The dilators (1050, 1052) may assist in smoothly advancing and / or retracting the pulsed electric field device (1000) through one or more body cavities or lumens and may assist in preventing the expandable member from catching on tissue. For example, the dilators (1050, 1052) may be configured to protect an edge of the expandable member (1030) andsecond elongate body (e.g., canister) from contacting tissue as it is being advanced through a body cavity. In some variations, an outer surface at the end of the actuator adjacent the expandable member may be level with (e.g., at the same height) as the expandable member in the expanded configuration, be lower than or be higher than the expandable member. Accordingly, the dilators (1050, 1052) may allow the pulsed electric field device (1000) to be smoothly translated through one or more body cavities, as described in more detail herein.

[0141] The expandable member (1030) may be disposed between the distal dilator (1050) and the proximal dilator (1052). The length and taper of the dilators of the device may be the same or different. For example, a distal dilator (1050) may have a steeper taper than the proximal dilator (1052) and vice versa. In some variations, the distal dilator may have a longer length than a proximal dilator and vice versa. In some variations, the pulsed electric field device may comprise just a single distal dilator.

[0142] In some variations, a dilator may comprise a recess configured to facilitate mating or coupling with another elongate member such as a visualization device (e.g., endoscope). For example, this may enable the dilator and expandable member to removably couple to a visualization device during a treatment procedure.

[0143] FIG. 10D depicts a variation of a dilator (2000) including a lumen (2010) and one or more flanges (2020) configured to provide variable stiffness along a length of the dilator (2000) to facilitate translation through a tortuous body cavity or lumen. For example, a conventional dilator having insufficient stiffness may deflect and buckle when navigating through a curvature (e.g., around a comer) while a dilator having too much stiffness may traumatically engage with tissue during navigation through a body cavity. By contrast, the increasing stiffness provided distally along a length of the dilator (2000) enables a proximal end of the dilator (2000) to deflect more easily than a distal end while the distal end of the dilator (2000) comprising the flanges (2020) provides stiffness such that the dilator (2000) does not buckle or deform. In some variations, the stiffness may increase from a distal end of the dilator to a proximal end of the dilator by up to 10%, by about to about 20%, by about to about 30%, by about to about 40%, by about to about 50%, including all ranges and sub-values in-between. In some variations, the stiffness of the dilator mayincrease linearly or non-lineaiiy along a length of the dilator. The dilator (2000) may further comprise an atraumatic enlarged bulbous distal tip. The lumen (2010) may be configured to receive one or more of a guidewire, visualization device, and the like. The flanges (2020) may comprise one or more rings disposed along and perpendicular to a longitudinal axis of the dilator (2000). The dilator (2000) may comprise additional lumens. Alternatively, the dilator (2000) may not include a lumen. In some variations, the first dilator (200) may comprise one or more fiducial markers (e.g., radiopaque markers). For example, the fiducial marker may comprise a metal-based radiopaque marker comprising one or more of a ring, band, and ink (e.g. platinum, platinum-iridium, gold, nitinol, palladium) configured to permit fluoroscopic visualization.Signal Generator

[0144] In some variations, the signal generator may comprise a processor, memory, energy source (e.g., current source), and user interface. The processor may 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 to 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, procedure data, safety data, and / or the like.

[0145] Generally, the processor (e.g., CPU) of a signal generator described here 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, compute, 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., temperature sensor) and a storage medium (e.g., memory, flash drive, memory card). In some variations, the processor may be any suitable processing device configured to run and / or execute a set of instructions or code and may include one or more data processors, image processors, graphics processing units (GPU), physics processing units, digital signal processors (DSP), analog signal processors, mixed-signal processors, machine learning processors, deep learning processors, finite state machines (FSM), compression processors (e.g., data compression to reduce data rate and / or memory requirements), encryption processors(e.g., for secure wireless data and / or power transfer), and / or central processing units (CPU). The processor may be, for example, a general purpose processor, Field Programmable Gate Array (FPGA), an Application Specific Integrated Circuit (ASIC), a processor board, and / or the like. 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 like complementary metal-oxide semiconductor (CMOS), bipolar technologies like emitter-coupled logic (ECL), polymer technologies (e.g., silicon-conjugated polymer and metal-conjugated polymer-metal structures), mixed analog and digital, and / or the like.

