EP1735047A2 - Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar - Google Patents
Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugarInfo
- Publication number
- EP1735047A2 EP1735047A2 EP05718889A EP05718889A EP1735047A2 EP 1735047 A2 EP1735047 A2 EP 1735047A2 EP 05718889 A EP05718889 A EP 05718889A EP 05718889 A EP05718889 A EP 05718889A EP 1735047 A2 EP1735047 A2 EP 1735047A2
- Authority
- EP
- European Patent Office
- 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.)
- Withdrawn
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Classifications
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- 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
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- 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
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- 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, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, 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.
- the stimulation signal is desc ⁇ bed as being adapted to influence pancreatic secretions.
- PCT publication WO 98/57701 to Medtronic suggests providing a stimulating elect ⁇ c pulse to an islet, causing an early initiation of a burst and thus, mcreasing the frequency of the bursts and increasing insulin secretion
- the above PCT publication to Medtronic suggests providing a stimulating (e g., above stimulation threshold) pulse durmg a burst, thereby stopping the burst and reducmg msulm secretion
- This publication also suggests stimulating different parts of the pancreas m sequence, thereby allowing unstrmulated parts to rest.
- 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 electric field is applied using electrodes on opposite sides of the stomach, so that a main conductive pathway between the electrode, which cannot pass through the hollow of the stomach, circumvents the stomach and passes through a portion of the pancreas.
- the electric field has little or no effect on other organs, such as the stomach.
- the electric field has a beneficial effect (e.g., glucose reduction) on one or more nearby organs.
- a potential advantage of placing electrodes on the stomach is that the stomach is relatively stable and relatively immune to injury. In particular, the problem of pancreatic perforation or infection may be avoided.
- An aspect of some embodiments of the invention relates to timing a glucose control therapy to prevent or reduce an initial raise in blood glucose levels when eating.
- 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.
- the control may be achieved using pure electrical stimulation, or possibly using one or more pharmaceuticals and/or other molecules to interact with the electrical stimulation in a desired manner.
- the pharmaceuticals may prevent the pancreatic cells from producing and/or secreting a hormone.
- the pharmaceuticals may prevent the action of the hormone, for example by blocking the receptors or disabling the hormone.
- hormones such as insulin, Somatostatin or glucagon may be provided from outside the body or using an insulin pump.
- the control is non-excitatory (defined below). In other embodiments of the invention, the control is excitatory or a combination of excitatory and non-excitatory control.
- 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 secretion of a counteracting type of hormone e.g., glucagon or insulin
- a target hormone e.g., insulm or glucagon
- the stimulation of secretion of the target hormone is maintained at low enough levels that do not cause a significant secretion of the counteracting hormone.
- the secretion time may be extended, so that the total amount of hormone is sufficient for a desired result.
- the stimulation of secretion of the target of hormone is controlled to be in bursts that are not long enough to stimulate a significant secretion of the counteracting hormone.
- the secretion may be sustained, to purposely cause secretion and/or production of the counteracting hormone to a desired degree.
- the secretion of the target hormone is maintained at a high enough level to overcome the counteracting effects.
- the stimulation of secretion of the target hormone is maintained at a high enough level to cause the generation of significant amounts of a secretion limiting hormone (e.g., Somatostatin), which secretion prevents the secretion of the counteracting hormone, but is not sufficient to prevent the stimulation from releasing of the target hormone.
- a secretion limiting hormone e.g., Somatostatin
- the secretion of several of pancreatic hormones is suppressed by hyper-polarizing the pancreas.
- hyper-polarization can be electrical in nature or chemical.
- Diazoxide causes hyper-polarization and reduces activity in the pancreas.
- beta cell response e.g., insulin secretion
- glucagon secretion is provided to prevent hyperglycemia, when high msulm levels persist m spite of reduced glucose intake.
- dampmg of msulm response and/or provision of glucagon are used to prevent overshoots caused, for example, by a delayed response to the artificial control of the pancreas
- the insulin (or other hormone) mcreasing or decreasmg pulse is applied and/or removed gradually (e g , with regard to effect or temporal frequency), to prevent such an overshoot
- an active measure such as providing an antagomstic hormone
- a stimulation when a stimulation is used to effect a large msulm secretion, glucose levels are also mcreased to prevent hypoglycemia In one example, this is provided by a glucose pump In another, th s is provided by directly stimulating the release of glucagon In another example, the insulin secretion is large or fast enough so it directly or indirectly causes glucagon secretion In one example, msulm is secreted faster than it can be cleared away by
- the liver may be overwhelmed with glucose and/or insulin, without associated hyperglycemia, so as to force complete filling of glycogen reserves and/or prevent hepatic absorption of glucose at a later time.
- insulin levels may be reduced so that less glycogen is stored in the liver. This may be useful in von Gierke's over-storage disorder and/or in other over-storage disorders.
- An aspect of some embodiments of the invention relates to mapping the response and/or feedback behavior of a pancreas. Such mapping may be used for, for example, a particular patient and/or for a type of patient and/or pancreatic disorder.
- one or more of the following properties of a pancreas is determined: (a) the interaction between two or more hormones, including one or more of the amplification gain (positive or negative), the effect of short vs. long sustained changes in one hormone level on another, delay times for effect of one hormone on another, and/or natural sequences of hormone activation; (b) response of hormone secretion and/or production to various stimulatory and inhibitor ⁇ ' effects, such as electrical fields, pharmaceuticals and/or nervous stimulation; (c) the effect of glucose levels, previous stimulation of the pancreas and/or pharmaceutical levels on the hormone interactions and responses to stimulation and to levels of other pancreatic hormones and/or other physiological parameters, for example levels of digestive enzymes; (d) burst ability vs.
- the mapping also determines the effect of non- pancreatic hormones, for example pituitary, thyroid and adrenal hormones. Some of these hormones may increase or reduce blood glucose level by direct effect on the liver.
- a direct measurement of absolute or relative hormone levels and/or a measurement of glucose levels and/or other physiological parameters is/are used to determine the effect of various stimulation. Such measurements may be on-line or off-line.
- the adaptation of the pancreas to various physiological states and/or the adaptation of the body to various pancreatic states and/or blood hormone levels is also measured. Such measuring may be performed in a laboratory.
- an ambulatory or implanted device is provided to a patent, to measure the above pancreatic behaviors over time.
- the above measured behaviors are used as parameters for a predictive model of the behavior of the pancreas.
- a new model for example a neural network type model is created from the measurements. Such a model is possibly sued to predict the effect of a therapy and/or to choose between alternative therapies.
- such a model is used to select a therapy for glucose level reduction which increases insulin secretion but does not increase glucagon secretion.
- An aspect of some exemplar ⁇ ' embodiments of the invention relates to controlling pancreatic behavior indirectly by controlling the flow of blood to the pancreas, for affecting hormone generation and secretion and/or by controlling blood flow from the pancreas, to effect hormone dissemination and/or local levels of hormone in the pancreas.
- the blood flow is controlled usmg non-excitatory elect ⁇ cal fields that selectively contract or relax arte ⁇ es and/or vems to, from or inside some or all of the pancreas
- An aspect of one exemplary embodiment of the mvention relates to a method of increasing msulm secretion, while avoiding unacceptable calcium level profiles
- insulin output is mcreased by extending a burst duration, ⁇ vhile maintaining a suitably lengthy mterval between bursts, thus allowing calcium levels to decay during the interv al
- insulin output is increased by increasing the effectiveness of calcium inflow du ⁇ ng a burst, possibly without changmg the burst frequency and/or duty cycle
- the burst frequency may be reduced and/or the mterval mcreased, while allowing higher insulin output levels or maintaining same output levels
- the effects on insulin secretion are
- 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.
- an aspect of some exemplary embodiments of the invention relates to reducing calcium levels in beta islet cells.
- the levels are reduced by providing an oral drug.
- the levels are reduced by increasing the interval between bursts. The intervals may be increased, for example, by suppressing bursts of action potentials, for example using excitatory or non-excitatory pulses.
- an electro-physiological drug is provided for that purpose.
- Procainamide HCL and Quinidine sulfate are Na channel antagonists
- Minoxidil and Pinacidil are K channel activators
- Amiloride HCL is an Na channel and epithelial antagonist.
- 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
- a pulse optionally synchronized to individual action potentials in an islet, is used to control the action potential, for example to increase or decrease its plateau duration.
- a reduction in action potential frequency towards the end of a burst is counteracted, for example by pacing the cells to have a desired frequency or to be more excitable.
- action potential propagation is controlled, for example enhanced or blocked, by selectively sensitizing or desensitizing the beta cells in an islet, using chemical and/or electrical therapy. Enhancement of action potential may be useful for increasing insulin production rates, especially if the glucose sending mechanism in some cells are damaged.
- 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 control unit is adapted to d ⁇ ve the first subset responsive to a detection of eatmg by the patient
- the implantation site includes an antrum of a stomach of the patient, and wherem the set of electrodes includes at least two pairs of electrodes, adapted to be fixed to the antrum
- the set of electrodes includes at least four pairs of electrodes, adapted to be fixed to the antrum.
- one of the pairs is adapted to be fixed to a poste ⁇ or portion of the antrum, and wherein another one of the pairs is adapted to be fixed to an anterior portion of the antrum.
- 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.
- control unit is adapted to initiate applying the signal having the first frequency component during a refractory period of the implantation site induced by the pacing pulse. In an embodiment, the control unit is adapted to initiate applying the signal having the first frequency component within 500 ms following the pacing pulse. In an embodiment, the first frequency component is less than 10 Hz, and wherein the second frequency component is greater than 10 Hz. In an embodiment, the second frequency component is between 60 Hz and 100 Hz. In an embodiment, the fust frequency component is less than half of the second frequency component. In an embodiment, the first frequency component is less than one fifth of the second frequency component.
- a method including: fixing at least two pairs of electrodes to a stomach site of a patient, in a longitudinal 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.
- method including: fixing at least two pairs of electrodes to a stomach site of a patient, in a perpendicular 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.
- 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.
