CN101516441A

CN101516441A - GI and pancreatic device for treating obesity and diabetes

Info

Publication number: CN101516441A
Application number: CNA2006800300902A
Authority: CN
Inventors: 约西·格罗斯; 雅各布·贝纳里; 拉德温·哈瓦莱; 露丝·阿隆
Original assignee: BETASTIM Ltd
Current assignee: BETASTIM Ltd
Priority date: 2005-07-13
Filing date: 2006-07-13
Publication date: 2009-08-26

Abstract

The invention provides a method, including placing first and second electrodes (90) at respective first and second sites of a duodenum (40) of a subject, and activating the electrodes (90) to increase a blood insulin level of the subject. Other embodiments are also described.

Description

The gastrointestinal and the pancreas device that are used for the treatment of obesity and diabetes

The cross reference related application

Present patent application is the part continuation application that the name of submission on April 11st, 2006 is called the U. S. application 11/279,355 of " GI and the pancreas device that are used for the treatment of obesity and diabetes ", requires following priority:

(a) name submitted on July 13rd, 2005 of Alon and Gross be called " GI and the pancreas device that are used for the treatment of obesity and diabetes " U.S. Provisional Patent Application 60/699,442 and

(b) Alon and Gross are called the U.S. Provisional Patent Application 60/720,951 of " GI and the pancreas device that are used for the treatment of obesity and diabetes " in the name of JIUYUE in 2005 submission on the 26th.More than all applications incorporate this paper by reference into.

Technical field

Generality of the present invention relates to treatment of obesity and diabetes, is specifically related to the method and apparatus of treatment of obesity and diabetes in gastrointestinal tract and pancreas.

Background technology

Obesity often is relevant disease with diabetes, although some patients only suffer from wherein a kind of disease.The Different types of etiopathogenises of obesity is the object of always studying.Insulin resistant and β cell dysfunction are two key factors that cause onset diabetes.Relation between these two factors is furtherd investigate, and the effect of obesity in diabetes also furtherd investigate.Particularly, generally observed the principal element that obesity is an insulin resistant.The patient that great majority suffer from type ii diabetes is fat.

Paper " The enteric nervous system:A secondbrain " (Hospital Practice as Michael Gershon, July, 1999) (incorporate this paper by reference into) described in, enteric nervous system (ENS) is an autonomic part, and it is made up of two-layer.Ground floor is called myenteric nervous plexus (Auerbach ' s plexus), between the circular layer and longitudinal muscle layer that cover intestinal wall.The second layer is called submucosal nervous plexus, between circular layer and tela submucosa.Myenteric nervous plexus contains the neuron of being responsible for motion and being responsible for regulating the enzyme release of adjacent organs.The neuron that less submucosal nervous plexus (Meissner ' s plexus) contains with myenteric nervous plexus transmits the sensory cell of information and stimulates the excretory motor fiber that enters enteric cavity from the epithelium follicular cells.Electrical connection between the smooth muscle cell makes signal can change the transmembrane potential of those even the cell that not directly do not contact with neuron fast, guarantees that big intestinal district rather than little myocyte group reply nerve stimulation.

The PCT patent gazette WO2005/007232 (incorporating this paper by reference into) of Ben-Haim etc. has described a kind of curee's of being used for the treatment of method and apparatus.Stomach position, at least one place to the curee applies the signal of telecommunication.The signal of telecommunication is set to reduce the rising of curee's blood glucose levels, to treat described curee.Also described a kind of colon stimulation system, it comprises control unit and one or more electrode, and described electrode is suitable for being administered to patient's colon or near the corresponding site the small intestine distal end.Described control unit drive electrode applies the signal of telecommunication and gives described position, and makes described signal stimulus L-cell or other target tissue, and it responds to such stimulation increases glucagon-like-peptide-1 (glucagon-like-peptide-1, secretion GLP-1).This GLP-1 secretion is described as the glycemic control that generality is improved the patient, therefore and be used for the treatment of the patient who suffers from the insulin resistant associated conditions, for example obesity, NIDDM, heart disease and hypertension perhaps are considered to have the healthy patients of the risk of suffering from above disease.For some application, the colon stimulation system also comprises the feed detecting unit, and control unit is configured to feed detected and replys and drive electrode applies signal.

The United States Patent (USP) 6,091,992 (incorporating this paper by reference into) of Bourgeois etc. has been described a kind of method and apparatus that gastrointestinal tract is provided electricity irritation.Described device be characterized as the implantable pulse generator, it can be connected to the intestinal system by one or more medical electrical lead.In a preferred embodiment, lead is connected to the circular layer of stomach.In one embodiment, implantable system comprises the implantable pulse generator of sealing, the electricity irritation that described pulse generator produces the first kind with first rate, the electricity irritation that produces second type with second speed.

Following patent application and document may be interested, and its full content is incorporated this paper by reference into:

The United States Patent (USP) 6,191,102 of DiMarchi etc.

Todd JF etc., and " Glucagon-like peptide-1 (GLP-I): a trial oftreatment in non-insulin-dependent diabetes mellitus, " Eur J ClinInvest 27 (6): 533-6 (1997)

Gutniak MK etc., " Subcutaneous injection of the incretin hormoneglucagon-like peptide 1 abolishes postprandial glycemia in NIDDM, " Diabetes Care 17 (9): 1039-44 (1994)

Robertson MD etc., " The influence of the colon on postprandialglucagon-like peptide 1 (7-36) amide concentration in man, " JEndocrinol 161 (1): 25-31 (1999)

Schirra J etc., " Mechanisms of the antidiabetic action ofsubcutaneous glucagon-like peptide-1 (7-36) amide in non-insulindependent diabetes mellitus, " J Endocrinol 156 (1): 177-86 (1998)

Todd JF etc., " Subcutaneous glucagon-like peptide-1 improvespostprandial glycaemic control over a 3-week period in patients withearly type 2 diabetes, " Clin Sci (Lond) 95 (3): 325-9 (1998)

Vilsboll T etc., " Reduced postprandial concentrations of intactbiologically active glucagon-like peptide 1 in type 2 diabetic patients, " Diabetes 50 (3): 609-13 (2001)

Zhao XT etc., " Electric stimulation of small intestine delays gastricemptying in the dog model " [abstract], Neurogastroenterol Motil14:457 (2002)

Qian LW etc., " Normalization of atropine-induced postprandialdysrhythmias with gastric pacing, " Am J Physiol 276:G387-92 (1999)

Chen JDZ etc., " Gastric electrical stimulation with short pulsesreduces vomiting but not dysrhythmias in dogs, " Gastroenterology124:401-9 (2003).

The United States Patent (USP) 6,322,560 (incorporating this paper by reference into) of Garbagnati etc. has been described a kind of conduit for the treatment of tumor by the high temperature that is caused by radio frequency or other energy.Described conduit comprises having the tubular body that can be used as the cool metal dish of exciting electrode.Described a kind of application is to import and treat pancreas tumor by utilizing endoscope or at the surgery intra-operative described conduit being passed main pancreatic duct.

Rittman, the United States Patent (USP) 6,575,969 (incorporating this paper by reference into) of III etc. have described a kind of fluid-cooled (pouring into refrigerative) high-frequency electrode.In one embodiment, described electrode comprises the structure of " support (stint) ", air bag or the similar contraceptive cover that can insert in the ductus pancreaticus, it is by suitably cooling can be with in heat " throwing " pancreas tumor with the RF heating, and the structure of not destroying ductus pancreaticus simultaneously is to keep the normal process to biofluid.

The United States Patent (USP) 5 of Wernicke etc., 188,104 (incorporating this paper by reference into) were described a kind of method for the treatment of mandatory feed disorders patient, it comprises the preselected incident that press for of indication to interested specific feed disorder treatment that detect, and by replying of detected preselected incident applied the pre-determined stimulus signal that is suitable for alleviating the disorderly effect of interested feed to patient's vagus nerve.For example, preselected incident can be the food consumption of patient's specified level in the setting-up time interval, perhaps according to the beginning of custom meal time of the patient physiological rhythm and pace of moving things, perhaps pass through each interval in a series of predetermined time intervals, perhaps patient oneself thinks that need independently begin to apply stimulus signal arrives vagal treatment.In described disorder is mandatory the feed to the situation of excess, and stimulus signal is described as being predefined in and produces satiety in patient's body.

The US patent application publication 2005/0021101 of Chen etc. (incorporating this paper by reference into) has been described a kind of stimulating electrode and pick off of using and has been controlled the active method of the gastrointestinal of regulating the curee so that the negative feedback to the gastrointestinal electricity irritation to be provided.Also described the method for a kind of curee's of alleviating body weight, this method uses stimulating electrode and pick off so that the negative feedback control to the electricity irritation of stomach to be provided.Also having described a kind ofly provides the method for electrical field stimulation and a kind of method that potential gradient is provided to the gastrointestinal organ in the gastrointestinal organ.Also described a kind of by stimulating vagal method of curee among the gastrointestinal organ who stimulating electrode is positioned the curee.Described in addition a kind of use the pin that inserts device with this device from the external curee's of being positioned over of curee gastrointestinal tract or the method the gastrointestinal wall.

The PCT communique WO00/53257 (incorporating this paper by reference into) of Darwish etc. has described a kind of pancreas controller, and it comprises glucose sensor; At least one electrode is used for insulin production cell or cell mass energising; Being used for counter electrode applies the power supply of electric pulse, and described electric pulse does not cause action potential and has the effect that increases insulin secretion in cell; And controller, it receives the sensing level and controls the energising of power supply counter electrode so that it produces required effect to described level.

The US patent application publication 2003/0055464 of Darvish etc. (incorporating this paper by reference into) has been described a kind of pancreas controller, and it comprises at least one electrode that is suitable for the energising of at least a portion pancreas; And controller, it is programmed the counter electrode energising so that at least two the effect of Shaozheng in the blood levels of control blood glucose levels, blood insulin level and another kind of pancreatic hormone.

The PCT communique WO04/021858 of Harel etc. and WO05/023081 (incorporating this paper by reference into) have described a kind of method of glucose level control, it comprises providing and is suitable for pancreas is applied at least one electrode of electric field and uses described electrode pair pancreas to apply electric field so that blood glucose levels significantly reduces and the blood insulin level does not significantly increase.

The PCT communique WO03/045493 (incorporating this paper by reference into) of Harel etc. has described a kind of device that is used for sensing pancreas electrical activity.Described device comprises the group of one or more electrodes, and it is applicable to the active signal that is connected to pancreas and produces the pancreatic cell electrical activity of indicating a plurality of islets of langerhans that are arranged in pancreas.

The US patent application publication 2004/0249421 of Harel etc. (incorporating this paper by reference into) has been described a kind of method of glucose level control, it comprises that at least one electrode pair pancreas of use applies electric field, feasible replying with same people's insulin regular compared, and blood glucose levels significantly reduces and the blood insulin level does not significantly raise.Also described a kind of in pancreas the method for implant electrode, comprising: (a) endoscope is moved forward to bile duct, for example pass through stomach, and endoscope is moved forward along pancreas by bile duct; (b) endoscope is moved forward to the other parts of duodenum or the intestinal adjacent, then electrode is stretched into the pancreas from intestinal with pancreas.

The United States Patent (USP) 6,853,862 (incorporating this paper by reference into) of Marchal etc. has been described a kind of stomach electrostimulator, comprises that the nerve stimulator that produces stimulus signal, at least one electric lead and at least two electrically contact.Described stimulus signal is suitable for influencing pancreatic secretion.

The United States Patent (USP) 5,919,216 (incorporating this paper by reference into) of Houben etc. has been described a kind of system of automatic-answering back device insulin requirements, and it does not need outer monitoring or to the diabetics insulin injection.Described system provide to the inside sensing of glucose level and by stimulating pancreas or islet cells and islet to increase replying that insulin produces.To send enhanced stimulation than the bigger speed of outburst speed (burst rate), perhaps otherwise control enhanced stimulation so that the depolarization outburst constitutes the major part in each islets of langerhans electricity cycle, the insulin that causes thus increasing produces.In another embodiment, described system is replied the outside or inner signal of ingesting that produces, and provides the natural stimulation of replying of simulation to strengthen insulin replies by the operate time response algorithm.

The United States Patent (USP) 6,135,978 (incorporating this paper by reference into) of Houben etc. has been described a kind of pancreatic beta cell electrical activity of monitored patient to obtain implantable system and the method to the measurement of patient's insulin requirements and blood glucose levels.The control stimulus generator so that the depolarization of pancreatic beta cell is synchronous, produces the enhancing signal of telecommunication sensed and that handle to send boost pulse thus.The insulin that the insulin requirements signal is used to control from the insulin pump of implanting is sent, and the pancreas of perhaps controlling the form of ongoing enhancing insulin generation stimulates.

