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Publication numberWO2013143603 A1
Publication typeApplication
Application numberPCT/EP2012/055813
Publication date3 Oct 2013
Filing date30 Mar 2012
Priority date30 Mar 2012
Publication numberPCT/2012/55813, PCT/EP/12/055813, PCT/EP/12/55813, PCT/EP/2012/055813, PCT/EP/2012/55813, PCT/EP12/055813, PCT/EP12/55813, PCT/EP12055813, PCT/EP1255813, PCT/EP2012/055813, PCT/EP2012/55813, PCT/EP2012055813, PCT/EP201255813, WO 2013/143603 A1, WO 2013143603 A1, WO 2013143603A1, WO-A1-2013143603, WO2013/143603A1, WO2013143603 A1, WO2013143603A1
InventorsKevin D. Felder, Gary L. Long, Mark Steven Ortiz, Alessandro Pastorelli, Michele D'arcangelo, Toralf Bork, Rocco Crivelli, Mathilde MIGURAS, Martin Pfleiderer, Yanik S. TARDY
ApplicantEthicon Endo-Surgery, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: Patentscope, Espacenet
Devices and methods for the treatment of metabolic disorders
WO 2013143603 A1
Abstract
A system for stimulating the release of satiety hormone in a subject includes a stimulus device (1) having an electrical pulse generator (2) and stimulus electrodes (3) adapted to apply an electrical stimulus to a tissue, the stimulus device (1) being adapted to be endoluminally introduced in a gastrointestinal system of the subject, and means (9, 16, 17, 42) for anchoring the stimulus device permanently in a target location inside the gastrointestinal system in a position in which the stimulus electrodes engage a tissue of said gastrointestinal system.
Claims  (OCR text may contain errors)
Claims
1. A system for stimulating the release of satiety hormone in a subject, the system comprising:
- a stimulus device (1) having an electrical pulse generator (2) and stimulus electrodes (3) adapted to apply an electrical stimulus to a tissue, said stimulus device (1) being adapted to be endoluminally introduced in a gastrointestinal system of the subject,
- means (9, 16, 17, 42) for anchoring the stimulus device in a target location inside the gastrointestinal system in a position in which the stimulus electrodes engage a tissue of said gastrointestinal system.
2. System according to claim 1 , in which the anchoring means comprise an expandable balloon or coil shaped anchoring body (9) which is endoluminally insertable inside a stomach (10) of the subject and expandable to hold itself inside the stomach (10).
3. System according to claim 2, wherein the pulse generator (2) is housed in the anchoring body (9) and the stimulus electrodes (3) are provided at a distance from the anchoring body (9) and in signal communication with the pulse generator (2).
4. System according to claim 2 or 3, comprising at least one food detecting sensor (5, 6, 7) arranged on the anchoring body (9) and adapted to detect a presence of food in the stomach (10).
5. System according to claim 1 , in which the anchoring means comprise:
- an a proximal annular flange (16) adapted to be endoluminally seated in an antrum of a stomach without migrating distally through the pylorus, and
- a distal annular flange (17) adapted to be endoluminally seated in a proximal duodenum without migrating proximally through the pylorus back into the stomach,
the proximal and distal flanges (16, 17) being connected to each other by a tether (18) such that the flanges (16, 17) can hold the pylorus between them.
6. System according to claim 5, comprising at least one food detecting sensor (5, 6, 7) arranged on the proximal flange (16) and adapted to detect a presence of food in the stomach (10).
7. System according to claim 5 or 6, in which the pulse generator (2) is arranged in the proximal flange (16) and said stimulus electrodes (3) are provided at the distal flange (17) and in signal communication with said pulse generator (2).
8. System according to claim 1 , in which the anchoring means comprise an expandable colonic stent (20) adapted to be endoluminally placed and expanded within a colon (19) of the subject, said pulse generator (2) being attached to the colonic stent (20) and said stimulus electrodes (3) being arranged at a distance from the colonic stent (20) and in signal communication with the pulse generator (2).
9. System according to claim 1 , in which the stimulus electrodes (3) are provided on a metal mesh stent arrangement adapted to be expanded from an initially compacted shape to a radially expanded shape for engaging an intestinal wall by contact pressure, said stimulus electrodes (3) forming two non-isolated electrically conductive paths (22, 23) that are arranged to one another in an overlapping manner and that are expandable from a collapsed shape to an expanded shape, wherein said conductive paths (22, 23) are isolated from each other at overlapping points by means of an isolating component (24) defining a hinge between both conductive paths (22, 23).
10. System according to claim 1 , in which the stimulus electrodes (3) are arranged on an external surface of a flexible endoluminal sleeve (25).
11. System according to claim 1 , in which the stimulus electrodes (3) are arranged on an external surface of an endoluminal bile diverting sleeve (25') which has a proximal end portion (35) adapted to be placed inside a biliary tree (34) and a distal portion (36) adapted to be extended inside a duodenum (13).
12. System according to any one of the preceding claims, wherein the stimulus electrodes (3) are selected in the group consisting of:
- plate like electrode pads;
- plate like electrode pads with an adhesive layer;
- coiled electrode arrangements;
- metal mesh stent arrangements adapted to be expanded from an initially compacted shape to a radially expanded shape;
- corkscrew shaped electrode arrangements;
13. System according to any one of the preceding claims, wherein the electrical pulse generator (2) is connected to an RF transmitter circuit and antennae (14) for a wireless transmission of the electrical stimulation energy and signals, and the stimulus electrodes (3) are connected to an RF receiving circuit and antenna (15) for a wireless reception of the stimulation energy and signals.
