Electroporation for the treatment of obesity or diabetes

Abstract

This invention provides intraluminal devices and methods that can be used for the treatment of health conditions, including obesity and diabetes. [Solution] The method and system reduce weight or control diabetes by decreasing an individual's calorie absorption. For example, obesity and diabetes are treated by regulating the duodenal mucosa using electroporation. Furthermore, a portion of the digestive tract is bypassed to reduce nutrient intake.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Patent Application No. 62 / 238,191, filed on October 7, 2015. The disclosure of the prior application is considered to be a part of (and incorporated by reference in) the disclosure of this application.

[0002] 1. Technical Field This document relates to devices and methods for the treatment of health conditions including obesity and diabetes. For example, this document relates to devices and methods for treating obesity and diabetes using endoscopic electroporation.

Background Art

[0003] Obesity is a worldwide problem that transcends age, ethnicity, and socioeconomic boundaries. Generally, obesity means having too much body fat. Morbid obesity is a serious health condition that can interfere with basic physical functions such as breathing or walking. Individuals with morbid obesity are at high risk of developing diseases including diabetes, hypertension, sleep apnea, gastroesophageal reflux disease, infertility, low back pain, asthma, gallstones, osteoarthritis, heart disease, and cancer. Billions of dollars are spent every year to treat millions of people around the world who suffer from such diseases. Many people suffering from morbid obesity feel that it is almost impossible to lose weight through diet restriction and exercise.

[0004] Type 2 diabetes is a chronic condition that affects how the body metabolizes sugar (glucose). In type 2 diabetes, the body either resists the effects of insulin, a hormone that regulates the movement of sugar into cells, or fails to produce enough insulin to maintain normal glucose levels. While type 2 diabetes is more common in adults, its prevalence in children is increasing as childhood obesity rises. There is no established cure for type 2 diabetes. In some cases, the condition is managed by a healthy diet, exercise, and maintaining a healthy weight. If blood sugar levels cannot be adequately controlled through diet and exercise, diabetes medications and / or insulin therapy may be necessary.

[0005] Ablation / electroporation therapy is a type of minimally invasive procedure used to destroy tissue associated with various conditions. For example, ablation can be used to treat tumors or destroy cardiac tissue that causes tachycardia. Ablation therapy may be performed using a probe inserted through the skin or a flexible tube (catheter) inserted through a body tube, or by delivering an energy beam to the area to be treated. Imaging techniques can be used to induce ablation. Tissue is damaged or destroyed by heat (e.g., radiofrequency ablation), cryogenic (cryoexcision), laser, or chemicals. [Overview of the Initiative] [Means for solving the problem]

[0006] This document provides devices and methods for treating health conditions, including obesity and diabetes. In some embodiments, the methods and systems disclosed herein can reduce weight and / or control diabetes by reducing an individual's calorie absorption, increasing levels of intestinal hormones important for appetite regulation and insulin secretion, and / or reshaping the mucosa of the small intestine. For example, this document provides several devices and methods for treating obesity and diabetes by modifying the duodenal mucosa using electroporation. Furthermore, this document provides devices and methods for reducing nutrient intake by bypassing a portion of the gastrointestinal tract (GI).

[0007] In one aspect, the electroporation device includes a shaft defining a first lumen through which it passes; a proximal balloon mounted around the distal portion of the shaft; an intermediate portion extending distal to the proximal balloon; and a distal balloon extending distal to the intermediate portion. The intermediate portion defines an intermediate lumen communicating with the first lumen. The intermediate portion includes one or more electrodes configured to provide electroporation energy. The intermediate portion includes one or more apertures penetrating the walls of the intermediate portion and communicating with the intermediate lumen. The intermediate portion has a longitudinally contracted state and a longitudinally expanded state which is longer than the longitudinally contracted state. In some embodiments, the length of the intermediate portion is fixed.

[0008] This electroporation device may optionally include one or more of the following features: The distal balloon may have an internal distal balloon lumen that communicates with the intermediate lumen. The distal balloon lumen may be defined by a distal shaft around which the distal balloon is mounted. The shaft may define a proximal balloon inflation lumen that communicates with the proximal balloon. The shaft and intermediate section may define a distal balloon inflation lumen that communicates with the distal balloon. The intermediate section may include an accordion configuration that changes the configuration of the intermediate section between a longitudinally contracted state and a longitudinally expanded state. The first lumen and the intermediate lumen may receive an endoscope or pass through the working channel of the endoscope. The catheter may pass over a guidewire under endoscopic and / or fluoroscopic guidance.

[0009] Another aspect of the method for delivering electroporation energy to a patient includes deploying an electroporation device at a target location within the patient, energizing one or more electrodes to supply electroporation energy, and supplying a conductive liquid to the electroporation device while energizing one or more electrodes, so that the conductive liquid flows through one or more apertures. The electroporation device includes a shaft defining a first lumen through which it passes; a proximal balloon mounted around the distal portion of the shaft; an intermediate portion extending distal to the proximal balloon; and a distal balloon extending distal to the intermediate portion. The intermediate portion defines an intermediate lumen communicating with the first lumen. The intermediate portion includes one or more electrodes configured to provide electroporation energy. The intermediate portion includes one or more apertures penetrating the walls of the intermediate portion and communicating with the intermediate lumen. The intermediate portion has a longitudinally retracted state and a longitudinally expanded state which is longer than the longitudinally retracted state. In some embodiments, the length of the intermediate section is fixed.

[0010] This method of delivering electroporation energy to a patient may optionally include one or more of the following features: The target site may be the duodenum or jejunum. The method may further include inflating the proximal and distal balloons before supplying conductive fluid to the electroporation device. The method may further include expanding the intermediate section and reconfiguring it from a longitudinally contracted state to a longitudinally expanded state before supplying conductive fluid to the electroporation device. The conductive fluid may deliver electroporation energy to the patient's tissue from one or more electrodes. The method may further include attaching an endoscope shaft to the first lumen and the intermediate lumen, and deploying the electroporation device and / or injecting conductive fluid using a single-channel or dual-channel endoscope. The catheter may be guided along a guidewire under endoscopic and / or fluoroscopic guidance.

