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WO2018122319A1 - Dispositif et procédé de détermination non-invasive d'analytes - Google Patents

Dispositif et procédé de détermination non-invasive d'analytes Download PDF

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Publication number
WO2018122319A1
WO2018122319A1 PCT/EP2017/084729 EP2017084729W WO2018122319A1 WO 2018122319 A1 WO2018122319 A1 WO 2018122319A1 EP 2017084729 W EP2017084729 W EP 2017084729W WO 2018122319 A1 WO2018122319 A1 WO 2018122319A1
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WO
WIPO (PCT)
Prior art keywords
radiation
wavelength
reflected
μιη
analyte
Prior art date
Application number
PCT/EP2017/084729
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German (de)
English (en)
Inventor
Mathias Reichl
Dieter Ebert
Rolf-Dieter Klein
Original Assignee
Swiss Spectral Ag
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Filing date
Publication date
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Publication of WO2018122319A1 publication Critical patent/WO2018122319A1/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
    • A61B5/1455—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 using optical sensors, e.g. spectral photometrical oximeters
    • 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
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy

Definitions

  • the present invention relates to an apparatus and a method for the non-invasive quantitative determination of an analyte in blood, in particular for the non-invasive quantitative determination of glucose in capillary blood.
  • glucose in blood is based primarily on invasive methods.
  • a blood sample is taken from the patient in question and then subjected to an in vitro test or a sensor is implanted, which serves for the determination of glucose in vivo.
  • a disadvantage of such invasive methods is that they are painful and uncomfortable for the patient.
  • WO 2014/0206549 describes a device for measuring raw data for the non-invasive determination of a blood parameter, for example the concentration of glucose, wherein infrared (IR) radiation is coupled in a planar manner at several measuring points into the body surface of the patient to be examined and in the body surface generated IR radiation at several measuring points of one Sensor device is detected.
  • IR infrared
  • the present invention provides an apparatus and a method for the non-invasive quantitative determination of an analyte in a body fluid, with which the disadvantages of the prior art can be avoided.
  • the invention is based on the finding that a simple, rapid and sufficiently accurate quantitative determination of an analyte in the blood of a test subject by non-invasive methods is possible.
  • IR radiation from one or more radiation sources is irradiated into a predetermined body region of the test subject and the IR radiation reflected from this body region at at least two different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ , preferably 3-20 ⁇ , more preferably from 8-12 ⁇ , recorded separately.
  • the detection takes place at a first wavelength or a first wavelength range, where the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined, and independently at a second wavelength or a second wavelength range, where the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined.
  • concentration of the analyte can be determined.
  • the analyte to be determined may not only be present in the blood, but also in the epidermal and / or dermal tissue, the tissue concentration, for example in the case of glucose, being markedly different from that of the tissue Can differentiate blood concentration.
  • the IR radiation reflected from the irradiated body region is not necessarily specific to the concentration of the analyte in blood. This can lead to an incorrect interpretation of the measurement result.
  • a selective evaluation of reflected IR radiation in the region of 0.7-20 ⁇ , preferably 3-20 ⁇ , particularly preferably from 8-12 ⁇ takes place according to the present invention , from near-surface blood vessels of the irradiated body region, in particular a selective evaluation of reflected IR radiation from the capillary blood vessels of the dermis. It is preferred that the IR radiation radiated into the body surface reaches a maximum penetration depth of about 2.5 to 3 mm.
  • the inventors have now found that the IR radiation reflected from an irradiated body is composed of several components that can be separately analyzed.
  • the component of the reflected IR radiation originating from near-surface blood vessels has a temporal variation dependent on the arterial pulse frequency of the test subject. Due to this variation, a discrimination between signals that change with the pulse rate and signals that are independent of the pulse rate can be made as part of the evaluation. In this way, surprisingly, the concentration of the analyte in the blood of the test subject, for example the concentration of glucose, can be determined with high accuracy.