14. System according to any one of the preceding claims, wherein the stimulus electrodes (3) are electrically connected to the pulse generator (2) by an electrical wire (1 1 ) which mechanically connects the stimulus electrodes (3) to the anchoring means.
15. System according to claim 1 , comprising an orally swallowable pill (37) adapted to travel endoluminally to a target section of a gastrointestinal system, said swallowable pill (37) housing said electrical pulse generator (2) and supporting said stimulus electrodes (3).
16. System according to claim 15, comprising food detecting sensors (5, 7, 6) adapted to detect the presence of food in the gastrointestinal system and arranged on said swallowable pill (37).
17. System accordi ng to clai m 1 5 or 16, comprising magnetic anchoring means connectable to said subject and having a magnetic field source (38) adapted to cooperate with an onboard magnet (39) of the swallowable pill (37) to block the swallowable pill (37) in place.
18. System according to claim 17, wherein said magnetic anchoring means comprise a magnetic adhesive patch (42) which can be extracorporeal^ fastened to the skin of the subject.
19. System according to claim 17, wherein said magnetic anchoring means comprise a magnetic anchoring band adapted to be applied from outside around a target section of intestinal lumen.
20. System according to claim 15 or 16, comprising a temperature sensitive shape memory anchor (40) connected to the pill (37) and adapted to deform from a collapsed shape to an expanded shape in response to a thermal activation.
21. System according to claim 20, wherein the pill comprises a heater (41 ) in heat exchanging relationship with the shape memory anchor (40).
22. System according to claim 20, wherein the stimulus electrodes (3) are supported by the shape memory anchor (40) for intimately engaging an intestinal mucosa.
23. A system for stimulating the release of satiety hormone in a subject, the system comprising:
- a stimulus band (26) configured to be deformable from an open shape to a closed ring shape and lockable in the closed ring shape,
- multiple stimulation electrodes (3) arranged at the stimulus band (26) such that they can contact a section of small intestine when the stimulus band (26) is placed from outside around the section of small intestine,
- an electrical pulse generator (2) arranged at the stimulus band (26) and operable to energize the stimulus electrodes (3).
24. A system according to claim 23, wherein the stimulus electrodes (3) are provided on a radially internal surface of the stimulus band (26) when the stimulus band (26) is in the closed ring shape.
25. A system according to claim 23 or 24, wherein a ridge (27) is formed on a radially internal surface of the stimulus band (26) in a direction that the ridge (27) circumferentially engages a section of small intestine when the stimulus band (26) is placed from outside around said section of small intestine.
26. A system according to any one of claims 23 to 25, wherein the stimulus band (26) houses an RF receiving circuit and antennae for a wireless reception of stimulus control signals.
27. A system for stimulating the release of satiety hormone in a subject, the system comprising:
- a plurality of stimulus patches (31) having each an electromagnetic field generator (32) and an adhesive surface (33) for extracorporeal ly fixating the stimulus patch (31) on the skin of the subject,
- a control unit (4) linked to the field generators (32) of each stimulus patch (31 ) and operable to control the field generators (32) such that they generate electromagnetic fields overlapping in a target region.
28. System according to claim 27, adapted to modulate and orient the electromagnetic fields such that their vector sum provides sufficient energy to stimulate the release of GLP-1 only in the target region, while in the remaining regions of the generated electromagnetic fields, the field intensity remains lower than in the target region.
29. System according to claim 27 or 28, comprising a marker (43) which can be implanted in a target section of the gastrointestinal system and which responds to or can be visualized by exposure to electromagnetic fields, the control unit (4) being adapted to generate the electromagnetic fields in dependency of one of a response by the marker (43) or a visualized location of the marker (43).
30. System according to any one of claims 37 to 29, wherein the control unit (4) is adapted to generate the electromagnetic fields in a predetermined sequence which periodically stimulates a plurality of target zones.
31. Method of stimulating the release of satiety hormone in a subject, the method comprising:
- providing an electrical stimulus device (1) having an electrical pulse generator (2) and electrical stimulus electrodes (3),
- transporting the electrical stimulus device (1) endoluminally to a target location in a gastrointestinal system of the subject,
- permanently anchoring the stimulus device (1) in the target location such that the stimulus electrodes (3) engage a tissue of the gastrointestinal system, and
- applying an electrical stimulus to the tissue by means of the stimulus device (1).
32. A method of stimulating the release of satiety hormone in a subject, the method comprising:
- providing an electrical stimulus device (1 ) having an electrical pulse generator (2) and electrical stimulus electrodes (3),
- placing the stimulus device (1) in an abdominal space of the subject at the outside of a target lumen of intestine,
- anchoring the stimulus device (1) at the target lumen such that the stimulus electrodes (3) engage a tissue of the target lumen from outside the target lumen, and
- applying an electrical stimulus to the tissue by means of the stimulus device (1).
33. A method of stimulating the release of satiety hormone in a subject, the method comprising extracorporeal ly generating a plurality of electromagnetic fields in a plurality of positions at the body of the subject and overlapping the generated electromagnetic fields at a target location of a gastrointestinal system of the subject.
Description  (OCR text may contain errors)