- fixing the at least two pairs of electrodes includes fixing at least four pairs of electrodes to the antrum. In an embodiment, fixing the at least two pairs of electrodes includes fixing one of the pairs to a posterior portion of the antrum and fixing another one of the pairs to an anterior portion of the antrum. In an embodiment, driving the electrodes to apply the signal includes driving the electrodes to apply an ETC signal having a frequency component. In an embodiment, the method includes driving the electrodes to apply the ETC signal includes driving the electrodes to apply the ETC signal without driving the electrodes to apply a pacing pulse prior to applying the ETC signal. In an embodiment, the method includes driving the electrodes to alternate application of (a) a pacing pulse and (b) the ETC signal.
- the method includes initiating applying the ETC signal during a refractory period of the stomach site induced by the pacing pulse. In an embodiment, the method includes initiating applying the ETC signal within 500 ms following the pacing pulse. In an embodiment, driving the electrodes includes setting the frequency component to be less than 10 Hz. In an embodiment, driving the electrodes includes setting the frequency component to be greater than 10 Hz.
- 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 controller comprises a casing suitable for long term implantation inside the body.
- said electrode is adapted for long term contact with bile fluids.
- the apparatus comprises an electrical activity sensor for sensing electrical activity of said cell and wherein said power source electrifies said electrode at a frequency higher than a sensed depolarization frequency of said cell, thereby causing said cell to depolarize at the higher frequency.
- said pulse is designed to extend a plateau duration of an action potential of said cell, thereby allowing more calcium inflow into the cell.
- said pulse is deigned to reduce an action potential frequency of said cell, while not reducing insulin secretion from said cell.
- 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 comp ⁇ ses selectively modifying only one of said at least two members, while at least reducing a causative interaction between said two members.
- controlling comprises mamtai iing at least one of said members within a desired physiologic range.
- said at least two members comprise glucose level and insulin level.
- controlling comprises modulating an effect of said insulin not related to carbohydrate metabolism.
- at least one of said two members comprise glucagon.
- controlling comprises increasing glucagon secretion, to contract an effect of insulin.
- controlling comprises increasing glucagon secretion, to achieve higher blood glucose levels.
- 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 molecules suppress the secretion of at least one pancreatic hormone. Alternatively or additionally, wherein said molecules suppress the effect of at least one pancreatic hormone. Alternatively or additionally, said molecules enhance the secretion of at least one pancreatic hormone. Alternatively or additionally, said molecules enhance the effect of at least one pancreatic hormone.
- controlling a member hormone comprises suppressing a secretion of an antagonistic hormone. Alternatively or additionally, controlling a member hormone comprises enhancing a secretion of an antagonistic hormone.
- said controller comprises a learning memory module for storing therein feedback interaction of said pancreas. Optionally, said feedback interactions comprises interactions between hormone levels.
- 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.
- said electrode modifies blood flow associated with said pancreas to effect said control.
- said modified blood flow comprises blood flow to hormone generating cells of said pancreas.
- said modified blood flow comprises blood flow from said pancreas.
- said modified blood flow comprises blood flow from hormone generating cells of said pancreas.
- said at least one electrode comprises at least two electrodes that selectively electrify different parts of said pancreas, to achieve a desired control of said at least two members.
- controlling comprises controlling secretion.
- controlling comprises controlling production.
- controlling comprises controlling physiological activity.
- 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.
- said sets of conditions are naturally occurrmg Alternatively, said sets of conditions are at least partially artificially induced
- the method comp ⁇ ses controlling said pancreas responsive to said determmed behavior
- a method of controlling burst activity of a pancreas comp ⁇ sing applying an elect ⁇ cal field to at least part of a pancreas such that burst activity is initiated a few seconds after said application, and repeating said application a plurality of times such that substantially all burst activity of said part of a pancreas during a time pe ⁇ od spanning said applications is synchronized to said application and repeated application
- the method comp ⁇ ses varying a repetition rate of said application to control a burst rate of said at least part of a 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.
- a method for treating a subject including: applying an electrical signal to a colon or a distal small intestine of the subject; and configuring the signal to stimulate cells to increase secretion of glucagon-like- peptide-1 (GLP-1), in order to treat the subject.
- the method includes detecting eating by the subject, and applying the electrical signal includes applying the signal responsive to detecting the eating.
- a method for treating a subject including: applying an electrical signal to a stomach of the subject; and configuring the electrical signal to reduce a blood glucose level of the subject, in order to treat the subject.
- 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 elect ⁇ cal signal to at least one stomach site of the subject, and configu ⁇ ng the elect ⁇ cal signal to reduce a ⁇ se m a blood glucose level of the subject, m order to treat the subject
- applying the elect ⁇ cal signal includes applying an Excitable-Tissue Control (ETC) signal
- 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 corpus site includes a poste ⁇ or gast ⁇ c corpus site
- applying the signal includes applying the signal between the poste ⁇ or gast ⁇ c corpus site and the gast ⁇ c antrum site
- the gast ⁇ c antrum site mcludes a poste ⁇ or gast ⁇ c antrum site
- applying the signal includes applying the signal between the poste ⁇ or gast ⁇ c corpus site and the poste ⁇ or gast ⁇ c antrum site.
- the gast ⁇ c antrum site includes an ante ⁇ or gast ⁇ c antrum site
- applying the signal includes applying the signal between the poste ⁇ or gast ⁇ c corpus site and the ante ⁇ or gast ⁇ c antrum site
- the gast ⁇ c corpus site mcludes an ante ⁇ or gast ⁇ c corpus site, and applymg the signal mcludes applying the signal between the ante ⁇ or 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 second gast ⁇ c corpus site mcludes a poste ⁇ or second gast ⁇ c corpus site, and applying the signal includes applymg the signal between the poste ⁇ or first gast ⁇ c corpus site and the poste ⁇ or second gast ⁇ c corpus site
- the second gast ⁇ c corpus site includes an ante ⁇ or second gast ⁇ c corpus site
- applymg the signal includes applying the signal between the poste ⁇ or first gast ⁇ c corpus site and the ante ⁇ or second gast ⁇ c corpus site
- the first gast ⁇ c corpus site includes an ante ⁇ or first gastnc corpus site, and applying the signal mcludes applying the signal between the ante ⁇ or first gast ⁇ c corpus site and the second gast ⁇ c corpus site
- the second gast ⁇ c corpus site mcludes a poste ⁇ or second gast ⁇ c corpus site, and applymg the signal mcludes applymg the signal between the ante ⁇ or first gast ⁇ c corpus site and the poste ⁇ or second gast ⁇ c corpus site
- the second gast ⁇ c corpus site mcludes an antenor second gast ⁇ c corpus site, and applymg the signal mcludes applying the signal between the ante ⁇ or first gast ⁇ c corpus site and the ante ⁇ or second gastric corpus site
- the at least one site includes a first gast ⁇ c antrum site and a second gast ⁇ c antrum site, and applymg the signal mcludes applying the signal between the first gast ⁇ c antrum site and the second gastnc antrum 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 gastnc antrum site includes a postenor second gastnc antrum site
- applying the signal includes applying the signal between the antenor first gastnc antrum site and the poste ⁇ or 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 applying five or more pulses to the site during each of a plurality of slow wave cycles of the subject. In an embodiment, applying the electrical signal includes applying 1 to 5 pulses to the site during each of a plurality of slow wave cycles of the subject. In an embodiment, applying 1 to 5 pulses includes applying one pulse to the site during each of the plurality of slow wave cycles. In an embodiment, applying the electrical signal includes configuring a frequency of the electrical signal to be between 1 and 30 Hz. In an embodiment, configuring the frequency includes configuring the frequency to be between 10 and 30 Hz. In an embodiment, configuring the frequency includes configuring the frequency to be between 1 and 10 Hz. In an embodiment, configuring the frequency includes configuring the frequency to be between 2.5 and 7.5 Hz.
- 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
- applying the burst of pulse includes initiating applying the burst of pulses between 100 and 500 ms following the termination of the initiating pulse.
- applying the initiating pulse includes configuring a duration of the initiating pulse to be between 50 and 500 ms.
- configuring the duration includes configuring the duration to be between 50 and 150 ms.
- FIG. 1 is a block diagram of a pancreatic controller, in accordance with an exemplary embodiment of the invention
- Fig. 2 is a diagram of an exemplary electrical activity of a single beta cell, operating at slightly elevated glucose levels
- Fig. 3A is a flowchart of an exemplar ⁇ ' control logic scheme, in accordance with an exemplary embodiment of the invention
- Fig. 3B is a flowchart of another exemplary control logic scheme, in accordance with an exemplary embodiment of the invention
- Figs. 4A-4D illustrate different types of electrodes that may be suitable for pancreatic electrification, in accordance with exemplary embodiments of the invention
- Fig. 4E illustrates an electrode, in which the body of the controller of Fig.
- Fig. 1 serves as at least one electrode, in accordance with an exemplary embodiment of the invention
- Fig. 5 illustrates a pancreas subdivided into a plurality of control regions, each region being electrified by a different electrode, in accordance with an exemplar ⁇ ' embodiment of the invention
- FIGS. 6A and 6B are flowcharts of implantation methods, in accordance with exemplary embodiments of the invention
- Fig 6C is a schematic illustration of an abdominal cavity showing electrode placement on a stomach m proximity to a pancreas
- Fig 7 is a flowchart of an exemplary method of controller implantation and programming, in accordance with an exemplary embodiment of the mvention
- Fig 8A is a chart showmg the effect of electncal stimulation on msulm levels
- Fig 9 is a graphic showmg the effect of elect ⁇ cal stimulation on blood glucose levels, m an experiment m which glucose levels are mcreased faster than would be expected solely by inhibition of insulin secretion.
- Figs 10A-10B are a chart and a pulse diagram, respectively, of an expenment showmg reduction in glucose le els as a result of applymg an elect ⁇ cal pulse in accordance with an exemplary embodiment of the invention
- Figs 11 A-l IB are a chart and a pulse diagram, respectively, of an experiment showmg reduction m glucose levels as a result of applymg an elect ⁇ cal pulse in accordance with an exemplary embodiment of the mvention
- Figs 12A-12B are a chart and a pulse diagram, respectively, of an expenment showing reduction in glucose levels as a result of applymg an electncal pulse in accordance with an exemplary embodiment of the mvention.