  • a first aspect of the present invention thus relates to a device for the non-invasive quantitative determination of an analyte in the blood of a test subject, comprising:
  • an IR radiation generating unit comprising one or more IR radiation sources, in particular one or more broadband IR radiation sources, arranged to irradiate a body region originating from the test subject,
  • a unit for detecting reflected IR radiation from the irradiated body region which is capable of separately detecting IR radiation at at least two different wavelengths or wavelength ranges in the body Region of 0.7-20 ⁇ , preferably from 3-20 ⁇ , more preferably from 8-12 ⁇ , is set up,
  • the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined
  • the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined and wherein the unit is optionally arranged in addition to the nonspecific detection of reflected IR radiation, and
  • a unit which is set up to evaluate the signals originating from the detection unit (c) and to determine the concentration of the analyte on the basis of the signals evaluated,
  • the unit is adapted for selective evaluation of reflected IR radiation originating from blood vessels of the irradiated body region, in particular from capillary blood vessels of the dermis.
  • the device according to the invention comprises a unit for generating IR radiation (a), which contains one or more IR radiation sources.
  • the IR radiation sources are selected from broadband IR radiation sources, such as glow plugs or resistors, for example, heater resistors and / or attenuators.
  • the device includes a single IR radiation source, such as a glow plug, in other embodiments, multiple IR radiation sources, such as multiple resistors, particularly heater resistors or attenuators.
  • a plurality of IR radiation sources it may be preferred that these are in the form of areal arrays, for example in an annular arrangement. Particularly preferred is the use of radiation sources with low residual heat such as attenuators.
  • pulsed IR radiation sources such as flash lamps can also be used.
  • the duration of a pulse is usually 0.01-0.2 s.
  • the one or more Radiation sources originating IR radiation is irradiated as broadband radiation in the body region to be examined. In other embodiments, it is also possible to irradiate IR radiation with specifically selected wavelengths or wavelength ranges.
  • a plurality of IR radiation sources with different optical filter elements can be used which are particularly preferred for emitting IR radiation at at least two different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ , preferably 3-20 ⁇ 8-12 pm), wherein at a first wavelength or a first wavelength range the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined, and wherein at a second wavelength or a second wavelength range the intensity the reflected IR radiation changes depending on the concentration of the analyte to be determined.
  • Thin-film, gradient-layer or rugate filter systems can be used as optical filter elements.
  • partially IR filtered radiation sources may also be used.
  • suitable filter elements eg bandpass, highpass or lowpass filter elements or combinations of several such filter elements can be used. If radiation with specific wavelengths is to be generated, narrow bandpass filter elements with a transmission width of, for example, up to 0.8 ⁇ m, up to 0.6 ⁇ m, up to 0.4 ⁇ m or up to 0.2 ⁇ m can be arranged around the first or second emission wavelength can be used.
  • the filter elements may comprise combinations of wide bandpass filter elements having a transmission width of eg 2-12 pm, preferably 3-8 pm, with high-pass filter elements and / or low-pass filter elements.
  • the filter elements are selected such that one of the radiation sources IR radiation having the first wavelength or the first wavelength range, where the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined, and another of the radiation sources IR-. Radiation having the second wavelength or the second wavelength range, where the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined, emitted. That is, the high-pass and / or low-pass filter elements are permeable only in one of the two wavelength ranges.
  • the unit for generating IR radiation (a) furthermore comprises a cooling element for the one or more IR radiation sources.
  • a cooling element for the one or more IR radiation sources.
  • Peltier elements can be used for this purpose.
  • the outside temperature of the radiation source is set to 30 ° C or less, 25 ° C or less or 22 ° C or less by means of cooling elements.
  • the total energy output of the IR radiation radiated into the body region to be examined is chosen so as to obtain sufficient signal intensity of the radiation reflected from the irradiated body region.
  • the total energy output of the radiation source (s) is in the range of a few milliwatts, e.g. in the range of about 1 to 100 mW, in particular in the range of about 1 to 50 mW.