DESCRIPTION

"DEVICES AND METHODS FOR THE TREATMENT OF METABOLIC DISORDERS"

FIELD OF THE INVENTION

[0001] The present invention relates generally to devices and methods for the treatment of metabolic disorders using stimulation of the gastrointestinal tract. More specifically, the present invention relates to devices and methods for stimulating the intestine in order to trigger metabolic effects. The present invention further relates to a combined system for meal detection and stimulation of the small intestine (duodenum, jejunum or ileum) aiming at an increased secretion of endogenous GLP-1 during meal intake.

BACKGROUND OF THE INVENTION

[0002] The human ability to store excess energy has contributed to an increased frequency of morbidly obese patients and those with Type 2 Diabetes. Patients having such conditions have increased morbidity and mortality resulting from associated comorbidities, including cardiovascular disease and arthritis.

[0003] A sufficient release of Glucagon-Like Peptide (GLP-1), a known key hormone that regulates the body's glucose control hormone, is believed to alleviate Type 2 Diabetes and obesity. Normally, the presence of nutrients, which arise from a meal consisting of carbohydrates, fats and proteins, termed 'digesta' in the digestive tract, stimulates release of the body's own GLP-1 key hormone into the blood stream. Key hormones, released by specialized L-cells located in the mucosa, which is the innermost interior (luminal) wall of the intestines, coordinate the body's response to a meal. The hormones produce this effect by inducing a sense of fullness and cessation of eating (satiety), triggering the release of insulin to maintain proper glucose levels (incretin effect) and slowing the passage of contents through the digestive tract (delaying gastric emptying and slowing small intestinal transit). Altogether, these effects have been referred to as the "ileal brake" mechanism which involves both the hormones that play a role (such as PYY, GLP-1 , and GLP-2, among others), as well as the multiplicity of effects of release of those hormones (gastric emptying, a feeling of fullness cessation of eating, triggering of insulin secretion).

[0004] An insufficient ileal brake, i .e. , the inability of the body to release sufficient quantities of these hormones in response to a meal, is a contributory factor in obesity and Type 2 Diabetes. While in non-obese non-diabetic individuals fasting levels of GLP-1 are observed to be in the range of 5-10 pmol/L and to increase rapidly to 15-50 pmol/L after a meal, in T2D patients, the meal-related increase in GLP-1 is significantly less. The decreased insulin levels of such patients are attributable to an insufficient level of GLP-1. Similarly, also in obese subjects lower basal fasting hormone levels and smaller meal- associated rise of the hormone levels have been observed. Therefore, enhancing the body's endogenous levels of GLP-1 is believed to have impact on both obesity and diabetes.

[0005] There are known pharmaceutical means to increasing the endogenous active forms of GLP-1 , e. g. by inhibition of its breakdown by dipeptidyl peptidase-4 (DPP-4) inhibitors, such as vildagliptin. In diabetic patients, improvement in glucose control is obtained by increasing the circulating levels of GLP-1 by vildagliptin.

[0006] As an alternative to pharmacological treatments, the most effective treatment for morbid obesity is bariatric surgery. A number of studies in patients after bariatric surgery suggest that there are increases in meal-related circulating GLP-1 levels after surgery, which contribute to the improvements in T2D and weight loss noted. However, bariatric surgery is perceived as a highly invasive measure recommended only for morbidly obese patients. A less invasive approach using a duodenal impermeable sleeve placed via an endoscope and fastened e.g. with a barbed metal anchor at the duodenal entrance has also shown to improve the glucose control.

[0007] It has been hypothesized that the manipulation of the intestine during and after surgery resulted in a stimulation of the mucosa which resulted in an increased release of the satiety hormone(s). US2010/0056948 describes a method of stimulating the release of satiety hormones in a subject comprising applying an electrical stimulus to a tissue in the gastrointestinal system of the subject contemporaneously with the contacting of L-cells of the tissue with a nutrient stimulus.

[0008] However, there remains sti ll a need of improved methods and devices for stimulating the gastrointestinal system which better address the patients' fear of surgery, which are less invasive and which assure an improved patient comfort during treatment. Moreover, there is a need of improved methods and devices for accessing the stimulation site in the Gl system, as well as for positioning and anchoring stimulus equipment on the patient. Further there is a need of improved methods and devices for an easier adaption of the stimulation to the specific metabolic disease and organic situation of a patient, as well as to any desired therapeutic treatment plan.

SUMMARY OF THE INVENTION

[0009] In an aspect of the invention there is provided a method of stimulating the release of satiety hormone in a subject, the method comprising providing an electrical stimulus device having an electrical pulse generator and electrical stimulus electrodes, transporting the electrical stimulus device endoluminally to a target location in a gastrointestinal system of the subject, anchoring the stimulus device in the target location such that the stimulus electrodes engage a tissue of the gastrointestinal system, and applying an electrical stimulus to the tissue by means of the stimulus device.

[0010] In a further aspect of the invention, a system is provided for stimulating the release of satiety hormone in a subject, the system comprising a stimulus device having an electrical pulse generator and stimulus electrodes adapted to apply an electrical stimulus to a tissue, the stimulus device being adapted to be endoluminally introduced in a gastrointestinal system of the subject, the system further comprising means for permanently anchoring the stimulus device in a target location inside the gastrointestinal system i n a positi on i n which the sti m u l us el ectrodes engage a tissue of the gastrointestinal system at the target location.

[0011] In accordance with a further aspect, a method of stimulating the release of satiety hormone in a subject comprises providing an electrical stimulus device having an electrical pulse generator and electrical stimulus electrodes, placing the stimulus device in an abdominal space of the subject at the outside of a target lumen of intestine, anchoring the stimulus device at the target lumen such that the stimulus electrodes engage a tissue of the target lumen from outside the target lumen, and applying an electrical stimulus to the tissue by means of the stimulus device.

[0012] In accordance with an aspect of the invention, a system for stimulating the release of satiety hormone in a subject comprises a stimulus band configured to be deformable from an open shape to a closed ring shape and lockable in the closed ring shape, multiple stimulation electrodes arranged at the stimulus band such that they can contact a section of small intestine when the stimulus band is placed from outside around said section of small intestine, an electrical pulse generator arranged at the stimulus band and operable to energize the stimulus electrodes.

[0013] In a yet further aspect of the invention, a method is provided of stimulating the release of satiety hormone in a subject, the method comprising applying one of an electrical and electromagnetic stimulus to a tissue of a gastrointestinal system of the subject and time dependency changing the location of application of the stimulus at the tissue.