[0146] The systems, devices, and / or methods described herein may be performed by software (executed on hardware), hardware, or a combination thereof. Hardware modules may include, for example, a general-purpose processor (or microprocessor or microcontroller), a field programmable gate array (FPGA), and / or an application specific integrated circuit (ASIC). Software modules (executed on hardware) may be expressed in a variety of software languages (e.g., computer code), including C, C++, lava®, Python, Ruby, Visual Basic®, and / or other object-oriented, procedural, or other programming language and development tools. Examples of computer code include, but are not limited to, micro-code or micro-instructions, machine instructions, such as produced by a compiler, code used to produce a web service, and files containing higher-level instructions that are executed by a computer using an interpreter. Additional examples of computer code include, but are not limited to, control signals, encrypted code, and compressed code.

[0147] Generally, the pulsed electric field device described here may comprise a memory configured to store data and / or information. In some variations, the memory may comprise one or more of a random access memory (RAM), static RAM (SRAM), dynamic RAM (DRAM), a memory buffer, an erasable programmable read-only memory (EPROM), an electrically erasable read-only memory (EEPROM), a read-only memory (ROM), flash memory, volatile memory, nonvolatile memory, combinations thereof, and the like. In some variations, the memory may store instructions to cause the processor to execute modules, processes, and / or functions associated with a 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. Somevariations described herein may relate to a computer storage product with a non-transitory computer-readable medium (also may be referred to as a non-transitory processor-readable medium) having instructions or computer code thereon for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include transitory propagating signals per se (e.g., a propagating electromagnetic wave carrying information on a transmission medium such as space or a cable). The media and computer code (also may be referred to as code or algorithm) may be those designed and constructed for the specific purpose or purposes.EXAMPLE

[0148] The duodenum is an organ that plays an important role in nutrient sensing and iron absorption, and which also influences the incretin response and pathology of Type 2 diabetes. Accordingly, dysrcgulatcd iron homeostasis and duodenal inflammation may be potential targets of pulsed electric field therapy. In this example, a study is described that evaluates Endoscopic Re- Cellularization via Electroporation Therapy (ReCET™) using non-thermal pulsed electric fields (PEF) for duodenal regeneration in Type 2 diabetes.

[0149] In the study, participants (aged 18-70 years, BMI 24-40 kg / m2, HbAlc 7.5%-l 1.0%, on 1- 4 non-insulin anti-diabetics) received endoscopic PEF therapy in the duodenum. The primary endpoints were serious adverse events at 12 weeks, with secondary endpoints including efficacy, glycemic changes, and response predictors (e.g., Time In Range (percentage of time that a patient spends with their blood glucose levels in a target range) (TIR), % Total Body Weight Loss (%TBWL), HOMA-IR (Homeostatic Model Assessment of insulin resistance), serum triglyceride levels, and ferritin levels) at 24 weeks. Seventy-one (71) patients (average age 53.6, 73% male, BMI 31.7 kg / m2, Type 2 diabetes duration 5.8 years, baseline HbAlc 8.6%) participated. Treatment groups received either low or high energy doses. Significant adverse effects did not occur.

[0150] Results from the study showed a significant glycemic improvement in the high energy group (-1.11 HbAlc reduction vs. -0.32 in the low energy group, p=0.015) (data not shown), as well as improved (TIR), %TBWL, HOMA-IR, serum triglyceride levels, and ferritin levels, indicating that endoscopic PEF therapy in the duodenum may improve glycemic control in Type 2 diabeteswithout significant adverse effects, and without impacting weight, lipid profile, and iron metabolism. FIGS. 7A-7C illustrate that baseline serum ferritin levels and baseline HbAlc levels at 24 weeks after an intestinal procedure may be predictors of a positive response, i.e., an improvement in HbAlc level. A subgroup of patients treated with high energy having a baseline ferritin level of greater than or equal to 200 and a HbAlc level of greater than or equal to 8% showed a -2.04 (95% CI -3.94, -0.14) HbAlc reduction at 24 weeks (data not shown).