  • the unit for generating the IR radiation may also contain controls for controlling the radiation output.
  • a continuous radiation output or a pulsed or radiation emission e.g. with a frequency of 10-50 Hz, such as 30 Hz.
  • the IR radiation can be diffused or focused into the body area.
  • the radiation sources can be provided with optical focusing elements, eg lenses made of IR-transparent materials such as germanium or zinc selenide.
  • optical focusing elements eg lenses made of IR-transparent materials such as germanium or zinc selenide.
  • convex lenses for example planoconvex or biconvex lenses, can be applied to the radiation source for this purpose.
  • the lens diameter is adapted to the diameter of the radiation source.
  • the device according to the invention is for receiving a body region of a test subject, in particular for receiving a body region of a human test subject, e.g. a fingertip, an earlobe or a heel or parts thereof, to allow for irradiation of that body area.
  • the device comprises a unit for receiving the body region to be irradiated which, for example, has a support element for the relevant body region, e.g. the fingertip, may include.
  • the shape of the support element is adapted to the body area where the determination is made. For example, a planar support element can be provided.
  • the support element is at least partially transparent to IR radiation in the region of 0.7-20 ⁇ , preferably from 3-20 ⁇ , particularly preferably from 8-12 ⁇ , to allow unhindered penetration of the radiated into the body region to be examined IR To allow radiation and the IR radiation reflected therefrom in the range of the first and second measuring wavelength.
  • suitable materials are silicon, germanium or organic IR-transparent polymers.
  • the support element may be formed in any suitable form, for example as a disk.
  • the support element is provided with a cooling element, in particular with a Peltier element, in order to avoid unwanted heating of the examination body region due to IR irradiation.
  • the cooling element may be configured to set a temperature of 30 ° C or less, 25 ° C or less, or 22 ° C or less at the surface of the body region to be irradiated.
  • the support element preferably comprises means, eg sensors, for detecting and / or checking the support position and / or the contact pressure for the body region to be irradiated.
  • the support position and / or the contact pressure can be detected individually for each body region and optionally adapted.
  • the individual adaptation may comprise, for example, a one or more adjustment of the measurement signal originating from the noninvasive device according to the invention with a reference signal which is conventional, for example via a invasive determination has been obtained. This adjustment can take place during the first use of the device according to the invention and - if necessary - at intervals, eg daily, every other day, weekly, etc., be repeated.
  • the adjustment is effected by adjusting the support position and / or contact pressure for the body region to be irradiated in order to obtain a stable, reproducible measurement signal which corresponds as closely as possible to the reference signal.
  • the device can sensors for detecting and / or controlling the support position of the body region to be irradiated, for example with respect to the x, y and z coordinates with respect to the support element, and / or for detecting and / or control of the contact pressure, eg in one area of about 0.5-10 N, preferably in a range of about 1-5 N, and more preferably about 2 N.
  • a sensor for detecting and / or controlling the contact pressure may include a load cell.
  • the settings for support position and / or contact pressure determined by adaptation are preferably registered and stored by the device.
  • the correct placement position or the correct contact pressure can then be indicated by a signal, e.g. by an optical and / or acoustic signal.
  • the measurement of the analyte to be determined is not started until the specified correct settings have been verified.
  • the device contains a unit (c) for detecting reflected IR radiation from the irradiated body region, which is used for separate detection of IR radiation at at least two different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ , preferably of 3 -20 ⁇ , more preferably from 8-12 ⁇ , is established.
  • this unit is adapted for the separate detection of IR radiation at at least two different wavelengths or wavelength ranges in the region of 5-15 ⁇ , in particular 7-12 ⁇ and most preferably of 8-10 ⁇ .
  • the detection unit (c) includes a plurality of sensors for separately detecting IR radiation having at least two different ones Wavelengths or wavelength ranges are provided.
  • the device may in turn comprise a sensor which is provided for the time-dependent separate detection of IR radiation with at least two different wavelengths or wavelength ranges.