- Figs 13A-13B are a chart and a pulse diagram, respectively, of an expenment showing reduction in glucose levels as a result of applying an electncal pulse m accordance with an exemplar ⁇ ' embodiment of the mvention.
- Fig 14 is a chart showmg an expenment in which applymg stimulation pulses increased the amplitude of bursts but did not induce new bursts
- Figs 15A-15C are a chart and two enlargements thereof of an expenment showmg that a stimulation pulse synchronizes burst activity, possibly without immediately generating a new burst
- Figs 1 A-16C are a chart and two enlargements thereof of an expenment showmg new burst induction by a stimulation pulse.
- Fig 17 is a chart of an experiment showing that a stimulation in the middle of a burst did not stop the burst
- Figs. 18A and 18B are charts showing changes in insulin level apparently caused by stimulation
- Fig. 19 is a chart showing relative constant glucose levels in a perfused rat pancreas without stimulation
- Fig. 20A is a chart showing changes in insulin levels with and without stimulation, in a live mini-pig given sugar cubes to eat
- Fig. 20B is a chart co ⁇ esponding to chart 20A, showing for the stimulation case the relationship between glucose level and insulin level
- Fig. 20C is a chart co ⁇ esponding to chart 20A, showing for the non- stimulation cases, the relationship between glucose and insulin level
- 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. 27 is a chart showing the effect, in a human, on glucose levels, of a stimulation in accordance with an exemplar ⁇ ' embodiment of the invention
- Fig. 28 is a chart showing the effect, in a human, on insulin levels, of a stimulation in accordance with an exemplary embodiment of the invention
- Fig. 29 is a chart showing the effect, in a human, on c-peptide levels, of a stimulation in accordance with an exemplary embodiment of the invention
- Figs. 30A and 30B are charts showing a lack of dangerous effect of stimulation in accordance with an exemplar,' embodiment of the invention, on the glucose levels of a fasting human
- 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. 34 shows accumulated levels of glucose under various field application conditions, in accordance with exemplary embodiments of the invention
- Figs. 35 A and 35B are charts showing glucose and insulin reduction in another pig, in accordance with an exemplary embodiment of the invention
- Figs. 35C and 35D show accumulated levels of glucose and insulin in the pig of Figs. 35A and 35B
- Fig. 36 shows glucose level reduction in another pig, in accordance with an exemplary embodiment of the invention
- Figs. 37A and 37B are charts showing glucose and insulin reduction in a dog, in accordance with an exemplary embodiment of the invention
- Figs. 35 A and 35B are charts showing glucose and insulin reduction in another pig, in accordance with an exemplary embodiment of the invention
- Figs. 35C and 35D show accumulated levels of glucose and insulin in the pig of Figs. 35A and 35B
- Fig. 36 shows glucose level reduction in another pig, in accordance with an exemplary embodiment of the invention
- FIGS. 38A and 3 SB are charts showing glucose reduction in two dogs, where electrodes were placed on a stomach, in accordance with an exemplary embodiment of the invention
- FIG 38C is a chart showing varying effect of experiments with intermittent and experiments with contmuous signal application to a dog, in accordance with exemplary embodiment of the mvention
- Fig 38D is a schematic showmg of the relative locations of a nght lobe of a pancreas and a stomach m a dog
- Figs 39A and 39B are charts showing glucose reduction in two dogs, where electrodes were placed on a stomach, m accordance with an exemplary embodiment of the invention
- Figs 40-48 are charts showing experimental results, de ⁇ ved in accordance with exemplary embodiments of the present mvention
- Figs 49A, 49B, and 49C are schematic illustrations of implantation protocols, m accordance with respective embodiments of the present rm ention
- Fig 50 is a schematic illustration of a signal application protocol, in accord
- Fig 1 is a block diagram of a pancreatic controller 102, in accordance with an exemplary embodiment of the mvention
- device 102 is used to provide controlling pulses of elect ⁇ city to a pancreas 100
- controlling pulses may include excitatory stimulating pulses and non- excitatory pulses
- such pulses can include pacmg pulses and action potential modifying pulses
- the controlling pulses are used to control the glucose and insulm level of a patient
- a particular desired profile of glucose and/or insulm may be achieved Alternatively or additionally, the secretion and/or generation of other pancreatic hormones may be controlled
- controller 102 will be evident from the descnption below and can mclude, for example, training, healing and preventmg damage of pancreatic cells Exemplar ' and non-limiting examples of metabolic and/or hormonal disorders that may be treated
- EXEMPLARY DEVICE Pancreatic controller 102 includes generally a field source 104 for generating electric fields across pancreas 100 or portions thereof, which field source is controlled by control circuitry 106.
- a power source 108 optionally powers field source 104 and control circuitry 106.
- the electrification is applied using a plurality of electrodes, for example a common electrode 110 and a plurality of individual electrodes 1 12. Alternatively other electrode schemes are used, for example a plurality of electrode pairs.
- Electrical and other sensors may be provided as well, for input into controller 106.
- the electrodes may also serve as electrical sensors, in an exemplary embodiment of the invention, separate sensors, such as a pancreatic sensor 114 or a glucose blood sensor 118 on a blood vessel 120, are provided. Extra-cellular sensors, for measuring inter-cellular glucose levels, may also be provided.
- Controller 102 may also include an external unit 116, for example for transmitting power or programming to control circuitry 106 and/or power source 108.
- the external unit may be used to provide indications from a patient and/or sensor information.
- the external unit may be used to provide alerts to the patient, for example if the glucose level is not properly under control.
- alerts may be provided from inside the body, for example using low frequency sounds or by electrical stimulation of a nerve, a muscle or the intestines. Additional details of this and other exemplary implementations will be provided below.
- controller 102 may utilize elements and design principles used for other electro-physiological controllers, for example as descnbed in PCT publications WO97/25098, WO98/10831, WO98/10S32 and US patent application 09/260, 76°>, issued as patent 6,292,693 the disclosures of which are incorporated herem by reference
- the frequencies, power levels and duration of pulses m the pancreas may be different from those used, for example, m the heart In particular, the power levels may be lower
- the immediate effects of an error in applying a pulse to the pancreas are not expected to be as life threatening as a similar e ⁇ or in the heart would be, excepting the possibility of tissue damage, which could cause an increase m se ⁇ enty of disease of the patient TISSUE TO WHICH THE CONTROLLER IS APPLIED
- the present mvention is desc ⁇ bed mamly with reference to pancreatic tissues
- 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
- the entire islet may be generally silent or contain only sporadic depolanzation events Individual cells may operate at higher frequencies, foi example, 5-20 Hz Alternatively or additionally, a slow wave may provide an envelope of about 3-5 cycles/min.
- the synchronization and or co ⁇ elation between cells in an islet may depend on gap junctions between beta and other cells. The resistance or such gap junctions may depend on the glucose and/or hormone levels, and as such, may also be determined and controlled, in accordance with some embodiments of the invention. Alternatively or additionally, the level of synchronization in an islet and/or between islets may be used as an indicator for glucose and/or hormone levels.
- the secretion of insulin may be increased in several ways, in accordance with exemplary embodiments of the invention.
- the following methods may be applied together or separately. Also, these methods may be applied locally, to selected parts of the pancreas, or globally, to the pancreas as a whole.
- a first method the duration of a burst 132 is increased, thus allowing more calcium to enter the beta cells. It is believed that the level of calcium in the cell is directly related to the amount of insulin released by the cell.
- One type of pulse which may be applied is a pacing pulse, which forces the cells in the islet to depolarize.
- Such a pulse is optionally applied at the same frequency as individual action potentials, e.g., 10 Hz. However, it may not be necessary to pace every action potential, a periodic pacing signal may be sufficient to force continuous depolarization events.
- a periodic pacing signal may be sufficient to force continuous depolarization events.
- many techniques can be applied to increase the capture probability of the pacing signal, for example, double pacing, pulse shape and duration. These methods may also be applied, with suitable modifications, to the pacing of the pancreas.
- An alternative method of increasing burst length is by increasing the sensitivity of the beta cells to depolarization, for example, by sub- threshold pulses.
- insulin secretion is increasing by increasing the calcium inflow efficiency of the individual action potentials. In an exemplary embodiment of the invention, this is achieved by increasing the length of the plateau durations 144, for example by applying an electric pulse during the repolarization period associated with each of depolarization events 142.
- depolarization period 142 is optionally extended, for example by applying an additional depolarizing pulse during the depolarization or very shortly after.
- a pharmaceutical that enhances repolarization may be provided, so that the repolarization time is shorter and more of the duration of a burst 132 can be spent in depolarization events.
- a plateau duration can be shortened by applying a suitable pulse during the plateau.
- applying a pulse after the calcium channels close is expected to shorten the repolarization time.
- the individual action potentials are paced, at a rate higher than normal for the glucose level. This pacing can override the end of repolarization and force more frequent depolarization events. It is noted that a considerably higher pacing rate can be achieved by pacing than would naturally occur for same physiological conditions. Possibly, the pacing rate is higher than physiologically normal for an islet at any glucose level.
- the insulin secretion is enhanced by pacing the islets to have a higher frequency of bursts (as opposed to a higher frequency of action potentials, described above).
- the resulting shortening in intervals 134 may have undesirable effects, for example by maintaining high calcium levels in a cell for too long a period of time.
- this potential shortcoming is overcome by increasing the interval durations, for example, by applying a hyper-polarizing pulse during the interval, thus allowing calcium to leak out of the beta cells. It is noted however, that in some cases, sustained elevated calcium levels may be desirable, in which case, the intervals may be artificially shortened. In compensation, the effectiveness of the burst in causing the secretion of insulin may be reduced.
