Methods and systems for treating one or more metabolic conditions of a patient

Abstract

Systems, devices, and methods for treating a medical condition of a patient are disclosed herein. The system includes: a catheter for insertion into the intestine, the catheter having an elongate shaft comprising a distal portion; and a functional assembly positioned on the shaft distal portion and having at least one treatment element. The at least one treatment element treats target tissue is located in the small intestine of the patient.

Description

METHODS AND SYSTEMS FOR TREATING ONE OR MORE METABOLICCONDITIONS OF A PATIENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to: United States Provisional Patent Application Serial Number 63 / 499,451 (Attorney Docket No. 41714-730.101; Client Docket No. MCT-059- PR1), entitled “Methods and Systems for Treating One or More Metabolic Conditions of a Patient”, filed May 1, 2023; the contents of which is incorporated herein by reference in its entirety for all purposes.

[0002] The subject matter of this application is related to that of: United States Patent Application Serial Number 17 / 222,480 (Attorney Docket No. 41714-703.303; Client Docket No. MCT-001-US-CON2), entitled “Devices and Methods for the Treatment of Tissue”, filed April 5, 2021; United States Patent Application Serial Number 17 / 864,855 (Attorney Docket No. 41714-704.303; Client Docket No. MCT-002-US-CON2), entitled “Heat Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed July 14, 2022; United States Patent Application Serial Number 17 / 868,076 (Attorney Docket No. 41714-705.302; Client Docket No. MCT-003-US-CON1), entitled “Tissue Expansion Devices, Systems and Methods”, filed July 19, 2022; United States Patent Application Serial Number 17 / 879,222 (Attorney Docket No. 41714-706.303; Client Docket No. MCT-004-US-CON2), entitled “Electrical Energy Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed August 2, 2022; United States Patent Application Serial Number 17 / 192,671 (Attorney Docket No. 41714-707.302; Client Docket No. MCT-005-US-CON1), entitled “Ablation Systems, Devices, and Methods for the Treatment of Tissue”, filed March 4, 2021; United States Patent Application Serial Number 17 / 568,145 (Attorney Docket No. 41714-708.302; Client Docket No. MCT-009-US-CON1), entitled “Methods, Systems and Devices for Performing Multiple Treatments on a Patient”, filed January 4, 2022; United States Patent Application Serial Number 17 / 021,798 (Attorney Docket No. 41714-709.303; Client Docket No. MCT-013-US-CON2), entitled “Methods, Systems and Devices for Reducing the Luminal Surface Area of the Gastrointestinal Tract”, filed September 15, 2020; United States Patent Application Serial Number 18 / 605,655 (Attorney Docket No. 41714-710.302; Client Docket No. MCT-023-US-CON1), entitled “Systems, Methods and Devices for Treatment of Target Tissue”, filed March 14, 2024; United States Patent Application Serial Number 18 / 467,589 (Attorney Docket No. 41714-711.304; Client Docket No. MCT-024- US-CON3), entitled “Systems, Devices and Methods for the Creation of a Therapeutic Restriction in the Gastrointestinal Tract”, filed September 14, 2023; United States PatentApplication Serial Number 16 / 742,645 (Attorney Docket No. 41714-715.301; Client Docket No. MCT-025-US), entitled “Intestinal Catheter Device and System”, filed January 14, 2020; United States Patent Application Serial Number 17 / 494,277 (Attorney Docket No. 41714-712.303; Client Docket No. MCT-027-US-CIP1-CON2), entitled “Injectate Delivery Devices, Systems and Methods”, filed October 5, 2021; United States Patent Application Serial Number 16 / 798,117 (Attorney Docket No. 41714-714.303; Client Docket No. MCT-028-US-CIP1- CON2), entitled “Systems, Devices and Methods for Performing Medical Procedures in the Intestine”, filed February 21, 2020; United States Patent Application Serial Number 18 / 526,542 (Attorney Docket No. 41714-714.305; Client Docket No. MCT-028-US-CIP2-CON3), entitled “Systems, Devices and Methods for Performing Medical Procedures in the Intestine”, filed July 23, 2021; United States Patent Application Serial Number 17 / 096,855 (Attorney Docket No. 41714-713.302; Client Docket No. MCT-029-US-CON1), entitled “Methods and Systems for Treating Diabetes and Related Diseases and Disorders”, filed November 12, 2020; United States Patent Application Serial Number 17 / 181,969 (Attorney Docket No. 41714-713.501; Client Docket No. MCT-029-US-CIP1), entitled “Methods and Systems for Treating Diabetes and Related Diseases and Disorders”, filed February 22, 2021; United States Patent Application Serial Number 17 / 516,503 (Attorney Docket No. 41714-713.304; Client Docket No. MCT-029- US-CIP1-CON2), entitled “Methods and Systems for Treating Diabetes and Related Diseases and Disorders”, filed November 1, 2021; United States Patent Application Serial Number 16 / 400,491 (Attorney Docket No. 41714-716.301; Client Docket No. MCT-035-US), entitled “Systems, Devices and Methods for Performing Medical Procedures in the Intestine”, filed May 1, 2019; United States Patent Application Serial Number 17 / 859,137 (Attorney Docket No. 41714-721.301; Client Docket No. MCT-039-US), entitled “Tissue Treatment Devices, Systems, and Methods”, filed July 7, 2022; United States Patent Application Serial Number 17 / 490,947 (Attorney Docket No. 41714-719.301; Client Docket No. MCT-040-US), entitled “Systems, Devices and Methods for Treating Metabolic Medical Conditions”, filed September 30, 2021; United States Patent Application Serial Number 17 / 942,914 (Attorney Docket No. 41714- 723.301; Client Docket No. MCT-041-US), entitled “Systems, Devices and Methods for Treating Diabetes”, filed September 12, 2022; United States Patent Application Serial Number 17 / 721,937 (Attorney Docket No. 41714-720.301; Client Docket No. MCT-050-US), entitled “Systems, Devices, and Methods for Performing Medical Procedures in the Intestine”, filed April 15, 2022; United States Patent Application Serial Number 17 / 863,016 (Attorney Docket No. 41714-722.301; Client Docket No. MCT-051-US), entitled “Automated Tissue Treatment Devices, Systems, and Methods”, filed July 12, 2022; United States Patent Application SerialNumber 18 / 062,331 (Attorney Docket No. 41714-724.301; Client Docket No. MCT-034-US), entitled “Tissue Treatment System with Fluid Delivery Console”, filed December 6, 2022; “International PCT Patent Application Serial Number PCT / US2022 / 053531 (Attorney Docket No. 41714-727.601; Client Docket No. MCT-056-PCT), entitled “Methods and Systems for Treating Mucosal Hyperplasia and other Medical Conditions of a Patient”, filed December 20, 2022; United States Provisional Patent Application Serial Number 63 / 385,717 (Attorney Docket No. 41714-728.101; Client Docket No. MCT-057-PR1), entitled “Tissue Treatment Devices, Systems, and Methods”, filed December 1, 2022; and United States Provisional Patent Application Serial Number 63 / 506,574 (Attorney Docket No. 41714-731.101; Client Docket No. MCT-060-PR1), entitled “Tissue Treatment System”, filed June 6, 2023; the contents of each of which is incorporated herein by reference in its entirety for all purposes.TECHNICAL FIELD

[0003] The embodiments disclosed herein relate generally to methods, systems, and devices for treating a patient, particularly for treating tissue of the gastrointestinal tract to provide a therapy.BACKGROUND

[0004] The current paradigm for medical therapy for type 2 diabetes (T2D) begins with improvements in diet and exercise. The vast majority of patients do not achieve sustained good glycemic control with lifestyle changes alone. Several classes of pharmacologic therapy are available, including drugs that increase insulin secretion from the pancreas, drugs that enhance the body’s sensitivity to insulin, and a variety of other drug classes. Despite these oral therapies, diabetes control will usually deteriorate over time and treatment with insulin will become necessary. All told however, a large proportion of patients remain poorly controlled despite all of these measures.

[0005] There are many reasons for the limited effectiveness of current pharmacologic interventions in the general population. First, today’s medicines may lower blood sugar but they do not address the fundamental pathogenesis of type 2 Diabetes. Second, poor compliance to complicated pharmacologic regimens is well documented and a structural barrier to better glycemic control. Third, clinical inertia on the part of physicians prevents drug regimen escalation even in patients with access to excellent medical care. Fourth, psychological resistance to insulin prevents the use of this class of agents. Fifth, hypoglycemia (and the risk thereof) limits the degree of pharmacologic intervention with which physicians and patients feelcomfort. Taken together, nearly 50% of patients remain poorly controlled throughout Europe and the United States.

[0006] Interestingly, certain forms of bariatric surgery have a profound anti-diabetic effect in ways that clinicians have only begun to appreciate and characterize. Though the mechanisms underlying this improvement in glucose homeostasis are not completely understood, certain compelling observations have been made. In particular, surgeries that divert the passage of nutrients around the duodenum (or first portion of the small intestine) appear to lead to nearly immediate, extremely durable, and weight-independent anti-diabetic effects. Because the GI tract is the largest endocrine organ in the body, the bypass of the proximal small bowel leads to hormonal changes that improve glucose homeostasis. This effect appears to occur without substantial changes in absorption from the intestine. Rather, these hormonal changes restore the ability of the liver and muscle to suppress endogenous glucose production in response to insulin, a physiologic process that is otherwise impaired in patients with diabetes.

[0007] There are two main theories as to why bypass of the proximal small bowel exerts such a strong anti-diabetic effect, both of which are likely at least partial contributors. First, some believe that the delivery of excess nutrients to the distal small bowel leads to enhanced secretion of GLP-1 (and perhaps additional related insulin secreting hormones) from the GLP-l-rich entero-endocrine cells of the terminal ileum and colon. Enhanced GLP-1 release into the blood stream after an ingested meal has a number of beneficial effects on glucose homeostasis. A second theory is that patients with diabetes acquire mucosal alterations in their proximal small bowel that contribute to insulin resistance and glucose intolerance. Data from rats and humans suggest that prolonged exposure to a Western diet leads to an increase in enteroendocrine cell numbers and subsequent gastric inhibitory peptide (GIP) after a meal. Other studies have demonstrated dysfunction of the mucosa of the small bowel in patients with diabetes, such as duodenal mucosal hyperplasia. In this way, the body’s insulin resistance arises from dysfunctional signaling produced by the proximal small bowel as a consequence of these mucosal alterations. Bypass of nutrients around the duodenum prevents dysfunctional signaling from the duodenum and therefore immediately leads to an improvement in glucose tolerance after surgery.

[0008] Unfortunately, as effective as these bariatric surgeries are, one cannot imagine that surgery can be offered to enough patients to adequately address the diabetes pandemic. There are several reasons for this limitation. The primary indication for bariatric surgery remains morbid obesity, yet most diabetics are not morbidly obese. Also, the risks (of major morbidity, mortality, and need for re-operation) from bypass surgeries are quite real and pose a significantbarrier to its wholesale adoption as a treatment for type 2 diabetes. Finally, surgery is invasive, psychologically difficult, and physically demanding. For all these reasons, only a minority of patients with diabetes currently undergoes surgery as a treatment for their diabetes.

[0009] For these and other reasons, there is a need for improved systems, devices, and methods for the treatment of diabetes and similar patient diseases and disorders.BRIEF SUMMARY

[0010] According to an aspect of the present inventive concepts, a system and / or a method for treating a medical condition of a patient comprises: a catheter for insertion into the intestine, the catheter comprising an elongate shaft comprising a distal portion; and a functional assembly positioned on the shaft distal portion and comprising at least one treatment element. The at least one treatment element is configured to treat target tissue located in the small intestine of the patient. The system and / or method is configured to treat a medical condition of the patient.[Oi l] In some embodiments, the target tissue comprises duodenal tissue. The target tissue can comprise tissue selected from the group consisting of mucosal tissue; submucosal tissue; nerve tissue; and combinations thereof.

[0012] In some embodiments, the medical condition comprises a metabolic condition. The metabolic condition can comprise insulin resistance. The metabolic condition can comprise Type 2 diabetes.

[0013] In some embodiments, the metabolic condition comprises a medical condition selected from the group consisting of: type 2 diabetes; type 1 diabetes; "Double diabetes"; gestational diabetes; hyperglycemia; pre-diabetes; impaired glucose tolerance; insulin resistance; nonalcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic dysfunction-associated steatohepatitis (MASH); obesity; obesity-related disorder; polycystic ovarian syndrome; hypertriglyceridemia; hypercholesterolemia; psoriasis; GERD; coronary artery disease (e.g., as a secondary prevention); stroke / TIA; cognitive decline or dementia (e.g., Alzheimer's); diabetic nephropathy; neuropathy; retinopathy; diabetic heart disease and / or heart failure; and combinations thereof.

[0014] In some embodiments, the at least one treatment element comprises one, two, or more treatment elements selected from the group consisting of: ablative fluid delivered to a balloon or other expandable fluid reservoir; ablative fluid comprising at least steam delivered directly or indirectly to tissue; an energy delivery element mounted to an expandable functional assembly such as an electrode or other energy delivery element configured to deliver radiofrequencyenergy and / or microwave energy; an electrode or other energy delivery element configured to deliver electroporation energy, such as reversible and / or irreversible electroporation energy; an electrode, fluid delivery element, and / or other delivery element configured to deliver both reversible electroporation energy and an agent such as a tissue ablating agent whose ablation can be triggered and / or enhanced with the delivery of electroporation energy; light delivery element configured to deliver laser or other light energy; fluid delivery element, such as a needle or nozzle, configured to deliver a necrosis-causing fluid and / or other ablative fluid directly onto and / or into tissue; sound delivery element such as an ultrasonic and / or subsonic sound delivery element; and combinations thereof.

[0015] In some embodiments, the functional assembly is constructed and arranged to transition between a first geometry comprising a first coiled geometry and a second geometry. The functional assembly can be constructed and arranged to self-expand, manually expand, and / or controllably expand. The functional assembly can be constructed and arranged to self-compact, manually compact, and / or controllably compact. The second geometry can comprise a relatively straight geometry. The functional assembly can be resiliently biased in the first geometry. The functional assembly can be resiliently biased in the second geometry. The second geometry can comprise a second coiled geometry, and the first coiled geometry can comprise a first diameter, and the second coiled geometry can comprise a second diameter that is larger than the first diameter. The functional assembly can be resiliently biased in the first geometry. The functional assembly can be resiliently biased in the second geometry. The functional assembly can comprise two tubes constructed and arranged in a side-by-side geometry. The functional assembly can comprise a flat ribbon. The at least one treatment element can comprise one, two, or more electrodes. The one, two, or more electrodes can be configured to deliver electroporation energy. The one, two, or more electrodes can be configured to deliver irreversible electroporation energy. The at least one treatment element can comprise one, two, or more elements selected from the group consisting of electrode such as an electrode configured to deliver RF energy and / or electroporation energy; a fluid delivery element such as a needle, fluid jet, nozzle, and / or other fluid delivery element configured to deliver an ablative fluid onto and / or into tissue; a light delivery element; a sound delivery element such as an ultrasound delivery element; a heat energy delivery element; a cryogenic energy delivery element; and combinations thereof.

[0016] In some embodiments, the treatment element is configured to treat a set of one, two, or more axial segments of the duodenum of the patient. The one, two, or more axial segments of the duodenum collectively can comprise at least 10%, at least 15%, at least 20%, at least 25%, atleast 30% or at least 50% of the length of the duodenum distal to the ampulla of Vater. At least 50% of the surface area of each axial segment can be ablated and / or otherwise caused to necrose. The one, two, or more axial segments of the duodenum can collectively comprise at least 50% of the length of the duodenum distal to the ampulla of Vater.

[0017] In some embodiments, the patient selected for treatment comprises one, two, three, and / or all of the following criteria: age between 21 and 70 years; BMI of between 24 and 40kg / m2; a background of use of glucose lowering agents; an HbAlc level of between 7.5 and 9.5%; an FPG off insulin level of greater than or equal to 180mg / dL and less than 270mg / dL; a fasting C-peptide level of greater than or equal to 0.6 ng / ml; and / or a daily long-acting insulin requirement of between 20 and 60 U / day. The treatment of the target tissue by the system can result in one, two, three, or all of the following effects on the patient: a reduction in total body weight of approximately -9.3%; a reduction in HbAlc levels of approximately -1.5%; a reduction in FPG off insulin level of approximately 82 mg / dL; and / or a reduction in daily long- acting insulin requirement.

[0018] In some embodiments, the system and / or method is configured to provide a therapeutic benefit selected from the group consisting of: a reduction from pre-treatment in expression of SGLT1 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT5 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; and combinations thereof.

[0019] In some embodiments, the system and / or method is configured to provide at least two therapeutic benefits selected from the group consisting of: a reduction from pre-treatment in expression of SGLT1 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; and / or a reduction in expression of GLUT5 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%.

[0020] In some embodiments, the system and / or method is configured to provide the following three therapeutic benefits: a reduction from pre-treatment in expression of SGLT1 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; and a reduction in expression of GLUT5 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%.

[0021] In some embodiments, the system and / or method is configured to provide a therapeutic benefit selected from the group consisting of: a reduction in expression of SGLT1 transporters inthe enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT5 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; and combinations thereof.

[0022] In some embodiments, the system and / or method is configured to provide at least two therapeutic benefits selected from the group consisting of: a reduction in expression of SGLT1 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40% or 50%; a reduction in expression of GLUT2 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; and / or a reduction in expression of GLUT5 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%.

[0023] In some embodiments, the system and / or method is configured to provide the following three therapeutic benefits: a reduction in expression of SGLT1 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; and a reduction in expression of GLUT5 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%. The patient selected for treatment can comprise one, two, three, and / or all of the following criteria: presence of diabetes; daily long-acting insulin requirement of between 20 units and 60 units; receives metformin; and / or an HbAlc level of greater than 7.5. After the tissue treatment the patient receives a pharmaceutical treatment of SGLT2i / Empagliflozin comprising a lOmg initial dose given to the patient on Day 1 after the tissue treatment, and the dose is increased to 25mg by Day 15 post the tissue treatment. The patient can receive an administration of GLP-1 after the tissue treatment.

[0024] In some embodiments, the at least one treatment element is configured to treat the target tissue by delivering electrical energy to the target tissue. The delivery of the electrical energy can be configured to irreversibly electroporate the cells of the target tissue. The functional assembly can comprise a coil-shaped geometry. The functional assembly can be constructed and arranged to transition between a compact coiled geometry and an expanded coiled geometry.

[0025] The technology described herein, along with the attributes and attendant advantages thereof, will best be appreciated and understood in view of the following detailed description taken in conjunction with the accompanying drawings in which representative embodiments are described by way of example.INCORPORATION BY REFERENCE

[0026] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The content of all publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety for all purposes.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The foregoing and other objects, features, and advantages of embodiments of the present inventive concepts will be apparent from the more particular description of preferred embodiments, as illustrated in the accompanying drawings in which like reference characters refer to the same or like elements. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the preferred embodiments.

[0028] Fig. 1 illustrates a schematic view of a system for treating target tissue of a patient, consistent with the present inventive concepts.

[0029] Figs. 1A and IB illustrate side views of the distal portion of two embodiments of a tissue treatment device, consistent with the present inventive concepts.

[0030] Figs. 2A-2D illustrate side views of an embodiment of a tissue treatment device comprising a coiled functional assembly, consistent with the present inventive concepts.

[0031] Fig. 3 illustrates a flow chart of a method for treating target tissue of a patient, consistent with the present inventive concepts.

[0032] Fig. 4 illustrates a side sectional view of the distal portion of a tissue treatment device inserted into a curvilinear section of duodenum, consistent with the present inventive concepts.

[0033] Figs. 4A, 4B and 4C illustrate perspective, side, and end views, respectively, of an expandable element comprising a balloon, consistent with the present inventive concepts.

[0034] Fig. 5 illustrates a side sectional view of the distal portion of a tissue treatment device including an agent dispensing element, consistent with the present inventive concepts.

[0035] Figs. 5A-5E illustrate side sectional views of a series of steps for treating a surface of gastrointestinal tissue using the tissue treatment device of Fig. 5, consistent with the present inventive concepts.

[0036] Fig. 6 illustrates a schematic view of a system for treating target tissue of a patient, consistent with the present inventive concepts.

[0037] Fig. 7 illustrates a schematic view of a system for performing a medical procedure in the intestine of a patient, consistent with the present inventive concepts.

[0038] Fig. 8 illustrates a flow chart of a method for performing a medical procedure in the intestine of a patient, consistent with the present inventive concepts.

[0039] Fig. 8A illustrates a flow chart of a method for performing a medical procedure in the intestine of a patient, consistent with the present inventive concepts.

[0040] Fig. 9 illustrates a schematic view of a system for performing a medical procedure in the intestine of a patient, consistent with the present inventive concepts.

[0041] Figs. 10 and 10A-10B illustrate an anatomic view of a system for performing a medical procedure comprising a catheter and a sheath for inserting the catheter into the intestine of the patient, consistent with the present inventive concepts.

[0042] Fig. 11 illustrates a sectional view of the distal portion of a system for performing a medical procedure including an endoscope and a tissue treatment device inserted into a duodenum of a patient, consistent with the present inventive concepts.

[0043] Figs. 12A-12B illustrate end and side views of the distal portion of a catheter including recessed ports and a shaft-located vacuum port, consistent with the present inventive concepts.

[0044] Fig. 13 illustrates a flow chart of a method of treating a patient, consistent with the present inventive concepts.

[0045] Fig. 14 illustrates a flow chart of a method of preparing a treatment device, consistent with the present inventive concepts.

[0046] Fig. 15 illustrates a flow chart of a method of expanding tissue with a treatment device, consistent with the present inventive concepts.

[0047] Fig. 16 illustrates a flow chart of a method of ablating or otherwise treating tissue with a tissue treatment device, consistent with the present inventive concepts.

[0048] Figs. 17-20D illustrate results from studies conducted by applicant to investigate the safety and efficacy of a duodenal mucosal ablation procedure on glycemic and hepatic parameters in patients with type 2 diabetes (T2D), consistent with the present inventive concepts.

[0049] Fig. 21 is a chart showing the number of patients receiving numbers of treatments, consistent with the present inventive concepts.

[0050] Fig. 22 is a table of cumulative demographic information, consistent with the present inventive concepts.

[0051] Fig. 23 illustrates a table showing results of applicant’s studies, consistent with the present inventive concepts.

[0052] Fig. 24 illustrates a graph illustrating HbAlc reductions in patients receiving three or more ablations, consistent with the present inventive concepts.

[0053] Fig. 25 illustrates a graph illustrating reduction in FPG levels, consistent with the present inventive concepts.

[0054] Fig. 26 illustrates a graph illustrating improvement in 2hPG measurements, consistent with the present inventive concepts.

[0055] Fig. 27 illustrates a graph showing treatment response rates, consistent with the present inventive concepts.

[0056] Fig. 28 illustrates a graph of HbAlc percentages measured for at least 120 days post treatment, consistent with the present inventive concepts.

[0057] Fig. 29 illustrates a graph of fasting insulin change data over a 3-month period, consistent with the present inventive concepts.

[0058] Fig. 30 illustrates a graph of SF-36 mental value changes, consistent with the present inventive concepts.

[0059] Fig. 31 illustrates a graph of weight change in study patients, consistent with the present inventive concepts.

[0060] Fig. 32 illustrates a graph regarding weight loss and HbAlc, consistent with the present inventive concepts.

[0061] Fig. 33 illustrates a graph of HbAlc percentages over a six-week period comparing responders and non-responders, consistent with the present inventive concepts.

[0062] Fig. 34 illustrates a graph of fasting glucose change over a twenty-six-week period comparing responders and non-responders, consistent with the present inventive concepts.

[0063] Fig. 35 illustrates a graph of change under the curve of a mixed meal tolerance test, consistent with the present inventive concepts.

[0064] Fig. 36 illustrates a graph of three patients exhibiting a large treatment effect, consistent with the present inventive concepts.

[0065] Fig. 37 illustrates a table presenting the large effect size of high dose cohort, consistent with the present inventive concepts.

[0066] Fig. 38 illustrates a table presenting the patient demographics of the 39 patients from which the data were collected, consistent with the present inventive concepts.

[0067] Fig. 39 illustrates a graph showing the average HbAlc in all available subjects treated by the systems, devices, and methods of the present inventive concepts.

[0068] Fig. 40 illustrates a graph showing the average change in HbAlC from baseline in patients treated with an LS-DMR and SS-DMR procedure, consistent with the present inventive concepts.

[0069] Fig. 41 illustrates a table presenting the number of patients in each treatment arm with medication changes preceding the six-month post-procedure follow-up visit, consistent with the present inventive concepts.

[0070] Fig. 42 illustrates graphs showing the average fasting plasma glucose in LS-DMR treated patients with a baseline HbAlC between 7.5% and 10%, consistent with the present inventive concepts.

[0071] Fig. 43 illustrates a graph showing mean HbAlC in LS-DMR treated patients with baseline HbAlc between 7.5% and 10% and consistent antidiabetic medications, consistent with the present inventive concepts.

[0072] Fig. 44 illustrates a graph showing HbAlc over time in a single patient receiving two treatments at different intervals, consistent with the present inventive concepts.

[0073] Fig. 45 illustrates a table presenting patient data prior to performance of a tissue treatment, consistent with the present inventive concepts.

[0074] Fig. 46 illustrates a table presenting data of the tissue treatment procedures performed by the applicant, consistent with the present inventive concepts.

[0075] Fig. 47 illustrates a table presenting data collected at a follow-up procedure performed on 13 patients, approximately 3 months after the duodenal treatment procedure, consistent with the present inventive concepts.

[0076] Fig. 48 illustrates a table presenting data collected at a follow-up procedure performed on 13 patients, approximately 3 months after the duodenal treatment procedure, consistent with the present inventive concepts.

[0077] Fig. 49 illustrates a table presenting data collected at a follow-up procedure performed approximately 6 months after the duodenal treatment procedure, consistent with the present inventive concepts.

[0078] Fig. 50 illustrates a table presenting the fluid temperatures and respective ablation times of a tissue treatment procedure, consistent with the present inventive concepts.

[0079] Figs. 51A-51C illustrate photographs of a cross section of mammalian duodenal tissue prior and subsequent to target tissue treatment, consistent with the present inventive concepts.

[0080] Figs. 52A-52E illustrate photographs of hematoxylin and eosin-stained cross sections demonstrating changes in the dimension and morphology of the duodenumjejunum, ileum, and colon, respectively, consistent with the present inventive concepts.

[0081] Figs. 52F-52M illustrate data demonstrating hormonal and transcriptional changes in the small intestine of high-fat, diet-induced obese rodents, consistent with the present inventive concepts.

[0082] Fig. 53 illustrates a table presenting data collected at baseline, 3 months post duodenal mucosal ablation, and 6 months post duodenal mucosal ablation, consistent with the present inventive concepts.

[0083] Figs. 54A-54E illustrate graphs showing postprandial concentrations of glucose, insulin, glucagon during mixed meal tests at baseline and 3 months post duodenal mucosal ablation.

[0084] Figs. 55A-55B illustrate tables presenting various data collected at baseline, 24 weeks post duodenal mucosal ablation, and 48 weeks post duodenal mucosal ablation, consistent with the present inventive concepts.

[0085] Figs. 56A-56E illustrate graphs showing changes in HbAlc levels, insulin total daily dosages, weight, % weight change, and FPG levels over a time period of 48 weeks post duodenal mucosal ablation, consistent with the present inventive concepts.

[0086] Figs. 57A-57C illustrate tables presenting various data collected over a time period of 48 weeks post duodenal mucosal ablation, consistent with the present inventive concepts.

[0087] Fig. 58 illustrates a flow chart for an exemplary method for performing a duodenal treatment clinical study, consistent with the present inventive concepts.DETAILED DESCRIPTION OF THE DRAWINGS

[0088] Reference will now be made in detail to the present embodiments of the technology, examples of which are illustrated in the accompanying drawings. Similar reference numbers may be used to refer to similar components. However, the description is not intended to limit the present disclosure to particular embodiments, and it should be construed as including various modifications, equivalents, and / or alternatives of the embodiments described herein.

[0089] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. For example, it will be appreciated that all features set out in any of the claims (whether independent or dependent) can be combined in any given way.It is to be understood that at least some of the figures and descriptions of the invention have been simplified to focus on elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the invention. However, because such elements arewell known in the art, and because they do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.

[0090] Terms defined in the present disclosure are only used for describing specific embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. Terms provided in singular forms are intended to include plural forms as well, unless the context clearly indicates otherwise. All of the terms used herein, including technical or scientific terms, have the same meanings as those generally understood by an ordinary person skilled in the related art, unless otherwise defined herein. Terms defined in a generally used dictionary should be interpreted as having meanings that are the same as or similar to the contextual meanings of the relevant technology and should not be interpreted as having ideal or exaggerated meanings, unless expressly so defined herein. In some cases, terms defined in the present disclosure should not be interpreted to exclude the embodiments of the present disclosure.

[0091] It will be understood that the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") when used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0092] It will be further understood that, although the terms first, second, third, etc. may be used herein to describe various limitations, elements, components, regions, layers and / or sections, these limitations, elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one limitation, element, component, region, layer or section from another limitation, element, component, region, layer or section. Thus, a first limitation, element, component, region, layer or section discussed below could be termed a second limitation, element, component, region, layer or section without departing from the teachings of the present application.

[0093] It will be further understood that when an element is referred to as being "on", "attached", "connected" or "coupled" to another element, it can be directly on or above, or connected or coupled to, the other element, or one or more intervening elements can be present. In contrast, when an element is referred to as being "directly on", "directly attached", "directly connected" or "directly coupled" to another element, there are no intervening elements present.Other words used to describe the relationship between elements should be interpreted in a like fashion (e.g., "between" versus "directly between," "adjacent" versus "directly adjacent," etc.).

[0094] As used herein, the terms “operably attached”, “operably connected”, “operatively coupled”, and similar terms related to attachment of components shall refer to attachment of two or more components that results in one, two, or more of: electrical attachment; fluid attachment; magnetic attachment; mechanical attachment; optical attachment; sonic attachment; and / or other operable attachment arrangements. The operable attachment of two or more components can facilitate the transmission between the two or more components of: power; signals; electrical energy; fluids or other flowable materials; magnetism; mechanical linkages; light; sound such as ultrasound; and / or other materials and / or components.

[0095] It will be further understood that when a first element is referred to as being "in", "on" and / or "within" a second element, the first element can be positioned: within an internal space of the second element, within a portion of the second element (e.g., within a wall of the second element); positioned on an external and / or internal surface of the second element; and combinations of two or more of these.

[0096] As used herein, the term “proximate”, when used to describe proximity of a first component or location to a second component or location, is to be taken to include one or more locations near to the second component or location, as well as locations in, on and / or within the second component or location. For example, a component positioned proximate an anatomical site (e.g., a target tissue location), shall include components positioned near to the anatomical site, as well as components positioned in, on and / or within the anatomical site.

