Patent Application
20070060812
The present invention relates generally to electrical sensing, and specifically to invasive devices and methods for sensing electrical activity of the pancreas.
The human pancreas performs two functions: producing pancreatic endocrine hormones, which affect the behavior of cells throughout the body, and producing pancreatic digestive enzymes, which assist in the digestion of food. Among other endocrine hormones produced by the pancreas, insulin is the most well-known, because of the large number of diabetic patients who regularly monitor their glucose levels to determine whether to self-administer a dose of insulin. The general function of insulin is to regulate blood glucose levels, by causing peripheral cells of the body to absorb glucose as a person's blood sugar rises. Some types of diabetes, for example, arise as a consequence of inadequate insulin release by the pancreas. Normal, physiological insulin generation and uptake, however, allow peripheral cells to properly manage the body's energy needs.
It is well known in the art to measure the electrical activity of individual pancreatic beta cells, for example, by micropipetting. It is also known to measure the collective activity of the cluster of cells in a pancreatic islet of Langerhans.
An article by Jaremko and Rorstad, entitled, “Advances toward the implantable artificial pancreas for treatment of diabetes,” Diabetes Care, 21(3), March 1998, which is incorporated herein by reference, describes enzymatic glucose sensors and optical glucose sensors for use in an artificial pancreas. They note that “ . . . implantable enzymatic sensors are not yet clinically applicable because of problems with biocompatibility. Clinical research is necessary on the effect of chronic subcutaneous implantation and local inflammation on glucose sensor performance.” Moreover, with respect to optical sensors, they write: “It appears that despite recent press releases, we are still some way from having a widely applicable long-term optical blood glucose sensor. This technology avoids the biocompatibility problems of enzymatic sensors but improvements in precision and reductions in cost are needed. Basic research is required as to the effects of environmental and metabolic variations on absorption spectra before a reliable and clinically practical optical sensor will become available.” They similarly describe subcutaneous microdialysis probes and a transcutaneous glucose extraction device as not yet being suitable for regular clinical use. They conclude, “the quest for a reliable, long-term, wearable, or implantable blood glucose sensor has been frustrating so far and few clinical studies have been carried out.”
PCT Publication WO 01/91854 to Harel et al., which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for sensing electrical activity of a pancreas, including one or more electrodes, adapted to be coupled to the pancreas, and a control unit, adapted to receive electrical signals from the electrodes indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas, and to generate an output responsive thereto.
U.S. Pat. Nos. 6,093,167 and 6,261,280 to Houben et al., which are incorporated herein by reference, describe implantable apparatus for monitoring pancreatic beta cell electrical activity in a patient in order to obtain a measure of the patient's insulin demand and blood glucose level. A stimulus generator delivers stimulus pulses, which are intended to synchronize pancreatic beta cell depolarization and to thereby produce an electrical response in the pancreas. This response is analyzed so as to determine an indication of insulin demand, whereupon insulin from an implanted pump is released, or the pancreas is stimulated so as to enhance insulin production.
U.S. Pat. No. 5,919,216 to Houben et al., which is incorporated herein by reference, describes a system for automatically responding to insulin demand without any need for external monitoring or injecting of insulin into a diabetic patient. The system as described senses glucose levels internally, and responds by stimulating either the pancreas or a transplant of pancreatic islets in order to enhance insulin production.
U.S. Pat. No. 5,741,211 to Renirie et al., which is incorporated herein by reference, describes apparatus which evaluates an electrocardiographic signal in order to determine an indication of blood insulin and/or glucose levels.
U.S. Pat. Nos. 5,101,814 and 5,190,041 to Palti, which are incorporated herein by reference, describe a system which utilizes implanted glucose-sensitive living cells to monitor blood glucose levels. The implanted cells produce a detectable electrical or optical signal in response to changes in glucose concentration in surrounding tissue. The signal is then detected and interpreted to give a reading indicative of blood glucose levels. U.S. Pat. No. 5,368,028 to Palti, which is incorporated herein by reference, describes a system which utilizes implanted chemo-sensitive living cells to monitor tissue or blood concentration levels of chemicals such as glucose.
The following articles, which are incorporated herein by reference, may be of interest. In particular, methods and apparatus described in one or more of these articles may be adapted for use with some preferred embodiments of the present invention.
It is an object of some aspects of the present invention to provide improved methods and apparatus for sensing pancreatic electrical activity.
It is also an object of some aspects of the present invention to provide methods and apparatus for sensing electrical activity of a substantial portion of the pancreas.
It is a further object of some aspects of the present invention to provide improved methods and apparatus for modifying pancreatic function.
It is yet a further object of some aspects of the present invention to provide improved methods and apparatus for treating physiological disorders resulting from improper functioning of the pancreas.
It is still a further object of some aspects of the present invention to provide improved methods and apparatus for monitoring glucose and/or insulin levels in the blood.
In preferred embodiments of the present invention, pancreatic apparatus comprises a control unit and one or more electrodes, adapted to be coupled to respective sites on, in, or near the pancreas of a human subject. Preferably, the electrodes convey to the control unit electrical signals which are generated within a substantial portion of the pancreas. Typically, but not necessarily, the control unit analyzes various aspects of the signals, and drives the electrodes to apply pancreatic control signals to the pancreas responsive to the analysis. The term “substantial portion of the pancreas,” as used in the context of the present patent application and in the claims, is to be understood as a portion of the pancreas larger than two or more islets. Typically, the portion includes ten or more islets.
By way of analogy, the behavior of the heart cannot be adequately summarized by assessing the electrical activity of any one bundle of cells; instead, an electrocardiogram is used. Some embodiments of the present invention, similarly, assess the electrical activity of a substantial portion of the pancreas, typically in order to determine whether a treatment is appropriate (e.g., stimulating the pancreas to secrete more insulin, or generating a signal to activate an implanted insulin pump). For this reason, the inventors call the process of sensing the electrical activity of a substantial portion of the pancreas, as described herein, electropancreatography (EPG). Experiments performed by the inventors have shown that electropancreatography is sensitive to clinically-significant phenomena, e.g., an increase in blood glucose- and/or insulin levels from normal to supraphysiological values.
In some preferred embodiments, the control unit drives some or all of the electrodes to apply signals to the pancreas responsive to detecting EPG signals which are indicative of a particular physiological condition, such as elevated blood glucose and/or insulin levels. Preferably, these signals are applied using methods and apparatus similar to those described in one or more of the following applications/publications: (a) U.S. Provisional Patent Application 60/123,532, filed Mar. 5, 1999, entitled “Modulation of insulin secretion,” (b) PCT Publication WO 00/53257 to Darwish et al., and the corresponding U.S. patent application Ser. No. 09/914,889, filed Sep. 4, 2001, or (c) PCT Publication WO 01/66183 to Darvish et al., and the corresponding U.S. patent application Ser. No. 10/237,263, filed Sep. 5, 2002, all of which are assigned to the assignee of the present patent application and are incorporated herein by reference. Typically, each electrode conveys a particular waveform to the pancreas, which may differ in certain aspects from the waveforms applied to other electrodes. The particular waveform to be applied to each electrode is preferably determined by the control unit, initially under the control of a physician during a calibration period of the unit. After the initial calibration period, the unit is generally able to automatically modify the waveforms as needed to maintain a desired level of performance of the apparatus.
In some preferred embodiments, one or more physiological sensors (e.g., for measuring blood sugar, blood pH, pCO2, pO2, blood insulin levels, blood ketone levels, ketone levels in expired air, blood pressure, respiration rate, respiration depth, a metabolic indicator (e.g., NADH), or heart rate) send physiological-sensor signals to the control unit. The various sensor signals serve as feedback, to enable the control unit to iteratively adjust the signals applied to the pancreas. Alternatively or additionally, other sensors are coupled to the pancreas or elsewhere on the patient's body, and send signals to the control unit which are used in determining modifications to parameters of the applied signals.
As appropriate, methods and apparatus described in U.S. Provisional Patent Application 60/208,157, entitled, “Electrical Activity Sensor for the Whole Pancreas,” filed May 31, 2000, which is assigned to the assignee of the present patent application and is incorporated herein by reference, may be adapted for use with embodiments of the present invention. Alternatively or additionally, methods and apparatus described in the above-cited PCT Publication WO 01/91854 to Harel et al., may be adapted for use with embodiments of the present invention.
In some preferred embodiments of the present invention, one or more of the electrodes comprise wire electrodes fixed to a clip mount. For some applications, each wire electrode is looped through two holes in the clip, so that the curved portion of the wire electrode is exposed to the surface of the skin. Alternatively, the end of the wire electrode penetrates the pancreas.
In some preferred embodiments, one or more of the electrodes is fixed to a patch, which is coupled to tissue of the patient. For some applications, the electrodes comprise a monopolar wire electrode surrounded by an insulating ring. Preferably a patch comprises two such electrodes. Alternatively, the electrodes comprise concentric electrode assemblies, comprising an inner wire electrode and an outer ring electrode, with an inner insulating ring separating the inner wire electrode and the outer ring electrode. The assemblies preferably also comprise an outer insulating ring surrounding the outer ring electrode. Preferably, but not necessarily, the surface areas of the inner wire electrode and the outer ring electrode in contact with the tissue are within between about 2% and about 5% of each other, and, for some applications, are substantially equal.
