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WO2022020734A1 - Dispositif de mesure non invasive de la concentration en glucose - Google Patents

Dispositif de mesure non invasive de la concentration en glucose Download PDF

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Publication number
WO2022020734A1
WO2022020734A1 PCT/US2021/043003 US2021043003W WO2022020734A1 WO 2022020734 A1 WO2022020734 A1 WO 2022020734A1 US 2021043003 W US2021043003 W US 2021043003W WO 2022020734 A1 WO2022020734 A1 WO 2022020734A1
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WO
WIPO (PCT)
Prior art keywords
subject
sensor
sensors
sensor information
tissue
Prior art date
Application number
PCT/US2021/043003
Other languages
English (en)
Inventor
Avner Gal
Alexander M. Raykhman
Eugene Naidis
Yulia Mayzel
Alexander Klionsky
Anatoly Diber
Original Assignee
A.D. Integrity Applications Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/938,327 external-priority patent/US20200352482A1/en
Application filed by A.D. Integrity Applications Ltd. filed Critical A.D. Integrity Applications Ltd.
Publication of WO2022020734A1 publication Critical patent/WO2022020734A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6814—Head
    • A61B5/6815—Ear
    • A61B5/6816—Ear lobe
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7203—Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal

Definitions

  • 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 glucose concentration of a subject patient.
  • 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).
  • 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).
  • SMBG blood glucose
  • 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 lifestyle components and blood glucose concentration lowering medications, thus helping to achieve specific glycemic goals.
  • 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 industry-acceptable results, despite the fact that no direct blood measurement is performed.
  • 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.
  • a measuring instrument’s performance is evaluated by statistical variables including accuracy and precision, and also by variables characterizing the instrument’s trending pattern regardless of which variable is being measured.
  • Smoothing includes the application of some variant of averaging to a set of measurements produced by a measuring instrument. Increasing the number of individual measurements used by the averaging procedure yields a “smoother,” or less-disturbed, final sequence of readings generated by the instrument if the smoothing is performed under the conditions of a stationary system. From a statistical point of view, smoothing can be interpreted as a way to increase the confidence level of a representative sample of measurements.
  • a measured variable may be a blood glucose concentration (BG).
  • BG blood glucose concentration
  • u(t) denotes the smoothed measured variable
  • X j i denotes the i th instance of the measured variable value generated by the/* MC before the smoothing procedure has been performed
  • n denotes the number of MCs in the measuring instrument
  • m denotes the number of times the measurement was performed by each MC within a time window of a moving average procedure.
  • FIG. 1 illustrates a table depicting a simplest numerical example of hypothetical readings from three MCs with identical measurement precision measuring a constant BG value of 100 mg/dL and exemplifies the value of the method of Freger.
  • Columns MCI, MC2, MC3 of FIG. 1 are the readings from the three glucose measuring channels in units of mg/dL.
  • P denotes the precision of the measuring channel working under the stationary conditions
  • ⁇ 7 denotes the standard deviation of the measuring channel’s output
  • ⁇ denotes the measuring channel’s output sample mean.
  • Cells PrcMCl, PrcMC2, and PrcMC3 of FIG. 1 denote the precision of each measurement channel as described in the expression (2)
  • DevPrc denotes the precision of the measuring device comprised of the above measurement channels.
  • Freger discloses non-invasive methods (but not devices) for measurements of the speed of sound traveling through a subject’s tissue, the electrical conductivity of the subject’s tissue, and the heat capacity of the subject’s tissue where the glucose is present in the subject’s blood cells and in the interstitium. Thereafter, the glucose concentration 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.
  • a measurement channel producing the BG measurement by monitoring any physical variable related to the alternating electrical current flowing through media including the subject’s tissue will be labeled the Electromagnetic Measurement Channel (EMC).
  • EMC Electromagnetic Measurement Channel
  • TMC Thermodynamic Measurement Channel
  • a common disturbance that is, an error-inducing variable
  • each MC of the apparatus of the present disclose may be the ambient temperature.
  • a pair of two MCs out of three available MCs may be identified where the outputs of the MCs comprising the pair will trend in opposite directions with regards to the direction of change of the ambient temperature. That is, measurements generated by the two MCs exhibit “orthogonality” with respect to one another inasmuch as, while ambient temperature increases, measurements from a first MC of the two MCs will increase as a result of the ambient temperature increasing and measurements from a second MC of the two MCs will decrease as a result of the ambient temperature increasing.
  • the ambient temperature induces a “positive error” with respect to an output of the first MC, or induces an error in a “positive direction,” inasmuch as ambient temperature causes the measurements of the first MC to increase (for example, erroneously past an actual target value), thereby inducing an error that may overshoot a target value.
  • ambient temperature decreases, measurements from the second MC of the two MCs will increase as a result of the ambient temperature decreasing and measurements from the first MC of the two MCs will decrease as a result of the ambient temperature decreasing.
  • the ambient temperature induces a “negative error” with respect to an output of the second MC, or induces an error in a “negative direction,” inasmuch as ambient temperature causes the measurements from the second MC to decrease (for example, erroneously below an actual target value), thereby inducing an error that may undershoot a target value.
  • a pair of subchannels may thus be considered “orthogonal” where a positive error is induced in one subchannel and a negative error is induced in the other subchannel, at least because a disturbance variable, such as ambient temperature, induces an error in opposite directions from the target value.
  • Improved methods for processing acquired data is further disclosed to further improve measurement performance.
  • a typical performance of the known invasive and minimally invasive devices for the spot measurement of the BG is characterized by the Mean Absolute Relative Difference (MARD) variable and is between 7 to 10% Full Scale when the measurement range includes high values of the BG.
  • MARD Mean Absolute Relative Difference
  • the MARD value for the BG measurement at low BG, down from 100 mg/dL, is required to be no larger than 15 mg/dL by ISO 15197:2013.