  • the detection unit (c) is set up for the separate detection of IR radiation at at least one first wavelength or a first wavelength range and at at least one second wavelength or at least one second wavelength range.
  • the first wavelength or the first wavelength range is preferably in the region of an absorption minimum for the analyte to be determined.
  • the second wavelength or the second wavelength range is preferably in the region of an absorption band of the analyte to be determined, i. in a region in which the analyte shows a strong absorption, preferably an absorption maximum.
  • the device includes at least one first sensor and at least one second sensor, each for separate detection of IR radiation having different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ , preferably 3-20 ⁇ , especially preferably from 8 to 12 ⁇ , are set up.
  • a first sensor is selected so that it is set up to detect IR radiation having a first wavelength or with a first wavelength range, where the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined.
  • a second sensor is selected such that it is set up to detect IR radiation having a second wavelength or a second wavelength range, where the intensity of the reflected IR radiation changes as a function of the concentration of the analyte to be determined.
  • the device according to the invention may each contain one or more first and second sensors.
  • the first and / or the second sensor can be embodied as wavelength unspecific radiation sensors, for example as bolometers, which are equipped with optical filter elements which are permeable to a respective wavelength to be detected or a wavelength range to be detected, in order in this way to produce a Wavelength (area) -specific detection of IR To allow radiation.
  • suitable filter elements for example bandpass, high-pass or low-pass filter elements or combinations of several such filter elements can be used.
  • bolometers of high precision are used as first and / or second sensor.
  • the first and / or the second sensor may be provided with narrow bandpass filter elements having a transmission width of, e.g. up to 0.8 pm, up to 0.4 pm, up to 0.3 pm or up to 0.2 pm around the first or second measurement wavelength.
  • the filter elements of the first and / or the second sensor may comprise combinations of wide bandpass filter elements having a transmission width of e.g. 2-12 pm, preferably 3-8 pm, high pass filter elements and / or low pass filter elements.
  • a wide bandpass filter element can be provided, which is permeable to IR radiation in a region covering the entire measuring wavelength range, for example in a region of 8-10.5 pm or 7-14 pm.
  • This bandpass filter element can be used in combination with low-pass and / or high-pass filter elements in order to allow separate detection of IR radiation of different wavelengths or wavelength ranges for the first and second sensor.
  • one of the two sensors may include a low-pass filter element which is transparent to IR radiation down to a cut-off wavelength which lies between the first wavelength or the first wavelength range and the second wavelength or the second wavelength range.
  • the other of the two sensors may include a high-pass filter element which is transparent to IR radiation up to a second cut-off wavelength which is also between the first measurement wavelength and the first measurement wavelength range and the second measurement wavelength and the second measurement wavelength range, respectively.
  • one of the two sensors may include a wide bandpass filter in combination with a low-pass filter and the other of the two sensors may include a wide bandpass filter in combination with a high pass filter.
  • one of the two sensors optionally only a broad bandpass filter and the other of the two sensors containing the combination of a bandpass filter with a low-pass filter or alternatively the combination of a bandpass filter with a high-pass filter.
  • the wavelength ranges detected by the two sensors overlap, so that this overlapping region has to be eliminated during the evaluation.
  • the first sensor and / or the second sensor may also be embodied as wavelength-domain-specific sensors, for example as quantum cascade sensors.
  • the detection unit (c) contains at least one sensor which is set up for the time-dependent separate detection of IR radiation with at least two different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ , preferably 3-20 ⁇ , particularly preferably from 8 to 12 ⁇ ,
  • the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined
  • the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined.
  • the senor provided for the time-dependent separate detection of radiation with different wavelengths or wavelength ranges can be designed as a Fabry-Perot interferometer, for example as a MEMS spectrometer for the MIR / TIR range of about 3-12 ⁇ m (see, for example, Tuohinieni et al., Micromech, Microeng 22 (2012), 1 15004, Tuohinieni et al., J. Micromech, Microeng 23 (2013), 07501 1).
