CROSS REFERENCE TO RELATED APPLICATIONS
This application is based on and claims domestic priority benefits under 35 U.S.C. 120 of U.S. Provisional patent application 61/328,344, filed 27 Apr. 2010. The entire Provisional application is hereby incorporated by reference herein.
FIELD OF THE INVENTION
This invention relates to the medical field and the treatment of specified diseases and, in particular, to a device for non-invasive measurement of the blood glucose level of a subject patient.
BACKGROUND OF THE INVENTION
Diabetes and its complications impose significant economic consequences on individuals, families, health systems and countries. The annual expenditure for diabetes in 2007 in the USA alone was estimated to be over $170 billion, attributed to both direct and indirect costs (American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care. 2008 March, 31(3): 1-20). In 2010, Healthcare expenditures on diabetes are expected to account for 11.6% of the total worldwide healthcare expenditure. It is estimated that approximately 285 million people around the globe will have diabetes in 2010, representing 6.6% of the world's adult population, with a prediction for 438 million by 2030 (International Diabetes Federation. Diabetes Atlas, Fourth edition. International Diabetes Federation, 2009).
In the recent years, research has conclusively shown that improved glucose control reduces the long-term complications of diabetes (DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. North England Journal of Medicine. 1993 Sep. 30; 329(14): 977-986; UKPDS Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in subjects with type 2 diabetes (UKPDS33). The Lancet. 1998 Sep. 12; 352(9131): 837-853). According to the American Diabetes Association (ADA), self-monitoring of blood glucose (SMBG) has a positive impact on the outcome of therapy with insulin, oral agents and medical nutrition (American Diabetes Association. Clinical Practice Recommendations, Standards of medical care in diabetes. Diabetes Care. 2006 Jan. 29: S4-S42). In its publication “Consensus Statement: A European Perspective”, the Diabetes Research Institute in Munich recommends SMBG for all types of diabetes treatment approaches, in order to achieve proper glucose control and values which are close to normal, without increasing the risk of hypoglycemia (Schnell O et al., Diabetes, Stoffwechsel and Herz, 2009; 4:285-289). Furthermore, special guidelines with proper recommendations were issued recently by the International Diabetes Federation (IDF), to support SMBG for non-insulin treated T2DM patients (Recommendations based on a workshop of the International Diabetes Federation Clinical Guidelines Taskforce in collaboration with the SMBG International Working group. Guidelines on Self-Monitoring of Blood Glucose in Non-Insulin Treated Type 2 Diabetics. International Diabetes Federation, 2009).
SMBG presents several benefits in both diabetes education and treatment. It can help facilitate individuals' diabetes management by providing an instrument for objective feedback on the impact of daily lifestyle habits, individual glucose profiles, including exercise and food intake impact on that profile, and thereby empower the individual to make necessary changes. Moreover, SMBG can support the healthcare team in providing individually tailored advice about life style components and blood glucose (BG) lowering medications, thus helping to achieve specific glycemic goals.
The inconvenience, expenses, pain and complexity involved in conventional (invasive) SMBG, however, lead to its underutilization, mainly in people with type 2 diabetes (Mollema E D, Snoek F J, Heine R J, Van der Ploeg H M. Phobia of self-injecting and self-testing in insulin treated diabetes patients: Opportunities for screening. Diabet Med. 2001; 18:671-674; Davidson M B, Castellanos M, Kain D, Duran P. The effect of self monitoring of blood glucose concentrations on glycated hemoglobin levels in diabetic patients not taking insulin: a blinded, randomized trial. Am J Med. 2005; 118(4):422-425; Hall R F, Joseph D H, Schwartz-Barcott D: Overcoming obstacles to behavior change in diabetes self-management. Diabetes Educ. 2003; 29:303-311). Availability of an accurate, painless, inexpensive and easy to operate device will encourage more frequent testing (Wagner J, Malchoff C, Abbott G. Invasiveness as a Bather to Self-Monitoring of Blood Glucose in Diabetes. Diabetes Technology & Therapeutics. 2005 August; 7(4): 612-619; Soumerai S B, Mah C, Zhan F, Adams A, Baron M, Fajtova V, Ross-Degnan D. Effects of health maintenance organization coverage of self-monitoring devices on diabetes self-care and glycemic control. Arch Intern Med. 2004; 164:645-652), leading to tighter glucose control and delay/decrease of long-term complications and their associated healthcare costs.