  • Reducing measurement errors may be particularly advantageous in non- invasive or minimally invasive blood glucose measuring devices. While certain existing non-invasive BG measuring devices may be intended only for supplementing use of invasive BG measuring devices — for example, because the non-invasive or minimally invasive BG measuring device yields measurement errors that are not acceptable — examples discussed herein yield measurement errors that are sufficiently low as to enable a standalone non- invasive or minimally invasive BG measuring device, that is, one that need not be supplemented by an invasive BG measuring device. Examples of non-invasive or minimally invasive BG measuring devices described herein may therefore replace invasive BG measuring devices in certain therapeutic situations where insulin dose adjustments are involved, at least because an accuracy of such example devices is sufficiently high as to enable the devices to be used as standalone devices.
  • a device of the unitary or distributed structure that is capable of non-invasively measuring the body’s glucose concentration by a combination of readings from a multitude of measuring channels.
  • Each measuring channel may include a pair of sub-measuring channels.
  • Each sub-measuring channel of said pair produces the BG measurement by means of monitoring a distinct physical variable linked to the BG and possesses the orthogonality property toward a common disturbance when viewed from the point of output of said measuring channel. That is, the sub-measuring channels of the pair of sub-measuring channels produce measurements that are orthogonal with respect to one another relative to a common variable, which may include ambient temperature.
  • the proposed information structure thus supports the BG measurements with greater performance than the performance of each individual component of said structure at least in part by utilizing the principle of orthogonality to offset an error produced in individual measurement channels.
  • One example of the disclosure includes three distinct sub-measuring channels.
  • one example device includes a sensory network and signal/data processing means.
  • a functional member may include the sensory network and signal/data processing means and can be implemented in a single module or separate communicated modules.
  • One example includes a Processing Unit, containing hardware and software applications, and a Sensor Unit(s)/external device(s) (for example, an ear clip or other fastener) contained within a housing for affixing to the patient. That is, the housing may include the Sensor Unit(s) (and, consequently, one or more sensors within the Sensor Unit[s]) and one or more fasteners for affixing the Sensor Unit(s) to a patient or subject.
  • the Sensor Unit includes a first member and a second member which are connected to each other, wherein the first member and the second member are located at opposing sides of a part of the subject, to which said Sensor Unit is affixed.
  • the two opposing members are located on the two opposing sides of the ear lobe.
  • said first and second members are located at the same side of the subject’s tissue.
  • the unitary Sensor Unit may be incorporated with at least one of three members, which effect three separate and distinct non-invasive measurements of glucose. Additionally, it is further preferred to provide at least two or three members 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 members to effect three separate and distinct non-invasive measurements of glucose are provided within a single, unitary external device, for example, within a single housing. [0025] 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).
  • a transmitter such as an ultrasonic transmitter
  • a receiver such as an ultrasonic receiver
  • a portion of the patient’ s body is situated between the transmitter and receiver.
  • the receiver Upon receipt of a resultant signal after the signal passes through the patient, the receiver sends the signal to the Processing Unit for processing by appropriate algorithms.
  • membranes may be used to cover and protect the transmitter and receiver.
  • a capacitor is defined in the
  • 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 Sensor Unit serves as the dielectric.
  • the membranes used to shield or cover the transmitter and receiver can serve also as the capacitor plates.
  • the third measurement channel is based on the thermodynamic technology to measure the glucose concentration.
  • a heater and a temperature sensor are provided at the external device.
  • the heater and the temperature sensor may be provided at opposing sides of the external device. According to another example, however, it is preferred to mount the heater and the temperature sensor on the same side of one of the two opposing sides, for example, on the tip of one side of the Sensor Unit the heater and the temperature sensor are positioned.
  • a unitary device for non-invasively measuring glucose concentration in a subject comprises: ultrasonic piezo transducers positioned on opposing members of the device and surrounding a part of the subject’s body to which the device is attachable; capacitor plates positioned on opposing members of said device and surrounding said part of the subject’s body to which the external means is attachable, a temperature sensor and a heater positioned in close juxtaposition to said part of the subject’s body to which the device is attachable.
  • the device further comprises an external means (such as an ear clip) to be affixed to the subject’s body, wherein the ultrasonic piezo transducers, the capacitor plates, the heater, and the temperature sensor are contained within said external means.
  • an external means such as an ear clip
  • the ultrasonic piezo transducers, the capacitor plates, the heater, and the temperature sensor are contained within said external means.
  • membranes cover the ultrasonic piezo transducers.
  • the ultrasonic piezo transducers may include a transducer and a receiver.
  • the capacitor plates comprise membranes.
  • the membranes may also cover the ultrasonic piezo transducers.
  • An embodiment may include means for determining a distance between opposing portions of said external means.
  • this means may include a magnet and a sensor.
  • an ambient temperature sensor may be included.
  • the individual measurements channels may be separately utilized.
  • a device for non-invasively measuring glucose concentration 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.
  • this device also includes a processing means for calculating the glucose concentration based on the tissue impedance and means for communicating the tissue impedance signal to the processing means.
  • This example may include capacitor plates comprised of membranes.
  • ultrasonic piezo transducers positioned on opposing members 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 transducers.
  • Another example may include ultrasonic piezo transducers positioned on opposing members 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 concentration based on the phase shift and being in communication with the means for detecting.
  • 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 the glucose concentration.
  • a device for non-invasively measuring glucose concentration affixed to a part of a subject’s body, comprises ultrasonic piezo transducers positioned on opposing members 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.
  • Some examples may include a processing means for calculating the glucose concentration based on said phase shift and being in communication with the means for detecting.
  • 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 the glucose concentration.
  • a device for non-invasively measuring glucose concentration 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 concentration.
  • an apparatus for non-invasively measuring a blood glucose concentration in a subject comprising a plurality of sensors, each sensor of the plurality of sensors being configured to determine sensor information indicative of a respective physical variable of a plurality of physical variables, each respective physical variable being indicative of the blood glucose concentration in the subject, and a controller coupled to the plurality of sensors, the controller being configured to receive respective sensor information from each sensor of the plurality of sensors, determine at least one measurement channel each including an orthogonal pair of sensors from the plurality of sensors, each orthogonal pair of sensors including a first sensor to determine first sensor information indicative of the blood glucose concentration of the subject and a second sensor to determine second sensor information indicative of the blood glucose concentration of the subject, wherein the orthogonal pair of sensors is orthogonal with respect to a disturbance variable that induces a positive error in one of the first sensor information and the second sensor information and that induces a negative error in the other of the first sensor information and the second sensor information, and determine a blood glucose measurement
  • the at least one orthogonal pair of sensors includes a single pair of sensors.