- 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 article is '"Contraction-Induced Fatty Acid Translocase/CD36 Translocation in Rat Cardiac Myocytes Is Mediated Through AMP-Activated Protein Kinase Signaling", in Diabetes 2003 Jul;52(7): 1627-34, by Luiken JJ, Coort SL, Willems J, Coumans WA, Bonen A, Van Der Vusse GJ, Glatz JF, of the Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University,
- insulin levels are indirectly controlled by reducing glucose levels.
- glucose levels are reduced using electrical stimulation as described below.
- the electrical stimulation reduces glucagon levels.
- FIG. 3A is a flowchart of an exemplary control logic scheme 200, in accordance with an exemplary embodiment of the invention. In this scheme, the intensity of pancreatic activity (and associated dangers) is increased with the increase in glucose level. The various methods of increasing and decreasing pancreatic activity are described in more detail above or below. Alerts are optionally provided to the patient at extreme glucose levels.
- the method possibly prefers to enor on the side of causing hyperglycemia, whose adverse effects are less critical than those of hypoglycemia, whose adverse effects are immediate. It is noted than automated control logic for controlling glucose levels have been developed previously for insulin pumps and may also be applied for controller 102. An added ability of controller 102 is to suppress the body's own production of insulin. .An added limitation which controller 102 optionally takes into account is the avoidance of damaging the pancreas by over stimulation.
- the glucose level is determined. Many methods may be used to determine glucose level. In an exemplary embodiment of the invention, in cases of hyperglycemia, the measurement is repeated several times before starting treatment.
- 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.
- the action taken can depend on the degree of change, direction of change and/or rate of change of glucose levels.
- a model of insulin secretion, digestion and/or effect on blood glucose level are used to assess the significance of changes in glucose level. If the glucose level is between 250 and 300 (220), an even higher pulse application rate, such as 1 : 1, can be applied (222). Glucose levels higher than 300 can be quite dangerous. Thus, if such high rates are determined, a faster pacing rate, to the burst or to the individual action potentials (224), may be applied. Alternatively or additionally, a non-excitatory pulse to enhance secretion is also applied to at least some of the pacing pulses.
- a bi-phasic pacing pulse for the individual action potentials (228) may be provided. Such a pulse is expected at its first phase to induce depolarization and at its second phase to extend a plateau duration such that calcium inflow is increased.
- control of multiple pancreatic regions may be provided, to increase the total portion of the pancreas being used to secret insulin at a higher rate.
- emergency measures may be required, for example alerting the patient or his physician (232) and dumping all available insulin in the pancreas (234). A store of available insulin may be maintained in the pancreas or in device 102 (or an associated insulin pump) for just these cases.
- This control method utilizes delayed closed loop control circuits.
- open-loop circuits, winch are similar to conventional glucose level management, may be provided.
- the amount of insulin output from a particular pulse application is known and is applied responsive to an infrequent measurement of the glucose level, for example using a blood test.
- Periodic glucose level testing may be applied to detect failed control.
- Intermediate control loops, control circuits having a smaller delay and combined control loops may be used in other exemplar ⁇ ' embodiments of the invention.
- short term effects include, for example effects on of insulin secretion and production.
- Long term effects include, for example, effects on tissue viability and capability and electrode polarization. As will be described below, long terms effects may be negative, such as cell death, or positive, such as training or promoting healing.
- Polarization and encrustation of the electrodes are optionally avoided by using ionic electrodes and applying balanced pulses (with substantially equal positive and negative charges).
- special coated electrodes such as those coated with Indium oxide or titanium nitride, may be used.
- 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.
- Over stressing can kill the cell.
- the level of stress that enhances the cells' operation may need to be determined by trail and enor for each patient.
- the trial and errors are performed on different parts of the pancreas, optionally with a bias to under-stressing rather than for over stressing.
- over stressing is determined by a marked reduction in insulin output or by reduced or abnormal electrical response.
- a pancreatic cell insensitive to medium glucose levels may be trained to be sensitive to lower glucose level, by exciting it more frequently and/or exciting it at times of slightly elevated glucose levels.
- 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.
- Fig. 3B for clarity presentation.
- the reference numbers in Fig. 3B are 40 more than for corresponding elements in Fig. 3A.
- Fig. 3B illustrates controlling hormonal levels, increasing glucagon secretion and selecting a treatment protocol or parameter based on the effect on pancreatic hormones other than insulin.
- a glucose level sensing (242)
- insulin secretion is optionally suppressed (246).
- glucagon secretion is increased (245).
- an additional test is optionally performed, as to whether the hormonal levels are normal (251).
- 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.
- the pancreas may be capable of responding correctly, however, the pancreas is not sensitive enough in detection so that its response is delayed and/or is smaller than it should be to changes in blood glucose levels and/or digestion events.
- the pancreas is capable of a second, slower response (e.g., elevating insulin levels sufficiently after several tens of minutes) but not of an initial response
- controller 102 is used to ensure that the pancreas responds (as indicated below) with a sufficient amplitude and/or minimal delay.
- 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
- the total effect of such a bolus may be to reduce the amount of msulm actually secreted by the pancreas
- such a bolus is applied before ingestion
- a normal pancreas is expected to exhibit an acute response to an mgestion event by providing an initial bolus of Glucose and to cause the shutting down of glucose secretion by the liver (albeit, at a time delay)
- controller 102 For example, at least 20%, 40%, 60%, 80% or more of the peaks may be reduced by 50%>, 70% or more relative to baseline values OPEN LOOP LOGIC
- over stimulation has fewer and/or less dangerous side effects than under stimulation
- this reduction in side effects is used to design control schemes which err on the side of over stimulation, I e ,
- open loop is meant that the pulse series is applied using a fixed protocol without checking its effect at all.
- some of the pulse series described below do not require synchronization to pancreatic activity and no measurement of pancreatic electrical activity is necessary, at least not during application of the pulse series.
- some types of electrical stimulation reduce high glucose levels but do not substantially reduce normal glucose levels.
- general suppression of the pancreas when glucose levels are near normal (or even on the rise in some cases) may prevent secretion of insulin and/or glucagon which might upset the balance.
- open loop stimulation is used to reduce glucose levels prior to digestion and/'or during digestion of a meal.
- open loop stimulation is used to periodically or semi-continuously reduce glucose levels.
- a pulse series as shown below, which does not substantially affect normal glucose levels, is used.
- a user has an external controller, for example a magnetic or RF control wand which communicates the fact of eating with controller 102.
- a signal (for example to decrease glucagon secretion) is sent prior to eating, as stopping glucose secretion by the liver (e.g., as a result of glucagon increase or other mechanism) may take tens of minutes.
- Another safety feature of a stimulation in accordance with some embodiments of the invention is that prolonged stimulation appears to have no significant side effects on any of pancreatic viability, pancreatic endocrine function and pancreatic exocrine function.
- PULSE SHAPES AND PARAMETERS The range of pulse forms that may be applied usefully is very wide. It must be noted that the response of the cells in different patients or of different cells in a same patient, even to same pulses, is expected to differ considerably, for example due to genetics and disease state. Also, the conduction of electrical signals in the vicinity of the pancreas is affected by the irregular geometrical form of the pancreas and the layers of fat surrounding it. These isolating layers may require the application of higher than expected amplitudes.
- the application of the pulse is for affecting a certain portion of the pancreas and not the entire pancreas.
- the lack of significant propagation of action potentials from one islet of the pancreas to another may require a relatively uniform field m the part of the pancreas to be affected
- completely uniform fields are not required as any edge effects are contamed only to the islets with the intermediate electric field strengths and/or because it is expected that the cell behavior does not vary sharply with the applied amplitude, except perhaps at certain threshold levels
- the beta cells' behavior may be dependent on glucose level, on cellular msulm storage lev el and or on prev IOUS activity of the cells Unlike cardiac cells, which operate continuously and typically at a limit of their ability and/or oxygen usage, normal pancreatic cells are provided with long rests and are operated at sub- maximal levels
- a first parameter of the pulse is whether it is AC or DC As the pulse may be applied penodically, the term DC pulse is used for a pulse that
- vanous duty cycles can be used, for example 10%, 50%>, 90% and 100%)
- the percentages may reflect the on/off time of the pulse or they may reflect the relative charge densities dunng the on and off times
- a 50%> duty cycle may be providing, on the average, 50% of the maximum charge flow of the pulse
- a pulse may be unipolar or bipolar
- balanced pulses havmg a total of zero charge transfer, are used Alternatively, however, the balancing may also be achieved over a train of pulses or over a longer penod It is expected that at least for some pulse effects, the islets will act mdependently of the polanty of the applied pulse However, changes in polanty may still have desirable effects, for example by creating lomc currents
- Different pulse envelopes are known to mteract with cell membranes m different ways
- the pulse envelope may be, for example, sinusoid, triangular
- the pulse envelope is selected to take into account vanations in tissue impedance dunng the pulse application and/or efficiency and/or simplicity of the power electronics
- the pulse current is controlled, for example to remain within a range
- the pulse voltage is controlled, for example to remain within a range.
- both current and voltage are at least partly controlled, for example maintained in certain ranges Possibly, a pulse is defined by its total charge.
- pulses will generally, but not necessa ⁇ ly, have different amplitudes
- the different effects of the pulse may also be a function of the cell activity phase and especially the sensitivity of the cell to electric fields at the time of application
- Exemplar ⁇ ' pulse amplitude types are sub-threshold pulses that affect the depolanzation state of the cell and channel affectmg pulses
- These pulses are non- limitmg examples of non-excitatory pulses, which do not cause a propagating action potential in the islet, either because of absolute low amplitude or due to relative low amplitude (relative to cell sensitivity).
- Pacing pulses definitely cause a propagating action potential, unless the pacing pulse captures all the cells in the islet, in which case there may be nowhere for the action potential to propagate to.
- "Defibrillation" pulses are stronger than pacing pulses and cause a rest in the electrical state of the affected cells. Pore forming pulses, for example high voltage pulses, create pores in the membrane of the affected cells, allowing calcium to leak in or out and/or allowing insulin to leak out.
- the above pulse types were listed in order of increasing typical amplitude. Exemplary amplitudes depend on many factors, as noted above. However, an exemplary pacing pulse is between 1 and 20 mA.
