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WO2005087310A2 - Procedes et appareils gastro-intestinaux destines a etre utilises dans le traitement des troubles et le controle de glycemie - Google Patents

Procedes et appareils gastro-intestinaux destines a etre utilises dans le traitement des troubles et le controle de glycemie Download PDF

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Publication number
WO2005087310A2
WO2005087310A2 PCT/IL2005/000316 IL2005000316W WO2005087310A2 WO 2005087310 A2 WO2005087310 A2 WO 2005087310A2 IL 2005000316 W IL2005000316 W IL 2005000316W WO 2005087310 A2 WO2005087310 A2 WO 2005087310A2
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WO
WIPO (PCT)
Prior art keywords
electrodes
pancreas
signal
pulse
glucose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IL2005/000316
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English (en)
Other versions
WO2005087310A3 (fr
Inventor
Tami Harel
Yuval Mika
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Metacure NV
Original Assignee
Metacure NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/804,560 external-priority patent/US20040249421A1/en
Priority claimed from PCT/IL2004/000551 external-priority patent/WO2004112883A2/fr
Priority claimed from PCT/IL2004/000550 external-priority patent/WO2004112563A2/fr
Priority claimed from PCT/IL2004/000664 external-priority patent/WO2005007232A2/fr
Priority to EP05718889A priority Critical patent/EP1735047A4/fr
Priority to US10/599,015 priority patent/US8666495B2/en
Application filed by Metacure NV filed Critical Metacure NV
Publication of WO2005087310A2 publication Critical patent/WO2005087310A2/fr
Publication of WO2005087310A3 publication Critical patent/WO2005087310A3/fr
Priority to US11/792,811 priority patent/US9931503B2/en
Priority to CA002594673A priority patent/CA2594673A1/fr
Priority to PCT/US2005/044557 priority patent/WO2006073671A1/fr
Priority to EP05853465.2A priority patent/EP1827571B1/fr
Priority to EP06711186.4A priority patent/EP1868679B1/fr
Priority to PCT/IL2006/000204 priority patent/WO2006087717A2/fr
Priority to US11/884,389 priority patent/US9101765B2/en
Priority to PCT/IL2006/000345 priority patent/WO2006097934A2/fr
Priority to US11/886,154 priority patent/US8244371B2/en
Anticipated expiration legal-status Critical
Priority to US14/821,848 priority patent/US9821158B2/en
Priority to US15/942,637 priority patent/US11439815B2/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36007—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of urogenital or gastrointestinal organs, e.g. for incontinence control
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4222—Evaluating particular parts, e.g. particular organs
    • A61B5/425—Evaluating particular parts, e.g. particular organs pancreas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement

Definitions

  • PCT/IL03/00736, which was filed on September 4, 2003 and which is a continuation-in-part of U.S. Application No. 10/237,263, filed on September 5, 2002, which is a continuation-in- part of PCT Application PCT/IL00/00566, filed on September 13, 2000, now published as WO 01/66183, which designates the US, (b) US Application No. 09/914,889, filed on January 24, 2002, which is the US national phase application of PCT Application PCT/JJL00/00132, filed on March 5, 2000, which designates the US and which claims the benefit under 35 U.S.C.
  • the present invention is related to controlling physiology of a subject, for example, using electricity.
  • the physiology may be controlled, for example, in order to regulate blood serum glucose levels and/or to treat obesity.
  • BACKGROUND OF THE INVENTION Control of insulin secretion is important, as there are many living diabetes patients whose pancreas is not operating correctly. In some types of diabetes, the total level of insulin is reduced below that required to maintain normal blood glucose levels. In others, the required insulin is generated, but only at an unacceptable delay after the increase in blood glucose levels. In others, the body is, for some reason, resistant to the effects of insulin. Although continuous control (e.g., avoiding dangerous spikes and dips) of blood glucose level is desirable, it cannot currently be achieved in some patients.
  • the insulin secretion process operates as follows: glucose levels in the blood are coupled to depolarization rates of beta islet cells in the Pancreas. It is postulated that when there is a higher glucose level, a higher ratio of ATP/ADP is available in the beta cell and this closes potassium channels, causing a depolarization of the beta cell. When a beta cell depolarizes, the level of calcium in the cell goes up and this elevated calcium level causes the conversion of pro-insulm to insulin and causes secretion of insulin from the cell
  • the beta cells are arranged in islets, within a reasonable range of blood glucose levels, an action potential is propagated in the islet.
  • the elect ⁇ cal activity of a beta cell m an islet is in the form of bursts, each burst comprises a large number of small action potentials.
  • PCT Patent Publication WO 99/03533 to Ben-Haim et al. entitled, "Smooth muscle controller,” and US Patent Application 09/481,253 in the national phase thereof, both of which are incorporated herein by reference, desc ⁇ be apparatus and methods for applying signals to smooth muscle so as to modify the behavior thereof.
  • apparatus for controlling the stomach is desc ⁇ bed in which a controller applies an elect ⁇ cal field to electrodes on the stomach wall so as to modify the reaction of muscle tissue therein to an activation signal, while not generating a propagating action potential in the tissue
  • a controller applies an elect ⁇ cal field to electrodes on the stomach wall so as to modify the reaction of muscle tissue therein to an activation signal, while not generating a propagating action potential in the tissue
  • ETC Excitable-Tissue Control
  • PCT Publication WO 99/03533 the disclosure of which is incorporated herem by reference, it was suggested to reduce the output of a pancreas using a non-excitatory elect ⁇ c field.
  • US Patent Application Publication 2005/0033375 which is incorporated herein by reference, desc ⁇ bes a gastroelect ⁇ c stimulator that includes a neurostimulator for producing a stimulation signal, at least one elect ⁇ cal lead, and at least two elect ⁇ cal contacts.
  • the elect ⁇ cal lead has a proximal end and a distal end, the proximal end bemg connected to the neurostimulator and the distal end positionable in a lead position within the patient's abdomen.
  • the electrodes are earned near the elect ⁇ cal lead distal end.
  • the electrodes are electrically connected through the elect ⁇ cal lead to the neurostimulator to receive the stimulation signal and convey this signal to an electrode position within the patient's digestive system.
  • Somatostatm reduces the secretion of both msulm and glucagon.
  • This publication also desc ⁇ bes an experiment in which sympathetic nervous stimulation caused an increase m Somatostatm secretion It is suggested in this paper that normal glucose levels in a healthy human may be maintained with the aid of glucagon secretion.
  • An aspect of some embodiments of the invention relates to reducing glucose levels while not appreciably increasing insulin levels, at least not for more than small amounts and/or short pe ⁇ ods of time and/or compared to a regular response in a same person.
  • an elect ⁇ c field is applied to a pancreas in a manner which reduces blood glucose levels and does not significantly raise insulin levels or even reduces such insulin levels
  • reducmg glucose levels prevents insulin levels from rising This may have a beneficial effect on the pancreas by preventing exhaustion
  • insulin is not raised by more than 20%, 15%, 10%, 5% or less, or even reduced, by 5%, 10% or more.
  • a duration of insulin raise may be, for example, limited to less than 10 minutes, less than 5 minutes or less than 1 minute.
  • glucose reduction and, in some embodiments, insulin reduction is achieved by applying an electrical field to the pancreas.
  • the electrical field reduces glucagon secretion, directly or indirectly.
  • the electric field causes the release of other non-insulin factors which reduce blood glucose levels in the blood and/or glucose uptake.
  • an electric field or other control means is used to delay gastric emptying, thereby reducing availability of glucose.
  • glucose levels are also reduced by the application of a stimulation to the same or a different part of the pancreas, wl ⁇ ch stimulation causes a reduction in glucose levels via insulin secretion.
  • An aspect of some embodiments of the invention relates to electrically stimulating or otherwise applying a field to a pancreas, with electrodes located away from the pancreas. In an exemplary embodiment of the invention, the electrodes are placed near the pancreas such that an electric field applied by the electrodes has a significant value at or about the pancreas.
  • the therapy for example the application of an electric field to the pancreas, is timed to reduce glucagon levels quickly so that digesting food will not cause a large glucose peak.
  • the pancreas is controlled to give a fast bolus of insulin.
  • delaying of gastric emptying reduces and/or delays a glucose peak. It is believed that for some patient suitable reduction or delay of such a peak will reduce peak insulin output and possibly prevent overshooting by the pancreas. Eating may be detected, for example, automatically, for example by a gastric activity sensor.
  • a pharmaceutical pump provides pharmaceuticals, for example to slow gastric emptying.
  • a glucose peak due to eating is delayed by at least 5, 10, 15 or 20 minutes.
  • such a peak has its amplitude reduced (relative to a baseline value) by at least 10%, 20%, 30%, 50%, 60% or more.
  • such a peak has its duration shortened (duration where its value is more than 40% over the baseline) by at least 10%, 20%), 30%>, 50%, 60% or more.
  • an integral over the increased glucose levels due to eating is reduced by at least 10%, 20%, 30%, 50%, 60% or more.
  • an insulin peak due to eating is delayed by at least 5, 10, 15 or 20 minutes.
  • such a peak has its amplitude reduced (relative to a baseline value) by at least 10%, 20%, 30%, 50%), 60% or more.
  • such a peak has its duration shortened (duration where its value is more than 40% over the baseline) by at least 10%, 20%, 30%), 50%, 60% or more.
  • an integral over the increased insulin le ⁇ 'els due to eating is reduced by at least 10%, 20%o, 30%, 50%>, 60%) or more.
  • these differences are measured over a time period corresponding to the body response to an event of ingesting glucose, for example, about 60 minutes.
  • these reductions or lack of significant increase is relative to an expected increase if no control were exerted (e.g., after eating). In some embodiments and/or cases, the lack of increase is relative to a base-line condition.
  • blood insulin values are maintained at a relatively low value, for example, under 30, 20, 15 or 10 micro-units per ml.
  • An aspect of some embodiments of the invention relates to a method of glucose control by electrically stimulating a pancreas with a built-in safety effect. In an exemplary embodiment of the invention, the applied field does not substantially reduce glucose levels once baseline glucose levels are achieved.
  • glucose level reduction below baseline is less than 30%, 20%o, 10% or less.
  • glucose levels at which further substantial reduction is not provided is less than 40%, 30%, 20%) or less over a baseline glucose level.
  • An aspect of some embodiments of the invention relates to selective and/or integrative control of the various hormones generated by the pancreas and which affect blood glucose level, to provide a control of blood glucose levels.
  • control is not merely of the blood glucose levels but also of the hormone levels required to provide a satisfactory physiological effect, rather than merely prevention of symptomatic effects of incorrect blood glucose levels.
  • control may be effected, for example to achieved desirable short term effects alternatively or additionally to achieving desirable long term effects.
  • This type of positive control of two parameters should be distinguished from merely controlling blood glucose by varying the insulin level. Such mere controlling may not allow both desired blood glucose levels and insulin levels to be achieved, possibly leading to over-exertion of the pancreas.
  • the pulse may be synchronized to the cycle of changes in msulm level in the blood (typically a 12 rrunute cycle m healthy humans)
  • the pulse may be unsynchromzed to local or global pancreatic elect ⁇ cal activity
  • the applied pulse may cause synchronization of a plurality of islets in the pancreas, for example by initiating a burst.
  • a two part pulse may be provided, one part to synchronize and one part to provide the non-excitatory activity of the pulse
  • the term "pulse" is used, it is noted that the applied electric field may have a duration longer than an action potential or even longer than a burst.
  • This reduction in calcium levels may be performed to reduce the responsiveness of the pancreas to glucose levels in the blood. Alternatively or additionally, this reduction is used to offset negative side effects of drugs or other treatment methods and/or to enforce a rest of at least a part of the pancreas. Alternatively or additionally, this reduction may be offset by increasing the effectiveness of insulin secretion.
  • An aspect of some exemplary embodiments of the invention relates to pacing at least a portion of the pancreas and, at a delay after the pacing, applying a non- excitatory pulse.
  • the non-excitatory pulse may be provided to enhance or suppress insulin secretion or for other reasons.
  • the pacing pulse provides a synclironization so that the non-excitatory pulse reaches a plurality of cells at substantially a same phase of their action potentials.
  • a further pulse, stimulating or non-excitatory may then be provided based on the expected effect of the non-excitatory pulse on the action potential.
  • the stimulation pulse that is used to affect the insulin production is also used to cause pacing.
  • the pulse resets the electrical activity in the pancreas, possibly in a manner similar to that of a defibrillation pulse applied to the heart.
  • the stimulation pulse may cause an immediate burst to occur, causing later pulses to be automatically delayed relative to that pulse.
  • a stimulation pulse is used which causes a short delay of a few seconds after the pulse before a new, (at least nominally) normal length burst is generated.
  • An aspect of some exemplary embodiments of the invention relates to simultaneously providing pharmaceuticals and electrical control of a pancreas.
  • the electrical control counteracts negative effects of the pharmaceuticals.
  • the pharmaceutical counteracts negative effects of the electrical control.
  • the electrical control and the pharmaceutical complement each other, for example, the pharmaceutical affecting the insulin production mechanisms and the electrical control affecting the insulin secretion mechanism.
  • the electrical control and/or the pharmaceutical control may be used to control various facets of the endocrinic pancreatic activity, including one or more of: glucose level sensing, insulm production, insulin secretion, cellular regeneration, healing and tiaining mechanisms and/or action potential propagation.
  • electrical and/or pharmaceutical mechanisms are used to replace or support pancreatic mechanisms that do not work well, for example, to replace feedback mechanisms that turn off insulin production when a desired blood glucose level is achieved.
  • the pharmaceuticals that interact with the pancreatic controller may be provided for affecting the pancreas. Alternatively, they may be for other parts of the body, for example for the nervous system or the cardiovascular system.
  • An aspect of some exemplary embodiments of the invention relates to activating pancreatic cells in various activation profiles, for example to achieve training, regeneration, healing and/or optimal utilization.
  • such activating can include one or more of excitatory pulses, non-excitatory pulses and application of pharmaceuticals and/or glucose. It is expected that diseased cells cannot cope with normal loads and will degenerate if such loads are applied. However, by providing sub-normal loads, these cells can continue working and possibly heal after a while using self healing mechanisms. In particular, it is expected that certain diseased cells, when stimulated at at least a minimal activation level, will heal, rather than degenerate.
  • the approp ⁇ ate activation profiles may need to be determined on a patient by patient basis Possibly, different activation profiles are tested on one part of the pancreas, and if they work as desired, are applied to other parts of the pancreas These other parts of the pancreas may be suppressed durmg the testmg, to prev ent over stressing thereof . Alternatively, they may be maintained at what is deemed to be a "safe" lev el of activity, for example by elect ⁇ cal control or by pharmaceutical or msulm control
  • An aspect of some exemplary embodiments of the mvention relates to elect ⁇ cally affecting and preferably controlling msulm generation, alternatively or additionally to affecting msulin secretion
  • msulin production is enhanced by "milking" insulin out of beta cells so that their supplies of insulm are always under par Alternatively or additionally, by under- milking such cells (e g , prevention of secretion), msulm production is decreased
  • An aspect of some exemplary embodiments of the invention relates to indirectly affecting the pancreatic activity by changing pancreatic response parameters, such as response time to increases in glucose level and response gain to increases in glucose level.
  • pancreatic response parameters such as response time to increases in glucose level and response gain to increases in glucose level.
  • a non-responsive pancreas can be sensitized, so that even small changes in glucose level will cause an outflow of insulin.
  • a weak or over-responsive pancreas can be desensitized, so that it isn't required to generate (large amounts of) insulin for every small fluctuation in blood glucose level. It is noted that the two treatments can be simultaneously applied to different parts of a single pancreas.
  • An aspect of some exemplary embodiments of the invention relates to synchronizing the activities of different parts of the pancreas.
  • Such synchronization may take the form of all the different parts being activated together.
  • the synchronization comprises activating one part (or allowing it be become active) while suppressing other parts of the pancreas (or allowing them to remain inactive).
  • the synchronization is applied to enforce rest on different parts of the pancreas.
  • the synchronization is provided to selectively activate fast-responding parts of the pancreas or slow responding parts of the pancreas.
  • synchronization between islets or within islets is enhanced by providing pharmaceuticals, for example Connexin, to reduce gap resistance.
  • Such pharmaceuticals may be administered, for example, orally, systemically via the blood locally or locally, for example via the bile duct.
  • such pharmaceuticals are provided by genetically altering the cells in the pancreas, for example using genetic engineering methods.
  • An aspect of some exemplary embodiments of the invention relates to implanting electrodes (and/or sensors) in the pancreas.
  • the electrodes are provided via the bile duct.
  • a controller, attached to the electrode is also provided via the bile duct.
  • the implantation procedure does not require general anesthesia and is applied using an endoscope.