The United States Patent (USP) 6 of Whitehurst etc., 832, describe a kind ofly importing one or more stimulating drugs and/or the nerve fiber of pancreas and/or domination pancreas is applied the technology of electricity irritation 114 (incorporating this paper by reference into), it is in order to treatment or prevent diabetes and/or regulate pancreatic endocrine.

Existing be used to reduce the description of stomach volume with the intragastric balloon of treatment of obesity, be included in following patent and the patent application gazette, its full content is all incorporated the United States Patent (USP) 4 of this paper: Garren etc. by reference into, 416,267 and 4,899,747, the United States Patent (USP) 4,694 of Weiner etc., 827, the United States Patent (USP) 4,723 of Kullas etc., 547, the United States Patent (USP) 4,739 of Lai etc., 758, the United States Patent (USP) 5,234 of Bangs, 454, the United States Patent (USP) 6,454,785 of De Hoyos Garza, the United States Patent (USP) 6 of McGhan, 733,512, the US patent application publication 2003/0158569 of Wazne, the US patent application publication 2005/0004430 of Lee etc., the PCT communique WO03/055420 of Lointier etc., the PCT communique WO 04/089262 of Paganon and the PCT communique WO 87/00034 of Taylor.

The United States Patent (USP) 6 of Bales etc., 579,301 (incorporating this paper by reference into) were described a kind of intragastric balloon device, comprise flexible bags, connect described capsule and be fit to hold the capsule expansion fluid relative stiffness container and be suitable for mobile fluid or allow fluid to move to the expansion system of described capsule from container.This intragastric balloon device size makes it integral body be positioned at gastral cavity.Can use multiple systems to come mobile fluid or permission fluid to move.Provide control system with automatic activate inflation/pinch system.Can activate automatic activation by the combination of one or more following key elements: timer, stomach temperature, intragastric pressure, gastric mechanical stress or other sensing condition.

The United States Patent (USP) 5,868,141 (incorporating this paper by reference into) of Ellias has been described a kind of endoscopic gastric insert, and it is used for treating people's obesity by reducing appetite, and described endoscopic gastric insert comprises that size is fit to pass the pedestal of population and esophagus; The a plurality of soft blade that one end connects pedestal and arranges around pedestal axis circumference, wherein said blade biasing outwards and is downwards extended to be radial substantially from described pedestal; And the keeper that is used for releasable connection blade distal portions, described blade is very close to each other around described pedestal axis.Therefore described insert is suitable for passing mouthful and esophagus enters stomach, when keeper when gastric discharges, described blade biasing is outwards opened and is formed dome shape cage, and stomach is exerted pressure, and therefore causes at gastric to be full of sense and reduction appetite.

The PCT communique WO05/051486 (incorporating this paper by reference into) of Mintchev has described a kind of method and apparatus of gastrointestinal motility control.An aspect of this invention is described as being used for suppressing at gastrointestinal tract, in given gastrointestinal organ or in its part the method and apparatus of the complete nonsynchronous artificial wriggling of mechanical phenomenon of gastrointestinal (GI) motion of spontaneous existence and generation and spontaneous existence, its use have wide range of frequencies (5-50,000Hz), a series of external voltages of wide region working cycle (10-100%) and wide region amplitude (3-30V peak-to-peak value).A kind of method and apparatus that preliminary external control is shunk that produces in the sphincter zone or in a GI organic region or its part (for example, the pylorus in the stomach) has also been described.Owing to the contraction of inducing that prolongs, adjacent acetylcholine (ACh) speckle (patch) at sphincter region adjacent place exhausts, and the result makes sphincter inevitably lax.In addition, device causes the GI wriggling of external control after realizing sphincter dilatation, make content be pushed through sphincter.Also described the MO implantable microsystem device of a kind of treatment, it can use identical device.

The PCT communique WO02/092165 (incorporating this paper by reference into) of King but described and be suitable for blocking the embodiment that activated device is organized in electrostimulation, more specifically be used for producing required effect and being used for by reducing the side effect of not expecting accordingly in the activation of second predetermined position blocking-up tissue or the conduction of action potential by activate tissue at first predetermined position.Required effect can be patient's enterokinesia; The effect of not expecting can be the sealing of patient's ileocecal valve to patient's colon.First position can be patient's intestinal wall smooth muscle, hypogastric plexus or the nerve that leads to hypogastric plexus; Second position can be patient's ileocecal valve, mesentery neuroganglion, Dorsal root nerve, columna posterior medullae spinalis or a visceral nerve.

Following list of references, it incorporates this paper by reference into, also may be interested:

The EP1392393 of King

The United States Patent (USP) 6,895,279 of Loeb etc.

The United States Patent (USP) 5,423,872 of Cigaina

The US patent application publication 2002/0072779 of Loeb

United States Patent (USP) 6,571,127 to of Ben-Haim etc.

The United States Patent (USP) 6,826,428 of Chen etc.

The US patent application publication 2003/0055467 of Ben-Haim etc.

The US patent application publication 2005/0085923 of Levine etc.

The United States Patent (USP) 6,684,105 of Cohen etc.

The PCT patent gazette WO 03/018118 of Cohen etc. and the U.S. Patent application 10/488,334 in its country's stage

The United States Patent (USP) 6,993,391 of Flesler etc.

The U.S. of Darvish etc. is newspaper 7,006,871 specially

The PCT communique WO 06/018851 of Kliger etc.

The PCT communique WO 04/112563 of Ben-Haim etc.

The PCT communique WO 05/087310 of Harel etc.

The US patent application publication 2006/0085045 of Harel etc.

Kalloo etc. are entitled as " Flexible transgastric peritoneoscopy:A novelapproach to diagnostic and therapeutic interventions in the peritonealcavity " Gastrointest Endosc.2004 Jul; 60 (l): endoscope's per os that the paper of l 14-7 (incorporating this paper by reference into) has been described in pig model acute experiment and long-term surviving experiment is worn the test that stomach arrives the abdominal cavity.In the 50kg pig, estimate and wear stomach peritoneoscope (peritoneoscopy)., enter the abdominal cavity, then enlarge otch by after the upper digestive tract in endoscope by pin-cutter puncture coat of the stomach with tractive type sphincterotome or by airbag inflation.Check the abdominal cavity, obtain the liver biopsy sample.Seal gastric wall incision with clip.12 routine acute experiments and 5 example survival experiments have been carried out.Two kinds of coat of the stomach incision technology do not have complication.Acute experiment shows the technical feasibility of this therapy.In the survival experiment, all pigs are rehabilitation and weight increase all.The conclusion of this paper is that per os is worn stomach to arrive the abdominal cavity be feasible technically, and has the potentiality as the replacement scheme of laparoscopy (laparoscopy) and laparotomy ventrotomy (laparotomy).

Sun etc. are entitled as " Intestinal electric stimulation decreases fatabsorption in rats:Therapeutic potential for obesity, " Obes Res.2004Aug; 12 (8): the paper of 1235-42 (incorporating this paper by reference into) has described (whether intestinal electric stimulation IES) reduces fat absorption and whether therefore can be used as the research that potential obesity therapy is carried out about the intestinal electricity irritation.To implant serous coat electrode (serosalelectrode) and two telescopic 40 rats of jejunum are divided into 4 groups, every group 10: matched group (non-stimulated), use the IES of long pulse, use the IES of a series of short pulses and use the IES of a series of short pulses to add the lignocaine processing.Applying or do not applying 45 minutes time durations of IES, the jejunum of research 20cm jejunum fragment (two sleeve pipe between) by and fat absorption.Discovery is than matched group, the intestinal that two kinds of IES methods are all quickened to measure by phenol red recovery by and increase the percentage ratio of the triglyceride that reclaims from distal cannula.The IES that uses a series of short pulses quicken jejunum by and reduce on the fat absorption more effective than IES with long pulse.Two kinds of IES methods do not change from the fat of distal cannula output.The IES that uses a series of short pulses by with fat absorption on effect eliminated by the lignocaine processing section.Conclusion is that IES acceleration intestinal passes through and reduce fat absorption, and prompting is for the treatment potentiality of obesity.Find to use the IES of a series of short pulses more effective than the IES with long pulse, its agency part is regulated by enteric nervous, jejunum.

Giralt M etc., Neurogastroenterol Motil.April, 2000,12 (2): 173-80, the paper (incorporating this paper by reference into) that is entitled as " Inhibition by CCK of ascending contraction elicited by mucosalstimulation in the duodenum of the rat " has been described by the activity of intracavity stimulation release CCK change duodenum, and it causes the decline of gastric emptying.Described paper points out that the neuromechanism of CCK controlled motion is unknown.The purpose of this research is to be used for study interaction CCK and enteric nervous system between in the excitement by research CCK-8 strengthening.Preparation is sewed with the anesthesia Sprague-Dawley rat of strain gauge on duodenal wall.Electrode holder is positioned over the duodenum intracavity to produce enhanced contraction.(4Hz, 0.6ms 30V) cause enhanced excitement, and it can be blocked by pregnancy quaternary amine and atropine, but are amplified by L-NNA to the electrical field stimulation of duodenal mucosa.CCK-8 blocks enhanced excitement, observe on the contrary the inhibition of the phase place activity of inducing (phasic activity).In a word, CCK-8 blocking-up activates the enhancing that the duodenal mucosa electrical field stimulation that produces causes by by CCK-A and CCK-B receptor the time and shrinks.

Mukhopadhyay AK etc., Am J Physiol.January, 1977,232 (l): E44-7, the paper (incorporating this paper by reference into) that is entitled as " Effect of cholecystokinin on myoelectric activity of small bowelof the dog " have described and determined the experiment of cholecystokinin in the effect of small intestinal myoelectrical activity in clear-headed Canis familiaris L.s.Electrode is implanted in six animals along small intestinal, and placed sleeve pipe under one's belt.In three animals, second sleeve pipe is inserted in the duodenum preparation pancreas fistula in three animals.Carrying out record during perfusion saline or the L-tryptophan during the fasting, during intravenous pours into saline or cholecystokinin-octapeptide (CCK-OP), in duodenum and on the feed.CCK-OP destroys the fasting pattern of myoelectrical activity, causes the dose dependent of spike potential to increase, and causes the dose dependent of pancreas protein secreting to increase.The stimulation of myoelectrical activity takes place when producing the dosage of inferior maximum dose (submaximal) protein secreting; But that sees when this stimulation and feed is inconsistent.Perfusion L-tryptophan increases the pancreas protein secreting in the duodenum, and the fasting pattern of interfering activity is induced the pattern of seeing when being similar to feed.Described paper infers that CCK changes the small intestinal activity and also may work in movable change of small intestinal of causing that ingest.

Following paper, it incorporates this paper by reference into, may be interested:

Bergman, RN etc., " The evolution of β-cell dysfunction and insulinresistance in type 2 diabetes, " Eur J Clin Invest 32 (Suppl.3): 35-45 (2002)

Chiasson, JL etc., " Prevention of type 2 diabetes:Insulin resistanceand β-cell function, " Diabetes 53 (Suppl.3): S34-S38 (2004)

Kahn SE，“The relative contributions of insulin resistance andbeta-cell dysfunction to the pathophysiology of Type 2 diabetes，”Diabetologia 46：3-19(2003)

Toyama MT etc., " Effect of ethanol on pancreatic interstitial pHand blood flow in cats with chronic pancreatitis, " Annals of Surgery225 (2): 223-228 (1997)

Liu S etc., " Therapeutic potential of duodenal electrical stimulationfor obesity:Acute effects on gastric emptying and water intake; " Am JGastroenterol, 100 (4): 792-6 (2005).

Summary of the invention

In some embodiments of the present invention, the system of a kind of curee's of treatment obesity and diabetes comprises control unit, feed pick off, intragastric balloon, nervous tissue's stimulator and pancreas stimulator.Nervous tissue's stimulator comprises, the stimulator that for example is suitable for the stimulator of vagus nerve stimulation and/or is suitable for stimulating enteric nervous system (ENS).Detected feed is replied to the feed pick off, control unit driving nervous tissue's stimulator vagus nerve stimulation or ENS are with reduction curee's appetite, and/or driving pancreas stimulator stimulating pancreas β cell is to control (for example increasing or minimizing) insulin generation and/or to regulate blood-glucose in addition.Therefore described system solves the correlative factor of appetite control and β cell dysfunction in many overweight diabetes curees simultaneously.