[0011] In other aspects, the electroporation device includes a shaft defining a lumen through which it passes; a balloon mounted around the distal portion of the shaft, with a longitudinal length of 5 to 20 cm; and one or more electrodes positioned on the outer surface of the balloon. The lumen is configured to receive an endoscope into it. In some embodiments, the balloon is formed from a porous material that allows a conductive liquid to pass through. The catheter may pass over a guidewire under endoscopic and / or fluoroscopic guidance.

[0012] Another aspect of the treatment method involves deploying an electroporation device to a target location within the patient's intestines. The electroporation device comprises a shaft defining a first lumen through which it passes; a distal balloon attached around the distal portion of the shaft; a middle section extending proximal to the distal balloon and to which an electroporation electrode is attached; and an overtube having a proximal balloon delivered via a single-channel or dual-channel endoscope, which can be inflated and deflated independently of the distal balloon. The electroporation catheter passes through the working channel of the single-channel or dual-channel endoscope to deliver the treatment to the target tissue. The inflated distal balloon on the electroporation catheter and the inflated proximal balloon on the overtube on the endoscope provide a seal for forming a column of conductive fluid injected through the working channel of the endoscope.

[0013] Another aspect of the treatment method involves deploying an electroporation device to a targeted location within the patient's intestines. The electroporation device / catheter includes a shaft defining a first lumen through which the device passes; this shaft is balloon-free, and only electrodes are delivered via the working channel of a single-channel or dual-channel endoscope. An overtube, separated by tissue support structures and having two balloons (proximal and distal balloons) to widen the folds of the duodenum or jejunum, is delivered to the target small intestinal segment via a single-channel or dual-channel endoscope. The endoscope is retracted from the distal overtube balloon, closing a self-closing valve in the lumen of the distal portion of the overtube / distal balloon. After the proximal balloon inflates, a conductive fluid is injected through the working channel of the endoscope to form a fluid column. The electroporation catheter is then delivered to the fluid column via the endoscope to deliver the electroporation current. In one example, the tissue support structure may be a foldable / expandable stent or mesh, which, when expanded, widens the folds of the mucosa and increases the surface area of ​​the mucosa that is in contact with or exposed to the conductive fluid.

[0014] Another aspect of the treatment method for a patient involves deploying an electroporation device to a targeted location within the patient's intestines. The electroporation device includes a shaft defining a first lumen through which it passes; a proximal balloon mounted around the distal portion of the shaft; an intermediate portion extending distal to the proximal balloon; and a distal balloon extending distal to the intermediate portion. The intermediate portion defines an intermediate lumen communicating with the first lumen. The intermediate portion includes one or more electrodes configured to provide electroporation energy. The intermediate portion includes one or more apertures penetrating the walls of the intermediate portion and communicating with the intermediate lumen. The intermediate portion has a longitudinally contracted state and a longitudinally expanded state which is longer than the longitudinally contracted state.

[0015] This method for treating a patient may optionally include one or more of the following features: The method may further include energizing one or more electrodes to supply electroporation energy. The method may further include supplying a liquid to an electroporation device so that the liquid flows into the intestine through one or more apertures. The liquid may include a medicinal solution or drug. The method may further include stretching at least a portion of the intestine to increase the surface area of ​​the intestine in contact with the liquid.

[0016] This method for treating a patient may optionally include one or more of the following features: The fluid may contain a drug solution or agent that can be delivered to target intestinal cells by the process of reversible electroporation. The method may further include stretching at least a portion of the intestine to increase the surface area of ​​the intestine in contact with the fluid. The method may further include stretching the intestinal surface across an endoscopic overtube having a tissue traction structure between two balloons delivered via the endoscope to form a fluid column, thereby effectively delivering the electroporation current delivered via a catheter delivered through the working channel of the endoscope. Finally, any of the electroporation catheters described herein can be delivered on a guidewire under fluoroscopic guidance.

[0017] Certain embodiments of the subject matter disclosed herein can achieve one or more of the following advantages. In some embodiments, the methods and systems disclosed herein provide minimally invasive weight loss and / or diabetes treatment. For example, in some embodiments, electroporation of the duodenal mucosa is performed endoscopically. Such minimally invasive techniques can reduce recovery time, patient discomfort, and treatment costs. In some embodiments, the methods and systems disclosed herein can alter the body's ability to process sugar and improve blood glucose management in patients with type 2 diabetes. Furthermore, these catheters and / or overtubes can be used to resect other parts of the gastrointestinal tract where superficial mucosal resection can be applied in the treatment of metaplasia, dysplasia, etc., or superficial neoplasms of the gastrointestinal tract and / or cystic neoplasms of the pancreas, and the electroporation catheter with electrodes is delivered to the cyst via a 19-gauge endoscopic ultrasound needle under the guidance of an endoscopic ultrasound.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art relating to the present invention. While the present invention may also be carried out using methods and materials similar to or equivalent to those described herein, appropriate methods and materials are disclosed here. All publications, patent applications, patents, and other references referenced herein are incorporated herein by reference in their entirety. In the event of any conflict therein, including definitions of terms, the descriptions herein shall prevail. Furthermore, the materials, methods, and examples are illustrative and not intended to be limiting.

[0019] Details of one or more embodiments of the present invention are described in the accompanying drawings and this description. Other features, purposes and advantages of the present invention will become apparent from the description and drawings and the claims. [Brief explanation of the drawing]

[0020] [Figure 1] This is a cross-sectional view of a portion of the human digestive tract, including the stomach and duodenum. [Figure 2] A plan view showing an expanded state of a device for performing electroporation on the digestive tract (e.g., duodenum) based on some embodiments disclosed herein. [Figure 3] A plan view of the reduced delivery configuration of the device of FIG. 2. [Figure 4] A view showing the devices of FIGS. 2 and 3 deployed in the duodenum so as to provide an electroporation treatment for regulating the duodenal mucosa. [Figure 5] A plan view showing an expanded state of another device for performing electroporation on the digestive tract (e.g., duodenum) based on some embodiments disclosed herein. [Figure 6] A longitudinal sectional view showing an expanded state of another device for performing electroporation on the digestive tract (e.g., duodenum) based on some embodiments disclosed herein. [Figure 7] A view showing the devices of FIGS. 5 and 6 deployed in the duodenum so as to provide an electroporation treatment for regulating the duodenal mucosa. [Figure 8] A plan view of another device for performing electroporation on the digestive tract, which uses a proximal balloon attached to an overtube of an endoscope and in which an electroporation catheter having a distal balloon is delivered through a working channel of the endoscope to provide electroporation, based on some embodiments. [Figure 9] A view showing the device of FIG. 8 deployed in the duodenum so as to provide an electroporation treatment for regulating the duodenal mucosa. [Figure 10] A plan view of another device for performing electroporation on the digestive tract based on some embodiments. [Figure 11] A view showing the device of FIG. 10 deployed in the duodenum so as to provide an electroporation treatment for regulating the duodenal mucosa. [Figure 12]A plan view of another device for performing electroporation on the digestive tract, based on some embodiments. [Figure 13] A diagram showing the device of FIG. 12 deployed in the duodenum so as to provide an electroporation treatment for regulating the duodenal mucosa.