  • the electrodes are provided through the intestines.
  • the device which controls the electrification of the electrodes is provided through the intestines.
  • the device remains in the intestines, possibly in a folded out portion of the intestines, while the electrodes poke out through the intestines and into the vicinity or the body of the pancreas.
  • the electrodes may be provided through blood vessels, for example the portal vein.
  • the electrodes are elongated electrodes with a plurality of dependent or independent contact points along the electrodes. The electrodes may be straight or curved.
  • the electrodes are poked into the pancreas in a curved manner, for example being guided by the endoscope, so that the electrodes cover a desired surface or volume of the pancreas.
  • the exact coverage may be determined by imaging, or by the detection of the electric field emitted by the electrodes, during a post implantation calibration step.
  • An aspect of some exemplary embodiments of the invention relates to a pancreatic controller adapted to perform one or more of the above methods.
  • the controller is implanted inside the body.
  • An exemplary controller includes one or more electrodes, a power source for electrifying the electrodes and control circuitry for controlling the electrification.
  • a glucose or other sensor is provided for feedback control.
  • apparatus including: a set of electrodes, adapted to be implanted at an implantation site in a patient; and a control unit, adapted to drive a first subset of the set of electrodes to apply a signal to the site configured to reduce a blood glucose level of the patient, and to drive a second subset of the set of electrodes to apply a signal to the site configured to treat obesity of the patient.
  • the control unit is adapted to configure the signal applied by the first subset to include an ETC signal.
  • the control unit is adapted to configure the signal applied by the second subset to include an ETC signal.
  • the first subset and the second subset include at least one electrode in common.
  • first subset and the second subset are identical. In an embodiment, the first subset and the second subset have no electrodes in common.
  • the implantation site includes a stomach of the patient, and wherein the set of electrodes are adapted to be fixed to the stomach. In an embodiment, the implantation site includes an antrum of a stomach of the patient, and wherein the set of electrodes are adapted to be fixed to the antrum. In an embodiment, the implantation site includes a non-gastric site of the patient, and wherein the set of electrodes are adapted to be fixed to the non-gastric site. In an embodiment, the implantation site includes an intestinal site of the patient, and wherein the set of electrodes are adapted to be fixed to the intestinal site. In an embodiment, the control unit is adapted to drive the first subset even in the absence of a detection of eating by the patient, and to drive the second subset responsive to a detection of eating by the patient.
  • the at least two pairs of electrodes are adapted to be fixed to the antrum m a longitudinal o ⁇ entation with respect to an axis of the stomach. In an embodiment, the at least two pairs of electrodes are adapted to be fixed to the antrum in a perpendicular o ⁇ entation with respect to an axis of the stomach. In an embodiment, the at least two pairs of electrodes are adapted to be fixed to the antrum m a mixed o ⁇ entation with respect to an axis of the stomach.
  • the at least two pairs of electrodes include a first pair and a second pair of electrodes, adapted to be fixed to the antrum at different respective o ⁇ entations with respect to an axis of the stomach, wherem the first pair of electrodes is in the first subset of the set of electrodes, and wherem the second pair of electrodes is in the second subset of the set of electrodes.
  • the first pair of electrodes is adapted to be fixed to the antrum m a longitudinal o ⁇ entation with respect to the axis of the stomach
  • the second pair of electrodes is adapted to be fixed to the antrum m a perpendicular o ⁇ entation with respect to the axis of the stomach.
  • control unit is adapted to d ⁇ ve the first subset with a signal havmg a first frequency component, and to d ⁇ ve the second subset with a signal havmg a second frequency component, the first frequency component bemg smaller than the second frequency component
  • control unit is adapted to drive the second subset to apply the signal having the second frequency component without driving the second subset to apply a pacing pulse prior to applying the signal.
  • the signal having the first frequency component is non- excitatory.
  • the signal having the second frequency component is non- excitatory.
  • control unit is adapted to drive the first subset to alternate application of (a) a pacing pulse and (b) the signal having the first frequency component.
  • a method including: fixing at least two pairs of electrodes to a stomach site of a patient, in a mixed orientation with respect to an axis of the stomach; and driving the electrodes to apply a signal to the site configured to treat a pathology of the patient.
  • the pathology includes diabetes.
  • the pathology includes obesity.
  • driving the electrodes includes driving the electrodes even in the absence of a detection of eating by the patient.
  • driving the electrodes includes driving the electrodes responsive to a detection of eating by the patient.
  • fixing the at least two pairs of electrodes includes fixing the at least two pairs of electrodes to an antrum of the stomach of the patient.
  • a pancreatic controller comprising: a glucose sensor, for sensing a level of glucose or insulin in a body serum; at least one electrode, for electrifying an insulin producing cell or group of cells; a power source for electrifying said at least one electrode with a pulse that does not initiate an action potential in said cell and has an effect of increasing insulin secretion; and a controller which receives the sensed level and controls said power source to electrify said at least one electrode to have a desired effect on said level.
  • said insulin producing cell is contiguous with a pancreas and wherein said electrode is adapted for being placed adjacent said pancreas.
  • said pulse is designed to extend a duration of a burst activity of said cell.
  • said pulse has an amplitude sufficient to recruit non-participating insulin secreting cells of said group of cells.
  • the apparatus comprises at least a second electrode adjacent for electrifying a second cell of group of insulin secreting cells, wherein said controller electrifies said second electrode with a second pulse different from said first electrode.
  • said second pulse is designed to suppress insulin secretion.
  • said controller is programmed to electrify said second electrode at a later time to forcefully secrete said insulin whose secretion is suppressed earlier.
  • said second pulse is designed to hyper-polarize said second cells.
  • said controller electrifies said at least one electrode with a pacing pulse having a sufficient amplitude to force a significant portion of said cells to depolarize, thus aligning the cells' action potentials with respect to the non-excitatory pulse electrification.
  • said controller synchronizes the electrification of said electrode to a burst activity of said cell.
  • said controller synchronizes the electrification of said electrode to an individual action potential of said cell.
  • said controller does not synclironize the electrification of said electrode to electrical activity of said cell.
  • said controller does not apply said pulse at every action potential of said cell. In an exemplary embodiment of the invention, said controller does not apply said pulse at every burst activity of said cell. In an exemplary embodiment of the invention, said pulse has a duration of less than a single action potential of said cell. Optionally, said pulse has a duration of less than a plateau duration of said cell. In an exemplary embodiment of the invention, said pulse has a duration of longer than a single action potential of said cell. In an exemplary embodiment of the invention, said pulse has a duration of longer than a burst activity duration of said cell. In an exemplary embodiment of the mvention, said controller determines said electrification m response to a pharmaceutical treatment applied to the cell.
  • said pharmaceutical treatment comp ⁇ ses a pancreatic treatment
  • said controller applies said pulse to counteract adverse effects of said pharmaceutical treatment
  • said controller applies said pulse to synergistically interact with said pharmaceutical treatment
  • said controller applies said pulse to counteract adverse effects of pacing stimulation of said cell
  • said apparatus comp ⁇ ses an alert generator
  • said controller activates said alert generator if said glucose level is below a threshold
  • said controller activates said alert generator if said glucose level is above a threshold.
  • a pancreatic controller comp ⁇ sing: at least one electrode adapted for electrifying at least a portion of a pancreas; and a controller programmed to elect ⁇ fy said electrode so as to positively control at least the effect of at least two members of a group consistmg of blood glucose level, blood insulm level and blood level of another pancreatic hormone
  • controlling comp ⁇ ses are thus provided in accordance with an exemplary embodiment of the invention.
  • controlling comprises reducing the secretion of glucagon, when insulin secretion is increased.
  • at least one of said two members comprise Somatostatin.
  • at least one of said members comprises glucose level.
  • said controller selects between alternative control therapies, a therapy that has a least disrupting effect on said glucose levels.
  • said controller uses solely electrical fields to control said members.
  • said controller takes molecules provided in the body, into account, for said control.
  • said molecules are provided without a control of said controller.
  • said molecules are provided under a control of said controller.
  • said feedback interactions comprises interactions between hormone levels.
  • said feedback interactions are dependent on blood glucose levels.
  • said feedback interactions are determined by said controller, by tracking a behavior of said pancreas.
  • said controller actively modifies at least one of a glucose level and a pancreatic hormone level, to collect feedback interaction information.
  • the controller comprises a sensor for sensing a level of said controlled member.
  • the controller comprises an estimator for estimating a level of said controlled member.
  • said electrode applies a non-excitatory pulse to effect said control.
  • said electrode applies an excitatory pulse to effect said control.
  • a method of mapping pancreatic behavior of a pancreas comprising: determining a behavior of a pancreas at a first set of conditions; dete ⁇ riining a behavior of a pancreas at a second set of conditions; and analyzing the behavior of the pancreas and the sets of conditions, to determine a behavior pattern of the pancreas.
  • said behavior pattern comprises an inte ⁇ elationship between two hormones of said pancreas.
  • the method comp ⁇ ses t ⁇ ggenng said elect ⁇ c field by a glucose ingestion event.
  • said elect ⁇ c field is applied irrespectively of an mgestion event.
  • said elect ⁇ c field is applied at least part of the time irrespective of a blood glucose level.
  • said elect ⁇ c field is applied contmuously for at least 24 hours
  • said elect ⁇ c field is applied for a pe ⁇ od of at least 15 minutes without sensmg of its effect
  • said electric field is of a magnitude and temporal extent so that it does not significantly change blood insulin and glucose levels in the absence of an ingestion event.
  • said electric field reduces blood glucose levels by at least 20%) of an elevation of the glucose level above a fasting baseline glucose level.
  • said electric field does not increase blood insulin levels, as measured by an average over five minutes, by more than 20%.
  • said electric field reduces blood insulin levels, as measured by an accumulated amount for a glucose ingestion event and in comparison to a regular response of said person, by more than 20%).
  • the method comprises delaying a gastric emptying by applying a treatment to the stomach.
  • said electric field is operative to delay a glucose peak at least by a duration of its application.
  • said electric field is operative to delay a glucose peak at least by
  • a method of glucose level control comprising: providing at least one electrode adapted to apply an electric field to a pancreas; and applying an electric field to the pancreas operative to reduce blood glucose levels if elevated and not significantly reduce such levels in an acute manner if not substantially elevated.
  • said electric field reduces elevated glucose levels by at least 20%).
  • apparatus for blood glucose control comprising: ?o at least one electrode adapted to apply an electric field to a pancreas; and circuitry adapted to electrify said at least one electrode and configured to electrify said electrode with a non-excitatory field in a manner which compensates for a loss of acute response by said pancreas.
  • said circuitry compensates by causing the secretion of an insulin bolus.
  • said circuitry compensates by reducing glucose levels in a non- insulin manner.
  • said circuitry compensates by reducing glucagon secretion.
  • said circuitry reduces or prevents a substantial increase in insulin secretion during said compensation.
  • said circuitry applies only an acute control of insulin levels.
  • said apparatus is programmed with a knowledge of a slow acting chemical-based insulin therapy provided to said pancreas.
  • the apparatus comprises an automatic ingestion sensor for automatically detecting an ingestion event.
  • the apparatus comprises an automatic glucose sensor for automatically detecting a situation requiring an acute response.
  • the apparatus comprises an automatic glucose sensor for automatically detecting a situation requiring an acute insulin response.
  • said response is an acute insulin response.
  • said electrode is adapted for attachment to a pancreas.
  • said electrode is adapted for attachment to a muscular organ.
  • apparatus for blood glucose control comprising: at least one electrode adapted to apply an electric field to a pancreas; and circuitry adapted to electrify said at least one electrode and configured to electrify said electrode in a manner which significantly reduces elevated blood glucose levels, said circuitry configured to apply said field also when glucose levels are not elevated.
  • said circuitry is a closed loop system including sensing of the effect of the electrification and wherein said circuitry is configured to over stimulate in cases of doubt.
  • said circuitry is a semi-open loop system where a relatively long stimulation series is applied without feedback.
  • said circuitry is an open loop system where a stimulation series is applied responsive to a trigger and without feedback.
  • apparatus for blood glucose control comprising: at least one electrode adapted to apply an electric field to pancreatic tissue; and circuitry adapted to electrify said at least one electrode and configured to electrify said electrode in a manner which reduces glucose levels and does not substantially elevate insulin levels above a baseline value, when glucose levels are elevated.
  • said circuitry is a closed loop system including sensing of the effect of the electrification and wherein said circuitry is configured to over stimulate in cases of doubt.
  • said circuitry is a semi-open loop system where a relatively long stimulation series is applied without feedback.
  • said circuitry is an open loop system where a stimulation series is applied responsive to a trigger and without feedback.
  • said circuitry applies a constant voltage field.
  • said circuitry applies a constant current field.
  • said pancreatic tissue comprises an in-vivo pancreas.
  • said pancreatic tissue comprises a pancreatic tissue implant.
  • said baseline is a baseline insulin response of a person for which the apparatus is used.
  • a method of insulin level control comprising: providing at least one electrode adapted to apply an electric field to a pancreas; and applying an electric field to the pancreas using said at least one electrode such that blood glucose levels are not significantly increased and blood insulin levels are significantly reduced.
  • a method of applying an electric field to a pancreas or functionally and positionally associated tissue comprising: attaching at least one electrode to a tissue other than said pancreas; and electrifying said electrode such that a significant field is applied to said pancreas or associated tissue to control at least one of a level of a pancreas secretion and a blood glucose level.