In some embodiments of the present invention, the pancreas stimulator comprises one or more pancreas electrodes, and it is suitable for being inserted into ductus pancreaticus normally in the main pancreatic duct.Usually utilize endoscope that the pancreas electrode is implanted in the main pancreatic duct, its through port, stomach and duodenum move forward to main pancreatic duct.For some application, described electrode comprises ring electrode, and it is set to not block basically pancreatic juice flowing by ductus pancreaticus.

In some embodiments of the present invention, the feed pick off is suitable for placing under one's belt or other gastrointestinal tract position.For some application, the feed pick off comprises one or more electrodes, is set to experience the electrical activity in the coat of the stomach of indicating curee's feed.In some embodiments, described feed pick off is introduced in the intragastric balloon.Use for some, described electrode is fixed in the surface of described air bag.As selecting or additionally, described feed pick off comprises pressure transducer, its intragastric pressure that is suitable for experiencing indication curee feed changes.

For some application, nervous tissue's stimulator is suitable for being placed in the duodenum, is subjected to the tissue of the duodenal wall of vagus nerve and/or ENS domination with stimulation.For some application, described control unit is suitable for being placed in the intragastric balloon.Perhaps, described control unit is suitable for implanting interior other position of abdomen or is positioned over the external of curee.

Therefore, according to one embodiment of the invention, provide a kind of device, it comprises:

One or more electrodes, it is suitable for inserting in the ductus pancreaticus of curee's pancreas; With

Control unit, it is suitable for drive electrode pancreas is applied electric current, and sets electric current to regulate the insulin production of pancreatic beta cell.

In one embodiment, described electrode comprises ring electrode.Use for some, each described ring electrode comprises a plurality of conductive segments of arranging around described ring electrode.As selecting or additionally, described device comprises and is suitable for unfolded support in ductus pancreaticus, opens one or more electrodes thus in ductus pancreaticus.

In one embodiment, described one or more electrode is suitable for being inserted in the main pancreatic duct of pancreas.

In one embodiment, described electrode is set to allow pancreatic juice to pass through described electrode.

In one embodiment, described one or more electrodes comprise a plurality of electrodes, and described control unit is suitable for only driving a part of electrode to apply electric current arbitrarily preset time.For example, described device can comprise the lead group that connects described control unit and described a plurality of electrodes, described control unit is suitable for transmitting multiple signals by this lead group and gives a plurality of electrodes, and each in described a plurality of electrode comprises microchip respectively, is suitable for driving described electrode in definite signal addressing during to described microchip and applies electric current.

According to one embodiment of the invention, a kind of device also is provided, it comprises:

One or more electrodes, it is suitable for contacting placement with curee's duodenal lumen wall;

Control unit, it is suitable for driving described electrode pair duodenal lumen wall and applies electric current, and sets electric current with stimulation curee's vagus nerve or curee's ENS.

For some application, described device comprises the feed pick off, and described control unit is suitable for driving described electrode and applying electric current replying from the signal of the indication curee feed of feed pick off.

For some application, described control unit is suitable for (a) according to current parameters configuration set electric current, this parameter group comprises the pulsewidth of current impulse and frequency that described pulse applies and the closure of (b) selecting parameter group to make to strengthen curee's pylorus and reduces glucose level in curee's blood.As selecting or additionally, described control unit is suitable for (a) according to current parameters configuration set electric current, this parameter group comprises the pulsewidth of current impulse and frequency that described pulse applies and the closure of (b) selecting parameter group to make to strengthen curee's pylorus and improves insulin level in curee's blood.

For some application, in described one or more electrode two, when contacting, spaced a certain distance with described wall, this distance is greater than any other two spacings between when contacting with described wall in described one or more electrodes, and described distance is less than 3cm.

For some application, described control unit is suitable for (a) configuration electric current and is 0.1Hz at least to comprise a plurality of pulses and (b) to set the frequency apply pulse.For some application, it is two-phase pulse that described control unit is adapted for application to fewer pulses.As selecting or additionally, it is monophasic pulses if that described control unit is adapted for application to fewer pulses.

For some application, described control unit is suitable for setpoint frequency and is 1Hz at least, for example 3Hz at least.

For some application, described control unit is suitable for disposing electric current to comprise a plurality of pulses, and each of at least two continuous impulses has the pulsewidth less than 75ms respectively, for example less than 30ms, for example less than 15ms.

In one embodiment, described control unit is suitable for (a) configuration electric current to comprise a plurality of pulses, (b) setting the frequency that applies pulse is required frequency values, (c) pulsewidth of at least two continuous impulses of setting is less than the threshold value pulsewidth, wherein the ratio of threshold value pulsewidth and required frequency values is less than 1000ms/Hz, as less than 100ms/Hz, for example less than 10ms/Hz.

In one embodiment, described control unit is suitable for disposing the feasible closure that is enough to cause curee's pylorus of electric current.Use for some, described control unit is suitable for disposing the feasible closure that is enough to cause by the neural mediation path pylorus of electric current, but is not enough to cause by stimulus of direct current pylorus muscular tissue the closure of pylorus.

Use for some, described one or more electrodes comprise and are suitable for being placed on apart from pylorus 2～5cm or are suitable for being placed on apart from pylorus 1～2cm with at least two interior electrodes.Use for some, all electrodes in described one or more electrodes are suitable for being placed on apart from pylorus 2～5cm or are suitable for being placed on apart from pylorus 1～2cm.

In one embodiment, described control unit is suitable for being placed in curee's the gastrointestinal tract.For example, described control unit can be suitable for being positioned in curee's the stomach.Perhaps, described control unit is suitable for the place beyond implanted curee's the stomach, and with described electrode wireless connections.Again or, described control unit is suitable for being placed on the external of curee, and with described electrode wireless connections.

According to one embodiment of the invention, a kind of device further is provided, this device comprises:

The feed pick off, it is suitable for being placed on curee's the signal that body is interior and generation indication curee takes food;

Vagus nerve stimulator or ENS stimulator, it is suitable for being placed in curee's the gastrointestinal tract;

One or more pancreas electrodes, it is suitable for being inserted in curee's the pancreas by endoscope; With

Control unit, it is suitable for receiving the feed signal, and this feed signal is replied to drive vagus nerve stimulator or ENS stimulator the pancreatic beta cell that curee's vagus nerve or ENS applies first electric current and driving pancreas electrode pair curee is applied second electric current.

According to one embodiment of the invention, a kind of device also is provided, this device comprises:

The feed pick off, it is suitable for being placed in curee's the body, and produces the signal of indication curee feed;

One or more electrodes, it is suitable for being implanted to by peritoneoscope, endoscope or other form curee's corresponding duodenum position; With

Control unit, it is suitable for receiving the feed signal, and this feed signal replied to drive vagus nerve stimulator or ENS stimulator curee's vagus nerve or ENS are applied first electric current and drive described electrode applies active second electric current of adjusting curee's pancreatic beta cell.

In one embodiment, described control unit is suitable for setting first electric current and makes its frequency equal at least three times of second power frequency.

In one embodiment, described device comprises intragastric balloon, and this intragastric balloon is suitable for being placed on curee's gastric.For some application, described intragastric balloon comprises described feed pick off.

According to one embodiment of the invention, a kind of method also is provided, this method comprises:

One or more electrodes are inserted in the ductus pancreaticus of curee's pancreas;

Drive described electrode so that pancreas is applied electric current; With

Dispose described electric current to regulate the insulin production of pancreatic beta cell.

In one embodiment, insert the one or more electrodes of insertion in the main pancreatic duct that is included in pancreas.As selecting or additionally, inserting electrode and comprise the mouth insertion electrode that utilizes the process curee of endoscope.

Control unit, it is suitable for driving the described duodenal lumen wall of described electrode pair and applies electric current and configuration electric current and be selected from position in curee's vagus nerve and curee's enteric nervous system (ENS) tissue with stimulation.

In one embodiment, described position comprises curee's vagus nerve, and described control unit is suitable for disposing electric current to stimulate described vagus nerve.

In one embodiment, described position comprises curee's ENS tissue, and described control unit is suitable for disposing electric current to stimulate described ENS tissue.

In one embodiment, described control unit is suitable for being placed in curee's the gastrointestinal tract.

In one embodiment, described control unit is suitable for being placed in curee's the stomach.

In one embodiment, described control unit is suitable for being implanted to the place beyond the stomach among the curee, and with described electrode wireless connections.

In one embodiment, described control unit is suitable for being implanted to the stomach place in addition among the curee, and described device comprises the lead that is configured to connect described control unit and described electrode.

In one embodiment, described control unit is suitable for being placed on the external of curee, and with described electrode wireless connections.

Stimulator, it is suitable for stimulating the position in the vagus nerve that is selected from the curee and curee's enteric nervous system (ENS) tissue, and is suitable for being placed in curee's the gastrointestinal tract;

One or more pancreas electrodes, it is suitable for being inserted in curee's the pancreas by peritoneoscope; With

Control unit, it is suitable for receiving the feed signal, and this feed signal is replied to drive described stimulator the pancreatic beta cell that curee's selected position applies first electric current and driving pancreas electrode pair curee is applied second electric current.

In one embodiment, described control unit is suitable for setting first electric current and it is had equal the triple at least frequency of second electric current.

In one embodiment, described device comprises intragastric balloon, and this intragastric balloon is suitable for being placed on curee's gastric.

In one embodiment, described intragastric balloon comprises described feed pick off.

In the ductus pancreaticus of curee's pancreas, insert one or more electrodes;

Drive described electrode so that pancreas is applied electric current; With

Set described electric current to regulate the insulin production of pancreatic beta cell.

In one embodiment, insert the one or more electrodes of insertion in the main pancreatic duct that is included in pancreas.

In one embodiment, insert electrode and comprise the mouth insertion electrode that utilizes the process curee of endoscope.

One or more screw electrodes are inserted in curee's the duodenum;

Stretching described one or more electrode electrically contacts to set up between described one or more electrodes and duodenal wall;

Drive current is by described one or more electrodes; With

Dispose described electric current to induce duodenal contraction.

The support that will comprise one or more electrodes is inserted in curee's the duodenum;

Drive current is by described one or more electrodes; With

Dispose described electric current to induce duodenal contraction.

Drive current enters the duodenal position of curee; With

Dispose described electric current to strengthen curee's satiety by enteric nervous system (ENS) tissue that stimulates the curee.

Drive current enters the duodenal position of curee; With

Dispose described electric current to strengthen curee's satiety by cholecystokinin (CCK) blood levels that improves the curee.

Drive current enters the duodenal position of curee; With

Dispose described electric current to strengthen curee's satiety by the GLP-1 blood levels that improves the curee.

First and second electrodes are placed on duodenal first and second positions of curee respectively; With

Activate described electrode to improve curee's blood insulin level.

In one embodiment, placement comprises that placing electrode makes the straight line of connection electrode pass curee's pancreas.

In one embodiment, described method comprises the signal of sensing curee feed, and this signal is replied the described electrode of activation.

In one embodiment, placement comprises that placing first and second electrodes makes it at least at a distance of 5cm.

In one embodiment, active electrode comprises that the amplitude of applying is 2mA to 8mA, and frequency is the signal of 3Hz to 20Hz.

In one embodiment, apply signal and comprise that (a) applies signal and be less than 5 seconds, (b) stop signal is greater than 10 seconds, and (c) at (a) with circulation (b).

In one embodiment, described method comprises that drive current enters duodenum, and this current arrangements is the satiety that causes the curee.

In one embodiment, drive current comprises the delay gastric emptying.

In one embodiment, thus drive current comprises the configuration electric current to be imported vagal signal into and reduces curee's feed to induce.

In one embodiment, described method comprises that drive current enters duodenum, and this current arrangements is for causing duodenal contraction.

In one embodiment, drive current comprises that the configuration electric current is to cause wriggling.

In one embodiment, drive current comprises the speed that increases wriggling.

In one embodiment, drive current comprise the configuration electric current with induce at least one dividing a word with a hyphen at the end of a line property motion complex wave (migratory motor complex, MMC).

In one embodiment, described method comprises regularly drive current, makes the time of origin of MMC early than time of the natural generation of MMC.

First and second electrodes are placed on curee's the first and second abdominal part positions respectively; With

Activate described electrode to suppress the effect level of Digestive system.

In one embodiment, described Digestive system comprises bile, and activation comprises that the described electrode of activation is to suppress biliary effect level.

In one embodiment, described Digestive system comprises pancreatic juice, and activation comprises that the described electrode of activation is to suppress the effect level of pancreatic juice.

In one embodiment, the described first and second abdominal part positions comprise the first and second duodenum positions, and placement comprises that placing said electrodes arrives the described first and second duodenum positions, makes the straight line that connects described electrode pass curee's pancreas.