In some preferred embodiments, the electrodes comprise sets of two button-electrodes attached to a preamplifier fixed to a patch. One end of a wire is connected to each electrode, and the other end of the wire comprises a needle, which is used to suture the electrode to the tissue. After suturing, the needle is preferably broken, and the remaining portion of the needle is inserted into the preamplifier. The patch is then coupled to the tissue at a distance from the suture site in the tissue selected so as to keep the wire moderately slack, thereby avoiding disturbing of the electrode during movement of the tissue.
In some preferred embodiments, the pancreatic apparatus comprises a signal-processing patch assembly, for implantation on the pancreas. The patch assembly preferably comprises one or more electrodes, and signal-processing components, such as a preamplifier, filters, amplifiers, a preprocessor, and a transmitter, some or all of which are preferably physically located on the patch assembly. Alternatively, the patch assembly does not comprise any electrodes, and electrodes are implanted in a vicinity of the patch and electrically coupled to the patch, which may be implanted on the pancreas or near the pancreas, such as on the duodenum.
There is therefore provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including:
a set of one or more electrodes, adapted to be coupled to the pancreas, and to generate activity signals indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas; and
a control unit, adapted to receive the activity signals, and to generate an output signal responsive thereto.
In an embodiment, a single electrode in the set of one or more electrodes is adapted to convey to the control unit an activity signal indicative of electrical activity of pancreatic cells which are in two or more of the islets.
There is also provided, in accordance with a preferred embodiment of the present invention, apparatus for analyzing electrical activity of a pancreas of a patient, including:
a set of one or more electrodes, each electrode adapted to be coupled to the pancreas and to generate an activity signal indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas; and
a control unit, adapted to:
receive the activity signals from the one or more electrodes,
analyze the received activity signals, and
generate an output signal responsive to the analysis.
In an embodiment, the set of electrodes is adapted to generate activity signals indicative of electrical activity of pancreatic cells which are in five or more of the islets. In an embodiment, the set of electrodes is adapted to generate activity signals indicative of electrical activity of pancreatic cells which are in ten or more of the islets.
In an embodiment, a first one of the one or more electrodes is adapted to generate a first activity signal, indicative of electrical activity of pancreatic cells which are in a first one of the islets, and a second one of the one or more electrodes is adapted to generate a second activity signal, indicative of electrical activity of pancreatic cells which are in a second one of the islets, which is different from the first one of the islets, and the control unit is adapted to receive the first and second activity signals.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify an aspect thereof indicative of activity of a type of cell selected from the list consisting of: pancreatic alpha cells, pancreatic beta cells, pancreatic delta cells, and polypeptide cells, and the control unit is adapted to generate the output signal responsive to identifying the aspect.
There is further provided, in accordance with a preferred embodiment of the present invention, apparatus for monitoring a blood glucose level of a patient, including:
a set of one or more electrodes, adapted to be coupled to a pancreas of the patient, and to generate respective activity signals indicative of spontaneous electrical activity of pancreatic cells; and
a control unit, adapted to receive the respective activity signals, to analyze the activity signals so as to determine a change in the glucose level, and to generate an output signal responsive to determining the change.
There is still further provided, in accordance with a preferred embodiment of the present invention, apparatus for monitoring a blood insulin level of a patient, including:
a set of one or more electrodes, adapted to be coupled to a pancreas of the patient, and to generate respective activity signals indicative of spontaneous electrical activity of pancreatic cells; and
a control unit, adapted to receive the respective activity signals, to analyze the activity signals so as to determine a change in the insulin level, and to generate an output signal responsive to determining the change.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify an aspect thereof indicative of activity of a type of cell selected from the list consisting of: pancreatic alpha cells, pancreatic beta cells, pancreatic delta cells, and polypeptide cells, and the control unit is adapted to generate the output signal responsive to identifying the aspect.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a frequency aspect thereof, and to generate the output signal responsive to identifying the frequency aspect.
There is also provided, in accordance with a preferred embodiment of the present invention, apparatus for analyzing electrical activity of a pancreas of a patient, including:
a set of one or more electrodes, adapted to be coupled to the pancreas, and to generate activity signals; and
a control unit, adapted to receive the activity signals, adapted to analyze the activity signals so as to identify an aspect thereof which is indicative of activity of pancreatic alpha cells, and adapted to generate an output signal responsive to identifying the aspect.
There is additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for analyzing electrical activity of a pancreas of a patient, including:
a set of one or more electrodes, adapted to be coupled to the pancreas, and to generate activity signals; and
a control unit, adapted to receive the activity signals, adapted to analyze the activity signals so as to identify an aspect thereof which is indicative of activity of pancreatic beta cells, and adapted to generate an output signal responsive to identifying the aspect.
In an embodiment, the control unit is adapted to analyze the activity signals so as to distinguish between the aspect thereof which is indicative of the activity of the beta cells and an aspect thereof which is indicative of activity of pancreatic alpha cells, and the control unit is adapted to generate the output signal responsive to distinguishing between the aspects.
There is yet additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for analyzing electrical activity of a pancreas of a patient, including:
a set of one or more electrodes, adapted to be coupled to the pancreas, and to generate activity signals; and
a control unit, adapted to receive the activity signals, adapted to analyze the activity signals so as to identify an aspect thereof which is indicative of activity of pancreatic delta cells, and adapted to generate an output signal responsive to identifying the aspect.
There is still additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for analyzing electrical activity of a pancreas of a patient, including:
a set of one or more electrodes, adapted to be coupled to the pancreas, and to generate activity signals; and
a control unit, adapted to receive the activity signals, adapted to analyze the activity signals so as to identify an aspect thereof which is indicative of activity of polypeptide cells, and adapted to generate an output signal responsive to identifying the aspect.
In an embodiment, the control unit is adapted to compare the aspect of the activity signals with a stored pattern that is indicative of activity of the cells, and to generate the output signal responsive thereto.
In an embodiment, the control unit is adapted to analyze the activity signals under an assumption that the activity of the cells is dependent on electrical activity of another type of pancreatic cell, and to generate the output signal responsive thereto.
In an embodiment, the control unit is adapted to analyze the activity signals under an assumption that the activity of the cells is substantially independent of electrical activity of another type of pancreatic cell, and to generate the output signal responsive thereto.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a frequency aspect thereof, and to generate the output signal responsive to identifying the frequency aspect.
In an embodiment, the control unit is adapted to analyze the activity signals so as to differentiate between a first frequency aspect of the activity signals which is indicative of the activity of the cells, and a second frequency aspect of the activity signals, different from the first frequency aspect, which is indicative of activity of another type of pancreatic cell.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify over time a change in the frequency aspect that is characteristic of the cells.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a magnitude aspect thereof, the control unit is adapted to analyze the frequency aspect and the magnitude aspect in combination, and the control unit is adapted to generate the output signal responsive to analyzing the aspects.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a duration aspect thereof, the control unit is adapted to analyze the frequency aspect and the duration aspect in combination, and the control unit is adapted to generate the output signal responsive to analyzing the aspects.
In an embodiment, the set of electrodes is adapted to generate the activity signals responsive to spontaneous electrical activity of the pancreatic cells. In an embodiment, the control unit is adapted to apply a synchronizing signal to the pancreas.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a magnitude of a fluctuation of the activity signals, and to generate the output signal responsive to the analysis.
In an embodiment, the control unit is adapted to analyze the activity signals by means of a technique selected from the list consisting of: single value decomposition and principal component analysis, and to generate the output signal responsive thereto.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a duration aspect thereof, and to generate the output signal responsive to identifying the duration aspect.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify an aspect of morphology of a waveform thereof, and to generate the output signal responsive to identifying the aspect of the morphology.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify an aspect of a number of threshold-crossings thereof, and to generate the output signal responsive to identifying the aspect of the number of threshold-crossings.
In an embodiment, the control unit is adapted to analyze the activity signals using a moving window, and to generate the output signal responsive to the analysis.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a measure of energy thereof, and to generate the output signal responsive to identifying the measure of energy.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a correlation thereof with a stored pattern, and to generate the output signal responsive to identifying the correlation.
In an embodiment, the control unit is adapted to analyze the activity signals so as to determine an average pattern thereof, and so as to identify a correlation of the activity signals with the average pattern, and the control unit is adapted to generate the output signal responsive to identifying the correlation.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a magnitude aspect thereof and a duration aspect thereof, the control unit is adapted to analyze the aspects in combination, and the control unit is adapted to generate the output signal responsive to analyzing the aspects.
In an embodiment, the control unit is adapted to analyze the activity signals so as to determine a measure of organization of the activity signals.
In an embodiment, a first electrode and a second electrode of the set of electrodes are adapted to be coupled to a first site and a second site of the pancreas, respectively, and the control unit is adapted to measure a delay between sensed electrical activity at the first and second sites, and to analyze the activity signals responsive to the measured delay.
In an embodiment, the control unit is adapted to detect mechanical artifacts by identifying a pattern of the activity signals, the pattern selected from the list consisting of: a spectral pattern and a time pattern.