  • the disturbance variable includes an ambient temperature.
  • the plurality of physical variables includes one or more of a property of an ultrasonic wave propagating through a tissue of the subject, a property of an electromagnetic impedance of the tissue of the subject, and a property of a heatwave propagating through the tissue of the subject.
  • the apparatus includes a housing including the plurality of sensors and a fastener configured to affix the housing to the subject.
  • the plurality of sensors includes a first ultrasonic piezo transducer and a second ultrasonic piezo transducer, and wherein the first ultrasonic piezo transducer and the second ultrasonic piezo transducer are configured to be coupled to opposing sides of a portion of a body of the subject.
  • the apparatus includes a respective membrane covering each of the first ultrasonic piezo transducer and the second ultrasonic piezo transducer.
  • at least one of the first ultrasonic piezo transducer includes an ultrasonic-wave transmitter and the second ultrasonic piezo transducer includes an ultrasonic-wave receiver, wherein the first ultrasonic piezo transducer is configured to transmit an ultrasonic wave to the body of the subject, and wherein the second ultrasonic piezo transducer is configured to receive the ultrasonic wave from the body of the subject.
  • the first sensor includes the first ultrasonic piezo transducer and the second ultrasonic piezo transducer, and wherein the first sensor information includes a phase shift between the transmitted ultrasonic wave and the received ultrasonic wave.
  • the plurality of sensors includes a first capacitor plate, a second capacitor plate, and an auto-oscillator configured to generate an oscillating signal between the first capacitor plate and the second capacitor plate, and wherein the first capacitor plate and the second capacitor plate are configured to be positioned on opposing sides of a portion of a body of the subject.
  • the apparatus includes a respective membrane covering each of the first capacitor plate and the second capacitor plate.
  • the first sensor includes the first capacitor plate and the second capacitor plate, and wherein the first sensor information includes a tissue impedance of the subject.
  • the plurality of sensors includes a heater and a heat sensor configured to be coupled to a portion of a body of the subject.
  • the first sensor includes the heater and the heat sensor, and the first sensor information includes heat transfer characteristics of the subject.
  • the fastener includes opposing sides configured to affix the housing to a body of the subject, the apparatus further comprising at least one distance sensor configured to measure a distance between the opposing sides of the fastener.
  • the at least one distance sensor includes a magnet and a magnetic-field sensor.
  • the apparatus includes an adjustment screw configured to set the distance between the opposing sides of the fastener.
  • the at least one measuring channel includes a first measuring channel and a second measuring channel, the first measuring channel including a first orthogonal pair of sensors, the first orthogonal pair of sensors being configured to measure a first and a second of the property of the ultrasonic wave propagating through the tissue of the subject, the property of the electromagnetic impedance of the tissue of the subject, and the property of the heatwave propagating through the tissue of the subject, and the second orthogonal pair of sensors being configured to measure the first and a third of the property of the ultrasonic wave propagating through the tissue of the subject, the property of the electromagnetic impedance of the tissue of the subject, and the property of the heatwave propagating through the tissue of the subject.
  • a method for non-invasively measuring a blood glucose concentration in a subject comprising determining, with each sensor of a plurality of sensors, sensor information indicative of a respective physical variable of a plurality of physical variables, each respective physical variable being indicative of the blood glucose concentration in the subject, determining at least one measurement channel each including an orthogonal pair of sensors from the plurality of sensors, each orthogonal pair of sensors including a first sensor to determine first sensor information indicative of the blood glucose concentration of the subject and a second sensor to determine second sensor information indicative of the blood glucose concentration of the subject, wherein the orthogonal pair of sensors is orthogonal with respect to a disturbance variable that induces a positive error in one of the first sensor information and the second sensor information and that induces a negative error in the other of the first sensor information and the second sensor information, and determining a blood glucose measurement of the subject based on the first sensor information and the second sensor information.
  • a system for non-invasively measuring a blood glucose concentration in a subject comprising a plurality of sensors, each sensor of the plurality of sensors being configured to determine sensor information indicative of a respective physical variable of a plurality of physical variables, each respective physical variable being indicative of the blood glucose concentration in the subject, and means for determining a blood glucose measurement of the subject based on sensor information from at least one orthogonal pair of sensors more accurately and more precisely than any individual sensor of the at least one orthogonal pair of sensors.
  • Figure 1 illustrates a table depicting an example of readings from three measurement channels of a blood glucose concentration, and processed data produced based on the readings, according to an example
  • Figure 2 illustrates an information flow block diagram of a blood glucose measuring apparatus according to an example
  • Figure 3 illustrates a perspective view of a blood glucose measuring device including a Processing Unit (PU) and a personal ear clip (PEC) according to an example;
  • Figure 4 illustrates a side cross-sectional view of the PEC according to an example;
  • Figure 5 illustrates a view of a sensor-tissue structure for one embodiment of the Thermodynamic channel of measurement according to an example
  • Figure 6 illustrates a graph showing the non-temperature-corrected process of heating the sensor-tissue structure in a subject, reflecting different glucose concentrations according to an example
  • Figure 7 illustrates a graph showing an integrated and temperature-corrected equivalent thermal signal in a subject versus glucose concentration according to an example
  • Figure 8A illustrates a schematic representation of the earlobe between the two ultrasonic piezo transducers for the Ultra Sound channel of measurement according to an example
  • Figure 8B illustrates a graph showing the Phase shift between the received and transmitted waves, measured as Df according to an example
  • Figure 9 illustrates a graph showing the phase shift versus the transducer’ s frequency-of-excitation in the low-frequency region; and, the amplified phase-shift values are viewed at a chosen frequency value determined during a calibration procedure for a subject according to an example;
  • Figure 10 illustrates a graph for a subject, in the Ultrasonic Measuring channel, showing a temperature-corrected phase shift measured at a chosen frequency versus glucose concentration for a subject in the Ultrasonic measuring channel according to an example
  • FIG. 11 illustrates the Electromagnetic Measuring Channel’s information block diagram according to an example
  • Figure 12 illustrates a graph showing a temperature-corrected Electromagntic signal frequency versus glucose concentration for a subject according to an example
  • Figure 13 illustrates a perspective view of the PEC according to an example
  • Figure 14 illustrates a side view of the PEC according to an example
  • Figure 15 illustrates a side cross-sectional view of the PEC according to an example
  • Figure 16A illustrates a perspective view of the members of the thermal channel according to an example
  • Figure 16B illustrates an end view, partially in section, of the members of an alternate embodiment of the thermal channel according to an example
  • Figure 16C illustrates an end view, partially in section, of the members of an alternate embodiment of the thermal channel according to an example ;
  • Figure 17 illustrates a side cross-sectional view of a first membrane for the ultrasonic transducer, which may also serve as one of the plates of the capacitor for the electromagnetic channel according to an example;
  • Figure 18 illustrates a side cross-sectional view of a second membrane for the ultrasonic transducer, which may also serve as one of the plates of the capacitor for the electromagnetic channel according to an example;
  • Figure 19A illustrates an enlarged side cross-sectional view of the tip of the
  • Figure 19B illustrates an enlarged top cross-sectional view of a portion of the tip of the PEC according to an example.