Mode for Carrying Out the Invention

[0021] In this specification, corresponding parts are denoted by like reference numerals.

[0022] This document provides devices and methods for the treatment of health conditions including obesity and diabetes. In some embodiments, the methods and systems disclosed herein can reduce an individual's calorie absorption, increase the levels of gut hormones important for appetite regulation and insulin secretion, and / or reform the mucosa of the small intestine, thereby reducing weight and / or controlling diabetes. For example, this document provides some devices and methods for treating obesity and diabetes by using electroporation to regulate the duodenal mucosa. Further, this document provides devices and methods for bypassing a part of the digestive tract to reduce nutrient intake.

[0023] As shown in FIG. 1, the human digestive tract portion 100 includes a stomach 110 and a duodenum 120. The inner layer of the duodenum 120 is formed by the duodenal mucosa 122. The duodenal mucosa 122 is composed of a plurality of short tubular depressions called crypts, where intestinal stem cells (cells that can differentiate into different cell types) and Paneth cells (cells that promote the activity of stem cells) are present. Also, the duodenal mucosa 122 includes villi, where enterocytes (a layer of tall rectangular cells involved in absorbing nutrients from the intestine), goblet cells (cells that produce alkaline mucus to protect the small intestine), and enteroendocrine cells (special endocrine cells of the digestive tract that produce gastrointestinal hormones important for digestion and glucose control) are present.

[0024] As further described below, we provide a device and method for performing electroporation to modulate the duodenal mucosa 122. Furthermore, the device and method for performing electroporation provided herein can also be used to modulate the depth and cellular composition of the crypts and villi of the duodenal mucosa 122. Using such a device and technique, weight loss and / or control of diabetes can be achieved by increasing gastrointestinal hormones and / or by reconstructing the affected intestinal mucosa of an individual.

[0025] An exemplary mucosal electroporation device 200 shown in Figure 2 includes a proximal shaft 210a, a proximal balloon 220, a distal balloon 230, a distal shaft 210b, and an intermediate section 240. The proximal balloon 220 is attached to the circumference of the proximal shaft 210a. The intermediate section 240 is attached to the proximal shaft 210a and extends distally from the proximal shaft 210a. The distal end of the intermediate section 240 is attached to the distal shaft 210b. The distal balloon 230 is attached to the circumference of the distal shaft 210b.

[0026] The proximal shaft 210a, the intermediate section 240, and the distal shaft 210b define the lumen 212. In some embodiments, the lumen 212 is dimensioned to slidably receive the endoscope shaft. In some embodiments, the lumen 212 is dimensioned to slidably receive the guidewire.

[0027] The proximal balloon 220 and the distal balloon 230 are inflatable components. Therefore, when an inflation medium (e.g., saline solution, water, CO2, air, etc.) is supplied to the proximal balloon 220 and the distal balloon 230, they inflate. In some embodiments, the wall of the proximal shaft 210a defines an inflation lumen for supplying the inflation medium to the proximal balloon 220. In some embodiments, (i) the wall of the proximal shaft 210a, (ii) the wall of the intermediate section 240, and (iii) the wall of the distal shaft 210b define an inflation lumen for supplying the inflation medium to the distal balloon 230. Therefore, in some embodiments, the inflation and deflation of the proximal balloon 220 and the distal balloon 230 can be controlled separately. Alternatively, in some embodiments, the inflation and deflation of the proximal balloon 220 and the distal balloon 230 are controlled integrally. In some embodiments, the mucosal electroporation device 200 can pass through the working channel of the endoscope while the balloons 220 and 230 are deflated.

[0028] The proximal balloon 220 and distal balloon 230 are flexible, elastic, and adaptable balloon members. In some embodiments, the proximal balloon 220 and distal balloon 230 are formed from silicone, latex, or other types of conformable materials. Thus, when inflated, the proximal balloon 220 and distal balloon 230 conform to the shape of the digestive tract. Thus, when inflated, the proximal balloon 220 and distal balloon 230 substantially seal the wall of the digestive tract. In some embodiments, the proximal balloon 220 and distal balloon 230 are made from the same material, but in some other embodiments, the proximal balloon 220 and distal balloon 230 are made from different materials.

[0029] In some embodiments, the maximum inflated outer diameter of the proximal balloon 220 and / or distal balloon 230 is approximately 30 mm to approximately 50 mm. The maximum inflated outer diameters of the proximal balloon 220 and distal balloon 230 are scalable to any suitable size. For example, in some embodiments, the maximum inflated outer diameters of the proximal balloon 220 and / or distal balloon 230 are approximately 35 mm to approximately 45 mm, approximately 40 mm to approximately 50 mm, approximately 30 mm to approximately 40 mm, approximately 25 mm to approximately 35 mm, or approximately 30 mm to approximately 60 mm. In some embodiments, the maximum outer diameters of the proximal balloon 220 and distal balloon 230 are equal to each other. In some embodiments, the maximum outer diameters of the proximal balloon 220 and distal balloon 230 are not equal.

[0030] As will be further described below, the distal shaft 210b or distal balloon 230 includes a valve 232 located within the lumen 212. The valve 232 allows the passage of instruments (e.g., endoscopes or guidewires). However, when such instruments are not in contact with the valve 232, the valve 232 functions as a closure at the distal end of the lumen 212, and the lumen 212 is closed at or near the distal balloon 230.