In an embodiment, the control unit includes a memory, and the control unit is adapted to store the activity signals in the memory for subsequent off-line analysis.
In an embodiment, the control unit is adapted to receive the activity signals from at least one of the electrodes when the at least one of the electrodes is not in physical contact with any islet of the pancreas.
In an embodiment, the control unit is adapted to receive the activity signals from at least one of the electrodes when the at least one of the electrodes is not in physical contact with the pancreas.
In an embodiment, the control unit is adapted to generate the output signal so as to facilitate an evaluation of a state of the patient.
In an embodiment, the set of electrodes includes at least ten electrodes. In an embodiment, the set of electrodes includes at least 50 electrodes.
In an embodiment, the apparatus includes a clip mount, coupled to at least one of the electrodes, which is adapted for securing the at least one of the electrodes to the pancreas.
In an embodiment, at least one of the electrodes is adapted to be physically coupled to the pancreas by peeling back a portion of connective tissue surrounding the pancreas, so as to create a pocket, inserting the electrode into the pocket, and suturing the electrode to the connective tissue.
In an embodiment, the set of one or more electrodes includes an array of electrodes, the array including at least two electrodes adapted to be coupled to the pancreas at respective sites, and adapted to generate an impedance-indicating signal responsive to a level of electrical impedance between the two sites.
In an embodiment, the apparatus includes at least one supplemental sensor, adapted to be coupled to a site of a body of the patient, sense a parameter of the patient, and generate a supplemental signal responsive to the parameter, and the control unit is adapted to receive the supplemental signal. In an embodiment, the parameter is selected from the list consisting of: blood sugar, SvO2, pH, pCO2, pO2, blood insulin levels, blood ketone levels, ketone levels in expired air, blood pressure, respiration rate, respiration depth, an electrocardiogram measurement, a metabolic indicator, and heart rate, and the supplemental sensor is adapted to sense the parameter. In an embodiment, the metabolic indicator includes a measure of NADH, and the supplemental sensor is adapted to sense the measure of NADH. In an embodiment, the supplemental sensor includes an accelerometer, adapted to detect a motion of an organ of the patient. In an embodiment, the control unit is adapted to apply to the activity signals a noise reduction algorithm, an input of which includes the supplemental signal.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a magnitude aspect thereof, and to generate the output signal responsive to identifying the magnitude aspect. In an embodiment, the control unit is adapted to analyze the activity signals so as to identify the magnitude aspect thereof at a frequency, and to generate the output signal responsive to identifying the magnitude aspect at the frequency.
In an embodiment, the control unit is adapted to apply a Fourier transform to the activity signals. In an embodiment, the control unit is adapted to analyze the Fourier-transformed activity signals so as to calculate a ratio of (a) a first frequency component at a first frequency of the activity signals to (b) a second frequency component at a second frequency of the activity signals, the first frequency different from the second frequency, and the control unit is adapted to generate the output signal responsive to the analysis. In an embodiment, the control unit is adapted to analyze the Fourier-transformed activity signals so as to identify a pattern thereof, and to generate the output signal responsive to identifying the pattern.
In an embodiment, the control unit is adapted to analyze the activity signals so as to identify an aspect of a frequency of spike generation thereof, and to generate the output signal responsive to identifying the aspect. In an embodiment, the control unit is adapted to analyze the activity signals so as to identify the aspect of the frequency of spike generation responsive to an occurrence of spikes within a certain range of durations of spikes, and to generate the output signal responsive to the aspect. In an embodiment, the control unit is adapted to analyze the activity signals so as to identify the aspect of the frequency of spike generation responsive to a ratio of spikes with a first amplitude to spikes with a second amplitude, the first amplitude different from the second amplitude, and to generate the output signal responsive to the aspect. In an embodiment, the control unit is adapted to analyze the activity signals so as to identify the aspect of the frequency of spike generation responsive to, for each spike, a product of a duration of the spike and an amplitude of the spike, and to generate the output signal responsive to the aspect. In an embodiment, the control unit is adapted to analyze the activity signals so as to identify a change in the aspect of the frequency of spike generation, and to generate the output signal responsive to identifying the change in the aspect of the frequency.
In an embodiment, the control unit is adapted to analyze the activity signals so as to determine a change in a rate of secretion of insulin by the pancreas. In an embodiment, the control unit is adapted to determine a change in a rate of spike generation, so as to determine the change in the rate of secretion of insulin by the pancreas.
In an embodiment, the control unit is adapted to analyze the activity signals with respect to calibration data indicative of aspects of pancreatic electrical activity recorded at respective times, in which respective measurements of a parameter of the patient generated respective values. In an embodiment, the parameter includes a blood glucose level of the patient, and the control unit is adapted to analyze the activity signals with respect to the calibration data. In an embodiment, the parameter includes a blood insulin level of the patient, and the control unit is adapted to analyze the activity signals with respect to the calibration data.
In an embodiment, the apparatus includes at least one reference electrode, adapted to be coupled to tissue in a vicinity of the pancreas, and to generate reference signals, and the control unit is adapted to receive the reference signals, and to generate the output signal responsive to the reference signals and the activity signals. In an embodiment, the reference electrode is adapted to be coupled to an organ of the patient in a vicinity of the pancreas, and to generate reference signals indicative of a motion of the organ. In an embodiment, the organ includes a stomach of the patient, and the reference electrode includes two reference electrodes, adapted to be coupled to the stomach at respective stomach sites, and adapted to generate an impedance-indicating signal responsive to a level of electrical impedance between the two stomach sites. In an embodiment, the organ includes a pancreas of the patient, and the reference electrode includes two reference electrodes, adapted to be coupled to the pancreas at respective pancreas sites, and adapted to generate an impedance-indicating signal responsive to a level of electrical impedance between the two pancreas sites. In an embodiment, the organ includes a duodenum of the patient, and the reference electrode includes two reference electrodes, adapted to be coupled to the duodenum at respective duodenum sites, and adapted to generate an impedance-indicating signal responsive to a level of electrical impedance between the two duodenum sites.
In an embodiment, the electrodes are adapted to be placed in physical contact with the pancreas. In an embodiment, at least one of the electrodes is adapted to be placed in physical contact with the head of the pancreas. In an embodiment, at least one of the electrodes is adapted to be placed in physical contact with the body of the pancreas. In an embodiment, at least one of the electrodes is adapted to be placed in physical contact with the tail of the pancreas. In an embodiment, at least one of the electrodes is adapted to be placed in physical contact with a vein or artery of the pancreas. In an embodiment, at least one of the electrodes is adapted to be placed in physical contact with a blood vessel in a vicinity of the pancreas.
In an embodiment, at least one of the electrodes has a characteristic diameter less than about 3 millimeters. In an embodiment, the at least one of the electrodes has a characteristic diameter less than about 300 microns. In an embodiment, the at least one of the electrodes has a characteristic diameter less than about 30 microns.
In an embodiment, the apparatus includes a treatment unit, adapted to receive the output signal and to apply a treatment to the patient responsive to the output signal.
In an embodiment, the control unit is adapted to generate the output signal responsive to an aspect of timing of the activity signals, and the treatment unit is adapted to apply the treatment responsive to the timing aspect. In an embodiment, the control unit is adapted to generate the output signal responsive to an aspect of the timing of the activity signals indicative of a phase in an oscillation of an insulin level.
In an embodiment, including at least one supplemental sensor, adapted to
be coupled to a site of a body of the patient,
sense a parameter of the patient, and
generate a supplemental signal responsive to the parameter,
and the control unit is adapted to receive the supplemental signal, and to generate the output signal responsive to the supplemental signal and the activity signals, and the treatment unit is adapted to apply the treatment responsive to the output signal. In an embodiment, the supplemental sensor includes an accelerometer, adapted to detect a motion of an organ of the patient. In an embodiment, the parameter is selected from the list consisting of: blood sugar, SvO2, pH, pCO2, pO2, blood insulin levels, blood ketone levels, ketone levels in expired air, blood pressure, respiration rate, respiration depth, an electrocardiogram measurement, a metabolic indicator, and heart rate, and the supplemental sensor is adapted to sense the parameter. In an embodiment, the metabolic indicator includes a measure of NADH, and the supplemental sensor is adapted to sense the measure of NADH.
In an embodiment, the control unit is adapted to configure the output signal to the treatment unit so as to be capable of modifying an amount of glucose in blood in the patient. In an embodiment, the control unit is adapted to configure the output signal to the treatment unit so as to be capable of increasing an amount of glucose in blood in the patient. In an embodiment, the control unit is adapted to configure the output signal so as to be capable of decreasing an amount of glucose in blood in the patient.
In an embodiment, the treatment unit includes a signal-application electrode, and the control unit is adapted to drive the signal-application electrode to apply current to the pancreas capable of treating a condition of the patient. In an embodiment, the signal-application electrode includes at least one electrode of the set of electrodes. In an embodiment, the control unit is adapted to drive the signal-application electrode to apply the current in a waveform selected from the list consisting of: a monophasic square wave pulse, a sinusoid wave, a series of biphasic square waves, and a waveform including an exponentially-varying characteristic. In an embodiment, the signal-application electrode includes a first and a second signal-application electrode, and the control unit is adapted to drive the first and second signal-application electrodes to apply the current in different waveforms. In an embodiment, the control unit is adapted to drive the signal-application electrode to apply the current so as to modulate insulin secretion by the pancreas.