  • FIG. 2 illustrates an information flow block diagram of a blood glucose concentration determination scheme according to at least one example.
  • Each individual blood glucose concentration measurement BG t is generated by a measurement channel having a pair of two sub-measuring channels.
  • the proposed information structure thus supports the BG measurements with greater performance than the performance of each individual component of said structure by collectively offsetting an error introduced by a variable such as ambient temperature.
  • u denotes a subchannel’s useful (relevant to BG) variable;
  • x denotes a subchannel’s vector of glucose-irrelevant variables (which may include error- inducing variables) including the sub-channel’s disturbing variables, such as an ambient temperature.
  • One example of the present invention includes three distinct measuring channels.
  • the device includes a Processing
  • the Sensor Unit 12 may be placed on a subject’s ear lobe, such that the Sensor Unit 12 may be configured as an ear clip in some examples.
  • a cable 14 is preferably used to provide a working connection between the
  • wireless for example, Bluetooth
  • the cable 14 may also be used in lieu of, or in addition to, the cable 14.
  • the Sensor 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 second finger (forefinger), and so forth.
  • the Sensor Unit 12 may be placed on a body part that has skin and tissue characteristics similar to those of the ear lobe. When the Sensor 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 may not be uniform over the entire body.
  • Said device measures three values of the BG by means of three measuring channels. It is to be appreciated that, in some examples, a device may measure a different number of values of BG, and that three BG values are provided for purposes of example. These glucose values are employed to calculate the final BG value, which may be output as the device’s reading.
  • the device preferably uses a combination of more than one non-invasive method implemented within more than one measuring channel: ultrasonic, electromagnetic, and thermodynamic.
  • These measuring channels utilize the tissue's physiological response to glucose variations, resulting in changes of physical properties such as electromagnetic and acoustic impedance, and heat transfer (HT) characteristics of the cellular, interstitial and plasma compartments, due to changes in ion concentration, density, compressibility, thermal diffusivity, and hydration of those compartments.
  • tissue's physiological response to glucose variations resulting in changes of physical properties such as electromagnetic and acoustic impedance, and heat transfer (HT) characteristics of the cellular, interstitial and plasma compartments, due to changes in ion concentration, density, compressibility, thermal diffusivity, and hydration of those compartments.
  • HT heat transfer
  • this non-invasive glucose monitor comprises a PU 10, which drives a plurality of different sensor channels, such as three different sensor channels (preferably one per technology), located on the Sensor Unit 12 configured as a personal ear clip (PEC).
  • PEC personal ear clip
  • the PEC 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 existing wireless [for example, Bluetooth] technology) connects these two components of the device.
  • the (single) Sensor Unit 12 houses more than one measuring channel. More preferably it houses all members to effect a plurality of separate and distinct non-invasive glucose measurements. Preferably, the Sensor Unit houses members 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.
  • the Sensor Unit 12 is configured as an ear clip, as illustrated in FIG. 4.
  • the “ear clip,” or “PEC,” may be an example of, include, or be included within, the Sensor Unit 12, and the terms ear clip or PEC may therefore be used interchangeably with the Sensor Unit 12 in some examples.
  • each measuring channel is new and novel in and of themselves.
  • each measurement sub channel may be used in isolation by itself (or in combination with other measuring channels).
  • combining the three unique measuring channels in one unitary device creates a foundation for the generation of final measurements (readings) with higher accuracy and precision than of each component measuring channel and under the improved ergonomic conditions.
  • TMC Thermodynamic Measuring Channel
  • the sensor(s) for example, therm istor
  • the Sensor Unit 12 is (are) preferably mounted/affixed on the epidermis layer of a subject, the measured rate and magnitude of the temperature change of the subject responsive to heating is greater than in the internal tissues.
  • the Thermodynamic method applies a specific amount of energy to the tissue.
  • 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.
  • the device according to the present invention provides means such that the glucose concentration is preferably evaluated indirectly by measuring changes in the HT characteristics, obtained after tissue heating for a predetermined duration of time.
  • Figure 5 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 Figures 19A, 19B).
  • a thermal sensor 22 is located in the middle between the conductors 20. As shown in Figure 4, the thermal sensor is located on the tip 24 of the PEC.
  • the thermistor module which preferably comprises a plurality of thermistor components such as a thermal sensor 22, a heater 18 and conductors 20, is located on an ear 26 extending from the end of one side of the PEC (for example on the first portion of the PEC).
  • the opposing surface 28 (that is, the second portion of the PEC) (see Figure 19A) is preferably empty with no thermistor components.
  • the heater 18 and the thermal sensor 22 may be located on the same side of the PEC.
  • it is preferred that the heater 18 and the temperature sensor 22 are located on the same side with regard to an ear lobe, when the Sensor Unit 12 is attached to the ear lobe.
  • the heater 18 may be 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 conductors. This may be done by adhering, gluing, bonding, or any other suitable means.
  • the plates 20 are aluminum, but any heat-conducting material may be used.