[0097] Spatially relative terms, such as "beneath," "below," "lower," "above," "upper", “under”, and the like may be used to describe an element and / or feature's relationship to another element(s) and / or feature(s) as, for example, illustrated in the figures. It will be further understood that the spatially relative terms are intended to encompass different orientations of the device in use and / or operation in addition to the orientation depicted in the figures. For example, if the device in a figure is turned over, elements described as "below" and / or "beneath" other elements or features would then be oriented "above" the other elements or features. The device can be otherwise oriented (e.g., rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

[0098] The terms “reduce”, “reducing”, “reduction” and the like, where used herein, are to include a reduction in a quantity, including a reduction to zero. Reducing the likelihood of an occurrence shall include prevention of the occurrence. Correspondingly, the terms “prevent”,“preventing”, and “prevention” shall include the acts of “reduce”, “reducing”, and “reduction”, respectively.

[0099] The term "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, "A and / or B" is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.

[0100] The term “one or more”, where used herein can mean one, two, three, four, five, six, seven, eight, nine, ten, or more, up to any number.

[0101] The terms “and combinations thereof’ and “and combinations of these” can each be used herein after a list of items that are to be included singly or collectively. For example, a component, process, and / or other item selected from the group consisting of: A; B; C; and combinations thereof, shall include a set of one or more components that comprise: one, two, three or more of item A; one, two, three or more of item B; and / or one, two, three, or more of item C.

[0102] In this specification, unless explicitly stated otherwise, “and” can mean “or”, and “or” can mean “and”. For example, if a feature is described as having A, B, or C, the feature can haveA, B, and C, or any combination of A, B, and C. Similarly, if a feature is described as having A,B, and C, the feature can have only one or two of A, B, or C.

[0103] The expression “configured (or set) to” used in the present disclosure may be used interchangeably with, for example, the expressions “suitable for”, “having the capacity to”, “designed to”, “adapted to”, “made to” and “capable of’ according to a situation. The expression “configured (or set) to” does not mean only “specifically designed to” in hardware. Alternatively, in some situations, the expression “a device configured to” may mean that the device “can” operate together with another device or component.

[0104] As used herein, the term “threshold” refers to a maximum level, a minimum level, and / or range of values correlating to a desired or undesired state. In some embodiments, a system parameter is maintained above a minimum threshold, below a maximum threshold, within a threshold range of values, and / or outside a threshold range of values, such as to cause a desired effect (e.g., efficacious therapy) and / or to prevent or otherwise reduce (hereinafter “prevent”) an undesired event (e.g., a device and / or clinical adverse event). In some embodiments, a system parameter is maintained above a first threshold (e.g., above a first temperature threshold to cause a desired therapeutic effect to tissue) and below a second threshold (e.g., below a second temperature threshold to prevent undesired tissue damage). In some embodiments, a threshold value is determined to include a safety margin, such as toaccount for patient variability, system variability, tolerances, and the like. As used herein, “exceeding a threshold” relates to a parameter going above a maximum threshold, below a minimum threshold, within a range of threshold values and / or outside of a range of threshold values.

[0105] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. For example, it will be appreciated that all features set out in any of the claims (whether independent or dependent) can be combined in any given way.

[0106] As described herein, “room pressure” shall mean pressure of the environment surrounding the systems and devices of the present inventive concepts. Positive pressure includes pressure above room pressure or simply a pressure that is greater than another pressure, such as a positive differential pressure across a fluid pathway component such as a valve. Negative pressure includes pressure below room pressure or a pressure that is less than another pressure, such as a negative differential pressure across a fluid component pathway such as a valve. Negative pressure can include a vacuum but does not imply a pressure below a vacuum. As used herein, the term “vacuum” can be used to refer to a full or partial vacuum, or any negative pressure as described herein.

[0107] The term “diameter” where used herein to describe a non-circular geometry is to be taken as the diameter of a hypothetical circle approximating the geometry being described. For example, when describing a cross section, such as the cross section of a component, the term “diameter” shall be taken to represent the diameter of a hypothetical circle with the same cross- sectional area as the cross section of the component being described.

[0108] The terms “major axis” and “minor axis” of a component where used herein are the length and diameter, respectively, of the smallest volume hypothetical cylinder which can completely surround the component.

[0109] As used herein, the term “fluid” can refer to a liquid, gas, gel, or any flowable material, such as a material which can be propelled through a lumen and / or opening.

[0110] As used herein, the term “material” can refer to a single material, or a combination of two, three, four, or more materials.

[0111] As used herein, the term “transducer” is to be taken to include any component or combination of components that receives energy or any input and produces an output. For example, a transducer can include an electrode that receives electrical energy and distributes theelectrical energy to tissue (e.g., based on the size of the electrode). In some configurations, a transducer converts an electrical signal into any output, such as: light (e.g., a transducer comprising a light emitting diode or light bulb), sound (e.g., a transducer comprising a piezo crystal configured to deliver ultrasound energy); pressure (e.g., an applied pressure or force); heat energy; cryogenic energy; chemical energy; mechanical energy (e.g., a transducer comprising a motor or a solenoid); magnetic energy; and / or a different electrical signal (e.g., different than the input signal to the transducer). Alternatively or additionally, a transducer can convert a physical quantity (e.g., variations in a physical quantity) into an electrical signal. A transducer can include any component that delivers energy and / or an agent to tissue, such as a transducer configured to deliver one or more of: heat energy to tissue; cryogenic energy to tissue; electrical energy to tissue (e.g., a transducer comprising one or more electrodes); light energy to tissue (e.g., a transducer comprising a laser, light emitting diode and / or optical component such as a lens or prism); mechanical energy to tissue (e.g., a transducer comprising a tissue manipulating element); sound energy to tissue (e.g., a transducer comprising a piezo crystal); chemical energy; electromagnetic energy; magnetic energy; and combinations of two or more of these. A transducer can include a component configured to neutralize an ablative process, such as a transducer configured to cool tissue prior to and / or after a heat ablation of tissue, and / or a transducer configured to warm tissue prior to and / or after a cryogenic ablation of tissue. Alternatively or additionally, a transducer can comprise a mechanism, such as: a valve; a grasping element; an anchoring mechanism; an electrically activated mechanism; a mechanically-activated mechanism; and / or a thermally activated mechanism.

[0112] As used herein, the term “functional element” is to be taken to include one or more elements constructed and arranged to perform a function. A functional element can comprise one or more sensors and / or one or more transducers. In some embodiments, a functional element is configured to deliver energy and / or otherwise treat tissue (e.g., a functional element configured as a treatment element). Alternatively or additionally, a functional element (e.g., comprising one or more sensors) can be configured to record one or more parameters, such as a patient physiologic parameter; a patient anatomical parameter (e.g., a tissue parameter); a patient environment parameter; and / or a system parameter (e.g., temperature and / or pressure within the system). In some embodiments, a sensor or other functional element is configured to perform a diagnostic function (e.g., to gather data used to perform a diagnosis). In some embodiments, a functional element is configured to perform a therapeutic function (e.g., to deliver therapeutic energy and / or a therapeutic agent). In some embodiments, a functional element comprises one or more elements constructed and arranged to perform a function selected from the group consistingof: deliver energy; extract energy (e.g., to cool a component); deliver a drug or other agent; manipulate a system component or patient tissue; record or otherwise sense a parameter such as a patient physiologic parameter or a patient anatomical parameter; and combinations of two or more of these. A functional element can comprise a fluid, such as an ablative fluid (as described herein) comprising a liquid, gel, and / or gas configured to ablate or otherwise treat tissue. A functional element can comprise a reservoir, such as an expandable balloon configured to receive an ablative fluid. A “functional assembly” can comprise an assembly constructed and arranged to perform a function, such as is described herein, such as a therapeutic function or a diagnostic function. In some embodiments, a functional assembly is configured to deliver energy and / or otherwise treat tissue (e.g., a functional assembly configured as a tissue treatment assembly). Alternatively or additionally, a functional assembly can be configured to record one or more parameters, such as a patient physiologic parameter; a patient anatomical parameter; a patient environment parameter; and / or a system parameter. A functional assembly can comprise an expandable assembly. A functional assembly can comprise one or more functional elements.

[0113] As used herein, the term “ablative temperature” refers to a temperature at which tissue necrosis or other desired tissue treatment occurs (e.g., a temperature sufficiently hot or sufficiently cold to cause tissue necrosis). As used herein, the term “ablative fluid” refers to one or more liquids, gases, gels, or other fluids whose thermal properties cause tissue necrosis and / or another desired tissue treatment (e.g., one or more fluids at an ablative temperature). Alternatively or additionally, “ablative fluid” refers to one or more fluids whose chemical properties (at room temperature, body temperature or otherwise) cause tissue necrosis or another desired tissue treatment. A tissue treatment element (e.g., a functional element) of the present inventive concepts can comprise one or more ablative fluids.

[0114] As used herein, the term “tissue contacting surface” refers to a surface of a system or device component that makes physical contact with tissue, such as a portion of an external surface of an expandable component (e.g., a portion of a balloon’s surface) which contacts tissue once expanded. In some embodiments, tissue contacting a tissue contacting surface directly receives energy from the tissue contacting surface of the expandable components, however tissue in proximity (e.g., below or alongside) also receives energy (e.g., via conduction of the delivered energy and / or a resultant heat energy).

[0115] As used herein, the term “normal level” refers to the level of a physiologic parameter that would be expected to be found in human subjects that are not afflicted with the disease or disorder being treated by the systems and / or methods of the present inventive concepts. In some embodiments, a normal level comprises the level of a physiologic parameter that would beexpected to be found in human subjects that are: not afflicted with the disease or disorder being treated by the systems and / or methods of the present inventive concepts (e.g., diabetes, insulin resistance, and / or other metabolic condition); and also are not afflicted with one or more other adverse medical conditions (e.g., a cardiovascular condition). A normal level can be associated with human subjects (e.g., healthy human subjects) that are of similar age, race, and / or sex as the patient being treated by the systems and / or methods of the present inventive concepts.

[0116] It is an object of the present inventive concepts to provide systems, methods, and devices for safely and effectively treating and / or diagnosing a volume of tissue (the "target tissue"), such as to treat and / or diagnose a patient disease or disorder. Target tissue can comprise one or more target tissue segments or other target tissue portions, such as target tissue located in the intestine of a patient. Clinical procedures in the duodenum and other locations of the small intestine are challenging for a number of reasons, such as those caused by the long distance between the mouth and the intestine and the complexities of the gastrointestinal passageway encountered (including passage through the stomach) during device (e.g., catheter) insertion and operation. Intestinal diameter varies along its length, and effective devices must accommodate this variation. The intestine is quite distensible in the longitudinal and radial directions, further complicating device (e.g., catheter) manipulation and operation (e.g., delivery of energy to tissue). Mobility of intestinal mucosa relative to muscularis is present, as well as mobility of the full wall, but can result in undesired stretching, compression, and intussusception. The duodenum is normally closed, and it can require insufflation to open (e.g., for visualization). The insufflation medium (e.g., gas) moves through the intestine, so more must be delivered, while excess gas causes discomfort or other adverse effect for the patient. Duodenal and other intestinal tissue tends to stretch or compress as a device is advanced or retracted, respectively, such as to cause retrograde expulsion of devices if a stabilization force is not maintained. It is difficult to manipulate and control devices that include treatment and other elements positioned in the small intestine. The small intestine wraps around the pancreas, and the curvature is quite variable from patient to patient. The length of the intestine along an outer curve is longer than that along an inner curve. In many procedures, there is a desire to avoid damage to the ampulla of Vater (e.g., to avoid restricting bile and / or pancreatic fluid), tissue which can be difficult to visualize or otherwise identify. There are relatively few endoscopically visualizable landmarks in the intestine, making it difficult to know where in the intestine a portion (e.g., a distal portion) of a device is positioned. Access to the intestine through the stomach via an over-the wire catheter loses one-to-one motion between a proximal handle and a distal portion of the device, as slack can accumulate in the stomach during advancement and slack can be relieved from thestomach during withdrawal. Accessing the intestine can include entering the intestine through the pylorus, a small sphincter, from the stomach, and in obese patients, large stretchable stomachs make it difficult to direct a device to the pylorus. The intestinal mucosa has a very irregular surface due to plicae circulares and mucosal villi, and performing a treatment (e.g., an ablation treatment) of the intestinal mucosa is quite different from a treatment procedure performed in the stomach or esophagus, because of this irregularity. Peristalsis present in the small intestine is dynamic and unpredictable and can alter functional element, functional assembly and / or other device component position and / or contact level with tissue. The intestine is not only thin walled, but the thickness of the wall is highly variable, even within small axial segments of the small intestine, thus complicating preferential ablation of inner layers versus outer layers of the small intestine. The muscularis is innervated and scars and / or stenoses easily, and as such, even minimal trauma to the muscularis should be avoided.

[0117] Target tissue can comprise one or more layers of a portion of tubular or non-tubular tissue, such as tissue of an organ or tissue of the gastrointestinal (GI) tract of a patient, such as tissue of the small intestine or large intestine. The systems and devices of the present inventive concepts can include one or more functional assemblies and / or functional elements configured to treat target tissue, such as a treatment element comprising fluid at an ablative temperature delivered to a balloon (ablative temperature fluid and / or balloon filled with ablative fluid each referred to singly or collectively as a “functional element” or a “treatment element” of the present inventive concepts). One or more functional elements can be provided in, on and / or within an expandable functional assembly or other radially deployable mechanism. Functional assemblies and / or functional elements can be configured to treat target tissue (e.g., deliver energy to target tissue), such as to modify target tissue (e.g., to modify the secretions from the target tissue and / or absorption of the target tissue), ablate target tissue (e.g., to cause the replacement of the target tissue with “new tissue”) and / or to cause a reduction in the surface area of target tissue (e.g., the luminal surface area of an inner wall of tubular tissue) at and / or proximate to one or more locations where the treatment was performed (e.g., at and / or proximate the location where energy was delivered). The luminal or other tissue treatment can occur acutely and / or it can take place over time, such as days, weeks, or months. A tissue surface area reduction can correspond to a reduction in mucosal surface area available to function in an absorptive, neuronal signaling, and / or a hormonal secretory capacity. A target tissue treatment can result in the replacement of target tissue with new tissue with different absorptive and / or secretory capacity and / or other desirable effect related to replacement and / or modification of target tissue. The treatment of target tissue with the systems, devices and methods of the presentinventive concepts can provide a therapeutic benefit to the patient, such as to treat one or more diseases or disorders of the patient, as described in detail herein.

[0118] Each functional assembly (e.g., a functional assembly configured as a tissue treatment assembly) can comprise at least one functional element (e.g., at least one tissue treatment element) such as one, two, or more tissue treatment elements selected from the group consisting of ablative fluid delivered to a balloon or other expandable fluid reservoir; ablative fluid comprising at least steam delivered directly or indirectly to tissue; an energy delivery element mounted to an expandable functional assembly such as an electrode or other energy delivery element configured to deliver radiofrequency (RF) energy and / or microwave energy; an electrode or other energy delivery element configured to deliver electroporation energy, such as reversible and / or irreversible electroporation energy; an electrode, fluid delivery element, and / or other delivery element configured to deliver both reversible electroporation energy and an agent (e.g., a tissue ablating agent whose ablation is triggered and / or enhanced with the delivery of electroporation energy); light delivery element configured to deliver laser or other light energy; fluid delivery element (e.g., needle or nozzle) configured to deliver a necrosis-causing fluid and / or other ablative fluid directly onto and / or into tissue; sound delivery element such as an ultrasonic and / or subsonic sound delivery element; and combinations of two or more of these. Numerous forms of functional assemblies and / or functional elements can be included. In some embodiments, the functional assemblies and / or the one or more functional elements contained therein are configured as described in: applicant’s co-pending United States Patent Application Serial Number 17 / 222,480 (Attorney Docket No. 41714-703.303; Client Docket No. MCT-001- US-CON2), entitled “Devices and Methods for the Treatment of Tissue”, filed April 5, 2021; applicant’s co-pending United States Patent Application Serial Number 17 / 864,855 (Attorney Docket No. 41714-704.303; Client Docket No. MCT-002-US-CON2), entitled “Heat Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed July 14, 2022; applicant’s copending United States Patent Application Serial Number 17 / 879,222 (Attorney Docket No. 41714-706.303; Client Docket No. MCT-004-US-CON2), entitled “Electrical Energy Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed August 2, 2022; and / or applicant’s co-pending United States Patent Application Serial Number 17 / 192,671 (Attorney Docket No. 41714-707.302; Client Docket No. MCT-005-US-CON1), entitled “Ablation Systems, Devices, and Methods for the Treatment of Tissue”, filed March 4, 2021.

[0119] The functional assemblies and / or treatment elements of the present inventive concepts can be constructed and arranged to deliver one or more treatments (e.g., deliver energy, deliver a chemically ablative fluid, mechanically abrade and / or otherwise treat tissue) directly to aparticular area of tissue, the “delivery zone”. The area of tissue treated can comprise a segment of the small intestine, or other body lumen, where the delivery zone comprises a length representing the axial length of the segment treated, and a width such as a width representing a full or partial circumferential portion of the segment. A treatment element can be configured to ablate or otherwise treat an energy delivery zone with a “treatment length” and a “treatment width”. During a single delivery of treatment, a treatment element can be constructed and arranged to deliver treatment to a relatively continuous surface of tissue (e.g., a continuous surface of tissue in contact with a balloon filled with ablative fluid or a surface of tissue onto which a chemically ablative fluid is sprayed, coated, or otherwise delivered). In these continuous-surface treatment delivery embodiments, the delivery zone comprises the continuous surface of tissue receiving the treatment directly. Alternatively, a treatment element can be constructed and arranged to deliver treatment to multiple discrete portions of a tissue surface, with one or more tissue surface portions in-between other surface portions that do not directly receive energy or other treatment from the treatment element. In these segmented-surface treatment delivery embodiments, the delivery zone is defined by a periphery of the multiple tissue surface area portions receiving treatment, similar to a “convex hull” or “convex envelope” used in mathematics to define an area including a number of discrete locations that define a periphery. A delivery zone can comprise two or more contiguous or non-contiguous delivery zones, and multiple delivery zones can be treated sequentially and / or simultaneously.

[0120] For example, in embodiments where the treatment element is hot fluid (e.g., ablative fluid at a sufficiently high temperature to cause tissue necrosis) positioned within a balloon, the delivery zone comprises all tissue surfaces contacted by the balloon that directly receive ablative thermal energy from the ablative fluid through the balloon. In embodiments where the treatment element is a balloon filled with cold fluid (e.g., ablative fluid at a sufficiently low temperature to cause tissue necrosis), the delivery zone can comprise all tissue surfaces contacted by the balloon that have heat directly extracted from them by the cold fluid (e.g., at a sufficient cold temperature to treat the tissue). In embodiments where the treatment element is an array of electrodes configured to deliver electrical energy (e.g., radiofrequency and / or other electromagnetic energy) to tissue, the delivery zone can comprise an area defined by the electrodes on the periphery of the array (e.g., a convex hull as described above), such as when the electrodes are positioned and energy is delivered to treat relatively the entire surface of tissue within the periphery. In embodiments where the treatment element comprises one or more fluid delivery elements delivering ablative fluid directly onto tissue (e.g., an ablative fluid whose chemical nature modifies tissue, at body temperature or otherwise), the delivery zone cancomprise a surface defined by the periphery of tissue locations receiving the ablative fluid, such as when the ablative fluid is delivered (e.g., sprayed or otherwise applied, such as via a sponge) to relatively the entire surface within the periphery. In embodiments where the treatment element comprises one or more light delivery elements such as those that deliver laser energy to tissue, the delivery zone can comprise a surface area defined by the periphery of tissue locations receiving the light energy, such as when light is delivered at a set of locations and with a magnitude of energy configured to treat relatively the entire surface of tissue within the periphery. In these embodiments, light can be delivered to relatively the entire energy delivery zone, or to a large number (e.g., greater than 100) of tissue locations within the periphery of the delivery zone (e.g., making up less than 50%, less than 20% or less than 10% of the total surface area of the delivery zone). In embodiments where the treatment element comprises one or more sound delivery elements such as those that deliver sub-sonic and / or ultrasonic sound energy to tissue, the delivery zone can comprise a surface area defined by the periphery of tissue locations receiving the sound energy, such as when ablative sound energy is delivered at a set of locations and with a magnitude of energy configured to treat relatively the entire surface of tissue within the periphery. In embodiments in which the treatment element comprises a mechanical cutter or other abrasion element, the delivery zone can comprise a surface defined by all tissue dissected, cut, mechanically disrupted and / or otherwise modified during a single abrading step of the mechanical abrader.

[0121] A delivery zone can comprise a cumulative set of delivery zones that receive treatment simultaneously and / or sequentially, by one or more tissue treatment elements, such as those described herein. A delivery zone can comprise a first delivery zone defined when a treatment element treats target tissue in a first treatment delivery, plus a second delivery zone defined when the treatment element treats target tissue in a second treatment delivery, and so on. In these embodiments, the treatment element can be translated, rotated and / or otherwise repositioned between treatments (e.g., energy delivery), where each delivery zone is associated with the position of the treatment element during each treatment. Multiple delivery zones can receive treatment in a single procedure, such as within a period of less than twenty-four hours. A delivery zone can comprise a set of multiple delivery zones treated by two or more treatment elements.

[0122] Target tissue treated by each energy delivery and / or other treatment delivery comprises the tissue directly receiving treatment (i.e., the tissue defined by the delivery zone) plus “neighboring tissue” which is also modified by the associated treatment delivery. The neighboring tissue can comprise tissue alongside, below (e.g., in a deeper tissue layer) and / orotherwise proximate the delivery zone tissue. The neighboring tissue treatment can be due to one or more of: conduction and / or convection of heat or cold from the delivery zone; flow of ablative fluid from the delivery zone; flow of toxins or other agents that occur during cell degradation and / or cell death; radiation; luminescence, light dissipation; and other energy and / or chemical propagation mechanisms. In some embodiments, an area (i.e., the delivery zone) comprising an inner surface of mucosal tissue directly receives treatment from one or more treatment elements (e.g., an ablative fluid contained within a balloon), and the total volume of target tissue treated by that single treatment delivery includes: the delivery zone tissue (i.e., surface mucosal tissue directly receiving energy and / or other treatment from the treatment element); surface mucosal tissue in close proximity (e.g., adjacent) to the delivery zone tissue; and mucosal and potentially submucosal tissue layers beneath (deeper than) the delivery zone tissue and the treated adjacent surface mucosal tissue.

[0123] In some embodiments, a “treatment neutralizing” procedure is performed after one or more treatments (e.g., energy deliveries), such as a treatment neutralizing cooling procedure performed after one or more treatment elements deliver heat to treat target tissue, or a treatment neutralizing warming procedure performed after one or more treatment elements deliver cryogenic energy to treat target tissue. In these embodiments, the treatment neutralizing cooling or warming fluid can be delivered to the same functional assembly (e.g., an expandable functional assembly comprising a balloon) delivering the heat or cryogenic treatment, respectively, and / or the neutralizing fluid can be delivered directly to tissue by the same or different functional assembly or functional element. In some embodiments, a functional element delivers an ablating agent to target tissue (e.g., a chemical or other agent configured to cause target tissue necrosis or otherwise treat target tissue), and a treatment neutralizing procedure comprises delivery of a neutralizing agent (by the same or different functional element) to target and / or non-target tissue to reduce continued ablation due to the delivered caustic ablative fluid (e.g., a base to neutralize a delivered acid or an acid to neutralize a delivered base).

[0124] Each functional assembly and / or functional element of the present inventive concepts can be configured to be positioned in one or more intestinal and / or other locations of the patient, such as to perform a function (e.g., perform a treatment, deliver fluid and / or record data) at one or more contiguous or discontiguous tissue locations. Target tissue to be treated (e.g., ablated) comprises a three-dimensional volume of tissue, and can include a first portion, a treatment portion, whose treatment has a therapeutic benefit to a patient; as well as a second portion, a “safety-margin” portion, whose treatment has minimal or no adverse effects to the patient. “Non-target tissue” can be identified (e.g., prior to and / or during the medical procedure),wherein the non-target tissue comprises tissue whose treatment by the functional assembly (e.g., a tissue treatment assembly) and / or treatment element should be reduced or avoided such as to reduce or prevent an undesired effect to the patient.

[0125] The target tissue treatment can cause one or more modifications of the target tissue such as a modification selected from the group consisting of: modification of cellular function; cell death; apoptosis; instant cell death; cell necrosis; denaturing of cells; removal of cells; and combinations of two or more of these. In some embodiments, the target tissue treatment is configured to create scar tissue. Target tissue can be selected such that after treatment the treated target tissue and / or the tissue that replaces the target tissue functions differently than the pretreated target tissue, such as to have a therapeutic benefit for the patient. The modified and / or replacement tissue (singly or collectively “treated tissue”) can exhibit different properties than the pre-treated target tissue, such as different properties that are used to treat a patient disease or disorder. The treated tissue can have different secretions and / or quantities of secretions than the pre-treated target tissue, such as to treat diabetes, hypercholesterolemia and / or another patient disease or disorder. The treated tissue can have different absorptive properties than the target tissue, such as to treat diabetes, hypercholesterolemia and / or another patient disease or disorder. The treated tissue can have a different surface topography than the target tissue, such as a modification of the topography of the inner wall of the GI tract that includes a smoothing or flattening of its inner surface, such as a modification in which the luminal surface area of one or more segments of the GI tract is reduced after treatment. The effect of the treatment (e.g., the effect on the target tissue) can occur acutely, such as within twenty-four hours, or after longer periods of time, such as greater than twenty-four hours or greater than one week.

[0126] Target tissue to be treated can comprise two or more discrete tissue segments, such as two or more axial segments of the GI tract. Each tissue segment can comprise a full (e.g., approximately 360°) or partial circumferential segment of the tissue segment. Multiple tissue segments can be treated with the same or different functional elements (e.g., treatment elements), and they can be treated simultaneously or in sequential steps (e.g., sequential energy delivery steps that deliver energy to multiple delivery zones). Multiple tissue segments can be treated in the same or different clinical procedures (e.g., procedures performed on different days). In some embodiments, a series of tissue segments comprising a series of axial segments of the GI tract are treated in a single clinical procedure. The first and second tissue segments can be directly adjacent, they can contain overlapping portions of tissue, and / or there can be gaps between the segments. Dissimilarities in treatment elements can include type and / or amount of energy to be delivered by an energy delivery-based treatment element. Dissimilarities in target tissuetreatments can include: target tissue area treated; target tissue volume treated; target tissue length treated; target tissue depth treated; target tissue circumferential portion treated; ablative fluid type, volume and / or temperature delivered to a reservoir such as a balloon; ablative fluid type, volume and / or temperature delivered directly to tissue; energy delivery type; energy delivery rate and / or amount; peak energy delivered; average temperature of target tissue achieved during target tissue treatment; maximum temperature achieved during target tissue treatment; temperature profile of target tissue treatment; duration of target tissue treatment; surface area reduction achieved by target tissue treatment; and combinations of two or more of these.

[0127] Target tissue can include tissue of the duodenum, such as tissue including substantially all or a portion of the mucosal layer of one or more axial segments of the duodenum (e.g., including all or a portion of the plicae circulares), such as to treat diabetes, hypercholesterolemia and / or another patient disease or disorder, such as while leaving the duodenum anatomically connected after treatment. Target tissue can include one or more portions of a tissue layer selected from the group consisting of: mucosa; mucosa through superficial submucosa; mucosa through mid-submucosa; mucosa through deep submucosa; and combinations of two or more of these. Replacement tissue can comprise cells that have migrated from one or more of: gastric mucosa; jejunal mucosa; an untreated portion of the duodenum whose mucosal tissue functions differently than the treated mucosal tissue functions prior to treatment; and combinations of two or more of these. Replacement tissue can include one or more tissue types selected from the group consisting of: scar tissue; normal intestinal mucosa; gastric mucosa; and combinations of two or more of these. In some embodiments, replacement tissue comprises tissue that has been delivered onto and / or into tissue by a catheter of the present inventive concepts. In some embodiments, target tissue includes a treatment portion comprising the mucosal layer of the duodenum, and a safety-margin portion comprising a near-full or partial layer of the submucosal layer of the duodenum. In some embodiments, the target tissue comprises nearly the entire mucosal layer of the duodenum, and this tissue can include a portion of the pylorus contiguous with the duodenal mucosa and / or a portion of the jejunum contiguous with the duodenal mucosa. In some embodiments, the target tissue comprises all or a portion of the duodenal mucosa distal to the ampulla of Vater (e.g., avoiding tissue within at least 0.5cm, 1.0cm or 1.5cm from the ampulla of Vater while including tissue within 5cm, 10cm or 15cm distal to the ampulla of Vater). In these embodiments, the target tissue can comprise at least 10%, at least 15%, at least 25%, at least 30% or at least 50% of the duodenal mucosa distal to the ampulla of Vater. Alternatively or additionally, the target tissue can comprise no more than 70% or no more than 90% of the duodenal mucosa distal to the ampulla of Vater. In these embodiments, tissueproximal to and / or proximate the ampulla of Vater can comprise non-target tissue (i.e., tissue whose treatment is avoided or at least reduced).

[0128] In some embodiments, the target tissue comprises neuronal cells of duodenal mucosal tissue. In some embodiments, the target tissue comprises neuronal cells of duodenal submucosa tissue.

[0129] In some embodiments, the target tissue comprises at least a portion of duodenal mucosal tissue, and the systems, methods and devices of the present inventive concepts are configured to counteract duodenal mucosal changes that cause an intestinal hormonal impairment leading to insulin resistance in patients. In these embodiments, the therapy provided can improve the body’s ability to process sugar and dramatically improve glycemic control for patients with insulin resistance and / or type 2 diabetes. In some embodiments, target tissue is treated to prevent and / or reduce cognitive decline (e.g., Alzheimer’s Disease), such as by improving sugar metabolism in the brain, overcoming insulin resistance in the brain, reducing toxicity of beta amyloid, reducing oxidative stress, and / or reducing inflammation in the brain associated with neuronal death. In some embodiments, target tissue is treated to prevent liver fibrosis and / or cirrhosis (e.g., non-alcoholic fatty liver disease NAFLD or non-alcoholic steatohepatitis NASH); metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic dysfunction-associated steatohepatitis (MASH); reduce liver fat; reduce oxidative stress; and / or reduce inflammation in the liver associated with liver fibrosis and toxicity. The systems and methods of the present inventive concepts can be configured to lower insulin requirements by improving insulin resistance (e.g., as opposed to improving insulin secretion), and / or by direct glucose lowering (e.g., by causing an increase in glucose excretion in the urine). Alternatively or additionally, the systems and methods of the present inventive concepts can be configured to lower insulin requirements by improving hepatic insulin resistance and / or by improving muscle insulin resistance.

[0130] Hormones released from the intestinal mucosa play an important role in modulating glucose homeostasis, and different axial segments of the intestinal mucosa release different hormones in the fasting and post-prandial state, in order to modulate blood glucose in the fasting and post-prandial states, respectively. After a meal, the proximal intestinal mucosa senses the intestine for ingested glucose and releases a collection of hormones in response to this signal. These hormones initiate the process of insulin release into the bloodstream after a meal, but they also induce some insulin resistance to prevent the released insulin from causing hypoglycemia before the body has a chance to absorb the ingested glucose. One such hormone that plays a role in this is GIP. Distal gut hormones (produced in the jejunum or a more distal location), on thecontrary, allow the release of more insulin but also play a role in helping the body now become sensitive to its circulating insulin. Teleologically, the explanation for this difference in the type of gut hormones produced by different segments of the intestine is that enough glucose will have been absorbed by the time nutrients reach the distal intestine to allow the insulin to begin to function to reduce blood glucose levels. Releasing different hormones at different times (e.g., from different segments of the intestine) enables the body to absorb and process glucose in such a way as to avoid hypoglycemia (blood sugars that are too low) and hyperglycemia (blood sugars that are too high). In this way, intestinal hormonal signaling is important for whole body glucose homeostasis in the fasting and post-prandial states. The treatment can also lead to weight loss through decreased absorption of nutrients, increased sensation of satiety, altered food preferences, increased energy expenditure, and combinations of two or more of these.