- 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.
- the delay between the pacing pulse and the action potential control pulse can depend, for example, in the shape of the action potential and especially on the timing of opening and closing of the different ionic channels and pumps. Exemplary delays are 10, 50, 200 and 400 ms.
- a graded pulse is applied. A first part of the pulse blocks first cells from responding to a second part of the pulse. Such a pulse may be used, for example, to differentiate between different cell types, between cells having different stimulation levels and/or between cells having a fast response and cells having a slow response. The exact behavior of such a pulse and/or suitable parameters may be determined during a training stage, described with reference to
- Fig. 7, below With the caveat that different experiments were performed on different animals species, in different stages of life, the experimental, it appears that as a general rule pulses of 20 HZ and 100 Hz, under some parameter settings, induce new bursts (and increase insulin secretion). Pulses of 5 Hz, at least in-situ do not appear to induce new burst and are therefore non-excitatory.
- a particular 5 Hz pulse which is shown to reduce glucose without substantially increasing, or even decreasing insulin is a bi-phasic pulse, with each phase being 5 ms long and 190 ms between individual pulses, i.e., a 5 Hz carrier. This pulse is applied without synchronization to pancreatic electrical activity.
- a pulse which consists of a short duty cycle repeated at a low frequency can be viewed as a low frequency wave (e.g., 5 Hz) overlaid with a higher frequency wave (bi-phasic pulse of 10 ms duration).
- the low frequency is used carry the effects of the electrical field into the pancreas.
- the pulse low- frequency components are selected to have periodicity similar to that of (normal) pancreatic cells, of the type targeted.
- pulse width e.g., the high-frequency components
- pulse width are selected to specifically target certain cell types, for example, beta cells, alpha cells and nervous cells. For example, it appears, but is not certain, that lower frequencies (e.g., the 5 Hz component) affects islet activity and higher frequencies affect neural pathways.
- lower frequency pulses e.g., even DC
- hyper polarization of cells are used for hyper polarization of cells.
- va ⁇ ous pulse forms contemplated, also different variations in their periodicity are contemplated.
- a first consideration is whether to synchronize an excitatory and/or a non- excitatory pulse to the pancreatic activity or not. If the pulse is synchronized, it can be synchronized to the activity of particular cells or islets being measured. As noted above, a pacing pulse to the pancreas can force synchronization. The pulse may be synchronized to individual action potentials and/or to burst activity.
- a pulse may be synchronized to the start or end of the burst or to changes m the burst envelope, for example, significant reductions m the action potential frequency or amplitude
- synchronization to an event m cludes being applied at a delay relative to the event occurring or at a delay to when the event is expected to occur (positive or negative delay)
- Such a delay can be constant or can v ary, for example bemg dependent on the action potential or the burst activity
- the pulse may be applied at every event to which it is synchronized for example every action potential or every burst Alternatively, pulses are applied to fewer than all events, for example at a ratio of 1 2, 1 3, 1 10 or 1 20 An exemplary reason for reducing the pulse application ratio is to prevent overs
- glucose sensors are known in the art and may be used for the purposes of the present invention, including, for example optical, chemical, ultrasonic, heart rate, biologic (e.g., encapsulated beta cells) and electric (tracking beta cell and/or islet electrical behavior). These sensors may be inside the body or outside of it., connected to controller 102 by wired or wireless means, be in contact with the blood or outside of blood vessels.
- Digestion sensors for example for detecting the ingestion- or upcoming intake- of meals, and, for example, prompting the production of insulin or increase in cell sensitivity.
- Digestion sensing cells are inherently problematic in some embodiments of the invention if they do not provide a measure of glucose actually ingested.
- they are used in combination with other sensors and/or only if the digestion system is activated in a profile matching eating, for example a long duration activation or activation that advances along the digestive system.
- stimulation during the digestion may be stopped, to at least some parts of the pancreas (e.g., ones comprising fewer islets), to avoid interfering with other cell types in the pancreas, for example those that produce digestive juices.
- the application of stimulation in general may be optimized to reduce interaction with non-beta cells, for example alpha cells.
- alpha cells generate glucagon
- their stimulation may be determined by tracking serum glucagon levels.
- glucagon reduction is a desirable effect and in some embodiments no interference with exocrine function is expected.
- Pancreatic activity sensors for example electrodes coupled to the entire pancreas, small parts of it, individual islet(s) or individual cell(s) in an islet.
- Such sensors are useful not only for providing feedback on the activity of the pancreas and whether the applied pulses had a desired electncal (as opposed to glucose-) effect, but also for synchronizing to the pancreatic electncal act ⁇ lty
- Exemplary sensors are descnbed for example m PCT publication WO 03/045493, the disclosure of which is incorporated herem by reference (d) Calcium sensors, both for lntracellular spaces and for extra-cellular spaces
- measuring calcium mside a cell may affect the behavior of the cell
- only one or a few cells are used as a sample for the state of the other cells
- An exemplary method of lntracellular calcium measurement is to stam the cell with a calcium sensitive dye and track its optical charactenstics It is noted that both mtra- and extra- cellular calcium levels may affect the elect ⁇ cal and secretary activity of beta cells
- Insulin sensors of any type known in the art ma ⁇ be used to measure the response of a single islet, the pancreas as a whole and/or to determine blood lev els of msulm
- Sensors for other pancreatic hormones for example, for glucagon and/or
- the levels vanous pancreatic hormones may be estimated based on changes in blood glucose levels, which changes correspond to prev iously observed changes dunng which the hormone levels were measured
- the measurements of the above sensors are optionally used to modify the pulse parameters or pulse application regime Alternat ⁇ ely or additionally, the sensors are used to track the response to the regime and/or lack of application of pulses, or for calibration
- Different sensmg regiments may be use, including continuous sensmg, and penodic sensing
- Some sensors may provide a frequent measurement, for example ever ⁇ ' few seconds or mmutes Other sensors may be considerably slower, for example taking a measurement every ten mmutes or hour If only a penodic measurement is required, the measurement ma ⁇ be an average over the time between measurements or it may be an average over a shorter time or an instantaneous v alue
- a long term mtegrative sensing for example of total msulm production, is desirable
- a one-time chemical sensor may be
- This information may be used for suitably configuring the glucose control treatment to have a desired effect, for example, by setting stimulation duration and part of pancreas affected.
- TYPES OF ELECTRODES The electrodes used may be single functionality electrodes, for example only for pacing or only for non-excitatory pulses. Also, different types of non-excitatory pulses, such as hyper-polarization and plateau extension pulses, may use different types of electrode geometries. Alternatively, a combination electrode, comprising both a pacing portion and a pulse application portion, may be provided. The different types of electrodes may have different shapes, for example due to the pacing electrode being designed for efficiency and the pulse electrode being designed for field uniformity. The two electrode functions may share a same lead or them may use different leads.
- a single electrode form is used for both pacing and non- excitatory pulse application.
- Figs. 4A-4D illustrate different types of electrodes that may be suitable for pancreatic electrification, in accordance with exemplary embodiments of the invention.
- Fig. 4A illustrates a point electrode 300 having a single electrical contact area at a tip 304 of a lead 302 thereof.
- Fig, 4B illustrates a line electrode 306 having a plurality of electric contacts
- Fig. 4C illustrates a mesh electrode 312, including a lead 314 and having a plurality of contact points 318 at meeting points of mesh wires 316.
- some of the wire segments between meeting points provide elongate electrical contacts.
- Each of the contact points can be made small, for example slightly larger than an islet. Alternatively, larger contact areas are used.
- exemplary contact areas are 0.2, 0.5, 1, 2 or 5 mm long.
- FIG. 4D illustrates various volume excitation electrodes.
- a plate electrode 320 includes a plate 322 that can simultaneously excite a large area.
- a ball electrode 324 includes a ball shaped contact area 326, with a radius of, for example, 2 or 4 mm, for exciting tissue surrounding ball 326.
- a hollow volume electrode 328 for example, includes an open volume contact area 330, for example a mesh ball or a goblet, which cane be used to excite tissue in contact with any part of ball 330, including its interior. Another possibility is a coil electrode.
- the coils have a significant radius, such as 2 or 5 mm, so they enclose significant pancreatic tissue.
- volume (and other electrodes as well) electrodes may encompass a small or large part of the pancreas or even be situated to electrify substantially all the insulin producing parts of the pancreas.
- Amy of the above electrodes can be unipolar or bipolar.
- a single contact area may be spilt or the bi-polar activity may be exhibited between adjacent contact points.
- the above multi-contact point electrodes may have all the contact points shorted together. Alternatively, at least some of the contact points can be electrified separately and, optionally, independently, of other contact points in a same electrode.
- Fig. 4E illustrates a different type of electrode, in which a casing 332 of controller 102 serves as one or multiple electrodes. Casing 332 may be concave, convex or have a more complex geometry. Possibly, no external electrodes outside of casing 332 are used. Optionally, casing 332 is then made concave, to receive the pancreas. Alternatively, at least a common electrode 336 outside of controller 102 is provided.
- casing 332 of controller 102 serves as a common electrode.
- a plurality of electrodes 334 are formed in casing 332.
- the electrode types can be any of those described above, for example.
- electrodes 334 stick out of casing 332.
- controller 102 is placed in contact with pancreas 100, as an electrically insulating layer of fat usually encapsulates the pancreas.
- the geometry of casing 332 is made to conform to the shape of the pancreas, thus assuring contact with the pancreas and minimal trauma to the pancreas by the implantation.
- a flexible or multi-part lunged casing is provided, to better conform the casing to the pancreas.
- the electrodes can be fixed to the pancreas in many means, including, for example, using one or more sutures or clips, providing coils or roughness in the electrode body, using adhesive or by impaling the pancreas or nearby tissue.
- An electrode may include a loop, a hole or other structure in it for fixing the suture or clip thereto. It is noted that the pancreas does not move around as much as the heart, so less resilient electrode and lead materials and attachment methods may be used.
- the above electrodes may be used in a single device, for example a combination of a mesh electrode underneath the pancreas and a ground needle electrode above the pancreas. Such a ground electrode may also be inserted in nearby structures, such as the abdominal muscles.