  • soldering pads 30 are provided which may be used to connect the heater 18 to integrated circuit boards 42 (see Figure 15).
  • a housing contains all the sensor (for example, thermistor) modular components.
  • the resistor for example, the heater plate
  • the resistor has a resistance between 23 and 43 Ohms and is preferably 33 Ohms. It produces temperatures in the range of about 15° to 45° C and is preferably about 42 - 45° Centigrade. Any suitable heat sensor may be used.
  • the heater sends heat energy into the earlobe. It begins the heating process at standard ambient temperature 15 - 35° C. Usually the ear lobe is a little warmer at 25 - 28° C.
  • the power of the heater provides preferably a maximum of 0.5 W and preferably a minimum of 0.2 W. Usually the heater heats for 20 seconds. According to other preferred embodiments, however, a smaller heat energy may be used which preferably heat for longer times. Also, a larger heat energy may be used which preferably heat for a shorter time in other examples.
  • the thermistor module should be small enough to fit on the tip of the PEC.
  • the resistor plate, constituting the heater 18, is about 5 mm long, 0.6 mm thick, and 2.4 mm wide.
  • the conductors 20 are preferably 1.5 mm long, 0.7 mm thick, and 2.4 mm wide.
  • the sensor 22 it is preferably 1.30 mm long, 0.8 mm thick, and 2.0 mm wide.
  • the ambient temperature that defines the boundary condition of the surface skin temperature and the sensor’s initial temperature affects the process also. Therefore, the electrical signal TMC reflecting the thermodynamic process is conditioned and normalized to consider the initial skin surface temperature, followed by the compensation for the difference between the ambient and skin temperatures.
  • the integrated, temperature- corrected, and compensated signal u(t) is shown in the time diagram of Figure 7, as a function of the glucose concentration. Furthermore, the signal u(t) may be expressed as, where t 0 and t f are the starting and the finishing time of the heating process; T e and T a are the tissue and the ambient temperatures, respectively, and q TM is the temperature correction factor.
  • Changes in the glucose concentration can be indirectly evaluated by the measurement of the velocity of sound propagating through the tissue. As the glucose concentration increases, the sound propagation velocity increases and the time during which the acoustic wave travels from one side of the body tissue to an opposite side of the body tissue decreases, as discussed in Zhao Z. Pulsed Photoacoustic Techniques and Glucose Determination in Human Blood and Tissue. Acta Univ. Oul C 169. Oulu, Finland, 2002; 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; US Patent 5,119,819.
  • the UMC includes, in one example, of piezo transducers, specifically an ultrasonic transmitter 34 and an ultrasonic receiver 36, attached (or attachable) near the subject’s ear lobe 16.
  • an electronic circuit is also provided for the ultrasonic measurement channel.
  • the transmitter 34 (ultrasonic piezo transducer) is located in the external device (that is, the Sensor Unit 12), such that, when the external device is attached to the ear lobe, a continuous ultrasonic wave produced by the transmitter travels through the ear lobe with the characteristic velocity, causing a phase shift D f between the transmitted and received wave (Fig. 8B).
  • the piezo transducers that is, the transmitter 34 and the receiver 36 (optionally followed by an amplifier) — are arranged one on each side of a subject’s ear lobe (see, for example, Fig. 8A).
  • the PU 10 sends a signal to the transmitter 34 to transmit a signal.
  • the receiver 36 receives the propagated signal, steps up the received signal, and sends the stepped-up signal back to the PU 10 for processing with an algorithm to determine the corresponding value of the blood glucose concentration.
  • the piezo transducers On opposing sides of the PEC, the piezo transducers — that is, the transmitter 36 and the receiver 34 — are disposed. Generally, these ultrasonic transducers are sensitive to mechanical pressure. In order to protect the piezo transducers and to maintain the efficacy of the transducers, membranes 38 and 40 are preferably placed over the ultrasonic piezo transducers (see Figures 17 and 18). Preferably, an ultrasound-conductive adhesive or glue, such as epoxy, is placed between the membranes and the ultrasonic piezo transducers to hold the membranes firmly on the ultrasonic piezo transducers. Generally the adhesive or glue or epoxy should be suitable for conducting ultrasonic waves at a smallest signal loss. A layer of 0.05 mm is generally adequate for the adhering material.
  • the ultrasonic piezo transducers could be of any suitable size for being disposed in the PEC.
  • the transducers may be round and about 9.0 mm in diameter with less than 3.0 mm thickness in one example.
  • the membranes 38, 40 may be made round and have a diameter of about 9.5 millimeters. It may be appreciated that any size is acceptable as long as it fits in the ear clip.
  • An electrically conductive and biocompatible coating is preferably placed on the outer surface of the membrane 38, 40 to enhance propagation of the signal. Typically, a coating of 0.01 mm is adequate.
  • the membranes may be made of nickel, which is generally biologically stable and conducts signals well. Any other suitable material, such as gold or titanium, may be used.
  • the membranes 38, 40 are made of copper with a nickel coating. In an alternate embodiment, the membranes may be made of stainless steel and no coating would be needed.
  • the ultrasonic wave’s frequencies can range from 180 KHz to 10 MHz and transmitted amplitudes may vary from 0.5 V to 3 V in some examples.
  • the received amplitudes may vary up to 50 mV.
  • the receiver amplifies the signal by about 20 times.
  • the ultrasonic piezo transducers preferably fit into the respective membranes with the adhesive (or epoxy) layer between them.
  • the velocity v of the acoustic wave’s propagation through media and the monitored phase shift are related as follows.
  • / denotes the acoustic wave frequency (Hz);
  • a f denotes the phase shift (radians); and
  • d denotes the distance between piezo-transducers (m).
  • two frequencies are identified and selected as optimal frequencies, one from a low-frequency range and one from a high-frequency range, where the frequency ranges are non-overlapping, as discussed in greater detail below with respect to a calibration procedure.
  • the measurements are conducted at the two chosen frequencies.
  • Figure 9 illustrates a graph of the measured phase-shift values as a family of functions having the frequency of excitation as an argument and the glucose concentration value as a parameter of the family.
  • This graph in Figure 9 shows the phase shift versus input transducer frequency in the low-frequency region.