[0031] The intermediate section 240 is stretchable in the longitudinal direction and has lateral flexibility and pliability. In the embodiment shown in the figure, the intermediate section 240 is configured as an accordion member having a plurality of folds and a plurality of flexible and stretchable portions 242. In some embodiments, the intermediate section 240 has other configurations that are stretchable in the longitudinal direction and flexible in the transverse direction. For example, but not limited to, in some embodiments, the intermediate section 240 is configured as a coil (e.g., helical), an elastic member, a foldable member, a roll-up member, a nesting member, and combinations thereof.

[0032] In some embodiments, the intermediate section 240 has a length of approximately 30 cm when fully extended in the longitudinal direction. The length of the intermediate section 240 when fully extended in the longitudinal direction is scalable to any suitable size. For example, in some embodiments, the length of the intermediate section 240 when fully extended in the longitudinal direction is approximately 25 cm to approximately 35 cm, approximately 30 cm to approximately 40 cm, approximately 20 cm to approximately 30 cm, approximately 15 cm to approximately 35 cm, or approximately 25 cm to approximately 50 cm.

[0033] The intermediate section 240 is configured to assist electroporation. Therefore, the intermediate section 240 includes one or more electrodes 244. The electrodes 244 may be of different types, and / or the electrodes 244 may be configured to deliver different types of energy in different embodiments of the electroporation device 200. For example, in the illustrated embodiment, the electrode 244 is a DC electrode. Alternatively or in addition thereto, the mucosal electroporation device 200 may be configured to deliver other types of electroporation energy, such as, for example, radio frequency (RF), AC, cryogenic, chemicals, etc. In some embodiments, these energy sources may be used in combination within a single embodiment of the electroporation device 200 (for example, in some embodiments, RF and DC are used in combination). The electroporation energy may be unipolar or bipolar. The electrode 244 can be electrically connected to an electroporation energy source (not shown) located outside the patient. In some specific examples, two or more types of electroporation energy sources can be connected to the electrode 244. For example, in one specific, non-limiting example, both an RF source and an AngioDynamics NANOKNIFE® irreversible electroporation system are connected to electrode 244, and a switchbox is used to select between the two energy sources.

[0034] Furthermore, the intermediate section 240 includes one or more apertures 246. The apertures 246 are openings that penetrate the walls of the intermediate section 240, thereby allowing the lumen 212 to fluidly communicate with the outside of the electroporation device 200 through the apertures 246. Alternatively or in addition to this, in some embodiments, the material comprising the intermediate section 240 is porous, thereby allowing the lumen 212 to fluidly communicate with the outside of the mucosal electroporation device 200 through the pores of the material. As will be further described below, the apertures 246 provide a passage for a conductive fluid that transports electroporation energy from the electrode 244 to the wall of the tissue structure (e.g., the duodenum) in which the electroporation device 200 resides.

[0035] As shown in Figure 3, in some embodiments, the electroporation device 200 can be configured in a contracted state for deployment that minimizes invasiveness to the gastrointestinal tract. For example, in the configuration shown in this figure, the electroporation device 200 is positioned on an endoscope 300 (only the distal end of the endoscope 300 is shown in the figure), and the electroporation device 200 is in a radially and longitudinally contracted state (compared to the radially and longitudinally expanded state in Figure 2). The endoscope 300 is positioned within a lumen 212. The proximal balloon 220 and distal balloon 230 are contracted, and their outer diameters are reduced compared to their outer diameters when inflated. The intermediate section 240 is longitudinally contracted (compared to the longitudinally expanded state in Figure 2). In this configuration, the electroporation device 200 is configured to be deployed endoscopically into the patient's gastrointestinal tract using the endoscope 300.

[0036] In some embodiments, the electroporation device 200 is configured to be deployed via a working channel of an endoscope or laparoscope. In some embodiments, the electroporation device 200 is configured to be deployed on a guidewire instead of an endoscope 300. One or more radiopaque markers or echogenic markers, or both, may be placed at one or more locations or on one or more parts of the electroporation device 200 (e.g., on balloons 220 and / or balloons 230).

[0037] As shown in Figure 4, the electroporation device 200 can be deployed into the duodenum 120 to provide the patient with electroporation treatment. The electroporation device 200 can treat obesity and diabetes by modifying the duodenal mucosa 122 using electroporation.

[0038] Here, the electroporation device 200 is shown after the removal of a delivery device such as the endoscope 300 (Figure 3). In some deployment techniques, the endoscope 300 is used to position the distal balloon 230 at a desired location within the duodenum 120 or distal small intestine (e.g., jejunum). In some deployment techniques, the electroporation device 200 is positioned within the working channel of the endoscope. Next, the distal balloon 230 is inflated to temporarily fix it in the desired position. Then, the endoscope 300 is withdrawn proximally. This causes the middle section 240 to extend longitudinally and bend laterally within the duodenum 120. Once the proximal balloon 220 is positioned at the desired location within the duodenum 120, the proximal balloon 220 is inflated, thereby temporarily fixing it in the desired position. The endoscope 300 can then be withdrawn further proximally (may be completely removed from the electroporation device 200).

[0039] When fully deployed, the proximal balloon 220 inflates, occluding the proximal portion of the duodenum 120, and the distal balloon 230 inflates, occluding the distal portion of the duodenum 120. The internal space of the duodenum 120 defined between the proximal balloon 220 and the distal balloon 230 is substantially sealed off from the rest of the digestive tract 100.

[0040] With balloons 220 and 230 inflated, conductive liquid 400 can be delivered into the internal space between balloons 220 and 230 by injection through lumen 212 and aperture 246 (see Figure 2). In some specific examples, physiological saline is used as conductive liquid 400. In some specific examples, hypertonic saline is used as conductive liquid 400. In some specific examples, dextrose is used as conductive liquid 400. Other types of conductive liquid 400 can also be used. Conductive liquid 400 can include, but is not limited to, cation-rich solutions of various concentrations of sodium ions, potassium ions, calcium ions, magnesium ions, etc., for example, 3% sodium chloride, calcium chloride, calcium carbonate, potassium chloride, potassium carbonate, etc. Similarly, ionized known medicinal solutions or drugs used for both stimulation, regeneration, and other targeted therapies for obesity and diabetes may be injected into the internal space between balloons 220 and 230 for delivery into target cells, for example, into cells of the duodenal mucosa. Electroporation and / or current sources serve as vehicles for intracellular delivery, and electron transfer of electroporation energy is achieved by ionization of these solutions. In some specific examples, combinations of different types of drugs and / or other types of conductive liquids are used.