In an embodiment, the control unit is adapted to select a parameter of the current, and to drive the signal-application electrode to apply the current, so as to modulate insulin secretion, the parameter selected from the list consisting of: a magnitude of the current, a duration of the current, and a frequency of the current. In an embodiment, the signal-application electrode includes a first and a second signal-application electrode, and the control unit is adapted to drive the first and the second signal-application electrodes to reverse a polarity of the current applied to the pancreas so as to stimulate the change in insulin secretion.
In an embodiment, the treatment unit includes a substance delivery unit, adapted to deliver a therapeutic substance to the patient, and the control unit is adapted to drive the signal-application electrode to apply the current, and, in combination, to drive the substance delivery unit to deliver the therapeutic substance. In an embodiment, the treatment unit includes a patient-alert unit, adapted to generate a patient-alert signal. In an embodiment, the treatment unit includes a substance delivery unit, adapted to deliver a therapeutic substance to the patient. In an embodiment, the substance delivery unit includes a pump. In an embodiment, the substance includes insulin, and the substance delivery unit is adapted to deliver the insulin to the patient. In an embodiment, the substance includes a drug, and the substance delivery unit is adapted to deliver the drug to the patient. In an embodiment, the drug is selected from the list consisting of: glyburide, glipizide, and chlorpropamide.
There is further provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including an electrode assembly, which includes:
one or more wire electrodes, each wire electrode including a curved portion, which curved portion is adapted to be brought in contact with the pancreas, and each wire electrode adapted to generate an activity signal indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas; and
a clip mount, to which the wire electrodes are fixed, which is adapted to secure the wire electrodes to the pancreas.
There is yet further provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including an electrode assembly, which includes:
a plurality of wire electrodes, adapted to be brought in contact with and to penetrate a surface of the pancreas, and to generate respective activity signals indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas; and
a mount, to which the wire electrodes are fixed, which is adapted to secure the wire electrodes to the pancreas.
There is still further provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including a patch assembly, which includes:
a patch, adapted to be coupled to tissue of the patient in a vicinity of the pancreas; and
one or more electrode assemblies, adapted to be coupled to the patch such that the electrode assemblies are in electrical contact with the tissue, and adapted to generate respective activity signals indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas.
In an embodiment, the apparatus includes a balloon, coupled to a surface of the patch not in contact with the tissue. In an embodiment, the apparatus includes a hydrogel, adapted to be applied to a surface of the patch not in contact with the tissue, so as to flexibly harden and maintain coupling of the patch to the tissue.
In an embodiment, the apparatus includes a sheet, coupled to a surface of the patch not in contact with the tissue, so as to protect the patch from motion of organs of the patient.
In an embodiment, the patch is adapted to have one or more sutures pass therethrough, to couple the patch to the tissue.
In an embodiment, the apparatus includes an adhesive, adapted to couple the patch to the tissue.
In an embodiment, the electrode assemblies include two electrode assemblies, adapted to facilitate a differential measurement of the electrical activity of the pancreas.
In an embodiment, each of the electrode assemblies includes:
a wire electrode; and
an insulating ring, surrounding the wire electrode.
In an embodiment, the patch includes one or more signal-processing components fixed thereto.
In an embodiment, at least one of the signal-processing components is selected; from the list consisting of: a preamplifier, a filter, an amplifier, an analog-to-digital converter, a preprocessor, and a transmitter.
In an embodiment, at least one of the signal-processing components is adapted to drive at least one of the electrode assemblies to apply a signal to a portion of the tissue, the signal configured so as to treat a condition of the patient.
In an embodiment, each of the electrode assemblies includes:
an inner wire electrode, adapted to function as a first pole of the electrode assembly;
an inner insulating ring, adapted to surround the inner wire electrode;
an outer ring electrode, adapted to surround the inner insulating ring, and to function as a second pole of the electrode assembly; and
an outer insulating ring, adapted to surround the outer ring electrode.
In an embodiment, the inner wire electrode is adapted to have a tissue-contact surface area approximately equal to a tissue-contact surface area of the outer ring electrode.
There is yet further provided, in accordance with a preferred embodiment of the present invention, apparatus including a patch, adapted to be implanted in contact with tissue of a patient, the tissue in a vicinity of a pancreas of the patient, the patch including one or more signal-processing components fixed thereto, which are adapted to process pancreatic electrical signals.
In an embodiment, at least one of the signal-processing components is selected from the list consisting of: a preamplifier, a filter, an amplifier, an analog-to-digital converter, a preprocessor, and a transmitter.
In an embodiment, the tissue includes tissue of the pancreas of the patient, and the patch is adapted to be coupled to the tissue of the pancreas.
In an embodiment, the tissue includes tissue of a duodenum of the patient, and the patch is adapted to be coupled to the tissue of the duodenum.
In an embodiment, the apparatus includes an electrode, adapted
to be coupled to tissue of the patient in a vicinity of the pancreas,
to generate an activity signal indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas, and
to be electrically coupled to at least one of the signal-processing components.
In an embodiment, at least one of the signal-processing components is adapted to drive the electrode to apply a signal to the pancreas, the signal configured so as to treat a condition of the patient.
There is also provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including:
a patch, adapted to be coupled to first tissue of the patient in a vicinity of the pancreas, the patch including a signal-processing component;
at least one electrode assembly, including:
an electrode, adapted to be coupled to second tissue of the patient in a vicinity of the pancreas and in a vicinity of the patch, and to generate an activity signal indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas; and
a wire having a first end and a second end, the first end physically and electrically coupled to the electrode, the second end including a surgical needle, adapted to be electrically coupled to the second end, the wire adapted to function as a suture for use with the needle, and the second end adapted to be physically and electrically coupled to the preamplifier.
In an embodiment, the signal-processing component includes a preamplifier.
In an embodiment, the second end is adapted to be physically and electrically coupled to the preamplifier by inserting the needle into the preamplifier.
In an embodiment, the needle is adapted to be broken after the wire is sutured to the second tissue, thereby leaving a broken portion of the needle fixed to the second end of the wire, and the second end of the wire is adapted to be physically and electrically coupled to the preamplifier by inserting the broken portion of the needle into the preamplifier.
There is additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including an electrode, adapted to be coupled to tissue of the patient in a vicinity of the pancreas, and adapted to generate an activity signal indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas, the electrode including a hooking element, which includes a plurality of prongs, the prongs adapted to be collapsible while being inserted into the tissue, and to expand after insertion, thereby generally securing the electrode in the tissue.
There is yet additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including an electrode, adapted to be coupled to tissue of the patient in a vicinity of the pancreas, and adapted to generate an activity signal indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas, the electrode including a spiral stopper element, adapted to secure the electrode in the tissue.
There is still additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including an electrode, adapted to be coupled to tissue of the patient in a vicinity of the pancreas, and adapted to generate an activity signal indicative of electrical activity of pancreatic cells which are in a plurality of islets of the pancreas, the electrode including a corkscrew element, adapted to secure the electrode in the tissue.
There is further provided, in accordance with a preferred embodiment of the present invention, apparatus for sensing electrical activity of a pancreas of a patient, including an electrode assembly; including:
a connecting element;
an amplifier;
at least two wires, each wire having a proximal end and a distal end, the distal end of each wire adapted to be attached to the connecting element, and the proximal end of each wire adapted to be attached to the amplifier, each wire including an electrically-insulating coating attached thereto, adapted to cover a portion of the wire and to not cover at least one exposed site on the wire, so as to provide electrical contact between the exposed site and tissue of the pancreas; and
a suture, having a proximal end and a distal end, the proximal end adapted to be attached to the amplifier, and the distal end adapted to be connected to the connecting element.
In an embodiment, one of the exposed sites on a first one of the wires and one of the exposed sites on a second one of the wires are adapted to facilitate a differential measurement of the electrical activity of the pancreas.
In an embodiment, the apparatus includes a needle, attached to the distal end of the suture.
There is yet further provided, in accordance with a preferred embodiment of the present invention, apparatus for analyzing electrical activity of a pancreas of a patient, including:
a set of one or more electrodes, adapted to be coupled to the pancreas and to generate respective activity signals indicative of electrical activity of pancreatic cells; and
a control unit, adapted to:
receive the activity signals from the one or more electrodes,
analyze a frequency component of the received activity signals, and
generate an output signal responsive to the analysis.
There is still further provided, in accordance with a preferred embodiment of the present invention, apparatus for analyzing activity of a pancreas of a patient, including:
a set of one or more calcium electrodes, each of the calcium electrodes adapted to be coupled to the pancreas and to generate a signal indicative of a calcium level; and
a control unit, adapted to:
receive the signals from the one or more calcium electrodes,
analyze the received activity signals, and
generate an output signal responsive to the analysis.
In an embodiment, each of the electrodes is adapted to generate the signal indicative of an intracellular calcium level. In an embodiment, each of the electrodes is adapted to generate the signal indicative of an interstitial calcium level.