[0151] It should be understood that the examples and illustrations in this disclosure serve exemplary purposes and departures and variations such as the number of electrodes and devices, and so on can be built and deployed according to the teachings herein without departing from the scope of this invention.

[0152] 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 near’ to a recited numerical value and / or range. In some instances, the terms “about” and “approximately” may mean within ± 10% of the recited value. For example, in some instances, “about 100 [units]” may mean within ± 10% of 100 (e.g., from 90 to 110). The terms “about” and “approximately” may be used interchangeably.

[0153] The specific examples and descriptions herein are exemplary in nature and variations may be developed by those skilled in the art based on the material taught herein without departing from the scope of the present invention, which is limited only by the attached claims.

Claims

CLAIMS1. A method of predicting response to an intestinal procedure, comprising: obtaining a baseline level of a first biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition, wherein the first biomarker is ferritin; and predicting a positive response to the intestinal procedure based on the baseline level of ferritin, wherein the intestinal procedure comprises delivery of a pulsed electric field to a target tissue in an intestine and the positive response corresponds to a reduction in a level of a second biomarker of the patient.

2. The method of claim 1, wherein the metabolic disorder is one or more of obesity, Nonalcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), Type 1 diabetes, and Type 2 diabetes.

3. The method of claim 2, wherein the metabolic disorder is Type 2 diabetes.

4. The method of claim 1, wherein the inflammatory condition is one or more of rheumatoid arthritis, a thyroid disorder, and a viral infection.

5. The method of claim 1, wherein the reduction in the level of the second biomarker is predicted when the baseline level of ferritin is at least about 100 pg / L.

6. The method of claim 5, wherein the reduction in the level of the second biomarker is predicted when the baseline level of ferritin is at least about 400 pg / L.

7. The method of claim 1, wherein the second biomarker is a biomarker indicative of glycemic control.

8. The method of claim 7, wherein the biomarker indicative of glycemic control is HbAlc.

9. The method of claim 8, wherein the positive response corresponds to the reduction in the level of HbAlc by at least about 0.5%.

10. The method of claim 1, wherein predicting the positive response to the intestinal procedure is further based on a baseline HbAlc level of the patient.

11. The method of claim 9, wherein the positive response is predicted when the baseline HbAlc level is at least about 8%.

12. The method of claim 1, wherein the target tissue comprises one or more portions of the duodenum or the jejunum.

13. The method of claim 1, wherein the target tissue comprises one or more of a proximal portion of the duodenum, a proximal and a middle portion of the duodenum, and a portion of the duodenum and the jejunum.

14. The method of claim 1, wherein the intestinal procedure recellularizes at least a portion of a duodenum of the patient.

15. The method of claim 1, further comprising administering a drug therapy to the patient.

16. The method of claim 15, wherein the drug therapy is administered concurrently with the intestinal procedure.

17. The method of claim 1, further comprising performing the intestinal procedure on the patient.

18. A method for treating patients, comprising:obtaining a baseline level of a first biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition, wherein the first biomarker is ferritin; selecting the patient for treatment with an intestinal procedure based on the baseline level of ferritin, wherein the intestinal procedure comprises the delivery of energy to a target tissue in an intestine; and performing the intestinal procedure to achieve a reduction in a level of a second biomarker of the patient.

19. The method of claim 18, wherein the metabolic disorder is one or more of obesity, Nonalcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), Type 1 diabetes, and Type 2 diabetes.

20. The method of claim 19, wherein the metabolic disorder is Type 2 diabetes.

21. The method of claim 18, wherein the inflammatory condition is one or more of rheumatoid arthritis, a thyroid disorder, and a viral infection.

22. The method of claim 18, wherein selecting the patient for treatment with the intestinal procedure is based on the baseline level of ferritin being at least about 100 ng / mL.

23. The method of claim 22, wherein selecting the patient for treatment with the intestinal procedure is based on the baseline level of ferritin being at least about 400 pg / L.