[0041] Electrode 244 can be energized to provide a source of electroporation energy. The conductive liquid 400 in the internal space between balloons 220 and 230 transports electrical energy from electrode 244 to the duodenal mucosa 122. The pressure of the conductive liquid 400 in the internal space needs to be adjusted to be sufficiently high so that the conductive liquid 400 is pushed into the crypts of the duodenal mucosa 122.

[0042] In some specific examples, a sequential ablation technique is used, in which saline and dextrose are sequentially circulated in the internal space while electroporation energy is supplied between balloons 220 and 230. This is a mechanical method that achieves stepwise ablation that minimizes sloughing and substantially prevents bleeding or stricture. Here, stepwise delivery is performed using a time sequence with two pre-timed pump sets. In this setup, the first pump continuously injects saline, and the second pump, via a tube, varies the supply rate of dextrose or Ringer's lactate solution. The electroporation source may be kept constant, or two or more electrodes may be provided along the electroporation device 200 to realize a more standard electronic phasing circuit.

[0043] In some embodiments, a hydrogel is used to electrically transport the electroporation energy. In some cases, the hydrogel can prolong the effect of the electroporation energy on the duodenal mucosa 122, including within the crypts of the duodenal mucosa 122.

[0044] In some embodiments, the proximal balloon 220 is used to cover the ampulla and protect it during electroporation. Therefore, in some embodiments, the proximal balloon 220 is highly adapted to thus protect the ampulla.

[0045] After performing electroporation using the electroporation device 200 and conductive liquid 400, the delivery of electroporation energy can be stopped. Next, the balloons 220 and 230 can be deflated, and the electroporation device 200 can be removed from the patient's gastrointestinal tract 100.

[0046] Figure 5 shows another embodiment of the electroporation device 500. The electroporation device 500 includes a balloon 510, a shaft 520, and one or more electrodes 530. The balloon 510 is mounted on the circumference of the shaft 520. The electrodes 530 are positioned on the outer surface of the balloon 510.

[0047] The shaft 520 defines a lumen 522 similar to the lumen 212 of the electroporation device 200. In some embodiments, the shaft 520 defines one or more apertures 526. These apertures 526 allow a conductive liquid to flow from the lumen 522 into the internal space of the balloon 510. Such a conductive liquid is optional. That is, in some embodiments, the electrode 530 delivers electroporation energy to the duodenal mucosa 122 without using a conductive liquid.

[0048] The balloon 510 can be made from the same material as described above for the balloons 220 and 230 of the electroporation device 200, for example. In some embodiments, the longitudinal length of the balloon 510 is approximately 15 cm. The longitudinal length of the balloon 510 is scalable to any suitable size. For example, in some embodiments, the longitudinal length of the balloon 510 is approximately 10 cm to 20 cm, approximately 15 cm to 25 cm, approximately 10 cm to 25 cm, approximately 15 cm to 20 mm, or approximately 10 cm to 15 cm. The maximum outer diameter of the balloon 510 when inflated may be the same as the dimensions described above with reference to the balloons 220 and 230 of the electroporation device 200.

[0049] In some embodiments, the electroporation device 500 is an example of a weeping balloon design. That is, the balloon 510 is formed from a partially or completely porous or microporous material, and a conductive liquid elutes, weeps, or otherwise permeates the balloon 510 to form droplets 540. Thus, the droplets 540 of the conductive liquid can deliver electroporation energy from the electrode 530 to the duodenal mucosa 122. In some embodiments, a hydrogel is used to electrically deliver the electroporation energy. In some cases, the hydrogel enables a more sustained action of the electroporation energy with the duodenal mucosa 122, including within the crypts of the duodenal mucosa 122. The electrode 530 may be the same as the electrode 244 of the electroporation device 200 described above.

[0050] Figure 6 shows another exemplary embodiment of an electroporation device 600. The electroporation device 600 is an example of a weeping balloon design. Specifically, the electroporation device 600 includes a balloon 610 formed from a partially or completely porous or microporous material, and a conductive liquid or gel permeates the balloon 610 by dissolution, leaching, or other means to form droplets 640. The electroporation device 600 is shown along with a longitudinal cross-section of the balloon 610 to visualize the internal space defined by the balloon 610.

[0051] The electroporation device 600 includes a balloon 610, a shaft 620, and one or more electrodes 630. The balloon 610 is mounted on the circumference of the shaft 620. The electrodes 630 are positioned on the outer surface of the shaft 620. The electrodes 630 may be similar to the electrodes 244 of the electroporation device 200 described above. The size and material of the balloon 610 structure may be similar to those of the balloon 510 described above.

[0052] The shaft 620 defines a lumen 622 similar to the lumen 212 of the electroporation device 200. The shaft 620 also defines one or more apertures 626. These apertures 626 allow the conductive liquid to flow from the lumen 622 into the internal space of the balloon 610, and the conductive liquid can be energized by the electroporation energy from the electrode 630. The energized conductive liquid can then dissolve, leach, or otherwise permeate the balloon 610 to form droplets 640 that deliver the electroporation energy to the duodenal mucosa 122, including within the crypts of the duodenal mucosa 122.

[0053] As shown in Figure 7, the electroporation device 600 can be deployed within the duodenum 120 or distal to the small intestine, for example, the jejunum, thereby allowing electroporation treatment to be administered to the patient. The electroporation device 600 can treat obesity and diabetes by regulating the duodenal or distal small intestinal mucosa 122 using electroporation. A similar method can also be applied to the electroporation device 500 (Figure 5).

[0054] Here, the electroporation device 600 is shown after the removal of the endoscope 300 (Figure 3) or a delivery device such as a guidewire. In some deployment techniques, the endoscope 300 is used to position the balloon 620 at a desired location within the duodenum 120. The balloon 620 is then inflated to temporarily fix it in the desired position. The endoscope 300 can then be withdrawn further proximal (or completely removed from the electroporation device 600).

[0055] When balloon 620 is inflated, a conductive liquid can be injected into the internal space of balloon 620 by injection through lumen 622 and aperture 626 (see Figure 6). In some specific examples, physiological saline is used as the conductive liquid. In some specific examples, hypertonic saline is used as the conductive liquid. In some specific examples, dextrose is used as the conductive liquid. Other types of conductive liquids can also be used. In some specific examples, combinations of different types of conductive liquids are used.