- the pancreas may be controlled as plurality of controlled regions.
- a single electrode may be shared between several regions.
- a plurality of different electrodes may be provided for the different regions or even for a single region.
- the electrodes, or tips thereof are coated with a cortisone or other anti-inflammatory, to prevent an inflammatory response by the organ with wliich the electrode is in contact with.
- Control regions 340 may overlap (as shown) or they may be none-overlapping. Possibly, the entire pancreas is also a control region, for example for insulin secretion suppression. Although a significant percentage of the pancreas is optionally controlled, for example 10%, 20%,
- part of the pancreas may remain uncontrolled, for example as a control region or as a safety measure.
- the number of control regions can vary, being for example, two, three, four, six or even ten or more. In many of the experiments described below, it is estimated that between about 10% and 30% of the pancreas was activated.
- One possible of different control regions is to allow one part of the pancreas to rest while another part is being stimulated to exert itself. Another possible use is for testing different treatment protocols on different regions.
- Another possible use is to provide different control logic for parts of the pancreas with different capabilities, to better utilize those regions or to prevent damage to those reasons. For example, different pulses may be applied to fast responding or slow responding portions.
- the density and/or size of the electrodes placement on the pancreas varies and is dependent, for example, on the distribution and density of islet cells in the pancreas.
- a more densely populated section of the pancreas may be provided with finer electrical control.
- the distribution may be the original distribution or may be the distribution after the pancreas is diseased and some of the cells died or were damaged.
- different parts of the pancreas may produce different types and/or relative amounts of various hormones. Thus, selective spatial control may be utilized to achieve a desired hormone level and/or mix.
- controller 102 can include implantation of electrodes and implantation of the controller itself.
- the two implantations are performed as a single procedure.
- each implantation has its own characteristics, hnplanting a small casing into the stomach is a well-known technique and may be performed, for example using a laparoscope, using open surgery or using keyhole surgery.
- Implantation of electrodes in the pancreas is not a standard procedure.
- elongate, uncoiling or unfolding electrodes are used so that electrode implantation is simplified.
- the electrodes are implanted using a laparoscopic or endoscopic procedure.
- controller 102 is inserted using a laparoscope or endoscope.
- the geometry of controller 102 is that of a cylinder, so it better passes through an endoscope (flexible, relatively narrow diameter tube) or a laparoscope (rigid, relatively large diameter tube).
- controller 102 is implanted separately from the electrodes.
- the electrodes are implanted with a connection part (e.g., wire ends) of the electrodes easily available. A second entry wound is made and the controller is attached to the connection parts. Possibly, the electrodes are implanted connection part first. Alternatively, after the electrodes are implanted, the endoscope is retracted, leaving the connection part in the body. Figs.
- FIG. 6A and 6B are flowcharts of implantation methods, in accordance with exemplar ⁇ ' embodiments of the invention.
- Fig. 6A is a flowchart 400 of a bile duct approach.
- an endoscope is brought to a bile duct, for example through the stomach (402).
- the endoscope then enters the bile duct (404) for example using methods known in the art.
- the endoscope may travel though the bile ducts along the pancreas.
- the electrodes may be provided by a catheterization of the splenic artery or vein.
- the portal vein may be catheterized, for example via a laparoscopic opening in the abdomen.
- the electrodes are implanted in, or alongside, the pancreas, for example in the blood vessels or the bile ducts, the pancreas being an elongated gland (406).
- the endoscope (or an extension thereof) is first advanced to the far end of the pancreas, the electrodes are attached to the pancreas and then the endoscope is retracted, leaving the electrodes behind.
- the electrodes may be advanced out of the pancreas, by themselves or using a relative rigid and/or navigable jacket.
- imaging techniques such as light, ultrasound or x-ray imaging, are used to track the electrode and/or the endoscope.
- the imaging may be from outside the body or from inside the body, for example from the tip of the endoscope. Any damage to body structures is optionally repaired during endoscope/catheter retraction (408). Alternatively, other arterial and/or venous techniques may be used. In some techniques, controller 102 is implanted and then the electrodes are guided along or inside a blood vessel or other body structure to the pancreas. In bile duct implantation, a special coating may be provided on the electrode or leads, to protect against the bile fluids. The contact part of the electrode may be embedded in tissue to prevent bile fluid damage thereto.
- Fig. 6B is a flowchart 420 of an alternative implantation method.
- Electrodes are extended from the intestines into the pancreas (424), while controller 102 remains in the intestines.
- the electrodes may also extend part way along the inside of the intestines. Electrodes on the far side of the pancreas may be implanted from a different part of the intestines or they pass through the pancreas.
- the controller is pushed out through a hole formed in the side of the intestines.
- the controller is enclosed in a pocket of the intestines, the pocket optionally formed by suturing or clipping together part of the intestines.
- controller 102 may be a wireless device, with the control circuitry separate from the electrodes.
- the electrodes can have individual power sources or they may be powered (or recharged) using beamed power.
- controller 102 is a multi part device, for example comprising a plurality of mini-controllers, each mini controller controlling a different part of the pancreas. The activities of the mini-controllers may be synchronized by communication between the controllers or by a master controller, for example in the separate, possibly external unit 116.
- Unit 116 may directly synchronize the mini controllers and/or may provide programming to cause them to act in a synchronized manner.
- An exemplar,' geometry for a mini-controller is that of two balls connected by a wire. Each ball is an electrode, one ball contains a power source and the other ball contains control circuitry. Communication between the mini controllers may be, for example using radio waves, optionally low frequency, or using ultrasound. Suitable transmitter and/or receiver elements (not shown) are optionally provided in the mini-controllers.
- the controller may be external to the body with the electrodes being inserted percutaneously to the pancreas, or even remaining on the out side of the body. Alternatively, the controller and the electrodes may be completely enclosed by the intestines.
- 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.
- stomach Another potential benefit of the stomach is that as the bulk of the stomach is an insulator, any electric field will generally travel around the stomach (and therefore through or by the pancreas). Another potential benefit is that laparoscopic surgery to the stomach is well known. While some effect of the field on the stomach may occur, optionally, the effect is small and/or counteracted by applying a field to the stomach to correct the effect.
- the pancreatic control signals are synchronized to the electrical activity of the stomach, for example to have a minimal effect on the stomach.
- the delay and or sequence length is optimized by experimentation, for example, to be 0, 1 , 2, 4, 6 or other number of seconds, or intermediate or greater values.
- the pulse may be applied during a refractory or during a depolarization phase of the stomach (or other) smooth muscle.
- the delay and/or sequence length are varied so that no single effect on the stomach (if any) dominates.
- the delay is calculated using a local sensing electrode (maybe the same as the stimulating electrode) at the application location.
- an expected or measured activation time at another part of the stomach is taken into account.
- various inter-electrode distances may be used, for example, 1 cm, 2 cm, 3 cm, 4 cm or smaller, intermediate or larger values. As can be appreciated, the larger the distance, in general, the larger the field strength at points not directly between the electrodes.
- the exact electrification level of the electrodes will depend on various factors, for example, distance between the electrodes, tissue types, tissue properties and electrode orientation.
- a calibration stage is carried out in which a suitable field strength is found.
- cu ⁇ ent and/or voltage are varied in a staircase manner over a series of trials until a significant effect is determined, for example, each step can be carried out under a different glucose ingestion event.
- the calibration is also used to determine that few or no undesirable effects are being caused by effect of the electric field on other tissue.
- the results of such calibration can dete ⁇ nine, for example, which electrodes to stimulate, simulation strength, stimulation polarity, timing (e.g., delay and/or duration), triggers for stimulating or not stimulating (e.g., not when colon is full, detected using an impedance sensor), and or which of several possible sequences to use.
- an insulating backing is provided on the electrodes to assist in directing the field.
- a backing may be provided between an electrode and the tissue to which it is attached, to prevent or reduce the effects of the field on the tissue.
- the backing comprises a silicone pad of dimensions 20 mm x 40 mm.
- FIG. 6C illustrates exemplary locations for electrodes on a stomach 600 and/or a duodenum 604, near a pancreas 602.
- a plurality of electrode locations 610-632 are shown and many other locations are possible as well, h addition to the organs shown, attacltment can be to one or more of the following organs: abdominal muscles, the liver, other abdominal organs, other parts of the GI tract, such as the small intestines or the colon, for example the transverse colon, ligaments, blood vessels and/or fatty tissue.
- the organs can be on any of the six cardinal sides of the pancreas.
- solid electrodes are above the organs and dashed electrodes are below the organ (e.g., the stomach).
- the exemplary electrode location shown are, electrodes 610-618 along the duodenum, electrodes 620-624 along the stomach opposite the duodenum, electrodes 626 and 628 near the center of the stomach, electrode 629 near the top of the stomach, two lines of electrodes 630 and 632 generally along the pancreas on the far side of the stomach, a line of electrodes 634 offset from electrodes 630 and a line of electrodes 636 between the pancreas and the stomach.
- Other electrode locations can be used as well, for example, generally any point on a surface of the organs near the pancreas or positioned so that there is a significant current through the pancreas.
- the electrodes will be provided with an electrification sequence so that different organs and/or parts of organs are electrified at different stimulation sessions of the pancreas.
- Various electrode configurations can be used, for example, two electrodes with opposite polarities, or one electrode and the casing of the device, or pairs of electrodes, with opposite polarities or groups of electrodes, where each group has a same polarity.
- the electrodes are wire electrodes. Such wire electrodes may be curved or coiled. Optionally, however, the wires are substantially straight and have and orientation. The orientation may be, for example, parallel to, perpendicular to or oblique to the pancreas and/or each other (e.g., in pairs of electrodes).
- the electrodes When electrodes that are meant for stimulating a pancreas are attached to the stomach, the electrodes may be placed in the gastric muscle. Optionally, however, the electrodes are sutured to the muscle but remain on the outside of the stomach (or other organ).
- One potential advantage is utilizing the insulative properties of various organ covering membranes.