  • the method comprises using said at least one electrode to also control eating habits.
  • the mvention apparatus for applying an electric field to a pancreas or functionally and positionally associated tissue, comprising: at least one electrode adapted to be attached to a tissue other than said pancreas; and means for electrifying said electrode such that a significant field is applied to said pancreas or associated tissue to control at least one of a level of a pancreas secretion and a blood glucose level.
  • the method includes detecting eating by the subject, wherein applying the electrical signal includes applying the electrical signal responsive to detecting the eating.
  • applying the electrical signal includes applying an Excitable-Tissue Control (ETC) signal.
  • ETC Excitable-Tissue Control
  • a method for treating a subject including: applymg an elect ⁇ cal signal to a small mtestme of the subject, and configu ⁇ ng the elect ⁇ cal signal to reduce a blood glucose level of the subject, m order to treat the subject
  • a method for treating a subject including applying an Excitable-Tissue Control (ETC) signal to a smooth muscle of the subject, and configu ⁇ ng the ETC signal to reduce a blood glucose level of the subject, m order to treat the subject
  • applying the ETC signal includes applying the ETC signal to a site of a gastrointestinal tract of the subject
  • applymg the ETC signal includes applying the ETC signal to a duodenal site of the subject
  • applymg the ETC signal includes applying the ETC signal to a site of a colon of the subject
  • a method for treating a subject mcludmg applymg an Excitable-Tissue Control (ETC) signal to cardiac muscle tissue of the subject, and configu ⁇ ng the ETC signal to reduce a blood glucose level of the subject, m order to treat the subject
  • a method for treating a subject mcludmg applying an electrical signal to at least one small intestine site of the subject, and configuring the electrical signal to reduce a ⁇ se m a blood glucose level of the subject, m order to treat the subject
  • a method for treating a subject mcludmg: applymg an Excitable-Tissue Control (ETC) elect ⁇ cal signal to at least one smooth muscle site of the subject, and configu ⁇ ng the ETC elect ⁇ cal signal to reduce a nse m a blood glucose level of the subject, in order to treat the subject
  • the smooth muscle site mcludes a gastrointestinal tract site of the subject
  • applymg the ETC electrical signal mcludes applying the ETC elect ⁇ cal signal to the gastromtestinal tract site
  • the gastrointestinal tract site mcludes a duodenal site of the subject
  • applymg the ETC elect ⁇ cal signal mcludes applymg the ETC elect ⁇ cal signal to the duodenal site
  • the gastrointestinal tract site m cludes a colon site of the subject, and applymg the ETC elect ⁇ cal signal includes applymg the ETC elect ⁇ cal signal to the
  • the at least one site mcludes a gast ⁇ c corpus site and a gast ⁇ c antrum site, and applymg the signal mcludes applymg the signal between the gast ⁇ c corpus site and the gast ⁇ c antrum site
  • the gast ⁇ c antrum site mcludes a poste ⁇ or gast ⁇ c antrum site, and applymg the signal includes applying the signal between the ante ⁇ or gast ⁇ c corpus site and the poste ⁇ or gast ⁇ c antrum site
  • the gast ⁇ c antrum site mcludes an ante ⁇ or gast ⁇ c antrum site, and applymg the signal mcludes applymg the signal between the ante ⁇ or gast ⁇ c corpus site and the ante ⁇ or gast ⁇ c antrum site
  • the at least one site includes a first gast ⁇ c corpus site and a second gast ⁇ c corpus site, and applying the signal mcludes applying the signal between the first gast ⁇ c corpus site and the second gast ⁇ c corpus site
  • the first gast ⁇ c corpus site includes a poste ⁇ or first gast ⁇ c corpus site, and applying the signal mcludes applying the signal between the poste ⁇ or first gast ⁇ c corpus site and the second gast ⁇ c corpus site
  • the first gast ⁇ c antrum site mcludes a poste ⁇ or first gastnc antrum site, and applying the signal includes applying the signal between the poste ⁇ or first gast ⁇ c antrum site and the second gastnc antrum site
  • the second gastnc antrum site includes a postenor second gast ⁇ c antrum site, and applying the signal includes applymg the signal between the postenor first gastnc antrum site and the postenor second gast ⁇ c antrum site
  • the second gast ⁇ c antrum site includes an antenor second gast ⁇ c antrum site, and applymg the signal mcludes applying the signal between the poste ⁇ or first gastnc antrum site and the antenor second gast ⁇ c antrum site
  • the first gastnc antrum site mcludes an antenor first gast ⁇ c antrum site
  • applying the signal includes applying the signal between the ante ⁇ or first gastnc antrum site and the second gastnc antrum site
  • the second gast ⁇ c antrum site includes an antenor second gast ⁇ c antrum site
  • applying the signal includes applying the signal between the ante ⁇ or first gastnc antrum site and the antenor second gastnc antrum site
  • a method for treating a subject mcludmg applying an Excitable-Tissue Control (ETC) elect ⁇ cal signal to at least one cardiac muscle tissue site of the subject, and configuring the ETC electrical signal to reduce a rise in a blood glucose level of the subject, in order to treat the subject.
  • configuring the electrical signal includes configuring the electrical signal to reduce a rise in a blood insulin level of the subject.
  • applying the electrical signal includes configuring a frequency of the electrical signal to be between 30 and 200 Hz. In an embodiment, configuring the frequency includes configuring the frequency to be between 100 and 200 Hz. In an embodiment, configuring the frequency includes configuring the frequency to be between 30 and 100 Hz. In an embodiment, configuring the frequency includes configuring the frequency to be between 60 and 100 Hz. In an embodiment, applying the electrical signal includes applying pulses and configuring a pulse amplitude of the pulses to be between 2 and 15 mA. In an embodiment, configuring the pulse amplitude includes configuring the pulse amplitude to be between 2.5 and 7.5 mA.
  • applying the electrical signal includes applying pulses in a pulse train and configuring a length of the pulse train to be between 1 and 6 seconds. In an embodiment, configuring the length of the pulse train includes configuring the length of the pulse train to be between 3 and 6 seconds.
  • applymg the elect ⁇ cal signal includes applymg a tram of biphasic pulses
  • applymg the tram of biphasic pulses mcludes settmg a duration of each phase of the biphasic pulses to be between 1 and 10 ms
  • settmg the duration mcludes settmg the duration of each phase of the biphasic pulses to be between 4 and 6 ms
  • applymg the electncal signal includes sensmg a physiological attnbute of the subject and applying the electncal signal responsive thereto
  • sensing the physiological attnbute of the subject cludes sensmg that the subject is eatmg
  • sensmg the physiological att ⁇ bute m cludes sensmg a gastrointestinal tract att ⁇ bute
  • applymg the electncal signal includes applying an initiating pulse, and
  • 21 A is a chart showing changes in insulin levels with and without stimulation, in a live mini-pig given food
  • Fig. 2 IB is a chart corresponding to chart 21 A, showing blood glucose levels
  • Fig. 22A is a chart showing a delay in glucose peaking and reduction in levels thereof under conditions of stimulation in a series of experiments in a first pig, in accordance with an exemplar ⁇ ' embodiment of the invention
  • Fig. 22B is a chart showing a delay in insulin peaking and reduction in levels thereof in a series of experiments under conditions of stimulation in the first pig in accordance with an exemplary embodiment of the invention
  • Fig. 22C is a chart showing glucagon reduction as a result of the application of a stimulation in accordance with an exemplary embodiment of the invention
  • Fig. 22A is a chart showing changes in insulin levels with and without stimulation, in a live mini-pig given food
  • Fig. 2 IB is a chart corresponding to chart 21 A, showing blood glucose levels
  • Fig. 22A is a
  • Fig. 23 is a chart showing a reduction in glucose levels under conditions of stimulation in a series of experiments in a second pig, in accordance with an exemplary embodiment of the invention
  • Fig. 24 is a chart showing a reduction in glucose levels under conditions of stimulation in a series of experiments in a third pig, in accordance with an exemplary embodiment of the invention
  • Fig. 25 is a chart illustrating that a glucose reduction stimulation in accordance with an exemplary embodiment of the invention, works under conditions of IV hyperglycemic clamping
  • Fig. 26 is a chart showing a lack of dangerous effect of stimulation in accordance with an exemplar ⁇ ' embodiment of the invention, on normal glucose levels
  • FIG. 31A and 3 IB are charts showing a lack of dangerous effect of stimulation in accordance with an exemplary embodiment of the invention, on the insulm levels of a fasting human;
  • FIGs. 32A and 32B are charts showing glucose and insulin reduction in a pig, in accordance with an exemplary embodiment of the invention;
  • Figs. 32C and 32D show accumulated levels of glucose and insulin in the pig of Figs. 32A and 32B;
  • Figs. 33A and 33B are charts showing glucose and insulin reduction in another pig, in accordance with an exemplary embodiment of the invention;
  • Figs. 33C and 33D show accumulated levels of glucose and insulin in the pig of Figs. 33A nd 33B;
  • Fig 2 is a diagram of an exemplary electncal activity of a single beta cell, operating at slightly elevated glucose levels
  • the activity of a smgle cell is shown as compnsmg a plurality of burst pe ⁇ ods 132 compnsmg a plurality of individual action potentials and separated by a plurality of interval pe ⁇ ods 134, m which penods there are substantially no action potentials
  • each burst comprises a plurality of depola ⁇ zation events
  • a potential advantage of pacing is that the pacing signal will cause depolarization and associated recruitment of beta cells that would not otherwise take part in the activity of the pancreas. It is expected that as intra-cellular calcium levels rise (or some other control mechanism), some cells will cease to participate in electrical activity. By applying a pacing pulse, such cells are expected to be forced to participate and, thus, continue to secret insulin.
  • Another potential advantage of pacing is related to the synchronization problem. As can be appreciated, some types of controlling pulses need to be applied at a certain phase in the cellular action potential, hi a propagating action potential situation, it may be difficult to provide a single pulse with timing that matches all the cells, especially as the depolarization frequency increases.
  • the phases are synchronized, making a desirable pulse timing easier to achieve. It is noted, however, that even if there is no pacing, some pulses, such as for extending a plateau of an action potentials, can be applied at a time that is effective for a large fraction of the cells in the islet. In some exemplary methods of insulin secretion increase, the amplitude of the islets depolarization is apparently increased. This may be, for example, by recruitment of otherwise non-participating cells, or be a result of synchronization of cells so that the electrical signals are additive.
  • the electrical field also directly releases insulin from the REP of the cell and/or from other organelles in the cell.
  • INSULIN SECRETION SUPPRESSION In some cases, for example if the glucose level is too low, suppression of insulin secretion may be desirable.
  • the following methods may be applied together or separately. Also, as noted above, different methods may be applied to different parts of the pancreas, for example, by differently electrifying electrodes 112 of Fig.
  • the beta cells are hyper- polanzed, for example by applying a DC pulse
  • the cells will not respond to elevated glucose levels by depolanzation and msulm secretion
  • the applied pulse does not need to be synchronized to the electncal activity It is expected that the hyper polanzation will last a short while after the pulse is terminated Possibly, only the length of the mterval is increased, mstead of completely stopping the burst activ lty
  • the msulin stores of the pancreas are dumped, so that at later times, the cells will not have significant amounts of insulin
  • the beta cells are stimulated to release insulin.
  • insulin Depending on the cell, it is expected that if a cell is over stimulated, it becomes tired out and requires a significant amount of time to recover, during which time it does not produce insulin. If a cell is under stimulated, it is expected that it will, over time produce less insulin, as it adapts to its new conditions. If a cell is stimulated enough, it will continuously produce insulin at a maximal rate.
  • PANCREATIC RESPONSE CONTROL rather than directly control insulin secretion levels, the response parameters of the pancreas are modified, to respond differently to glucose levels. One parameter that may be varied is the response time. Another parameter is the gain (amplitude) of the response.
  • the response time of the pancreas is increased or reduced by blocking or priming the fast-responding portions of the pancreas, in patients that have both fast and slow responding portions.
  • Blocking may be achieved, for example, by partial or complete hyper-polarization.
  • Priming may be achieved, for example, by applying a sub-threshold pulse, for example, just before depolarization.
  • a potential advantage of such a sub-threshold pulse is that it may use less power than other pulses.
  • the gain of the response may be controlled, for example, by blocking or by priming parts of the pancreas, to control the total amount of pancreatic tissue taking part in the response. It is noted that priming "slow response" cells causes them to act as fast response cells, thereby increasing the gain of the fast response. In some cases, the priming and/or blocking may need to be repeated periodically, to maintain the sensitivity profile of the pancreas as described. Alternatively or additionally, the sensitivity of the pancreas may be enhanced
  • the secretion and/or production ability of part or all of the pancreas is modified, by controlling the blood flow to and/or from the pancreas. It is hypothesized that reducing the blood flow to the pancreas will reduce the production and/or secretion rate of various pancreatic hormones. Alternatively or additionally, by preventing hormone laden blood from leaving the pancreas, the local concentration of the various hormones increases and exhibits a stronger secretion enhancing or inhibiting effect (as the case may be) for other hormones.
  • pancreas responds to increased glucose levels by providing increased insulin levels. However, this response is delayed and therefore increased in magnitude. As a result, or due to a different mechanism, the response of the body to insulin is reduced and or delayed, forcing an even greater output of insulin.
  • the control of pancreatic response is used to prevent this feedback loop from occurring.
  • the pancreas is prevented from secreting increased amounts of insulin.
  • glucagon secretion is reduced when or before glucose levels increase (e.g., at a user indication prior to eating), which prevents (or reduces) a fast glucose peak from occurring due to eating.
  • gastric emptying is delayed, for example electrically or using pharmaceutical control.
  • one or both of the following acts may be performed: (a) suppress pancreatic response; and (b) increase pancreatic response (e.g., insulin secretion and/or glucagon reduction) to be faster and/or greater than usual, to quickly reverse the physiological situation to which an abnormal response is expected.
  • pancreatic response e.g., insulin secretion and/or glucagon reduction
  • selective control of hormones allows a patient to be provided with selective hormone ratios, for example providing a higher (or lower) glucagon to an insulin output ratio than would be without the electrical stimulation.
  • controller 102 tests this possibility periodically, by not applying its control or by reducing a degree of the control and detenriining if the pancreatic response is normal. NON-INSULIN CONTROL Alternatively or additionally to controlling the secretion of production of insulin, the secretion and/or production of other pancreatic hormones may be controlled.
  • Exemplary such hormones include glucagon, Somatostatin and pancreatic poly-peptide (PP).
  • the levels and/or profile of level of these hormones may be controlled while also controlling insulin levels or while allowing insulin levels to change without direct control.
  • the hormones may be controlled partially independently of insulin. It should be noted that in some cases control of factors other than insulin will indirectly control insulin levels. For example, reducing glucose levels will generally cause a reduction in insulin levels.