  • the detection unit (c) may optionally contain at least one further sensor which is set up for non-specific detection of reflected IR radiation from the irradiated body region of the test subject and can be used for referencing, eg for referencing the energy output of the excitation source.
  • the size of the sensors of the device according to the invention can be selected as needed. For example, they may have a cross-sectional area in the range of 0.5-10 mm 2.
  • the sensors of the device according to the invention are preferably in a target state of thermal equilibration, e.g. by being in contact with a common thermally conductive carrier such as a block, body, plate or foil of metal, e.g. Copper or brass, standing or embedded in it.
  • a common thermally conductive carrier such as a block, body, plate or foil of metal, e.g. Copper or brass, standing or embedded in it.
  • optical focusing elements e.g. Lens elements, arranged to allow a point-like focusing of the reflected IR radiation on the sensor or the sensors of the detection unit (c).
  • the first and / or second sensor may be provided with optical focusing elements, e.g. Plano-convex lenses or biconvex lenses made of IR-transparent materials such as germanium or zinc selenide, wherein the lens diameter is favorably adapted to the diameter of the sensor.
  • optical focusing elements e.g. Plano-convex lenses or biconvex lenses made of IR-transparent materials such as germanium or zinc selenide, wherein the lens diameter is favorably adapted to the diameter of the sensor.
  • the device according to the invention can be used for the determination of analytes be that have characteristic absorption bands in the IR range, especially in the aforementioned wavelength regions, for example in the regions of 3-20 ⁇ and in particular of 7-15 ⁇ and most preferably of 8-12 ⁇ .
  • analytes are glucose or other clinically relevant analytes such as lactate, troponin or C-reactive protein.
  • the device according to the invention is designed for the non-invasive determination of glucose in blood, in particular in capillary blood of the dermis.
  • the first wavelength or the first wavelength range comprises an absorption minimum of glucose and the second wavelength or the second wavelength range comprises an absorption band of glucose or a part thereof.
  • the second wavelength may be in the region of 9.1 ⁇ 0.3 ⁇ , 9.3 ⁇ 0.3 ⁇ and / or 9.6 ⁇ 0.3 ⁇ , of 9.1 ⁇ 0.2 ⁇ , 9.3 ⁇ 0.2 ⁇ and / or 9.6 ⁇ 0.2 ⁇ and in particular in the region of 9.1 ⁇ 0.1 ⁇ , 9.3 ⁇ 0.1 ⁇ and / or 9.6 ⁇ 0.1 ⁇ or at least one of these regions.
  • glucose has an absorption band with multiple absorption maxima.
  • Another component of the device is a unit for evaluating the signals originating from the detection unit and for determining the concentration of the analyte on the basis of the evaluated signals.
  • the evaluation of the signals is based on the fact that the reflected IR radiation at a wavelength or a wavelength range from an absorption minimum of the analyte, eg glucose, is independent of the analyte concentration present in the blood of the test subject.
  • the reflected IR radiation having a wavelength or a wavelength range from an absorption band of the analyte depends on the concentration of the respective analyte in the blood of the test subject.
  • a sufficiently accurate determination of the analyte concentration can be carried out, in particular if a selective evaluation of IR radiation which originates from blood vessels, for example from blood vessels of the dermis and / or subcutis, preferably from capillary blood vessels of the dermis.
  • Yet another part of the device according to the invention is a panel or a housing, which causes a thermal insulation from the environment. Suitable materials for this purpose are not thermally or only slightly conductive plastics.
  • the cladding or the housing may be designed such that the body region to be examined introduced in the receiving unit (a) is at least substantially thermally insulated from the environment, e.g. in that an expandable sheath or membrane of thermally non or only slightly conductive material is provided.
  • a further aspect of the invention is a method for the non-invasive quantitative determination of an analyte in the blood of a test subject, comprising the steps:
  • the device and the method are particularly suitable for the determination of glucose in blood.
  • a unit for generating IR radiation which comprises one or more IR radiation sources, in particular one or more broadband IR radiation sources, for irradiating a body region originating from the test subject, and a plurality of IR radiation sources, in particular IR radiation sources.