[0131] In patients with type 2 diabetes, a lifetime of exposure to fat and sugar can lead to intestinal changes that occur in regions with the highest exposure to these nutrients, predominantly in the proximal intestine. These changes are characterized by an excess proximal intestinal mucosa’s hormonal contribution to the fasting and post-prandial glucose homeostasis. The net result of these intestinal changes is to create a condition of insulin resistance and impaired glucose tolerance. Treatment of duodenal mucosal tissue with the systems, devices and methods of the present inventive concepts can be performed to alter the intestinal mucosal hormone production from the region of treated tissue. The treated tissue can then have an altered hormonal secretion pattern that affects blood glucose levels in the fasting and post-prandial states. The tissue treatment of the present inventive concepts can be performed to effect duodenal mucosal tissue secretion of GIP and / or GLP-1. The tissue treatment can lead to changes in the blood levels of GIP and / or GLP-1 (and other gut hormones) that can lead to changes in glucose homeostasis in the fasting and / or post-prandial states. The treatment can lead to changes in insulin and / or glucagon secretion from the pancreas and / or insulin and / or glucagon levels in the bloodstream. The treatment can lead to changes in pancreatic beta cell function and / or health through direct hormonal consequences of the treated duodenal tissue and / or indirectly through improved blood glucose levels. In some embodiments, the treatment of the present inventive concepts is configured to at least one of reduce a blood glucose level and / or reduce a lipoprotein level.

[0132] Treatment of intestinal tissue (e.g., duodenal mucosal tissue) using the systems, devices, and methods of the present inventive concepts can be performed to treat a medical condition (e.g., a disease and / or disorder) selected from the group consisting of: diabetes; prediabetes; impaired glucose tolerance; insulin resistance; a condition caused by or otherwiserelated to insulin resistance; obesity or otherwise being overweight; a metabolic disorder and / or disease; a condition caused by or otherwise related to a metabolic disorder and / or disease; and combinations of two or more of these. In some embodiments, treatment of intestinal tissue (e.g., at least duodenal mucosal tissue) using the systems, devices and / or methods of the present inventive concepts can be performed to treat one or more medical conditions selected from the group consisting of: type 2 diabetes; type 1 diabetes; "Double diabetes"; gestational diabetes; hyperglycemia; pre-diabetes; impaired glucose tolerance; insulin resistance; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic dysfunction-associated steatohepatitis (MASH); obesity; obesity-related disorder; polycystic ovarian syndrome (PCOS); hypertriglyceridemia; hypercholesterolemia; psoriasis; GERD; coronary artery disease (e.g., as a secondary prevention); stroke; TIA; cognitive decline; dementia; Alzheimer's disease; neuropathy; diabetic nephropathy; retinopathy; heart disease; diabetic heart disease; heart failure; diabetic heart failure; hirsutism; hyperandrogenism; fertility issues; menstrual dysfunction; cancer such as liver cancer, ovarian cancer, breast cancer, endometrial cancer, cholangiocarcinoma, adenocarcinoma, glandular tissue tumor(s), stomach cancer, large bowel cancer, and / or prostate cancer; diastolic dysfunction; hypertension; myocardial infarction; microvascular disease related to diabetes; sleep apnea; arthritis; rheumatoid arthritis; hypogonadism; insufficient total testosterone levels; insufficient free testosterone levels; and combinations of two or more of these. In some embodiments, two, three, or more of the above medical conditions listed immediately hereabove are treated using the systems, devices, and methods of the present inventive concepts. A near full circumferential portion (e.g., approximately 360°) of the mucosal layer of one or more axial segments of GI tissue can be treated. In some embodiments, less than 360° of one or more axial segments of tubular tissue is treated, such as one or more circumferential portions less than 350°, or between 300° and 350°, such as to prevent a full circumferential scar from being created at the one or more axial segment locations. In order to achieve a desired therapeutic benefit, a minimum amount of mucosal tissue can be treated, such as is described herein.

[0133] In some embodiments, the systems, devices, and methods of the present inventive concepts are used to treat arthritis, such as rheumatoid arthritis. In these embodiments, arthritis and another disease or disorder of the patient can be treated, such as when one, two, or more of the following are treated in addition to arthritis: insulin resistance, diabetes, non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic dysfunction-associated steatohepatitis (MASH); polycystic ovarian syndrome (PCOS); and combinations of these. For example, patients witharthritis may exhibit abnormal and / or dysfunctional glucose metabolism. In some embodiments, a patient exhibiting insulin resistance as well as arthritis (e.g., rheumatoid arthritis) has their small intestinal mucosa (e.g., their duodenal mucosa) treated with the systems of the present inventive concepts.

[0134] Target tissue can be selected to treat two or more patient diseases or disorders, such as two or more patient diseases or disorders as described herein.

[0135] Target tissue can comprise tissue of the terminal ileum, such as to treat hypercholesterolemia and / or diabetes. In these embodiments, the target tissue can extend into the proximal ileum and / or the colon.

[0136] Target tissue can comprise gastric mucosal tissue, such as tissue regions that produce ghrelin and / or other appetite regulating hormones, such as to treat obesity and / or an appetite disorder.

[0137] Target tissue can comprise tissue selected from the group consisting of large and / or flat colonic polyps; margin tissue remaining after a polypectomy; and combinations of two or more of these. These tissue locations can be treated to treat residual cancer cells.

[0138] Target tissue can comprise at least a portion of the intestinal tract afflicted with inflammatory bowel disease (e.g., chronic inflammatory bowel disease), such that Crohn’s disease and / or ulcerative colitis can be treated.

[0139] Target tissue can comprise GI tissue selected to treat Celiac disease and / or to improve intestinal barrier function.

[0140] The functional assemblies, functional elements, systems, devices, and methods of the present inventive concepts can be configured to avoid ablating or otherwise adversely affecting certain tissue, termed “non-target tissue” herein. Depending on the location of tissue intended for treatment (i.e., target tissue), different non-target tissue can be applicable. In certain embodiments, non-target tissue can comprise tissue selected from the group consisting of gastrointestinal adventitia; duodenal adventitia; the tunica serosa; the tunica muscularis; the outermost partial layer of the submucosa; ampulla of Vater; papilla; pancreas; bile duct; pylorus; and combinations of two or more of these.

[0141] In some embodiments, two or more clinical procedures are performed in which one or more volumes of target tissue are treated in each clinical procedure, such as is described in applicant’s co-pending United States Patent Application Serial Number 17 / 568,145 (Attorney Docket No. 41714-708.302; Client Docket No. MCT-009-US-CON1), entitled “Methods, Systems and Devices for Performing Multiple Treatments on a Patient”, filed January 4, 2022. For example, a second clinical procedure can be performed at least twenty-four hours after thefirst clinical procedure, such as a second clinical procedure performed within six months of a first clinical procedure, or a clinical procedure performed after at least six months after the first clinical procedure. The first and second clinical procedures can be performed using similar or dissimilar methods, and they can be performed using similar or dissimilar systems and / or devices (e.g., performed with similar or dissimilar treatment and / or other functional elements). The first and second clinical procedures can treat similar or dissimilar volumes of target tissue (e.g., similar or dissimilar amounts of tissue treated and / or locations of tissue treated), and they can deliver energy to similar or dissimilar sets of multiple delivery zones. In some embodiments, the first and second clinical procedures can include treating and / or delivering energy to contiguous and / or overlapping regions of the GI tract either in the circumferential and / or axial dimensions. In other embodiments, the first and second clinical procedures can include the treatment of disparate regions of the GI tract (such as disparate regions of the duodenum, ileum, and / or stomach). The first and second clinical procedures can be performed using similar or dissimilar devices (e.g., catheters). The first and second clinical procedures can comprise similar or dissimilar deliveries of energy to treat the target tissue. The first and second clinical procedures can be performed at similar or dissimilar temperatures. The second clinical procedure can be performed based on diagnostic results collected after the first clinical procedure has been performed, such as when the diagnostic results are based on a biopsy of mucosal tissue.

[0142] The functional assemblies (also referred to as treatment assemblies and tissue treatment assemblies), treatment elements and other functional elements of the present inventive concepts can comprise an expandable element or otherwise be configured to automatically and / or manually expand or traverse in at least one radial direction. Typical expandable elements include but are not limited to an inflatable balloon; a radially expandable cage or stent; one or more radially deployable arms; an expandable helix; an unfurlable compacted coiled structure; an unfurlable sheet; an unfoldable compacted structure; and combinations of two or more of these. In some embodiments, an expandable element can comprise a radially expandable tube, such as a sheet of material resiliently biased in a radially expanded condition that can be compacted through a furling operation, or a sheet of material resiliently biased in a radially compact condition that can be expanded through an unfurling operation. An expandable element can comprise a foldable sheet, such as a sheet configured to be folded to be radially compacted and / or to be unfolded to radially expand. In some embodiments, an expandable element expands to contact tissue, such as to expand to a diameter similar to the diameter of the luminal wall tissue into which the expandable element has been placed. In some embodiments, an expandable element expands to be closer to wall tissue, but the element remains at a distance (e.g., a fixed orpre-determined distance) from the tissue surface, such as when the tissue is subsequently brought into contact with all or a portion of an expanded functional assembly or functional element (e.g., using insufflation fluid withdrawal techniques). In some embodiments, an expandable element expands to be larger than the diameter of the luminal wall tissue into which the expandable element has been placed, such as to improve the quality of the apposition of the expandable element against the uneven surface of the tissue. In these embodiments, the fully expanded diameter of an expandable element would be configured to avoid a diameter large enough to cause lasting mechanical damage to the apposed tissue and / or to tissue proximate the apposed tissue. In some embodiments, the expansion of an expandable element (e.g., the expansion of an expandable functional assembly) is monitored and / or varied (e.g., decreased and / or increased), such as to accommodate or otherwise compensate for peristalsis or other muscle contractions that occur in the GI tract (e.g., contractions that occur when a foreign body is present in the GI tract) and / or varied to accommodate changes in GI lumen diameter imposed by aspects of the procedure itself.

[0143] Any device (e.g., catheter) of the present inventive concepts can include one or more functional elements comprising one or more treatment elements configured to deliver energy to one or more delivery zones, to treat at least a portion of target tissue. Any device can include one or more functional elements comprising one or more fluid delivery elements, such as one or more nozzles or needles configured to deliver fluid toward and / or into tissue. The fluid delivery elements can be constructed and arranged to deliver fluid to perform a function selected from the group consisting of expanding one or more tissue layers; warming or cooling tissue; removing debris or other substance from a tissue surface; delivering energy to a delivery zone comprising a continuous or segmented surface; treating target tissue; and combinations of two or more of these. Any of the expandable functional assemblies of the present inventive concepts can include one or more other functional elements, such as are described herein. The treatment elements and / or other functional elements (e.g., fluid delivery elements) can be mounted on, within (e.g., within the wall) and / or inside of an expandable element such as a balloon or expandable cage. In some embodiments, one or more functional elements is not mounted to an expandable element, such as those attached to a shaft or other non-expandable catheter component.

[0144] In some embodiments, a catheter comprises at least one functional element configured to deliver energy to a delivery zone such as to ablate target tissue. Examples of ablation-based functional elements include but are not limited to: ablative fluids, such as hot or cold ablative fluids delivered to a balloon and / or directly to target tissue; one or more fluid delivery elementsconfigured to deliver ablative fluid directly to target tissue; a radiofrequency (RF) and / or microwave energy delivery element such as one or more electrodes; an ultrasonic and / or subsonic transducer such as one or more piezo crystals configured to ablate tissue with ultrasonic or subsonic energy, respectively, sound waves; a laser energy delivery element such as one or more optical fibers, laser diodes, prisms and / or lenses; a rotating ablation element; a circumferential array of ablation elements; and combinations of two or more of these.

[0145] The expandable elements comprising balloons of the present inventive concepts can be divided into two general categories: those that are composed of a substantially elastic material, such as silicone, latex, low-durometer polyurethane, and the like; and those that are composed of a substantially inelastic material, such as polyethylene terephthalate (PET), nylon, high- durometer polyurethane, and the like. A third category includes balloons which include both elastic and inelastic portions. Within the category of elastic balloons, two subcategories exist: a first sub-category wherein a combination of material properties and / or wall thickness can be combined to produce a balloon that exhibits a measurable pressure-threshold for inflation (i.e., the balloon becomes inflated only after a minimum fluidic pressure is applied to the interior of the balloon); and a second sub-category, wherein the balloon expands elastically until an elastic limit is reached which effectively restricts the balloon diameter to a maximum value. The individual properties of the balloons in each of these categories can be applied to one or more advantages in the specific embodiments disclosed herein, these properties integrated singly or in combination. By way of example only, one or more of the following configurations can be employed: a highly elastic balloon can be used to achieve a wide range of operating diameters during treatment (e.g., during operation a desired balloon diameter can be achieved by adjustment of a combination of fluid temperature and pressure); a substantially inelastic balloon or a balloon that reaches its elastic limit within a diameter approximating a target tissue diameter (e.g., a duodenal mucosal diameter) can be used to achieve a relatively constant operating diameter that will be substantially independent of operating pressure and temperature; a balloon with a pressure-threshold for inflation can be used to maintain an uninflated diameter during relatively low pressure conditions of fluid flow and then achieve a larger operating diameter at higher pressure conditions of flow. Pressure-thresholded balloons can be configured in numerous ways. In one embodiment, a balloon is configured to have a relatively thick wall in its uninflated state, such as to maximize an electrically and / or thermally insulating effect while the balloon is maintained in this uninflated state. The balloon can be further configured such that its wall thickness decreases during radial expansion (e.g., to decrease an electrically and / or thermally insulating effect). In another embodiment, a balloon is configured to have a relativelysmall diameter in its uninflated state (e.g., a diameter that is small relative to the inner diameter of tubular target tissue such as the diameter of the mucosal layer of duodenal wall tissue), such as to minimize or completely eliminate apposition between the balloon and the surrounding tissue to minimize heat, RF and / or other energy transfer into the surrounding tissue until the balloon is fully inflated. In another embodiment, a balloon and an ablation system or catheter are configured to circulate a flow of fluid through the balloon (e.g., an elastic balloon or an inelastic balloon) at a sufficiently low enough pressure to prevent apposition of the balloon or other catheter component with target tissue, such as to pre-heat one or more surfaces of the ablation system or ablation device that are in fluid communication with the balloon. In this configuration, when the balloon or other ablation element is positioned to deliver energy to target tissue, the temperature of the balloon or other ablation element will be at a desired level or it will rapidly and efficiently reach the desired level for treatment (i.e., minimal heat loss to the fluid path components due to the pre-heating or pre-cooling). These configurations provide a method of delivering energy to tissue with an ablative fluid filled balloon. A “thermal priming” procedure can be performed prior to one or more target tissue treatments, such as to improve thermal response time of one or more portions of the catheter. Ablative fluid filled balloon catheters as well as thermal priming devices and methods can be configured as is described in applicant’s copending United States Patent Application Serial Number 17 / 864,855 (Attorney Docket No. 41714-704.303; Client Docket No. MCT-002-US-CON2), entitled “Heat Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed July 14, 2022.

[0146] A fluid evacuation procedure can be performed on one or more internal locations of the catheters, functional assemblies and / or functional elements of the present inventive concepts, such as when a negative pressure is applied to purge or otherwise evacuate fluid from one or more locations. A fluid evacuation procedure can be performed prior to a thermal priming procedure and / or prior to delivering ablative fluid to a treatment element.

[0147] At times during target tissue treatment when it is desirable to initiate, increase and / or otherwise modify the treatment of tissue by one or more treatment elements (e.g., a fluid delivery element delivering ablative fluid, a mechanically abrasive element, a hot or cold fluid balloon delivering a thermal energy to tissue and / or an electrode delivering RF energy), the diameter of the tissue treatment assembly and / or treatment element (e.g., the diameter of a balloon, deployable cage, expandable tube or other expandable assembly) can be increased in situ to move a treatment element closer to target tissue and / or to change the contact force between the treatment element and the target tissue. At times during treatment when it is desirable to stop or otherwise decrease the amount of tissue treatment, the diameter of the tissue treatment assemblyand / or treatment element can be reduced in situ, such as to prevent or otherwise reduce delivery of energy or other treatment to the target tissue by eliminating or reducing tissue contact of one or more treatment elements (e.g., electrodes, abrasive surfaces, or ablative fluid-filled balloons). For those cases where the native diameter of the target tissue varies substantially within a delivery zone, then a highly elastic or compliant balloon or other expandable element can be employed, such as a balloon or deployable cage which can be adjusted to achieve a wide range of operating diameters.

[0148] Alternatively or additionally, to initiate, increase and / or otherwise modify the treatment of tissue by one or more functional elements (e.g., a fluid delivery element delivering ablative fluid, a mechanically abrasive element, a hot or cold fluid balloon delivering thermal energy to or from tissue and / or an electrode delivering RF energy), the diameter of the target tissue can be decreased in situ to move target tissue closer to a treatment element and / or to change the contact force between the target tissue and the treatment element. To stop or otherwise decrease ablation of tissue, the diameter of tissue neighboring a treatment element can be increased in situ, such as to prevent or otherwise reduce delivery of energy or other treatment to the target tissue by eliminating or reducing tissue contact of one or more treatment elements (e.g., electrodes, abrasive surfaces or ablative fluid filled balloons). The diameter of the tissue proximate a functional assembly can be increased or decreased, independent of the functional assembly diameter, by means of delivering and / or withdrawing a fluid, to and / or from a body lumen (e.g., a lumen of a segment of the intestine) surrounded by target tissue, such as by using standard GI insufflation techniques. Typical insufflation fluids include but are not limited to gases such as carbon dioxide or air; liquids such as water or saline solution; and combinations of two or more of these. The insufflation fluids can be introduced through a catheter, through an endoscope such as an endoscope through which the catheter is inserted, and / or via another device placed proximate the target tissue. Delivery of insufflation fluids can be performed to move target tissue away from one or more functional elements, such as to stop transfer of energy to target tissue at the end of a treatment of target tissue as described herein. Alternatively or additionally, delivery of insufflation fluids can be performed to manipulate tissue, such as to distend and / or elongate tissue. Extraction of these insufflation fluids and / or the application of a vacuum or other negative pressure can be used to decrease the diameter of the target tissue, such as to bring the target tissue in closer proximity to one or more functional elements and / or to increase the contact force between target tissue and one or more functional elements, also as described herein. In this tissue diameter-controlled approach, a functional assembly including a balloon that can bemaintained at a substantially constant diameter can be desirable, such as a substantially inelastic balloon such as a balloon with an elastic-limit.

[0149] The systems of the present inventive concepts can include one or more tissue expansion catheters that comprise one or more functional elements configured as fluid delivery elements. In these embodiments, the one or more functional elements can comprise one or more needles, nozzles and / or fluid jets configured to deliver one or more fluids or other injectates to tissue, such as to expand target tissue and / or tissue proximate the target tissue (e.g., safety margin tissue) prior to treatment of target tissue by a tissue treatment element. The expanded tissue layer acts as a safety volume of tissue, reducing the specificity of the treatment (e.g., ablation) required and / or the need to protect the underlying non-target tissue from damage. In some embodiments, a vacuum pressure can be used to manipulate tissue and / or to maintain proximity between a portion of a tissue expansion device and tissue. The vacuum can be provided by one or more vacuum sources, such as via one or more operator adjustable vacuum sources.

[0150] Many patients with type 2 diabetes (T2D) are prescribed insulin therapy, “daily insulin”, in order to treat high blood sugar. While insulin administration is a mainstay of type 2 diabetes therapy, more than half of patients do not achieve glycemic targets. Typically, insulin- treated patients have a higher prevalence of severe comorbidities, such as cardiovascular, renal, and / or hepatic comorbidities, than non-insulin-treated patients. Further, insulin therapy for type 2 diabetes is associated with weight gain (an increase in visceral adiposity), loss of beta-cell function, worsening of insulin resistance, and / or a high frequency of hypoglycemia, which is associated with poorer health outcomes and increased mortality. Moreover, insulin therapy in T2D is a symptomatic treatment of high blood sugar rather than a pharmacotherapy targeting the underlying insulin resistance that leads to the progressive nature of the disease. As such, insulin therapy quickly becomes insufficient and treatment intensification is needed. These factors taken together lead to tremendous dissatisfaction on the part of patients, poor clinical outcomes, and high cost of care. Therapies that reduce the need for insulin enable improved glycemic control with reduced rates of hypoglycemia and reduced rates of weight gain. The systems and methods (e.g., treatments) of the present inventive concepts provide improved glycemic control with reduced rates of hypoglycemia, weight loss, improvements to hepatic disease (such as improved liver fat content), and other benefits. These systems and methods can be configured to not require significant adherence to a drug protocol by the patient (e.g., including minimization or complete avoidance of taking one or more drugs previously part of the patient’s treatment). Similarly, undesirable side-effects of these drugs can be avoided (e.g., nausea with GLP-1, or increased rates of urologic infections with SGLT2 inhibitors). The systems and methods of thepresent inventive concepts can be configured to allow an operator to perform a tissue treatment procedure (e.g., a tissue ablation procedure) on one or more segments of the patient’s duodenum and / or other portions of the patient’s gastrointestinal (GI) tract. The systems and methods of the present inventive concepts can reduce insulin intake by the patient without requiring the patient to adhere to a special diet (e.g., differing from diet-based approaches to insulin reduction). The systems and methods of the present inventive concepts can be configured to provide a reduction in therapeutic complications (e.g., as compared to a previous therapy in which the patient was treated) such as a reduction in microvascular complications (e.g., diabetic kidney disease, diabetic retinopathy) and / or macrovascular complications (e.g., myocardial infarction, stroke). The therapeutic benefits provided by the present inventive concepts can also include improvements in blood pressure, microalbuminuria, glomerular filtration rate, and / or other microvascular and macrovascular risk factors. The therapeutic benefits provided by the present inventive concepts can include a reduction in total body weight. The therapeutic benefits provided by the present inventive concepts can include a reduction in the likelihood of liver disease such as cirrhosis or liver carcinoma.

[0151] The systems, devices, and methods of the present inventive concepts can be configured to treat various duodenal dysfunctions, such as are described herein. Furthermore, and also as described herein, duodenal mucosal hyperplasia is a potential therapeutic target for metabolic diseases related to insulin-resistance. Applicant has demonstrated that treatment of intestinal mucosa (e.g., one or more portions of duodenal mucosa) can correspondingly therapeutically treat intestinal hyperplasia (e.g., duodenal mucosal hyperplasia), such as by reducing at least one of duodenal mucosal surface area; duodenal mucosal volume; duodenal mucosal weight; duodenal mucosal villous height; quantity of duodenal villi; duodenal mucosal crypt density; duodenal mucosal enteroendocrine cell quantity; and / or duodenum-specific hormone production (e.g., GIP and / or CCK).

[0152] Referring now to Fig. 1, a schematic view of a system and device for performing a medical procedure on the small intestine of a patient is illustrated, consistent with the present inventive concepts. System 10 can be constructed and arranged to perform the method described in Fig. 3 herebelow, such as to treat one or more patient diseases or disorders, also as described herein. System 10 comprises one or more tissue treatment devices, device 100, and one or more consoles, console 200, each as shown. Treatment device 100 is constructed and arranged to treat target tissue, such as via the delivery of energy and / or an ablating agent to target tissue. Device 100 includes connector 103 which operably attaches to connector 203 of console 200. In some embodiments, system 10 further comprises a tissue expansion device, device 20 shown, which isconstructed and arranged to expand one or more layers of tissue, such as one or more layers of target tissue and / or one or more layers of tissue proximate target tissue (e.g., one or more layers of safety-margin tissue as described herein). In some embodiments, system 10 further comprises one or more lumen diameter sizing devices, device 30, which is constructed and arranged to collect information correlated to the diameter of a portion of tubular tissue (e.g., one, two or more diameters of a GI lumen within and / or proximate target tissue). In some embodiments, system 10 comprises one or more multi-function devices, device 40, which is constructed and arranged to perform two or more functions selected from the group consisting of: tissue treatment (e.g., tissue ablation); tissue expansion; luminal diameter sizing; and combinations of two or more of these. In some embodiments, system 10 comprises multi -function device 40, and does not include one or more of: device 100, tissue expansion device 20 and / or sizing device 30.

[0153] System 10 can further comprise a body introduction device, device 50, such as a vascular introducer, laparoscopic port, and / or endoscope, such as endoscope 50a shown. System 10 can further comprise one or more guidewires, such as guidewires 60a and 60b (singly or collectively guidewire 60). In some embodiments, one or more guidewires 60 comprise a guidewire selected from the group consisting of: a Savary-Gilliard® 400cm guidewire; a Dreamwire™ guidewire; a super stiff Jagwire™ guidewire; and / or a similar guidewire. In some embodiments, system 10 includes a scope attached sheath, sheath 80 shown. Sheath 80 can comprise an elongate hollow tube which attaches (e.g., in a side-by-side manner) at one or more points along endoscope 50a. Sheath 80 can attach to endoscope 50a along a majority of its length. In some embodiments, sheath 80 comprises the Reach® overtube manufactured by U.S. Endoscopy, or similar.

[0154] Device 100, tissue expansion device 20, lumen diameter sizing device 30 and multifunction device 40 comprise handles 102, 22, 32 and 42, respectively. Handles 102, 22, 32 and 42 each comprise one or more controls, controls 104, 24, 34 and 44, respectively. Controls 104, 24, 34 and 44 are configured to allow an operator to control one or more functions of the associated device, such as a function selected from the group consisting of: inflate or otherwise expand a functional assembly (e.g., functional assembly 130); deliver energy; modify energy delivery; deliver an insufflation fluid; insufflate a portion of the GI tract; desufflate a portion of the GI tract; deliver an inj ectate (e.g., into tissue and / or onto the surface of tissue); deliver a tissue expanding fluid (e.g., into tissue); steer the distal portion of a shaft; translate a control cable or control rod (hereinafter “control rod”); activate a sensor (e.g., record a signal); activate a transducer; and combinations of two or more of these. In some embodiments, handles 102, 22, 32 and / or 42 comprise a user interface configured to control one or more components of system10, such as controls 104, 24, 34 and / or 44, respectively, each of which can be constructed and arranged to control operation of one or more of: device 100, device 20, device 30, device 40 and / or console 200. In some embodiments, controls 104, 24, 34 and / or 44 comprise one or more user input and / or user output components, such as a component selected from the group consisting of: screen; touchscreen; light; audible transducer such as a beeper or speaker; tactical transducer such as a vibratory motor assembly; a keyboard; a membrane keypad; a switch; a safety-switch such as a foot-activated switch; a mouse; a microphone; and combinations of two or more of these.

[0155] Handles 102, 22, 32 and 42 each attach to the proximal end of shafts 110, 21, 31 and 41, respectively. Shafts 110, 21, 31 and 41 each typically comprise a relatively flexible shaft comprising one or more internal lumens or other passageways. Shafts 110, 21, 31 and / or 41 can comprise a lumen, such as lumen 116 of shaft 110 shown, that is sized and configured to perform a function selected from the group consisting of: provide for the delivery or extraction of one or more fluids such as ablation fluids, cooling fluids, insufflation fluids, pneumatic fluids, hydraulic fluids and / or balloon expanding fluids; allow over the guidewire delivery of the associated device; surround an electrical wire providing electrical energy and / or signals; slidingly receive a control shaft or other control filament such as a control filament used to expand or contract a functional assembly (e.g., functional assembly 130) or otherwise modify the shape of a portion of the device; and combinations of two or more of these. Shafts 110, 21, 31 and / or 41 can comprise a braided or otherwise reinforced shaft or they can include one or more portions which are reinforced. Shafts 110, 21, 31 and / or 41 can comprise a multi-layer construction, such as a construction including a braid, a friction-reduced (e.g., PTFE) liner, a thermally insulating layer and / or an electrically insulating layer. Shafts 110, 21, 31 and / or 41 can include a bulbous distal end, such as tip 115 of shaft 110 shown, a circular or elliptical shaped enlarged end configured to improve traversing the innermost tissue of the duodenum or other luminal tissue of the GI tract (e.g., to smoothly advance within a lumen whose walls include villi and / or one or more folds). As described herein, shafts 110, 21, 31 and / or 41 can include a guidewire lumen, such as lumen 116 of shaft 110.

[0156] Positioned on the distal end or on a distal portion of shafts 110, 21, 31 and 41 is an expandable functional assembly, functional assemblies 130, 25, 35 and 45, respectively. Functional assemblies 130, 25, 35 and 45 are each constructed and arranged to be radially expanded and subsequently radially compacted (each shown in their radially expanded state in Fig. 1), one or more times during use. Each of functional assemblies 130, 25, 35 and 45 can include an expandable element selected from the group consisting of: an inflatable balloon; aradially expandable cage or stent; one or more radially deployable arms; an expandable helix; an unfurlable compacted coiled structure; an unfurlable sheet; an unfoldable compacted structure; and combinations of two or more of these. Each functional assembly 130, 25, 35, and 45 can comprise a balloon, balloons 136, 26, 36, and 46, respectively, as shown. Functional assemblies 130 and / or 45 can each comprise one or more treatment elements, treatment elements 135 and / or 135’ shown, respectively, each an element which can be configured to treat target tissue. Treatment element 135 and / or 135’ (singly or collectively treatment element 135) can be similar to one or more functional elements 139 described herein in reference to device 100.

[0157] In some embodiments, device 100, tissue expansion device 20, lumen diameter sizing device 30 and / or multi -function device 40, with their functional assemblies 130, 25, 35 and 45 (respectively) in their radially compacted state, are sized and configured to be inserted through a working channel of endoscope 50a and / or sheath 80, after endoscope 50a and / or sheath 80 have been inserted into a patient (e.g., through the mouth and advanced such that their distal end resides in the duodenum or other GI tract location). In some embodiments, device 100, tissue expansion device 20, sizing device 30 and / or multi -function device 40 are sized and configured to be inserted through the mouth and into a patient’s GI tract alongside endoscope 50a. In some embodiments, device 100, tissue expansion device 20, lumen diameter sizing device 30 and / or multi -function device 40 are sized and configured to be inserted into a patient over one or more guidewires 60. For insertion over a guidewire, the shafts 110, 21, 31 and / or 41 and the distal portions of the associated device 100, 20, 30 and / or 40 can comprise a distal portion with sufficient length and flexibility to traverse the pylorus and enter the duodenum, while having sufficient column strength, torsional strength, and length to be advanced through the duodenum. In some embodiments, one or more portions of the shafts 110, 21, 31 and / or 41 have variable stiffness (e.g., stiffer in a proximal portion of the shaft) and / or include a lumen configured to accept a stiffening wire or other stiffening mandrel (e.g., a tapered mandrel), such as stiffening wire 67. Alternatively or additionally, stiffening wire 67 can be inserted into endoscope 50a and / or sheath 80, such as to facilitate their advancement through the stomach and into the duodenum. In some embodiments, shaft 110, 21, 31, and / or 41 comprises at least a braided portion. In some embodiments, shaft 110, 21, 31, and / or 41 comprises a tapered portion.