  • the amplified phase shift values are viewed at the calibration-selected frequency value, which was found to be the optimal frequency during the calibration. That is, the calibration-selected frequency value is a frequency value that is determined during calibration to be an optimal frequency at which to perform phase shift measurements. Different curves on the graph apply to different glucose concentrations.
  • the velocity of the ultrasonic waves depends on the propagation medium temperature, as noted in US Patent 5,119,819; Zips A, Faust U. Determination of biomass by ultrasonic measurements. Appl Environ Microbiol. 1989 July; 55(7):1801-1807; Sarvazyan A, Tatarinov A, Sarvazyan N.
  • the temperature correction includes readings of both ambient and tissue temperature.
  • the temperature correction is performed on the measured amplified phase shift signal p M ( ) (Fig. 10), using the following formula: wher UM C t)denotes the temperature-corrected amplified phase shift signal; and q U mc denotes the correction factor.
  • Figure 10 is a graph showing the phase shift (measured at the chosen frequency) versus the BG with temperature correction enabled for a subject.
  • EMC Electromangnetic Measuring Channel
  • a glucose-induced water and ion transport across the cellular membrane leads to changes in the electrical properties of the cellular and consequently extracellular compartments, as indicated in Genet S, Costalat R, Burger J. The Influence of plasma membrane electrostatic properties on the stability of cell ionic composition. Biophys J. 2001 Nov; 81(5):2442-2457; Hayashi Y, Livshits L, Caduff A, Feldman Y. Dielectric spectroscopy study of specific glucose influence on human erythrocyte membranes. J Phys D: Appl Phys. 2003; 36:369-374. For example, a change in the dielectric properties is observed, as is known from Gudivaka R, Schoeller D, Kushner RF.
  • the EMC includes a capacitor configured to be coupled to a user’s body, such as the user’s earlobe.
  • the capacitor may include two capacitor plates configured to be positioned on opposing sides of the user’s earlobe, such that the user’s earlobe acts as a dielectric material to the capacitor, as illustrated in FIG. 11.
  • the EMC may further include a signal-generating component, such as an electromagnetic field generator, configured to generate and provide an oscillating signal to at least one plate of the capacitor, such that oscillating electromagnetic radiation is provided across the capacitor plates through the user’ s earlobe.
  • a signal-generating component such as an electromagnetic field generator
  • the EMC may include an auto-oscillating circuit including two capacitor plates on opposite sides of a portion of a user’s body, such as around the user’s earlobe, where the portion of the user’ s body acts as a dielectric material in the auto-oscillating circuit.
  • the capacitor may therefore be an active device or a passive device in certain examples.
  • properties of electromagnetic radiation between the capacitor plates, which reflect an impedance of a tissue of the user may be analyzed to determine a glucose concentration of the user to whom the capacitor is coupled.
  • FIG 11 shows the EMC wherein R in denotes the input resistance; Z(D, ⁇ ),
  • D ⁇ d t denotes the transfer operator of the sensing unit, which may include an EMC integrator including the earlobe tissue in the feedback; the transfer operator time constants depend on the tissue’s electric permittivity denoted e; C p denotes the parasitic capacitance; f- meter is the auto-oscillation frequency (/) measuring circuit; T denotes the Relay unit with hysteresis creating a positive feedback in the auto-oscillating circuit; E s denotes the electrical potential on the skin surface.
  • the same membranes 38 and 40 that were used in the UMC may preferably serve as capacitor plates having the earlobe 16 positioned between those plates as media with certain dielectric properties.
  • An oscillator is used to generate signals and these signals depend on the parameters of the ear lobe. Frequencies may range from 5 kHz to 100 kHz and the amplitudes vary from about 0.1 V to 1.5 V.
  • the earlobe temperature is also considered in the measurement, since the tissue’s impedance is temperature-dependent, as discussed in Gudivaka R, Schoeller D, Kushner RF. Effect of skin temperature on multi-frequency bioelectrical impedance analysis. Appl Physiol. 1996 Aug; 81(2):838-845. Among the disturbance-representing variables of the EM Channel, the ambient temperature plays two roles: a) influencing the tissue parameters; b) affecting the sensor’s electromagnetic parameters such as parasitic capacitance of electrodes.
  • the electromagnetic signal is corrected for both, ambient and ear temperatures, governed by the expression below and as illustrated in Figure 12 wherein denotes the temperature-corrected EMC-generated signal proportional to the oscillating circuit’s frequency; denotes the non-corrected EMC-generated signal proportional to the oscillating circuit’s frequency; and denotes the correction factor.
  • the distance sensor may include a magnet 44 on one side of the PEC and a sensor 46 on the other side.
  • the sensor 46 preferably a magnetic-field-measuring sensor, measures magnetic field intensity to ensure the distance between the membranes is the same as at a calibration stage.
  • Figure 13 shows an example of the PEC.
  • it is made of ABS plastic, but any suitable material will be effective.
  • the size is dependent on the earlobe size of the subject. In a preferred embodiment, it is preferably about 25 mm long and about wide. It may be tapered. Preferably there will be different size clips to accommodate subjects of different sizes of earlobes.
  • one side pivots about the other.
  • One side has a pivot pin which fits into an appropriate seat in the other piece of the ear clip.
  • a spring is used for biasing.
  • an ambient temperature sensor 52 ( Figure 3) is also provided which may be located at the Sensor Unit 12, the PU 10, and/or may be placed on the cable 14.
  • integrated circuit boards 42 are mounted within the ear clip 12 ( Figure 15).
  • the aforesaid components of the three measuring sub-channels — ultrasonic, electromagnetic, and thermodynamic — are mounted on them. Then, either through the cable 14 or through wireless technology (such as Bluetooth), communication is established with the PU 10. As required, the PU 10 issues signals for activating each measurement channel and for then collecting data and thereafter calculating the blood glucose concentration value.
  • the sensor is individually adjusted for optimal fit (PEC Positioning Adjustment Step), according to the thickness of the subject’s earlobe, prior to calibration.
  • the adjustment screw 50 ( Figures 4, 13, and 15) is used to adjust the distance between the sensors and consequently the pressure on the earlobe for optimal fit. This action may be guided by the PU 10.