There is also provided, in accordance with a preferred embodiment of the present invention, a method for sensing electrical activity of a pancreas of a patient, including:
sensing electrical activity of pancreatic cells which are in a plurality of islets of the pancreas;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals; and
generating an output signal responsive to the analysis.
There is additionally provided, in accordance with a preferred embodiment of the present invention, a method for sensing electrical activity of a pancreas of a patient, including:
sensing, at each of one or more sites of the pancreas, electrical activity of pancreatic cells in a respective plurality of islets;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals; and
generating an output signal responsive to the analysis.
There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a method for monitoring a blood glucose level of a patient, including:
sensing spontaneous electrical activity of pancreatic cells;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals so as to determine a change in the glucose level; and
generating an output signal responsive to determining the change.
There is still additionally provided, in accordance with a preferred embodiment of the present invention, a method for monitoring a blood insulin level of a patient, including:
sensing spontaneous electrical activity of pancreatic cells;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals so as to determine a change in the insulin level; and
generating an output signal responsive to determining the change.
There is also provided, in accordance with a preferred embodiment of the present invention, a method for analyzing electrical activity of a pancreas of a patient, including:
sensing electrical activity at one or more pancreatic sites;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals so as to identify an aspect thereof which is indicative of activity of pancreatic alpha cells; and
generating an output signal responsive to identifying the aspect.
There is further provided, in accordance with a preferred embodiment of the present invention, a method for analyzing electrical activity of a pancreas of a patient, including:
sensing electrical activity at one or more pancreatic sites;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals so as to identify an aspect thereof which is indicative of activity of pancreatic beta cells; and
generating an output signal responsive to identifying the aspect.
There is still further provided, in accordance with a preferred embodiment of the present invention, a method for analyzing electrical activity of a pancreas of a patient, including:
sensing electrical activity at one or more pancreatic sites;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals so as to identify an aspect thereof which is indicative of activity of pancreatic delta cells; and
generating an output signal responsive to identifying the aspect.
There is yet further provided, in accordance with a preferred embodiment of the present invention, a method for analyzing electrical activity of a pancreas of a patient, including:
sensing electrical activity at one or more pancreatic sites;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals so as to identify an aspect thereof which is indicative of activity of polypeptide cells; and
generating an output signal responsive to identifying the aspect.
There is also provided, in accordance with a preferred embodiment of the present invention, a method for coupling an electrode to a pancreas of a patient, including:
peeling back a portion of connective tissue surrounding the pancreas, so as to create a pocket;
inserting the electrode into the pocket; and
suturing the electrode to the connective tissue.
There is additionally provided, in accordance with a preferred embodiment of the present invention, a method for sensing electrical activity of a pancreas of a patient, including:
sensing, at each of one or more sites of the pancreas, electrical activity of pancreatic cells;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing a frequency component of the activity signals; and
generating an output signal responsive to the analysis.
There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a method for sensing activity of a pancreas of a patient, including:
sensing, at each of one or more sites of the pancreas, a calcium level;
generating activity signals responsive thereto;
receiving the activity signals;
analyzing the activity signals; and
generating an output signal responsive to the analysis.
The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings, in which:
In a preferred embodiment, recorded electrical activity signals detected by electrodes 100 are amplified and transferred by wires out of the patient's body and/or transferred to a signal-receiving device which interacts with a device that produces a therapy (e.g., modulating insulin secretion).
For some applications in which communication with an external unit is desired, in order to avoid long wires and skin crossing, wireless transmission is used. For example, transmission may be in the ISM frequency band, typically in frequencies of 13-27 MHz. Since the transmission utilized is typically for short distances, e.g., tens of centimeters, working in the low frequencies is preferably accomplished by means of the magnetic field produced by a loop antenna. More than one loop (e.g., mutually-perpendicular loops, or loops at another angular offset) are used in some applications. The transmission method can be analog, e.g., by amplitude modulation (AM) or by frequency modulation (FM), or it may be digital, as described hereinbelow. For digital transmission, the signal is sampled (preferably after suitable filtering), and then transmitted.
On-Off keying (OOK) is a preferred digital transmission method. Alternatively, other digital transmission methods known in the art are used, such as frequency shift keying (FSK) or phase shift keying (PSK, BPSK, QPSK).
In a preferred OOK embodiment, the output of a serial analog-to-digital converter is input into a resonator, which may resonate, for example, by the interaction between a coil and a capacitor, or by means of a SAW-based resonator or other circuit known in the art, connected to the coil.
In order to reduce power consumption for the data transmission, it is possible to avoid active transmission at the pancreatic site, and instead use an externally-driven magnetic field. In this case, the internal unit on the pancreas preferably includes a switched coil. The coil is either connected or disconnected according to the data bits to be transmitted to the external unit. Switching of the coil may be accomplished with FET's or any suitable technique known in the art.
The switching of the switching coil at the pancreas is detected by the external unit (outside of the patient's body) as slight pulses in the current consumption of the external coil, due to the changes in the coupling between the external coil and the internal switching coil. (Changing the load is detectable as transient current changes in the external emitter coil.)
Pre-processing of the recorded data is preferably performed prior to transmission to the external unit. For example, the data may be analyzed, and the data stream compressed and/or encoded, such as with error-correcting codes, e.g., repetitions, convolutions, and interleaves.
For some applications, in order to further reduce power consumption by the internal circuitry coupled to the pancreas, the energy source for all of the circuitry (e.g., amplifiers, filters, A/D, pre-processing, transmission, therapy application, etc.) is based on induction. In this method, an externally-driven magnetic field transfers energy into the circuit. Low frequencies (e.g., a few KHz) are typically used, although other frequencies can be used as well.
In the internal unit, the energy is received by a coil which resonates at the transmitted frequency. The received signal is preferably converted into DC, filtered and regulated. For some applications, this energy charges an internal energy source (e.g., a battery or capacitor). For other applications, the energy directly supplies the operation of the internal circuitry.
In an embodiment, most of the internal circuitry is implemented in a single chip, with direct links to only a few off-chip components, such as electrodes 100 and coils. Preferably, the chip performs signal amplification, conditioning, sampling, analysis, encoding, and modulation, and switches the switching coil to pass information to the external unit.
Alternatively or additionally, the internal unit wirelessly receives commands from the external unit, using the techniques described herein (e.g., OOK) or others known in the art. For example, these commands may include: turn on/off, change gain, and change filter parameters.
Electrodes 100 comprise one or more of the following: (a) local sense electrodes 74, configured to sense electrical activity of pancreas 20 and generate activity signals responsive to the electrical activity, (b) signal application electrodes 76, configured to apply signal-applications to pancreas 20, (c) electrodes configured to function both as local sense electrodes and signal application electrodes, and generate respective activity and signal-applications, and/or (d) a combination of (a), (b) and (c). Electrodes 100 preferably comprise one or more of the electrodes described hereinbelow with reference to
In a preferred embodiment of the present invention, in response to receiving and analyzing activity signals and/or supplemental signals, generated by electrodes 100 and/or supplemental sensors 72, respectively, control unit 90 applies a treatment by means of a treatment unit 101, comprising, for example, one or more of electrodes 100, which are driven by the control unit to apply signal-applications to at least a portion of pancreas 20. Alternatively or additionally, treatment unit 101 may comprise other apparatus known in the art (not shown), including, but not limited to:
For some applications, a pump delivers, and/or a patient-alert unit instructs the patient to self-administer, a drug that blocks glucagon, the production of which may be stimulated by signals applied by electrodes 100 functioning as treatment unit 101. When treatment unit 101 comprises one or more of electrodes 100, control unit 90 preferably modifies the signal-applications applied through the electrodes responsive to signals from supplemental sensors 72 and/or activity signals generated by electrodes 100 functioning as local sense electrodes, as described hereinbelow. Alternatively or additionally, apparatus 18 is configured to operate in a diagnostic mode, and electrical measurements made by the apparatus are stored for later analysis, such as by a physician or by an automated analysis system, such as a computer system. For some applications, control unit 90 applies the treatment with respect to a time that a patient commences eating, e.g., 10 minutes before eating, during eating, or 10 minutes after commencement of eating.
Typically, electrodes 100 convey activity signals to control unit 90 responsive to spontaneous electrical activity of the pancreas, e.g., activity which occurs in the course of natural, ongoing processes of the pancreas. For some applications, however, a synchronizing signal is first applied (e.g., using techniques described in the above-cited U.S. Pat. Nos. 5,919,216, 6,093,167 and/or 6,261,280 to Houben et al.), and pancreatic electrical activity is measured subsequent thereto. Preferably, the synchronizing signal is applied by one or more of electrodes 100.
In a preferred embodiment, one or more reference electrodes 78 are placed near the pancreas or elsewhere in or on the patient's body. Optionally, at least one of electrodes 78 comprises a metal case of control unit 90. In some applications, the reference electrodes are used to reduce any effects of artifacts on recording pancreatic electrical activity, which may arise due to respiratory movements, neural activity, cardiac electrical phenomena, electromyographic phenomena, smooth muscle electrical activity, and/or gastrointestinal tract electrical phenomena.