[0014] In accordance with an aspect of the invention, a system for stimulating the release of satiety hormone in a subject comprises a stimulus device having an electrical pulse generator and stimulus electrodes adapted to apply an electrical stimulus to a tissue, the stimulus device being configured to time dependency move at least one of the stimulus electrodes for time-dependently changing the location of application of the stimulus.

[0015] In a yet further aspect of the invention, a system for stimulating the release of satiety hormone in a subject comprises a stimulus device having an electrical pulse generator and multiple stimulus electrodes adapted to apply electrical stimuli to a tissue of a gastrointestinal system of the subject, said stimulus electrodes being arranged at a distance to one another in multiple positions and the stimulus device being configured to time dependency switch selected ones of the stimulus electrodes from an energized state to a non-energized state and vice versa for time-dependently changing the location of application of the stimulus.

[0016] In accordance with an aspect of the invention, a method of stimulating the release of satiety hormone in a subject comprises extracorporeally generating a plurality of electromagnetic fields in a plurality of positions at the body of the subject and stimulating a tissue of a target location of a gastrointestinal system of the subject by overlapping the generated electromagnetic fields at the target location.

[0017] In an aspect of the invention, a system is provided for stimulating the release of satiety hormone in a subject, the system comprising a plurality of stimulus patches having each an electromagnetic field generator and an adhesive surface for extracorporeally fixating the stimulus patch on the skin of the subject, a control unit linked to the field generators of each stimulus patch and operable to control the field generators such that they generate electromagnetic fields overlapping in a target section of a gastrointestinal system of the subject.

[0018] I n accordance with a yet further aspect, the method comprises continuously monitoring at least one characteristic of the subject to detect an ingestion of food by the subject, and applying the electrical or electromagnetic stimulus to the gastrointestinal system in response to a detected ingestion of food. For this purpose, the proposed system comprises a detection device which is implantable in the subject and adapted to continuously monitoring at least one of a mechanical characteristic and an electrical characteristic of the subject to detect an ingestion of food by the subject, and the detection device cooperates with the stimulus device such that the stimulus device applies the electrical stimulus in response to a detected ingestion of food.

[0019] These and other aspects and advantages of the present invention shall be made apparent from the accompanying drawings and the description thereof, which illustrate embodiments of the invention and, together with the general description of the invention given above, and the detailed description of the embodiments given below, serve to explain the principles of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

- Figure 1 shows a schematic block diagram of a meal detection and electrical stimulation system for stimulating the release of satiety hormones in accordance with an embodiment;

- Figure 2 illustrates a first embodiment of an electrical stimulation system for stimulating the release of satiety hormones, the system being endoluminally implanted in a Gl tract;

- Figure 3 illustrates a second embodiment of an electrical stimulation system for stimulating the release of satiety hormones, the system being endoluminally implanted in a Gl tract;

- Figure 4 illustrates a third embodiment of an electrical stimulation system for stimulating the release of satiety hormones, the system being endoluminally implanted in a Gl tract;

- Figures 5 through 10 illustrate further embodiments of an electrical stimulation system for stimulating the release of satiety hormones, the systems being endoluminally implanted in a Gl tract;

- Figure 1 1 illustrates an embodiment of an electrical stimulation system for stimulating the release of satiety hormones, the system having a stimulus band laparoscopically inserted in an abdominal space placed around a lumen of a Gl tract;

- Figure 12 shows the stimulus band of figure 1 1 in a frontal view and in a longitudinal section;

- Figure 13 illustrates a further embodiment of an electrical stimulation system for stimulating the release of satiety hormones, the system being endoluminally placed in a section of the ileum and in a section of colon of a patient;

- Figures 14 and 15 illustrate electrical stimulation systems in accordance with further exemplary embodiments;

- Figures 16 and 17 are schematic illustrations of an electrical stimulation system for stimulating the release of satiety hormones in accordance with embodiments, in which the location of stimulation can be varied over time;

- Figure 18 illustrates a further embodiment of an electrical stimulation system for stimulating the release of satiety hormones;

- Figure 19 illustrates a yet further embodiment of an electrical stimulation system for stimulating the release of satiety hormones;

- Figure 20 illustrates a detail of an electrical stimulation device for stimulating the release of satiety hormones, in accordance with an embodiment; - Figure 21 illustrates an adhesive patch electromagnetic stimulation device in accordance with an embodiment;

- Figure 22 shows a method of stimulating the release of satiety hormones involving an extracorporeal application of adhesive patch stimulating devices of figure 21 ;

- Figure 23 shows a method for stimulating the release of satiety hormones involving stimulation devices of the invention;

- Figure 24 shows a method and devices for stimulating the release of satiety hormones in accordance with a further embodiment;

- Figure 25, 26 and 27 illustrate a swallowable electrical stimulating pill in accordance with embodiments of the invention;

- Figure 25A illustrates an extracorporeal adhesive magnetic patch for holding the swallowable pill of figure 25 in a planned position in a Gl tract;

- Figure 25A illustrates an extracorporeal adhesive magnetic patch for holding the swallowable pill of figure 25 in a planned position in a Gl tract;

- Figures 28A, 28B, 28C, 28D illustrate electrode movement devices in accordance with embodiments of the invention.

DETAILED DESCRIPTION OF EMBODIMENTS

[0020] Referring to the drawings in which like numerals denote like anatomical structures and components throughout the several views, methods and devices are provided for stimulating the release of satiety hormone, specifically GLP-1 , in a human subject.

DETAILED DESCRIPTION OF EMBODIMENTS OF FIGURES 1-10, 13,23-27

[0021] In accordance with a first aspect of the invention (Figures 1 - 10, 13), a method of stimulating the release of satiety hormone in a subject comprises:

- providing an electrical stimulus device 1 having an electrical pulse generator 2 and electrical stimulus electrodes 3,

- transporting the electrical stimulus device 1 endoluminally to a target location in a gastrointestinal system of the subject,

- anchoring the stimulus device 1 in the target location such that the stimulus electrodes 3 engage a tissue of the gastrointestinal system, and

- applying an electrical stimulus to the tissue by means of the stimulus device 1.