[0056] The electrode 630 can be energized to provide a source of electroporation energy. The conductive liquid in the internal space of the balloon 610 delivers electrical energy from the electrode 630 through the wall of the balloon 610 to the duodenal mucosa 122, including the crypts of the duodenal mucosa 122.

[0057] In some embodiments, a hydrogel is used to electrically transport the electroporation energy. In some cases, the hydrogel enables a more sustained action of the electroporation energy with the duodenal mucosa 122, including within the crypts of the duodenal mucosa 122.

[0058] After performing electroporation using the electroporation device 600 and conductive liquid, the delivery of electroporation energy can be stopped. Next, the balloon 620 can be deflated, and the electroporation device 600 can be removed from the patient's gastrointestinal tract 100.

[0059] Figures 8 and 9 show another embodiment of the electroporation device 700. Using the electroporation device 700, symptoms such as obesity and / or diabetes can be treated by modifying, for example, the duodenal mucosa 122 through electroporation.

[0060] In the embodiment shown in the figure, the electroporation device 700 includes an endoscope 710, a proximal balloon 720, a distal balloon 730, and a catheter 740 including one or more electrodes 742. The proximal balloon 720 is located in the distal end region of the endoscope 710. The catheter 740 is configured to be slidably positioned within the working channel of the endoscope 710. The distal balloon 730 is attached to the distal end region of the catheter 740. The electrodes 742 are attached at multiple positions spaced apart along the length of the catheter 740.

[0061] In some embodiments, the proximal balloon 720 is attached to the distal end region of the endoscope 710 (and the endoscope 710 includes an inflation lumen). In some embodiments, the proximal balloon 720 is attached to the distal portion of a sheath (not shown), which includes an inflation lumen and defines a larger lumen that can slidably receive the endoscope 710.

[0062] Balloons 720 and 730 may be balloons having the same dimensions and configuration as, for example, balloons 220 and 230 of the electroporation device 200. Electrode 742 may be similar to electrode 244 of the electroporation device 200 described above.

[0063] The endoscope 710 includes a lumen (e.g., an irrigation lumen) through which the conductive fluid 400 can flow. When the electroporation device 700 is in use (Figure 9), the conductive fluid 400 can flow through the lumen of the endoscope 710, thereby allowing it to be present in the duodenum 120 between the proximal balloon 720 and the distal balloon 730. In this configuration, energy from the energized electrode 742 is transmitted by the conductive fluid 400 to the duodenal mucosa 122, including within the crypts of the duodenal mucosa 122.

[0064] Figures 10 and 11 show another embodiment of the electroporation device 800. The electroporation device 800 can be used to modify, for example, the duodenal mucosa 122 and to treat conditions such as obesity and diabetes using electroporation. In some embodiments, the electroporation device 800 is configured to be slidably positioned within the working channel of an endoscope, thereby allowing the electroporation device 800 to be delivered via the endoscope. In some embodiments, the electroporation device 800 can slidably receive a guidewire, thereby allowing the electroporation device 800 to be delivered on the wire.

[0065] In the illustrated embodiment, the electroporation device 800 includes a catheter shaft 810, a proximal balloon 820, a distal balloon 830, one or more electrodes 812, and one or more apertures 814. The proximal balloon 820 is attached to the catheter shaft 810 at an arbitrary appropriate distance proximal to the distal end of the catheter shaft 810. The distal balloon 830 is attached to the distal end region of the catheter shaft 810. The electrodes 812 are attached at multiple spaced positions along the length of the catheter shaft 810. The apertures 814 are opened at multiple spaced positions along the length of the catheter shaft 810.

[0066] Balloons 820 and 830 may be balloons having the same dimensions and configuration as balloons 220 and 230 of the electroporation device 200. Electrode 812 may be the same as electrode 244 of the electroporation device 200 described above.

[0067] The catheter shaft 810 defines one or more apertures 814 through which the conductive fluid 400 can flow. When the electroporation device 800 is in use (Figure 11), the conductive fluid 400 can flow through the lumen of the catheter shaft 810 and exit the catheter shaft 810 through the apertures 814, thereby being present in the duodenum 120 between the proximal balloon 820 and the distal balloon 830. In this configuration, energy from the energized electrode 812 is transmitted by the conductive fluid 400 to the duodenal mucosa 122, including within the crypts of the duodenal mucosa 122.

[0068] Figures 12 and 13 show another embodiment of the electroporation device 900. The electroporation device 900 can be used to modify, for example, the duodenal mucosa 122 using electroporation to treat conditions such as obesity and diabetes.

[0069] In the illustrated embodiment, the electroporation device 900 includes an endoscope overtube 910, a proximal balloon 920, a distal balloon 930, an intermediate section 940 expandable radially and / or longitudinally, and an electroporation catheter 950 including one or more electrodes 952. The endoscope 300, together with the electroporation device 900, constitutes an electroporation device system.

[0070] The proximal balloon 920 is attached to the circumference of the overtube 910. The intermediate section 940 extends between the proximal balloon 920 and the distal balloon 930. Each of the overtube 910, the proximal balloon 920, the distal balloon 930, and the intermediate section 940 defines a lumen from which the endoscope 300 can be slidably received.

[0071] A distal valve 932 is provided within the lumen of the distal balloon 930. The valve 932 allows the passage of instruments (e.g., an endoscope 300 or a guidewire). When such instruments are not in contact with the valve 932, the valve 932 functions as a fluid closure at the distal end of the lumen, thereby closing the lumen in or near the distal balloon 930.

[0072] The electroporation catheter 950 is configured to be slidably positioned within the working channel of the endoscope 300 (as shown in Figure 13, the endoscope 300 is retracted so that its distal end is located within the proximal balloon 920). Electrodes 952 are attached at multiple spaced positions along the length of the electroporation catheter 950.

[0073] Balloons 920 and 930 may be balloons having the same dimensions and configuration as balloons 220 and 230 of the electroporation device 200. Electrode 952 may be the same as electrode 244 of the electroporation device 200 described above.