[0158] Console 200 can be constructed and arranged in a similar fashion to console 200 of Figs. 6 and / or 9 described herein. Console 200 can comprise an operator (e.g., clinician) accessible user interface 205. User interface 205 can comprise one or more user output and / or user input components, such as a component selected from the group consisting of: screen; touchscreen; light; audible transducer such as a beeper or speaker; tactical transducer such as avibratory motor assembly; a keyboard; a membrane keypad; a switch; a safety-switch, such as switch 206 shown (e.g., a foot-activated switch); a mouse; a microphone; and combinations of two or more of these.

[0159] Console 200 can comprise a controller, such as controller 250. Controller 250 can comprise one or more components or assemblies selected from the group consisting of: an electronics module; a power supply; memory (e.g., volatile or non-volatile memory circuitry); a microcontroller; a microprocessor; a signal analyzer; an analog to digital converter; a digital to analog converter; a sensor interface; transducer drive circuitry; software; and combinations of two or more of these. Controller 250 can be configured to perform and / or facilitate one or more functions of system 10, such as one or more processes, energy deliveries (e.g., ablative energy deliveries), data collections, data analyses, data transfers, signal processing, and / or other functions (“functions” herein). Controller 250 can include one or more processors, memory, and / or algorithms. For example, controller 250 can comprise one or more algorithms 251. The memory of controller 250 can be coupled to the processor and can store instructions for the processor to perform algorithm 251. Algorithm 251 can be constructed and arranged to automatically and / or manually control and / or monitor one or more devices, assemblies and / or components of system 10. Algorithm 251 can comprise one or more algorithms, such as one or more machine learning, neural net, and / or other artificial intelligence algorithms (“Al algorithm” herein). Algorithm 251 of controller 250 can be configured to determine one or more tissue expansion, tissue ablation, and / or other tissue treatment parameters. In some embodiments, algorithm 251 processes one or more sensor signals (e.g., signals from functional elements 139, 29, 39 and / or 49 described herein) to modify one or more of: volume of tissue expansion fluid delivered; rate of tissue expansion fluid delivery; temperature of tissue expansion fluid delivery; amount of ablative fluid delivered; rate of ablative fluid delivery; energy delivered; power of energy delivered; voltage of energy delivered; current of energy delivered; temperature of ablative fluid or energy delivered; device and / or treatment element location within the GI tract; functional assembly pressure (e.g., balloon pressure); and combinations of two or more of these. Treatment elements 135 and / or 135’ can deliver energy to a surface of tissue, such as to a delivery zone as described herein, which comprises a subset of the target tissue treated by that energy delivery (e.g., due to the conduction of heat or other energy to neighboring tissue). Algorithm 251 can comprise an algorithm configured to determine a delivery zone parameter such as a delivery zone parameter selected from the group consisting of: anatomical location of a delivery zone; size of delivery zone; percentage of delivery zone to receive energy; type of energy to be delivered to a delivery zone; amount of energy to be delivered to a delivery zone;and combinations of two or more of these. Information regarding the delivery zone parameter can be provided to an operator of system 10 (e.g., a clinician), such as via user interface 205. This information can be employed to set a delivery zone parameter, assist the operator in determining the completion status of the procedure (e.g., determining when the procedure is sufficiently complete) and / or to advise the operator to continue to complete a pre-specified area or volume of target tissue. The total area of treatment or number of delivery zones or number of treatments during a particular procedure (any of which can be employed in algorithm 251) can be defined by clinical and / or demographic data of the patient.

[0160] Console 200 can comprise one or more reservoirs or other sources of fluid, such as reservoir 220. Reservoir 220 can be configured to provide one or more of: fluid at an ablative temperature (e.g., sufficiently hot or cold to ablate tissue); a treatment neutralizing (e.g., cooling or warming) fluid configured to reduce and / or limit ablative effects; an insufflation fluid, inj ectate 221 (e.g., similar to inj ectate 221 described herein in reference to Fig. 9); an agent (e.g., agent 420 described herein in reference to Figs. 6 and / or 9); and / or another fluid. Console 200 can comprise an energy delivery unit, such as EDU 260, configured to deliver energy to treatment element 135, treatment element 135’, and / or one or more other components of system 10, such as one or more components of devices 100, 20, 30 and / or 40 (e.g., to functional assemblies 130, 25, 35, and / or 45, respectively). Controller 250, reservoir 220 and / or EDU 260 can be of similar construction and arrangement as controller 250, reservoir 220 and / or EDU 260, respectively, of Figs. 6 and / or 9 described herein.

[0161] Console 200 can comprise a pressure or other fluid pumping assembly, such as pumping assembly 225 constructed and arranged to deliver positive pressure or vacuum pressure (e.g., any pressure below another pressure) to one or more fluid pathways (e.g., lumens), fluid delivery elements, and / or balloons of system 10. Pumping assembly 225 can be constructed and arranged to provide and / or extract fluid to radially expand and / or radially compact, respectively, one or more expandable assemblies, such as functional assemblies 130, 25, 35 and / or 45 comprising a balloon or other fluid expandable structure (“balloon” herein). Pumping assembly 225 can comprise one or more pumps or other fluid delivery mechanisms, and / or other pressure or vacuum generators. In some embodiments, pumping assembly 225 is constructed and arranged to provide a recirculating ablative fluid (e.g., hot or cold) to device 100 and / or device 40 (e.g., to balloon 136 and / or 46, respectively). In these embodiments, pumping assembly 225 can be constructed and arranged to further provide a recirculating “neutralizing fluid” (e.g., a cooling or warming fluid, respectively, to counteract the ablative effects of the previously circulated ablative fluid) to balloon 136 and / or 46, respectively. Pumping assembly 225 can beof similar construction and arrangement as pumping assembly 225 of Fig. 9 described herein. In some embodiments, pumping assembly 225 is constructed and arranged to deliver inj ectate 221 to a functional assembly 130, 25, 35 and / or 45, such as an injectate configured to expand tissue and / or to create a therapeutic restriction, as described herein, such as an injectate similar to injectate 221 described herein in reference to Fig. 9.

[0162] Console 200 includes connector 203, which is operably attached to one or more of: user interface 205 (e.g., safety-switch 206 or another component of user interface 205), controller 250, reservoir 220 and / or pumping assembly 225. Connector 203 is constructed and arranged to operably attach (e.g., fluidly, electrically, optically, acoustically, mechanically and / or otherwise operably attach) to one or more of connectors 103, 23, 33 and 43 of devices 100, 20, 30 and 40, respectively. Console 200 can be constructed and arranged to deliver fluids and / or energy via connector 203 to one or more of devices 100, 20, 30 and 40. In some embodiments, an inflation fluid and / or a fluid at an ablative temperature is provided and / or recovered by console 200, such as a fluid at an ablative temperature delivered to functional assembly 130 of device 100 and / or functional assembly 45 of device 40. In some embodiments, insufflation, pneumatic and / or hydraulic fluids are delivered and / or recovered by console 200 via connector 203. In some embodiments, an injectate 221 is delivered by console 200, such as is described herein in reference to tissue expansion device 20 and multi -function device 40. In some embodiments, one or more control rods (not shown) are translated (e.g., advanced and / or retracted) within one or more lumens or other openings of device 100, 20, 30 and / or 40, such as to expand a cage, deploy a radially deployable arm, change the shape of an assembly, translate an assembly, rotate an assembly and / or otherwise control the position, shape and / or configuration of an assembly of system 10.

[0163] Console 200 can provide energy to send information to and / or record and / or receive a signal from one or more other elements of device 100, such as functional elements 139, 29, 39 and / or 49 described herein.

[0164] Device 100 and / or device 40 can be constructed and arranged to treat target tissue of a patient. In some embodiments, device 100 and / or device 40 is of similar construction and arrangement as device 100 of Figs. 6 and / or 9 described herein. Device 100 comprises handle 102 which attaches to a proximal end of shaft 110 and includes connector 103 for operable attachment to console 200. Positioned on the distal end or on a distal portion of shaft 110 is functional assembly 130. Device 40 comprises handle 42 which attaches to a proximal end of shaft 41 and includes connector 43 for operable attachment to console 200. Positioned on the distal end or on a distal portion of shaft 41 is functional assembly 45. Functional assembly 130or 45 can comprise an expandable element selected from the group consisting of: an inflatable balloon such as balloons 136 and 46 shown; a radially expandable cage or stent; one or more radially deployable arms; an expandable helix; an unfurlable compacted coiled structure; an unfurlable sheet; an unfoldable compacted structure; and combinations of two or more of these. Functional assembly 130 or 45 can comprise an energy delivery element or other tissue treatment element, elements 135 and 135’, respectively, such as an energy delivery element configured to deliver thermal, electrical, light, sound and / or ablative chemical energy to target tissue. In some embodiments, treatment element 135 or 135’ comprises a mechanical abrader configured to treat tissue through abrasion. In some embodiments, functional assembly 130 or 45 comprises a balloon, balloon 136 and 46, respectively, which can be configured to receive one or more expansion and / or ablative fluids. Balloon 136 or 46 can comprise a compliant balloon, a non- compliant balloon, a pressure-thresholded balloon and / or otherwise be constructed and arranged as described in detail herein. Functional assembly 130 or 45 can be configured to both ablate (e.g., via a hot or cold ablative fluid) and neutralize the ablation (e.g., via a cooling or warming fluid, respectively), prior to and / or after the ablation, as described herein.

[0165] Via connectors 103 or 43, console 200 can provide and / or extract one or more fluids to and / or from one or more lumens or other flow pathways of devices 100 or 40, such as fluid provided by reservoir 220 and / or propelled by (i.e., delivered and / or extracted by) pumping assembly 225. Console 200, via EDU 260, can be configured to provide energy to one or more treatment elements 135 or 135’ of devices 100 or 40, respectively, such as energy contained in fluid at an ablative temperature (hot and / or cold), electrical energy (e.g., RF or microwave energy), light energy (e.g., laser light energy), or sound energy (e.g., subsonic or ultrasonic sound energy). In some embodiments, console 200 provides a fluid configured to treat target tissue with direct contact, such as an ablating agent (e.g., a sclerosant or other chemically ablative agent) and / or a fluid at an ablative temperature, either or both delivered directly to a target tissue surface.

[0166] In some embodiments, treatment elements 135 or 135’ comprises a fluid at an ablative temperature provided by console 200. In these embodiments, treatment elements 135 or 135’ can comprise a sufficiently hot fluid that is introduced into balloon 136 or 46, respectively, for a first time period to ablate target tissue, after which a cooling fluid is introduced into the balloon for a second time period, to extract heat from tissue (e.g., extract heat from target tissue and / or non-target tissue to reduce the ablation effect). Alternatively or additionally, a cooling fluid can be introduced into balloon 136 or 46 prior to the delivery of the hot fluid (e.g., for a third time period). In some embodiments, treatment element 135 or 135’ comprises a sufficiently cold fluidthat is introduced into balloon 136 or 46, respectively, for a first time period to ablate target tissue, after which a higher temperature fluid is introduced into the balloon for a second time period, to warm tissue (e.g., warm target tissue and / or non-target tissue to reduce the ablation effect). Alternatively or additionally, a warming fluid can be introduced into balloon 136 or 46 prior to the delivery of the cold fluid (e.g., for a third time period). Both the ablative and ablation-reducing fluids can be provided by console 200. These fluids can be provided in a recirculating manner as described in applicant’s co-pending application United States Patent Application Serial Number 17 / 864,855 (Attorney Docket No. 41714-704.303; Client Docket No. MCT-002-US-CON2), entitled “Heat Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed July 14, 2022. Alternatively or additionally, these fluids can be provided in a single bolus manner as described in applicant’s co-pending United States Patent Application Serial Number 18 / 605,655 (Attorney Docket No. 41714-710.302; Client Docket No. MCT-023- US-CON1), entitled “Systems, Methods and Devices for Treatment of Target Tissue”, filed March 14, 2024. In some embodiments, thermal ablation is performed using system 10 as described herein.

[0167] In some embodiments, target tissue and / or tissue proximate the target tissue is cooled, heated, and subsequently cooled again, such as via a procedure using device 100. In these embodiments, target tissue and / or tissue proximate the target tissue can be cooled during at least a portion of a first step, such as a first step including supplying a first fluid (e.g., a recirculating fluid) to functional assembly 130 or 45 for a first time period (e.g., a duration of at least 10 seconds or approximately between 15-30 seconds), wherein the first fluid is supplied at a cooling temperature (e.g., continuously supplied by reservoir 220 at a temperature of approximately 10°C-25°C). In a subsequent second step, target tissue and / or tissue proximate the target tissue can be heated (e.g., ablated) during at least a portion of the second step, such as a second step including supplying a second fluid (e.g., a recirculating fluid) to functional assembly 130 or 45 for a second time period (e.g., a duration of at least 5 seconds or approximately between 8-15 seconds), wherein the second fluid is supplied at a heat ablating temperature (e.g., continuously supplied by reservoir 220 at a temperature of approximately 85°C-95°C). In a subsequent third step, target tissue and / or tissue proximate the target tissue can be cooled during at least a portion of the third step, such as a third step including supplying a third fluid (e.g., a recirculating fluid) to functional assembly 130 or 45 for a third time period (e.g., a duration of at least 10 seconds or approximately between 15-30 seconds), wherein the second fluid is supplied at a cooling temperature (e.g., continuously supplied by reservoir 220 at a temperature of approximately 10°C-25°C). In some embodiments, other temperatures and / or durations for each heating orcooling cycle are used. In some embodiments, the second time period in which a hot fluid is supplied to functional assembly 130 or 45 comprises a time less than the first time period and / or the third time period. In some embodiments, the temperature of the fluid supplied to functional assembly 130 or 45 during the first time period and / or the third time period is at least 18°C less and / or at least 60°C less than the temperature of the fluid supplied to functional assembly 130 or 45 during the second time period. In some embodiments, the first temperature and the third temperature comprise a similar temperature. In some embodiments, a cooling fluid at approximately 10°C is delivered to functional assembly 130 or 45 for approximately 30 seconds, after which an ablative fluid at approximately 95°C is delivered to functional assembly 130 or 45 for approximately 12 seconds, after which a cooling fluid at approximately 10°C is delivered to functional assembly 130 or 45 for approximately 30 seconds. Alternatively, a warming fluid can be delivered to functional assembly 130 or 45 prior to and / or after the delivery of a cryogenically ablative fluid (e.g., for the similar time periods as described herein in reference to heat ablation). In some embodiments, the volume, temperature and / or duration of fluid delivered to functional assembly 130 or 45 is automatically and / or dynamically adjusted, such as an adjustment performed based on a signal provided by one or more sensors as described herein. For example, a temperature and / or duration can be adjusted during a first ablation of an axial segment of intestine and / or during a subsequent second ablation of the same or different axial segment of intestine. In some embodiments, a pre-cooling and / or post-cooling step is used to avoid the need for a tissue expansion step (e.g., tissue expansion proximate tissue to be ablated in a heat ablation step). In other embodiments, a tissue expansion step is included.

[0168] In some embodiments, a first axial segment of tubular tissue is cooled (e.g., non- ablatively cooled), via functional assembly 130 or 45, for a first time period TPi, and subsequently heat ablated for a second time period TP2. A first reservoir 220A includes the cooling fluid at a temperature TA, (e.g., fluid continuously maintained or at least initially provided at temperature TA) and a second reservoir 220B includes the (heat) ablative fluid at a temperature TB (e.g., fluid continuously maintained or at least initially provided at temperature TB). In some embodiments, after the heat ablation during time period TP2, an additional tissue cooling step is performed via functional assembly 130 or 45, for a third time period TP3. Additionally, axial segments of tubular tissue can subsequently be treated (e.g., additional axial segments treated via tissue cooling and subsequent heat ablation, with or without a subsequent tissue cooling step). TA can comprise a temperature at or below approximately 25°C, such as a temperature at or below approximately 20°C and / or 15°C, and TB can comprise a temperature at or above approximately 65°C, such as a temperature at or above approximately 75°C, 85°Cand / or 95°C. TPi can comprise a time duration of between 3 seconds and 60 seconds (e.g., between 20 seconds and 40 seconds); TP2 can comprise a time duration of between 1 seconds and 30 seconds (e.g., between 5 seconds and 15 seconds); and TP3 can comprise a time duration of between 3 seconds and 60 seconds (e.g., between 20 seconds and 40 seconds). In these embodiments, TA, TB, TPI, TP2 and / or TP3 can be varied (e.g., automatically by system 10), based on information recorded by a sensor of the present inventive concepts (e.g., a sensor measuring temperature, pressure, flow rate and / or other parameter at one or more locations of device 100 and / or 40, console 200 or other component of system 10). One or more of TA, TB, TPI, TP2 and / or TP3 can be held relatively constant or unchanged, during one or more axial tissue segment ablations. However, one or more of TA, TB, TPI, TP2 and / or TP3 can vary (e.g., be allowed to vary), such as when TA increases during an extraction of cooling fluid from device 100 (e.g., the recovered fluid warms the cooling fluid in the first reservoir 220A). These variations (e.g., as measured by one or more sensors of system 10) can result in an adjustment (e.g., an automatic adjustment) to another parameter (e.g., TA, TB, TPI, TP2 and / or TP3), such as an adjustment made by algorithm 251 (e.g., an algorithm comprising a lookup table including reservoir temperatures and corresponding treatment durations) based on a signal produced by one or more functional elements 109, 119, 139, 209, 229 and / or 309 described herein in reference to Fig. 9, that have been configured as a sensor (e.g., configured to provide a signal used to adjust one or more console settings 201). In some embodiments, TA, TB TPI, TP2 and / or TP3 are varied based on the value of TA and / or TB. For example, if the temperature TA of the cooling fluid were to increase during a multi-ablation procedure, the time period TP2 and / or temperature TB could be compensatingly adjusted (e.g., decreased). In some embodiments, time period TP2 is decreased by up to 2 seconds (e.g., from an initial time period of approximately 11 to 13 seconds, in one or more decrements), as the temperature TA increases by up to 16°C (e.g., from a starting temperature of approximately 9°C), such as during a clinical procedure comprising ablation of two or more axial segments (e.g., ablation of between two and six axial segments). While the previous embodiments have been described in reference to a cooling of tissue followed by a heat ablation of tissue (which may also include a subsequent tissue cooling step), alternatively, system 10 can be configured to (non-ablatively) warm tissue, followed by cryogenic ablation of tissue (which can also include a subsequent tissue warming step).

[0169] In some embodiments, treatment element 135 or 135’ comprises one or more energy or other tissue treatment elements positioned in, on and / or within functional assembly 130 or 45, respectively. Treatment element 135 or 135’ can comprise one or more energy delivery elements configured to deliver energy to target tissue, such as an energy delivery element selected fromthe group consisting of: a fixed or recirculating volume of fluid at a high enough temperature to ablate tissue; a fixed or recirculating volume of fluid at a low enough temperature to ablate tissue; one or more thermal energy delivery elements such as one or more elements configured to deliver heat energy or cryogenic energy; an array of electrodes such as an array of electrodes configured to deliver radiofrequency (RF) energy; one or more electromagnetic energy delivery elements such as one or more elements configured to deliver microwave energy; one or more optical elements configured to deliver light energy such as laser light energy; one or more sound energy delivery elements such as one or more elements configured to deliver subsonic and / or ultrasonic sound energy; one or more chemical or other agent delivery elements; and combinations of two or more of these. In some embodiments, device 100 or 40 is constructed and arranged to deliver RF energy, such as is described in applicant’s co-pending United States Patent Application Serial Number 17 / 879,222 (Attorney Docket No. 41714-706.303; Client Docket No. MCT-004-US-CON2), entitled “Electrical Energy Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed August 2, 2022; and / or to deliver ablative fluid directly to tissue, such as is described in applicant’s co-pending United States Patent Application Serial Number 17 / 192,671 (Attorney Docket No. 41714-707.302; Client Docket No. MCT-005- US-CON1), entitled “Ablation Systems, Devices, and Methods for the Treatment of Tissue”, filed March 4, 2021.

[0170] In some embodiments, device 100 or 40 is further constructed and arranged to provide geometric information (e.g., diameter information) of a luminal structure such as the duodenum. In these embodiments, device 100 or 40, and associated functional assembly 130 or 45, respectively, can be of similar construction and arrangement as lumen diameter sizing device 30 and its functional assembly 35, described herein.

[0171] In some embodiments, system 10 comprises one or more devices for expanding target tissue or tissue proximate target tissue, such as tissue expansion device 20 or multi -function device 40. In some embodiments, target tissue to be treated comprises mucosal tissue and the tissue to be expanded comprises submucosal tissue proximate the mucosal tissue to be treated. In some embodiments, tissue expansion device 20 or multi -function device 40 is of similar construction and arrangement as device 100 described herein in reference to Figs. 6 and / or 9. In some embodiments, tissue expansion device 20 or multi -function device 40 is of similar construction and arrangement as a tissue expansion device described in applicant’s co-pending United States Patent Application Serial Number 17 / 494,277 (Attorney Docket No. 41714- 712.303; Client Docket No. MCT-027-US-CIP1-CON2), entitled “Injectate Delivery Devices, Systems and Methods”, filed October 5, 2021. Device 20 or 40 can be configured to expand afull or partial circumferential segment of luminal wall tissue, such as to expand one or more layers of submucosal tissue in one or more axial segments of the duodenum or other portion of the GI tract. Device 20 or 40 can be configured to expand multiple segments of GI tract tissue, such as multiple relatively contiguous segments of submucosal tissue expanded as described in detail herein.

[0172] Tissue expansion device 20 comprises handle 22 which attaches to a proximal end of shaft 21 and includes connector 23 for operable attachment to console 200. Positioned on the distal end of shaft 21 or on a distal portion of device 20 is functional assembly 25. Functional assembly 25 can comprise an expandable element selected from the group consisting of: an inflatable balloon such as balloon 26 shown; a radially expandable cage or stent; one or more radially deployable arms; an expandable helix; an unfurlable compacted coiled structure; an unfurlable sheet; an unfoldable compacted structure; and combinations of two or more of these.

[0173] Balloon 26 or 46 can comprise a compliant balloon, a non-compliant balloon, a pressure-thresholded balloon and / or otherwise it can be constructed and arranged as described in detail herein. Balloon 26 or 46 can comprise a tissue-contacting length of between 20mm and 26mm, such as a tissue-contacting length of approximately 23mm. Balloon 26 can comprise a wall thickness of between 0.0002” and 0.0010”, such as a wall thickness of approximately 0.0005”. Functional assembly 25 or 45 can be configured to expand to a diameter between 27.5mm and 37.5mm, such as a diameter of approximately 32.5mm. Functional assembly 25 or 45 can be configured to be expanded via control 24 or 44, respectively, and / or via user interface 205 of console 200 (e.g., inflated and deflated by delivery and extraction, respectively, of air, water and / or other fluids by console 200).

[0174] Functional assembly 25 or 45 comprises one or more fluid delivery elements 28 or 48, respectively. The one or more fluid delivery elements 28 or 48 can each comprise an element selected from the group consisting of: needle such as a straight needle or a curved needle; nozzle; fluid jet; iontophoretic fluid delivery element; and combinations of two or more of these. The one or more fluid delivery elements 28 or 48 are configured to deliver inj ectate 221 and / or another fluid to tissue when functional assembly 25 or 45, respectively, is expanded (e.g., at least partially expanded with inflation fluid provided by console 200), positioning the fluid delivery elements 28 or 48 proximate (e.g., in contact with or close to) tissue to be expanded, such as luminal wall tissue of the GI tract.

[0175] The one or more fluid delivery elements 28 or 48 can be configured to be advanced (e.g., advanced into tissue) and retracted via control 24 of device 20 or control 44 of device 40, respectively. The one or more fluid delivery elements 28 or 48 can be positioned in one or moreports 27 or 47, respectively, as shown in Fig. 1. In some embodiments, a vacuum provided by console 200 causes tissue to tend toward and / or enter each port 27 or 47, such that each fluid delivery element 28 or 48, respectively, can inject fluid (e.g., injectate 221) into the engaged and / or captured tissue without having to extend significantly beyond the associated port 27 or 47 (e.g., each fluid delivery element can be configured to remain within the associated port during delivery of fluid into tissue captured within the port). By limiting excursion of fluid delivery element 28 or 48 out of port 27 or 47, respectively, risk of the fluid delivery element and / or injectate 221 penetrating through the outer surface of the GI tract is prevented or at least significantly reduced. In some embodiments, fluid can be delivered into tissue by fluid delivery element 28 or 48 with or without advancement of the fluid delivery element into the captured tissue (e.g., tissue is drawn into a port via an applied vacuum such that fluid delivery element penetrates or otherwise engages the tissue for fluid delivery without advancement of the fluid delivery element). In some embodiments, fluid delivery elements 28 or 48, ports 27 or 47, and / or other portions of tissue expansion device 20 or multi -function device 40, are of similar construction and arrangement as a tissue expansion device described in applicant’s co-pending United States Patent Application Serial Number 17 / 494,277 (Attorney Docket No. 41714- 712.303; Client Docket No. MCT-027-US-CIP1-CON2), entitled “Injectate Delivery Devices, Systems and Methods”, filed October 5, 2021.

[0176] In some embodiments, functional assembly 25 or 45 comprises three or more fluid delivery elements 28 or 48, respectively, which can be arranged in a circumferential pattern, such as three fluid delivery elements 28 or 48 arranged along a circumference and separated by approximately 120°. The multiple fluid delivery elements 28 or 48 can be configured to be advanced individually (e.g., via multiple controls 24 or 44 respectively), or simultaneously (e.g., via a single control 24 or 44). In some embodiments, two fluid delivery elements 28 or 48 are separated by approximately 180°. In some embodiments, four fluid delivery elements 28 or 48 are separated by approximately 90°.

[0177] In some embodiments, system 10 includes injectate 221 which can be provided by console 200 to device 20, and injectate 221 can be delivered into tissue by the one or more fluid delivery elements 28 or 48. Injectate 221 can comprise a material selected from the group consisting of water; saline; a fluid with a dye such as a visible dye such as indigo carmine; methylene blue; India ink; SPOT™ dye; a gel; a hydrogel; a protein hydrogel; a fluid containing a visualizable media such as a media visualizable under X-ray such as a radiopaque powder (e.g., tantalum powder), ultrasound imaging and / or magnetic resonance imaging; and combinations of these.

[0178] In some embodiments, device 20 and / or console 200 are configured to reduce the fluid (e.g., liquid or gas) in balloon 26 as inj ectate 221 is delivered into tissue such as submucosal tissue, such as to prevent excessive force being applied to tissue proximate the expanding tissue (i.e., due to the decreasing luminal diameter proximate the expanding tissue in contact with balloon 26). In some embodiments, system 10 is constructed and arranged to inflate balloon 26 to a first target pressure, such as a pressure of approximately 0.7psi. Injectate 221 can be delivered via fluid delivery elements 28 to submucosal tissue (e.g., simultaneously or sequentially). Fluid contained within balloon 26 can be removed or added to maintain the pressure at or below a second target pressure, for example a pressure higher than the first target pressure such as a pressure between 0.8psi and 0.9psi. Fluid of up to 10ml can be injected while maintaining the second target pressure (e.g., no more than the second target pressure) in the balloon (e.g., by decreasing the amount of fluid in the balloon to cause approximately 1mm steps of diameter decrease of balloon 26).

[0179] In some embodiments, tissue expansion device 20 is further constructed and arranged to provide geometric information (e.g., diameter information) of one or more axial segments of a luminal structure such as the duodenum. In these embodiments, device 20 and functional assembly 25 can be constructed and arranged similar to lumen diameter sizing device 30 and functional assembly 35, respectively, described herebelow.

[0180] In some embodiments, system 10 comprises one or more separate devices for estimating or otherwise measuring (e.g., “sizing”) the diameter of luminal tissue, such as lumen diameter sizing device 30. Sizing device 30 is constructed and arranged to be placed into one or more locations of the GI tract or other internal location of the patient and measure the diameter or other geometric parameter of tissue. In some embodiments, sizing device 30 is constructed and arranged similar to device 30 or device 100 described herebelow in reference to Fig. 9. Sizing device 30 can be configured to measure the diameter of multiple locations of GI tract tissue, such as multiple diameters along the length of one or more axial segments of the duodenum or other intestinal location.

[0181] Device 30 comprises handle 32 which attaches to a proximal end of shaft 31 and includes connector 33 for operable attachment to console 200. Positioned on the distal end of shaft 31 or on a distal portion of device 30 is functional assembly 35. Functional assembly 35 can comprise an expandable cage, balloon 36, or other expandable element as described herein, constructed and arranged to measure the inner surface diameter of tubular tissue (e.g., average diameter, equivalent diameter, minimum diameter, cross-sectional area and / or other geometric measure of the inner surface of tubular tissue), such as a diameter of the duodenum or jejunum.

[0182] Balloon 36 or 46 can comprise a compliant balloon, a non-compliant balloon, a pressure-thresholded balloon and / or otherwise be constructed and arranged as described in detail herein. Functional assembly 35 or 45 can be configured to be expanded via control 34 or 44, respectively, and / or via user interface 205 of console 200 (e.g., inflated and deflated by delivery and extraction, respectively, of fluids by console 200).

[0183] Fluids delivered by console 200 to functional assembly 35 or 45 (e.g., fluids supplied by reservoir 220) can be provided at one or more predetermined pressures, or pressure profiles. Diameter measurements can be accomplished by performing a visualization procedure (manual or automated) that assesses functional assembly 35 or 45 diameter. Alternatively or additionally, functional assembly 35 or 45 can be controllably filled with a fluid, and controller 250 can include an algorithm (e.g., algorithm 251 described herein in reference to Fig. 9) that correlates the fluid volume and / or fluid pressure to the diameter of tubular tissue in contact with functional assembly 35 or 45. In some embodiments, subsequent selection (e.g., device model or size selection) and / or expansion diameter (e.g., inflated diameter chosen for sufficient apposition) of functional assemblies 130, 25 and / or 45 of devices 100, 20 and / or 40, respectively, can be determined using the information provided by sizing device 30 and / or console 200. In some embodiments, device 30 or 40 performs one or more sizing procedures as described herein.

[0184] In some embodiments, functional assembly 35 or 45 comprises a balloon, expandable cage and / or other expandable element that includes two or more electrodes configured to provide a tissue impedance measurement whose value can be correlated to a level of apposition of functional assembly 35 or 45, respectively, and whose expanded diameter (e.g., visually or otherwise measured) correlates to a diameter of tubular tissue in contact with the expandable element. Alternatively or additionally, functional assembly 130 of device 100, functional assembly 25 of device 20 and / or functional assembly 45 of device 40 can be used to measure a diameter of the inner surface of tubular tissue, such as has been described herein in reference to functional assembly 35 and device 30.