  • some of the pancreatic hormones interact via biological feedback mechamsms, for example, an increase in glucagon also increases insulin. These interactions may be represented using a set of equations. In other embodiments, a neural network may be used.
  • the feedback equations are not linear. Instead, the equations typically include a time delay and different gains for different relative hormonal levels. Further, the physiological mechanism may depend on glucose levels, on nervous simulation, on previous activity of the pancreas and/or on various digestive hormone.
  • the particular equations and/or equation parameter for a particular patient may need to determined for that patient, for example by controlled experimentation (e.g., modifying one hormonal level and tracking the effect on others) or by observation. Once the equations are known, substantially independent (or less interdependent) control of one hormone relative to other hormones may be possible.
  • glucagon instead of providing a large increase in insulin, which will increase glucagon levels, a smaller increase, over a longer period of time, may have a similar effect on blood sugar, without prompting glucagon secretion (which would confound the glucose lowering effect of the insulin).
  • the increase in glucagon or, conversely, insulin or other pancreatic hormones
  • the secreted hormone performs its activity, it does not build up in the blood and/or in the pancreatic cells, to levels which will cause significant secretion of the antagonistic hormone.
  • a ratio between hormone secretion levels at a given physiological state may be changed by at least 10%, 20%, 30%, 40% or more, upwards or downwards, with the originally higher level as the denominator.
  • pharmaceuticals may be used to reduce the sensitivity of one cell type relative to other cell types (or to increase the sensitivity), thus modifying the feedback equations and allowing some leeway in selective control of the hormones.
  • the responses of the cells may be regularized by the pharmaceuticals, so all cell types respond in a more uniform manner.
  • Exemplary pharmaceuticals that selectively affect pancreatic behavior include streptozotocin and alloxan, which reduce insulin output from beta-cells and various drugs used for treatment of diabetes.
  • the pharmaceuticals that are provided block the receptors for the hormone to be selectively disabled.
  • the pharmaceuticals, for example anti-bodies disable the hormone in the blood stream.
  • differential modification of one hormone over other hormones may be achieved by selectively stimulating only certain pancreas portions and/or selectively blocking the activity of pancreas portions.
  • the response of different cell types to a same electrical field stimulation may be different, thus allowing differential control of different hormones.
  • controlling hormonal levels and controlling glucose levels by causing the secretion of hormones.
  • Glucose level control at least prevents the damage to the body cause by high or low glucose levels, however, it does not guarantee the availability of glucose to the body cells.
  • Maintaining desirable hormone levels can not only maintain glucose within a desired range, it can also guarantee that a sufficient level of insulin is available so the body cells can assimilate the glucose. Additionally, various desirable bodily effects caused by the hormones, such as control of fat and protein metabolism or prevention of insulin tolerance, can be achieved. It should be noted, that in some cases what is desirable is a hormone ratio or a temporal hormone profile, rather than a simple hormonal value. These effects can be achieved, for example, by temporally varying the control of the hormones. In an exemplary embodiment of the invention, a reduction of glucose levels is achieved by indirectly activating non-insulin dependent glucose transporters.
  • This effect may result from direct local stimulation of neural afferent pathways in the (or near) the pancreas or by the pancreas enhanced activity (resulting from the stimulation) that is sensed by these local afferents.
  • the neural signal that is induced can enhance activation of non-insulin dependent GLUT in remote tissue of the body thereby increasing glucose uptake and reducing blood glucose independently of Insulin or in parallel with low, temporary or local increase in Insulin secretion at the pancreas. Hormonal pathways are also possible.
  • stimulating cells in the heart can cause an increase in glucose uptake by the cells.
  • the existence of neural pathways that stimulate cells are also well known.
  • the measurements may be repeated few times or not at all, before starting treatment.
  • the cycle of treatment is optionally repeated every two to five minutes. Alternatively, in critical situations such as hypoglycemia, the cycle is repeated even more frequently.
  • the glucose level is under 60 (mg/dl) (step 204)
  • further insulin production is optionally suppressed (206) and, optionally, the patient is alerted (208).
  • the glucose level is between 60 and 150 (210)
  • no action is taken, as these are normal glucose levels.
  • the glucose level is between 150 and 200 (212)
  • the action taken depends on the previous action taken and the previous measured glucose level. If, for example the previous level was higher, the insulin secretion activity may be maintained or reduced.
  • the insulin secretion level may be increased.
  • a pulse application ratio of 1 :3 between burst that are modified and bursts that are not modified may be provided (214) if the glucose level is now reduced from its previous measurement.
  • the exact glucose levels and pulse parameters used for a particular patent will depend only on the patient's medical history, but also on that patient's particular response to the pulse parameters used. Some patients may not respond as well as other patients and a more powerful pancreatic activity modification schedule used. If the glucose level is between 200 and 250 (216), the action taken (218) can depend on the previous action taken for example providing a pulse application ratio between 1: 1 and 1 :2.
  • controller 102 stores in a memory associated therewith (not shown) a recording of the glucose levels, the applied electrical and or pharmaceutical control, food intake and/or the effect of the applied control on electrical activity of the pancreas and/or effects on the blood glucose level.
  • a memory associated therewith not shown
  • controller 102 stores in a memory associated therewith (not shown) a recording of the glucose levels, the applied electrical and or pharmaceutical control, food intake and/or the effect of the applied control on electrical activity of the pancreas and/or effects on the blood glucose level.
  • certain types of cells for example beta cells may die out, so different stimulation methods and/or protocols may be suitable for different stages of the disease. For example, insulin secretion enhancement at the start of the disease and glucagon secretion reduction at the later stages of the disease.
  • CELLULAR TRAINING the applied electrification and/or pharmaceutical profiles are used to modify the behavior of islet cells, in essence, training the cells to adapt to certain conditions. It is expected that slightly stressing a beta cell will cause the cell to compensate, for example by enlarging or by causing new beta cells to be produced. Such regeneration mechanism are known to exist, for example as described in "Amelioration of Diabetes Mellitus in partially Depancreatized Rats by poly(ADP-ribose) synthetase inhibitors. Evidence of Islet B- cell Regeneration", by Y Yonemura et.
  • Fig. 3B is a flowchart of another exemplary control logic scheme 240, in accordance with an exemplary embodiment of the invention. Fig. 3B is similar to Fig.
  • the hormone levels are directly measured using suitable sensors, for example fiber optic sensors or limited use chemical assay sensors.
  • suitable sensors for example fiber optic sensors or limited use chemical assay sensors.
  • the levels are estimated based on the variation in blood glucose levels and/or electrical activity of the pancreas. If hormone levels are too low, they are increased (253). Possibly, if the hormone levels are too high, stimulation is stopped and/or even suppressed (not shown). Possibly, a control logic similar to that of Figs. 3 A and 3B is prompted by a sensing of hormone levels. Skipping elements 252 through 258, wliich are the same as In Fig.
  • controller 102 senses gastnc activity, identifies it as digestive behavior or as release of food from the stomach and accordmgly stimulates the pancreas to secrete a bolus of msulm and/or reduce glucose m another way Alternati ely or additionally, the stimulation lowers the sensitivity threshold of the pancreas so that it responds properly to the natural stimuli, i e , it does not over-respond Alternatively or additionall ⁇ , the stimulation causes the pancreas to increase its response to raised glucose lev els, when its natural response is too low It is hypothesized that a large initial bolus of msulin, may have a non-l ear effect on the body, for example, causing a fast shut-down of glucose secretion by the liver, or shutdown of glucagon release by the pancreas The non-lmear effect may depend, for example on the total amount of insulm and/or on its rapid appearance
  • An exemplary non-excitatory pulse is between 1 and 7 mA.
  • a sub-threshold pulse may be, for example, between 0.1 and 0.5 mA. It is noted that the lack of excitation may be due to the timing of application of the pulse.
  • Simple pulse forms can be combined to form complex pulse shapes and especially to form pulse trains.
  • One example of a pulse train is a double pacing pulse (two pulses separated by a 20 ms delay) to ensure capture of a pacing signal.
  • Another example of a pulse train is a pacing pulse followed, at a short delay, by a plateau extending pulse and/or other action potential control pulses. Thus, not only is pacing forced, possibly at a higher than normal rate, but also the effectiveness of each action potential is increased.
  • stomach is a muscular organ and suturing or other attachment methods are generally more easily applied to it, than to the pancreas. This may also allow a greater number of electrodes and/or specificity to be used.
  • the controller itself is attached to the stomach.
  • stomach is that the same electrodes used for electrifying the pancreas may also be used for obesity control, for example as described in US patents 6,571,127, 6,630,123 and 6,600,953, US applications 09/734,358 and 10/250,714 and PCT publication WO02/082968, the disclosures of which are incorporated herein by reference.
  • the electrodes are needle electrodes suitable for laparoscopic implantation.
  • fewer or a greater number of such alternating electrodes may be used and various orders of electrodes (e.g., 2-1-2-1 - the numbers indicating electrodes of the same polarities) may be provided as well. In some such orders, the number of different electrodes of different polarities is not equal. The distances between the electrodes need not be uniform.
  • the acquired information is penodically- and/or continuously- reported to a treating physician, for example usmg external unit 1 16 .
  • a treating physician for example usmg external unit 1 16 .
  • the information acquisition also uses test control sequences to determine the pancreatic response to va ⁇ ous pulse forms and sequences
  • the information acquisition step is used to determme physiological pathologies and especially to detect and feedback- and/or feed-forward- mechamsms that are impaired Such mechamsms are optionally supplemented, replaced and or overndden by controller 102 Alternatively or additionally, the information acquisition is geared to detecting feed-back and feed-forward interactions m the pancreas, especially mteractions between hormones, possibly dependent on glucose levels, hormone levels and/or stimulation history This information may be used to provide parameters for a predetermined model of the pancreas
  • Fig. 8 A is a chart showing the effect of such electrical stimulation on insulin levels, in six animals.
  • FIG. 20B is a chart co ⁇ esponding to chart 20A, showing for the stimulation case the relationship between glucose level and insulin level.
  • Fig. 21A there exist physiological mechanisms, such as glucagon secretion that increase glucose secretion if insulin level go high. In some embodiments of the invention, a smaller stimulation may be applied to reduce this glucose secretion.
  • Fig. 20C is a chart co ⁇ esponding to chart 20A, showing for the non- stimulation cases, the relationship between glucose and insulin level.
  • Fig. 21 A is a chart showing changes in insulin levels with and without stimulation, in a live mini-pig given food, about 700 grams, after starvation. It should be realized that provision of food is generally less controlled than provision of sugar.
  • Fig. 21B is a chart co ⁇ esponding to chart 21 A, showing blood glucose levels. While the blood glucose went up after the first st ⁇ nulation, it went up by less than the control situations and peaked sooner. This suggests that the pulse may have directly or indirectly affected glucose levels, one possible mechanism is that insulin secretion causes glucagon secretion or that glucagon secretion was directly induced by the pulse.
  • a 75g glucose load was administered orally. Blood samples were taken every 5 minutes for a total of about 100 minutes. Stimulation protocols were the same as the control protocols except that stimulation was applied immediately after the ingestion of the glucose. The pulse parameters were: biphasic waveform of 5ms each phase applied every 200ms (5Hz). The amplitude is 6- 10mA. Stimulation duration was 15 minutes in this and the following experiments.
  • Fig. 22A is a chart showing a delay in glucose peaking and reduction in levels thereof under conditions of stimulation in a series of experiments in a first pig, in accordance with an exemplary embodiment of the invention. Both control and stimulation values are averages of 9 days each. It should be noted that the glucose
  • 25 is a chart illustrating that a glucose reduction stimulation in accordance with an exemplary embodiment of the invention, works under conditions of IV hyper- glycemic clamping, for a single experiment. It should also be noted that the reduction in glucose levels was only to baseline levels and not below.
  • a pig was clamped to high glucose levels using an IV of Dextrose, using an initial bolus of 50%> Dextrose of about 20-25 cc and then a constant infusion of 70-90 ml/hour for the duration of the experiment, including the recovery of glucose values.
  • the experiment was started after the glucose levels stabilized.
  • the stimulation length is 15 minutes. As shown, the glucose level recovered after about 20 minutes.
  • 26 is a chart showing a lack of dangerous effect of stimulation in accordance with an exemplar,' embodiment of the invention, on normal glucose levels. An average of 2 control days and 4 stimulation days is shown. As noted above this may be used as a basis for design of open loop protocols in which a possible over stimulation is not considered as being dangerous (but possibly energy wasting).
  • two pigs were stimulated continuously for 24 hours a day for two weeks, using the 5Hz, 5ms, bi-phase, 5mA pulse series and no adverse reactions or effects on pancreatic function or pancreatic histology were visible. In particular, no effects on exocrine functions could be seen by way of changes in feces.
  • the Stomach and intestines were retracted respectively allowing exposure of about 7x5 cm of the pancreas.
  • Four commercial stainless steel temporary cardiac pacing wires manufactured by A&E medical corporation were inserted to the pancreatic tissue, one pair on one end and one pair on the other.
  • Two pancreatic recording leads were also attached, one between the two electrodes on one side of the pancreas and closer to one electtode and the other recording lead between the two PST electrodes.
  • the electrodes were channeled a 7 Fr JP abdominal drain harboring an electronic circuit and suture fixed to the pseudocapsule of the pancreas. The electrodes and the drain were routed and extracted through the left abdominal wall.
  • a second, negative pressure, drain was placed near the pancreas and routed to the right abdominal wall, the electrode attaching procedure took 1.25 hours. Amylase values were 127.5 U/L the first day and ⁇ 30 U/L the next day, indicating a good recovery. GI motility came back on the first day and no fever was found over and after the experimental period. On the sixth day following surgery the electrodes were removed, uneventfully. Several series of stimulation and measurement were conducted over the few days after the surgery. There have been no reported side effects of any type following the electrode placement, stimulation and removal. Two types of protocols were conducted. A control protocol and a stimulation protocol. In the control protocol, 3 blood samples were taken while the patient was fasting. At time 0 a 75 gr glucose load was administered orally.