Drive current between first and second electrodes that lay respectively at duodenal first and second positions of curee, described electrode gap is 5mm at least; With

Dispose described electric current to stimulate the tissue in the duodenum longitudinal muscle layer.

Drive current between first and second electrodes that lay respectively at duodenal first and second positions of curee, described electrode gap is less than 5mm; With

Dispose the feasible tissue that stimulates in the duodenum circular muscle layer of described electric current.

Be suitable for the capsule swallowed by the curee;

Pick off, it is suitable for being implanted in the curee, detecting described capsule to the distance of described pick off, and it is replied the generation sensor signal; With

The treatment unit, it is suitable for the sensor signal that is received is replied so that the curee is applied treatment.

In one embodiment, described capsule comprises magnet.

In one embodiment, described capsule diameter is less than 2mm.

In one embodiment, described treatment unit is suitable for applying the treatment that causes curee's satiety.

In one embodiment, described treatment unit is suitable for applying the treatment that improves blood insulin.

Duodenal lumen wall to the curee applies electric current; With

Dispose described electric current and be selected from position in curee's vagus nerve and curee's enteric nervous system (ENS) tissue with stimulation.

In curee's body, produce the signal that the indication curee takes food;

Place stimulator in curee's gastrointestinal tract, this stimulator is suitable for stimulating the position in the vagus nerve that is selected from the curee and curee's enteric nervous system (ENS) tissue;

One or more electrodes are implanted at corresponding duodenum position the curee; With

Receive the feed signal, and correspondingly drive stimulator and apply first electric current and drive one or more pancreas electrodes with selected position and regulate the activity of curee's pancreatic beta cell to apply second electric current to the curee.

By the detailed description of following embodiment and accompanying drawing is incited somebody to action the more complete the present invention that understands, wherein:

Description of drawings

Fig. 1 is the sketch map according to the system that is used for the treatment of obesity and diabetes of one embodiment of the invention;

Fig. 2 A-C is the schematic section according to the pancreas electrode configuration of corresponding embodiment of the present invention;

Fig. 3 A-C is the schematic section according to other configuration of pancreas electrode of corresponding embodiment of the present invention;

Fig. 4 is the sketch map according to the electric field of two contact configuration generations of passing through the pancreas electrode of one embodiment of the invention;

Fig. 5 is the sketch map according to the pancreas stimulator configuration of one embodiment of the invention;

Fig. 6 A, 6B and 6C are the sketch maps according to the electrode that uses with the tissue stimulation device configuration of corresponding embodiment of the present invention;

Fig. 7 is the sketch map according to the stimulator of one embodiment of the invention;

Fig. 8 is the sketch map according to the experimental provision of one embodiment of the invention, and it is used to study the electricity irritation of rat midgut to the mobile effect of duodenum nutrient;

Fig. 9 is the figure that shows the experimental result that experiment obtained of rat being carried out according to the device of above-mentioned Fig. 8 of use of one embodiment of the invention;

Figure 10 is the experimental provision sketch map according to one embodiment of the invention, and it is used to study the effect of rat midgut electricity irritation to gastric emptying;

Figure 11 and 12 is the figure that show the experimental result that experiment obtained of rat being carried out according to the device of above-mentioned Figure 10 of use of corresponding embodiment of the present invention;

Figure 13 is the figure that shows according to the experimental result that experiment obtained of corresponding embodiment of the present invention, the effect that its research rat midgut electricity irritation absorbs nutrient;

Figure 14-the 17th, the figure of the experimental result that is obtained in the demonstration experiment that corresponding embodiment is carried out according to the present invention.

Specific embodiments

Fig. 1 is the sketch map according to the system that is used for the treatment of obesity and diabetes 10 of one embodiment of the invention.System 10 generally includes the pancreas stimulator 28 of control unit 20, feed pick off 22, intragastric balloon 24, tissue stimulation device 26 and implantable curee's pancreas 30.Feed detection to feed pick off 22 is replied, control unit 20 drives tissue stimulation device 26 vagus nerve stimulations or enteric nervous system (ENS) reducing appetite, and/or drives pancreas stimulator 28 stimulating pancreas β cells to regulate insulin production and/or blood sugar regulation (dotted line 31 symbolically represent to arrange the vagus nerve of upper gastrointestinal and pancreas) otherwise.Described about nervous tissue being applied the tissue stimulation device 26 of stimulation although it should be noted that embodiments more of the present invention, scope of the present invention comprises that also driving 26 pairs of muscular tissues of stimulator applies stimulation.

After control unit 20 is normally implanted can outside programming, allowing calibration or to optimize multiple signal parameter off and on, for example working cycle (for example, the hourage of operation every day and/or regularly situation), signal frequency and signal amplitude.Similarly, the common permission of outside programming is controlled (for example, glucose is controlled, satiety is induced and induce wriggling or dividing a word with a hyphen at the end of a line property motion complex wave (MMC)) to the timetable of the plurality of operating modes of control unit 20.

In one embodiment of the invention, pancreas stimulator 28 comprises one or more pancreas electrodes 32, is connected the lead 34 of described electrode with at least one.Described electrode is suitable for inserting in the ductus pancreaticus of pancreas 30, is typically to insert in the main pancreatic duct 36.Usually, pancreas stimulator 28 uses endoscope's (not shown) to be implanted in the main pancreatic duct 36, and its mouth, stomach 38 and duodenum 40 by the curee is advanced to main pancreatic duct 36.Usually, pancreas stimulator 28 comprise about 1 to about 10 pancreas electrodes 32, for example about 1 to about 4 electrodes.Usually, electrode 32 comprises ring electrode.For some application, each ring electrode comprises a plurality of conductive segment, for example 2 to 4 conductive segment of arranging around ring electrode.Use for some, it is about electric current of 0.5 to about 3Hz to apply frequency that control unit 20 is suitable for driving pancreas electrode 32.Use for some, pancreas electrode 32 comprises the material of the pancreas ripple damage of anti-high pH, for example rustless steel 316L, titanium or proof gold.

In one embodiment, total forward current of being driven of the one or more electrodes 32 of control unit 20 balance in over a long time and total reverse current.Therefore, for example, continue surpassing about 15 minutes or surpassing in about 12 hours time period, is 0 by the net current of at least one driving in the described electrode.Use for some, guess that this charge balance makes the minimize variations of pH, the variation of described pH can apply institute by nonequilibrium electric charge and bring out.

Use for some, control unit 20 is suitable for only driving at least a portion electrode 32 in any given time, for example by circulating between described electrode.This non-constant stimulation that produces by arbitrary electrode reduces the excessively risk of work of pancreatic beta cell usually.For some application, control unit 20 only drives a part of electrode by transmitting multiple signals through the lead group to all electrodes.For example, control unit 20 can be used timesharing, frequency division or digital multi-channel technology.For this frequency multiplexing technique can be used, each electrode generally includes microchip, and whether its signal that control unit 20 is produced is used to make near the pancreatic tissue of described electrode pair it to apply electric current is translated.

In one embodiment, any pancreas instability that curee's application of substances is caused owing to insertion pancreas electrode 32 with counteracting.For example, described material can provide the stable of pH, enzyme and/or hormone.Use for some, described material is used with the form of tablet, and for other application, pancreas electrode 32 is coated with described material.Perhaps, described material storage enters ductus pancreaticus by pipe driving or the passive migration that links to each other with described air bag in air bag 24.

With reference to figure 2A-C, its be according to the present invention each embodiment the schematic section of pancreas electrode 32 configuration.In these embodiments, pancreas electrode 32 comprises ring electrode, and it is configured to not block basically the pancreatic juice stream that passes main pancreatic duct 36.In the embodiment shown in Fig. 2 A, pancreas electrode 32 comprises that two electrically contact 50, one as negative electrode, and another is as anode.For some application, each contact 50 is discontinuously as negative electrode with discontinuously as anode.In the embodiment shown in Fig. 2 B, described electrode comprises that 4 electrically contact 50, and wherein two usually as negative electrodes, other as anode.For some application, each contact 50 is discontinuously as negative electrode with discontinuously as anode.For other application, pancreas electrode 32 comprises 3 contacts, the perhaps contact of greater number, for example 5 to 10 contacts (configuration does not show).In one embodiment, 3 or more, even all contacts can be passed through control unit 20 independent addressing.

Usually, each contact 50 comprises electrical insulator 52, and it can comprise, for example, and siloxanes.Pancreas electrode 32 also comprises non-conductive structural support thing 54, and it can for example comprise net, for example mesh grid.Fig. 2 C shows the sectional view that pancreas electrode 32 is seen from the side.By it as seen, in this embodiment, contact 50 and insulator 52 are outstanding slightly to be entered in the main pancreatic duct 36.

Fig. 3 A-C is the schematic section according to the other configuration of the pancreas electrode 32 of each embodiment of the present invention.These configurations are similar to the configuration of Fig. 2 A-C mentioned above, except contact 50 and insulator 52 outstanding outwardly from holder 54, rather than outstanding inwardly.As a result, as Fig. 3 C finding, contact 50 and insulator 52 push the wall of main pancreatic duct 36 slightly, have stayed the sectional area of the mouth of pipe bigger than the configuration of Fig. 2 A-C.In one embodiment of the invention, pancreas electrode 32 comprises expansible support, is similar to coronary stent, and it can be configured to open electrode and promote described contact and enters described pipe.As selecting or additionally, air bag or other instrument are inserted electrode, inflation or otherwise expand to open described electrode is removed from described electrode then.

Fig. 4 is the sketch map that disposes imaginary electric current 60 in pancreas 30 cross sections that produced according to two contacts of passing through pancreas electrode 32 of one embodiment of the invention.

With reference to figure 5, it is the sketch map according to pancreas stimulator 28 configurations of one embodiment of the invention.In this embodiment, alternative pancreas electrode 32 comprises single negative electrode or anode (representing with letter C and A in the drawings) separately, and making (is not needing simultaneously) between the adjacent electrode or generation electric current 70 between two non-adjacent electrodes as shown in the figure.Pancreas electrode 32 is typically ring electrode, and can with reference to last Fig. 2 A-C or 3A-C is described be configured, and makes necessary correction.Each of electrode 32 all comprises one or more contacts, and it is typically inwardly insulating.

Again with reference to figure 1.For some application, control unit 20 is suitable for being placed in the intragastric balloon 24.Perhaps, described control unit is suitable for implanting other places of abdominal part, places perhaps that the curee's is external.Control unit 20 typically comprises microprocessor 80 and power supply 82.Described power supply is typically and comprises battery, uses for some, and it is suitable for carrying out induction charging from the external power supply of curee.

In one embodiment of the invention, system 10 comprises one or more stomach electrodes 84, and it is suitable for being placed in the stomach 38.Use for some, stomach electrode 84 is connected (as shown in the figure) with the surface of intragastric balloon 24, and uses for some other, and stomach electrode 84 is suitable for being implanted in the wall of stomach 38 (disposing demonstration).

In one embodiment of the invention, feed pick off 22 is suitable for being placed in the stomach 38.For some application, feed pick off 22 comprises one or more stomach electrodes 84, and it is configured to the interior electrical activity of coat of the stomach of sensing indication curee feed.

In one embodiment of the invention, control unit 20 is suitable for driving stomach electrode 84 to stimulate vagus nerve or the ENS through stomach 38.For such stimulation, control unit 20 is typically and is suitable for drive electrode 84 and has about 6 electric currents to about 30Hz frequency to apply, and for example about 10 to about 15Hz, for example about 12Hz.

In one embodiment of the invention, feed pick off 22 is incorporated in the intragastric balloon 24.Use for some, the stomach electrode 84 of feed pick off 22 is fixed in the surface of air bag, as mentioned above.As selecting or additionally, feed pick off 22 comprises pressure transducer 86, its pressure that are suitable in the stomach 38 of sensing indication curee feed change.Use for some, pressure transducer 86 is positioned over outside the described air bag and is suitable for the pressure of direct sensing gastric.Use for some other, pressure transducer 86 is positioned in the described air bag and is suitable for the described intracapsular pressure of sensing indication intragastric pressure.In one embodiment, feed pick off 22 comprises the blood-glucose pick off, and it is implantable interior or external to patient's body.In a back example, but described glucose sensor typically not must with control unit 20 radio communications.