Non-invasive (NI) glucose monitoring can decrease the cost of SMBG and increase meaningfully the frequency of testing. The main concern in NI methods is to achieve high accuracy results, despite the fact that no direct blood or interstitial fluid measurement is performed.
Therefore, as is well known in the medical arts, one of the more important blood components to measure for diagnostic purposes is glucose, especially for diabetic patients. The well-known and typical technique for determining blood glucose concentration is to secure a blood sample and apply that blood to an enzymatically medicated colorimetric strip or an electrochemical probe. Generally, this is accomplished from a finger prick. For diabetic patients who may need to measure blood glucose a few times a day, it can immediately be appreciated that this procedure causes a great deal of discomfort, considerable irritation to the skin and, particularly, the finger being pricked, and, of course, infection.
For many years, there have been a number of procedures for monitoring and measuring the glucose level in humans and animals. These methods, however, generally involve invasive techniques and, thus, have some degree of risk, or at least some discomfort, to the patient. Recently, some non-invasive procedures have been developed, but still they do not always provide optimum measurements of the blood glucose. At present, there has been no practical confirmed solution.
Most non-invasive monitoring techniques have focused on using incident radiation, which is capable of penetrating tissue and probing the blood. Currently known approaches to non-invasive glucose measurement are mainly based on optical technology. The less successful and relatively uncommon electrical measurements focus upon the dielectric properties of water solutions in a given frequency range, typically between 1-50 MHz. In one form or another, such methods attempt to monitor the influence of glucose or other analyzed concentration upon the dielectric frequency response of either the glucose itself or the secondary effect on the water.
Although investigations have been made into the use of acoustic monitoring, past studies have been primarily directed to the differences in acoustic velocity between organs. These studies have attempted to correlate acoustic velocity changes with chronic or continuous disease states. In addition, there is a large body of medical and scientific literature pertaining to the use of acoustic absorptive and scattering properties of organs for imaging, therapeutic and even diagnostic objectives.
In the prior art techniques, only one parameter is measured. Thus, the possibility of an error is increased.
Freger (U.S. Pat. No. 6,954,662) discloses a non-invasive technique and methods (but not devices) for measurements of the speed of sound through the blood, the conductivity of the blood, and the heat capacity of the blood. Thereafter, the glucose level for each of the three measurements is calculated and the final glucose value is determined by a weighted average of the three calculated glucose values.
While Freger mentions that measurements may be taken of the speed of sound through the blood, the conductivity of the blood, and the heat capacity of the blood, there is no disclosure of how any device can be constructed for effecting such measurements. The herein disclosed and claimed invention, therefore, is an improvement of Freger and specifies a specific device in which these measurements can be effected.
Therefore, there is a need for a more accurate non-invasive device for measuring glucose level, by means of monitoring multiple parameters in a single unitary device. It is, therefore, an object of the present invention to provide a device for non-invasively measuring glucose level in a subject. These objects are achieved by the features of the claims and the following description, in particular by the following preferred aspects of the invention relating to preferred additional and/or alternative embodiments.
SUMMARY OF THE INVENTION
This and other objects of the Invention are achieved by a device, preferably an unitary device, that is capable of non-invasively measuring the body's glucose level by three distinct protocols.
In particular, the device according to the present invention preferably includes a Main Unit, containing hardware and also the software applications, and preferably an external unit(s)/external device(s) (preferably an ear clip) for affixment to the patient. The external unit comprises first and second portions which are connected to each other, wherein the first and second portions are located on opposing sides of a part of the subject, to which said external unit is affixed. For instance, when the external unit is affixed to a patient's ear lobe, the two opposing sides are located on the two opposing sides of the ear lobe, respectively
It is preferable to incorporate in the unitary external unit at least one of the following three elements, which effect three separate and distinct non-invasive measurements of glucose. Additionally, it is further preferred to provide at least two or three elements to effect two or three separate and distinct non-invasive measurements of glucose, respectively. According to a preferred embodiment of the present invention, at least three different elements to effect three separate and distinct non-invasive measurements of glucose are provided within a single, unitary external device, e.g., within a single housing.