[0185] In some embodiments, system 10 comprises one or more devices, such as multifunction device 40 shown, that are constructed and arranged to perform two or more functions selected from the group consisting of treat target tissue such as to deliver energy or otherwise ablate target tissue; expand tissue such as to expand one or more layers of submucosal tissue (e.g., proximate to and / or including target tissue); and determine or estimate a diameter (e.g., an average diameter, equivalent diameter, minimum diameter, cross-sectional area and / or other geometric measure) of a lumen of tubular tissue; and combinations of two or more of these. Multi -function device 40 is constructed and arranged to be placed into one or more locations ofthe GI tract or other internal location of the patient and perform two or more of the functions listed above. In some embodiments, multi -function device 40 is of similar construction and arrangement as device 100 described herein in reference to Figs. 6 and / or 9. Multi -function device 40 can be configured to perform the multiple functions at multiple segments of GI tract, such as multiple relatively contiguous axial segments of the duodenum or other intestinal location as is described herein.

[0186] Device 40 comprises handle 42 which attaches to a proximal end of shaft 41 and includes connector 43 for operable attachment to console 200. Positioned on the distal end of shaft 41 or on a distal portion of device 40 is functional assembly 45. Functional assembly 45 can comprise an expandable cage, a balloon (e.g., balloon 46 shown), and / or other expandable element constructed and arranged to be positioned in apposition with and / or in close proximity to the inner wall of tubular tissue, such as tissue of the duodenumjejunum and / or other intestinal location. Balloon 46 can comprise a compliant balloon, a non-compliant balloon, a pressure- thresholded balloon and / or otherwise be constructed and arranged as described in detail herein. Functional assembly 45 can be configured to be expanded via control 44 and / or via user interface 205 of console 200 (e.g., inflated and deflated by delivery and extraction, respectively, of fluids by console 200).

[0187] Functional assembly 45 can comprise treatment element 135’, which can comprise a fluid at an ablative temperature delivered into functional assembly 45 by console 200 and / or an energy delivery element permanently positioned on, in and / or within functional assembly 45 (e.g., an energy delivery element configured to deliver thermal energy, electrical energy, light energy, sound energy and / or chemical energy as described herein). In some embodiments, treatment element 135’ comprises a mechanical abrader configured to treat tissue through abrasion. In some embodiments, treatment element 135’ is of similar construction and arrangement as treatment element 139a of device 100 of Fig. 9 and / or treatment element 135 of device 100 of Fig. 1. Functional assembly 45 can be configured to both ablate (e.g., via a hot or cold ablative fluid) and neutralize (e.g., via a cooling or warming fluid, respectively), prior to and / or after the ablation, as described herein.

[0188] Alternatively or additionally, functional assembly 45 can comprise one or more elements configured to expand tissue, such as fluid delivery elements 48. Fluid delivery elements 48 can each be positioned within one or more ports 47 as shown. Fluid delivery elements 48 and ports 47 can be constructed and arranged as described herein in reference to fluid delivery element 139c and ports 137, respectively, of device 100 of Fig. 9.

[0189] Devices 100, 20, 30 and / or 40 can comprise one or more functional elements, such as functional elements 139, 29, 39 and / or 49, respectively, shown positioned in, on and / or within functional assemblies 130, 25, 35 and 45, respectively. Alternatively or additionally, one or more functional elements 139, 29, 39 and / or 49 can be located at a different location of the associated device, such as in, on and / or within the associated shaft and / or handle of the device. In some embodiments, one or more functional elements 139, 29, 39 and / or 49 comprise a sensor, such as a sensor selected from the group consisting of: physiologic sensor; blood glucose sensor; blood gas sensor; blood sensor; respiration sensor; EKG sensor; EEG sensor; neuronal activity sensor; blood pressure sensor; flow sensor such as a flow rate sensor; volume sensor; pressure sensor; force sensor; sound sensor such as an ultrasound sensor; electromagnetic sensor such as an electromagnetic field sensor or an electrode; gas bubble detector such as an ultrasonic gas bubble detector; strain gauge; magnetic sensor; ultrasonic sensor; optical sensor such as a light sensor; chemical sensor; visual sensor such as a camera; temperature sensor such as a thermocouple, thermistor, resistance temperature detector or optical temperature sensor; impedance sensor such as a tissue impedance sensor; and combinations of two or more of these. Alternatively or additionally, one or more functional elements 139, 29, 39 and / or 49 comprise a transducer, such as a transducer selected from the group consisting of: an energy converting transducer; a heating element; a cooling element such as a Peltier cooling element; a drug delivery element such as an iontophoretic drug delivery element; a magnetic transducer; a magnetic field generator; an ultrasound wave generator such as a piezo crystal; a light producing element such as a visible and / or infrared light emitting diode; a motor; a pressure transducer; a vibrational transducer; a solenoid; a fluid agitating element; and combinations of two or more of these. Functional elements 139, 29, 39 and / or 49 can be electrically connected to EDU 260 (e.g., to receive power, send signals and / or receive signals), such as via an electrical connection provided by connector 203. Functional elements 139, 29, 39 and / or 49 can send or receive signals from controller 250 of console 200, such as one or more sensor signals used to control ablation energy provided by console 200. Functional elements 139, 29, 39 and / or 49 can be activated and / or otherwise controlled via controls 104, 24, 34 and / or 44, respectively.Alternatively or additionally, user interface 205 of console 200 can be configured to allow operator control of functional elements 139, 29, 39 and / or 49.

[0190] In some embodiments, console 200 comprises one or more functional elements 209, comprising a sensor or transducer as described herein. Functional element 209 can comprise one or more pressure sensors, such as one or more pressure sensors configured to provide a signal used to regulate fluid delivery provided to one or more of devices 100, 20, 30 and / or 40.Functional element 209 can comprise one or more temperature sensors, such as one or more temperature sensors that provide a signal used to regulate temperature of one or more fluids of console 200. Functional element 209 can be positioned to measure a parameter (e.g., temperature or pressure) of fluid within reservoir 220, within pumping assembly 225 and / or within a fluid conduit of console 200.

[0191] In some embodiments, system 10 comprises one or more agents configured to be delivered to the patient, such as agent 420 described herein. Agent 420 can be delivered by one or more of devices 100, 20, 30, 40 and / or 50, or by a separate device such as a syringe or other medication delivery device. In some embodiments, inj ectate 221 comprises agent 420, such as when agent 420 is delivered by one or more fluid delivery elements 139c as described herein. In some embodiments, agent 420 comprises an anti -peristaltic agent, such as L-menthol (i.e., oil of peppermint). Alternatively or additionally, agent 420 can comprise glucagon, buscopan, hyoscine, somatostatin, an opioid agent, and / or any anti-peristaltic agent. Agent 420 can be delivered into the GI tract, such as via endoscope 50a, sheath 80 and / or devices 100, 20, 30 and / or 40. Agent 420 can be delivered systemically, such as via an intravenous or intra-arterial access line, or injected directly into tissue. Agent 420 can comprise a drug or other agent as described herein in reference to agent 420 of Figs. 6 and / or 9.

[0192] As described above, user interface 205 can comprise safety-switch 206 such as a foot- activated switch. Safety-switch 206 can be configured to allow a clinician to activate, modify and / or maintain (e.g., maintain in an “on” state) one or more processes of system 10 without having to use his or her hands (e.g., without having to use a digit of the hand). In some embodiments, system 10 is constructed and arranged to perform a function selected from the group consisting of: automatic contraction (e.g., deflation) of an expandable assembly (e.g., functional assembly 130) if safety-switch 206 is not activated (e.g., depressed); automatic replacement of ablative fluid (e.g., hot fluid) with neutralizing fluid (e.g., cold fluid) if safetyswitch 206 is not activated; initiate introduction of ablative fluid (e.g., hot fluid) into functional assembly 130 by activation of safety-switch 206 (e.g., after functional assembly 130 has been pre-expanded with cold fluid and user has confirmed proper position for treatment); allow handsfree activation (e.g., initiation) of a treatment step such that one or more operators can maintain their hands to be operably placed upon, or otherwise in contact with, one or more of endoscope 50a and / or devices 100, 20, 30 and / or 40; allow hands-free activation (e.g., initiation) of a treatment step such that the required number of operators is reduced; cause a function to cease if safety-switch 206 is not activated (e.g., depressed); and combinations of these.

[0193] Each of devices 100, 20, 30 and / or 40 can be provided in one or more sizes, such as one or more lengths of the associated shaft 110, 21, 31 and / or 41, respectively, and / or one or more diameters (e.g., expanded diameter) of the associated functional assembly, assemblies 130, 25, 35 and / or 45, respectively. Luminal sizing as described herein or other anatomical information can be used to select the appropriately sized device to treat the patient. In some embodiments, system 10 of Fig. 1 is configured to perform a medical procedure on a patient as described herein in reference to Fig. 14.

[0194] In some embodiments, system 10 comprises one or more imaging devices, such as imaging device 70 shown in Fig. 1. Imaging device 70 can comprise an imaging device configured to provide images using in the performance of a tissue treatment of the present inventive concepts, such as an imaging device 70 comprising a device selected from the group consisting of: endoscope camera; visible light camera; infrared camera; fluoroscope or other X- ray imager; CT scanner; MRI; PET scanner; ultrasound imaging device; molecular imaging device; and combinations thereof. In some embodiments, imaging device 70 comprises one or more devices configured to gather diagnostic information about a patient, such as diagnostic information used to select a patient for treatment (e.g., as described in reference to Fig. 8A herein).

[0195] In some embodiments, the systems, devices, and methods of the present inventive concepts can reduce the need for insulin therapy in a larger proportion of patients, such as to provide durable glycemic control with or without the therapies administered to the patient prior to the treatment of the present inventive concepts, or with a decrease in dosage of one or more previously administered medications.

[0196] The systems, devices and methods of the present inventive concepts can be configured to treat patients with microvascular disease or patients with a high risk of microvascular disease, such as to improve patient health and / or eliminate or otherwise reduce the need for one or more medications (e.g., one or more insulin medications). System 10 can be configured to provide a treatment that reduces diabetic retinopathy (e.g., as shown in a reduction in diabetic retinopathy score), proteinuria and / or peripheral neuropathy severity. Additionally or alternatively, system 10 can be configured to provide a treatment that reduces the effects of macrovascular disease such as myocardial infarction, stroke, peripheral vascular disease, CV death, and combinations of two or more of these.

[0197] Duodenal mucosal hyperplasia is a root cause of T2D. Applicant has conducted studies, described herebelow in reference to Figs. 52A-52M, indicating mucosal thickening results from a high fat diet. Applicant has conducted additional studies, as described herebelowin reference to Figs. 51A-51C indicating the intestinal treatment procedure of the present inventive concepts modifies the mucosa (e.g., reduces thickness and surface area of the mucosa). System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously treat duodenal mucosal hyperplasia, such as is described in reference to Fig. 8A and otherwise herein.

[0198] In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, provide an efficacious treatment of mucosal hypoplasia, such as is described in reference to Fig. 8A and otherwise herein.

[0199] In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, provide an efficacious treatment to a patient that has already received a procedure to treat a metabolic condition, such as: an RYGB procedure; a DJB procedure; other bariatric surgery; and / or an endoscopic metabolic intervention (e.g., sleeve gastroplasty).

[0200] In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, are configured to treat inflammation. For example, system 10 can be configured to treat chronic inflammation of the thyroid gland.

[0201] In some embodiments, system 10, and the devices and / or methods of the present inventive concepts also described herein, are configured to treat autoimmune disease.

[0202] In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, provide an efficacious treatment of duodenal dysfunction, such as duodenal mucosal dysfunction. Dysfunction may include abnormal intestinal permeability, abnormal nutrient absorption, abnormal hormonal secretion, abnormal hormonal signaling, abnormal neurohormonal signaling, abnormal iron absorption, abnormal iron metabolism, abnormal intestinal gluconeogenesis, abnormal hormone receptor expression, abnormal microbiome, abnormal splanchnic metabolism, abnormal bile acid processing (such as dehydroxylation from primary to secondary bile acids), abnormal bile acid activation of the farnesoid X receptor (FXR), abnormal production of intestinal -mucosa-produced enzymes, abnormal enterocyte mass (such as measured via plasma biomarkers), and / or abnormal expression of fatty acid binding protein in the intestine.

[0203] In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, are configured to provide an efficacious treatment by altering duodenal function, such as by: altering amino acid transporter expression; modulating bile acidprocessing; altering bile acid activation of the farnesoid X receptor; and / or altering farnesoid X receptor expression.

[0204] Other intestinal dysfunction in patients with pre-diabetes and T2D includes an increase in intestinal permeability, and / or a re-arrangement and / or alteration of the tight junction (TJ) structure of the intestinal epithelium (the surface cell layer of the intestinal mucosa). In normal (e.g., healthy) intestines, the epithelial cells have proteins that span the membranes of adjacent cells to prevent leakage of solutes and water, and to seal the paracellular pathway. In prediabetes and T2D, these junction proteins are re-arranged and / or altered, and the intestinal cell barrier becomes permeable, primarily in the duodenum but also in other segments of the small intestine. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal and / or other intestinal mucosa and / or submucosa) to efficaciously treat abnormal intestinal permeability (e.g., to reduce intestinal permeability and / or reduce the abnormal arrangement of the tight junction structure), such as is described in reference to Fig. 8A and otherwise herein. In some embodiments, the reduced intestinal permeability achieved comprises a permeability reduction associated with at least a 25%, 35%, or 45% reduction in paracellular ions or fluid in the treated region. In some embodiments, the improved arrangement of the tight junction structure achieved comprises at least a 20%, 30%, or 40% improvement, such as an improvement that can be demonstrated by at least a 20%, 30%, or 40% increase in claudin-1 fluorescence in biopsy specimens taken from the treated region. In some embodiments, the improved arrangement of the tight junction structure achieved comprises at least a 20%, 30%, or 40% improvement, such as an improvement that can be demonstrated by at least a 20%, 30%, or 40% increase in claudin-2 fluorescence in biopsy specimens taken from the treated region. In some embodiments, the improved arrangement of the tight junction structure achieved comprises at least a 5%, 10%, or 20% improvement, such as an improvement that can be demonstrated by at least a 5%, 10%, or 20% increase in claudin-3 fluorescence in biopsy specimens taken from the treated region. In some embodiments, the improved arrangement of the tight junction structure achieved comprises at least a 4%, 6%, or 8% improvement, such as an improvement that can be demonstrated by at least a 4%, 6%, or 8% increase in zonulin fluorescence in biopsy specimens taken from the treated region.

[0205] Abnormal intestinal nutrient absorption can be a root cause of prediabetes and type 2 diabetes and can be due to an increase in the capacity of the intestine to absorb and / or metabolize monosaccharides (e.g., including glucose, fructose, galactose, mannose, xylose, allulose, arabinose and others), and / or a specific increase in the expression of the monosaccharidetransporters in the intestine (e.g., SGLT1, GLUT5, and GLUT2 transporters). Compared with healthy subjects, humans with T2D have higher expression of SGLT-1 and GLUT5 accompanying elevated rates of glucose uptake in isolated brush border membrane (the surface of the enterocyte facing the lumen where nutrients are absorbed) vesicles (e.g., as can be demonstrated via duodenal biopsies). In particular, in patients with noninsulin-dependent diabetes mellitus, SGLT1 mRNA and protein levels show a three-fold to four-fold increase in brush border membranes of enterocytes in the small intestine versus healthy individuals. Additionally, GLUT2 mRNA is elevated in the total duodenum in patients with T2D, suggesting that T2D in humans is also associated with higher expression of GLUT2 in the basolateral membrane (the opposite surface of the enterocyte, where nutrients are delivered to the body). In the setting of obesity and / or diabetes, insulin resistance provokes the loss of GLUT2 trafficking control leading to a permanent localization of GLUT2 in the apical and / or endosomal enterocyte membranes and to increased transepithelial glucose transport from lumen to blood circulation. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously treat abnormal intestinal nutrient absorption (e.g., to reduce intestinal nutrient monosaccharide absorption and / or reduce the expression of SGLT1, GLUT5, and / or GLUT2 transporters), such as is described in reference to Fig. 8A and otherwise herein. In some embodiments, the benefit achieved via a treatment provided by system 10 comprises a therapeutic benefit selected from the group consisting of: a reduction from pre-treatment in expression of SGLT1 transporters in the intestinal mucosa by at least 25%, 40% or 50%; a reduction in expression of GLUT2 transporters in the intestinal mucosa by at least 25%, 40% or 50%; a reduction in expression of GLUT5 transporters in the intestinal mucosa by at least 25%, 40% or 50%; and combinations of these. Alternatively or additionally, the benefit achieved via a treatment provided by system 10 comprises a therapeutic benefit selected from the group consisting of: a reduction in expression of SGLT1 transporters in the enteroendocrine cells by at least 25%, 40% or 50%; a reduction in expression of GLUT2 transporters in the enteroendocrine cells by at least 25%, 40% or 50%; a reduction in expression of GLUT5 transporters in the enteroendocrine cells by at least 25%, 40% or 50%; and combinations of these.

[0206] Dysregulation of intestinal lipoprotein metabolism is an intestinal dysfunction that occurs in insulin-resistant states including type 2 diabetes and NAFLD. For example, intestinal lipoprotein overproduction (and enhanced intestinal de novo lipogenesis) is associated with T2D. In the normal intestine (e.g., non-insulin-resistant, non-diabetic, intestine), dietary triglyceridesare absorbed by enterocytes in the intestinal epithelium and triglyceride-rich lipoproteins containing the protein apoB48 (called chylomicrons) are secreted from the basolateral membrane of those cells. In insulin-resistant states, an increase in intestinal production of the apoB48 protein occurs (versus normal subjects) along with a two-fold to four-fold increase in rate of secretion of apoB48-containing lipoproteins (chylomicrons), in both the fasting and post-prandial states. Additionally, in an animal model of whole-body and hepatic insulin resistance and metabolic dyslipidemia, chronic fructose feeding was associated with up-regulation of the key protein involved in intestinal lipoprotein assembly, microsomal triglyceride transfer protein (MTP). Rosiglitazone treatment has been shown to reduce insulin resistance and reduce the secretion of intestinally derived apoB48-containing lipoproteins in the fasting state of animal models of insulin resistance and diabetes. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously treat abnormal intestinal lipoprotein metabolism. In some embodiments, the treatment provided by system 10 achieves a therapeutic benefit selected from the group consisting of: reduction from pre-treatment in free fatty acids by at least 10%, 15% or 20%; reduction from pre-treatment in triglycerides by at least 10%, 20% or 30%; reduction from pretreatment in intestinal apoB48 secretion by at least 15%, 25%, or 33%; reduction from pretreatment in chylomicron production and / or secretion by at least 15%, 25%, or 33%; reduction from pre-treatment in cellular MTP mass by at least 10%, 15% or 20%; and combinations thereof.

[0207] Abnormal intestinal hormonal signaling, and abnormal intestinal hormone secretion are intestinal dysfunctions associated with T2D. The incretin effect (the phenomenon that oral glucose elicits a higher insulin response than intravenous glucose at identical plasma glucose profiles) is known to be conveyed by the two incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The intestine also may secrete other hormones such as glicentin, cholecystokinin (CCK), peptide YY (PYY), somatostatin (SST), 5- hydroxytryptamine (5-HT), glucagon-like peptide-2 (GLP-2) and substance P (encoded by the Tael gene) which may also contribute to intestinal hormonal signaling. The incretin effect is dysfunctional in type 2 diabetes, such that the insulin response is reduced compared to normal individuals. Patients with T2D have a higher level of fasting GIP than do non-diabetic individuals. The GIP response to oral glucose and mixed meals is increased in patients with type 2 diabetes. Higher fasting levels of GIP are associated with risk of higher total and death from cardiovascular disease (CVD). Decreases in fasting and / or post-prandial GIP and increases infasting and / or post-prandial GLP-1 caused by bariatric surgeries (e.g., Roux-en-y bypass, duodenal -jejunal bypass, bilio-pancreatic diversion, and others) have been shown to be beneficial to patients with type 2 diabetes. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously treat abnormal intestinal hormonal secretion, such as is described in reference to Fig. 8A and otherwise herein. In patients with pre-diabetes and type 2 diabetes, a treatment of the present inventive concepts can reduce fasting GIP by at least 10%, 15% or 20% from pretreatment levels. In human clinical studies conducted by applicant, patients achieved a decrease in fasting GIP from baseline median of 133.9 (interquartile range: 109.3 to 171.1) pg / ml to a fasting GIP three months post-treatment of median 116.7 (interquartile range: 69.5 to 149.0) pg / ml, a 13% decrease. In patients with pre-diabetes and type 2 diabetes, a treatment of the present inventive concepts can result in an increase fasting GLP-1 by at least 50%, 100% or 200% from pre-treatment levels. In some embodiments, the treatment provided using system 10 achieves a therapeutic benefit selected from the group consisting of: an increase in post-prandial GLP-1 by at least 50%, 100% or 200% from pre-treatment levels; an increase in post-prandial GLP-1 from pre-treatment levels without causing post-prandial hypoglycemia; a reduction from pre-treatment in fasting GIP of at least 10%, 20% or 30%; a reduction from pre-treatment in post-prandial GIP of at least 10%, 20% or 30%; a reduction from pre-treatment in post-prandial GIP without causing post-prandial hypoglycemia; improvements in more than one fasting intestinal hormone; improvements in more than one fasting intestinal hormone without causing hypoglycemia; reduction in GLP-1 from pre-treatment of at least 20%, 40% or 60% in patients with post-bariatric hypoglycemia; and combinations of these.

[0208] Body iron levels are principally controlled by modulation of iron absorption in the duodenum and proximal jejunum and alterations in intestinal iron absorption can be associated with type 2 diabetes. In patients with type 2 diabetes (T2D), increased levels of ferritin, a biomarker of increased body iron stores, and reduced levels of hepcidin, the hepatic hormone responsible for systemic iron homeostasis, have been detected in the blood, highlighting the systemic alteration of iron metabolism. In particular, in control subjects mean ferritin has been measured as being 82.7 pg / 1, while in patients with metabolic syndrome mean ferritin was measured as 124 pg / 1. High iron levels are associated with insulin resistance, disrupted insulin secretion, and islet morphology, as well as diabetic complications due to increased oxidative stress. Experiments performed in an obese / diabetic mouse model (leptin-deficient ob / ob mice) have shown increased iron absorption and retention. In another diabetes mouse model(streptozotocin-induced diabetes) iron uptake and the mRNA expression of iron importer divalent metal transporter 1 (DMT1) were shown to be significantly increased in the duodenum, with brush border membrane DMT1 expression increased by 210%, and a 60% increase in total DMT1. In a study of human patients with non-alcoholic steatohepatitis, a condition related to type 2 diabetes, iron absorption from the GI tract was shown to be increased through upregulation of DMT 1. Reducing iron absorption in the duodenum can lead to lower levels of systemic iron. Low iron levels can be associated with improved glucose tolerance and reduced risk for gestational diabetes. Iron chelation therapy, which can reduce iron levels, additionally protects from diabetes and loss of P-cell functioning, as has been demonstrated in obese mice. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously reduce intestinal iron absorption, such as is described in reference to Fig. 8A and otherwise herein. In some embodiments, the treatment provided by system 10 is configured to reduce iron absorption, such as a reduction in iron absorption that occurs without causing anemia. In some embodiments, the treatment provided by system 10 is configured to reduce ferritin levels in the blood, such as a reduction in ferritin levels in the blood that occurs without causing anemia. In some embodiments, the treatment provided by system 10 is configured to increase hepcidin levels in the blood, such as an increase in hepcidin levels in the blood that occurs without causing anemia. In some embodiments, the treatment provided by system 10 is configured to both reduce ferritin levels and increase hepcidin levels in the blood (e.g., without causing anemia). In some embodiments, the treatment provided by system 10 is configured to reduce iron transporter expression in the intestinal mucosa (e.g., a reduction that can be demonstrated in measurement of iron transporter RNA in biopsy samples taken from the treated region). In some embodiments, the treatment provided by system 10 is configured to reduce iron transporter activity in the intestinal mucosa.

[0209] Abnormal intestinal neurohormonal signaling can be a root cause of T2D. Enteroendocrine cells (EECs) exist as multiple subtypes and express receptors and transporters that allow them to monitor the chemical contents of the intestinal lumen. In response to detection of chemical cues, EECs release an array of hormones that include cholecystokinin (CCK), glucagon-like peptide 1 (GLP1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY), somatostatin (SST), 5-hydroxytryptamine (5-HT), and substance P (encoded by the Tael gene). These molecules can act on local sensory neurons in the lamina propria. Hormones secreted from the intestinal mucosa thus stimulate receptors on vagal afferents. For example,mucosal secretion of cholecystokinin stimulates CCK1 receptors on vagal afferents in the process of controlling gastric emptying, and glucagon-like peptide 1 acts as an insulinotropic, glucagonostatic secretion. Hormones secreted by the duodenal mucosa activate afferent neural pathways initiating in the gut or hepatic portal veins. Luminal glucose induces release of 5- hydroxytryptamine (5-HT) from enterochromaffin (EC) cells (a subset of EEC’s) in the gut wall. 5-HT activates intrinsic reflexes to regulate motor and secretory function. 5-HT also activates extrinsic, vagal afferent terminals located in the gut wall via 5-HT3 receptors (5- HT3Rs) to activate a vago-vagal reflex to inhibit gastric emptying and stimulate pancreatic exocrine secretion. Enteric neurons are also capable of sensing certain absorbed nutrients directly. For example, subsets of enteric neurons express the SCFA receptor FFAR3. Data from studies suggest that peptide-producing EECs also secrete small molecules (including glutamate25 and ATP26) that are capable of directly activating nerve terminals. These findings suggest that fast neurotransmitters released locally by EECs could directly trigger electrical activity in the afferent vagus. Gut hormones communicate with the brain via G-protein-coupled receptors on vagal afferent fibers which synapse in the nucleus of the solitary tract (NTS) and area postrema (AP) in the hindbrain dorsal vagal complex (DVC). Non-vagal, spinal afferent signaling for the detection of ingested glucose, either downstream of gut peptide secretion or by glucose sensors in the hepatic portal vein has been shown to result in downregulation of agouti- related peptide (AgRP) neuron activity in the arcuate nucleus (ARC) of the hypothalamus. Enteroendocrine cells also release other neurotransmitters / modulators such as adenosine triphosphate, providing an additional signal triggering vagal activation. Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway has been shown to be impaired in a rodent model of type 2 diabetes, and in particular, glucose-induced activation of 5- HT, GIP, GLP-1 containing cells, as well as neurons of the ENS and the vagal pathway have also been shown to be markedly impaired in diabetic rats. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously treat abnormal intestinal neurohormonal signaling, such as by modifying neurohormonal vagal afferent signaling, by modifying neurohormonal spinal afferent signaling, by ablation of vagal afferents, by ablation of spinal afferents, by modifying (increasing or decreasing fasting or post-prandial amounts of) EEC secretions of hormones, by modifying release of neuro-transmitters and / or modulators, and / or by modifying expression of hormone receptors in the intestinal epithelium or on the intestinal neurons, such as is described in reference to Fig. 8A and otherwise herein. Vagal afferent firing can be influenced by leptin, awide range of gut hormones, gut-derived lipid mediators, shifts in gut microbiota and / or gut inflammation. In some embodiments, the treatment provided using system 10 achieves a therapeutic benefit selected from the group consisting of: increase in fasting PYY by at least 10%, 20% or 30%; increase in post-prandial PYY by at least 10%, 20% or 30%; increase in PYY-mediated vagal afferent signaling by at least 10%, 20% or 30%; increase in GLP-1- mediated vagal afferent signaling by at least 10%, 20% or 30%; increase in fasting intestinal 5- HT by at least 10%, 20% or 30%; increase in glucose-induced activation of intestinal 5-HT containing cells by at least 10%, 20% or 30%; increase in glucose-induced cellular activation of enteroendocrine cells; increase in glucose-induced cellular activation of enterochromaffin cells; increase in glucose-induced activation of myenteric neurons by at least 30%, 50%, or 70%; increase in glucose-induced activation of myenteric plexus by at least 50%, 75% or 100%; increase in glucose-induced activation of vagal afferent neurons by at least 30%, 50%, or 70%; increase in glucose-induced activation of nodose ganglia by at least 20%, 40%, or 60%; increase in glucose-induced activation of nodose neurons by at least 30%, 50%, or 70%; and combinations thereof. In healthy patients (e.g., patients not afflicted with the medical condition being treated using system 10), increases in extracellular glucose concentration act presynaptically to increase the release of glutamate from the central terminals of vagal afferents. In patients with diabetes, this effect can be lost. In some embodiments, the treatment provided using system 10 achieves a therapeutic benefit of an increase in the release of responsiveness of vagal afferents to extracellular glucose, such as an increase of at least 10%, 15% or 20%.

[0210] Intestinal gluconeogenesis can be an important regulator of glucose control. Intestinal gluconeogenesis is defined as the production and secretion of glucose from the intestine into the portal circulation, where it is detected by a hepatoportal glucose sensor, the sodium glucose cotransporter 3, which signals to the brain via the peripheral neural system, initiating a neural gutbrain axis with benefits for energy homeostasis. Glucose 6 phosphatase (Glc6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), two major enzymes of gluconeogenesis, are present in the small intestine, exhibiting a decreasing gradient of expression from the duodenum to the ileum. These enzymes are present in the small intestine (SI) in both rat and human. An increase in intestinal gluconeogenesis (e.g., increases in intestinal Glc6Pase and / or PEPCK activity) can be associated with increased insulin sensitivity in the liver. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously improve intestinal gluconeogenesis, such as is described in reference to Fig. 8A and otherwise herein. In some embodiments, thetreatment provided by system 10 results in an improvement in intestinal gluconeogenesis that comprises an increase in Glc6Pase activity (e.g., in the treated region) by at least 20%, 50%, or 100%. In some embodiments, the improvement in intestinal gluconeogenesis comprises an increase in PEPCK activity (e.g., in the treated region) by at least 20%, 50%, or 100%.