In one embodiment of the invention, tissue stimulation device 26 comprises one or more intestinal electrodes 90, and it is suitable for being placed on curee's gastrointestinal (GI) road intracavity, and duodenum 40 intracavity for example are subjected to the tissue of the GI road wall of vagus nerve or ENS domination with stimulation.For some application, described intestinal electrode is placed against duodenal wall, and for other application, described intestinal electrode is implanted in the duodenal wall.Use for some, it is about electric current of 10 to about 20Hz to apply frequency that described control unit is set to drive intestinal electrode 90.For some application, described control unit is set electric current and is comprised a plurality of pulses, and the pulsewidth of setpoint frequency and pulse makes the ratio of pulsewidth and frequency less than 1000ms/Hz.For example, following pulsewidth and frequency satisfy such condition respectively: (a) 90ms and 0.1Hz, (b) 9ms and 0.1Hz, (c) 9ms and 1Hz, (d) 5ms and 1Hz and (e) 5ms and 3Hz.Use for some, tissue stimulation device 26 uses the technology of describing in relevant patent of one or more vagal stimulations of describing or the patent application gazette in background technology above.For some application, system 10 is suitable for using stomach electrode 84 and intestinal electrode 90 the two vagus nerve stimulation or ENS.

With reference to figure 6A, it is the sketch map according to electrode 90 configurations of the tissue stimulation device 26 of one embodiment of the invention.In this embodiment, electrode 90 is resilient and the chamber wall that is suitable for pasting duodenum 40 is placed.For some application, tissue stimulation device 26 comprises support, and this support is suitable for expansion and enters its position to promote described electrode.What described support was fit to usually is falsework; For example, it can be soluble or removable.

Fig. 6 B is the sketch map according to the tissue stimulation device 26 of one embodiment of the invention.In this embodiment, electrode 90 comprises one or more spiral electrodes,

electrode

94 and 96 for example, because their non-compression external diameter equals the internal diameter of duodenum 40 at least, so it is positioned at the position of pasting duodenal wall.As selecting or additionally, the fibrosis that low-level back takes place is enough to fixing described electrode usually on its position, even duodenal diameter increases.For some application, use stitching thread, nail, hook or other electrode to implant the known fixture in field electrode 90 or other electrode as herein described are fixed in its position.

In one embodiment,

electrode

94 and 96 is separately addressable, and isolates or make physics separative element (structure shows) by isolator 98 (as shown in the figure) electricity.

Fig. 6 C is the sketch map according to the tissue stimulation device 26 of another embodiment of the present invention.In this embodiment, electrode 90 comprises the one or more ring electrodes 101 that are placed on support 100 outer surfaces.As selecting or additionally, the main body of described support is as electrode.The size of described support is set to be fit to enter patient's duodenum, and provides reliable electrical contact between described ring electrode and described duodenal wall.

Refer again to Fig. 1.Intragastric balloon 24 is suitable for inflation in stomach 38, thereby reduces the stomach volume that can be used for food storage, reduces curee's appetite thus.In one embodiment of the invention, use the technology of describing in the relevant patent of one or more intragastric balloons in background technology above, described or the patent application gazette to implant intragastric balloon 24.For some application, intragastric balloon 24 is suitable for the lasting inflation state that keeps in back in inserting stomach 38.Perhaps, described air bag is suitable for changing shape and/or size after inserting gastric, for example reply for the detection of taking food or stop to take food.In one embodiment, system 10 is included in the endoscopic gastric insert of describing in the above-mentioned United States Patent (USP) 5,868,141, to replace intragastric balloon 24 or to exist simultaneously with intragastric balloon 24.

In one embodiment, general as mentioned described, between two in entering the pancreas electrode 32 of adjacent tissue and/or enter between in the stomach electrode 84 of adjacent tissue two and/or enter drive current between in the intestinal electrode 90 of adjacent tissue two.As selecting or additionally, drive current between an electrode 32 and electrode 84 makes electric current pass general tissue between them.Be re-used as and select or additionally, drive current between an electrode 32 and electrode 90 makes electric current pass general tissue between them.Be re-used as selecting or additionally, drive current between an electrode 84 and electrode 90 makes electric current pass general tissue between them.

As indicated above, use for some, detect curee's feed, and it is replied and drive current enters curee's tissue.As selecting or additionally, the blood-glucose sensing that uses blood-glucose pick off implantation or outside as known in the art being replied and drive current.

Fig. 7 is the sketch map that is used to regulate vagus nerve activity, ENS activity, endocrine pancreas activity, exocrine pancreas activity and/or the active stimulator of gastrointestinal tract according to one embodiment of the invention.Depend on the circumstances, hereinafter the technology of Fig. 7 description can be used with the technical combinations that last Fig. 1 describes.The group 120 of one or more electrodes for example comprises electrode 122,124,126,128,130 and/or 132, and this group 120 is usually placed in the duodenum or with it and is connected.For some application, one or more described electrodes (for example electrode 122) are arranged in the stomach 38.As selecting or additionally, one or more described electrodes (for example electrode 132) are arranged in the more position of far-end, for example at duodenojejunal flexure 102 places.Electrode in electrode group 120 can comprise electrode described with reference to Figure 6, perhaps, as selection, comprises other electrode known in the art that is arranged in a plurality of positions of gastrointestinal tract.

In one embodiment, two or more electrodes in electrode group 120 be connected to control unit 20 (in Fig. 1, be shown as under one's belt, but also can select to be arranged in the duodenum, in the subcutaneous or peritoneum).Control unit 20 drives described electrode and produces the active signal of adjusting pancreas, and this regulating action is (for example insulin, glucagon or the pancreatic juice) finished by the material secretion of regulating pancreas.Perhaps, described Signal Regulation pancreas 30 is another kind of movable.Use for some, based on the described electrode of the choice of location of the electrode in the electrode group 120 in duodenum 40 to regulate the pancreas activity.For example, can between electrode 122 and electrode 132, drive or produce electric current or electric field.Other selects for example to comprise the X labelling shown in the table 1:

Table 1

From/to	122	124	126	128	130	132
From/to	122	124	126	128	130	132	122	-	O	X	X	X	X
124	O	-	O	X	X	X	122	-	O	X	X	X	X
124	O	-	O	X	X	X	126	X	O	-	O	X	X
128	X	X	O	-	O		126	X	O	-	O	X	X
128	X	X	O	-	O		130	X	X	X	O	-	O
132	X	X	X		O	-	130	X	X	X	O	-	O

Inventor's guess, by being produced electric current or electric field between separated two electrodes (straight line that promptly connects described electrode passes pancreas) by the pancreatic tissue of signal portion, this electric current or electric field to the effect of described tissue usually greater than the situation of electric current that produces between electrode or electric field by two close proximity.

For some application, for example, cause satiety, in table 1, be labeled as and produce electric current or electric field between two electrodes of " O ", to regulate near ENS activity or vagus nerve activity in the vagus nerve branch of two electrodes.In one embodiment, apply electric current or electric field with about 3Hz to about 50Hz for example about 3 to about 20Hz.As selecting or additionally, technology of describing in the United States Patent (USP) 5,188,104 of Wernicke etc. and/or signal parameter are used to or are applicable to implement these application of the present invention.

Table 1 is interpreted as being used to regulate the active effective scheme of pancreas, ENS or vagus nerve.Nerve of describing in the list of references that this paper or the application's background technology are partly quoted and pancreas stimulus parameter are in conjunction with other technology described herein, even also still effectively general when incomplete guidance according to table 1 applies.

In one embodiment, whether according to whether needs are regulated neural activity (for example vagus nerve activity or ENS activity) or are needed to regulate the pancreas activity, come the different subclass of active electrode group 120.For example, can use regular time table or determine when and regulate ENS or vagus nerve activity, and when regulate the pancreas activity based on the timetable of sensing patient feed or blood glucose levels.In some patients, regulate pancreas and neural activity simultaneously.Perhaps, in given patient, but stimulator is configured to regulate neural activity does not directly regulate the pancreas activity basically, perhaps regulates the movable neural activity of still directly not regulating basically of pancreas.

Usually, by endoscope's implant electrode group 120.Described electrode can be on the gastrointestinal inwall (as shown in the figure), and is in the gastrointestinal tissue, perhaps outstanding or near duodenum from duodenum.As selecting or additionally, one or more described electrodes (for example electrode 132) pass with contact in duodenum 40 or penetrate pancreas 30.As selecting or additionally, some or all electrodes are implanted by peritoneoscope in the electrode group 120.For example, described electrode can be placed on (as shown in the figure) on the gastrointestinal inwall, outstanding or near duodenum in the gastrointestinal tissue or from duodenum.As selecting or additionally, one or more described electrodes being placed as contact or penetrating pancreas 30 by peritoneoscope.

The visual given patient's of described electrode situation and do long-term or short application use.Use for some, described electrode is connected to the duodenum short-term or contacts the pipe of placing for a long time.In one embodiment, after treatment, remove described pipe, for example after two weeks to one year.In one embodiment, technology described herein combines with the technology that the US patent application publication 2005/0085923 of the Levine that above quotes is described, and described patent application gazette is incorporated this paper by reference into.For example, electrode group 120 can be fixed in sleeve (sleeve) or other device, for example described in the communique of Levine.For the purpose of some embodiments of the present invention, other device described in the communique of described sleeve or Levine can be suitable for reducing the food calorie that enters patient's blood flow and absorb (as described in the communique of Levine).Perhaps, described sleeve also is not suitable for so, but it provides the structural support of counter electrode group 120.

In the embodiment that provides sleeve to be used for described electrode is installed, and in such telescopic embodiment was not provided, electrode group 120 was vertically arranged along duodenum 40 usually.Perhaps, one or more electrodes only are positioned at the single vertical position of gastrointestinal.For some application, a plurality of electrodes or ring electrode place each vertical position.

In one embodiment, the signal configures that applies by electrode group 120 is to regulate the external secretion activity of pancreas, for example by regulating (a) secretion, (b) level of activation, the perhaps decomposition rate of other composition in (c) enzyme or the Digestive system (for example bile or pancreatic juice).(a) and (b) and/or regulation and control (c) are regulated and control the effect of Digestive system in the digestion.For some application, in order to reduce biliary secretion, one or more electrodes are placed in the bile duct, perhaps on the liver or near the liver.As selecting or additionally, one or more electrodes are placed in bile duct or the ductus pancreaticus or near, and it is driven to apply electric field, this electric field decomposes the enzyme in bile or the pancreatic juice, perhaps otherwise makes at least a portion enzyme deactivation.For example, the resonant frequency that described electric field one of can be adjusted in the described enzyme, and in described enzymatic structure, cause the relevant change of heat.Be re-used as and select or additionally, drive in the duodenum or the one or more electrodes that are connected with duodenum to apply the electric field of destructive enzyme catalysis biochemical reaction ability, for example, by increasing the level of vibration of a part of described enzyme, and suppress described enzyme active sites thus and combine with the instantaneous of substrate.

Therefore, use, reduce the effect of Digestive system, reduce health thus caloric absorption from food so that the decomposition efficiency of the food that part digests in the duodenum descends for some.Depend on the circumstances, this embodiment can combine enforcement with other embodiment described herein, with the food that increases part digestion by duodenal speed.

For some application, 120 pairs of duodenums 40 of control unit 20 drive electrode groups apply signal, and this signal configures is for causing satiety by the blood levels that improves GLP-1 and/or cholecystokinin (CCK).

In one embodiment, electrode group 120 is set to cause dividing a word with a hyphen at the end of a line property motion complex wave (MMC) or one or more peristalsis in duodenum, to reduce the residence time of absorbable food calorie in duodenum.By this way, at least a portion can absorb the food calorie enter blood flow by duodenum originally and passes gastrointestinal tract on the contrary and discharge as feces.Depend on the circumstances, the technology that the paper of the Sun that above quotes etc. is described stimulates duodenal embodiment applicable to this.

Usually, induce MMC or peristalsis, for example make to take in and reduce by 25%, 50%, 75% from duodenal calorie according to timetable, or almost 100%.Use for some, reduce a calorie absorption based on the relation between patient's ABW and the patient's desired weight.Perhaps, the timetable of MMC or peristalsis is to make in servicely total duodenum calorie every day to be taken in reduce high value in a given week, in ensuing one all reductions in service than low value.Or, when the patient has big body weight, big intensity ground utilization other technology described herein, and along with the reduction of weight in patients reduces intensity gradually.

In one embodiment, inducing of MMC or peristalsis is periodic, stops desired time (for example about 1～10 minute) to allow detected feed in duodenum, and discharges duodenum in the time when not existing MMC or peristalsis to induce.Perhaps, cause MMC or wriggling at the scheduled time or the planned time (for example about thereafter 5～20 minutes or 20～60 minutes) that detect after beginning to take food.Use for some, except to being present in absorbed calorie in the duodenum indicate, patient's blood glucose levels is replied and begun to induce MMC or wriggling.