It should also be appreciated and understood that each of the measurement channels is new and novel in and of themselves. Hence each measurement channel may be used in isolation by itself (or with still other measurement channels). By combining the three measurement channels in one unitary device, measurements are obtained from three separate and unique measurement channels, thereby optimizing the final measurement.
For non-invasive measurement by use of ultra sound, preferably a transmitter (such as an ultra sound transmitter) and a receiver (such as an ultrasound receiver) are mounted on opposing sides of the external unit. When the external unit is fitted on the patient, a portion of the patient's body (such as an ear lobe) is situated between the transmitter and receiver. Upon receipt of the resultant signal, after it passes through the patient, the receiver sends the signal to the Main Unit for processing by appropriate algorithms. In some embodiments, membranes may be used to cover and protect the transmitter and receiver.
To effect an Electromagnetic measurement, a capacitor is defined in the external unit. The capacitor plates are positioned on opposing sides of the external device and the body part (such as an ear lobe) disposed between the parts of the external unit serves as the dielectric. In some cases the membranes used to shield or cover the transmitter and receiver can serve also as the capacitor plates.
The third technology is based on thermal technology to measure the glucose level. For this purpose, preferably a heater and a sensor are provided at the external device. It is preferred to provide the heater and the sensor (thermal sensor) at opposing sides of the external device. According to another preferred embodiment, however, it is preferred to mount the heater and the sensor on the same side of the two opposing sides, e.g., on the tip of one side of the external unit a heater and sensor are positioned.
The objects of the present invention are solved, for example, by the following aspects of the invention.
According to a first aspect, a unitary device for non-invasively measuring glucose level in a subject comprises: ultrasonic piezo elements positioned on opposing portions of the device and surrounding a part of the subject's body to which the device is attachable; capacitor plates positioned on opposing portions of said device and surrounding said part of the subject's body to which the external means is attachable, and auto-oscillating means connected to said capacitor plates; and a heater and a sensor positioned in close juxtaposition to said part of the subject's body to which the device is attachable.
In one preferred embodiment, the device further comprises an external means (such as an ear clip) for affixment to the subject's body, wherein the ultrasonic piezo elements, the capacitor plates and the heater and the sensor being contained within said external means.
There may also preferably be a main unit for controlling measurements and calculating glucose level; and, means for electrically connecting the main unit and the external means, either galvanic or wireless.
Preferably, membranes cover the ultrasonic piezo elements.
The ultrasonic piezo elements may preferably include a transducer and a receiver.
Preferably, the capacitor plates comprise membranes. In such an embodiment, the membranes may also cover the ultrasonic piezo elements.
A preferred embodiment may include means for determining a distance between opposing portions of said external means. In some embodiments, this means may include a magnet and a sensor.
There may also preferably be an adjustment screw setting the distance between opposing portions of said external means.
In some embodiments, an ambient temperature sensor may be included.
According to other aspects, the individual measurements channels may be separately utilized.
According to a second aspect of the invention, a device for non-invasively measuring glucose level in a subject may comprise a housing; and, capacitor plates positioned on opposing portions of the housing and surrounding a part of the subject's body to which the device is attachable, and auto-oscillating means connected to the capacitor plates.
In a preferred embodiment, this device also includes a processing means for calculating glucose level based on a tissue impedance signal, and means for communicating the tissue impedance signal to the processing means.
This embodiment may include capacitor plates comprised of membranes.
According to an alternate version of this embodiment, there may also be ultrasonic piezo elements positioned on opposing portions of the housing and surrounding said part of the subject's body to which the device is attachable. It may include capacitor plates comprised of membranes and the membranes may cover the ultrasonic piezo elements.
A different alternate version of this embodiment, may include ultrasonic piezo elements positioned on opposing portions of the housing and surrounding the part of the subject's body to which the device is attachable, means for detecting a phase shift between a transmitted and a received wave, and processing means for calculating glucose level based on the phase shift and being in communication with the means for detecting.