  • Broadband radiation sources such as attenuators, preferably in a ring-shaped arrangement,
  • a unit for detecting reflected IR radiation from the irradiated body region which is used for separate detection of IR radiation at at least two different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ m, preferably of 3-20 ⁇ m. particularly preferably from 8 to 12 ⁇ , is set up,
  • the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined
  • the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined
  • the unit is optionally arranged in addition to the non-selective detection of reflected IR radiation
  • a unit for generating IR radiation which comprises one or more IR radiation sources, in particular one or more broadband IR radiation sources, for irradiating a body region originating from the test subject, and furthermore a cooling element for the one or more IR radiation sources, in particular comprises a Peltier element,
  • a unit for detecting reflected IR radiation from the irradiated body region which is used for separately detecting IR radiation at at least two different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ , preferably of 3-20 ⁇ , particularly preferably from 8 to 12 ⁇ , is set up,
  • the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined
  • the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined
  • the unit is optionally arranged in addition to the non-selective detection of reflected IR radiation
  • (D) a unit which is set up for the evaluation of the signals from the detection unit (c) and for determining the concentration of the analyte on the basis of the evaluated signals.
  • an IR radiation generating unit comprising one or more IR radiation sources, in particular one or more broadband IR radiation sources, arranged to irradiate a body region originating from the test subject,
  • a unit for receiving the body region to be examined one for IR radiation in the wavelength region of 0.7-20 ⁇ m, preferably from 3 to 3 ⁇ m. 20 ⁇ , particularly preferably from 8-12 ⁇ , at least partially transparent element for supporting the body portion to be examined, which is provided with a cooling element, in particular a Peltier element,
  • a unit for detecting reflected IR radiation from the irradiated body region which is capable of separately detecting IR radiation at at least two different wavelengths or wavelength ranges in the region of 0.7-20 ⁇ m, preferably 3-20 ⁇ , particularly preferably from 8 to 12 ⁇ , is set up,
  • the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined
  • the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined
  • the unit is optionally arranged in addition to the non-selective detection of reflected IR radiation
  • (D) a unit which is set up for the evaluation of the signals from the detection unit (c) and for determining the concentration of the analyte on the basis of the evaluated signals.
  • an IR radiation generating unit comprising one or more IR radiation sources, in particular one or more broadband IR radiation sources, arranged to irradiate a body region originating from the test subject,
  • a unit for detecting reflected IR radiation from the irradiated body region which is capable of separately detecting IR radiation at at least two different wavelengths or wavelength ranges in the region of 0.7-20 pm, preferably 3-20 pm, particularly preferably from 8 to 12 pm, is set up,
  • the intensity of the reflected IR radiation is substantially independent of the concentration of the analyte to be determined, and wherein at a second wavelength or a second wavelength range, the intensity of the reflected IR radiation changes depending on the concentration of the analyte to be determined and
  • the unit is optionally arranged in addition to the non-selective detection of reflected IR radiation
  • the unit comprises at least one sensor arranged for the time-dependent separate detection of reflected IR radiation at the first wavelength or the first wavelength range and at the second wavelength or a second wavelength range, and
  • (D) a unit which is set up for the evaluation of the signals from the detection unit (c) and for determining the concentration of the analyte on the basis of the evaluated signals.
  • Apparatus for non-invasive quantitative determination of an analyte in the body of a test subject, in particular in blood comprising in particular means for detecting and / or controlling the support position and / or the contact pressure of the body region to be irradiated, in combination with an apparatus for invasive quantitative determination of the analyte as referencing of the measurement signal in the non-invasive quantitative determination of the analyte.
  • the features specifically disclosed above also relate to the latter devices and methods based on the use of these devices. These devices and methods are suitable, for example, for the determination of glucose in the body of a human test subject, in particular in blood.