[0074] The intermediate section 940 is formed from a foldable mesh or porous material. Thus, the intermediate section 940 can be compressed radially and / or longitudinally (as shown in Figure 12) to deliver the electroporation device 900 to the digestive tract. Furthermore, the intermediate section 940 can be expanded radially and / or longitudinally (as shown in Figure 13), during which time the electroporation device 900 can perform electroporation to modify the duodenal mucosa 122. As shown in Figure 13, the endoscope 300 includes a lumen (e.g., an irrigation lumen) for delivering the conductive liquid 400.

[0075] As shown in Figure 13, the depth and cellular composition of the crypts and villi of the duodenal mucosa 122 can be regulated by delivering electroporation using an electroporation device 900 and an endoscope 300. Using such devices and techniques, weight loss and / or control of diabetes can be achieved by reducing calorie absorption, increasing gastrointestinal hormones, and / or reconstructing the affected intestinal mucosa of an individual.

[0076] When using the electroporation device 900, the conductive liquid 400 flows through the lumen of the endoscope 300, passes through the porous material of the intermediate section 940, and can then be present in the duodenum 120 between the proximal balloon 920 and the distal balloon 930. In this configuration, energy from the energized electrode 952 is transmitted by the conductive liquid 400 to the duodenal mucosa 122, including within the crypts of the duodenal mucosa 122. In some cases, the mechanical force applied to the duodenal mucosa 122 by the electroporation device 900 causes the irregular wall shape and / or crypts of the duodenal mucosa 122 to become flatter. Further embodiments and / or further features

[0077] In some embodiments, the electroporation devices and systems disclosed herein may include design features to prevent or suppress undesirable electrical stimulation to untargeted body structures, such as the patient's heart and / or nervous system, but are not limited to the following. For example, some embodiments may include insulating elements on or adjacent to one or more parts of the electroporation devices disclosed herein. Such insulating elements shield energy emitted from a specific subsequent pathway, protecting untargeted body structures. In some embodiments, isolated bipolar electroporation is incorporated (for example, when electrodes are mounted inside or on a balloon, and / or when separate electrodes are located in the proximal duodenum). Such electrodes can be used as an anode or cathode when the cathode or anode, which is the opposite pole, is located inside, on, or as a separate electrode located in the distal duodenum. For example, the insulating element may be an insulating coating on a particular side of a balloon, an insulated second balloon, or an air sac covering one side of the outer surface of a balloon and acting as an insulating element. In some embodiments, such insulating techniques can be used to cover one side of the outer surface of the weeping balloon. In some embodiments, the energy delivery device utilizes the curvature of the duodenum to provide the desired electroporation without excessively stimulating the duodenum. Some embodiments include bipolar electrodes (e.g., a distal electrode and a proximal electrode on the electroporation device).

[0078] When the insulating elements described above are included, further treatment may be required on the duodenal tissue adjacent to the insulated surface for external insulation. For this reason, in some embodiments, a return electrode is used for the proximal duodenum within the larger curvature of the stomach, and electrodes for the distal and intermediate duodenum are placed in the proximal jejunum or other parts of the digestive tract. These embodiments may also include alternative or additional configurations of the configurations already described, in which the return electrode may be placed in the abdomen, back, or other external locations.

[0079] In some embodiments, a unique electroporation method can be used to precisely control and supply pulsed DC current at various timings throughout the cardiac cycle, thereby avoiding or suppressing undesirable electrical stimulation to untargeted body structures. In some embodiments, continuous electroporation is performed throughout the cardiac cycle, but if a deviation or change in the cardiac rhythm is detected, a trigger (e.g., a far-field ventricular electrogram) can be used as a sensor, where energy delivery may be limited, for example, to the first 200 milliseconds following the detected far-field QRS. In some embodiments, an internal ECG sensor and an electric field sensor may be provided on the insulating surface of the electroporation device. If there is no electric field directed toward the heart, there is virtually no risk of electroporation interfering with a normal cardiac rhythm, and continuous electroporation can be performed. If there is an electric field directed toward the heart, the signal from the internal ECG sensor can be used to time the electroporation pulse supply so that pulses are not supplied during the most vulnerable phases of the cardiac rhythm.

[0080] While the embodiments described herein relate to the delivery of electroporation to duodenal cells in connection with the management of diabetes and obesity, the duodenum and adjacent parts of the gastrointestinal tract also function as unique sites beneficial for delivering electroporation and other energies to adjacent structures. Such adjacent structures include, but are not limited to, the celiac ganglion and plexus, lymph nodes and plexuses, and renal nerves and associated plexuses. Because the gastrointestinal tract is intricate and curved, bipolar electroporation can be performed by deploying distal and proximal electrodes along the gastrointestinal tract so that the electric field formed between two points covers the visceral tissues and organs along the outer pathway of the gastrointestinal tract. Thus, using some of the embodiments disclosed herein, reversible and irreversible electroporation of ganglia can deliver therapies for the treatment of conditions such as, but are not limited to, pancreatic malignancies, pancreatic and deep visceral pain, and hypertension. Such hypertension management is also useful in managing metabolic syndrome resulting from a combination of obesity, diabetes, and hypertension.

[0081] In some additional embodiments, stent devices for treating health conditions including obesity and diabetes can be realized as composite devices that combine the advantages of arranging an internal conduit covering the surface of the duodenal mucosa with the advantages of more permanent electroporation-based adjustment. By combining these two (stent and electroporation electrodes), a system for fixing the stent is realized. The conduit is substantially a covered stent, but instead of a crisscrossing diamond-shaped framework, it includes linear struts. The purpose of the linear struts is to elute a gel by electroporation, adhere to the mucosa, and provide fixation. Between the linear struts, the covered stent is not adjacent to the duodenal mucosa and therefore secretions can exit and enter the duodenal lumen. Food passes through the stent, thus realizing a two-sided approach for treating this region. Further variations may include a one-way valve positioned between linear struts, or a blood glucose sensor / RF feedback for electroporation release that titrates an ideal total energy load to the solid to maintain blood glucose levels.