According to a third alternate version of this embodiment, there may also be a heater and a sensor positioned on the device in close juxtaposition to the part of the subject's body to which said device is attachable. It may include means for communicating heat transfer characteristics to the processing means for calculating glucose level.
According to a third aspect of the invention, a device, for non-invasively measuring glucose level affixed to a part of a subject's body, comprises ultrasonic piezo elements positioned on opposing portions of the device and surrounding a part of the subject's body to which the device is attachable; and means for detecting a phase shift between a transmitted and a received wave.
It may preferably include a processing means for calculating glucose level based on said phase shift and being in communication with the means for detecting.
According to an alternate version of this embodiment, there may also be a heater and a sensor positioned on the device in close juxtaposition to the part of the subject's body to which said device is attachable. It may include means for communicating heat transfer characteristics to the processing means for calculating glucose level.
According to a fourth aspect of the invention, a device, for non-invasively measuring glucose level affixed to a part of a subject's body, comprises a heater and a sensor positioned on the device in close juxtaposition to the part of the subject's body to which the device is attachable; and means for communicating heat transfer characteristics to a processing means for calculating glucose level.
Other objects, features and advantages of the present invention will become apparent upon reading the following detailed description in conjunction with the drawings and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings, which illustrate examples of embodiments of the invention, in which:
FIG. 1 is a view of the present invention, showing the Main Unit (MU) and the personal ear clip (PEC);
FIG. 2 is a side view, partially broken away and in section, of the PEC;
FIG. 3 is a view of Sensor-tissue structure for one embodiment of the Thermal channel of measurement;
FIG. 4 is a graph showing the raw process of heating the sensor-tissue structure in a subject, reflecting different glucose levels;
FIG. 5 is a graph showing integrated and temperature-corrected equivalent thermal signal in a subject versus glucose level;
FIG. 6A is a schematic representation of the earlobe between the two ultrasonic piezoelements for the Ultra Sound channel of measurement;
FIG. 6B is a graph showing the Phase shift between the received and transmitted waves, measured as Δφ;
FIG. 7 is a graph showing the phase shift versus input transducer frequency in the low frequency region; and, the amplified phase-shift values are viewed at a chosen frequency, which was found to be the optimal frequency during calibration for a subject;
FIG. 8 is a graph for a subject, in the Ultrasonic channel, showing phase shift (measured at chosen frequency), corrected for temperature vs. glucose level;
FIG. 9 is a schematic showing the Electromagnetic Channel;
FIG. 10 is a graph showing Electromagnetic signal (frequency) corrected for temperature versus glucose level, for a subject;
FIG. 11 is a perspective view of the ear clip;
FIG. 12 is a side view of the ear clip;
FIG. 13 is a side view, broken away and partially in section, of the ear clip;
FIG. 14A is a perspective view of the elements of the thermal channel;
FIG. 14B is an end view, partially in section, of the elements of an alternate embodiment of the thermal channel;
FIG. 14C is a view similar to FIG. 14b and showing an alternate embodiment;
FIG. 15 is a side view in cross section of a first membrane for the ultrasound transducer, which preferably also serves as one of the plates of the capacitor for the electromagnetic channel;
FIG. 16 is a side view in cross section of a second membrane for the ultrasound transducer, which preferably also serves as one of the plates of the capacitor for the electromagnetic channel;
FIG. 17A is an enlarged side cross sectional view of the tip of the ear clip and showing the elements constituting the measurement channels; and
FIG. 17B is an enlarged top cross sectional view of a portion of the tip of the ear clip.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.
The preferred embodiment of the system and its advantages are best understood by referring to the drawings and the following description where like numerals indicate like and corresponding parts of the various drawings. References to preferred embodiments are for illustration and understanding, and should not be taken as limiting.
While the herein description is with regard to a human patient, it may be appreciated that the herein device can be used to measure glucose in any subject, including animals.
In particular, the device includes a Main Unit 10 containing the software applications and an external unit 12 for affixment to the patient. Typically the external unit is placed on the patient\'s (or subject\'s or animal\'s) ear lobe, so the external unit will typically be configured as an ear clip.