  • the human skin consists of several layers from the outside to the inside: the epidermis with the horny layer, horny layer and germ layer, the dermis with the papillary layer and the mesh layer and the subcutis (subcutis).
  • the epidermis contains no blood vessels.
  • the dermis contains fine capillary blood vessels, which are associated with larger blood vessels in the subcutis.
  • An arterial pulse lies in the area of the dermis, which is traversed by capillaries, but not in overlying skin layers. for example, the epidermis, before.
  • IR radiation in particular IR radiation in the wavelength region of 0.7-20 ⁇ , preferably from 3-20 ⁇ , particularly preferably from 8-12 ⁇ , at least penetrates into the region of the dermis traversed by capillaries and then reflected again.
  • Substances with absorption bands in the IR region located in this region can absorb radiation in the region of these absorption bands, the extent of the absorption correlating with the concentration of the substance in question.
  • the reflected IR radiation originates from different regions of the irradiated body region, wherein a radiation reflected from the epidermis has no dependence on the arterial pulse of the test subject.
  • reflected IR radiation emanating from the capillary-engulfed area of the dermis has a signal dependent on the arterial pulse of the test subject.
  • the intensity of the IR radiation radiated into the skin surface is preferably selected such that a maximum penetration depth of the radiation into the body of about 2.5 to 3 mm is achieved, which corresponds to the area of the dermis drawn through by capillaries.
  • FIG. 1A An embodiment for the selective detection of a blood vessel-derived measurement signal is shown in FIG.
  • f1 represents the modulation frequency of the signal.
  • D can be calculated out of the signal if the modulation frequency is set to be large compared to the noise component.
  • a discriminator window as shown in FIG. 1C
  • a discriminator window can be set, which allows only a valid measurement if the value of the discriminator window is 1.
  • each for different Wavelengths or wavelength ranges are specific, resulting in two curves whose difference is proportional to the concentration of the analyte to be determined.
  • a differential analysis of these two curves gives the signal shown in FIG. 1 D) as a measurement result.
  • the schematic representation of an embodiment of the device according to the invention is shown in FIG.
  • the device contains an excitation source (10) for IR radiation (12), which is preferably designed as a diffused broadband heat source. Diffused IR radiation (12) emitted by the excitation source (10) irradiates a body region (14) of a test subject.
  • the excitation source (10) may be preceded by an optical lens element, e.g. a plano-convex lens element that allows focused emission of IR radiation into the body region.
  • the focusing of the radiation to a predetermined penetration depth of about 2.5 to 3 mm can be carried out in the body region to be irradiated.
  • a well-perfused body area such as a fingertip
  • the irradiated body region (14) rests on a support element (16) which at least partially, i.e., for, the IR radiation (12) originating from the excitation source (10). at least in the range of measuring wavelengths, is optically transparent.
  • the support element (16) may comprise means, e.g. Sensors for detecting and / or control of the support position and / or the contact pressure of the body region to be irradiated contain.
  • the IR radiation (12) penetrates into the irradiated body region (14) at least up to the near-surface blood capillaries in the region of the dermis (18).
  • the maximum penetration depth is preferably about 2.5 to 3 mm.
  • One in the blood capillaries or Any analyte present in the adjacent tissue will absorb the radiation in the region of its specific absorption band, with the extent of absorption correlating with the concentration of the analyte.
  • Unabsorbed diffused or focused radiation (20) is reflected and exits the body region (14) again.
  • the device further includes a first sensor (22a) and a second sensor (22b) for separately detecting the reflected IR radiation at different wavelengths or wavelength ranges (20) in the region of 0.7-20 ⁇ , preferably 3-20 ⁇ .
  • the first sensor (22a) is adapted to selectively detect reflected radiation having a first wavelength or a first wavelength range from an absorption minimum of the analyte, wherein a first filter element (24a) is provided which is for radiation having the first wavelength or the first wavelength range is selectively permeable. That is, the signal measured by the first sensor is essentially independent of the concentration of the analyte to be determined.