[0211] Receptors for hormones associated with glucose and lipid homeostasis are present in the intestinal mucosa, such as insulin receptors, and leptin receptors. Insulin Receptor isoform A (IR-A) expression predominates in intestinal epithelial stem cells and proliferative progenitor cells of the crypt, while Insulin Receptor isoform B (IR-B) expression is enriched in differentiated intestinal epithelial cells. IR-B is considered the metabolic insulin receptor and is highly expressed in tissues that are sensitive to the metabolic actions of insulin. In studies using a mouse model of high-fat-diet induced obesity, genetic deletion of the intestinal insulin receptor resulted in a lowering of plasma cholesterol. Further, experiments in mice demonstrate that genetic ablation of the intestinal insulin receptors alters intestinal epithelial gene expression, especially in pathways related to glucose uptake and metabolism. This loss of intestinal insulin receptors can reduce intestinal glucose uptake, and these mice retain normal glucose tolerance during aging as compared with controls, which indicate an age-dependent decline in glucose tolerance. Loss of the insulin receptors can also result in a reduction of glucose-dependent insulinotropic polypeptide (GIP) expression from enteroendocrine K-cells and decreased GIP release in vivo after glucose ingestion but has no effect on glucagon-like peptide 1 expression or secretion. Consequently, reduction in the quantity of insulin receptors in the intestine, reduction in IR-B receptors, and / or reduction in insulin receptor activity can lower plasma cholesterol. On the other hand, reductions in insulin receptor quantity and defects in insulin receptor activity can be associated with insulin resistance, such as in patients with type 2 diabetes, pre-diabetes, NAFLD / NASH, and other related diseases. Consequently, an increase in the quantity of insulin receptors or an increase in insulin receptor activity can restore insulin sensitivity of the intestine and / or improve glycemia. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously treat intestinal hormone receptors, such as is described in reference to Fig. 8A and otherwise herein. In some embodiments, the treatment provided by system 10 causes an increase in insulin receptor expression and / or activity in the intestinal mucosa. In some embodiments, the improvement in insulin receptor expression and / or activity achieved comprises an increase in the quantity of intestinal insulin receptors of at least 20%, 40% or 60% (e.g., in the treated region). Increase in insulin receptors can be demonstrated via measurement of insulin receptor RNA inbiopsy samples taken from the treated patient (e.g., biopsy samples taken from the treated region). In some embodiments, the improved intestinal hormone expression and / or activity achieved comprises an increase in insulin receptor expression and / or activity of at least 20%, 40% or 60% (e.g., in the treated region). In some embodiments, the improvement in insulin receptor expression and / or activity improves post-prandial blood glucose (e.g., without causing hypoglycemia). In some embodiments, the improvement in insulin receptor expression and / or activity comprises a reduction in insulin receptor expression in the treated region of the intestinal mucosa, such as a reduction in the number IR-B receptors. This reduction may be demonstrated by measuring RNA in biopsy samples (e.g., specimens taken from the treated region). In some embodiments, the improved intestinal hormone expression and / or activity comprises a decrease in insulin receptor expression and / or activity in the intestinal mucosa.

[0212] Leptin is an adipocyte hormone associated with obesity and metabolic regulation, and leptin receptors are present in the mouse, rat, and human small intestinal mucosa. Intestinal leptin receptors are a direct target of leptin signaling, and in a mouse model of obesity, intravenous leptin administration have been shown to cause a significant (e.g., 2-fold) reduction in the apolipoprotein AIV transcript levels in jejunum 90 min after a fat load, indicating that resistance to leptin action in this site can contribute to obesity and its related syndromes (e.g., pre-diabetes, type 2 diabetes, and / or NAFLD / NASH) by directly affecting lipid handling. Further, gastric leptin secretions have been shown to bind to intestinal leptin receptors to inhibit uptake of amino acids and sugars in the small intestinal mucosa. In a rat model, studies have shown the consumption of a high fructose diet for 2 months attenuates the expression of type b leptin receptors in the intestine. Thus, loss of leptin receptor expression can contribute to reduced leptin signaling and increased uptake of amino acids and sugars. With mice fed a high fat, high sugar diet, studies have demonstrated approximately a 100% increase in intestinal leptin with a 60% increase in intestinal leptin receptor expression. In that study, a decrease in adiponectin receptor expression was also seen in the high fat, high sugar fed mice. Obesity drives elevated levels of leptin (hyperleptinemia) which in turn drives leptin resistance, where cells lose the ability to activate the signaling pathways downstream of the leptin receptor. Thus, patients with leptin resistance such as those with obesity and / or type 2 diabetes, additional leptin receptor expression and / or activity is needed to achieve metabolic homeostasis. System 10 can be configured to provide a treatment that improves leptin receptor expression and / or activity in the intestinal mucosa. In some embodiments, the improved leptin receptor expression and / or activity comprises an increase in the quantity of intestinal leptin receptors of at least 20%, 40% or 60% (e.g., in the treated region). The increase in leptin receptors can be demonstrated viameasurement of leptin receptor RNA in biopsy samples (e.g., samples taken in the treated region). In some embodiments, the improved leptin receptor expression and / or activity comprises an increase in leptin receptor expression and / or activity of at least 20%, 40% or 60% in the treated region. In some embodiments, the improvement in leptin receptor expression and / or activity improves post-prandial blood glucose (e.g., without causing hypoglycemia). In some embodiments, system 10 can be configured to provide a treatment that improves adiponectin receptor expression and / or activity in the intestinal mucosa.

[0213] In some embodiments, system 10 is configured to provide a treatment that causes an effect selected from the group consisting of: an increase in enteroendocrine cell G-protein- coupled receptor 119 (GPR199) expression and / or activity; an increase in enteroendocrine cell G-protein-coupled receptor 40 (GPR40) expression and / or activity; an increase in enteroendocrine cell G-protein-coupled receptor 41 (GPR41) expression and / or activity; an increase in enteroendocrine cell G-protein-coupled receptor 120 (GPR120) expression and / or activity; an increase in enteroendocrine cell G Protein-Coupled Bile Acid Receptor TGR5 expression and / or activity; an increase in enteroendocrine cell somatostatin subtype receptor 2 (SSTR2) expression and / or activity; an increase in enteroendocrine cell somatostatin subtype receptor 5 (SSTR5) expression and / or activity; and combinations of these. Alternatively or additionally, system 10 can be configured to provide a treatment that causes an effect selected from the group consisting of: a decrease in enteroendocrine cell G-protein-coupled receptor 119 (GPR199) expression and / or activity; a decrease in enteroendocrine cell G-protein-coupled receptor 40 (GPR40) expression and / or activity; a decrease in enteroendocrine cell G-protein- coupled receptor 41 (GPR41) expression and / or activity; a decrease in enteroendocrine cell G- protein-coupled receptor 120 (GPR120) expression and / or activity; a decrease in enteroendocrine cell G Protein-Coupled Bile Acid Receptor TGR5 expression and / or activity; a decrease in enteroendocrine cell somatostatin subtype receptor 2 (SSTR2) expression and / or activity; a decrease in enteroendocrine cell somatostatin subtype receptor 5 (SSTR5) expression and / or activity; and combinations of these.

[0214] Circulating levels of branched-chain amino acids (BCAAs) are increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes (T2D). In the gastrointestinal tract, BCAAs regulate the release of hormones (for example, leptin, GLP-1 and ghrelin) that can potentially affect food intake and glycaemia levels. BCAA supplementation or BCAA-rich diets can be associated with positive effects on the regulation of body weight, muscle protein synthesis and glucose homeostasis. Conversely, reducing the dietary supply of all three BCAAs improves insulin sensitivity and glucosehomeostasis in rodent models of obesity. Enterocytes of the intestine have amino acid transporters on their apical membrane to amino acids from the lumen of the intestine. A different set of transporters is found in the basolateral membrane of the intestinal epithelium, allowing amino acids to be released into the blood stream after nutrient intake. Expression levels of these transporters are high in the small intestine, where the bulk of nutrient absorption occurs. In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously increase amino acid transporter expression in the apical and / or basolateral membranes of the enterocytes of the small intestinal mucosa. In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously decrease amino acid transporter expression in the apical and / or basolateral membranes of the enterocytes of the small intestinal mucosa. The change in amino acid transporter expression can be demonstrated via measurement of amino acid transporter RNA in biopsy samples (e.g., samples taken in the treated region).

[0215] In some embodiments, system 10 and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure to modulate bile acid processing and / or bile acid activation of the famesoid X receptor (FXR). FXR is a member of the nuclear hormone receptor superfamily. High expression of FXR is restricted to the liver, intestine, adrenal gland, and kidney. The primary bile acids, chenodeoxycholic acid and cholic acid, are the highest affinity endogenous activating ligands for FXR. In the enterohepatic system, FXR activation plays an important role in maintaining glucose, lipid, and bile acid homeostasis. In a T2D mouse model, treatment with FXR agonists have demonstrated simultaneous beneficial effects in various organs, including improved insulin resistance and lipid metabolism, improved hepatic steatosis and lipid metabolism in the kidney, liver, and adipose tissue and restored hypertrophy of the pancreatic islet cell aortic media and the heart. Increasing receptor expression can have similar benefits to treatment with receptor agonists. Thus system 10, and the devices and methods of the present inventive concepts, such as is described in reference to Fig. 8A and otherwise herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to increase intestinal farnesoid X receptor expression in the treated region. In some embodiments the intestinal farnesoid X receptor expression is increased by at least 15%, 25% or 35%. The change in intestinal famesoid X receptor expression can be demonstrated viameasurement of intestinal famesoid X receptor RNA in biopsy samples (e.g., samples taken in the treated region).

[0216] In some embodiments, system 10 and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure to reduce intestinal FXR expression. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signaling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. Genetic depletion or antagonism of intestinal FXR in mice, markedly ameliorates high-fat-diet-induced obesity, insulin resistance and fatty liver as a result of reductions in ceramide levels in the intestine and serum. The reduced intestinal and serum ceramide levels in intestine-specific-null mice mainly results from decreased expression of genes involved in ceramide synthesis, including sphingomyelin phosphodiesterase 3 and 4, serine palmitoyltransferase, long-chain base subunit 2 and ceramide synthase 4 in the intestine. In some embodiments, system 10 and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure to reduce intestinal farnesoid X receptor expression and / or activity in the treated region. In some embodiments the intestinal famesoid X receptor expression and / or activity is reduced by at least 15%, 25% or 35%. The change in intestinal famesoid X receptor expression can be demonstrated via measurement of intestinal farnesoid X receptor RNA in biopsy samples (e.g., samples taken in the treated region).

[0217] Reduction of intestinal-mucosal-produced enzymes (disaccharidases which break down complex sugars into simple sugars, and a-glucosidases which break down starch into simple sugars) can be an effective approach to treating type 2 diabetes. Increased intestinal enzyme activity (e.g., disaccharidases) can be associated with T2D. Specific and total activities of the disaccharidases maltase, sucrase, and lactase are increased in the mucosa of the small intestine of the diabetic non-human animal and human diabetics. The drugs acarbose, miglitol and voglibose act by inhibiting the a-glucosidases, a group of key intestinal enzymes involved in the digestion of carbohydrates, causing a decrease of both postprandial hyperglycaemia and hyperinsulinemia, and thereby possibly improve sensitivity to insulin and release the stress on P-cells. System 10, and the devices and methods of the present inventive concepts also described herein, can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously treat abnormal intestinal hormonal secretion, such as is described in reference to Fig. 8 A and otherwise herein. System 10 can be configured to treat abnormal processing of sugars in the small intestine. In some embodimentsthe treatment provided by system 10 results in a reduction in intestinal enzymes, such as a reduction in disaccharidases and / or a reduction in a-glucosidases. In some embodiments, the treatment provided by system 10 results in a reduction in sugar absorption. In some embodiments, the treatment of abnormal processing of sugars in the small intestine provided by system 10 results in a reduction of post-prandial hyperglycemia. In some embodiments the treatment provided by system 10 achieves one or more therapeutic benefits that are achieved without causing fasting hypoglycemia.

[0218] Plasma biomarkers of small intestine adaptations are known to be altered in metabolic disease such as prediabetes and type 2 diabetes. Plasma citrulline, a nonprotein amino acid produced by enterocytes in the small intestinal mucosa, is a marker of enterocyte mass. Plasma citrulline is significantly reduced in patients with insulin resistance and T2D compared to insulin sensitive men. Plasma citrulline is known to increase following bariatric surgeries such as gastric bypass or sleeve gastrectomy. Plasma intestinal-specific fatty acid binding protein levels (I-FABP) are significantly higher in patients with T2D. Plasma I-FABP-to-citrulline ratio is higher in patients with T2D than in patients with IR (such as pre-diabetes). Plasma I-FABP-to- citrulline ratio is higher in patients with IR (such as pre-diabetes) than in normal patients. The devices and methods of the present inventive concepts can be configured to perform an intestinal treatment procedure (e.g., a modification of duodenal mucosa and / or submucosa, also as described herein) to efficaciously alter plasma biomarkers of small intestine adaptations to improve small intestinal adaptation. The improvement in small intestinal adaptation achieved using system 10 can be determined by measuring improvements in plasma biomarkers of small intestinal adaptation, such as by detecting increases in plasma citrulline, reductions in plasma I- FABP, and / or reductions in the plasma I-FABP-to-citrulline ratio.

[0219] In some embodiments, system 10, and the devices and methods of the present inventive concepts also described herein, provide an efficacious treatment of diet-induced intestinal maladaptation. Diet-induced intestinal maladaptation can promote obesity and therefore underlie the pathogenesis of metabolic syndromes and their associated complications.

[0220] Other forms of duodenal mucosal dysfunction that can be treated by the systems, devices, and methods of the present inventive concepts include but are not limited to: abnormal intestinal permeability; abnormal nutrient absorption; abnormal hormonal secretion; abnormal hormonal signaling; abnormal neurohormonal signaling; abnormal iron absorption; abnormal intestinal gluconeogenesis; abnormal hormone receptor expression; abnormal microbiome; abnormal splanchnic metabolism; abnormal bile acid processing (e.g., dehydroxylation from primary to secondary bile acids); abnormal bile acid activation of the farnesoid X receptor(FXR); abnormal enterocyte mass (e.g., as measured via plasma biomarkers); abnormal expression of fatty acid binding protein in the intestine; and combinations of one, two, or more of these.

[0221] The duodenum has been shown to play a key role in glucose homeostasis. With obesogenic diets, intestinal maladaptation is associated with development of hyperglycemia and insulin resistance. In some embodiments, system 10 is configured to perform a duodenal mucosal ablation procedure, also referred to as a duodenal mucosal resurfacing (DMR) procedure, during which duodenal mucosal tissue is ablated, such as via hydrothermal energy, electroporation energy, and / or other form of energy. DMR can improve overall metabolic health of the patient, including glycemic control.

[0222] REVITA- 1 and REVITA-2 are open label human clinical studies which were conducted by the applicant to assess the effect of DMR on insulin resistance, insulin production capacity, and key metabolic hormones via a mixed meal tolerance test. As shown in Figs. 53 and 54, applicant has collected data that demonstrates post-DMR changes in glucoregulatory hormones and insulin sensitivity in a subset of patients with T2D in the REVITA- 1 and REVITA-2 studies. A post hoc mechanistic analysis of insulin sensitivity, beta cell function, and metabolic hormone assessment was performed in all patients who were treated in the REVITA-1 (n=13) and REVITA-2 (n=15) open label studies, during which mixed meal tolerance tests were performed at baseline and again at 3 months post-DMR. Patients selected for study inclusion had poorly controlled T2D (e.g., HbAlc 7.6-10.4%) for up to 10 years, were on oral glucose lowering medication, and had a BMI 24-40 kg / m2. All patients underwent a single, complete DMR procedure comprising five ablations, each ablation performed using a treatment element of the present inventive concepts. Baseline, 3 months, and 6 months follow-up data were collected and assessed with either Wilcoxon paired signed-rank test or mixed effect models. Changes in glucoregulatory hormone concentrations and insulin sensitivity indices (including HOMA-IR, Matsuda Index (MI), and Insulinogenic Index (IGI)) following MMTT were assessed.

[0223] Referring specifically to Fig. 53, applicant has demonstrated patient fasting plasma glucose (FPG), glycated hemoglobin (HbAlc), glucagon, c-peptide, and weight decrease significantly at 3 and 6 months post-DMR performed with system 10 of the present inventive concepts. HOMA-IR and MI also improve significantly. A decline in MMTT glucose, mainly driven by a decrease in fasting levels was observed, as well as MMTT glucagon; while there was no change in MMTT insulin. Applicant also demonstrated insulin sensitivity is improved (e.g., to the greatest extent in patients with high baseline FPG). Additionally, glucagon likepeptide-1 (GLP-1) and gastric inhibitory peptide (GIP) MMTT concentrations do change significantly.

[0224] Furthermore, results from the 28 subjects demonstrate the following findings at 3 months post- DMR: an improvement in glycemic control comprising an approximate 0.8%-point reduction in HbAlc (from baseline of 8.2%; p=0.002) and comprising an approximate 36 mg / dL reduction in FPG (from baseline 198 mg / dL; p<0.001); weight loss comprising an approximate 4.3 kg mean reduction in weight (4.7% total body weight loss; p<0.001); an improvement in insulin resistance comprising an approximate 33% improvement in HOMA-IR and comprising an approximate 32% improvement in MI, each of which represent a measure of insulin resistance associated with a heightened risk of T2D progression (p=0.005 for each); an improvement in beta cell function comprising an approximate 25% improvement in insulin secretion rate and comprising an approximate 37% improvement in Disposition Index, each of which represent a measure of pancreatic beta cell function associated with an improvement in the pancreas’ ability to produce and secrete insulin in response to a meal (p=0.002 and p=0.001, respectively); and the response of two key gut hormones known to regulate blood sugar (GIP and GLP-1) in response to a meal was unchanged post-DMR.

[0225] In some embodiments, system 10 is configured to perform a duodenal treatment procedure (e.g., a duodenal mucosal ablation procedure and / or other duodenal treatment procedure as described herein, such as DMR) that results in the patient having at least a 50%, 75%, and / or 85% likelihood of achieving at least a 0.3%, 0.5%, and / or 0.7%-point reduction in HbAlc (e.g., from a baseline of at least 8.0% or 8.2%), and / or of achieving at least a 15mg / dL, 22mg / dL, and / or 30mg / dL reduction in FPG (e.g., from a baseline of at least 175mg / dL and 185mg / dL).

[0226] In some embodiments, system 10 is configured to perform a duodenal treatment procedure (e.g., a duodenal mucosal ablation procedure and / or other duodenal treatment procedure as described herein, such as DMR) that results in the patient having at least a 50%, 75%, and / or 85% likelihood of achieving a physiologic change selected from the group consisting of weight loss of at least 2.5kg, 3.5kg, and / or 4.0kg; improvement in insulin resistance comprising at least a 20%, 25%, and / or 30% improvement in HOMA-IR and / or comprising at least a 20%, 25%, and / or 30% improvement in MI; an improvement in beta cell function comprising at least a 10%, 15%, and / or 20% improvement in insulin secretion rate and / or comprising at least a 20%, 27.5%, and / or 35% improvement in Disposition Index; and combinations of one, two, and / or more (e.g., all) of these.

[0227] Referring specifically to Figs. 54A-E, applicant has further demonstrated decreased HbAlc, glucagon, and insulin resistance (e.g., as shown via MI), and these changes were all correlated with decreased MMTT GIP. Applicant observed patient postprandial concentrations of glucose (as shown in Fig. 54A), insulin (as shown in Fig. 54B), and glucagon (as shown in Fig. 54C) during mixed meal tests at baseline and 3 months post-DMR (n= 28). Mixed effect models were used to assess differences between baseline and 3 months post-DMR. Applicant has demonstrated the correlation between baseline FPG and AIGI (as shown in Fig. 54D). Applicant has further demonstrated the correlation between AGIP AUC and AGIP iAUC and AMatsuda Index (as shown in Fig. 54E).

[0228] In this subset of patients with T2D, improvements in HOMA-IR and MI, following DMR as performed via system 10 of the present inventive concepts, indicate an improvement in whole-body insulin sensitivity with overall glucose control driven by a decline in FPG (as opposed to post-prandial glucose concentrations). A decreased glucagon level may be responsible for the beneficial effects of DMR. Applicant believes it is unlikely that incretin changes are solely responsible for the overall improved glucose control after DMR, yet improved glycemia and insulin sensitivity were both strongly correlated with decreased MMTT GIP.

[0229] In some embodiments, system 10 is configured to perform a duodenal treatment procedure (e.g., a duodenal mucosal ablation procedure and / or other duodenal treatment procedure as described herein, such as DMR) that results in the patient having at least a 50%, 75%, and / or 85% likelihood of achieving decreased HbAlc, glucagon, and / or insulin resistance (e.g., at 3 months post-DMR), wherein each these decreases can be accompanied by decreased MMTT GIP.

[0230] In some embodiments, system 10 is configured to perform a duodenal treatment procedure (e.g., a duodenal mucosal ablation procedure and / or other duodenal treatment procedure as described herein, such as DMR) that results in the patient having at least a 50%, 75%, and / or 85% likelihood of achieving decreased postprandial concentrations of glucose, insulin, and / or glucagon (e.g., at 3 months post-DMR).

[0231] Referring now to Figs. 1A and IB, side views of the distal portions of two embodiments of a tissue treatment device including a functional assembly comprising a coiled geometry are illustrated, consistent with the present inventive concepts. As described herein, each tissue treatment device 100 can comprise one or more functional assemblies 130 that are configured to ablate and / or otherwise treat target tissue of the patient (e.g., target tissue comprising duodenal mucosal tissue, duodenal submucosal tissue, and / or nerves of the intestine). In some embodiments, one or more functional assemblies 130 comprise an elongate structurethat can be arranged in a coiled geometry, such as is shown in Figs. 1 A and IB, such as a coiled geometry with a diameter that approximates and / or is slightly larger than the inner diameter of one or more segments of the small intestine to be treated. Each functional assembly 130 can be constructed and arranged to transition into a coiled geometry (e.g., transition from a relatively straight geometry into a coiled geometry) and / or to transition out of a coiled geometry (e.g., transition from a coiled geometry to a relatively straight geometry). In some embodiments functional assembly 130 is constructed and arranged to transition between (e.g., to and / or from) a first coiled geometry with a first diameter (e.g., a diameter that can be slidingly received by a working channel of an endoscope or other body introduction device) and a second coiled geometry with a second, larger diameter (e.g., a diameter that operably engages the luminal walls of the duodenum or other small intestine location). In these embodiments, the functional assembly can be resiliently biased in the first geometry, or the second geometry. Functional assembly 130 can be attached to the distal end of shaft 110 as shown in Figs. 1 A-1B. Alternatively, functional assembly 130 can be attached to a separate shaft that can be inserted through a lumen (e.g., a working channel) of shaft 110. In some embodiments, functional assembly 130 and / or other components of treatment device 100 of Figs. 1A and IB are of similar construction and arrangement to those described in applicant’s co-pending United States Patent Application Serial Number 17 / 879,222 (Attorney Docket No. 41714-706.303; Client Docket No. MCT-004-US-CON2), entitled “Electrical Energy Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed August 2, 2022.

[0232] In some embodiments, functional assembly 130 is resiliently biased in a coiled geometry. In these embodiments, the functional assembly 130 can be straightened (e.g., manually by an operator of system 10 and / or automatically by treatment device 100), such as to fit through the working channel of a body introduction device 50 (e.g., fit through the working channel of an endoscope 50a). Once advanced outside of a working channel, functional assembly 130 can be configured to self-expand, such as a self-expansion in which functional assembly 130 contacts a luminal wall (e.g., contacts the surface of the mucosal layer of the intestine). In other embodiments, a functional assembly 130 is resiliently biased in a relatively straight geometry, and the functional assembly 130 can transition into a coiled geometry (e.g., via one or more functional elements 199 comprising control cables which can be manipulated to cause the transition), such as a transition that is performed after the functional assembly 130 exits the distal end of a working channel of a body introduction device 50 (e.g., exits the distal end of a working channel of an endoscope 50a). Once expanded, functional assembly 130 can beconfigured (e.g., sized) to contact a luminal wall (e.g., contact the surface of the mucosal layer of the intestine).

[0233] In Fig. 1 A, functional assembly 130 comprises an assembly of two tubes (e.g., in a side-by-side geometry as shown) that can transition into and / or are resiliently biased in the coiled geometry shown (also referred to as “helical” or “spiral” geometry). Each tube can comprise a hollow tube or a solid tube. Each tube can comprise a circular, oval, and / or other cross-sectional geometry.

[0234] In Fig. IB, functional assembly 130 comprises an assembly that includes a flat ribbon construction that can transition into and / or is resiliently biased in the coiled geometry shown. The ribbon can comprise a width to thickness ratio of at least 3: 1, 4: 1, and / or 5: 1.

[0235] The functional assembly 130 of Figs. 1A and IB can include one, two, or three delivery elements 135 (six shown in Fig. 1 A and ten shown in Fig. IB). Each delivery element can be positioned such that when functional assembly 130 is expanded and in contact with a luminal wall (e.g., in contact with the mucosal surface of the intestine), each delivery element 135 is in contact with and / or is otherwise proximate to the luminal wall. Each delivery element 135 can comprise an energy delivery element selected from the group consisting of: electrode (e.g., an electrode configured to deliver RF energy, electroporation energy, and / or any electromagnetic energy); a fluid delivery element (e.g., a needle, fluid jet, nozzle, and / or other fluid delivery element configured to deliver an ablative fluid onto and / or into tissue, such as tissue of the intestine); a light delivery element; a sound delivery element (e.g., an ultrasound delivery element); a heat energy delivery element; a cryogenic energy delivery element; and combinations of these.

[0236] Each functional assembly 130 can be constructed and arranged to self-expand, manually expand, and / or controllably expand (e.g., via a functional element 199 comprising a pull wire). For example, the functional assembly 130 of Fig. 1 A and / or IB can be configured to expand to a diameter of at least 20mm, 24mm, 28mm, and / or 30mm. In some embodiments, functional assembly 130 comprises an expanded diameter that is adjustable by an operator of system 10 (e.g., via a functional element 199 comprising a diameter-adjustment mechanism). Alternatively or additionally, each functional assembly 130 can be constructed and arranged to self-compact, manually compact, and / or controllably compact (e.g., via a functional element 199 comprising a pull wire).

[0237] As described herein, each delivery element 135 can comprise an electrode configured to deliver electroporation energy (e.g., reversible and / or irreversible electroporation energy). Each delivery element 135 can comprise an electrode that is configured to deliver electrical energy ina monopolar arrangement (e.g., using a skin surface patch electrode, not shown, as a return electrode), a bipolar arrangement, or both. In some embodiments, sets of two, three, or four delivery elements 135 comprising electrodes can be arranged in a parallel arrangement, and system 10 can be configured to deliver bipolar energy between two or more electrodes of the set of electrodes (e.g., with or without also being configured to deliver monopolar energy via one or more of the electrodes). Alternatively or additionally, sets of two, three, or four delivery elements 135 comprising electrodes can be arranged in a linear arrangement, and system 10 can be configured to deliver bipolar energy between two or more electrodes of the set of electrodes (e.g., with or without also being configured to deliver monopolar energy via one or more of the electrodes).

[0238] In some embodiments, a functional assembly 130 comprising a coiled geometry (e.g., an assembly resiliently biased in a coiled geometry) can be advanced into (e.g., pushed into) a body introduction device 50 comprising an introducer sheath (e.g., sheath 1020 described in reference to Fig. 2A-D and otherwise herein) and then into an endoscope 50a, where the introducer sheath is of sufficient radial strength and / or lubricity to cause the functional assembly 130 to collapse into a relatively straight geometry, and advanced into and through a lumen of the device 50. In other embodiments, the functional assembly 130 can be advanced directly into the endoscope 50a (e.g., into a working channel of the endoscope 50a without a sheath), similarly causing the assembly 130 to collapse into a relatively straight geometry within the endoscope 50a. Device 100 can include a functional element 199 that comprises an elongate filament that can be used to transition the functional assembly from a coiled geometry into a relatively straight geometry via translation (advancement or retraction) of the filament (e.g., to assist in advancement of functional assembly 130 into an introducer device 50 and / or an endoscope 50a).

[0239] In some embodiments, a functional assembly 130 in a coiled geometry can be configured to be placed circumferentially around a distal portion of body introduction device 50 (e.g., around a distal portion of an endoscope 50a), and subsequently delivered through the stomach to the intestine of the patient while positioned about the device 50. In some embodiments, functional assembly 130 comprises a coiled geometry that is resiliently biased to a diameter that approximates the diameter of the intestinal location in which it is to be placed, thus a diameter that is larger than the diameter of the device 50. In these embodiments, a first filament can be attached to the distal end of assembly 130 (e.g., a filament that passes through a working channel of device 50 and / or passes alongside device 50), and a second filament can be attached to the proximal end of assembly 130 (e.g., a filament that passes alongside device 50). The first and second filaments can be positioned (e.g., first filament extended and second-n-filament retracted) such that assembly 130 is in tension such that its diameter is reduced to approximate the diameter of the portion of device 50 about which assembly 130 is placed (e.g., assembly 130 frictionally engages device 50). Once advanced to a desired treatment location, the first and second filaments can be re-positioned (e.g., first filament retracted and second filament advanced) such as to allow assembly 130 to expand to contact the luminal walls of the intestinal segment in which it is placed (e.g., assembly 130 resiliently expands and / or expands due to forces applied by the filaments). Once in contact, one or more energy deliveries can be performed at the location (e.g., with the distal portion of device 50 remaining within assembly 130 or with device 50 retracted). After the one or more energy deliveries, the filaments can be manipulated to cause assembly 130 to re-engage device 50 (e.g., once a distal portion of device 50 is properly positioned within assembly 130), and subsequently assembly 130 can be positioned at a different treatment location and the expansion and energy delivery steps repeated. In some embodiments, assembly 130 is translated (e.g., advanced or retracted) between treatment locations without being re-engaged with device 50, simply by advancement and / or retraction of either or both the first filament and the second filament.

[0240] In some embodiments, a functional assembly 130 in a coiled geometry can be positioned about an expandable element of device 100 (e.g., a functional assembly 130’ comprising a malecot or similar expansion element). The geometry of assembly 130 and / or 130’ can be resiliently biased in a diameter that is the same or smaller than the diameter of a distal portion of a body introduction device at which assembly 130 and 130’ are to be positioned. Assemblies 130 and 130’ can be attached to each other, such that expansion and / or contraction of either imparts a corresponding force on the other. The functional assemblies 130 and 130’ can collectively be positioned about a distal portion of a body introduction device 50 (e.g., about a distal portion of an endoscope 50a), and subsequently delivered through the stomach to the intestine of the patient while positioned about the device 50. Once assemblies 130 and 130’ are advanced to a treatment location (e.g., via advancement of device 50), one or more filaments or other control elements of device 100 can be activated (e.g., advanced or retracted) to cause assembly 130’ to expand, causing a corresponding expansion of assembly 130, such that assembly 130 expands to contact the luminal walls of the intestinal segment in which it is placed. Once in contact, one or more energy deliveries can be performed at the location (e.g., with device 50 remaining within assembly 130 and 130’, or with device 50 retracted). After the one or more energy deliveries, assembly 130’ can be manipulated to cause assembly 130 to reengage device 50 (e.g., via manipulation of the one or more filaments or other control elements and / or by resilient compression of assembly 130 and / or 130’), and subsequently assembly 130can be positioned at a different treatment location and the expansion and energy delivery steps repeated. In some embodiments, assembly 130 and 130’ are translated (e.g., advanced or retracted) between treatment locations without being re-engaged with device 50, simply by advancement and / or retraction of the filament or other control element. In some embodiments, assembly 130 and 130’ comprise the same component (e.g., a single expandable element attached to one or more filaments or other control elements).

[0241] In some embodiments, functional assembly 130 comprises a coil (e.g., a filament or other shaft with a coiled geometry), the coil including one or more fenestrations that fluidly connect to a lumen of device 100, such that a level of vacuum (i.e., negative pressure) can be applied to each fenestration. Application of the vacuum can be configured to cause a functional assembly 130 with a coiled geometry to engage or further engage (either or both, “engage” herein) a tissue wall of the intestine, such as to increase electrical contact to allow and / or improve delivery of energy (e.g., electroporation energy) between one or more energy delivery elements 135 and target tissue of the intestine. Alternatively or additionally, device 100 can comprise a separate assembly, a functional assembly 130’ which can be placed through the center of the coil of assembly 130, where the assembly 130’ includes a coil or tube with one or more fenestrations to which a level of vacuum can be applied to cause tissue to be drawn toward the coil of assembly 130 (e.g., drawn toward the energy delivery elements 135 of assembly 130). Assembly 130’ can be configured for advancement alongside and / or through a working channel of body introduction device 50.