[0022] As schematically shown in figure 1 , the entire stimulation system may be controlled by a control unit 4 (a microchip with a memory, a battery, and a data acquisition and elaboration software) which may be onboard the stimulus device 1 or remote from the stimulus device 1 and in signal communication (by conductive wire or wireless, e.g. by an RF transmitter-receiver communication channel) with the electrical pulse generator 2 and adapted to control the electrical pulse generator 2 in accordance with a preset stimulation program and or in dependency of signals received from an external controller 44 (Figure 23) or from food detection sensors 5, 6. For this purpose the control unit 4 may be adapted to elaborate the signals received from the food detection sensors (e.g. pressure sensors 5, electrical activity sensors 6, pH meter 7, glucose level sensor 8) to identify a condition of food intake and, in response to the identified condition of food intake, to generate a stimulus signal and provide the stimulus signal to the electrical pulse generator 2.

[0023] If provided , also the food detection sensors may be linked by a signal communication line (by conductive wire or wireless, e.g. by an RF transmitter-receiver communication channel) to the control unit 4.

[0024] The stimulus electrodes 3 are linked to the electrical pulse generator 2 and adapted to apply an electrical stimulus to a tissue. The stimulus device 1 itself is adapted to be endoluminally introduced (e.g. transorally or transanally) in the gastrointestinal system of the patient, and means are provided for permanently anchoring the stimulus device 1 in a target location inside the gastrointestinal system.

[0025] In accordance with an embodiment (Figure 2) the anchoring means may comprise an expandable balloon shaped or coil shaped anchoring body 9 which is endoluminally inserted inside a stomach 10 of the patient and then expanded to hold itself inside the stomach 10. Food detecting sensors, such as a pressure sensor 5 and/or a pH meter 7 and/or a pair of detecting electrodes 6 may be arranged on the anchoring body 9 so that after placement of the anchoring body 9, at least one of a pressure, pH and electrical current in the gastric wall can be monitored by the food detecting sensors and transmitted to the control unit 4. The control unit 4 and the pulse generator 2 are also received in the anchoring body 9 and one or more pairs of stimulus electrodes 3 are provided at a distance from the anchoring body 9 and connected by electrical wires 1 1 to the pulse generator 2, so that the wires 1 1 can extend from the anchoring body 9 which is placed inside the stomach 10 through the pylorus 12 down into the small intestine (ad es. duodenum 13) where the stimulus electrodes 3 engage and electrically stimulate an intestinal mucosa to produce endogenous GLP-1. In this embodiment, the electrical wires 1 1 (which can be united in one single wire bundle) accomplish both electrical energizing and pull resistant mechanical connection of the electrodes 3 to the anchoring body 9.

[0026] I n accordance with exemplary embodiments, the stimulus electrodes 3 may comprise plate like electrode pads (Figure 8) with or without an adhesive layer for a reliable attachment to the intestinal mucosa, coiled electrode arrangements (Figures 5, 7) or metal mesh stent arrangements (Figure 6) adapted to be expanded from an initially compacted shape to a radially expanded shape for engaging the intestinal wall by contact pressure, or corkscrew shaped electrode arrangements adapted to be screwed into an intestinal mucosa (Figure 9). The stimulus electrodes 3 may be elastically held in contact with the tissue by means of an elastic spring attached thereto, e.g. a Nitinol spring, or a flexible elastomeric sponge (Figure 18) which can also elastically follow peristalsis movements of the intestine.

[0027] I n accordance with a further embodiment, the electrical pulse generator 2 is connected to an RF transmitter circuit and antennae 14 for a wireless transmission of the electrical stimulation energy and signals, and the electrode 3 arrangement comprises an RF receiving circuit and antenna 15 for a wireless reception of the stimulation energy and signals (a wireless transmission of the stimulating energy can be obviated by providing the stimulus electrode arrangement 3 with an onboard power source or battery). I n this embodiment, the wires 1 1 are not necessary, however, the electrode 3 arrangement must be directly anchored inside the small intestine (Figure 6) or connected to the anchoring body 9 by means of a tether 18 (Figure 6).

[0028] I n accordance with a further embodiment (Figure 3), the anchoring means comprise a proximal annular flange 16 (forming the above said anchoring body 9) which may be rigid or expandable from an initially collapsed shape which allows endoluminal insertion thereof into the stomach 10 to an expanded shape which allows the proximal flange 16 to be seated in the antrum of the stomach without migrating distally through the pylorus. The anchoring means further comprise a distal annular flange 17 which may be rigid or expandable from an initially collapsed shape which allows endoluminal insertion thereof into the duodenum 13 to an expanded shape which allows the distal flange 17 to be seated in the proximal duodenum without migrating proximally through the pylorus back into the stomach. The proximal and distal flanges 16, 17 are connected to each other by a pull resistant tether 18 adapted to flexibly extend through the pylorus, such that the flanges 16, 17 hold the pylorus between them.

[0029] Also in this embodiment, food detecting sensors, such as a pressure sensor 5 and/or a pH meter 7 and/or a pair of detecting electrodes 6, the control unit 4 and the pulse generator 2 may be arranged in the proximal flange 16 and one or more pairs of stimulus electrodes 3 are provided at or connected to the distal flange 17 in intimate contact with the intestinal wall for electrically stimulating the mucosa to produce endogenous GLP-1. The stimulus electrodes 3 may be connected by electrical wires to the pulse generator 2 at the proximal flange 16, so that the electrical wires (which can be united in one single wire bundle) accomplish both electrical connection and pull resistant mechanical tethering between the two flanges 16, 17.