In one embodiment, in case detect that pylorus is opened or open in 5,15 or 30 minutes at pylorus, begin to induce MMC or wriggling, pylorus is opened and is allowed gastric content to be discharged in the duodenum.Usually, the opening of pylorus is relatively little (for example several millimeter), and (electromyographic, EMG) analysis detects opening of pylorus to the electromyogram that the physiology electrical activity that senses by 20 pairs of pylorus top electrodes of control unit carries out.Use EMG to analyze and determine that the technology that muscular states changes is known in the art.Perhaps, can use other to be suitable for experiencing that pylorus is opened or closed pick off, acceleration transducer for example, strain gauge, or sonac.

As selecting or additionally,, beginning to induce MMC and wriggling to replying of detected duodenum segmentation movement (segmentation); Inductive MMC of institute or wriggling stop described segmentation movement process usually.For some application, detect segmentation movement to replying along duodenal electrical activity pattern, described electrical activity is measured by electrode 120 and is analyzed by control unit 20.Although the electrical activity relevant with segmentation movement obviously is different from and the relevant electrical activity of wriggling, can provide 6～24 or 24～72 hours alignment epoch in particular patient, to differentiate the ability of segmentation movement and wriggling with optimal control unit 20 to every patient.Perhaps, with in the pre-programmed values introducing control unit 20 relevant with wriggling in the given patient colony with segmentation movement.

In one embodiment, with substituting of determining that segmentation movement takes place or except that it, can use other pick off in the duodenum, for example acceleration transducer, strain gauge or sonac as the sensing electrical activity.Aforesaid, these pick offs have determined when the segmentation movement process begins.No matter use which kind of pick off, in these embodiments to the detection of segmentation movement all as to initial triggering of inducing MMC or wriggling, the increase that makes the food calorie that caused by segmentation movement absorb minimizes.

Perhaps, implement inducing of MMC or wriggling do not replied any incident that senses.For example, can be in one or more time periods of every day (for example 5am-2pm and 4pm-8pm; Perhaps not by the pseudo-random known to the patient in the time period) manually began MMC or wriggling in per 20 minutes, perhaps carried out 5 minutes per 30 minute time period.In one embodiment, when the patient is sleeping, suppress inducing to MMC or wriggling.

In one embodiment, induce wriggling, thereby shrink duodenum muscular tissue, the duodenum content is moved towards far-end by the continuous electrode in the active electrode group 120 successively.In another embodiment, activate a small amount of electrode that is positioned at the relatively little common proximal end region of duodenum, and these electrodes " pace-making (pace) " duodenum, peristalsis induced.Usually, the physiologic rate of pace-making speed ratio peristalsis fast about 5% to about 50%.

For some application, driving in space on the duodenum greater than the electrode of about 5mm (for example greater than about 2mm or greater than about 7mm) between these electrodes, applying electric current, this electric current since electrode spacing thus penetrate duodenal in circular layer and outside duodenal, have substantive excitation in the longitudinal muscle layer.Because longitudinal muscle layer mainly is responsible for wriggling, and circular layer mainly is responsible for the duodenum content is mixed with Digestive system, therefore kind electrode arrange tend to the mixed phase that strengthens the duodenum content than promote more to strengthen wriggling (with respect to electrode gap more near the time result that obtains), suppress thus calorie to absorb.

As selecting or additionally, driving on the duodenum spaced apart by a distance less than the electrode of about 5mm (for example less than about 2mm or less than about 4mm) between these electrodes, applying electric current, this electric current since electrode spacing thus mainly stay duodenal in circular layer and outside the electrode pair far away of being separated by is duodenal longitudinal muscle layer have less effect.Usually, this current arrangements suppresses muscle contraction for using signaling plan known in the art, reduces the mixed-level of duodenum content thus and reduce calorie to absorb.

In one embodiment, the technology of describing in the paper with technology described herein and (2005) such as Liu of above quoting combines, and makes to postpone gastric emptying and therefore increase satiety.

Fig. 8 is the sketch map according to the experimental provision 200 of one embodiment of the invention, and device 200 is used to study in the influence of rat midgut electricity irritation to duodenum nutrition logistics.With each rat of isoflurane anesthesia, (midlaparotomy) opens the abdominal cavity by the center line laparotomy ventrotomy.First sleeve pipe 210 is passed pylorus 214, and to insert in the duodenal proximal part 212 about 1cm dark, and it is connected with the water storage tank 216 that is positioned at rats in vitro.Second sleeve pipe 216 is inserted in the duodenal distal portions 218, and be connected to pipe 220 (EppendorfAG), be used for collecting and measuring (by weighing) duodenal effluent.The about 7cm of length of the duodenum part between two sleeve pipes.The placement that first sleeve pipe 210 in the duodenum passes pylorus 214 makes it possible to measure by duodenal fluid under the influence that is not subjected to any electricity irritation that influences pylorus or gastric emptying.Two hearts (cardiac) pace-making line electrode 222 places apart from about 5～10mm around the duodenum proximal part 212, apart from pylorus 214 about 1cm.

Fig. 9 shows the figure that 5 rats is implemented the experimental result of experiment acquisition according to the described device of Fig. 8 in the use of one embodiment of the invention.This figure has reflected the average result from 5 rats.Starting from about 4 minutes and end in about 30 minutes control period, pumping into first sleeve pipe 210 with constant rate of speed from the water of storage tank 216.As seen in Fig., leaving duodenal standardized fluid through second sleeve pipe 216 is stable in this control period.Starting from about 30 minutes and ending in about 60 minutes stimulation period, water continues to pump into first sleeve pipe 210 with identical constant rate of speed, and 222 pairs of duodenums of drive electrode applied the biphase signal of telecommunication of 500ms in per 4 seconds.Described signal has the phase duration of 7ms, single-phase amplitude 3～5mA (i.e. 6～10mA peak-to-peak value), frequency 30Hz.As seen in FIG., leaving between duodenal fluid ratio control period many about 40% during the electricity irritation.

Figure 10 is the sketch map according to the experimental provision 250 of one embodiment of the invention, and described device is used in the influence of rat research intestinal electricity irritation to gastric emptying.With each rat of isoflurane anesthesia, open the abdominal cavity by the center line laparotomy ventrotomy.First sleeve pipe 260 is inserted in the rat stomach 262, and place apart from pylorus 263 about 5～10mm.Described sleeve pipe is connected with the water storage tank 264 that is positioned at rats in vitro.Second sleeve pipe 266 is inserted in the duodenal remote area 268, and be connected to pipe 270 (EppendorfAG), be used for collecting and measuring (weight) duodenal effluent.Two hearts (cardiac) pace-making line electrode 272 places apart from about 5～10mm around the duodenum proximal part 212, apart from pylorus 263 about 1cm.

Figure 11 shows the figure that 3 rats is implemented the experimental result of experiment acquisition according to the described device of Figure 10 in the use of one embodiment of the invention.This figure has reflected from the average result to 5 repeated experiments of 3 rats.Starting from about 4 minutes and ending in the first about 30 minutes control period and start from about 60 minutes and end in the second about 90 minutes control period, pumping into first sleeve pipe 260 with constant rate of speed from the water of storage tank 264.As seen in FIG., leaving duodenal standardized fluid through second sleeve pipe 266 is stable in first control period, and also is stable usually in second control period.Starting from about 30 minutes and ending in about 60 minutes stimulation period, water continues to pump into first sleeve pipe 260 with identical constant rate of speed, and 272 pairs of duodenums of drive electrode applied the biphase signal of telecommunication of 500ms in per 4 seconds.Described signal has the phase duration of 7ms, amplitude 3～5mA, frequency 30Hz.As seen in FIG., it is few about 85% to leave duodenal fluid ratio first control period in initial 5 minutes of electricity irritation, and keeps inhibitory state, the substantive reduction of described stimulations of this indication gastric emptying in whole stimulation period.The inventor guesses that the gastric emptying of this delay is directly because the pylorus closure that duodenal electricity irritation causes causes.

Figure 12 shows the figure that 5 rats is implemented the experimental result of experiment acquisition according to the described device of Figure 10 in the use of one embodiment of the invention.Use with above-mentioned experiment with reference to Figure 11 in identical device and stimulus parameter implement this experiment.As seen in Fig., the short stimulation period that has 5 minute persistent period separately causes the delay of gastric emptying.In addition, electricity irritation is in case stop the just fast quick-recovery of baseline gastric emptying after between each stimulation period.These results indicate duodenal electrical stimulation to control gastric emptying closely, and it seems that the gastric emptying that reduces be completely reversibility.

In one embodiment of the invention, for example use the techniques described herein to apply the intestinal electricity irritation, to induce the delay gastric emptying of short-term by closed pylorus.Such delay gastric emptying causes satiety usually when having dinner, therefore help the obesity patient to take food less, thereby reduces body weight.

Figure 13 be show according to the research of one embodiment of the invention the electricity irritation of rat midgut to the experiment of nutrient inhalation effects in the figure of experimental result of gained.Described experiment has been carried out three times.Each time, first rat accepted duodenal electrical stimulation, and second rat in contrast.This figure has reflected the average result of three irriate rats and three control rats.With every irriate rat of isoflurane anesthesia, open the abdominal cavity by the center line laparotomy ventrotomy.With two hearts) the pace-making line electrode places apart from about 5～10mm around the duodenum proximal part, apart from the about 1cm of pylorus place.Control rats is implant electrode not.From afterbody blood sampling sample, (Accu-check Active Roche) measures blood glucose levels by glucose meter.

In contrast and irriate rat, during fasting in 60 minutes, blood glucose levels of measurement in per five minutes.In 60 minutes control rats and in 61 minutes the irriate rat, glucose solution (2.5cc, 50%) is injected in the stomach.In the irriate rat, between the stimulation period of beginning in about 60 minutes and end in about 90 minutes, drive the biphase signal of telecommunication that described electrode pair duodenum applied 500ms in per 4 seconds.Described signal has the phase duration of 7ms, amplitude 3～5mA, frequency 30Hz.From about 60 minutes in about 120 minutes time, all rats were measured blood glucose levels in per 2.5 minutes, afterwards to measure than large-spacing.

As seen in FIG., during fasting in initial 60 minutes, glucose level all is stable in contrast and the irriate rat body.In case inject glucose solution to stomach, the blood glucose levels in the control rats begins unexpected rising.The peak value that occurred blood glucose levels after after the injection about 50 minutes slowly drops to control level afterwards.In the rat of irriate, in case inject glucose, blood glucose levels increases comparatively lentamente than control rats, and reaches a lower peak value.The area under curve relevant with total glucose absorption (being every curve and the area between the standardization baseline of determining during the fasting in 60 minutes) comparison in the irriate rat lacks about 66% according to rat.Inventor's guess is as above proved in Fig. 8～12, and the decline of the inductive glucose absorption of this electricity irritation is to be caused by the gastric emptying that postpones and the intestinal stream of increase.As selecting or additionally, electricity irritation causes that by other approach glucose absorption reduces.

The case of most of type ii diabetes and β cell can't reply that peripheral tissues increases insulin requirements and the increase insulin secretion is relevant.The known phase I insulin secretion that reduces is the early sign of β cell dysfunction, and it was exactly tangible before absolute concentration of glucose significantly changes.(impaired glucose tolerance, studies have shown that of people of being treated IGT) has multiple unusual in the qualitative and quantitative measurement of insulin secretion to having glucose intolerance.In these were unusual, the phase I insulin secretion obviously reduced.Because phase I secretion reduces, so the type ii diabetes patient often can't improve the blood insulin level fast, and this is that to help blood-glucose to enter peripheral cells necessary.

In one embodiment of the invention, for example use stimulating technology as herein described to apply the intestinal electricity irritation, to induce the gastric emptying of delay.Delay and/or deceleration that the blood glucose concentration of gained rises, as above described in Figure 13, make the second stage of insulin secretion can reach the blood-glucose balance, or even be issued to the blood-glucose balance in the situation that does not have the phase I insulin secretion.As a result, the great fluctuation process of the post-prandial blood glucose that often runs into of diabetics reduces.For some application, when taking food, the curee applies this stimulation detecting, perhaps after detecting feed, postpone to apply.

In one embodiment of the invention, provide a kind of endoscopic surgery method, wherein with one or more electrodes from gastrointestinal tract by and be connected to vagus nerve.Usually, but optional, described one or more electrodes are assembled into nerve cuff (nerve cuff) (for example, as known in the art) usually.In implementing endoscopic procedure, usually described electrode is passed the gastric otch and place the part of domination pancreas 30 vagal around, posterior vagal trunk for example.Depend on the circumstances, the technology of describing in the paper of the Kalloo that above quotes etc. is connected to vagus nerve applicable to promoting with described electrode.