- a covering of the pancreas is removed or reduced, to assist in electric conduction to the pancreas.
- One exemplary electrode configuration is two sets of electrodes on a same side of the pancreas.
- electrodes 620 and 624 or 610 and 612 can apply between them a field wliich will also cover part of the pancreas.
- electtodes 634 paired with electrodes 630 is another example.
- electrodes on a same side of the pancreas are also oriented so a significant portion of the field will not flow through the pancreas as no part of the pancreas is directly between or slightly offset from being directly between the electrodes.
- Another exemplar,' electrode configuration is on opposite sides of the pancreas. For example, electrodes from set 630 (or 636) paired with electrodes from sets 632. Optionally, a plurality of electrodes are chosen from each set, to allow selective electrification of different parts of the pancreas. Another example is one electrode from set 636 and one electrode of 610-618 and/or the transverse colon (not shown).
- Another exemplary electrode configuration is electrodes spaced from the pancreas, for example, electrodes 626 and 628.
- electrodes 626 and 628 are electrodes spaced from the pancreas.
- Another exemplary electrode configuration is electrodes whose field will travel around an organ, for example the stomach. The stomach is hollow, and thus generally a good insulator.
- Another exemplary electrode configuration is as follows. Four electrodes are attached or placed at the top of the pancreas, with alternate electrodes are shorted together, for example the left most electrode being positive or negative. In an exemplary embodiment of the invention, the leftmost electrode is 2-3 cm from a head of the pancreas.
- 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 electrodes need not lie on a straight line
- the electrodes are placed at a location easy to reach usmg a minimally invasive technique CALIBRATION AND PROGRAMMING
- Pancreatic controller 102 may be implanted not only, after a stable disease state is known, but also dunng an ongomg disease progression Under these conditions and even m the steady state, cells that are to be controlled by controller 102 are expected to be diseased and/or over-stressed and may behave somewhat unpredictably
- optimizing the control of the pancreas may require calibrating the controller after it is implanted
- such calibration is not an essential feature of the mvention and may even be superfluous, especially if a reasonable estimate of the pancreatic physiological state can be determined before implantation
- Fig 7 is a flowchart of an exemplary method of controller implantation and programming, m accordance with an exemplary embodiment of the mvention Other methods may also be practiced Before
- 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
- a first reprogramming may be performed.
- Such reprogramming may use any means known in the art such as magnetic fields and electromagnetic waves.
- the reprogramming optionally implements partial control of the pancreas (510). Such partial control may be used to avoid overstressing the entire pancreas. Some of the controlled parts may be suppressed, for example using hyper-polarizing pulses as described above.
- the interaction of pharmaceutical or hormonal treatment with the controller may be determined.
- cardiac and nerve electro-physiological pharmaceuticals may be useful also for treatment of pancreatic disorders.
- pancreatic control may be desirable to offset negative side effects of such pharmaceuticals taken for non-metabolic disorders.
- the effect of pharmaceuticals on pancreatic cell behavior and/or feedback interactions is determined.
- Steps 508-512 may be repeated a plurality of times before settling down to a final prograrnrning 514. It is noted that even such final programming may be penodically re-assessed (516) and then modified (518), for example, as the pancreas and/or the rest of the patient improves or degrades, or to apply various long-term effect control sequences.
- a tissue viability testing of the controlled and or/uncontrolled parts of the pancreas is optionally performed periodically, for example to assess patient state, to update the patient base line and to assess the efficiency of the therapy. Exemplary methods of viability testing include analyzing electrical activity, responses to changes in glucose level or insulin levels and/or responses to various types of electrical stimulation.
- the programming, measurements and/or pnor attempted treatments are stored in a memory portion of controller 102.
- the programming may include special sequences that take into account taking of pharmaceuticals.
- when a patient takes a pharmaceutical or insulin controller 102 is notified, for example by manual input into external unit 116 or automatically by the administration method. If the patient neglected to take the pharmaceutical, insulin, and/or glucose, a compensatory control sequence is provided, possibly irrespective of whether an alert is provided to the patient.
- a mesh unipolar electrode was placed under a pig pancreas and a needle electrode was inserted into the overlying abdominal wall as a ground.
- Fig. 8 A is a chart showing the effect of such electrical stimulation on insulin levels, in six animals.
- Figs. 8B-8D are charts of an experiment in an in-situ pancreas, showing an increase in insulin secretion, in accordance with an exemplar ⁇ ' embodiment of the invention.
- a pulse of bi-phasic, 5Hz, 5ms was applied for one second of every minute.
- Fig. 8B shows the electrical activity measured. The area between 30 and 60 minutes is where the stimulation was applied.
- Fig. 8C shows a significant increase in insulin during the application of the signal, which indicates that in a practical system an increase, of, for example, more than 20%, 40%, 60%, 80%o, 100%o, 200% or more can be achieved.
- Fig. 8D shows measurement during a control experiment with no stimulation.
- Fig. 9 is a chart showing the effect of electrical stimulation on blood glucose levels, in an experiment in which glucose levels are increased faster than would be expected solely by inhibition of insulin secretion.
- glucose levels are reduced by the application of a stimulation pulse SI .
- glucose levels are increased by the application of a stimulation pulse S2 and then reduced by an application of pulse SI again. It is hypothesized that merely reducing insulin secretion would not be sufficient to explain such a fast and large increase in glucose levels.
- Chart 900 is from an experiment on a rat which was anesthetized with pentobarbitone (40 mg/lKg). After fasting the rat was given a continuous infusion of 5%o glucose at a rate of 2 cc/Hr. During the experiment, the rat was ventilated with oxygen.
- the sample shown on chart 900 are the results of an analysis by a glucometer "Glucotrend", by Rosche, of blood from the right jugular vein every 5 minutes.
- SI and S2 have a similar form, except that S2 has a 2mA amplitude and a 3.5 minute duration, while SI has a 1mA amplitude and a 5 minute duration.
- the pulse includes an initial spike followed by a 150 ms delay and a train of 7 50% duty cycle spikes spread over 400 ms. The entire pulse is repeated every 10 seconds. The initial spike is 50 ms long.
- Both electrodes were Iridium Oxide coated Titanium.
- the geometry of the electrodes was a coil, 8 mm long, 1.2 mm diameter, with a 100 ⁇ diameter 3 fillar wire. The coil was glued on a silicone pad (for insulation and prevention of mechanical damage.
- Figs. 10A-10B, 1 1A-11B, 12A-12B and 13A-13B are pairs of figures, each pair showing a chart and a pulse diagram, of additional experiments using a similar setup to that of Fig. 9.
- Figs. 10, 12 and 13 both electrodes were above the pancreas and the signal was applied for 5 minutes.
- Fig. 11 both electrodes were under the pancreas and the signal was applied for 5 minutes.
- ADDITIONAL EXPERIMENTS IN A PERFUSED RAT PANCREAS A series of experiments were carried out on a perfused rat pancreas.
- the pancreas is actually disconnected from any control system (e.g., blood, nerves), but not disconnected from its ligaments and surrounding organs.
- any control system e.g., blood, nerves
- all main blood vessels are tied off around the pancreas and a cannula is inserted to the descending aorta, the thoracic aorta is tied off last and the circulation of blood substitute (with glucose) is allowed through the celiac trunk to the liver, pancreas and duodenum.
- the perfusate is then collected from the portal vein for further examination. Tins does kill the rat.
- the application rate of once a minute was chosen since it generally matches the natural burst rate of the pancreas.
- Fig. 14 is a chart showing an experiment in which applying stimulation pulses increased the amplitude of bursts but did not induce new bursts. Due to the electrical nature of the measurement, stimulation pulses appear as lines that span the entire vertical range of the chart. This is generally true in the other charts as well. For clarity, (some) bursts are measured with the letter "B", and stimulation pulses with the letter "S".
- the pulse was a bi-phasic rectangular balanced pulse at 5 Hz, 10 ms pulse length, 10 mA maximum amplitude, 0.5 second application duration and was applied every minute.
- This pulse apparently did not induce significant new bursts when applied at a non- bursting time and increased the amplitude of bursts occurring and/or during after the pulse. Possibly a burst did occur during the pulse and is not detected due to measurement system limitations.
- the rate of the bursts appeared not to change, however, it is believed that using other parameters, burst rate can be controlled electrically, not only using direct pacing.
- Fig. 18B shows a measurement of insulin levels (shown in this and other charts in units of micro-units per milliliter). Stimulation apparently caused a corresponding increase in insulin level. However, in the first two stimulations, the level apparently did not increase immediately or during the stimulation, but only towards the end or after the end of the pulse. It is hypothesized, that a pulse may have two effects on beta cells, one of priming them for insulin secretion (e.g., promoting generation) and one of initiating or suppressing secretion.
- Fig. 17 is a chart of an experiment showing that a stimulation in the middle of a burst did not stop the burst, in some embodiments of the invention. The burst on the left is shown for comparison, so that the effect of the pulse on the burst (e.g., on length) may be seen.
- Fig. 14 shows an increase in amplitude as a result of such a stimulation.
- the pulse parameters are 10 mA, 2 ms, at 20 Hz, for 500 ms, applied every 1 minute.
- Figs. ISA and 1SB are charts showing changes in insulin level apparently caused by stimulation.
- Fig. 1SB was discussed above.
- Fig. I SA shows two duplicate sets of measurements, made on the same samples, for ensuring accuracy of the insulin measurement. As can be seen, insulin levels increase during or after stimulation relative to during stimulation.
- the rightmost increase in insulin level may be a delayed effect of the stimulation which causes a generally increased activity of beta cells, as well possibly a momentary increase in output.
- Stimulation (using these pulse parameters) apparently causes enhancement in insulin values that may be delayed. Possibly, the stimulation period itself does not allow an increase, even though the stimulation effect is that of an increase.
- Samples are made three minutes apart. The pulse parameters were 10 mA, 10 ms, at 20 Hz, for 500 ms, repeated every 1 minute.
- Fig. 19 is a chart showing baseline relatively constant insulin levels in a perfused rat pancreas, without stimulation. .ADDITIONAL EXPERIMENTS IN LIVING MINI PIGS Two mini-pigs (named Venus and Shifra) were utilized for these experiments.