For applications in which control unit 90 applies signal-application signals to the pancreas, methods and techniques are preferably employed which are described in one or more of the following applications/publications cited hereinabove: (a) U.S. Provisional Patent Application 60/123,532, filed Mar. 5, 1999, entitled “Modulation of insulin secretion,” (b) PCT Publication WO 00/53257 to Darwish et al., and the corresponding U.S. patent application Ser. No. 09/914,889, filed Jan. 24, 2002, or (c) PCT Publication WO 01/66183 to Darvish et al.
In an embodiment, the signal-application signals are synchronized with respect to a phase or state of the pancreas. For example, the signal-application signals may be applied with respect to a phase in a metabolic and/or insulin oscillation. NADH is a metabolic indicator suitable for facilitating this approach. Alternatively or additionally, insulin oscillations measured using techniques described herein are used to coordinate the timing of application of the signal-application signals. Depending on application, the signal-application signals may be applied during high- or low-points in the measured insulin oscillations. Further alternatively or additionally, signal-application signals are timed with respect to the beginning, middle, or end of a recorded burst or group of bursts. Still further alternatively or additionally, the signal-application signals are applied during an inter-burst period.
Preferably, block 82 conveys results of its analysis to a “parameter search and tuning” block 84 of control unit 90, which iteratively modifies characteristics of the electrical signals applied to the pancreas in order to attain a desired response. Further preferably, operating parameters of block 84 are entered during an initial calibration period by a human operator of the control unit using operator controls 71, which comprise an input unit, comprising, for example, a keyboard, a keypad, one or more buttons, and/or a mouse. Block 84 typically utilizes multivariate optimization and control methods known in the art in order to cause one or more electrical parameters (e.g., burst magnitude, amplitude of different burst spectral components, and/or burst rate or duration), chemical parameters (e.g., glucose or insulin values) and/or other measured parameters to converge to desired values.
In general, each one of electrodes 100, when functioning as a signal application electrode, may convey a particular waveform to pancreas 20, differing in certain aspects from the waveforms applied by the other electrodes. The particular waveform to be applied by each electrode is determined by control unit 90, initially under the control of the operator. Aspects of the waveforms which are set by the control unit, and may differ from electrode to electrode, typically include parameters such as time shifts between application of waveforms at different electrodes, waveform shapes, amplitudes, DC offsets, durations, and duty cycles. For example, the waveforms applied to some or all of electrodes 100 may comprise a monophasic square wave pulse, a sinusoid, a series of biphasic square waves, or a waveform including an exponentially-varying characteristic. Generally, the shape, magnitude, and timing of the waveforms are optimized for each patient and for each electrode, using suitable optimization algorithms as are known in the art. For example, one electrode may be driven to apply a signal, while a second electrode on the pancreas is not applying a signal. Subsequently, the electrodes may change functions, whereby the second electrode applies a signal, while the first electrode is not applying a signal.
For the purposes of these embodiments of the present invention, block 84 typically modifies a set of controllable parameters of the signal-application signals, responsive to the measured parameters, in accordance with values in a look-up table and/or pre-programmed formulae stored in an electronic memory of control unit 90. The controllable parameters may comprise, for example, pulse timing, magnitude, offset, monophasic or biphasic shape, applied signal frequency, and pulse width. In a preferred embodiment, signal-application signals are applied in biphasic rectangular pulses, having pulse widths of: (a) between about 2 and about 100 ms, most preferably about 5 ms, in the positive phase, and (b) between about 2 and about 100 ms, most preferably about 5 ms, in its negative phase, and having a frequency of between about 5 and about 100 Hz, most preferably 5 Hz, 20 Hz or 100 Hz. In this embodiment, the signals are applied either as single pulses, or in a burst with a duration preferably between about 500 ms and about several seconds. Preferably, the application of the signals is repeated approximately every 1-10 minutes. Preferably, the controllable parameters are conveyed by block 84 to a signal generation block 86 of control unit 90, which generates, responsive to the parameters, electrical signal-application signals that are applied by electrodes 100, when functioning as signal application electrodes, to pancreas 20. Block 86 preferably comprises amplifiers, isolation units, and other standard circuitry known in the art of electrical signal generation. It is to be understood that although the components of control unit 90 are shown in the figures as incorporated in an integrated unit, this is for the sake of illustration only. In some embodiments of the present invention, one or more of the components of control unit 90 are located in one or more separate units, for example implantable patches, as described hereinbelow, coupled to one another and/or control unit 90 over wires or wirelessly.
In the preferred embodiment shown in
Wire electrodes 112 preferably comprise a biocompatible material, such as platinum/iridium (Pt/Ir), titanium, titanium nitride, or MP35N. The length D1 and width D2 of patch 118 are preferably between about 2 mm and about 20 mm, and between about 2 mm and about 10 mm, respectively. Most preferably, D1 equals 4 mm and D2 equals 1.2 cm. Preferably, the diameter D3 of wire electrodes 112 is between about 0.5 mm and about 5 mm, most preferably 0.7 mm, and the diameter D4 of insulating rings 114 is between about 0.5 mm and about 5 mm, most preferably 1.6 mm. When the electrode assemblies are of these dimensions, the distance D5 between the centers of the electrode assemblies is preferably between about 2 and about 10 mm, most preferably 4 mm.
Reference is made to
The electrodes preferably comprise a biocompatible material, such as platinum/iridium (Pt/Ir), titanium, titanium nitride or MP35N. The width D7 and length D8 of patch 119 are preferably between about 2 mm and about 10 mm, and between about 2 mm and about 20 mm, respectively. Most preferably, patch 119 is generally square, and D7 and D8 each equal about 7 mm. Preferably, (a) the diameter D10 of inner wire electrode 122 is between about 0.5 mm and 5 mm, most preferably 1.2 mm, (b) the inner diameter D11 of outer ring electrode 124 is between about 1 mm and about 5 mm, most preferably 3.1 mm, (c) the outer diameter D12 of outer ring electrode 124 is between about 1 mm and about 10 mm, most preferably 3.2 mm, such that D12−D11 is typically between 0.1 mm and 0.5 mm, and (d) the diameter D13 of outer insulating ring 128 is between about 1 mm and about 10 mm, most preferably 3.8 mm. Preferably, insulating rings 126 and 128 protrude from the top surface of patch 119 by a distance of between about 0.5 mm and about 2.0 mm, most preferably about 1.5 mm. Preferably, inner wire electrode 122 and outer ring electrode 124 are recessed in the insulating rings by a distance of between about 0.5 mm and about 2.0 mm, most preferably about 1.5 mm. (These latter dimensions can best be seen in
Reference is now made to
Preferably, in order to improve the attachment and contact of the electrodes described hereinabove to tissue of the patient, a hydrogel is applied on top of the patch or mount containing the electrodes, and/or around this patch (e.g., 1-10 mm from the edge of the patch or mount), so as to flexibly harden and maintain the mechanical coupling of the patch or mount to the pancreas and/or act as a shock absorber, protecting the patch or mount during contact with or motion of organs of the subject, such as the stomach. Alternatively or additionally, a balloon filled with a gas, such as CO2, or a liquid, such as saline solution, is placed on the top surface of the patch or mount, so as to act as a shock absorber, protecting the patch or mount during contact with or motion of organs of the subject, such as the stomach. Further alternatively or additionally, in order to reduce the likelihood that organs near the electrodes catch on the top of the electrodes, a sheet made of Teflon® or other similar material is attached to the top of the electrode patch or mount. Thus, organs near the electrode move smoothly against this sheet.
The assembly further comprises a suture 304, which preferably comprises braided metal or silk. A needle 308 is attached to the end of the suture, for suturing electrode assembly 330 to tissue of the pancreas. After suturing, needle 308 is preferably removed. The distal ends of wires 302 preferably are joined in a shrink wrapping or connecting element 310 by glue, such as epoxy glue; suture 304 passes through (as shown) or adjacent to connecting element 310. The proximal ends of the wires are electrically and mechanically coupled to a preamplifier or amplifier 312. The proximal end of the suture is preferably mechanically coupled to the amplifier. A cable 314 is connected at one end of the cable to the proximal end of the amplifier. The other end of the cable is connected to an implanted patch or to a control unit. (For wireless transmission applications, the cable may be replaced by data transmission apparatus.) Preferably, the length D23 of the amplifier is between about 3 and about 4 mm. The distance D24 between the amplifier and connecting element 310 is preferably between about 15 and about 25 mm, most preferably about 20 mm. All electrical components of electrode assembly 330, other than electrodes 306, are preferably isolated against fluid, such as by using an epoxy or Parylene.