Use for some, control unit 20 remains on gastric and is wirelessly connected to the electrode on the vagus nerve or is attached thereto by the line that passes gastrointestinal tract wall.Perhaps, the described control unit otch that also passes gastric is implanted in the peritoneum.Described control unit usually drives described electrode and produces the action potential propagated towards pancreas to regulate insulin production.As selecting or additionally, described control unit drives described electrode generation and indicates the natural insulin generation signal of the blood glucose levels that raises towards the action potential of brain propagation with simulation, and causes the natural blood glucose levels of brain startup to reduce machine-processed thus.In any situation, described control unit drives described electrode usually indication is taken food and/or indicate the signal of the blood glucose levels that raises to reply.Usually, cause that by the electric current that applies with about 3 to about 50Hz (for example about 3 to about 20Hz, and perhaps about 10 to about 20Hz) or electric field biography is to pancreas or the action potential that spreads out of from pancreas.As selecting or additionally, the United States Patent (USP) 5 of incorporating (a) Wernicke etc. of this paper by reference into, 188,104, (b) United States Patent (USP) 6,684,105 of Cohen etc., or (c) the PCT patent gazette WO 03/018118 of Cohen etc. or its U.S. Patent application 10/488,334 that enters country's stage are used for or are suitable for implementing these application of the present invention.

Figure 14 is the figure that shows the experimental result that experiment obtained of carrying out according to one embodiment of the invention in rat.Glucose solution perfusion rat original position pancreas with controlled concentration.Based on the sample that takes out from portal vein, per a few minutes kind is measured a blood insulin level.Two conductor loop electrodes are placed around the duodenum, and its position is probably corresponding to the position of electrode among Fig. 7 124 and 130.In experiment shown in Figure 14, do not apply signal and give duodenum by electrode.The 5.6mM of the concentration of glucose from first period changes to the 16.7mM in second period in the primer solution, is returned to 5.6mM again in the 3rd period.Each period continues 20 minutes.The blood insulin level keeps not raising in the first and the 3rd period, and raises in second period and demonstrate the distinctive first and second stage insulin replies.

Figure 15 shows according to the figure of one embodiment of the invention in the experimental result that experiment obtained that different rats are carried out.In three each during successive, continue about 15 minutes separately, be to apply the signal phase after the no signal phase.As seen apply interim insulin level peak value at each signal and be higher than the high insulin levels of measuring in any no signal phase.The signal that applies during described three is as follows:

1-2.3mA during this time, 15Hz

2-5mA during this time, 15Hz is about 5 minutes 8mA afterwards, 15Hz; With

3-8mA during this time, 30Hz.

Figure 16 is the figure that shows the experimental result that experiment obtained of carrying out according to one embodiment of the invention in different rats.In the process of the about 1.3h of Therapy lasted, two contrasts (no signal) period back is that the signal that insulin level significantly rises applies the period.The final contrast period that secondary signal applied after the period shows that insulin level applies period decline with respect to secondary signal.Signal parameter during two signals apply the period is respectively (i) 5～8mA, 30Hz and (ii) 3mA, 30Hz.

In each of these experiments, with (a) apply signal one second and (b) signal stop repetition period of 44 seconds and apply signal.

Figure 17 is the block diagram according to one embodiment of the invention, and it shows the analysis to data shown in Figure 16.As seen, blood insulin is significantly higher than between control period during two signals apply.

In one embodiment of the invention, a kind of method of implant electrode is provided, wherein will comprise that by peritoneoscope or endoscope the lead of two or more independently addressable electrodes is inserted in the tissue of duodenal wall, enter in the described tissue and the end of described lead exposes from described tissue until two electrodes.Usually, but optional, the one or more positions on the stitching lead are so that described lead remains on the position in the tissue.Perhaps, the fibrosis of described lead induces part to cause the fibrosis of described part, makes described lead keep its position thus.In one embodiment, described electrode has that a plurality of it partly or entirely is arranged in the tissue of duodenal wall from its foot that extends out, and keeps the position of described electrode partly or entirely to be arranged in described wall tissue.The lead that extends out from described electrode can pass duodenal lumen or pass outside the duodenum, to arrive control unit 20.

For some application, except that insulin electricity regulation technology described herein or as it, substitute, use implanted pump or outside infusing insulin or another kind of hormone or enzyme, with the level of control blood glucose levels or one or more other blood constituents.

It should be noted that this paper has mainly described in some embodiments of the present invention about obesity and/or treatment of diabetes.Inventor's guess, the embodiment of treatment patient obesity is also treated diabetes directly or indirectly among the present invention.The inventor also guesses, the also treatment of obesity directly or indirectly of embodiment of treatment patient diabetes among the present invention.Scope of the present invention comprises that also using technology described herein treats other disease.

This paper has described some embodiment of the present invention that enter tissue about drive current.Scope of the present invention comprises the electric field of generation with corresponding form influence tissue.For example, can produce 100 or 1000 volts electric field, it has the drive current that the similar or identical time distributes and has milliampere range format to substitute with described electric current usually.In one embodiment, produce such electric field by the electrode that is embedded in the sleeve, described in the communique of the Levine that for example above quotes, the tissue that described electrode does not need to be influenced with them contacts.

It should be noted that and the invention describes some embodiments about the electrode that links to each other with control unit by lead.Scope of the present invention also comprises described electrode is wirelessly connected to described control unit.

It should be noted that and the invention describes some about contacting with muscular tissue or the embodiment of adjacent electrode.Scope of the present invention comprises by the direct muscular irritation of described electrode and/or by the direct or indirect nerve fiber stimulation of described electrode treats disease (for example obesity or diabetes), and described nerve fiber is arranged described muscular tissue (for example enteric nervous system nerve fiber) or enough influenced with the electric field that is produced by described electrode near described electrode.As selecting or additionally, can be according to muscular irritation or neural stimulation scheme, simultaneously or do not drive identical electrode simultaneously.

It should be noted that and above described the multiple technologies that are used for detecting feed or a plurality of digestion phase (pyloric valve activity, wriggling, segmentation movement).Depend on the circumstances, the multiple sensors that comprises electromyography transducer, acceleration transducer, sonac or other pick off known in the art can be used for this purpose, and they can be positioned near esophagus, stomach, cardia or pyloric valve or duodenal inside or its.Therefore, for example, sonac can place near the duodenum, to determine when duodenum is full of.Determine to reply to this, can implement as described above one or more for obesity or treatment of diabetes.

In one embodiment, therapy equipment comprises capsule and pick off.When described pick off is suitable for the sensing capsule near described pick off.Described pick off is implanted near the patient's gastrointestinal tract position.The patient swallows described capsule in ante cibum or meal, the startup of passing through and be used to cause obesity or treating diabetes scheme of described sensor in to capsule from the very short distance of the described pick off of distance.For some application, use device described herein to implement therapeutic scheme.In one embodiment, described capsule comprises magnet, and described pick off comprises magnetic switch, and it is owing to the approaching of magnet opens or closes.Perhaps, described capsule comprises coil or other passive element, and described pick off uses the approaching of known technology sensing coil of the present invention or other passive element.Again or, described capsule comprises active component, it transmits the low-power signal by pick off detected.

Be connected to the duodenal application of near-end for described pick off, described capsular diameter is usually less than 1 or 2 millimeter, is beneficial to its commitment in digestion and passes pylorus and be discharged from.The patient uses for convenience, and described capsule can be by rapidly-soluble outer coatings parcel, and its overall diameter is similar to the medicinal pill of standard.Be connected to the application of stomach for described pick off, described capsule diameter can be greater than 2 millimeters.

In one embodiment of the invention, system described herein comprises implanted or outside blood-glucose pick off, and the blood glucose levels of sensing is replied to apply or to regulate stimulation.For some application, only when surpassing certain threshold level, blood glucose levels applies stimulation, for example be considered to be higher than the level of normal glucose level.Perhaps, stimulus intensity increases with blood glucose levels.In this embodiment, described system applies closed feedback loop.

In one embodiment of the invention, technology described herein is used to regulate blood cholesterol levels, reduces LDL usually and/or increases HDL.Use for some, the method for regulating at least a blood cholesterol levels composition level comprises the curee that determines to suffer from dyslipidemia and determines to reply and use one or more technology described herein to regulate described level described.

It will be understood by those skilled in the art that the invention is not restricted to above the concrete content that shows and describe.On the contrary, scope of the present invention comprises a plurality of combination of features mentioned above and time combination, and unexistent its variation and modification in the prior art, and this can be obtained when reading above description by those skilled in the art.

Claims

1. device comprises:

One or more electrodes, it is suitable for inserting in curee's the ductus pancreaticus of pancreas; With

Control unit, it is suitable for driving described electrode so that pancreas is applied electric current, and the configuration electric current is to regulate the insulin production of pancreatic beta cell.

2. according to the device of claim 1, wherein said electrode comprises ring electrode.

3. according to the device of claim 2, wherein each ring electrode comprises a plurality of conductive segment of arranging around described ring electrode.

4. according to the device of claim 2, comprise support, described support is suitable for expanding in ductus pancreaticus, opens described one or more electrode thus in described ductus pancreaticus.

5. according to the device of claim 1, wherein said one or more electrodes are suitable for being inserted in the main pancreatic duct of pancreas.

6. according to the device of claim 1, wherein said electrode is configured to allow pancreatic juice to pass through described electrode.

7. according to the device of claim 1, wherein said one or more electrodes comprise a plurality of electrodes, and wherein said control unit is suitable for only driving a part of described electrode to apply electric current preset time arbitrarily.

8. according to the device of claim 7, comprise the lead group that connects described control unit and described a plurality of electrodes, wherein said control unit is suitable for transmitting multiple signals by described lead group and gives described a plurality of electrodes, in wherein said a plurality of electrode each comprises corresponding microchip, and described microchip is suitable for driving described electrode in definite signal addressing during to described microchip and applies electric current.

9. device comprises:

Control unit, it is suitable for driving described electrode pair duodenal lumen wall and applies electric current, and the configuration electric current is selected from position in curee's vagus nerve and curee's enteric nervous system (ENS) tissue with stimulation.

10. according to the device of claim 9, wherein said position comprises curee's vagus nerve, and wherein said control unit is suitable for disposing electric current to stimulate described vagus nerve.

11. according to the device of claim 9, described position comprises curee's ENS tissue, and wherein said control unit is suitable for disposing electric current to stimulate described ENS tissue.

12. according to the device of claim 9, comprise the feed pick off, and wherein said control unit is suitable for applying electric current to replying to drive described electrode from the signal of the indication curee of described feed pick off feed.

13. device according to claim 9, wherein said control unit is suitable for (a) according to current parameters configuration set electric current, this parameter group comprise the pulsewidth of current impulse and frequency that described pulse applies and (b) select described parameter group so that its to strengthen curee's pylorus closed and reduce glucose level in curee's blood.

14. device according to claim 9, wherein said control unit is suitable for (a) according to current parameters configuration set electric current, this parameter group comprise the pulsewidth of current impulse and frequency that described pulse applies and (b) select described parameter group so that its to strengthen curee's pylorus closed and improve insulin level in curee's blood.

15. device according to claim 9, in wherein said one or more electrode two are spaced a certain distance when contacting with described wall, described distance is greater than any other two spacings when contacting with described wall in described one or more electrodes, and wherein said distance is less than 3cm.

16. according to each device in the claim 9～15, described control unit is suitable for (a) configuration electric current and is 0.1Hz at least to comprise a plurality of pulses and (b) to set the frequency that applies pulse.

17. according to the device of claim 16, it is two-phase pulse that wherein said control unit is adapted for application to fewer pulses.

18. according to the device of claim 16, it is monophasic pulses if that wherein said control unit is adapted for application to fewer pulses.

19. according to the device of claim 16, wherein said control unit is suitable for setpoint frequency and is 1Hz at least.

20. according to the device of claim 19, wherein said control unit is suitable for setpoint frequency and is 3Hz at least.

21. according to each device in the claim 9～15, wherein said control unit is suitable for disposing electric current comprising a plurality of pulses, and wherein each at least two continuous impulses has pulsewidth less than 75ms respectively.

22. according to the device of claim 21, it is less than 30ms that wherein said control unit is suitable for disposing described pulsewidth.

23. according to the device of claim 22, it is less than 15ms that wherein said control unit is suitable for disposing described pulsewidth.