[0242] In some embodiments, functional assembly 130 comprises a furled geometry (not shown, but such as a sheet that can be furled and / or unfurled). The assembly 130 can comprise one, two or more energy delivery elements 135 (e.g., electrodes) fixedly attached to the furled structure. The functional assembly 130 can be configured to circumferentially wrap around a distal portion of body introduction device 50 (e.g., around a distal portion of an endoscope 50a), as described herein. In these embodiments, assembly 130 can be resiliently biased to frictionally engage the device 50 and / or to frictionally engage a lumen of the intestine, as described herein. Delivery of assembly 130 can be performed via advancement of device 50, also as described herein. Expansion and / or contraction of assembly 130 can be performed via one, two, or more filaments attached to either or both ends of assembly 130, and / or via a malecot or other expandable assembly (e.g., an assembly 130’ comprising a malecot or other expandable construction). The functional assembly 130 comprising a furled geometry can be advanced and / or retracted within the intestine using the device 50 and / or attached filaments, similar to thetranslation described hereinabove in reference to a functional assembly 130 comprising a coiled geometry.

[0243] Referring now to Figs. 2A-D, side views of an embodiment of a tissue treatment device comprising a coiled functional assembly are illustrated, consistent with the present inventive concepts. Treatment device 100 and / or other components of system 10 of Figs. 2A-D can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. As described herein, treatment device 100 can include a functional assembly 130 that is configured as a treatment assembly, for example functional assembly 130 can comprise treatment assembly 1300, as shown, where assembly 1300 is configured to treat tissue via the delivery of energy to the tissue. Treatment assembly 1300 can comprise similar construction and arrangement to functional assembly 130 of Figs. 1 A and IB described herein. Treatment assembly 1300 can be configured to deliver energy (e.g., RF energy, electroporation energy, and / or other electromagnetic energy) to thermally ablate target tissue and / or to electroporate or otherwise non-thermally ablate target tissue, such as when configured to reversibly electroporate target tissue, irreversibly electroporate target tissue, or both. As shown in Figs. 2A and 2B, treatment assembly 1300 can comprise a coil-shaped geometry. Treatment assembly 1300 can include a flexible elongate member, shaft 1310 shown. Shaft 1310 can be arranged in a coiled geometry. In some embodiments, shaft 1310 is configured to transition between a compact coiled geometry, as shown in Fig. 2A, and an expanded coiled geometry, as shown in Fig. 2B. Fig. 2A shows treatment assembly 1300 coiled about a portion of body introduction device 50 (e.g., the distal portion of body introduction device 50, as described herein). Fig. 2B shows treatment assembly 1300 in an expanded coiled geometry, positioned distal to body introduction device 50. In some embodiments, shaft 1310 is biased in the compacted geometry shown in Fig. 3A. Treatment assembly 1300 can comprise array 1320 of electrodes 1321 that are located on shaft 1310. Electrodes 1321 can comprise similar construction and arrangement to delivery elements 135 of Figs. 1 A and IB and otherwise herein. Body introduction device 50 (e.g., an endoscope, such as endoscope 50a described herein) can comprise an elongate body, shaft 5010, that includes proximal end 5011, proximal portion 5012, distal portion 5018, and distal end 5019. Shaft 5010 can include one or more lumens therethrough, such as lumen 51, described herein. Body introduction device 50 can include a handle 5020 that is attached to proximal end 5011 of shaft 5010, as shown in Fig. 2C. Handle 5020 can include one or more user controls, such as steering control 5021. For example, body introduction device 50 can comprise a steerable device, such as when at least a portion of shaft 5010, such as distal portion 5018, is configured to be steerable, and steeringcontrol 5021 can operably attach to one or more steering wires, not shown, but configured to control the articulation of shaft 5010.

[0244] Treatment assembly 1300 can be configured to be positioned about (e.g., coiled around) distal portion 5018 of shaft 5010, as shown in Fig. 2A. Treatment device 100 can include shaft 110, as described herein. Shaft 110 can include proximal end 1101, proximal portion 1102, distal portion 1108, and distal end 1109. In some embodiments, shaft 1310 comprises distal portion 1108 of shaft 110, for example when at least distal portion 1108 of shaft 110 comprises a coiled structure configured to be positioned around distal portion 5018 of shaft 5010. Alternatively, or additionally, shaft 1310 can comprise a shaft that is fixedly attached to shaft 110, such as when the proximal end of shaft 1310 is fixedly attached to distal end 1109 of shaft 110, as shown. In some embodiments, at least a portion of shaft 110 comprises a coiled geometry, for example when shaft 110 comprises a coiled geometry that is configured to slidingly receive shaft 5010 of body introduction device 50, as shown. In some embodiments, shaft 1310 comprises a flexible material and / or an insulative material, such as PTFE (polytetrafluoroethylene), PFA (perfluoroalkoxy), or FEP (fluorinated ethylene propylene). In some embodiments, treatment assembly 1300 includes one or more filaments, such as wires 1314 shown, that connect portions of the coiled structure, such as to limit the maximum distance between the coils (e.g., prevent the loops of the coil from separating beyond a fixed maximum distance), for example a maximum distance of no more than 10mm, such as no more than 5mm, 2.5mm, or 1mm.

[0245] In some embodiments, treatment device 100 is configured to be slidingly advanced along shaft 5010 of body introduction device 50, such that treatment assembly 1300 is positioned distal to distal end 5019 of shaft 5010 of introduction device 50, for example as shown in Fig. 2B. Shaft 1310 can be configured to transition to an expanded geometry (e.g., from a compacted geometry), such that electrodes 1321 contact tissue, for example after treatment assembly 1300 has been advanced beyond distal end 5019. Alternatively or additionally, treatment assembly 1300 can transition to an expanded geometry while positioned about distal portion 5018 of shaft 5010 of introduction device 50. In some embodiments, treatment device 100 comprises one or more tubes configured to surround a portion of shaft 110, shaft 1310, and / or shaft 5010 of body introduction device 50, such as sheath 1020 shown. In some embodiments, shaft 110 and / or shaft 1310 are configured to rotate within sheath 1020. Sheath 1020 can comprise a lubricious material, such as PTFE. In some embodiments, treatment assembly 1300 is biased in an expanded geometry (e.g., shaft 1310 is biased in an expanded geometry), and is configured to expand when advanced from sheath 1020. For example, sheath 1020 can surround treatmentassembly 1300 and at least distal portion 5018 of shaft 5010 when treatment assembly 1300 is in a retracted position, such that shaft 1310 is coiled about distal portion 5018 of shaft 5010. Shaft 1310 can be configured to be advanced beyond distal end 5019 of shaft 5010, exiting sheath 1020, for example as shown in Fig. 2B. In some embodiments, sheath 1020 extends from a proximal portion of body introduction device 50 (e.g., proximate handle 5020) to distal portion 5018 of shaft 5010. In some embodiments, sheath 1020 comprises a helical profile that mates with the coiled shape of shaft 110 and / or shaft 1310, such that rotation of treatment device 100 within sheath 1024, about the longitudinal axis of body introduction device 50 (e.g., while sheath 1020 and / or body introduction device 50 remain stationary) causes the translation of treatment device 100 relative to body introduction device 50 (e.g., causes treatment assembly 1300 to extend from and / or retract into sheath 1020). In some embodiments, sheath 1020 is configured to temporarily attach (e.g., reversibly attach) to body introduction device 50. For example, sheath 1020 can be “tightened” onto shaft 5010 (e.g., the inner diameter of sheath 1020 can be reduced to securely engage shaft 5010), such as when the proximal end of sheath 1020 is rotated to contract sheath 1020 onto shaft 5010 (e.g., sheath 1020 comprises a geometry that is configured to reduce in diameter when a first portion of sheath 1020 is rotated relative to a second portion of sheath 1020).

[0246] In some embodiments, shaft 1310 comprises a coiled ribbon configured to be expanded and compacted (e.g., shaft 1310 comprises a flat ribbon-like shaft that is arranged in a coiled geometry). Alternatively, or additionally, shaft 1310 can comprise a tube-like shaft that is arranged in a helical geometry, for example a tube comprising a heat-set helical arrangement. Treatment assembly 1300 can be configured to expand and / or contract when a lateral force is applied, such as when the proximal end of shaft 1310 is held in a stationary position, and a linkage, such as linkage 1307 shown in Fig. 2B, that is attached to the distal end of shaft 1310, is advanced or retracted to apply a lateral force. For example, linkage 1307 can be advanced and / or retracted (e.g., advanced and / or retracted relative to the proximal end of shaft 1310) to expand and / or contract treatment assembly 1300. Alternatively or additionally, treatment assembly 1300 can be configured to expand and / or contract when a torsional force is applied, such as when the proximal end of shaft 1310 is held in a stationary position and / or orientation (e.g., prevented from rotating) and linkage 1307 (e.g., linkage 1307 attached to the distal end of shaft 1310) is rotated to expand and / or contract treatment assembly 1300. In some embodiments, one or more linkages 1307 extend from outside of the patient to treatment assembly 1300 through a lumen 51 of body introduction device 50, and / or alongside shaft 5010 of body introduction device 50, such as within sheath 1020. In some embodiments, a first linkage 1307 comprises a linkageconfigured to advance treatment assembly 1300 from beyond distal end 5019 of body introduction device 50, and a second linkage 1307 comprises a linkage configured to expand and / or contract treatment assembly 1300 (e.g., by applying a force relative to the first linkage 1307).

[0247] In some embodiments, system 10 is configured to deliver an agent (e.g., agent 420, not shown but described herein), such as an agent comprising saline and / or other conductive fluid, for example through lumen 51 of body introduction device 50. Agent 420 can be delivered to improve contact (e.g., improve electrical contact) of electrodes 1321 with tissue. In some embodiments, system 10 is configured to perform aspiration and / or insufflation, such as via lumen 51 of body introduction device 50.

[0248] Fig. 2C illustrates the proximal end of body introduction device 50 (e.g., an endoscope) including handle 5020. In some embodiments, treatment device 100 includes a user control element, control 1110 shown. Control 1110 can be configured to allow an operator of system 10 to adjust the position and / or geometry of treatment assembly 1300, such as by applying a force to a linkage, such as linkage 1307, and / or by adjusting the longitudinal position of treatment device 100 (e.g., relative to sheath 1020). Fig. 2D shows an end view of control 1110. Control 1110 of treatment device 100 can comprise a clamshell configuration, for example a clamshell geometry that is configured to be attached surrounding a portion of handle 5020 and / or shaft 5010.Control 1110 can be attached to proximal portion 5012 of shaft 5010. Control 1110 can be rotated about the longitudinal axis of shaft 5010, such as to rotate shaft 110 (e.g., shaft 110 comprising a coiled shaft) about body introduction device 50 and / or relative to sheath 1020, such as to advance and / or retract treatment assembly relative to body introduction device 50, such as described herein.

[0249] In an expanded geometry, treatment assembly 1300 comprises a diameter DE. When shaft 1310 is configured to collapse to a smaller diameter coil, the collapsed geometry comprises a diameter DC. In the collapsed coil geometry, shaft 1310 forms a coil with an inner diameter IDC. In some embodiments, diameter DE is at least 5% larger than diameter DC, such as at least 10%, 15%, 20% or 30% larger. In some embodiments, diameter IDC comprises a diameter that is greater than or equal to the outer diameter of shaft 5010 of body introduction device 50, for example such that shaft 5010 can be slidingly received within the coiled geometry of treatment device 100, as described herein. In some embodiments, diameter DE comprises a diameter of at least 20mm, such as at least 24mm, 28mm, or at least 30mm.

[0250] Referring now to Fig. 3, a flow chart of a method of treating target tissue of a patient is illustrated, consistent with the present inventive concepts. In some embodiments, Method5000 of Fig. 3 is accomplished using system 10 of Fig. 1 described hereabove, or system 10 of Fig. 6 described herebelow. In Step 510, a patient is selected for treatment. The patient can be selected to treat a patient disease or disorder selected from the group consisting of: type 2 diabetes; type 1 diabetes; "Double diabetes"; gestational diabetes; hyperglycemia; pre-diabetes; impaired glucose tolerance; insulin resistance; non-alcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic dysfunction-associated steatohepatitis (MASH); obesity; obesity-related disorder; polycystic ovarian syndrome; hypertriglyceridemia; hypercholesterolemia; psoriasis; GERD; coronary artery disease (e.g., as a secondary prevention); stroke / TIA; cognitive decline or dementia (e.g., Alzheimer's); diabetic nephropathy; neuropathy; retinopathy; diabetic heart disease and / or heart failure; and combinations of these. In some embodiments, the patient is selected to treat two or more of the above diseases or disorders, such as a patient selected to treat both a form of diabetes and hypercholesterolemia.

[0251] The patient selected can be taking one or more medicines to treat their diabetes. The patient selected can have an HbAlc level between 7.5% and 12.0%, between 7.5% and 10%, or between 7.5% and 9.0%. In some embodiments, the patient selected can have an HbAlc level between 6.0% and 12.0%. Patients with higher HbAlc levels and / or other higher disease burden can receive more aggressive treatments (e.g., more tissue treated and / or higher number of repeated treatments over time) as described herebelow in reference to Step 570.

[0252] Patient selection can be based on the current level of one or more parameters representing one or more various biomarkers or other representative values of physiologic conditions (e.g., as compared to an average among diabetic and / or non-diabetic patients), such as a level of a parameter selected from the group consisting of: body mass index (BMI) level; waist circumference; HbAlc level; fasting glucose; insulin resistance; liver fibrosis; cholesterol or triglyceride level; duration of years exhibiting type 2 diabetes; fasting C-peptide or C-Peptide stimulation in response to a meal; age; and combinations of these.

[0253] Prior to placing any device in the patient, or at any time thereafter (e.g., during or after the procedure), one or more agents can be introduced into the patient, such as an agent introduced into the GI tract directly, such as agent 420 described hereabove in reference to Fig.1. In some embodiments, agent 420 comprises L-menthol (i.e., oil of peppermint) or other agent configured to provide an anti-peristalsis effect. In these embodiments, a few drops of agent 420 can be placed in an irrigation lumen of an endoscope or other body inserted device with a fluid delivery channel. In some embodiments, approximately 8mL of L-menthol is mixed with approximately 0.2mL of Tween 80 (polysorbate 80) in approximately 500mL of distilled water(i.e., to create an approximately 1.6% solution). Approximately 20mL of this mixture can be sprayed through a working channel of endoscope 50a, or more as required to dampen peristalsis. In some embodiments, the solution can vary between approximately 1 .6% and 3.2%.Tween and / or sorbitan monostearate can be used as an emulsifier.

[0254] One or more agents can be delivered once the endoscope or other agent delivery device enters the duodenum. In other embodiments, agent 420 is delivered intravenously, and can comprise glucagon and / or buscopan.

[0255] In some embodiments, an endoscope is inserted into the patient (e.g., endoscope 50a of Fig. 1). In these embodiments, subsequently inserted devices can be placed through a working channel of the endoscope and / or alongside the endoscope. In some embodiments, an endoscope and an attachable sheath (e.g., scope attachable sheath 80 of Fig. 1) are both inserted into the patient, and subsequently inserted devices can be placed through a working channel of the endoscope, through the attachable sheath and / or alongside the endoscope and the attached sheath. Each patient inserted device can be inserted over a guidewire. In some embodiments, an endoscope stiffening device is used, such as an endoscope stiffening system provided by Zutron Medical of Lenexa, Kansas, USA.

[0256] In Step 520, non-target tissue can be identified. Non-target tissue can be identified with a visualization device, such as endoscope 50a of system 10 of Fig. 1. The non-target tissue can comprise the ampulla of Vater, also known as the papilla, the pancreas, or other tissue to which treatment may adversely affect the patient. Step 520 and / or another step of the method of Fig. 3 can include marking the non-target tissue (or tissue proximate the non-target tissue), such as with a tattoo, ink or other visualizable substance, such as a visual agent placed in the mucosa and / or submucosa in or proximate the ampulla of Vater. In some embodiments, one or more markers similar to marker 195 described herebelow in reference to Figs. 3 or 5A-E are deployed in the patient to provide a reference location relative to non-target tissue. Tissue expansion and / or tissue treatment performed in subsequent steps can avoid the non-target tissue identified and potentially marked (e.g., with one or more markers 195) in step 520.

[0257] In Step 530, a tissue expansion device is inserted into the patient. Step 530 can include selecting a particular model of tissue expansion device, such as a particular size or other configuration of a tissue expansion device. In some embodiments, the tissue expansion device is constructed and arranged similar to device 20 and / or device 40 of Fig. 1 described hereabove, or device 100 or device 20 described herebelow in reference to Fig. 6. The tissue expansion device can be inserted over a guidewire, such as a Savary-Gilliard® guidewire or other relatively stiff guidewire. The guidewire can be advanced such that its distal end is in the jejunum. Duringadvancement of the tissue expansion device, the guidewire can be held taut in order to prevent the tissue expansion device from forming a loop in the stomach. In some embodiments, the tissue expansion device is inserted through a working channel of an endoscope, such as endoscope 50a of Fig. 1. In other embodiments, the tissue expansion device is inserted alongside an endoscope.

[0258] The tissue expansion device is advanced into the duodenum (e.g., over a guidewire). One or more fluid delivery elements of the tissue expansion device can be positioned at least 1cm, but not more than 5cm or 10cm from the ampulla of Vater, to perform a first tissue expansion or otherwise a most-proximal tissue expansion (i.e., closest to the ampulla of Vater). In some embodiments, one or more fluid delivery elements of the tissue expansion device are positioned based on the location of a previously placed marker, such as marker 195 described hereabove in STEP 520. Prior to and / or during insertion, a stiffening wire can be inserted within the tissue expansion device. An endoscope can be positioned adjacent the tissue expansion device, such that both distal ends are beyond the ampulla of Vater (e.g., beyond a tattoo or other marker or marking identifying the ampulla of Vater, as described herein).

[0259] In some embodiments, prior to insertion of the tissue expansion device, a lumen diameter sizing device is inserted into the patient, such as device 30 of Fig. 1. Luminal diameter or other information provided by the sizing device can be used to select and / or control the tissue expansion device. The sizing device can be placed over a guidewire as described hereabove or it may be delivered through the working channel of an endoscope. Prior to and / or during insertion, a stiffening wire can be inserted within the sizing device.

[0260] The sizing device expandable element (e.g., balloon) is positioned in the post-papillary duodenum and inflated at a particular location within the duodenum with a fluid (such as air or saline) and the pressure of the fluid within the balloon is determined by a pressure sensor attached to the proximal end of the device. The volume of delivered fluid can be detected by the system. The fluid can be delivered slowly, such as until a stable pressure reading of approximately 0.7 psi (or approximately 0.9 psi or 2.0 psi) is determined by the pressure sensor (i.e., a threshold pressure is achieved). The volume of fluid within the balloon at a given pressure is used to ascertain the lumen diameter by reference-checking against a calibration step performed before the sizing procedure (e.g., via one or more algorithms of system 10 of Figs. 1 or 6). Measurements can be taken in at least two locations within the duodenum. An algorithm (e.g., algorithm 251 described herein) selects an appropriate ablation balloon size for the individual patient.

[0261] In Step 540, tissue is expanded. In some embodiments, saline or other fluid is injected by multiple fluid delivery elements of the tissue expansion device, such as three needles and / or other fluid delivery elements as described herein (e.g., fluid delivery elements 28), positioned in a tissue port and spaced approximately 120° apart along a circumference that deliver injectate (e.g., injectate 221 of Fig. 1) into tissue. Each injection can comprise at least 1ml, such as at least 2ml, at least 5ml or at least 8ml per fluid delivery element. Volumes injected by the multiple fluid delivery elements can be selected to achieve near full circumferential expansion of submucosal tissue (e.g., without gaps, full 360° expansion).

[0262] Subsequent injections of fluid into tissue can be delivered, such as at an axial separation distance of between 1cm and 2cm apart from a previous injection (e.g., 1cm to 2cm distally in the duodenum). In some embodiments, multiple injections are positioned at least 0.5cm apart along the axis of the duodenum, such as between 1.0cm and 5.0cm apart, such as approximately 1.0cm, 2.0cm, 3.0cm, 4.0cm and / or 5.0cm apart from one another along the axis of the duodenum. In some embodiments, axial separation of injection sites (i.e., translation distance of the tissue expansion device between injections) can approximate half the length of a balloon onto which the fluid delivery elements are mounted, such as half the length of balloon 26 of Fig. 1. In some embodiments, a series of 5-15 sets (e.g., 8-12 sets) of injections (e.g., each set comprising injections from 2, 3 or more fluid delivery elements) can be performed by delivering injectate (e.g., a fluid containing a visualizable dye) to the tissue to be expanded and subsequently translating the tissue expansion device to a new axial location (e.g., after proper expansion of tissue is confirmed visually or otherwise). Each advancement and / or retraction of the tissue expansion device can be made in unison with advancement and / or retraction of an endoscope positioned alongside the tissue expansion device.

[0263] Tissue expansion can begin at a location proximate but distal to the ampulla of Vater, such as at a location at least 1cm distal to but not more than 5cm or 10cm from the ampulla of Vater. A series of relatively contiguous, full circumferential submucosal tissue expansions can be performed (e.g., moving distally), for example up to the Ligament of Treitz. In alternate embodiments, multiple full circumferential tissue expansions are performed by moving the tissue expansion device from distal to proximal locations, or in a discontinuous manner.

[0264] Volumes of injections and / or axial separation of injections can be chosen to avoid axial gaps. After injections, gaps identified circumferentially and / or axially (e.g., via endoscope camera, fluoroscope, or ultrasound imaging device), can be filled in as deemed necessary via additional injection (e.g., with or without rotation and / or translation of the tissue expansion device).

[0265] In some embodiments, the amount of fluid (e.g., liquid such as water or gas such as air) in an expandable assembly supporting the fluid delivery elements is reduced as the inj ectate is delivered into tissue, such as to prevent excessive force being applied to tissue proximate the expanding tissue (i.e., due to the decreasing lumen proximate the expanding tissue in contact with expandable assembly), such as is described in detail hereabove in reference to Fig. 1.

[0266] In some embodiments, a first volume of fluid (e.g., air) is determined that causes a balloon of the tissue expansion device to get sufficient apposition with a lumen of the GI tract (e.g., a lumen of the duodenum), such as by measuring pressure achieved within the balloon. The balloon is subsequently compacted (i.e., fluid removed), and filled with a second volume that is less than the first volume, and a confirmation of a lower pressure can be performed. Vacuum is applied within the GI lumen (e.g., via an insufflation port of an endoscope or other inserted device), causing the lumen to collapse onto the balloon without compressing the luminal wall. A second vacuum is applied to one or more tissue ports on the balloon (e.g., tissue ports 27 of Fig. 1), causing tissue to be drawn into the tissue ports. One or more needles (e.g., fluid delivery elements 28 of Fig. 1) can be advanced into the tissue contained in the tissue ports, while avoiding the potential of the needles penetrating an outer layer and / or outside of the GI wall tissue, as has been described in detail hereabove. In some embodiments, tissue is penetrated by the fluid delivery elements at the time of the application of the vacuum, without the advancement of the fluid delivery element, also as described hereabove.

[0267] Multiple injections (e.g., three injections from three equally separated fluid delivery elements) can be performed simultaneously or sequentially. A vacuum can be applied prior to delivery of fluid, such as to draw tissue toward the fluid delivery element (e.g., into three associated ports as described in reference to Fig. 1). After fluid delivery, the vacuum can be removed and the tissue expansion device advanced (or retracted).

[0268] The inj ectate delivered can include an agent that is directly visualizable by an operator (e.g., via an endoscope camera or other camera), radiographically visualizable (e.g., via a fluoroscope or other X-ray imaging device) and / or ultrasonically reflectable or otherwise visualizable (e.g., via an ultrasound imaging device), such as an injectate 221 comprising visualizable material, as described hereabove in reference to Fig. 1. Visualization of the expanded tissue can be used to determine proper volume of injectate delivered as well as sufficient tissue expansion (e.g., sufficient thickness, axial length and / or circumferentiality of tissue expansion). The pressure of the expandable assembly (e.g., balloon) or the volume of fluid within the expandable assembly can also be monitored to determine if a proper volume of injectate has been delivered to achieve adequate tissue expansion.

[0269] In Step 550, the tissue expansion device is removed, for example using an over-the wire exchange leaving the guidewire in place. An endoscope and / or sheath can also be removed during this step. In some embodiments, the tissue expansion device is also configured to ablate or otherwise treat tissue (e.g., in addition to tissue expansion), and the tissue expansion device remains in place to perform Step 570.

[0270] In Step 560, a tissue treatment device is inserted into the patient (e.g., if not already in place to perform the tissue expansion step described above, such as when the tissue treatment device is of similar construction and arrangement to multi -function device 40 described hereabove in reference to Fig. 1). Step 560 can include selecting a particular model of a tissue treatment device, such as a particular size or other configuration of a tissue treatment device. In some embodiments, the tissue treatment device is constructed and arranged similar to device 100 and / or device 40 of Fig. 1 described hereabove, and / or device 100 of Fig. 6 described herebelow. In some embodiments, prior to selection of the tissue treatment device, a lumen diameter sizing device, such as device 30 of Fig. 1, is inserted and used to determine the size of a tissue treatment device to be used (e.g., to select a particular diameter of an expandable functional assembly of the treatment device).

[0271] The tissue treatment device can be placed through an endoscope, such as endoscope 50a of Fig. 1, or through a scope attached sheath, such as sheath 80 of Fig. 1. Alternatively or additionally, the tissue treatment device can be placed over a guidewire, such as guidewire 60 of Fig. 1. In some embodiments, the tissue treatment device is placed over the same guidewire used to introduce the tissue expansion device of Steps 530 - 550. The tissue treatment device can be advanced to the duodenum. In some embodiments, the tissue treatment device can be advanced to the duodenum over a guidewire without an endoscope in place, subsequent to which an endoscope can be advanced to a similar location in the duodenum. In some embodiments, prior to and / or during insertion, a stiffening wire can be inserted within the tissue treatment device.

[0272] In Step 570, target tissue is treated (e.g., ablated) by one or more treatment elements of the tissue treatment device, such as treatment element 135 positioned on an expandable assembly (e.g., functional assembly 130) of device 100 of Fig. 1. The target tissue can comprise one or more portions of the mucosal layer of the duodenum. Treated tissue can further comprise at least an inner layer of neighboring submucosal tissue. One or more circumferential ablations or other treatments can be performed along a length of the GI tract (e.g., along one or more axial segments of the GI tract), such as along a length of the duodenum at least 1cm distal to the ampulla of Vater, such as at a location at least 1cm distal to but within 3cm, 5cm or 10cm of the ampulla of Vater. In some embodiments, all ablations are performed at least 2cm or at least 3cmdistal to the ampulla of Vater (e.g., tissue within 1cm, 2cm or 3cm of the ampulla of Vater is not ablated). In some embodiments, one or more circumferential ablations (e.g., a most-proximal duodenal axial segment ablated) is performed based on the position of a previously placed marker, such as marker 195 described hereabove in STEP 520. In some embodiments, tissue treatments are only performed at locations that have had submucosal tissue expansion performed and / or confirmed (e.g., visually). In other embodiments, tissue treatments are performed without any tissue expansion, avoiding the need for Steps 530 - 550.

[0273] In some embodiments, a thermal treatment is provided by sufficiently hot or cold fluid introduced into a balloon of the tissue treatment device to ablate tissue. In other embodiments, different forms of energy delivery or other tissue treatments are performed, as described in detail in reference to system 10 of Fig. 1 or system 10 of Fig. 6.

[0274] The tissue treatment device can treat a series of axial segments of GI tract tissue comprising lengths between 1cm and 5cm each, such as approximately 3cm in length each. The tissue treatment device can treat a cumulative axial length of GI tract tissue (e.g., an axial length of duodenal mucosa tissue) of less than or equal to 3cm, 6cm, 9cm, 15cm, or 20cm. The tissue treatment device can be constructed and arranged to treat more than 3cm of axial length of duodenal mucosa, such as more than 3.4cm, more than 6cm, more than 7cm, more than 8cm or more than 9cm (e.g., approximately 9.3cm), such as to achieve a clinical benefit for a diabetes or other patient as described herebelow in reference to applicant’s clinical study (including the results presented in Figs. 21-44). In some embodiments, at least 10%, 15%, 25%, 30% and / or 50% of the duodenal mucosa distal to the ampulla of Vater is treated. The axial length and / or overall volume of tissue treated can correspond to a patient parameter, such as the longevity of the disease or other disease parameter as described in detail herebelow (e.g., higher disease burden correlating to larger volumes of tissue treated).

[0275] In some embodiments, at least 3 axial segments of duodenal mucosal tissue are treated (e.g., sequentially treated), such as with a treatment element configured to deliver energy to a delivery zone with a length between 1.0cm and 4.0cm (e.g., tissue contacting length of a balloon filled with ablative fluid), such as a delivery zone length between 1.9cm and 3.3cm, or approximately 3cm in length. In some embodiments, at least 4 axial segments of duodenal mucosal tissue are treated, such as at least 6 axial segments of duodenal mucosal tissue are treated. In these embodiments, the treatment element can be configured to deliver energy to a delivery zone with a length between 0.7cm and 2.0cm (e.g., tissue contacting length of a balloon filled with ablative fluid). In some embodiments, the treatment element comprises ablative fluid delivered into a balloon, such as balloon 136 described herein. Multiple tissue treatments areperformed by repositioning the treatment element (e.g., treatment element 135 of Fig. 1), which can further include expanding an expandable assembly (e.g., functional assembly 130 of Fig. 1) onto and / or into which the treatment element treating the tissue can be positioned. Contact between the target tissue and the treatment element can be accomplished using desufflation techniques to bring the tissue toward the treatment element, as described in detail hereabove. Tissue treatment is performed, such as by filling the functional assembly with ablative temperature fluid and / or delivering any form of energy to the target tissue such as is described herein. In embodiments where the tissue treatment device is delivered over a guidewire, the guidewire can be retracted (e.g., at least retracted to a location proximal to the treatment element) prior to any tissue treatments.

[0276] Multiple treatments can be performed by advancing or retracting the tissue treatment element and / or tissue treatment device. In some embodiments, the tissue treatment element is positioned at a distal location and a series of tissue treatments are performed, such as at least 3 tissue treatments performed in which the tissue treatment device is retracted approximately the length of the tissue contacting portion of the treatment element such as to treat relatively contiguous, non-overlapping, full circumferential axial segments of the duodenum. After each tissue treatment, confirmation of being away from (e.g., distal to) any non-target tissue marked and / or otherwise identified (e.g., in Step 520) can be performed (e.g., be visualizing a previously placed marker 195). In some embodiments, a marker 195 is placed to avoid any damage to the ampulla of Vater. In some embodiments, after three axial segments of duodenal mucosa are treated (e.g., treated distally to proximally), an assessment of the linear distance between the most proximal treatment segment and the ampulla of Vater is performed (e.g., one or more components of system 10 is used to determine the distance). If sufficient length is determined (e.g., the determined distance is above a threshold), additional (more proximal) axial tissue segments can be treated. During translation of the tissue treatment device over a guidewire, undesired movement of the guidewire is prevented or otherwise reduced by the operator.