  • Fig. 27 is a chart showing the effect, in a human, on glucose levels, of a stimulation in accordance with an exemplary embodiment of the invention. As with the mini-pigs, the glucose peaks are reduced and or delayed.
  • Fig. 28 is a chart showing the effect on insulin levels, of the experiments of
  • Fig. 27 Insulin levels were not measured in the first control case, but measured in others, as shown. Insulin peaks values were clearly reduced and delayed as compared to the control situation.
  • Fig. 29 is a chart showing the effect on c-peptide levels, of some of the experiments of Fig. 27. C-peptide values were reduced and the peak apparently delayed. These measurements were carried out only in one control protocol and one stimulation protocol. This measurement is used to validate the insulin measurements.
  • Figs. 30A and 30B show the effect of electrical stimulation during fasting on glucose levels, on two different occasions during the five day convalescence period of Fig. 27. No substantial reduction in glucose levels is observed.
  • Figs. 31A and 3 IB which co ⁇ espond to Figs.
  • FIGS. 32.A and 32B are charts showing glucose and insulin reduction in a pig, in accordance with an exemplary embodiment of the invention. Figs. 32C and 32D show accumulated levels of glucose and insulin in the pig of Figs.
  • the horizontal line in the figure shows the time of application of a pulse havmg the parameters, as used above, of a bi-phasic pulse havmg a positive 5 msec section immediately followed by a negative 5 msec, applied once every 200 msec (e g , a delay of 190 msec between electnf ⁇ cations), and continued for 1 hour
  • Glucose was measured usmg an AccuCheck glucometer, usmg blood from a jugular vem that was exttacted once every 5 or ten mmutes for both glucose and msulin level determination Insulm level was measured usmg a radio- lmmuno-assay
  • the same expenmental parameters were used for all the pigs, except where noted otherwise, for example, durations were v a ⁇ ed Except where noted otherwise, the stimulation device was implanted
  • the following electrode was used a stitched lme electrode, having a length of, for example, 15-22
  • Figs. 35C and 35D shows the accumulation over 15 minutes only. 7 control and 5 stimulus experiments were run.
  • Figs. 35A and 35B may include experimental results that were also used in Figs. 22A and 22B.
  • Fig. 36 shows glucose level reduction in another pig, in accordance with an exemplary embodiment of the invention, in which a stimulus was applied for 15 minutes, using an external stimulator (and internal electrodes). A reduction in peak and total glucose levels are seen. In addition, the glucose response does not appear to be delayed. It is noted that in some disease situations, it is desirable to delay this glucose peak.
  • FIGs. 37A and 37B are charts showing glucose and insulin reduction in a dog, in accordance with an exemplar ⁇ ' embodiment of the invention.
  • a stimulus was applied for 60 minutes to a right lobe of a pancreas of a dog, one repetition. As can be seen, glucose peaks and insulin peaks were reduced but not significantly delayed.
  • the pulse applied was the same as for the pigs.
  • the glucose was injected via a tube into the stomach and was provided at 1.5 grams per Kg body weight.
  • Figs. 38A and 38B are charts showing glucose reduction in two dogs, where electrodes were placed on a stomach, in accordance with an exemplary embodiment of the invention, there were 6 control repetitions and 5 stimulus repetitions, for the first dog and 7 and 6, for the second dog. Glucose peaks are shown to be reduced, possibly providing an effect of a truncated peak, rather than a delayed and/or na ⁇ owed peak.
  • Fig. 38A and 38B are charts showing glucose reduction in two dogs, where electrodes were placed on a stomach, in accordance with an exemplary embodiment of the invention, there were 6 control repetitions and 5 stimulus repetitions, for the first dog and 7 and 6, for the second dog. Glucose peaks are shown to be reduced, possibly providing an effect of a truncated peak, rather than a delayed and/or na ⁇ owed peak.
  • Fig. 38A and 38B are charts showing glucose reduction in two dogs, where electrodes were placed on a stomach, in accordance with an exemplary embodiment of the
  • the stimulation signal was applied every other sensed "local event". In the experiments with a less pronounced reduction, the signal was applied every "local event". It is hypothesized that less frequent excitation may allow recover ⁇ ' of whatever mechanism is operating, thereby allowing a greater effect to be achieved without an associated adaptation.
  • the application may be less frequent, for example at a ratio of 1:5, 1 :10 or less, or more frequent, for example at a ratio of 1 :1.5 or more.
  • the duration may be shorter than 4 seconds, for example, be 1 second or 2 seconds, or be longer, for example, 6 or 10.
  • Other intermediate numbers are possible as well. For reference, Fig.
  • FIG. 38D shows a line diagram of the pancreas (right lobe) and stomach of a dog.
  • Figs. 39A and 39B are charts showing glucose reduction in two dogs, where electrodes ⁇ vere placed on a stomach, in accordance with an exemplary embodiment of the invention. This was described in US provisional application, 60/488,964, filed July 21, 2003, the disclosure of which is incorporated herein by reference. Reference is made to Fig. 39 A, which is a graph showing measurements of blood glucose levels taken during experiments performed in accordance with an embodiment of the present invention.
  • a single dog was anesthetized, and 2 electrodes were implanted on an external anterior wall of the antrum of the dog, between about 2 cm and about 3 cm from the pylorus.
  • the electrodes were driven to apply an electrical signal with a square waveform having 100 biphasic pulses, each phase of each pulse having an amplitude of 8 mA and a duration of 6 ms.
  • the waveform was applied following detection of the onset of each slow wave of the stomach of the dog (about 4 to 5 times per minute). While this is a different pulse sequence from others used in experiments herein, it should be noted that there is some similarity between the sequences, thereby possibly explaining the effect. Measurements were taken on two separate days, at about the same time on each day, following twelve-hour fasting, while the dog was conscious. An electrical signal was applied on one of these days, and the other day served as a control.
  • Fig. 39B is a graph showing measurements of blood glucose levels taken during experiments performed in accordance with an embodiment of the present invention.
  • hormones may increase insulin effectiveness or sensitivity in various peripheral cells or the brain.
  • the secretion of glucagon or a different hormone that affects glucose secretion is reduced.
  • the electrical stimulation changed blood flow patterns in the pancreas, as described above, to have its effect.
  • the electrical stimulation affected adipose tissue levels in the pancreas itself.
  • the electrical stimulation affects neural pathways in the pancreas and/or the liver. Possibly such neural pathways control Glucagon secretion or activate non-insulin dependent glucose transporters in cells of remote tissue.
  • the nerves that are stimulated may be, for example, nerves that cause secretion and/or prevent secretion.
  • the nerves may be, for example, nerves that that sense pancreatic, glucemic and/or hormonal activities.
  • the gap junctions of nerves and/or other excitable pancreatic tissue may be affected. It should be noted that for some nervous tissue type effects, the percentage of pancreas simulated may be less important due to propagation of the effect of the stimulation by the propagation of nervous signals in the pancreas and/or outside of the pancreas.
  • nerves in or near the pancreas either directly or indirectly. Possibly, these nerves release materials that affect the muscles, brain or other organs. Possibly, the nerves directly affect the brain which then causes the release of such materials. Alternatively or additionally, the nerves affect other tissues to release such materials, possibly via ganglionic connections.
  • the signal application penod m cluded the application of a senes of biphasic pacmg pulses, each followed by an ETC signal. Signal parameters are descnbed hereinbelow with reference to Fig 50. Other expenments were performed m a control mode, m wluch no signal was applied to the stomach The control and signal application penods were designated m a random order Figs.
  • FIG. 40A and 40B show expenmental results obtamed with the first mmipig, denved using gast ⁇ c electrodes positioned m a longitudinal onentation with respect to the axis of the stomach Eleven control expenments were performed, and seven signal application expenments were performed Both glucose and insulm are seen to be substantially reduced m the signal application penods, compared to the control penod. Similar results are seen m Figs. 41 A and 41B (for the second mmipig), and Figs 42A and 42B (for the third mmipig) Fig. 43 shows a graph summanzmg the results of the expenments shown m
  • Figs 40-42 The area under the curve (ALTC) for both glucose and msulm in all three m ipigs was substantially reduced during the 60 minute signal application penod.
  • glucose AUC reduction ranged from 25% to 60%
  • msulin AUC reduction ranged from 25% to 40%.
  • Figs. 44-46 winch are graphs showmg the results of experiments earned out in accordance with some embodiments of the present invention.
  • Sinclair minipigs different from the minipigs descnbed heremabove
  • four pairs of electrodes were implanted in a perpendicular onentation with respect to the axis of the stomach.
  • Figs. 47 and 48 are graphs showing the results of experiments carried out in accordance with some embodiments of the present invention.
  • This mixed orientation includes two pairs of electrodes having a longitudinal orientation, and two pairs of electrodes having a perpendicular orientation.
  • Fig. 49C Further details of the mixed orientation are described hereinbelow with reference to Fig. 49C. It is noted that the implantation sites of the electrodes in the mixed orientation were generally the same as the implantation sites of the electrodes in the longitudinal and perpendicular orientations; only the orientation differed.
  • the experimental protocol was otherwise generally similar to that described hereinabove with reference to Figs. 40-43.
  • Figs. 47A and 47B show experimental results obtained with the first minipig in which gastric electrodes were sutured in a mixed orientation with respect to the axis of the stomach. No substantial reduction in glucose levels is seen in the signal application experiments compared to the control experiments (Fig. 47A). It is worthy of note that insulin levels were substantially lower in the signal application experiments, compared to the control experiments (Fig.
  • Figs. 48A and 48B show experimental results obtained with the second minipig, derived using gastric electrodes positioned in a mixed orientation with respect to the axis of the stomach. A significant reduction in glucose levels (Fig.
  • Fig. 49A is a schematic illustration of an anterior antrum 802 of a stomach 800, having implanted thereon two pairs of longitudinally-oriented electrodes 804, in accordance with an embodiment of the present invention.
  • this orientation of electrodes on the stomach is refe ⁇ ed to as a "longitudinal orientation with respect to the axis of the stomach.”
  • One of the pairs is sutured to the distal antrum, and the other pair is sutured to the proximal antrum, adjacent to the body of the stomach.
  • a distance D2 of between about 1 and about 5 cm typically separates the pairs of electrodes. In the longitudinal-orientation minipig experiments described hereinabove with reference to Figs. 40-43, D2 was between about 2 and about 3 cm.
  • FIG. 49B is a schematic illustration of anterior antrum 802, showing two pairs of perpendicularly-oriented electtodes 806, in accordance with an embodiment of the present invention.
  • the scope of the present invention includes a complete range of angles therebetween, e.g., 0-30 degrees from the axis of the stomach, 30-60 degrees from the axis of the stomach, and 60-90 degrees from the axis of the stomach.
  • the angle is selected during the implantation procedure of the electrodes, e.g., responsive to real-time monitoring of glucose or insulin levels when the electrode pairs are placed at different angles with respect to each other or with respect to the axis of the stomach.
  • 49C is a schematic illustration of anterior antrum 802, showing one pair of longitudinally-oriented electrodes 804 and one pair of perpendicularly-oriented electrodes 806, in accordance with an embodiment of the present invention. (An additional pair of electtodes 804 and an additional pair of electrodes 806, not shown, are at co ⁇ esponding locations on the posterior antrum.)
  • an orientation of electtodes on the stomach combining at least one longitudinal electrode and at least one pe ⁇ endicular electrode is refe ⁇ ed to as a "mixed orientation with respect to the axis of the stomach.”
  • a distance D4 of between about 1 cm and about 5 cm typically separates the pairs.
  • electrodes are sutured to the stomach in the longitudinal orientation, the pe ⁇ endicular orientation, or the mixed orientation (e.g., in order to derive results like those described hereinabove)
  • the distance between adjacent pairs of electrodes is regulated (e.g., in order to derive results like those described hereinabove), and the orientation is not necessarily regulated.
  • two adjacent pairs of antral electtodes may be separated by between about 1 and about 4 cm (e.g., 2-3 cm), and may be placed in any orientation described hereinabove, or in a different orientation.
  • the orientations of the electrodes are defined as a spatial relationship between a vector of the electtodes and a vector of the pancreas or the stomach.
  • the vector of the electrodes is defined as a vector interconnecting the centers of the electrodes.
  • the vector of the stomach can be, for example, a tangent to the main axis of the stomach near the electrodes and optionally along the surface of the stomach (e.g., a tangent to the stomach or a cylindrical approximation thereof).
  • the vector of the pancreas can be, for example, its main axis, or an axis of a lobe thereof.
  • Electrodes for providing such different vector effects on a same organ may be provided.
  • the electrodes are positioned to have a known angle between the vectors of the electrode and an organ vector.
  • One or more of a spatial angle and an angle relative to the vertical (or other axis) of the body may be considered.
  • the angle is selected to be, for example 0, 20, 40, 60, 80, 90 degrees, or intermediate angles. Angles greater than 0 or smaller than 90 may be provided, as changes in polarity.
  • the electrodes are positioned so that the electrode vector has a certain projection on the organ vector.
  • the projection size depends not only on the angle, but also on the amplitude of the field.
  • a desired electrode location is defined as a relative angle or projection which can then be achieved using various positions, spacings and/or locations of the electrodes.
  • the exact position may depend, for example, on organ position and shape and/or on a desired or undesired effect on nearby organs. Such effects may also be characterized by the vector angles.
  • the vector may be defined taking into account the field shape closer to the target organ.
  • the electrodes are rotated during implantation, so that a desired vector effect is measured at the target tissue.
  • a vector is selected in order to reduce a possible side effect of signal application, e.g., conscious sensation of the signal application, nausea, GI a ⁇ hythmia, or local tissue irritation.
  • different electrodes are selectively activated to provide different effective vectors. For example, to avoid adaptation to the signal application, or local irritation in response to prolonged use of a single vector, electrodes may be activated to define one vector on one day, and to define another vector on the next day.
  • the following electrode is used for the stomach electtodes: stitch electtodes having inner and outer silicone rubber sheathing, multifilar MP35N®/Silver DFT, helical coil, coaxial conductors and area of 25 mm2 titanium nitride coated, platinum-iridium electrode portions.
  • the electrodes are, for example, 5, 10, 15, 20 or 30 mm long.
  • a straight, tapered point stainless steel suture needle is affixed to the end of each stitch electrode.
  • a suture pad for example of silicone, is provided adjacent the electrode.
  • This pad is, for example, 3-7 mm in diameter and includes one or more apertures for thread.