  • the optional distance sensor 44, 46 preferably assures this preset distance is maintained.
  • the calibration procedure associates invasive basal and post-prandial blood glucose data (taken from the capillary blood of a fingertip and measured by a reference invasive device) with six sequential measurements timely produced by the apparatus and builds a calibration curve unique to each individual.
  • the first three calibration points are performed at the same (fasting) glucose concentration and help establishing an accurate initial point for the model used in the calibration. They are performed in the fasting state, consisting of one invasive and three consecutive non-invasive measurements, followed by food and drink consumption, in order to increase blood glucose by at least 30% from the fasting value. 20 minutes post-meal, a set of five sequential measurement pairs, with time intervals of about 10 minutes in between is taken. In total, the calibration process takes about 1.5 to 2 hours.
  • the distance is automatically measured (by means of the optional distance sensor 44, 46 provided in the PEC or by using an alternative method) and set as a reference distance (original location or preset reference point) of the sensors, which, in the following calibration points, as well as measurement points will be checked, prior to beginning the measurements.
  • the earlobe is a mostly parallel fiber tissue with a smooth surface. Therefore, if the distance in any of the calibration points, or in a regular measurement points differs (within a certain tolerance range) from the preset reference point, the user is guided by the device to move the PEC as required, in order to get to the reference distance.
  • a vector of an individual linear model’s parameters is set for each technology’s output.
  • the heating intensity (combined thermal diffusivity of the heating members) is checked during the measurement of the first point and the correction factor is calculated for the optimal heating intensity, to be used in the consequent measurements. This factor is individually calculated for each user, in order to assure increasing the tissue surface temperature above a minimal increment threshold.
  • the oscillations are performed at a certain frequency, which is found as a function of said frequency sensitivity to the BG changes during the calibration.
  • a sweeping of two frequencies' regions is performed in low- and high-frequency regions during calibration. In each region, the optimal frequency is selected, according to the signal’s amplitude (the strength of the propagated signal) and the sensitivity of the phase shift to glucose changes at that particular frequency. That is, an optimal frequency is a frequency at which an amplitude of the signal and the sensitivity of the phase shift to glucose changes is maximized.
  • the measurements are performed at these two “calibration-selected” optimal frequencies (one from the low region and one from the high region).
  • either the ambient temperature or the tissue temperature is acquired for being used in the temperature correction links of the device.
  • the BG spot measurements can be performed by clipping the PEC to the earlobe for the duration of the measurement (about one minute) and removing it afterwards.
  • each measuring channel produces several outputs, upon which a signal validation and recognition of outliers is automatically applied.
  • the signal For the signal validation of the UMC, the signal’s amplitude for each selected frequency is checked, to ensure the proper wave propagation through the tissue.
  • the members of the EMC and TMC channels are physically mounted on the same area on the tissue, the low measured amplitudes indicate a poor-quality mechanical contact. In this case the measurement is disregarded, and the failure notice is provided to the user.
  • the sensing thermistor within the PEC is mounted on a different tissue area than the electromagnetic and ultrasonic sensors. Therefore, a good- quality mechanical contact for the two latter technologies does not provide for the same for the thermodynamic channel. Thus, the heating process is checked for the allowed temperature interval. The out-of-range temperature signal is regarded as the product of the poor quality of the mechanical contact and a failure notice is provided to the user.
  • the received BG values from each measuring channel are used to generate the final measurement in accordance with the linear combination paradigm.
  • the readings from the measuring channels are analyzed based on the directions of their respective trendlines. Subsequently, weights are assigned to each of the three measuring channels’ outputs as described in Freger. Finally, a weighted linear combination of said three outputs produces a more precise BG reading than each participating measuring channel does if said measuring channels are characterized by the identical precision.
  • each said participating measuring channel lies approximately within ⁇ 10% of the precision values of other participating measuring channels. Accordingly, examples provided herein converge to the system of expression (1), above.
  • Non-invasive BG measuring devices perform their measurements by sensing physiological phenomena that develop within the tissue due to changes occurring with the BG . Because those physiological processes are affected by multiple factors unrelated to the BG factors, such as ambient temperature, the outcome of each non-invasive BG measurement carries errors.
  • the above-described temperature corrective techniques were designed to lower the adverse effect of the ambient and the earlobe-tissue temperatures by making the device’s data processing during each instantaneous measurement correspond with the environmental conditions existing at the time of calibration.
  • each measuring channel trends the BG because its calibration curve uniquely links some tissue property’s accessible physical variable (that is, the calibration curve’s input) to the BG as its output.
  • each measuring channel measures under the same set of disturbing factors. As was shown above, the simultaneous evaluation of the outputs of those measuring channels allows the improvement of the instrument’s performance and, in particular, the precision.
  • the EMC reflects changes in the tissue’s electrical impedance caused by the varying glucose concentration.
  • the EMC produces electrical current oscillations which period 1 depends on the electrical capacitance C of the space between the ear clip membranes having a human’s earlobe between them.
  • the capacitance depends on the values of the dielectric constant of the earlobe tissue ⁇ , which is proportional to the glucose concentration, and also on the so- called parasitic capacitance of the ear clip. Therefore, the blood glucose concentration can be represented by the following expression: wherein BG E MC denotes the blood glucose concentration measured by the EMC; and ⁇ EMC denotes a vector of parameters of the EMC unrelated to glucose concentration.
  • Those parameters characterize the mechanical and electrical construction of the ear clip and are the subjects to the disturbing effect of varying ambient temperature. Because the healthy human body temperature does not vary significantly as opposed to the ambient temperature, the dielectric constant of the earlobe tissue ⁇ is not affected by the ambient temperature variations.
  • the most sensitive to ambient temperature part of the EMC is the area of the mechanical contact between the ear clip membrane and the earlobe tissue.
  • the tissue’s sweat glands produce conductive secretions in relation with the ambient temperature T a .
  • the accumulation of the sweat glands’ secretion produces an effect commonly known as the “Supercapacitor” effect, thereby lowering the 2, thereby increasing the measured value of the BG.
  • the EMC-generated BG value can be approximated by the following expression: wherein, BGEMC denotes the true (undisturbed) glucose concentration measured via the EMC, and T denotes the reference value of the ambient temperature, for example, the ambient temperature obtained at the time of calibration.