[0030] Also in this embodiment, the stimulus electrodes 3 may comprise plate like electrode pads (Figure 8) with or without an adhesive layer for a reliable attachment to the intestinal mucosa, coiled electrode arrangements (Figures 5, 7) or metal mesh stent arrangements (Figure 6) adapted to be expanded from an initially compacted shape to a radially expanded shape for engaging the intestinal wall by contact pressure, or corkscrew shaped electrode arrangements adapted to be screwed into an intestinal mucosa (Figure 9). The stimulus electrodes 3 may be elastically held in contact with the tissue by means of an elastic spring attached thereto, e.g. a Nitinol spring, or a flexible elastomeric sponge (Figure 18) which can also elastically follow peristalsis movements of the intestine.

[0031] In accordance with a further embodiment, the electrical pulse generator 2 is connected to an RF transmitter circuit and antennae 14 at the proximal flange 16 for a wireless transmission of the electrical stimulation energy and signals, and the electrode 3 arrangement comprises an RF receiving circuit and antenna 15 (preferably at the distal flange 17) for a wireless reception of the stimulation energy and signals.

[0032] In accordance with a yet further embodiment (Figures 13, 14, 15) the anchoring means comprise an expandable colonic stent 20 which is endoluminally placed and expanded within a colon 19 of the patient. The control unit 4 and the pulse generator 2 may be connected to or received inside the colonic stent 20 and one or more pairs of stimulus electrodes 3 are arranged at a distance from the colonic stent 20 and adapted to intimately engage an ileal mucosa from inside an ileum 21 of the patient for electrically stimulating the ileal mucosa to produce endogenous GLP-1 . The stimulus electrodes 3 may be connected by electrical wires to the pulse generator 2 at the colonic stent 20 (Figure 15). Alternatively (Figures 13, 14), the electrical pulse generator 2 is connected to an RF transm itter circuit and antennae 14 at the colonic stent 20 for a wi reless transmission of the electrical stimulation energy and signals, and the electrode 3 arrangement comprises an RF receiving circuit and antenna 15 for a wireless reception of the stimulation energy and signals (a wireless transmission of the stimulating energy can be obviated by providing the stimulus electrode arrangement 3 with an onboard power source or battery). The control unit 4 can be further connected to a RF receiver for a wireless reception of food detection signals.

[0033] Also in this embodiment, the stimulus electrodes 3 may comprise plate like electrode pads with or without an adhesive layer for a reliable attachment to the intestinal mucosa, coiled electrode arrangements (Figures 13, 14, 15) or metal mesh stent arrangements adapted to be expanded from an initially compacted shape to a radially expanded shape for engaging the intestinal wall by contact pressure, or corkscrew shaped electrode arrangements adapted to be screwed into an intestinal mucosa. The stimulus electrodes 3 may be elastically held in contact with the tissue by means of an elastic spring attached thereto, e.g. a Nitinol spring, or a flexible elastomeric sponge (Figure 18) which can also elastically follow peristalsis movements of the intestine.

[0034] I n accordance with a yet further embodiment, the stimulus electrodes 3 may comprise a metal mesh stent arrangement adapted to be expanded from an initially compacted shape to a radially expanded shape for engaging the intestinal wall by contact pressure, wherein however the electrical pulse generator 2 is directly arranged onboard the electrode stent (Figure 7) and not carried by the anchoring means as in the previously described embodiments.

[0035] In general, a metal mesh stent stimulus electrode 3 arrangement contemplated by the invention may comprise two non-isolated electrically conductive paths 22, 23 that are arranged to one another in an overlapping manner and that are expandable from a first collapsed shape (adapted for endoscopic insertion) to a second expanded shape (adapted to engage the intestinal mucosa), both paths 22, 23 being isolated from each other at each overlapping point, e.g. by means of an isolating component 24 defining a hinge between both conductive paths 22, 23 (Figure 7).

[0036] In accordance with a yet further embodiment (Figure 10), the stimulus electrodes 3 may be arranged on an external surface of an endoluminal, e.g. duodenal, flexible sleeve 25 which is connected to the anchoring means (expandable gastric anchoring body 9, balloon, coil, flanges 16, 17) by a tether 18 or by electrical wire 1 1 acting both as electrical conductor and as tether.

[0037] In a yet further embodiment (Figure 24), the stimulus electrodes 3 may be arranged on an external surface of an endoluminal bile diverting sleeve 25' which has a proximal end portion 35 inserted inside the biliary tree 34 and a distal portion 36 extended inside the duodenum 13. The sleeve 25' may be anchored against undesired distal migration in the biliary tree or in the duodenum or in the stomach. The stimulus electrodes 3 may be arranged in discrete positions or continuous conductive paths anywhere on the sleeve 25'. [0038] In accordance with a yet further embodiment (Figures 25 to 27) the electrical stimulus device 1 may comprise an orally swallowable pill 37 which is orally administered to the patient and adapted to travel endoluminally to a target section of the gastrointestinal system. Food detecting sensors, such as a pressure sensor 5 and/or a pH meter 7 and/or a pair of detecting electrodes 6 may be arranged on the pill 37 so that, after placement of the pill 37, at least one of a pressure, pH or electrical current in the intestinal wall can be monitored by the food detecting sensors and transmitted to the control unit 4. The control unit 4 and the pulse generator 2 are also received in the pill 37 and one or more pairs of stimulus electrodes 3 are supported by the pill 37 and electrically connected to the pulse generator 2 such that they can engage and electrically stimulate an intestinal mucosa to produce endogenous GLP-1.