[0082] Another embodiment using a stent conduit combines the advantages of electroporation with the known advantages of the Roux-en-Y method. Here, a flexible catheter including an internal lumen for a wire, an RF electrode capable of supplying energy on the central wire, and a second monorail wire is guided outside the lumen of the proximal duodenum. The catheter is then moved to enter the proximal jejunum, bent back towards the initial entry site, and the central lumen wire is grasped using a snare through the monorail lumen. This creates a rail that substantially exits and re-enters the lumen and feeds back to itself. On this wire, at least three variations are possible: a) a stent / conduit covered on the distal wire is advanced, and sutures are advanced on the proximal and distal wires to secure it, and tightened over the duodenum. b) the conduit is positioned on the proximal wire along its path, forming a substantially external anastomosis, and held in place by a similar locking mechanism. c) The two combinations described above utilize all of the following in a given patient: a conduit, a covered stent, and a locking mechanism.

[0083] In some embodiments, the stent can be prepared by a non-invasive method including a magnet or an endoscopically positioned stent, and the stent itself may be delivered by a laparoscopic technique.

[0084] Furthermore, the devices and technologies disclosed herein can be applied to situations other than the duodenum. For example, the devices and technologies disclosed herein can be applied to the distal small and large intestines, as well as to other luminal tissues, such as the gallbladder, pancreas, and the mucosa of the arteriovenous system.

[0085] Furthermore, the devices and technologies disclosed herein can be applied to induce drug electrophoresis into cells within the mucosa of the duodenum to alter their function. For example, drugs such as rapamycin, which are known to modulate the effects of Paneth cells and stem cells in the crypts of the small intestine, can be ionized using electroporation and induced into these cells. Additionally, sweetening substances known to stimulate enteroendocrine cells in the villi of the duodenum may be applied. Similarly, in some cases, tacrolimus can be used to stimulate stem cells. Thus, these devices and technologies may circulate energy alone, drugs or substances alone, or a combination thereof, to treat obesity and diabetes.

[0086] Some of the devices and methods disclosed herein may incorporate stimulating electrodes or other devices that can be used to confirm cell death or cell activity, or to measure the temperature, electric field strength, and / or charge density of delivered electroporation therapy.

[0087] Some of the devices disclosed herein, incorporating balloons or balloon-like elements, may be used to stretch the intestine, thereby not only increasing the surface area of ​​contact with crypt cells but also inducing apoptosis by creating pores in the membrane through the stretching action itself.

[0088] Some embodiments of balloon or mesh-embedded devices are designed to increase the charge density of delivery through structures such as injection ports, which can be achieved by serrated surfaces or actual expandable, small-surface-area, pointed elements. These function as actual injection ports for charge- or electrolyte-rich solutions to transfer electroporation rendering energy, or, due to their shape, as areas of high electron density or other high electrical force density, thereby minimizing the risk of electrical or thermal damage to non-target sites.

[0089] Without departing from the scope of this disclosure, one or more features described herein can be combined with one or more other features described herein to realize a hybrid device and / or method.

[0090] This specification contains many details, but these details are not to be construed as limiting the scope of the claimed or claimable invention, but rather as descriptions of specific features of specific embodiments of the invention. Several features disclosed herein in the context of separate embodiments may be combined and realized as a single embodiment. Conversely, various features disclosed in the context of a single embodiment may be embodied separately in multiple embodiments, or as any appropriate partial combination. Furthermore, although some features are described above as functioning in a certain combination, even if initially claimed in this manner, one or more features from the claimed combination may be excluded from the combination in some cases, and the claimed combination may be changed to a partial combination or a variation of a partial combination.

[0091] Similarly, while the diagrams show operations in a specific order, such operations do not necessarily need to be performed in the specific or sequential order shown to achieve the desired result, nor do they need to be performed in all the illustrated operations. In certain situations, multitasking and parallel processing may be advantageous. Furthermore, the separation of various system components in the embodiments described above is not intended to be necessary in all embodiments, and the program components and systems described herein may be integrated comprehensively as a single product or packaged into multiple products.

[0092] Specific embodiments of the subject matter of the invention have been described. Other embodiments are also within the scope of the appended claims. For example, the processes described in the claims may be performed in a different order to achieve the desired results. As an example, the processes shown in the appended figures do not necessarily require the specific order or sequence of processes shown herein to achieve the desired results. In some specific examples, multitasking and parallel processing may be advantageous.

Claims

1. Electroporation device, shaft, An inflatable balloon surrounding the distal portion of the shaft, One or more electrodes associated with the inflatable balloon, An electroporation energy source configured to be operably connected to one or more electrodes and to generate and supply a therapeutically beneficial amount of irreversible electroporation energy to the one or more electrodes, Equipped with, The one or more electrodes are positioned in contact with the target region, thereby being configured to apply a therapeutically beneficial amount of irreversible electroporation energy to the target region. Electroporation device.

2. The one or more electrodes are arranged on the outer surface of the inflatable balloon. The electroporation device according to claim 1.

3. The inflatable balloon has multiple openings, The plurality of openings are configured to deliver fluid into the internal space of the target region through the plurality of openings. The electroporation device according to claim 1.

4. The electroporation device according to claim 3, wherein the fluid includes a conductive liquid.

5. The electroporation device according to claim 3, wherein the fluid comprises a hydrogel.

6. The inflatable balloon comprises a weeping balloon, The weeping balloon is made of at least partially porous or microporous material and is configured to allow fluid to leach through the weeping balloon into the internal space of the target region. The electroporation device according to claim 1.

7. The electroporation device according to claim 6, wherein the fluid includes a conductive liquid.

8. The inflatable balloon is configured to achieve an expanded state, and when in the expanded state, the inflatable balloon is configured to bring one or more electrodes into contact with the target region. The electroporation device according to claim 1.

9. When the inflatable balloon is in the expanded state, the inflatable balloon is configured to stretch the target region. The electroporation device according to claim 8.

10. The therapeutically beneficial amount of irreversible electroporation energy supplied is non-thermal. The electroporation device according to claim 1.

11. The electroporation device according to claim 1, wherein one or more electrodes include a bipolar electrode.

12. The therapeutically beneficial amount of irreversible electroporation energy is bipolar. The electroporation device according to claim 11.

13. The therapeutically beneficial amount of irreversible electroporation energy is unipolar. The electroporation device according to claim 1.

14. The one or more electrodes include a plurality of electrodes arranged at intervals. The electroporation device according to claim 1.

15. The therapeutically beneficial amount of irreversible electroporation energy includes an electric current pulse. The electroporation device according to claim 1.

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