  • the cathodic (-) conductor is indicated by a black dot in the suture pad.
  • Leads can be used in two lengths, for example, 60 and 52 centimeters.
  • the leads bifurcate into individual, monopolar leads at about the mid-point (e.g., 32.5 or 24.5 centimeters from the proximal ends, respectively) and may be used, for example, to attach to a different body organ such as the duodenum, and to provide strain relief.
  • the lead connectors are optionally IS-l-BI type. In an exemplary embodiment of the invention, when attached, lead retention force is greater than IO N.
  • Fig. 50 is a graph showing the signal application protocol used in the minipig experiments described hereinabove with reference to Figs. 40-48, in accordance with an embodiment of the present invention.
  • a biphasic pacing pulse was applied, each phase being 4 mA, and 100 ms in duration.
  • a 4-second ETC signal was applied, comprising a train of biphasic pulses, each phase being 4 mA, and 5 ms in duration.
  • the biphasic pulses in the ETC signal were applied at 5 Hz, i.e., with a 200 ms delay between the onset of each successive pulse.
  • the waiting period was set greater than 7.5 seconds, and produced reductions in both glucose and insulin.
  • the scope of the present invention includes applying pacing pulses without the ETC signal, as well as applying the ETC signal without applying pacing pulses.
  • the ETC signal and the pacing pulses may have different effects on the tissue which they affect (e.g., stomach, liver, pancreas tissue), and that these different effects may combine synergistically to produce the results described herein.
  • the effect of the ETC signal in the absence of pacing pulses, or of the pacing pulses in the absence of the ETC signal may still have value in the treatment of some patients or some pathologies (e.g., diabetes or obesity), and the scope of the present invention includes such protocols.
  • the effects of such protocols are hypothesized to include protection of affected tissue and/or improvement of the timing behavior of the affected tissue.
  • all four pairs of antral electrodes were activated simultaneously to apply their respective pacing and ETC signals.
  • Figs. 5 LA and 5 IB are graphs showing experimental results from a first human patient, from an experiment performed in accordance with an embodiment of the present invention. The patient had type U diabetes for a prolonged period, prior to initiation of this experiment.
  • Electrodes were implanted on the patient's stomach in the same configuration as that shown in and described with reference to Fig. 49A. Distances Dl and D2 were about 2 cm and about 2-3 cm, respectively.
  • a biphasic pacing pulse and ETC signal were applied to the antrum of the patient's stomach, simultaneously from all four pairs of electrodes.
  • the pacing pulse and ETC signal were configured as described hereinabove with reference to Fig. 50, except that the waiting period separating the end of the ETC signal from the onset of the next biphasic pacing pulse lasted for between 4.5 and 6.5 seconds.
  • the duration of an entire cycle from one biphasic pacing pulse to the next biphasic pacing pulse ranged from 9-11 seconds.
  • the inventors have noted an overall tendency towards an enhanced acute glucose and insulin response as the duration of the cycle is reduced. However, longer cycle lengths also reduce glucose and/or insulin levels.
  • the experimental protocol included two-hour signal application periods including alternating pacing pulses and ETC signals. Each signal application period commenced at the time of administration of an OGTT. This protocol lasted for about ten days, and is refe ⁇ ed to herein as the "acute" phase. During the acute phase, a total of three signal application periods occurred, on three different days. During a second, "chronic" phase of the experiment, the 2-hour signal application periods occu ⁇ ed three times a day, beginning at the onset of meals.
  • the scope of the present invention includes providing signal application periods unsynchronized to meals, not responsive to a blood glucose measurement obtained within the last several hours or the last day, and/or less frequently than once a day, e.g., once every 2-5 days.
  • the patient Prior to the onset of this experiment, the patient was on a regular medication regimen that included sulfonylurea and metformin. With these medications, the patient's fasting glucose levels were generally at the borderline of the normal and high ranges (typically 100-120 mg/dl), prior to the beginning of this experiment. Following several days of signal application as described hereinabove, the patient's fasting blood glucose levels dropped to a low value of 70 mg/dl.
  • Figs. 52A and 52B are graphs showing experimental results from a second human patient, from an experiment performed in accordance with an embodiment of the present invention.
  • This patient had type II diabetes for a prolonged period, prior to initiation of this experiment. Electrodes were implanted on the patient's stomach in the same manner as that described with respect to the first patient. Signal application protocols were generally the same as those described with respect to the first patient.
  • the second patient Prior to the onset of this experiment, the second patient was also on a regular medication regimen that included sulfonylurea and metformin. Even with these medications, the patient's fasting glucose levels were generally above the normal range, prior to the beginning of this experiment.
  • Mechanism 1 The application of the pacing pulses and/or ETC signal through electrodes attached to the stomach affects tissue of the stomach (e.g., muscle tissue, or, indirectly, nervous tissue), and thereby leads to the observed results.
  • signals are chemically or neurally transmitted from the stomach, to the pancreas, liver, ganglia, brain, or another structure, leading to a reduction in blood glucose and insulin.
  • Mechanism 2 The application of the pacing pulses and/or ETC signal through electrodes attached to the stomach affects tissue outside of the stomach, e.g.. the pancreas, liver, or another structure outside of the stomach.
  • tissue outside of the stomach e.g.. the pancreas, liver, or another structure outside of the stomach.
  • a first portion of the current driven through the electrodes enters the stomach directly, a second portion of the current does not enter the stomach. In this embodiment, this second portion of the current affects the functioning of the pancreas, liver, or other structure, thereby leading to a reduction in blood glucose and insulin.
  • a change in electtode orientation can vary the effect of an applied electric field.
  • one or more of the following mechanisms is provided, and may, for example, be used in designing electrode placements and/or sequences.
  • Mechanism 1 The affected tissue has an orientation sensitivity, for example, favoring a state in which the field voltage varies along a column of cells or along fibers or pe ⁇ endicular to tissue layers. As the field orientation varies from the tissue orientation, the effect is reduced. Different orientations elicit different behaviors, and, in some applications, overlapping of two behaviors occurs for certain orientation angles.
  • Mechanism 2 The current flow and/or density depends on the orientation.
  • Mechanism 3 The amount of relevant tissue within the field depends on the orientation (e.g., for anatomic / geometric reasons).
  • Mechanism 4 For certain desired effects, a plurality of tissues should act in concert (e.g., some active, some inactive and/or some modulated). At certain orientations, the co ⁇ ect tissues and/or tissue types are acted upon in a manner which generates a desired effect.
  • a device comprising a control unit and a plurality of electrode pairs implanted on a patient's antrum is configured to treat both obesity and diabetes of the patient.
  • the same electrodes apply the same signal (e.g., the biphasic pacing pulse and ETC signal described hereinabove), which in the short term improves diabetes-related blood measurements, and over the longer term leads to a reduction of the patient's weight.
  • the same electrodes apply a signal configured to treat diabetes (e.g., the biphasic pacing pulse and ETC signal described hereinabove), and, at a different time, apply a signal configured to treat obesity (e.g., by inducing satiety).
  • the signal configured to treat obesity includes a signal known in the art for application to the stomach in order to treat obesity.
  • the signal configured to tteat obesity includes a biphasic pacing pulse and an ETC signal, as described hereinabove with reference to Fig. 50.
  • the ETC signal is applied at between about 10 Hz and about 100 Hz, e.g., between about 50 Hz and about 90 Hz.
  • the ETC signal applied for obesity control is about 80 Hz.
  • the duration of each phase in the biphasic ETC pulses is between about 4 and about 9 ms, e.g., about 6 ms.
  • the total duration of the train of ETC pulses applied for obesity conttol is typically 1.2 seconds, but may also be shorter or longer than 1.2 seconds.
  • Such a signal treats obesity, it is believed, by inducing satiety at an earlier time than satiety would otherwise occur.
  • the sensation of satiety may be related to a reduction of a rate of slow waves in the antrum, which reduction is induced by the applied signal. Alternatively or additionally, the sensation of satiety may be related to shape changes in the stomach, which are induced by the applied signal.
  • the ETC signal applied for obesity and/or diabetes control is not applied following a biphasic pulse (as described hereinabove), but is instead applied following a sensed naturally-occurring depolarization, e.g., a slow wave in the antrum.
  • the ETC signal may be applied 10-500 ms (e.g., 300 ms) following the sensed depolarization.
  • the electrodes that are used for treating diabetes and treating obesity are applied to the stomach in a longitudinal orientation, in a pe ⁇ endicular orientation, or in a mixed orientation, with respect to the axis of the stomach.
  • electrodes that are used for treating diabetes are applied in one orientation (e.g., longitudinal), and electrodes that are used for treating obesity are applied in a different orientation (e.g., pe ⁇ endicular).
  • a pair of diabetes-treating electrodes and a pair of obesity-treating electrodes are applied to the stomach over a common site, e.g., in a tic-tac-toe board configuration, where the angle between the pairs may be 90 degrees, or less than 90 degrees (e.g., 0-30 degrees, 30-60 degrees, or 60-89 degrees).
  • the pair of diabetes-treating electrodes and the pair of obesity-treating electrodes are lined up next to each other, or end to end.
  • a patch which serves as a mount for a pair of diabetes-treating electrodes and a pair of obesity-treating electrodes.
  • an electrode design is provided which allows for providing electric fields of various orientations.
  • the orientations are changed during implantation and/or during use, for example to determine an optimal activation sequence or when a change in orientation is desired to achieved a different effect.
  • One example of such an electrode design is a net electrode, for example a 5x5 net, where the nodes or segments (depending on the design of the electtode) are each individually addressable. By using selective shorting together of individual nodes (or segments), various shaped and/or oriented electrodes may be created.
  • curved electrodes can be created.
  • a higher resolution of orientation angle can be achieved for higher resolution nets.
  • such a next electrode includes 25 wires that are connected to a controller.
  • transistors or other switches at the next electrode or nearby are used to select (by addressing) which segments are connected to which input lines (e.g., power lines from a controller).
  • two electrodes in an electrode pair are not parallel with each other, but instead are separated by an angle of 1-45 degrees, 45-90 degrees, or 90-180 degrees.
  • the obesity-treating electtodes are activated in response to detection of eating by a patient, in order to induce an early sensation of satiety.
  • the obesity-treating electrodes are typically (but not necessarily) activated for a relatively-short time, e.g., for half an hour, or for 10-20 minutes. Subsequently thereto, the diabetes-treating electrodes are activated, typically for a longer time (e.g., about 30 minutes to several hours). Alternatively, the diabetes-treating electrodes are activated during activation of the obesity-treating electrodes. Still further alternatively, the diabetes-treating electrodes are activated for a short time (e.g., 1-10 minutes) prior to the activation of the obesity-treating electrodes, and then, typically, following the activation of the obesity-treating electrodes. In an embodiment, the diabetes-treating electrodes are activated independently of any detection of eating.
  • the diabetes-treating electrodes may be activated once or twice every day, or once or twice every week.
  • the obesity-treating electrodes and/or the diabetes-treating electtodes are activated in response to a manually-entered signal from the patient, hi accordance with an embodiment of the present invention, the obesity-treating electrodes and/or the diabetes-treating electrodes are activated in response to an indication that the stomach is at a low level of activity (e.g., because the patient has not eaten for a long time).
  • activation of the diabetes-treating electrodes while the stomach is at a low level of activity rninimizes any interfering effect of the signal application on digestion, which might occur in some patients if the signal were applied when the stomach is at a high level of activity.
  • the obesity-treating electrodes are typically only activated in response to an indication of a moderate or otherwise suitable blood glucose level (e.g., as determined by an implanted or external sensor).
  • some embodiments of the present invention provide sensing or determining an indication of glucose or insulin levels, and driving or withholding driving the obesity-treating electrodes responsive thereto. Alternatively or additionally, some embodiments of the present invention provide sensing or determining an indication of glucose or insulin levels, and driving or withholding driving the diabetes-treating electtodes responsive thereto.
  • some embodiments and experimental results described herein relate to driving the diabetes-treating electrodes when the blood glucose level is high, or about to be high
  • the scope of the present invention includes a mode in which the diabetes-treating electrodes are activated responsive to an indication of a moderate (i.e., not high) blood glucose level. This mode typically provides chronic control of blood glucose levels, rather than an acute reduction of blood glucose levels.
  • the diabetes-treating electrodes and/or the obesity- treating electrodes are applied to the antrum (e.g., as shown in Figs. 49A, 49B, or 49C).
  • the diabetes-treating electrodes and/or the obesity- treating electrodes are applied to the body of the stomach, some on the posterior portion of the stomach and some on the anterior portion of the stomach, or else exclusively on either the anterior or the posterior portion of the stomach.
  • the diabetes-treating electrodes and/or the obesity-treating electrodes are implanted on other sites described herein, e.g., the abdominal wall or the duodenum.
  • the obesity-treating electtodes and diabetes-treating electrodes described hereinabove are the same electtodes being activated in different modes. It is further to be understood that whereas some embodiments of the present invention are described hereinabove with respect to fixing electrodes to a particular tissue (e.g., the stomach), the scope of the present invention includes implanting the electrodes near the tissue (e.g., within 1, 2, or 4 cm of the tissue).
  • the scope of the invention also includes apparatus programmed and/or designed to carry out the methods, for example using firmware or software programming, and methods for electrifying the apparatus to have the apparatus's desired function.
  • surgical kits which include sets of medical devices suitable for implanting a controller and such a controller. Section headers in this application are provided only to assist in navigating the application and should not be construed as necessarily limiting the contents described in a certain section, to that section. Measurements are provided to serve only as exemplary measurements for particular cases, the exact measurements applied will vary depending on the application.
  • the terms “comprises,” “comprising,” “includes,” “including,” or the like means “including but not limited to.” Additionally, in the context of the present patent application and in the claims, it is to be understood that a subset of a set may include one member of the set, some members of the set, or all of the members of the set. It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.