[0039] In order to hold the stimulus pill 37 in the desired position within the Gl tract, the system may further comprise magnetic anchoring means, such as an extracorporeal belt or adhesive patch 42 (Figure 25A) which can be fastened to the patient or an anchoring band adapted to be applied from outside around the target section of intestinal lumen. These anchoring means have a permanent magnetic or electromagnetic field source 38 adapted to cooperate with an onboard magnet 39 housed in the swallowable pill 37 to block the swallowable pill 37 in place, e.g. in the duodenum 13 or ileum 21. Alternative or additional mechanical anchoring means may include a temperature sensitive shape memory anchor 40 connected to the pill 37 and adapted to deform from a collapsed shape (broken line in Figures 26, 27, adapted for endoluminal transit) to an expanded shape (solid line in Figures 26, 27, adapted for anchoring). In order to trigger the transition of the anchor 40 from the collapsed shape to the expanded shape, the pill may comprise a heater, e.g. an electric resistance 41 , arranged in heat exchanging relationship with the shape memory anchor 40 and energized by the control unit 4. In accordance with non- limiting, exemplary embodiments, the shape memory anchor 40 may have:

- a coiled or spirally coiled shape and extend initially around the pill 37 (Figure 26, 27) and, after expansion, the anchor 40 may form a coiled tail (Figure 27) extending axially and radially away from the pill, or

- a coiled or spirally coiled shape and extend initially around the pill 37 (Figure 26, 27) and, after expansion, the anchor 40 may form a coiled envelop (Figure 26) extending only radially away from the pill. In both embodiments, the stimulus electrodes 3 may be supported by the shape memory anchor 40 to intimately engage the intestinal mucosa.

DETAILED DESCRIPTION OF EMBODIMENTS OF FIGURES 1. 1 1. 12 [0040] In accordance with a further aspect of the invention, a method of stimulating the release of satiety hormone in a subject comprises:

- providing an electrical stimulus device 1 having an electrical pulse generator 2 and electrical stimulus electrodes 3,

- placing the stimulus device 1 in an abdominal space of the subject at the outside of a target lumen of intestine,

- anchoring the stimulus device 1 at the target lumen such that the stimulus electrodes 3 engage a tissue of the target lumen from outside the target lumen, and

- applying an electrical stimulus to the tissue by means of the stimulus device 1.

[0041] In accordance with an embodiment, the stimulus device 1 may comprise a stimulus band 26 configured to be deformable from an open shape to a closed ring shape and lockable in the closed ring shape, multiple stimulation electrodes 3 arranged at the stimulus band 26 such that they can contact a section of small intestine when the stimulus band 26 is placed from outside around the section of small intestine, and an electrical pulse generator 2 arranged at the stimulus band 26 and operable to energize the stimulus electrodes 3.

[0042] The stimulus electrodes 3 may be provided on a radially internal surface of the stimulus band 26 to engage the intestine, e.g. the duodenum 13 from outside. Moreover a ridge 27 can be formed on the internal surface of the stimulus band 26 in a direction that the ridge 27 circumferentially engages the intestinal lumen around which the stimulus band 26 is fastened and prevents undesired displacement of the stimulus band 26 along the lumen.

[0043] Placement of the stimulus band 26 may be effected by open surgery or by laparoscopy, but also by endolumenal transportation of the band 26 to the desired site for stimulating the production of GLP-1 , translumenal placement of the band 26 from inside the intestine through an incision in the lumen wall to its outside and extension of the band from outside the lumen around the lumen.

[0044] After placement of the stimulus band 26 around the intestine, the pulse generator 2 can be activated to apply the electrical stimulus from the outside to the tissue.

[0045] The general operational scheme previously described and illustrated in figure 1 applies analogously. For instance, both the control unit 4 and the pulse generator 2 may be connected to or received inside the stimulus band 26 and the stimulus electrodes 3 may be connected by electrical wires to the pulse generator 2. Alternatively, the control unit 4 and/or the electrical pulse generator 2 (onboard the stimulus band 26 or remote from the stimulus band 2 is connected to an RF transmitter circuit and antennae for a wireless transmission of the electrical stimulation energy and/or signals, and the stimulus electrodes 3 at the band 26 are linked to an RF receiving circuit and antenna for a wireless reception of the stimulation energy and/or signals (a wireless transmission of the stimulating energy can be obviated by providing an onboard power source or battery in the stimulus band 26). The control unit 4 can be further connected to a RF receiver for a wireless reception of food detection signals.

DETAILED DESCRIPTION OF EMBODIMENTS OF FIGURES 1 ,16,17, 19,20

[0046] In accordance with a further aspect, a method is provided of stimulating the release of satiety hormone in a patient, the method comprising applying one of an electrical and electromagnetic stimulus to a tissue of a gastrointestinal system of the subject and time dependently changing the location of application of the stimulus at the tissue. A time- dependent change or variation of the location of application of the electrical stimulus may be desirable to optimize the treatment or maximize the release of GLP-1 , as well as to reducing a risk of tissue trauma (by burning) due to a continued electric stimulus.

[0047] In accordance with an embodiment (Figure 16), the method can be implemented by means of a stimulus device 1 which is configured to time dependently move at least one of the stimulus electrodes 3 for time-dependently changing the location of application of the electric stimulus to the intestinal mucosa for triggering release of GLP-1.

[0048] As schematically shown in figure 1 , the entire stimulation system may be controlled by a control unit 4 (a microchip with a memory, a battery, and a data acquisition and elaboration software) which may be onboard the stimulus device 1 or remote from the stimulus device 1 and in signal communication (by conductive wire or wireless, e.g. by an RF transmitter-receiver communication channel) with the electrical pulse generator 2 and adapted to control the electrical pulse generator 2 in accordance with a preset stimulation program and or in dependency of signals received from an external controller or from food detection sensors 5, 6. For this purpose the control unit 4 may be adapted to elaborate the signals received from the food detection sensors (e.g. pressure sensors 5, electrical activity sensors 6, pH meter 7, glucose level sensor 8) to identify a condition of food intake and, in response to the identified condition of food intake, to generate a stimulus signal and provide the stimulus signal to the electrical pulse generator 2.