Signal-processing patch assembly 130 additionally comprises signal-processing components, such as a preamplifier 134, filters 136, amplifiers 138, a preprocessor 142, and a transmitter 144, all preferably physically located on the patch assembly. In embodiments in which signal-processing patch assembly 130 comprises two electrode assemblies 132, both electrode assemblies are preferably connected to a single preamplifier 134. Preferably, the electrodes of electrode assemblies 132 are in direct physical contact with the inputs of preamplifier 134, with substantially no wires used for connection. Alternatively, the electrodes of electrode assemblies 132 are connected to the inputs of preamplifier 134 using wires. Signals generated by preamplifier 134 are preferably passed through filters 136 and then amplifiers 138. Filters 136 preferably comprise a high-pass filter, a low-pass filter, and a notch filter (not shown). The high-pass filter preferably has a frequency cutoff of about 0.05 Hz to about 10 Hz, e.g., 0.5 Hz, and the low-pass filter preferably has a frequency cutoff of about 40 Hz to about 500 Hz, e.g., 100 Hz. The notch filter is preferably configured to filter out the frequency of the local power grid, such as 50 or 60 Hz. Amplifiers 138 comprise a single amplifier, or, alternatively, a first-stage and second-stage amplifier (together, a dual-stage amplifier). Preferably the first- and second-stage amplifiers amplify, for example, by about 25× and about 50×, respectively, so as to generate a total amplification of between about 100× and about 10,000×. For some applications, signal-processing patch assembly 130 comprises an analog-to-digital converter 140, in which case preprocessor 142 and transmitter 144 are digital components. Amplifiers 138 send signals to preprocessor 142, either directly, or, if signal-processing patch assembly 130 comprises analog-to-digital converter 140, through the converter. Preprocessor 142 sends signals to transmitter 144.
For some applications, transmitter 144 transmits the generated signals to control unit 90. Alternatively, transmitter 144 transmits the signals directly to an external or implanted treatment unit, as described hereinabove. Transmitter 144 preferably transmits using transmission techniques known in the art, such as inductive transmission, near-field electromagnetic transmission, or radiofrequency transmission.
Alternatively, some or all of the signal-processing components of signal-processing patch assembly 130 are provided on a separate signal-processing patch assembly (not shown) that is connected to the electrodes of two-electrode patch assembly 110 (
In a preferred embodiment of the present invention, apparatus 18 undergoes a calibration procedure. In a typical initial calibration procedure, a bolus dose of glucose is administered to the patient, and electrical function analysis block 82 determines changes in the electrical activity of the pancreas responsive to the glucose. (Experimental results showing some such changes in activity are described hereinbelow.) Parameter search and tuning block 84 subsequently modifies a characteristic (e.g., timing, frequency, duration, magnitude, energy, and/or shape) of the signals applied through one of electrodes 100, typically so as to cause the pancreas to release a hormone such as insulin in greater quantities than would otherwise be produced. This release causes cells throughout the patient's body to increase their uptake of the glucose, which, in turn, lowers the levels of glucose in the blood and causes the electrical activity of the pancreas to return to baseline values. In a series of similar calibration steps, block 84 repeatedly modifies characteristics of the signals applied through each of the electrodes, such that those modifications that reduce blood sugar, accelerate the return of the electropancreatographic measurements to baseline values, and/or otherwise improve the EPG signals, are generally maintained, while modifications that cause it to worsen are typically eliminated or avoided.
It will be appreciated that whereas the calibration procedure described hereinabove is applied with respect to a single electrode, for some applications, multiple electrodes are calibrated substantially simultaneously, for example, in order to determine which electrodes should be driven simultaneously to apply current to the pancreas.
Optionally, during the initial calibration procedure, the locations of one or more of electrodes 100 are varied while EPG signals are measured and/or electrical signals are applied therethrough, so as to determine optimum placement of the electrodes.
Alternatively or additionally, the calibration procedure includes: (a) administration of insulin and/or a fasting period to reduce blood sugar levels, (b) detection of changes in pancreatic electrical activity responsive to the reduced blood sugar levels, and (c) application of electrical signals to the pancreas configured to enhance glucagon production and generally restore the EPG signals to their baseline values.
Preferably, the calibration procedure is additionally performed by a physician or other healthcare worker at subsequent follow-up visits and by unit 90 automatically during regular use of the apparatus (e.g., once per day, before and/or after a meal, or before and/or after physical activity), mutatis mutandis. When apparatus 18 is calibrated in the presence of a physician or healthcare worker, it is often desirable to administer to the patient glucose boluses having a range of concentrations, in order to derive a broader range of operating parameters, which are stored in control unit 90 and can be accessed responsive to signals from the sensors and electrodes coupled to the control unit.
It is to be understood that where preferred embodiments of the present invention are described herein with respect to glucose and insulin, this is by way of example only. In other embodiments, the effects of other chemicals, such as glucagon or somatostatin, on pancreatic electrical activity are monitored, and/or signals are applied to the pancreas so as to modulate the release of other hormones, such as glucagon or somatostatin. Additionally, for some applications, during calibration, glucose, insulin, a diazoxide-like compound, tolbutamide, and/or other chemicals that affect blood levels of glucose and/or insulin, are administered orally or intravenously.
Preferably, during calibration and during regular operation of control unit 90, a systemic function analysis block 80 of control unit 90 receives inputs from supplemental sensors 72, and evaluates these inputs, preferably to detect an indication that blood sugar levels may be too high or too low. Alternatively or additionally, block 80 evaluates these inputs to detect indications that insulin, glucagon, and/or somatostatin may be too high or too low. If appropriate, these inputs may be supplemented by user inputs entered by the patient through operator controls 71, indicating, for example, that the patient senses that her blood sugar is too low. In a preferred embodiment, parameter search and tuning block 84 utilizes the outputs of analysis blocks 80 and 82 in order to determine parameters of the signals which are applied through electrodes 100 to pancreas 20.
The electrodes were connected to a Cyber-Amp 320 (Axon Instruments) amplifier, in which total gain was set to 10000 and a band pass filter was to allow 0.1 to 40 Hz signals to pass. The Cyber-Amp was connected to a computer, and recorded signals which were sampled at 1000 Hz and saved for off-line analysis.
The lower trace in
Bipolar titanium wire electrodes, 300 microns in diameter, were placed in a mount similar to that shown in
The data in
The data in
It is hypothesized that increases in amplitudes and/or fluctuations of the recorded signals may correspond to “recruitment” (activation) of increasing numbers of cells in increasing numbers of islets of Langerhans, which in turn corresponds to the propagation of glucose through the pancreas.
In the experiment whose results are shown in
A similar analysis was performed with respect to the amplitudes of the spikes before and after tolbutamide injection.
The GI tract data shown in
In a preferred mode of analysis, control unit 90 analyzes the EPG signals so as to distinguish between portions thereof which are indicative of activity of alpha cells and beta cells of the pancreas. For some applications, analysis is also performed to determine changes in delta cell activity and/or polypeptide cell activity. Increases in beta cell activity typically are interpreted by the control unit to be indicative of the generation of insulin responsive to increased blood sugar, while increases in alpha cell activity typically correspond to the generation of glucagon responsive to decreased blood sugar. If appropriate, a treatment may be initiated or modified based on these determinations.
Figures in the above-cited article by Nadal show calcium-based fluorescence changes responsive to alpha, beta, and delta cell activity. Each cell produces its own characteristic form, which distinguishes it from the other types of cells. A particular distinguishing characteristic is the duration of each burst of electrical activity. In the Nadal article, alpha cells are seen to produce substantially more prolonged, long-duration bursts of fluorescence than do beta cells, whose activity is better characterized as a series of short-duration spikes. The data presented in the figures of the present patent application can also be analyzed to distinguish between the activity of the different types of pancreatic cells.
For some applications, EPG analysis is performed using the assumption that the various inputs to the EPG (e.g., alpha-, beta-, delta-, and polypeptide-cells) are generally mutually-independent. In this case, signal processing methods known in the art, such as single value decomposition (SVD) or principal component analysis, are preferably adapted for use with the techniques describes herein in order to separate the overall recorded activity into its various sources.
Alternatively, for some applications it is preferred to assume that the various components of the EPG are mutually-dependent, in which case techniques such as that described in the above-cited article by Gut are preferably adapted to enable a determination of the contribution to the EPG of alpha cells, beta cells, and/or other factors. In particular, the Gut article describes methods for distinguishing the contributions of individual finite-duration waveforms to an overall electromyographic (EMG) signal. In a preferred embodiment of the present invention, this method is adapted to facilitate a calculation of the contributions of groups of alpha and beta cells to the overall EPG signal.
In a preferred embodiment of the present invention, in combination with or separately from the analysis methods described hereinabove, EPG signals are interpreted by evaluating waveform frequencies, amplitudes, numbers of threshold-crossings, energy, correlations with predefined patterns or with an average pattern, and/or other characteristics.
It will be appreciated that the principles of the present invention can be embodied using a variety of types and configurations of hardware. For example, for some applications, it is appropriate to use a relatively small number of electrodes placed on or in the head and/or body and/or tail of the pancreas. Alternatively or additionally, a larger number of electrodes, e.g., more than ten, are placed on the pancreas, preferably but not necessarily incorporated into flexible or stiff electrode arrays. In a preferred embodiment, several arrays each comprising about 30-about 60 electrodes are placed on or implanted in the pancreas.
It is noted that the pin electrodes used in gathering the data shown in the figures had characteristic diameters of approximately 500 to 1000 microns, which, despite their large size, were able to record electrical activity over relatively long periods, e.g., up to several hours. Any injury which may have been induced (none was detected) would presumably have been limited to a local region around each electrode. For some clinical applications, it is preferable to use or adapt for use commercially-available electrodes such as those which have diameters of several microns and are designed for recording electrical activity in the brain. A range of electrodes are known or could be adapted to measure the characteristic 1-100 microvolt pancreatic electrical activity.