24. The method of claim 18, wherein the second biomarker is a biomarker indicative of glycemic control.

25. The method of claim 24, wherein the biomarker indicative of glycemic control is HbAlc.

26. The method of claim 25, wherein the level of HbAlc is reduced by at least about 0.5%.

27. The method of claim 18, wherein selecting the patient for treatment with the intestinal procedure is further based on a baseline HbAlc level of the patient.

28. The method of claim 27, wherein the baseline HbAlc level is at least about 8%.

29. The method of claim 18, wherein the target tissue comprises one or more portions of the duodenum or the jejunum.

30. The method of claim 18, wherein the intestinal procedure recellularizes at least a portion of a duodenum of the patient.31 . The method of claim 18, further comprising obtaining a second ferritin level after performing the intestinal procedure.

32. The method of claim 31, further comprising repeating the intestinal procedure based on the second ferritin level exceeding a predetermined threshold for the patient.

33. The method of claim 31, further comprising adjusting one or more parameters of the energy delivery based on the baseline ferritin level or the second ferritin level.

34. The method of claim 33, wherein the one or more parameters comprises one or more of a voltage, an amplitude, a pulse number, and a pulse duration of the energy delivery.

35. The method of claim 31, further comprising adjusting one or more components of a device configured to perform the intestinal procedure based on the second ferritin level.

36. The method of claim 35, wherein the one or more components of the device comprises one or more of an electrode spacing and an electrode length.

37. The method of claim 18, wherein selecting the patient for treatment with the intestinal procedure is further based on one or more patient characteristics.

38. The method of claim 37, wherein the one or more patient characteristics comprises one or more of an age of the patient, a duration of the metabolic disorder, a duration of the inflammatory condition, presence of a comorbid condition, a body mass index (BMI), concurrent use of a drug therapy, and an amount of liver fat.

39. A method of predicting response to an intestinal procedure, comprising; obtaining a baseline ferritin level of a patient having Type 2 diabetes; and predicting a positive response to the intestinal procedure based on the baseline ferritin level, wherein the intestinal procedure comprises delivery of a pulsed electric field from a device comprising an expandable member and a plurality of electrodes to at least a portion of a duodenum, and wherein the positive response corresponds to a reduction in a HbAlc level of the patient.

40. The method of claim 39, wherein the baseline ferritin level is at least about at least about 200 pg / L.

41. The method of claim 39, wherein predicting the positive response to the intestinal procedure is further based on a baseline HbAlc level of the patient.

42. The method of claim 40, wherein the baseline HbAlc level is at least about 8%.

43. The method of claim 39, further comprising performing the intestinal procedure on the patient.

44. A method for treating patients, comprising: obtaining a baseline ferritin level of a patient having Type 2 diabetes; selecting the patient for treatment with an intestinal procedure based on the baseline ferritin level, wherein the intestinal procedure comprises the delivery of a pulsed electric field from adevice comprising an expandable member and a plurality of electrodes to at least a portion of the duodenum; and performing the intestinal procedure to achieve a reduction in a level of a HbAlc level of the patient.

45. The method of claim 44, wherein the baseline ferritin level is at least about at least about 200 pg / L.

46. The method of claim 44, wherein selecting the patient for treatment with the intestinal procedure is further based on a baseline HbAlc level of the patient.

47. The method of claim 46, wherein the baseline HbAlc level is at least about 8%.

48. The method of claim 43, further comprising obtaining a second ferritin level after performing the intestinal procedure.

49. The method of claim 47, further comprising repeating the intestinal procedure based on the second ferritin level exceeding a predetermined threshold for the patient.

50. A method of predicting response to an intestinal procedure, comprising; obtaining a baseline level of an inflammatory biomarker of a patient having one or more of a metabolic disorder and an inflammatory condition; and predicting a positive response to the intestinal procedure based on the baseline level of the inflammatory biomarker, wherein the intestinal procedure comprises delivery of a pulsed electric field to a target tissue in an intestine and the positive response corresponds to a reduction in a level of a second biomarker of the patient.

51. The method of claim 50, wherein the inflammatory biomarker is ferritin.

52. The method of claim 50, wherein the second biomarker is HbAlc.

53. The method of claim 50, wherein the metabolic disorder is Type 2 diabetes.

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