[0049] I f provided , also the food detecti on sensors may be l i n ked by a sig nal communication line (by conductive wire or wireless, e.g. by an RF transmitter-receiver communication channel) to the control unit 4. [0050] The stimulus electrodes 3 are linked to the electrical pulse generator 2 and adapted to apply an electrical stimulus to a tissue. The stimulus electrodes 3 are movably supported on an electrode support 28 of the stimulus device 1 and an electrode moving device 29 is connected between the stimulus electrodes 3 and the electrode support 28 and adapted to move the stimulus electrodes 3 with respect to the electrode support 28. The moving device 29, e.g. a micromotor 45 with a rotating shaft 46 to which the stimulus electrodes 3 are attached for a rotational adjustment of their position, a micromotor 45 with jackscrew transmission 47 for a linear translational position adjustment, a thermally expandable and shrinkable element 48 with associated adjustable heat source 49, or a piezoelectric shape adjustable component 50, is linked to and controlled by the control unit 4 in dependency of a preset stimulus moving program and, if provided, of food detection signals or electrode movement signals received by the control unit 4.

[0051] In accordance with a further embodiment (Figure 17), the stimulus electrodes 3 of the electrical stimulus device 1 are arranged at a distance to one another in multiple positions and the stimulus device 1 is configured to time dependency switch selected ones of the stimulus electrodes 3 from an energized state to a non-energized state and vice versa for time-dependently changing the location of application of the stimulus.

[0052] The stimulus electrodes 3 are linked to the electrical pulse generator 2 and adapted to apply an electrical stimulus to a tissue. The control unit 4 is adapted to control the pulse generator and to energize the individual pairs of stimulus electrodes 3 such that a stimulus current is multiplexed in an adjustable sequence to selected ones of the stimulus electrodes 3 in dependency of a preset stimulus moving program and, if provided, of food detection signals or stimulus position signals received by the control unit 4. The alternation of the location of application of electric stimuli prevents the interested tissue from being "fried" or cauterized.

[0053] In accordance with a yet further embodiment (Figures 19, 20) an electrode support 28 of the stimulus device 1 comprises one or more bioabsorbable or time-dependently dissolvable or fragmentable isolating layers or coatings 30 which cover a plurality of the stimulus electrodes 3, such that each one of the initially coated electrodes 3 becomes exposed only after a planned time (during which the one or more coatings or layers 30 overlaying that specific electrode 3 dissolve). This allows to "replace" worn-out or dirty electrodes old with fresh unused electrodes to increase the lifetime of the stimulus electrode assembly and to alternate the location of exposed electrodes 3 over time. The skilled person will appreciate that this specific embodiment is combinable with many of the previously described methods and devices for stimulating the release of GLP-1.

DETAILED DESCRIPTION OF EMBODIMENTS OF FIGURES 1 , 21 , 22

[0054] In accordance with an aspect of the invention, a method of stimulating the release of satiety hormone in a subject comprises extracorporeally generating a plurality of electromagnetic fields in a plurality of positions at the body of the subject and overlapping the generated electromagnetic fields at a target location of a gastrointestinal system of the subject

[0055] The electromagnetic fields can be generated by means of a plurality of stimulus patches 31 (Figure 21 ) having each an electromagnetic field generator 32 and an adhesive surface 33 for extracorporeally fixating the stimulus patch 31 on the skin of the subject, as well as a control unit 4 linked to the field generators 32 of each stimulus patch 31 and operable to control the field generators 32 such that they generate electromagnetic fields overlapping in a target section of a gastrointestinal system of the subject. The electromagnetic fields can be modulated and oriented such that only in the region of desired gut stimulation their vector sum provides sufficient energy to stimulate the release of GLP-1 , while in the remaining regions of the body subject to the electromagnetic fields, the vector sum of the field intensity remains low.

[0056] In accordance with an embodiment, a marker 43 is provided which is implanted in the target section of the gastrointestinal system (Figure 22) and which responds to or can be visualized by exposure to electromagnetic fields. The positioning of the stimulus patches 31 and the generation of the electromagnetic fields are effected in dependency of the response by the marker 43 or in dependency of the visualized location of the marker 43.

[0057] In accordance with a yet further embodiment, the electromagnetic fields can be generated in a predetermined sequence which periodically stimulates one or more target zones of the gastrointestinal system, such that when nutrients are present in these target zones, the release of GLP-1 is triggered.

[0058] In exemplary embodiments, the electrical stimulus may be applied and varied at a frequency of about 0.1 Hz to about 90 Hz, at a voltage of about 0.5 V to about 25 V, with a pulse duration of about 0.1 ms to about 500 ms. The electrical current may have a charge of about 1 μθ to about 6000 μθ, inclusive. The electrical stimulus may be applied to a mucosal tissue of the gastrointestinal system of the subject, e.g in a duodenum, jejunum or ileum.

[0059] The present invention address the needs of reliable positioning of the stimulus device with respect to the desired location for stimulating the release of the satiety hormone GLP-1 , mini-invasively stimulating the gastrointestinal system and versatily adaption of the stimulation to the specific physiological situation and treatment plan. Moreover, a closed loop meal detection and intestinal electrical or electromagnetic stimulation is provided for a purposeful and timely release of the satiety hormone GLP-1 , resulting in an improved glycemic control and an appropriate feel of satiety in T2D and obese patients.

[0060] Although preferred embodiments of the invention have been described in detail, it is not the intention of the applicant to limit the scope of the claims to such particular embodiments, but to cover all modifications and alternative constructions falling within the scope of the invention.

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Classifications
International ClassificationA61N1/36, A61N1/05, A61N1/04
Cooperative ClassificationA61N1/0476, A61N1/0408, A61N1/0509, A61N1/36007
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