[0277] In some embodiments, the system of the present inventive concepts (e.g., system 10 of Figs. 1 or 6) is configured to allow only one ablation per (pre-determined) time period, such as to prevent two ablations within the time period such as to prevent repetitive ablation in the same or at least similar (e.g., overlapping) portions of the GI tract (e.g., rapid treatment of similar treatment zones).

[0278] In some embodiments, the tissue treatment of Step 570 should be completed within approximately 120 minutes or within approximately 60 minutes of the initiation of tissue expansion performed in Step 540, such as within approximately 45 minutes, 30 minutes and / or20 minutes. Performance of tissue treatment within this time window prevents an unacceptable amount of injectate dissipation from the expanded tissue (e.g., submucosal tissue) space. In some embodiments, the system of the present inventive concepts (e.g., system 10 of Figs. 1 or 6) is configured to prevent a tissue treatment (e.g., ablation) until a submucosal expansion step has been performed.

[0279] The amount of target tissue treated and / or the number of treatments performed can correlate to (e.g., be proportional to) one or more patient conditions (e.g., more severe correlates to more tissue treated and / or more treatments performed over time). This increased treatment can comprise an increased axial length of tissue treated (e.g., an increased cumulative axial length of duodenum ablated or otherwise treated), a deeper depth of treatment and / or a larger number of treatments performed over time in order to achieve a sustained treatment response. Increased treatments can correlate to a higher burden of the patient’s disease (e.g., relatively long duration since diagnosis, higher HbAlc level than a standard diabetic patient and / or more mucosal dysfunction than a standard diabetic patient). In some embodiments, the volume of target tissue treated and / or the number of treatments performed is proportional to the patient’s HbAlc level.

[0280] In some embodiments, the tissue treatment is modified to avoid creation of a duodenal stenosis or stricture, such as to limit one or more of amount of energy delivered; peak energy delivered; duration of energy delivered; length of tissue treated; depth of tissue treated; and combinations of these. In some embodiments, a duodenal stenosis or stricture is treated with balloon dilatation.

[0281] In some embodiments, tissue expansion is not performed prior to tissue treatment. In some embodiments, lumen diameter sizing is not performed, or is performed with a tissue expansion device and / or a tissue treatment device. In some embodiments, a single device is inserted into the patient to perform two or more of lumen diameter sizing; tissue expansion; and tissue treatment; such as a device similar to device 40 of Fig. 1.

[0282] In Step 580, the tissue treatment device is removed. In addition, any guidewires, endoscopes, scope attached sheaths, or other inserted devices are removed.

[0283] In Step 590, a step of managing the patient post-procedurally can be performed. Postprocedure patient management can comprise one or more of a liquid diet for at least 1 day, 4 days, 5 days, 7 days or 14 days; a soft diet for at least 1 day, 4 days, 5 days, 7 days, or 14 days; a low sugar and / or low fat diet for at least 1 week, 1 month or 1 year; a standardized diabetic (e.g., ADA) diet for at least 1 week, 1 month or 1 year; and nutritional counseling for at least 1 week, 1 month or 1 year.

[0284] The therapy provided by the systems, methods and devices of the present invention can lead to numerous therapeutic benefit outcomes to the patient receiving the treatment. In some embodiments, the patient has an outcome selected from the group consisting of: improvement in HbAlc, fasting glucose and / or post-prandial glucose; at least a 1% improvement in HbAlc; a resultant HbAlc of less than 7.5%, less than 7%, less than 6.5%, or less than 6% (e.g., at a time period after a tissue treatment procedure of at least 1 month, 3 months, 6 months or 12 months); improvement in one or more triglyceride levels; improvement in AST, ALT, liver fibrosis panel, liver fibrosis score, NAFLD assessment and / or or NASH assessment; improvement in risk of myocardial infarction, stroke, TIA and / or peripheral vascular disease or diabetic cardiomyopathy; improvement in microvascular disease risk such as nephropathy, retinopathy and / or neuropathy; reduced development of end-stage renal disease, blindness and / or amputation; reduced insulin requirement (e.g., in patients with insulin-dependent diabetes) or other injectable therapy requirement; reduced medication requirement (e.g., in patients with diabetes) either in number of medicines or dosage of medicines; improved fetal birth outcomes (e.g., in patients with gestational diabetes); improved fertility in patients with polycystic ovarian syndrome and / or reduced hirsutism; weight loss of at least 5% of excess body weight, or at least 10%, 20%, 30% or 40% of excess body weight; reduced blood pressure; reduced cardiovascular risk; improved diabetes control and / or reduced diabetic complications; reduced obesity and / or reduced weight; reduced cognitive decline or prevention of dementia; and combinations of these.

[0285] The therapy provided by the systems, methods and devices of the present invention can have a clinically significant durability that lasts for at least 3 months, at least 6 months, at least 1 year or at least 2 years. The durability of the treatment can be enhanced by treating more volumes of tissue, such as by treating deeper and / or longer lengths of duodenal mucosa, or by treating the patient multiple times in the same or different regions of the duodenum, small intestine and / or stomach. The durability can be improved by selecting patients with a prior history of dietary compliance and medication compliance and / or a duration of the disease within a particular time window such as less than 2 year or 5 years, or less than 7 years or 10 years.

[0286] The systems, methods and devices of the present invention can be constructed and arranged to avoid or reduce the likelihood of one or more adverse events. In some embodiments, pancreatitis is avoided by excluding the ampulla of Vater while performing tissue expansion (e.g., submucosal tissue expansion) and / or tissue treatment (e.g., hot fluid and / or other tissue ablation). In some embodiments, duodenal stenosis and / or stricture can be avoided by performing one or more of the following: ablating only mucosal tissue proximate expanded submucosal tissue layers; ablating only mucosal tissue proximate submucosal tissue layersexpanded within 15 minutes, 30 minutes or 45 minutes of ablation; avoiding a second ablation to a tissue segment ablated within 24 hours; and treating tissue (e.g., ablating) only when the operator has direct visualization (e.g., endoscopic visualization) and / or other visualization (e.g., via X-ray or ultrasonic visualization devices) of the tissue treatment element and the tissue being treated.

[0287] Applicant has conducted human studies with the systems, methods, and devices of the present inventive concepts.

[0288] Included below are results of early studies and associated data collected through July 18, 2014.

[0289] Some patients received treatment of approximately 9cm of relatively full- circumferential axial length of duodenal mucosa (via three approximately 3cm hot fluid balloonbased ablations), and some patients received treatment of less than or equal to 6cm of relatively full-circumferential axial length of duodenal mucosa (via two or less approximately 3cm hot fluid balloon-based ablations).

[0290] Early results showed: baseline HbAlc was 9.2% and FPG was 187 mg / dl at 1 month post-procedure, HbAlc was reduced by 1.1% in LS-DMR patients (patients receiving duodenal mucosa treatments of approximately 9cm (e.g., 9.3cm) of duodenal tissue) but only 0.1% in SS- DMR patients (patients receiving duodenal mucosa treatment of approximately 3cm (e.g., 3.4cm) of duodenal tissue, the data representing 12 LS-DMR patients versus 7 SS-DMR patients, each group at 1 month (p=0.058). By 3 months, HbAlc was reduced by approximately 2% in LS- DMR patients but was unchanged in SS-DMR patients (N=5 in each group at 3 months). FPG reductions in LS-DMR patients were -64 mg / dl and -67 mg / dl at 1 and 3 months.

[0291] Referring now to Fig. 4, a side sectional view of the distal portion of a tissue treatment device inserted into a curvilinear section of duodenum is illustrated, consistent with the present inventive concepts. Tissue treatment device 100 comprises shaft 110, a relatively flexible, biocompatible, elongate structure configured for insertion into a body lumen such as the duodenal lumen shown. Shaft 110 is typically connected to a handle on its proximal end, not shown but configured to allow an operator to advance, retract and otherwise manipulate or control device 100, such as is described hereabove in reference to device 100 of Fig. 1. Tissue treatment device 100 can be configured for delivery over a guidewire, via a lumen from a proximal portion of shaft 110 to a distal portion of shaft 110, or via a rapid exchange sidecar or other lumen in the distal portion of shaft 110 (guidewire lumen and sidecar not shown but known to those of skill in the art). Shaft 110 is shown inserted through body introduction device 50which can comprise an endoscope, sheath, vascular introducer, laparoscopic port, or other body introduction device.

[0292] Tissue treatment device 100 further comprises a functional assembly, functional assembly 130, which can include a balloon and / or be of similar construction and arrangement as functional assembly 130 of Fig. 1. Fluid at an ablative temperature (i.e., a sufficiently high or low temperature to ablate tissue), treatment element 135, has been delivered to functional assembly 130, as described hereabove, to deliver energy to one or more portions of a delivery zone and to treat one or more portions of target tissue.

[0293] A marker 195 has been positioned on the wall of the GI tract to be used as a reference to identify non-target tissue (e.g., a marker placed on tissue in relation to the ampulla of Vater, such as at a location distal to but proximate the ampulla of Vater). Marker 195 can comprise an element selected from the group consisting of: a visible marker (e.g., visible via camera 52 of endoscope 50a); a radiographic marker; an ultrasonically visualizable marker; a magnetic marker; ink; dye; and combinations of these. Marker 195 can comprise multiple markers positioned in various locations (e.g., various locations used as a reference to identify multiple different or similar segments of non-target tissue).

[0294] Functional assembly 130 has been positioned in a distal portion of duodenal tissue, such as a section that includes a previously expanded segment of submucosal tissue (submucosal tissue expansion not shown). Functional assembly 130 has been radially expanded such as to contact the mucosal surface of the duodenum at a discrete tissue segment of target tissue, tissue segment TS1 as shown. Tissue segment TS1 is located distal to a series of sequential tissue segments of target tissue, tissue segments TS2 through TS6 as shown. Functional assembly 130 and treatment element 135 (ablative fluid) are shown in Fig. 3 positioned to ablate or otherwise treat tissue segment TS1. Each of tissue segments TS1 through TS6 has a corresponding delivery zone (not shown) to which energy is delivered from functional assembly 130 to cause the appropriate treatment of target tissue. In some embodiments, a series of adjoining segments are treated sequentially (i.e., from distal segment TS1 to each correspondingly more proximal segment TS2 through TS6 or from proximal segment TS6 to each correspondingly more distal segment TS5 through TS1). In some embodiments, a complete treatment comprises treatment of at least three adjacent segments (e.g., TS1 through at least TS3, TS2 through at least TS4, TS3 through at least TS5 or TS4 through at least TS6). Alternatively, a non-continuous pattern can be treated (e.g., TS1 followed by TS3 followed by TS2, and the like). In some embodiments, marker 195 is positioned in reference to the ampulla of Vater (e.g., proximate the ampulla ofVater), and all segments to be treated are positioned distal to the ampulla of Vater, such as can be determined by visualizing marker 195.

[0295] Functional assembly 130 can be sized to allow positioning in curved segments of the GI tract with a minimum radius of curvature, such as a curved segment of the duodenum and / or jejunum with an average radius of curvature less than 5cm over a 75° arc, or less than 3cm over a 75°arc. In these curved segments (and straighter segments as well), functional assembly 130 can be expanded without exerting undesired force onto tissue (e.g., expanded to contact the tissue wall). In some embodiments, functional assembly 130 is constructed and arranged to treat curved segments of the GI tract and comprises a length less than or equal to 30mm, such as less than or equal to 25mm, less than or equal to 20mm, or less than or equal to 15mm.

[0296] After treatment of tissue segment TS1, functional assembly 130 can be repositioned to tissue segment TS2, just proximal to tissue segment TS1, with or without contracting functional assembly 130 prior to the repositioning. Subsequently, a second tissue treatment (e.g., a second energy delivery) can be performed. The steps of repositioning and treating portions of target tissue are repeated until one or more of tissue segments TS3, TS4, TS5, and TS6 have been treated. In some embodiments, an ablation reducing step is performed after each tissue segment treatment, such as by delivering a treatment neutralizing cooling fluid after a hot fluid ablation or delivery of a treatment neutralizing warming fluid after a cool (e.g., cryogenic) ablation, each as described herein. Alternatively or additionally, a cooling or warming fluid can be delivered, prior to a heat or cryogenic ablation, respectively, as described herein.

[0297] In a single clinical procedure, the combined length of target tissue segments TS1 through TS6 can represent between 10% and 100% of the length of the duodenal mucosa length distal to the ampulla of Vater, such as when between 2 and 50 axial segments of tissue receive between 2 and 50 energy deliveries from functional assembly 130 (e.g., ablative fluid is introduced into functional assembly 130 2 to 50 sequential times). In some embodiments, each of tissue segments TS1 through TS6 have a maximum axial length of less than 20cm, less than 15cm, less than 10cm, less than 5cm, less than 3cm or less than 2cm. In some embodiments, the cumulative axial length of tissue segments treated, (e.g., two or more of tissue segments TS1 through TS6) is less than 100cm, less than 50cm, less than 25cm, or less than 10cm. In some embodiments, at least 6cm or at least 9cm of the duodenum is treated. Alternatively or additionally, other tissue (e.g., other tissue of the GI tract) can be treated, such as has been described hereabove.

[0298] Target tissue segments TS1 through TS6 typically include common border or overlapping tissue segments, such as is shown in Fig. 4. While the embodiment of Fig. 3 showssix target tissue segments being treated, more or fewer segments can be treated. In some embodiments, three axial tissue segments are treated (e.g., TS1, TS2 and TS3). In some embodiments, four axial tissue segments are treated (e.g., TS1, TS2, TS3 and TS4). In some embodiments, five axial tissue segments are treated (e.g., TS1, TS2, TS3, TS4 and TS5). In some embodiments, all GI tract tissue treated is distal to the ampulla of Vater.

[0299] Tissue treatments can be performed in a contiguous manner (e.g., a 1st portion, followed by a 2nd portion whose distal end is proximate the proximal end of the 1st portion, followed by 3rd portion whose distal end is proximate the proximal end of the 2nd portion, and so on); however, any order can be performed. In some embodiments, multiple contiguous or discontiguous tissue segments are treated simultaneously. In some embodiments, contiguous tissue segments are treated by device 100 continuously, as functional assembly 130 is relatively continuously translated proximally and / or distally, such as via a manual or automated retraction and / or advancement, respectively, as is described in reference to Fig. 6 herebelow. In some embodiments, treatment of target tissue is performed as functional assembly 130 translates at a rate of at least 1cm per minute, at least 2cm per minute, at least 5cm per minute, or at least 10cm per minute. In some embodiments, a segment of non-treated GI tissue is positioned between two segments of treated GI tissue, such as a non-treated segment of GI tissue in a sharp bend.

[0300] Referring now to Figs. 4A, 4B and 4C, perspective, side, and end views, respectively, of an expandable element comprising a balloon is illustrated, consistent with the present inventive concepts. Balloon 136 comprises an expandable element of the present inventive concepts, which can be configured to receive a treatment device comprising fluid at an ablative temperature for treating target tissue, such as balloon 136 of Fig. 1 described hereabove. Balloon 136 can be constructed and arranged of one or more biocompatible materials, such as a material selected from the group consisting of: polyethylene terephthalate (PET); nylon; latex; polyurethane; and combinations of these. In some embodiments, balloon 136 comprises a wall thickness, Dim G, such as a wall thickness between 0.0002” and 0.0010”, such as a wall thickness of approximately 0.0005”.

[0301] In some embodiments, balloon 136 comprises a tissue contacting portion with a diameter of Dim A as shown. Dim A can comprise a diameter of approximately between 16.0mm and 35.0mm, such as a diameter between 19.0mm and 32.0mm. In some embodiments, balloon 136 comprises a tissue contacting portion, with a length defined by Dim D as shown. Dim D can comprise a length between 16.0mm and 35.0mm, such as a length between 19.5mm and 32.9mm. In some embodiments, balloon 136 comprises a tapered distal end, distal taper DT, which transitions from the tissue contacting portion with a curved segment, Dim B, with a radiusof curvature between 7mm and 9mm, such as a radius of curvature of approximately 8mm. Distal taper DT can comprise a taper, Dim F as shown, such as a taper between 27° and 33°, such as a taper of approximately 30°. In some embodiments, balloon 136 comprises a tapered proximal end, proximal taper PT, which transitions from the tissue contacting portion with a curved segment, Dim C, with a radius between 0.4mm and 0.6mm, such as a radius of approximately 0.5mm. Proximal taper PT can comprise a taper, Dim E as shown, such as a taper between 42° and 48°, such as a taper of approximately 45°.

[0302] In some embodiments, the tissue contacting portion of balloon 136 comprises a surface area of between 1750mm2and 2150mm2, such as a surface area of approximately 1950mm2. In some embodiments, a system of the present inventive concepts (e.g., system 10 of Fig. 1) comprises multiple tissue treatment devices (e.g., device 100 of Fig. 1), each comprising a balloon 136 with different tissue contacting portion lengths and / or diameters. In these embodiments, the surface area of the tissue contacting portion can comprise a relatively equivalent area for each device, such as when each tissue contacting portion surface area comprises an area of between 1750mm2and 2150mm2, such as a surface area of approximately 1950mm2. Similar surface areas for the different tissue treatment device’s tissue contacting portions provide the advantage of: similar ablative fluid delivery settings; similar change in balloon temperature with fluid replacement (i.e., between cold and hot water or hot and cold water) to allow a steep “shoulder” of thermal profile within the balloon; similar uniformity of thermal profile along the balloon surface such as during the replacement of cold / hot water with one another within the balloon; similar tissue contact along the surface of the balloon including in bends of the GI tract.

[0303] Balloon 136 can be constructed and arranged to be filled with a particular volume of fluid (e.g., ablative fluid), such as a volume of between 10ml and 35ml, such as a volume between 12.5ml and 30.0ml. Balloon 136 can comprise a tubular stem extending from each of distal taper DT and / or proximal taper PT, such as to facilitate fluid attachment of balloon 136 to a shaft, such as shaft 110 of Fig. 1.

[0304] In some embodiments, the systems of the present inventive concepts can comprise two or more balloons 136, such as a first balloon 136 used in a first tissue treatment device (e.g., device 100 of Fig. 1 or Fig. 6) and a second balloon 136 used in a second tissue treatment device (e.g., device 100’ of Fig. 6). The first balloon 136 and the second balloon 136 can comprise similar or dissimilar properties, such as similar or dissimilar tissue contacting lengths and / or diameters, such as to treat different segments of the GI tract.

[0305] Referring now to Fig. 5, a side sectional view of the distal portion of a tissue treatment device including an agent dispensing element is illustrated, consistent with the present inventive concepts. Tissue treatment device 100 comprises shaft 110 which includes lumen 116 exiting the distal end of shaft 110. Positioned on a distal portion of shaft 110 is an expandable functional assembly, functional assembly 130 which includes a tissue treatment element, agent dispensing element 136”. Shaft 110 and functional assembly 130 are constructed and arranged such that shaft 110 can be inserted within and / or alongside an endoscope, such as endoscope 50a of Fig. 1. Lumen 116 and / or another lumen of shaft 110 can be constructed and arranged to allow over-the-wire delivery of shaft 110. Shaft 110 can comprise a length (e.g., at least 100cm) such that functional assembly 130 can be positioned proximate the distal end of the duodenum of a patient.

[0306] Agent dispensing element 136” is constructed and arranged to coat or otherwise apply one or more agents to target tissue. Tissue treatment device 100 and / or an associated system 10 can comprise one or more agents to be delivered by agent dispensing element 136”, such as tissue modifying agent 135”; described herebelow in reference to Figs. 5A - 5E. Agent dispensing element 136” can comprise a material configured to expand, such as an expansion that occurs when agent dispensing element 136” comes into contact with a fluid (e.g., tissue modifying agent 135” or another fluid). Agent dispensing element 136” can be constructed and arranged to apply one or more tissue modifying agents 135” to target tissue. Tissue modifying agent 135” can comprise a chemical or other agent configured to cause target tissue necrosis or otherwise treat target tissue. Tissue modifying agent 135” can comprise an agent selected from the group consisting of: a chemical peeling agent; a mild acid such as glycolic acid; trichloroacetic acid; a mild base; phenol; retinoic acid; and combinations of these.

[0307] In some embodiments, agent dispensing element 136” comprises a material selected from the group consisting of: a sponge material (e.g., a natural or synthetic sponge material); a foamed polyurethane; a polyvinyl alcohol (PVA) sponge; a hydrogel; a super-absorbent polymer; and combinations thereof. Shaft 110 further includes lumen 117 which travels to a proximal portion of shaft 110 and is constructed and arranged to provide one or more fluids to agent dispensing element 136”.

[0308] Device 100 can comprise one or more deployable occluding elements, such as occluder 193a, shown positioned within lumen 116 of shaft 110. Device 100 can further include translatable control rod 196 configured to be advanced to deploy occluder 193a from the distal end of lumen 116. Occluder 193a can be configured to radially expand to at least partially occlude a segment of the gastrointestinal tract, as described herebelow in reference to Figs. 5A -5E, such as to prevent undesired migration of tissue modifying agent 135” to non-target tissue. Occluder 193 can comprise one or more expandable materials or elements such as an expandable balloon and / or an expandable sponge (e.g., similar to agent dispensing element 136”). Occluder 193 can include digestible and / or biodegradable materials. Occluder 193 can be configured to evacuate the body via the body’s natural digestive system and / or to be removed such as via a grasping element deployed through an endoscope. In some embodiments, additional occluders 193 can be deployed via rod 196 and lumen 116, such as two occluders 193 positioned at opposite ends of a segment of GI tract to be treated by agent dispensing element 136”, also as described herebelow in reference to Figs. 5A - 5E.

[0309] Device 100 of Fig. 5 can be included as part of a system, such as system 10 of Figs. 1 or Fig. 6. The system can include an agent delivery unit, such as a console 200, configured to deliver one or more agents to agent dispensing element 136”, and the system can include the agent to be applied onto target tissue, tissue modifying agent 135”. In some embodiments, agent 420 of Fig. 1 comprises tissue modifying agent 135”.

[0310] Referring now to Figs. 5A-5E, side sectional views of a series of steps for treating a surface of GI tissue with the tissue treatment device of Fig. 5 are illustrated, consistent with the present inventive concepts. In Fig. 5A, endoscope 50a has been inserted into a segment of GI tract as shown (e.g., the duodenum). Endoscope 50a includes multiple working channels, lumens 51 and 54, and a visualization device, camera 52. A marker 195 has been positioned on the wall of the GI tract to be used as a reference to identify non-target tissue (e.g., tissue of the ampulla of Vater that should not be treat...

Claims

WHAT IS CLAIMED IS:

1. A system and / or a method for treating a medical condition of a patient, the system comprising: a catheter for insertion into the intestine, the catheter comprising: an elongate shaft comprising a distal portion; and a functional assembly positioned on the shaft distal portion and comprising at least one treatment element; wherein the at least one treatment element is configured to treat target tissue located in the small intestine of the patient; wherein the system and / or method is configured to treat a medical condition of the patient.

2. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the target tissue comprises duodenal tissue.

3. The system and / or method according to claim 2 and / or any other one or more claims herein, wherein the target tissue comprises tissue selected from the group consisting of: mucosal tissue; submucosal tissue; nerve tissue; and combinations thereof.

4. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the medical condition comprises a metabolic condition.

5. The system and / or method according to claim 4 and / or any other one or more claims herein, wherein the metabolic condition comprises insulin resistance.

6. The system and / or method according to claim 4 and / or any other one or more claims herein, wherein the metabolic condition comprises Type 2 diabetes.

7. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the metabolic condition comprises a medical condition selected from the group consisting of: type 2 diabetes; type 1 diabetes; "Double diabetes"; gestational diabetes; hyperglycemia; pre-diabetes; impaired glucose tolerance; insulin resistance; nonalcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic dysfunction-associated steatohepatitis (MASH); obesity; obesity-related disorder; polycystic ovarian syndrome; hypertriglyceridemia; hypercholesterolemia; psoriasis; GERD; coronary artery disease (e.g., as a secondary prevention); stroke / TIA; cognitive decline or dementia (e.g., Alzheimer's); diabetic nephropathy; neuropathy; retinopathy; diabetic heart disease and / or heart failure; and combinations thereof.

8. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the at least one treatment element comprises one, two, or more treatment elements selected from the group consisting of: ablative fluid delivered to a balloon or other expandable fluid reservoir; ablative fluid comprising at least steam delivered directly or indirectly to tissue; an energy delivery element mounted to an expandable functional assembly such as an electrode or other energy delivery element configured to deliver radiofrequency energy and / or microwave energy; an electrode or other energy delivery element configured to deliver electroporation energy, such as reversible and / or irreversible electroporation energy; an electrode, fluid delivery element, and / or other delivery element configured to deliver both reversible electroporation energy and an agent such as a tissue ablating agent whose ablation is triggered and / or enhanced with the delivery of electroporation energy; light delivery element configured to deliver laser or other light energy; fluid delivery element, such as a needle or nozzle, configured to deliver a necrosis-causing fluid and / or other ablative fluid directly onto and / or into tissue; sound delivery element such as an ultrasonic and / or subsonic sound delivery element; and combinations thereof.

9. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the functional assembly is constructed and arranged to transition between a first geometry comprising a first coiled geometry and a second geometry.

10. The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the functional assembly is constructed and arranged to self-expand, manually expand, and / or controllably expand.

11. The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the functional assembly is constructed and arranged to selfcompact, manually compact, and / or controllably compact.

12. The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the second geometry comprises a relatively straight geometry.

13. The system and / or method according to claim 12 and / or any other one or more claims herein, wherein the functional assembly is resiliently biased in the first geometry.

14. The system and / or method according to claim 12 and / or any other one or more claims herein, wherein the functional assembly is resiliently biased in the second geometry.

15. The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the second geometry comprises a second coiled geometry, wherein the first coiled geometry comprises a first diameter, and wherein the second coiled geometry comprises a second diameter that is larger than the first diameter.

16. The system and / or method according to claim 15 and / or any other one or more claims herein, wherein the functional assembly is resiliently biased in the first geometry.

17. The system and / or method according to claim 15 and / or any other one or more claims herein, wherein the functional assembly is resiliently biased in the second geometry.

18. The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the functional assembly comprises two tubes constructed and arranged in a side-by-side geometry.

19. The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the functional assembly comprises a flat ribbon.20 The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the at least one treatment element comprises one, two, or more electrodes.

21. The system and / or method according to claim 20 and / or any other one or more claims herein, wherein the one, two, or more electrodes are configured to deliver electroporation energy.

22. The system and / or method according to claim 21 and / or any other one or more claims herein, wherein the one, two, or more electrodes are configured to deliver irreversible electroporation energy.

23. The system and / or method according to claim 9 and / or any other one or more claims herein, wherein the at least one treatment element comprises one, two, or more elements selected from the group consisting of: electrode such as an electrode configured to deliver RF energy and / or electroporation energy; a fluid delivery element such as a needle, fluid jet, nozzle, and / or other fluid delivery element configured to deliver an ablative fluid onto and / or into tissue; a light delivery element; a sound delivery element such as an ultrasound delivery element; a heat energy delivery element; a cryogenic energy delivery element; and combinations thereof.

24. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the treatment element is configured to treat a set of one, two, or more axial segments of the duodenum of the patient.

25. The system and / or method according to claim 24 and / or any other one or more claims herein, wherein the one, two, or more axial segments of the duodenum collectively comprise at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or at least 50% of the length of the duodenum distal to the ampulla of Vater.

26. The system and / or method according to claim 25 and / or any other one or more claims herein, wherein at least 50% of the surface area of each axial segment is ablated and / or otherwise caused to necrose.

27. The system and / or method according to claim 26 and / or any other one or more claims herein, wherein the one, two, or more axial segments of the duodenum collectively comprise at least 50% of the length of the duodenum distal to the ampulla of Vater.

28. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the patient selected for treatment comprises one, two, three, and / or all of the following criteria: age between 21 and 70 years;BMI of between 24 and 40kg / m2; a background of use of glucose lowering agents; an HbAlc level of between 7.5 and 9.5%; an FPG off insulin level of greater than or equal to 180mg / dL and less than 270mg / dL; a fasting C-peptide level of greater than or equal to 0.6 ng / ml; and / or a daily long-acting insulin requirement of between 20 and 60 U / day.

29. The system and / or method according to claim 28 and / or any other one or more claims herein, wherein the treatment of the target tissue by the system results in one, two, three, or all of the following effects on the patient: a reduction in total body weight of approximately -9.3%; a reduction in HbAlc levels of approximately -1.5%; a reduction in FPG off insulin level of approximately 82 mg / dL; and / or a reduction in daily long-acting insulin requirement.

30. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the system and / or method are configured to provide a therapeutic benefit selected from the group consisting of: a reduction from pre-treatment in expression of SGLT1 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT5 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; and combinations thereof.

31. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the system and / or method are configured to provide at least two therapeutic benefits selected from the group consisting of: a reduction from pre-treatment inexpression of SGLT1 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; and / or a reduction in expression of GLUT5 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%.

32. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the system and / or method are configured to provide the following three therapeutic benefits: a reduction from pre-treatment in expression of SGLT1 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%; and a reduction in expression of GLUT5 transporters in the intestinal mucosa by at least 10% , 25%, 20%, 25%, 40%, or 50%.

33. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the system and / or method are configured to provide a therapeutic benefit selected from the group consisting of: a reduction in expression of SGLT1 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT5 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; and combinations thereof.

34. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the system and / or method are configured to provide at least two therapeutic benefits selected from the group consisting of: a reduction in expression of SGLT1 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40% or 50%; a reduction in expression of GLUT2 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; and / or a reduction in expression of GLUT5 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%.

35. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the system and / or method are configured to provide the following three therapeutic benefits: a reduction in expression of SGLT1 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; a reduction in expression of GLUT2 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%; and a reduction in expression of GLUT5 transporters in the enteroendocrine cells by at least 10% , 25%, 20%, 25%, 40%, or 50%.

36. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the patient selected for treatment comprises one, two, three, and / or all of the following criteria: presence of diabetes; daily long-acting insulin requirement of between 20 units and 60 units; receives metformin; and / or an HbAlc level of greater than 7.5.

37. The system and / or method according to claim 36 and / or any other one or more claims herein, wherein after the tissue treatment the patient receives a pharmaceutical treatment of SGLT2i / Empagliflozin comprising a lOmg initial dose given to the patient on Day 1 after the tissue treatment, wherein the dose is increased to 25mg by Day 15 post the tissue treatment.

38. The system and / or method according to claim 37 and / or any other one or more claims herein, wherein the patient receives an administration of GLP-1 after the tissue treatment.

39. The system and / or method according to claim 1 and / or any other one or more claims herein, wherein the at least one treatment element is configured to treat the target tissue by delivering electrical energy to the target tissue.

40. The system and / or method according to claim 39 and / or any other one or more claims herein, wherein the delivery of the electrical energy is configured to irreversibly electroporate the cells of the target tissue.

41. The system and / or method according to claim 40 and / or any other one or more claims herein, wherein the functional assembly comprises a coil-shaped geometry.

42. The system and / or method according to claim 41 and / or any other one or more claims herein, wherein the functional assembly is constructed and arranged to transition between a compact coiled geometry and an expanded coiled geometry.

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