- the pigs of weight between 35 and 40 Kg had electrodes implanted into their pancreas. Either four or six electrodes were implanted, however, only four were utilized, with two electrodes implanted at each end of the pancreas and shorted together. The electrodes were wire electrodes separated 2 cm within the pair and inserted to a depth of 3-5 mm, this length being electrically conducting. The pigs were starved and then either fed pig feed or provided with sugar (sucrose) cubes to eat. The experiments were repeated for the same animal with and without stimulation, as will be described below. The pigs have remained alive and are apparently unharmed by the experimentation, which occurred over a period of several months. Fig.
- 20A is a chart showing changes in insulin levels with and without stimulation, in a live mini-pig given sugar cubes (30 cubes of 2.5 grams sucrose each, eaten in a few minutes), after starvation.
- a follow up experiment did not show considerable different between feeding sucrose and feeding glucose, which, being a fluid is technically more difficult to feed to a pig.
- Two stimulation series were applied, one 15 minutes long and the second 10 minutes long. Time zero is the start of feeding.
- the pulse was 100 Hz, 10 ms, 1 second length, every minute, amplitude is 5 mA.
- insulin increase in the stimulation experiment is faster and greater than without stimulation. Possibly this is an enhancement effect by which the insulin activity (response of the pancreas) is amplified by the stimulation.
- 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.
- Two stimulation series were applied, one 15 minutes long and the second 10 minutes long. Time zero is the start of feeding.
- the pulse was 100 Hz. 10 ms, 1 second length, every minutes, amplitude is 5 mA.
- the effect on insulin levels is significant after the first stimulation, but not after the second, possibly due to exhaustion of pancreas or due to low glucose levels (shown in Fig. 20B).
- the pulse, as applied does not arbitrarily cause the secretion of insulm, but amplifies or primes existing physiological mechanisms.
- stimulation when glucose levels are low does not cause necessarily increase insulin levels to high levels (which might be dangerous in this situation). This may be a direct property of the pulse or it may be caused by various physiological mechanisms.
- 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
- SS peak is both reduced and delayed 20 mmutes and also spread out over tune
- Fig 22B is a chart showing a delay m msulin peaking and reduction m levels thereof m some of the expenments of Fig 22A
- insulm levels are apparently reduced over nearly all the digestion time, as are total insulm levels and the size of the peak (but possibly the height of the peak is not substantially reduced)
- a non-msuhn factor is reducing glucose levels
- Reduction of both glucose levels and msulin levels is expected to reduce the strain on the pancreas for some disease conditions, for example, by reducmg disease-mduced over stimulation of the pancreas
- the delay and/or reduction in glucose peak ma ⁇ be sufficient to allow a patient to be free of the need for pharmaceutical or insulm intervention Alternatively or additionally, by spreading out the peak
- Fig 23 is a chart showmg a reduction in glucose levels under the same conditions of stimulation of Fig 22 m a senes of expenments in a second pig, in accordance with an exemplary embodiment of the mvention The results are an average of 3 control days and 4 stimulation days Fig.
- Fig. 24 is a chart showing a reduction in glucose levels under the same conditions of stimulation as Figs. 22 and 23, in a series of experiments in a third pig, in accordance with an exemplary embodiment of the invention.
- the results are an average of 5 control days and 12 stimulation days.
- Fig. 22C is a chart showing glucagon reduction as a result of the application of a stimulation pulse series, in accordance with an exemplary embodiment of the invention.
- the stimulation results are an average of three studies and one control study is used, all selected from the experiments of Fig. 22, for which glucagon levels were measured. It should be noted that the glucagon reduction is mostly relative to that of a baseline, where normal behavior is that glucagon increases when insulin and glucose do.
- 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.
- a pig i.e., of the type of Figs. 22ff was fed an oral amount of glucose of 75 grams glucose mixed with 14 grams of fish gelatin and 1 cup of water.
- the feeding lime is about 2-3 minutes, starting at time 0.
- 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
- Fig. 38 A the field was applied to both posterior and anterior walls of the stomach, simultaneously, with two electrodes at each side.
- a signal was applied only to the anterior wall.
- the field was the same sequence as used for the pigs and was synchronized to a sensing of electrical field in the antrum.
- a 4 second sequence of stimulation was applied.
- Fig. 38C shows a series of four experiments in dogs, in which a signal, as used in pigs, was applied only to the posterior side of the stomach. Six control experiments were carried out and four stimulation experiments. The stimulation experiments are divided into two pairs. A first pair, in which glucose reduction is greater and a second pair in which glucose reduction is less pronounced.
- 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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Abstract
Description
Claims
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/804,560 US20040249421A1 (en) | 2000-09-13 | 2004-03-18 | Blood glucose level control |
PCT/IL2004/000550 WO2004112563A2 (en) | 2003-06-20 | 2004-06-20 | Gastrointestinal methods and apparatus for use in treating disorders |
PCT/IL2004/000551 WO2004112883A2 (en) | 2003-06-20 | 2004-06-20 | Hepatic device for treatment or glucose detection |
PCT/IL2004/000664 WO2005007232A2 (en) | 2003-07-21 | 2004-07-21 | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
US60255004P | 2004-08-18 | 2004-08-18 | |
PCT/IL2004/000797 WO2005023081A2 (en) | 2003-09-04 | 2004-09-05 | Blood glucose level control |
US65405605P | 2005-02-17 | 2005-02-17 | |
PCT/IL2005/000316 WO2005087310A2 (en) | 2004-03-18 | 2005-03-18 | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
Publications (2)
Publication Number | Publication Date |
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EP1735047A2 true EP1735047A2 (en) | 2006-12-27 |
EP1735047A4 EP1735047A4 (en) | 2011-02-09 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP05718889A Withdrawn EP1735047A4 (en) | 2004-03-18 | 2005-03-18 | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
Country Status (2)
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EP (1) | EP1735047A4 (en) |
WO (1) | WO2005087310A2 (en) |
Families Citing this family (18)
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US9289618B1 (en) | 1996-01-08 | 2016-03-22 | Impulse Dynamics Nv | Electrical muscle controller |
JP4175662B2 (en) | 1996-01-08 | 2008-11-05 | インパルス ダイナミクス エヌ.ヴイ. | Electric muscle control device |
US9713723B2 (en) | 1996-01-11 | 2017-07-25 | Impulse Dynamics Nv | Signal delivery through the right ventricular septum |
ES2283020T3 (en) | 1997-07-16 | 2007-10-16 | Metacure Nv | SMOOTH MUSCLE CONTROLLER. |
US9101765B2 (en) | 1999-03-05 | 2015-08-11 | Metacure Limited | Non-immediate effects of therapy |
US11439815B2 (en) | 2003-03-10 | 2022-09-13 | Impulse Dynamics Nv | Protein activity modification |
US9931503B2 (en) | 2003-03-10 | 2018-04-03 | Impulse Dynamics Nv | Protein activity modification |
US11779768B2 (en) | 2004-03-10 | 2023-10-10 | Impulse Dynamics Nv | Protein activity modification |
US8548583B2 (en) | 2004-03-10 | 2013-10-01 | Impulse Dynamics Nv | Protein activity modification |
WO2006087712A2 (en) | 2005-02-17 | 2006-08-24 | Metacure N.V. | Charger with data transfer capabilities |
US8265758B2 (en) | 2005-03-24 | 2012-09-11 | Metacure Limited | Wireless leads for gastrointestinal tract applications |
US20070016262A1 (en) | 2005-07-13 | 2007-01-18 | Betastim, Ltd. | Gi and pancreatic device for treating obesity and diabetes |
EP1931319A2 (en) | 2005-08-09 | 2008-06-18 | Tylerton International Inc. | Satiety |
US8442841B2 (en) | 2005-10-20 | 2013-05-14 | Matacure N.V. | Patient selection method for assisting weight loss |
WO2008139463A2 (en) | 2007-05-09 | 2008-11-20 | Metacure Ltd. | Analysis and regulation of food intake |
US7634315B2 (en) | 2007-05-31 | 2009-12-15 | Pacesetter, Inc. | Techniques to monitor and trend nerve damage and recovery |
WO2011092710A2 (en) | 2010-02-01 | 2011-08-04 | Metacure Limited | Gastrointestinal electrical therapy |
US9486623B2 (en) | 2014-03-05 | 2016-11-08 | Rainbow Medical Ltd. | Electrical stimulation of a pancreas |
Citations (3)
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WO2001066183A1 (en) * | 1999-03-05 | 2001-09-13 | Impulse Dynamics (Israel), Ltd. | Blood glucose level control |
WO2002053093A2 (en) * | 2001-01-05 | 2002-07-11 | Impulse Dynamics Nv | Regulation of eating habits |
US6449511B1 (en) * | 1996-09-05 | 2002-09-10 | University Technologies International Inc. | Gastrointestinal electrical stimulator having a variable electrical stimulus |
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US6684104B2 (en) * | 1999-04-14 | 2004-01-27 | Transneuronix, Inc. | Gastric stimulator apparatus and method for installing |
-
2005
- 2005-03-18 EP EP05718889A patent/EP1735047A4/en not_active Withdrawn
- 2005-03-18 WO PCT/IL2005/000316 patent/WO2005087310A2/en active Application Filing
Patent Citations (3)
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US6449511B1 (en) * | 1996-09-05 | 2002-09-10 | University Technologies International Inc. | Gastrointestinal electrical stimulator having a variable electrical stimulus |
WO2001066183A1 (en) * | 1999-03-05 | 2001-09-13 | Impulse Dynamics (Israel), Ltd. | Blood glucose level control |
WO2002053093A2 (en) * | 2001-01-05 | 2002-07-11 | Impulse Dynamics Nv | Regulation of eating habits |
Non-Patent Citations (1)
Title |
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WO2005087310A2 (en) | 2005-09-22 |
WO2005087310A3 (en) | 2005-10-20 |
EP1735047A4 (en) | 2011-02-09 |
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