It is believed that the data shown in the following figures are not fundamentally dependent on the particular configurations of electrodes which are used. For example, for some experiments (not shown), a suction pipette electrode containing an Ag/AgCl wire was used to measure pancreatic electrical activity with respect to an Ag/AgCl wire reference electrode that was placed under the pancreas.
As shown in
For some pig experiments (not shown), differential recording was performed using two sets of the electrode apparatus shown in
The upper trace of
Tolbutamide was administered after the twelfth sample was collected, and insulin measurements showed a clear trend of increase for the next ten samples (until Diazoxide was administered). A corresponding clear increase in the rate and duration of bursts is seen during the tolbutamide administration period. Subsequent administration of Diazoxide induces a complete inhibition of measured pancreatic electrical activity, and the measured levels of secreted insulin dropped at least to baseline levels, or to lower than baseline levels. During subsequent tolbutamide administration, additional increases in insulin secretion levels were detected, and these were accompanied by corresponding increases in electrical activity.
For some applications, a slow wave or burst is detected, and a stimulus is applied at a specified time after the onset of the slow wave or burst (e.g., during the slow wave or burst, or after the slow wave or burst), in order to enhance or otherwise modulate insulin secretion. For example, the stimulus may be applied 0-1 ms, 1-10 ms, 10-100 ms, 100-1000 ms, or 1-10 seconds after the onset of the slow wave or burst. For some applications, because of the pancreatic refractory periods described hereinabove with reference to
Alternatively or additionally, sensing of pancreatic electrical activity is performed even with only one electrode, and an artificial stimulus is applied each time that a burst or slow wave is detected. The inventors believe that this develops in some patients a feedback loop, whereby the pancreas responds to elevated blood glucose by increasing its electrical activity (and increasing insulin secretion), and the stimulus applied to the pancreas further increases the insulin secretion, thereby supporting the pancreas in its effort to restore proper blood sugar levels. As blood sugar decreases, pancreatic electrical activity decreases and applied stimuli are consequently reduced.
It is hypothesized that a pancreatic equivalent of cardiac pacemaker cells may be responsible for controlling a significant portion of the slow wave or burst activity. In a preferred embodiment, a plurality of electrodes are placed at various sites on a patient's pancreas, and are driven in various sequences, using optimization algorithms known in the art, so as to determine a particular subset of the electrodes which maximally stimulate or modulate the propagation of slow waves or burst activity in the pancreas. Preferably, this calibration takes approximately a month, and is performed in cooperation with other tests (e.g., blood sampling) so as to determine stimulation protocols which achieve and then maintain glucose and/or insulin levels within desired ranges. Alternatively or additionally, one or more of the electrodes may be driven to induce slow waves or burst activity even without identifying the pancreatic equivalent of pacemaker cells.
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For some applications, the need to increase or decrease insulin secretion can be satisfied by reversing the polarity of the applied stimulus. Alternatively or additionally, other parameters, such as magnitude, duration, or frequency of the applied stimulus can be modified to achieve a desired change in insulin secretion.
In a preferred application, the applied stimulus includes a square wave between approximately several tens of microamps to several milliamps (or higher, depending on electrode configuration), has a frequency between about 1 and about 500 Hz, and a delay from the start of a burst or slow wave of about 0 to about 1 second. The duration of the signal is typically either (a) the width of a single pulse or (b) between about 50 ms and about 1 second.
It is also noted that the inventors have successfully sutured electrodes directly to a pig pancreas, and after a week no tissue rupture or dramatic inflammation was visible (as would be expected if the exocrine pancreas were damaged). Any of the surgical techniques described herein may typically be performed laparoscopically or using other known surgical methods.
Additionally, electrical impedance between two sites on the stomach was measured, by placing two wire electrodes therein, in order to facilitate a determination of the effect of motion of the stomach on the pancreatic electrical activity measurements. Two similar electrodes were placed on the pancreas to detect changes in pancreatic electrical impedance across a distance, so as to detect movement of the pancreas. A correlation was found between the activity measurements and motion of the stomach and of the pancreas. In a preferred embodiment of the present invention, apparatus 18 comprises one or more stomach “impedance electrodes” (not shown), configured to sense stomach motion. Control unit 90 receives a signal indicative of a measure of stomach motion from the stomach impedance electrodes, and adjusts the recorded pancreatic signals responsive thereto, such as by using a subtraction algorithm.
The wires of the electrodes (formed in a braid) were passed through the back of the minipig, under the skin of the left abdominal wall, and connected to an external device having a sensory channel. The external device was connected to a computer, which recorded signals sampled at between 0 and 500 Hz, and saved the recorded signals for off-line analysis. The analysis shown in
Readings from the pancreas were recorded during an hour-long period while the minipig was fasting, and without the administration of glucose or any drug. At minute 66 from the beginning of the recording, 30 cc of 50% dextrose was injected into the jugular vein. The injection was completed in 1.5 minutes. As is seen in
The wires of the electrodes were passed through the back of the minipig and connected to an external device comprising sensor and delivery channels. The external device was connected to a computer, which recorded signals sampled at 0 to 500 Hz, and saved the recorded signals for off-line analysis. The analysis was performed using a sampling rate of 200 Hz.
Readings from the pancreas were recorded during an hour-long period while the minipig was fasting, and without the administration of glucose or any drug. From minute 60 to minute 98 from the beginning of the recording, the minipig was fed. As is seen in
During the first approximately 64 minutes, electrical activity was relatively flat, and, correspondingly, glucose and insulin levels remained fairly steady. At approximately 64 minutes, 30 cc of 50% dextrose was administered intravenously. Within about 2 to about 3 minutes, a sharp spike in the magnitude of the 70 Hz frequency component was observed. At this point, blood glucose and insulin levels also jumped sharply. All three indicators of pancreatic activity gradually declined over the next approximately 35 minutes, at which point 20 cc of 50% dextrose was administered intravenously. In response to this lower dose, smaller spikes in the 70 Hz frequency component were observed, beginning at approximately 128 minutes. (Insulin and blood glucose samples were not collected at this point.) Blood glucose and insulin levels at about 150 minutes were very slightly lower than baseline levels.
In a preferred embodiment of the present invention, signals generated by electrodes are analyzed using a moving window. Preferably, the duration of each window is between about 1 and about 300 seconds, and sequential windows overlap one another by about 20 to about 80 percent of the duration of each window. A Fourier transform or other transform is applied to the signal for the time period of each window, and the amplitude of each frequency component is stored. One or more algorithms are used to detect indications of clinically-significant phenomena, such as an increase in blood glucose and/or insulin levels from normal to elevated or supraphysiological values. Preferably, responsive to the outputs of one or more such algorithms, a decision is made regarding whether to apply a therapeutic response.
Preferably, the algorithms calculate one or more of the following:
Alternatively or additionally, algorithms are used in order to identify one or more of the following:
Preferably, interference caused by non-pancreatic electrical activity sensed by the electrodes is reduced using one or more of the following methods:
For some applications, it is desirable to increase current density applied to the pancreas or associated connective tissue to a relatively high value, e.g., by driving 1-20 mA (preferably 5 mA) through an electrode having an area of 0.001 cm2 to 1 cm2 (preferably approximately 0.005 cm2).
It is to be understood that whereas preferred embodiments of the present invention are described with respect to sensing and/or stimulating a patient's natural pancreas, some of the same techniques may be adapted for sensing and/or stimulating implanted islets or beta cells, so as to regulate a patient's glucose and insulin levels. It is also to be understood that “magnitude” and “amplitude,” as used in the specification and the claims, are synonymous.
It is to be further understood that whereas preferred embodiments of the present invention are described with respect to sensing pancreatic electrical activity, similar measurements may be made, alternatively or additionally, of oscillations in calcium levels and/or oscillations in other pancreatic functions, e.g., pancreatic metabolic function, and analyzed, mutatis mutandis, to yield an indication of blood glucose and/or insulin level. For example, one or more calcium electrodes may be coupled to various sites on a patient's pancreas and activated to yield indications of intracellular or interstitial calcium levels. Alternatively or additionally, dyes or other indicators of calcium or ATP/ADP conversion may be used to indicate pancreatic functioning, for example, in combination with implanted light sources and/or detectors.
It is also to be understood that when, for example, electrodes 100 are described herein as “generating” an activity signal, this comprises recording electrical activity and conveying an activity signal, responsive thereto, to an element that receives the activity signal (e.g., signal amplification and processing circuitry).
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 sub-combinations 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.
This application is a continuation-in-part of PCT Patent Application No. PCT/IL01/00501, filed May 30, 2001, entitled, “Electropancreatography,” which claims priority from U.S. Provisional Patent Application No. 60/208,157, filed May 31, 2000, entitled, “Electrical activity sensor for the whole pancreas.” The '501 and '157 applications are assigned to the assignee of the present patent application and incorporated herein by reference. This application claims priority from U.S. Provisional Patent Application No. 60/334,017, filed Nov. 29, 2001, entitled, “In situ sensing of pancreatic electrical activity,” which is assigned to the assignee of the present patent application and incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IL02/00856 | 10/24/2002 | WO | 5/17/2005 |
| Number | Date | Country | |
|---|---|---|---|
| 60334017 | Nov 2001 | US |