A cable 14 is preferably used to provide a working connection between the Main Unit 10 and the external unit 12. It may be appreciated that wireless (for example, Bluetooth) technology may also be used, and the cable can be avoided.
It should be appreciated that the external unit 12 may be placed on any other suitable location of the subject\'s body, such as a toe, a finger, the web between the thumb and 2nd finger (forefinger). Generally it should be a body part that has skin and tissue characteristics similar to those of the ear lobe. When the external unit is placed on the body at a point other than the ear lobe, some adjustment of the algorithms may be necessary, as the skin and tissue characteristics are not uniform over the entire body.
Referring to FIG. 1, there is shown a unitary non-invasive device for measuring multiple glucose values and then obtaining a final glucose reading. In order to increase the accuracy of non-invasive glucose measurement, the device, according to the present invention, preferably uses a combination of more than one non-invasive methods, preferably three non-invasive methods: ultrasonic, electromagnetic and thermal. These methods account for the tissue\'s physiological response to glucose variations, resulting in changes of physical properties such as electric and acoustic impedance, as well as heat transfer (HT) characteristics of the cellular, interstitial and plasma compartments, due to changes in ion concentration, density, compressibility and hydration of both compartments.
As shown in FIG. 1, this non-invasive glucose monitor comprises a Main Unit (MU) 10, which drives a plurality of different sensor channels, preferably three different sensor channels (preferably one per technology), located on an external unit configured as a Personal Ear Clip (PEC) 12 (FIG. 1). In order to perform a spot measurement, the PEC 12 is clipped externally to the user\'s earlobe for the duration of the measurement (about a minute) and is removed afterwards. A cable 14 (or any well known wireless (for example, Bluetooth) technology) connects these two components of the device.
The unique aspect of the invention is that the (single) external unit 12 houses more than one measurement channel/protocol. More preferably it houses all elements to effect a plurality of separate and distinct non-invasive glucose measurements. Preferably, the external unit houses elements to effect three separate and distinct non-invasive glucose measurements by three separate and distinct technologies. This single external device provides the advantage, that only one single device has to be attached to the subject\'s body, which is convenient for a physician and/or a patient. In the preferred embodiment the external unit is configured as an ear clip 12.
It should also be appreciated and understood that each of the measurement channels is new and novel in and of themselves. Hence each measurement channel may be used in isolation by itself (or with still other measurement channels). By combining the three measurement channels in one unitary device, measurements are obtained from three separate and unique measurement channels, thereby optimizing the final reading.
Blood glucose variations affect Heat Transfer (HT) characteristics through changes of heat capacity (Zhao Z. Pulsed Photoacoustic Techniques and Glucose Determination in Human Blood and Tissue. Acta Univ. Oul C 169. Oulu, Finland, 2002), density (Toubal M, Asmani M, Radziszewski E, Nongaillard B. Acoustic measurement of compressibility and thermal expansion coefficient of erythrocytes. Phys Med Biol. 1999; 44:1277-1287) and thermal conductivity (Muramatsu Y, Tagawa A, Kasai T. Thermal Conductivity of Several Liquid Foods. Food Sci. Technol. Res. 2005; 11(3):288-294) of the tissue, due to water/electrolytes shifts (Hillier T A, Abbot R D, Barret E J. Hyponatremia: evaluating a correction factor for hyperglycemia. Am J Med. 1999 April; 106(4):399-403; Moran S M, R L Jamison. The variable hyponatremic response to hyperglycemia. West J Med. 1985 January; 142(1):49-53). Thus, the alteration of the heat transfer processes that occur in a multi-layer sensor-tissue mechanical structure is a direct result of changes in glucose concentration (Wissler E H. Pennes\' 1948 paper revisited. J Appl Physiol. 1998 July; 85(1):35-41). The higher the glucose concentration, the lower the heat capacity and the lower the thermal conductivity, thus causing greater temperature elevation in the exterior tissue layers in response to heating. Since the sensor(s) (e.g., thermistor(s)), according to the present invention, is (are) preferably mounted/affixed on the epidermis layer, the measured rate and magnitude of the temperature change upon heating is greater than in the internal tissues.