24. according to each device in the claim 9～15, wherein said control unit is suitable for (a) configuration electric current to comprise a plurality of pulses, (b) frequency that applies of the described pulse of setting is required frequency values, (c) pulsewidth of at least two continuous impulses of setting is less than the threshold value pulsewidth, and the ratio of wherein said threshold value pulsewidth and described required frequency values is less than 1000ms/Hz.

25. according to the device of claim 24, wherein said ratio is less than 100ms/Hz.

26. according to the device of claim 25, wherein said ratio is less than 10ms/Hz.

27. according to each device in the claim 9～15, wherein said control unit is suitable for disposing electric current to make and is enough to cause curee's pylorus closure.

28. according to the device of claim 27, wherein said control unit is suitable for disposing electric current to make and to be enough to cause the pylorus closure by the neural mediation path, but is not enough to cause the pylorus closure by the stimulus of direct current to pylorus muscular tissue.

29. according to the device of claim 27, wherein said one or more electrodes comprise at least two electrodes that are suitable for being placed on apart from pylorus 2～5cm place.

30. according to the device of claim 27, wherein said one or more electrodes comprise at least two electrodes that are suitable for being placed on apart from pylorus 1～2cm place.

31. according to the device of claim 27, all electrodes in wherein said one or more electrodes are suitable for being placed on the place apart from pylorus 2～5cm.

32. according to the device of claim 27, all electrodes in wherein said one or more electrodes are suitable for being placed on the place apart from pylorus 1～2cm.

33. according to each device in the claim 9～15, wherein said control unit is suitable for being placed in curee's the gastrointestinal tract.

34. according to the device of claim 33, wherein said control unit is suitable for being placed in curee's the stomach.

35. according to the device of claim 33, wherein said control unit is suitable for implanting position beyond the stomach among the curee, and with described electrode wireless connections.

36. according to the device of claim 33, wherein said control unit is suitable for implanting position beyond the stomach among the curee, and wherein said device comprises the lead that is configured to connect described control unit and described electrode.

37. according to the device of claim 33, wherein said control unit is suitable for being placed on the external of curee, and with described electrode wireless connections.

38. a device comprises:

Stimulator, it is suitable for stimulating the position in the vagus nerve that is selected from the curee and curee's enteric nervous system (ENS) tissue, and it is suitable for being placed in curee's the gastrointestinal tract;

One or more electrodes, it is suitable for being implanted to duodenal each position of curee; With

Control unit, it is suitable for receiving described feed signal, and described signal replied to drive described stimulator curee's selected position is applied first electric current, drive described one or more electrode and apply of the activity of second electric current with the pancreatic beta cell of regulating the curee.

39. according to the device of claim 38, wherein said control unit is suitable for setting described first electric current makes its frequency equal at least three times of described second power frequency.

40. according to each device in the claim 38～39, wherein said device comprises intragastric balloon, described intragastric balloon is suitable for being placed on curee's gastric.

41. according to the device of claim 40, wherein said intragastric balloon comprises described feed pick off.

42. a method comprises:

One or more electrodes are inserted in curee's the ductus pancreaticus of pancreas;

Drive described electrode so that pancreas is applied electric current; With

43., wherein insert and insert described one or more electrodes in the main pancreatic duct that is included in pancreas according to the method for claim 42.

44., wherein insert described electrode and comprise that the mouth that stands therapist inserts described electrode by endoscope according to the method for claim 42.

45. a method comprises:

One or more screw electrodes are inserted in curee's the duodenum;

Expand described one or more electrode, electrically contact between described one or more electrodes and duodenal wall, to set up;

Drive current is by described one or more electrodes; With

Dispose described electric current to induce duodenal contraction.

46. a method comprises:

Drive current is by described one or more electrodes; With

Dispose described electric current to induce duodenal contraction.

47. a method comprises:

Drive current enters curee's duodenum position; With

48. a method comprises:

Drive current enters curee's duodenum position; With

49. a method comprises:

Drive current enters curee's duodenum position; With

50. a method comprises:

First and second electrodes are placed on curee's duodenal corresponding first and second positions; With

Activate described electrode to increase curee's blood insulin level.

51., wherein place the straight line that comprises the described electrode of the feasible connection of placing said electrodes and pass curee's pancreas according to the method for claim 50.

52. according to the method for claim 50, it comprises the signal of sensing curee feed, and described signal is replied to activate described electrode.

53., wherein place and comprise described first and second electrodes are placed as at least at a distance of 5cm according to each method in the claim 50～52.

54., wherein activate described electrode and comprise that the amplitude of applying is that 2mA to 8mA, frequency are the signal of 3Hz to 20Hz according to the method for claim 53.

55., wherein apply described signal and comprise that (a) applies described signal and be less than 5 seconds, (b) stop described signal greater than 10 seconds, and (c) circulate at (a) with (b) according to the method for claim 54.

56. according to each method in the claim 50～52, described method comprises that drive current enters duodenum, described current arrangements is the satiety that causes the curee.

57., wherein drive described electric current and comprise the delay gastric emptying according to the method for claim 56.

58., wherein drive described electric current and comprise that the described electric current of configuration is to induce the vagal signal that imports into that reduces curee's feed according to the method for claim 56.

59. according to each method in the claim 50～52, comprise that drive current enters duodenum, described current arrangements is for causing duodenal contraction.

60., wherein drive described electric current and comprise that the described electric current of configuration is to cause wriggling according to the method for claim 59.

61., wherein drive the speed that described electric current comprises increases wriggling according to the method for claim 59.

62., wherein drive described electric current and comprise that the described electric current of configuration is to induce at least one dividing a word with a hyphen at the end of a line property motion complex wave (MMC) according to the method for claim 59.

63. according to the method for claim 62, comprise, make the time that the time of origin of described MMC takes place early than natural MMC to driving described electric current regularly.

64. a method comprises:

First and second electrodes are placed on curee's the corresponding first and second abdominal part positions; With

Activate described electrode to suppress the effect level of Digestive system.

65. according to the method for claim 64, wherein said Digestive system comprises bile, and wherein activation comprises that the described electrode of activation is to suppress biliary effect level.

66. according to each method in the claim 64～65, wherein said Digestive system comprises pancreatic juice, wherein activates to comprise and activate described electrode to suppress the effect level of pancreatic juice.

67. method according to claim 66, the wherein said first and second abdominal part positions comprise the first and second duodenum positions, wherein placement comprises placing said electrodes at the described first and second duodenum positions, makes the straight line that connects described electrode pass curee's pancreas.

68. a method comprises:

At drive current between first and second electrodes of 5mm at least at the interval at curee's duodenal corresponding first and second positions; With

69. a method comprises:

At drive current between the interval at curee's duodenal corresponding first and second positions is less than first and second electrodes of 5mm; With

Dispose described electric current to stimulate the tissue in the duodenum circular muscle layer.

70. a device comprises:

Be suitable for the capsule swallowed by the curee;

Pick off, it is suitable for being implanted in curee's body, detecting the nearness of described capsule and described pick off, and produces corresponding sensor-signal; With

71. according to the device of claim 70, wherein said capsule comprises magnet.

72. according to the device of claim 70, wherein said capsule diameter is less than 2mm.

73. according to the device of claim 70, wherein said treatment unit is suitable for applying the treatment that causes curee's satiety.

74. according to each device in the claim 70～73, wherein said treatment unit is suitable for applying the treatment that improves blood insulin.

75. a method comprises:

Duodenal lumen wall to the curee applies electric current; With

76. according to the method for claim 75, wherein said position comprises curee's vagus nerve, and wherein configuration comprises that the described electric current of configuration is to stimulate described vagus nerve.

77. according to the method for claim 75, wherein said position comprises curee's ENS tissue, wherein configuration comprises that the described electric current of configuration is to stimulate described ENS tissue.

78. according to the method for claim 75, it comprises sensing curee's feed, wherein applies described electric current and comprises and the feed of sensing is replied and apply described electric current.

79., wherein dispose described electric current and comprise according to the method for claim 75:

According to the described electric current of current parameters configuration set, described parameter group comprises the pulsewidth of current impulse and applies the frequency of pulse; With

Select the feasible curee's of enhancing of described parameter group pylorus closure and reduce curee's blood glucose levels.

80., wherein dispose described electric current and comprise according to the method for claim 75:

According to current parameters configuration set electric current, described parameter group comprises the pulsewidth of current impulse and applies the frequency of pulse; With

It is closed and improve insulin level in curee's the blood to select described parameter group make to strengthen curee's pylorus.

81., wherein apply described electric current and comprise according to the method for claim 75:

Placing a plurality of electrodes contacts with duodenal wall, make that two in described a plurality of electrodes are spaced a certain distance when contacting with described wall, described distance is greater than the spacing between any other two in described a plurality of electrodes, and wherein said distance is less than 3cm; With

Drive described a plurality of electrode to apply described electric current.

82. according to each method in the claim 75～81, wherein configuration comprises that the configuration electric current is 0.1Hz at least to comprise a plurality of pulses and to set the frequency that applies pulse.

83. 2 method wherein applies described electric current and comprises that applying at least some pulses is two-phase pulse according to Claim 8.

84. 2 method wherein applies described electric current and comprises that applying at least some pulses is monophasic pulses if according to Claim 8.

85. 2 method is according to Claim 8 wherein set described frequency and is comprised that setpoint frequency is 1Hz at least.

86. 5 method is according to Claim 8 wherein set described frequency and is comprised that setpoint frequency is 3Hz at least.

87. according to each method in the claim 75～81, wherein configuration comprises the configuration electric current to comprise a plurality of pulses, wherein each of at least two continuous impulses has the corresponding pulsewidth less than 75ms.

88. 7 method according to Claim 8, wherein configuration comprises that the configuration pulsewidth is for less than 30ms.

89. 8 method according to Claim 8, wherein configuration comprises that the configuration pulsewidth is for less than 15ms.

90. according to each method in the claim 75～81, wherein dispose described electric current and comprise that (a) configuration electric current is to comprise a plurality of pulses, (b) setting the frequency that applies pulse is required frequency values, (c) pulsewidth of at least two continuous impulses of setting is less than the threshold value pulsewidth, and the ratio of wherein said threshold value pulsewidth and described required frequency values is less than 1000ms/Hz.

91. according to the method for claim 90, wherein said ratio is less than 100ms/Hz.

92. according to the method for claim 91, wherein said ratio is less than 10ms/Hz.

93., wherein apply described electric current and comprise that the configuration electric current makes and be enough to cause curee's pylorus closure according to each method in the claim 75～81.

94., wherein dispose described electric current and comprise that the configuration electric current makes and be enough to cause the pylorus closure, but be not enough to cause the pylorus closure by stimulus of direct current to pylorus muscular tissue by the neural mediation path according to the method for claim 93.

95., wherein apply described electric current and comprise according to the method for claim 93:

Place a plurality of electrodes and contact, make in described a plurality of electrode at least two apart from pylorus 2～5cm with the duodenal lumen wall; With

Drive described electrode to apply described electric current.

96., wherein apply described electric current and comprise according to the method for claim 93:

Place a plurality of electrodes and contact, make in described a plurality of electrode at least two apart from pylorus 1～2cm with the duodenal lumen wall; With

Drive described electrode to apply described electric current.

97., wherein apply described electric current and comprise according to the method for claim 93:

Place one or more electrodes and contact, make all electrode distance pylorus 2～5cm in described one or more electrode with the duodenal lumen wall; With

Drive described electrode to apply described electric current.

98., wherein apply described electric current and comprise according to the method for claim 93:

Place one or more electrodes and contact, make all electrode distance pylorus 1～2cm in described one or more electrode with the duodenal lumen wall; With

Drive described electrode to apply described electric current.

99. according to each method in the claim 75～81, wherein apply in the gastrointestinal tract that described electric current is included in the curee and place control unit, described control unit is configured to apply described electric current.

100. according to the method for claim 99, wherein apply in the stomach that described electric current is included in the curee and place control unit, described control unit is configured to apply described electric current.

101. a method comprises:

In curee's body, produce the signal of indication curee feed;

Place stimulator in curee's gastrointestinal tract, described stimulator is suitable for stimulating the position in the vagus nerve that is selected from the curee and curee's enteric nervous system (ENS) tissue;

Receive described feed signal, and described signal replied to drive stimulator curee's selected position is applied first electric current and drives described one or more electrode apply the activity that second electric current is regulated curee's pancreatic beta cell.

102., wherein drive described stimulator and described one or more electrode and comprise that described first electric current is set to frequency and equals at least three times of described second power frequency according to the method for claim 101.

103. according to each method in the claim 101～102, its gastric that is included in the curee is placed intragastric balloon.

104., wherein produce described signal and be included in described intragastric balloon place and produce described signal according to the method for claim 103.