  • the a EMC is the coefficient of the second term of the Taylor series.
  • the velocity v and the phase shift are related: between the transmitted and received ultrasonic wave; and d is the distance between piezo- transducers of the sensors (m).
  • the UMC measures glucose concentration by monitoring the 10 phase shift ⁇ ⁇ between the sent and the received ultrasonic wave traveling through the earlobe.
  • the path of the ultrasonic wave has several regions and primarily includes the region between the piezo transducer emitting the ultrasonic wave at one end of the earlobe and the earlobe epidermis, earlobe-tissue region, and the region between the epidermis on other side of the earlobe and the piezo transducer receiving the generated ultrasonic wave.
  • the formula (12) can be simplified as follows: determined measurement of the glucose concentration more accurately represents the glucose concentration than any one of the measurements respectively received from the 20 measuring subchannels making an orthogonal pair. [00165] The same reasoning can be applied to a combination of outputs of another pair of measurement subchannels having the TMC as the pair’s component.
  • the TMC measures the amount of energy required to increase the heater’s temperature to a certain value over a given period of time.
  • the TMC evaluates 25 the measuring system’s thermal diffusivity ( ⁇ ): Where k denotes the material thermal conductivity, p denotes the material density, and C p denotes the material specific heat.
  • the material is a complex system comprised of the sensing clip and the earlobe tissue, thus
  • TMC TMC parameters unrelated to the BG
  • k T ,p T ,C pT denote the thermal conductivity, density, and specific heat of the tissue respectively.
  • thermodynamic equilibrium an attachment of the ear clip to the earlobe disturbs the thermodynamic equilibrium, thereby causing sweat glands to increase the production of their secretions and filling voids between the membrane and the earlobe epidermis, which increases the thermal conductivity of the area of contact between the clip membrane and the earlobe tissue.
  • BG EMC 90 + 18 mg/dL
  • BG TMC 90 + 10 mg/dL
  • BG UMC 90 — 15mg/dL.
  • a reduced measurement error may be achieved by using pairs of orthogonal subchannels, at least because as a disturbance variable (for example, temperature) increases a BG measurement of one subchannel in a pair (for example, the EMC or TMC subchannels), the disturbance variable decreases a BG measurement of another subchannel in a pair (for example, a UMC subchannel) such that errors induced by the disturbance variable are canceled out between the pair’ s measurements.
  • a disturbance variable for example, temperature
  • the disturbance variable decreases a BG measurement of another subchannel in a pair (for example, a UMC subchannel) such that errors induced by the disturbance variable are canceled out between the pair’ s measurements.
  • an application of the moving average procedure to the linear combination of the number of measuring channels created by adding outputs of pairs of measuring sub-channels (13), and (17) creates a configuration of the BG measuring apparatus with the improved accuracy and precision if compared with the accuracy and precision of each individual sub-channel.
  • the linear combination algorithm can be based on the weighted or non- weighted paradigm and the gain values of measuring subchannels in each measuring channel can be selected based on the peculiarities of the measuring apparatus implementation.
  • G denotes the controlled gain of a measuring subchannel and the of measuring channels comprised of pairs of subchannels.
  • measuring channels may include two subchannels
  • measuring channels may include a single subchannel.
  • measurement channels may include TMC and UMC and/or EMC and UMC
  • measurement channels may include only one of TMC, EMC, and 15 UMC.
  • a single BG measuring device may include several measurement channels, where each measurement channel may include one or more subchannels of the same or a different type, that is, TMC, EMC, or UMC. It is to be appreciated that each of the TMC, UMC, and EMC may be referred to as a subchannel.
  • TMC, UMC, and EMC may be referred to as a subchannel.
  • certain examples may include a PU 10 and a Sensor Unit 12, it is to be appreciated that alternate devices may be provided to execute certain functions.
  • certain devices may include one or more sensors (for example, disposed in, on, or in connection with, the Sensor Unit 12) configured to measure certain physical parameters, 25 such as temperature, electromagnetic radiation, and/or ultrasonic waves, and one or more controllers coupled to the sensor(s).
  • the one or more sensors may further include components acting in concert with physical-parameter-measuring components.
  • the one or more sensors may include a heater and a heat sensor, a capacitor and an auto- oscillator, and/or one or more ultrasonic piezo transducers.
  • the controller(s) may receive 30 information from the sensor(s) indicative of the physical variables, such as raw measurement data, and process the data pursuant to the examples provided above to yield a BG value.
  • a device may include one or more intermediate components between the sensor(s) and the controller(s) to at least partially modify or process the measurement data provided by the sensor(s) prior to providing the measurement data to the controller(s).
  • a device may include filtering components configured to filter or otherwise modify the measurement data prior to providing the modified measurement data to the controller(s) for further processing.
  • the device may include a controller configured to operate in a manner consistent with the information flow of FIG. 2, where the controller receives measurement data from measurement channels having pairs of orthogonal subchannels and determines a final BG value based on information received from the measurement channel(s).

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Abstract

Des exemples divulgués ici concernent une combinaison de canaux de mesure ayant chacun une paire de sous-canaux de mesure. Chaque sous-canal mesure la concentration de glucose par surveillance d'une variable physique dépendant de la concentration de glucose dans le tissu du sujet. Les sous-canaux de chaque canal de mesure sont orthogonaux à une perturbation commune agissant sur chaque sous-canal de l'appareil. Des canaux ultrasonores, électromagnétiques et thermiques peuvent être mis en œuvre. Le glucomètre non invasif comprend une unité de traitement, qui commande ces capteurs de sous-canaux. Les capteurs peuvent être situés sur une unité de détection conçue sous la forme d'un clip d'oreille. L'unité de détection peut comprendre des transducteurs piézoélectriques ultrasonores positionnés sur des parties opposées du clip d'oreille et ainsi conçus pour être sur des côtés opposés du lobe de l'oreille, des plaques de condensateur positionnées sur des parties opposées du clip d'oreille, et un dispositif de chauffage et un capteur positionné sur le clip d'oreille en juxtaposition étroite avec le lobe d'oreille.
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