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  • External Artificial Organs (AREA)

Abstract

La présente invention a trait à un procédé de contrôle de glycémie comprenant la mise à disposition d'une électrode apte à l'application d'un champ électrique à un pancréas ; et l'application d'un champ électrique au pancréas au moyen de ladite une électrode de sorte que les niveaux de glycémie soient réduits de manière significative et les niveaux d'insuline dans le sang ne soient pas accrus de manière significative par rapport à une réponse insulinique normale chez une même personne.
PCT/IL2005/000316 1999-03-05 2005-03-18 Procedes et appareils gastro-intestinaux destines a etre utilises dans le traitement des troubles et le controle de glycemie Ceased WO2005087310A2 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
EP05718889A EP1735047A4 (fr) 2004-03-18 2005-03-18 Procedes et appareils gastro-intestinaux destines a etre utilises dans le traitement des troubles et le controle de glycemie
US10/599,015 US8666495B2 (en) 1999-03-05 2005-03-18 Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar
EP05853465.2A EP1827571B1 (fr) 2004-12-09 2005-12-09 Modification de l'activite proteique
PCT/US2005/044557 WO2006073671A1 (fr) 2004-12-09 2005-12-09 Modification de l'activite proteique
US11/792,811 US9931503B2 (en) 2003-03-10 2005-12-09 Protein activity modification
CA002594673A CA2594673A1 (fr) 2004-12-09 2005-12-09 Modification de l'activite proteique
US11/884,389 US9101765B2 (en) 1999-03-05 2006-02-16 Non-immediate effects of therapy
PCT/IL2006/000204 WO2006087717A2 (fr) 2005-02-17 2006-02-16 Therapie exercant des effets non immediats
EP06711186.4A EP1868679B1 (fr) 2005-02-17 2006-02-16 Therapie exercant des effets non immediats
PCT/IL2006/000345 WO2006097934A2 (fr) 2005-03-18 2006-03-16 Electrode pour pancreas
US11/886,154 US8244371B2 (en) 2005-03-18 2006-03-16 Pancreas lead
US14/821,848 US9821158B2 (en) 2005-02-17 2015-08-10 Non-immediate effects of therapy
US15/942,637 US11439815B2 (en) 2003-03-10 2018-04-02 Protein activity modification

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US10/804,560 2004-03-18
US10/804,560 US20040249421A1 (en) 2000-09-13 2004-03-18 Blood glucose level control
ILPCT/IL2004/000550 2004-06-20
PCT/IL2004/000550 WO2004112563A2 (fr) 2003-06-20 2004-06-20 Procedes gastro-intestinaux et appareil d'utilisation de ces procedes dans le traitement de troubles
ILPCT/IL2004/000551 2004-06-20
PCT/IL2004/000551 WO2004112883A2 (fr) 2003-06-20 2004-06-20 Dispositif hepatique permettant de traiter un sujet et de detecter l'absorption d'aliments et les niveaux de glucose
ILPCT/IL2004/000664 2004-07-21
PCT/IL2004/000664 WO2005007232A2 (fr) 2003-07-21 2004-07-21 Methodes et appareil de traitement des troubles gastrointestinaux et de regulation de la glycemie
US60255004P 2004-08-18 2004-08-18
US60/602,550 2004-08-18
ILPCT/IL2004/000797 2004-09-05
PCT/IL2004/000797 WO2005023081A2 (fr) 2003-09-04 2004-09-05 Controle du niveau de glucose dans le sang
US65405605P 2005-02-17 2005-02-17
US60/654,056 2005-02-17

Related Parent Applications (5)

Application Number Title Priority Date Filing Date
US10/804,560 Continuation-In-Part US20040249421A1 (en) 1999-03-05 2004-03-18 Blood glucose level control
PCT/IL2004/000550 Continuation-In-Part WO2004112563A2 (fr) 1999-03-05 2004-06-20 Procedes gastro-intestinaux et appareil d'utilisation de ces procedes dans le traitement de troubles
PCT/IL2004/000664 Continuation-In-Part WO2005007232A2 (fr) 2003-03-10 2004-07-21 Methodes et appareil de traitement des troubles gastrointestinaux et de regulation de la glycemie
PCT/IL2004/000797 Continuation-In-Part WO2005023081A2 (fr) 1999-03-05 2004-09-05 Controle du niveau de glucose dans le sang
PCT/US2005/044557 Continuation-In-Part WO2006073671A1 (fr) 1999-03-05 2005-12-09 Modification de l'activite proteique

Related Child Applications (7)

Application Number Title Priority Date Filing Date
PCT/IL2003/000736 Continuation-In-Part WO2004021858A2 (fr) 1999-03-05 2003-09-04 Controle du niveau de glucose dans le sang
US10/526,708 Continuation-In-Part US8700161B2 (en) 1999-03-05 2003-09-04 Blood glucose level control
PCT/US2005/044557 Continuation-In-Part WO2006073671A1 (fr) 1999-03-05 2005-12-09 Modification de l'activite proteique
US11/792,811 Continuation-In-Part US9931503B2 (en) 2003-03-10 2005-12-09 Protein activity modification
PCT/IL2006/000204 Continuation-In-Part WO2006087717A2 (fr) 1999-03-05 2006-02-16 Therapie exercant des effets non immediats
US11/884,389 Continuation-In-Part US9101765B2 (en) 1999-03-05 2006-02-16 Non-immediate effects of therapy
US11/886,154 Continuation-In-Part US8244371B2 (en) 2005-03-18 2006-03-16 Pancreas lead

Publications (2)

Publication Number Publication Date
WO2005087310A2 true WO2005087310A2 (fr) 2005-09-22
WO2005087310A3 WO2005087310A3 (fr) 2005-10-20

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2005/000316 Ceased WO2005087310A2 (fr) 1999-03-05 2005-03-18 Procedes et appareils gastro-intestinaux destines a etre utilises dans le traitement des troubles et le controle de glycemie

Country Status (2)

Country Link
EP (1) EP1735047A4 (fr)
WO (1) WO2005087310A2 (fr)

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WO2006119467A2 (fr) 2005-05-04 2006-11-09 Impulse Dynamics Nv Modification d'activite de proteine
WO2008139463A2 (fr) 2007-05-09 2008-11-20 Metacure Ltd. Analyse et régulation d'une absorption de nourriture
US7634315B2 (en) 2007-05-31 2009-12-15 Pacesetter, Inc. Techniques to monitor and trend nerve damage and recovery
US8095218B2 (en) 2005-07-13 2012-01-10 Betastim, Ltd. GI and pancreatic device for treating obesity and diabetes
US8265758B2 (en) 2005-03-24 2012-09-11 Metacure Limited Wireless leads for gastrointestinal tract applications
US9233075B2 (en) 2005-08-09 2016-01-12 Metacure Limited Satiety
US9486623B2 (en) 2014-03-05 2016-11-08 Rainbow Medical Ltd. Electrical stimulation of a pancreas
US9713723B2 (en) 1996-01-11 2017-07-25 Impulse Dynamics Nv Signal delivery through the right ventricular septum
US9931503B2 (en) 2003-03-10 2018-04-03 Impulse Dynamics Nv Protein activity modification
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification

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US9289618B1 (en) 1996-01-08 2016-03-22 Impulse Dynamics Nv Electrical muscle controller
JP4175662B2 (ja) 1996-01-08 2008-11-05 インパルス ダイナミクス エヌ．ヴイ． 電気的筋肉制御装置
KR20010021797A (ko) 1997-07-16 2001-03-15 다비쉬 니심 민무늬근 조절기
US9101765B2 (en) 1999-03-05 2015-08-11 Metacure Limited Non-immediate effects of therapy
US6600953B2 (en) 2000-12-11 2003-07-29 Impulse Dynamics N.V. Acute and chronic electrical signal therapy for obesity
US7437195B2 (en) 2001-01-05 2008-10-14 Metalure N.V. Regulation of eating habits
CN1838978B (zh) 2003-06-20 2010-05-26 超治疗股份有限公司 用于治疗疾病的胃肠方法和装置
US9339190B2 (en) 2005-02-17 2016-05-17 Metacure Limited Charger with data transfer capabilities
US8442841B2 (en) 2005-10-20 2013-05-14 Matacure N.V. Patient selection method for assisting weight loss
US8934975B2 (en) 2010-02-01 2015-01-13 Metacure Limited Gastrointestinal electrical therapy

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AU4107297A (en) * 1996-09-05 1998-03-26 Governors Of The University Of Alberta, The Gastro-intestinal electrical pacemaker
DE60035181T2 (de) * 1999-03-05 2008-02-21 Metacure Ltd. Steuerung des blutzuckerspiegels
US6684104B2 (en) * 1999-04-14 2004-01-27 Transneuronix, Inc. Gastric stimulator apparatus and method for installing
US7437195B2 (en) * 2001-01-05 2008-10-14 Metalure N.V. Regulation of eating habits

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9713723B2 (en) 1996-01-11 2017-07-25 Impulse Dynamics Nv Signal delivery through the right ventricular septum
US9931503B2 (en) 2003-03-10 2018-04-03 Impulse Dynamics Nv Protein activity modification
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification
US10352948B2 (en) 2004-03-10 2019-07-16 Impulse Dynamics Nv Protein activity modification
US12268882B2 (en) 2004-12-09 2025-04-08 Impulse Dynamics Nv Beta blocker therapy with electrical administration
US8265758B2 (en) 2005-03-24 2012-09-11 Metacure Limited Wireless leads for gastrointestinal tract applications
WO2006119467A2 (fr) 2005-05-04 2006-11-09 Impulse Dynamics Nv Modification d'activite de proteine
US8095218B2 (en) 2005-07-13 2012-01-10 Betastim, Ltd. GI and pancreatic device for treating obesity and diabetes
US9233075B2 (en) 2005-08-09 2016-01-12 Metacure Limited Satiety
WO2008139463A2 (fr) 2007-05-09 2008-11-20 Metacure Ltd. Analyse et régulation d'une absorption de nourriture
US7634315B2 (en) 2007-05-31 2009-12-15 Pacesetter, Inc. Techniques to monitor and trend nerve damage and recovery
US9486623B2 (en) 2014-03-05 2016-11-08 Rainbow Medical Ltd. Electrical stimulation of a pancreas

Also Published As

Publication number Publication date
EP1735047A2 (fr) 2006-12-27
WO2005087310A3 (fr) 2005-10-20
EP1735047A4 (fr) 2011-02-09

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