The Thermal method, according to the present invention, applies a specific amount of energy to the tissue. Preferably both the rate and/or the magnitude of the temperature change, caused by the application of the known amount of energy to the tissue, are functions of the heat capacity, density and thermal conductivity of the tissue. Thus, the device according to the present invention provides means such that the glucose level is preferably evaluated indirectly by measuring changes in the HT characteristics, obtained after tissue heating for a predetermined duration of time.
FIG. 3 shows a sensor-tissue structure, according to a preferred embodiment of the present invention. A bottom plate serves as a heater 18 and heat conductors 20 are included (see FIG. 17). A thermal sensor 22 is located in the middle between the conductors 20. As shown in FIG. 2, the thermal sensor is located on the tip 24 of the ear clip (PEC) 12.
Referring now to FIGS. 12 and 13, the thermal module, which preferably comprises a thermistor 22, a heater 18 and conductors 20, located on an ear 26 extending from the end of one side of the ear clip 12 (e.g. on the first portion of the ear clip). The opposing surface 28 (i.e., the second portion of the ear clip) is preferably empty with no thermistor elements. In other words, it is preferred when the heater 18 and the thermal sensor 22 are located on the same side of the ear clip. In particular, it is preferred that the heater 18 and the thermal sensor 22 are located on the same side with regard to a ear lobe, when the external unit 12 is attached to the ear lobe.
As depicted in FIGS. 14A, 14B and 14C, the heater 18 is preferably made as a plate or block and is preferably constituted by a resistor. Two plates 20 are secured to the top of the plate to conduct heat energy and serve as the conductors 20. This may be done by adhering, gluing or bonding or any other suitable means. Preferably the conductors 20 are aluminum, but any heat conducting material may be used. On the bottom of the plate, preferably soldering pads 30 are provided which may be used to connect the heater 18 to integrated circuit boards 42 (see FIG. 13). Preferably, a housing contains all the sensor (e.g. thermistor) modular components. Ideally for a 4 Volt system, the resistor (e.g. the heater plate) has a resistance between 23 and 43 Ohms and is preferably 33 Ohms. It generates heat in the range of about 15°-45° C. and is preferably about 42-45° Centigrade. Any suitable heat sensor may be used.
The heater sends heat energy into the ear. It begins the heating process at standard ambient temperature 15-35° C. Usually the surface of the ear lobe is a little warmer at 28-32° C. The power of the heater provides preferably a maximum of 0.5 Watt and preferably a minimum of 0.1 Watt. According to other preferred embodiments, however, heaters with smaller hear energy may be used which preferably heat for longer times. Also a heater with a larger heat energy may be used which preferably heat for a shorter time.
As may be appreciated, the thermistor module should be small enough to fit on the tip of the ear clip. Preferably the resistor plate, constituting the heater 18, is about 5 millimeters long, 0.6 millimeters thick and 2.4 millimeters wide. The conductors 20 are preferably 1.5 millimeters long, 0.7 millimeters thick and 2.4 millimeters wide. As for the sensor 22, it is preferably 1.30 millimeters long, 0.8 millimeters thick and 2.0 millimeters wide. These are standard elements available in the marketplace; and, hence the standard available sensor is not as wide as the resistor plate and conductors and extends slightly above the conductors. A small difference in the overall dimensions is not critical.
There are several possible embodiments for the thermal channel. One preferred embodiment is shown in FIG. 14A. This embodiment consists of the thermo-sensor (thermistor) 22, the heater 18 and the thermo-conductors 20. The surface of the thermal module, which contacts the earlobe, is coated with a thermo-conductive biocompatible coating 64. When the heater 18 is switched on, heat flux passes through the thermo-conductors 20 and the thermistor 22 through the coating to the earlobe (or other part of the body). The heat absorption of the earlobe depends on the glucose level. The thermistor 22 measures the changes of temperature in the earlobe, which is influenced by the heating intensity and the absorption of the ear lobe. This temperature is used for analysis by data processing and to determine the glucose level.