  • the second sensor (22b) is in turn adapted for the selective detection of reflected radiation (20) having a second wavelength or a second wavelength range from an absorption band, preferably in the region of an absorption maximum of the analyte to be determined, wherein a second filter element (24b) is provided which is selectively transparent to radiation of the second wavelength or the second wavelength range. This means that the signal detected by the second sensor is dependent on the concentration of the analyte.
  • the device according to the invention further comprises a third sensor (22c) adapted for nonspecifically detecting reflected IR radiation (20) and for reference, e.g. for referencing the energy output of the excitation source (10).
  • a third sensor (22c) adapted for nonspecifically detecting reflected IR radiation (20) and for reference, e.g. for referencing the energy output of the excitation source (10).
  • the sensors (22a, 22b and optionally 22c) may optionally be equipped with optical filter elements, eg biconvex lenses, to allow focusing of the incident reflected IR radiation.
  • the signals from the sensors (22a, 22b and optionally 22c) are transmitted to a CPU unit (26) for their evaluation. Based on this evaluation, the concentration of the analyte is determined. The result can then be displayed in a display (28).
  • the inside (30) of the measuring system can be coated with a surface of a material which does not reflect the radiation (12) originating from the excitation source (10).
  • the measuring system may further include a shroud or housing that provides thermal isolation from the environment.
  • Figure 3 shows a practical embodiment of a device according to the invention with a glow plug as the excitation source (40), a first sensor (42a) and a second sensor (42b), which as a bolometer with a specific for the sensor to be detected wavelength wavelength filter, e.g. a bandpass filter with narrow transmission for a specific wavelength are formed.
  • the first sensor (42a) is preferably arranged for the selective detection of reflected IR radiation with a wavelength of 8.5 ⁇ 0.2 ⁇ , i. at an absorption minimum of glucose.
  • the second sensor (42b) is preferably adapted to selectively detect reflected IR radiation having a wavelength in the range of 9.6 ⁇ 0.2 ⁇ , i. in an area where there is an absorption band of glucose.
  • the device can also have separating elements (44a, 44b, 46) in order to shield the sensors (42a, 42b) from irradiation with radiation originating directly from the excitation source (40), so that substantially only the body of the test subject (not shown) reflected radiation falls on the sensors.
  • the excitation source (40) and / or the sensors (42a, 42b) may be equipped with lens elements.
  • the measuring system may have a thermal insulation from the environment.
  • the sensors (42a, 42b) are in thermal equilibration by being in contact with a thermally conductive material, eg, a body, a plate or foil made of metal, stand.
  • a thermally conductive material eg, a body, a plate or foil made of metal, stand.
  • FIG. 1 An alternative embodiment for separately detecting reflected IR radiation at different wavelengths is shown in FIG.
  • the absorption curve of glucose in the region between 8 and 14 ⁇ is shown in bold line (G).
  • two sensors are used which comprise different combinations of bandpass, highpass and / or lowpass filter elements.
  • both sensors include a wide bandpass filter (C) with a transmittance in the region between 8 and 14 ⁇ .
  • filter (C) is combined with a high pass filter (A) suitable for IR radiation having a wavelength of about 8 , 5 ⁇ or less permeable.
  • a sensor equipped with the filters (A) and (C) will therefore detect a signal from the region of 8-8.5 ⁇ , which is substantially independent of the concentration of glucose.
  • the second sensor is equipped with a combination of the bandpass filter (C) with a low-pass filter (B), which is transparent to IR radiation with a wavelength of 8.5 ⁇ or higher.
  • the signal detected with this sensor comprises an absorption band of glucose localized in the region of about 9-10 ⁇ and is therefore dependent on the glucose concentration.
  • a first sensor can also be equipped with the bandpass filter (C) and the high-pass filter (A), while a second sensor is equipped only with the bandpass filter (C).
  • the signal detected by the first sensor is independent of the glucose concentration, while the signal detected by the second sensor changes with the glucose concentration.
  • FIG. 5 shows the schematic representation of the cross section of another embodiment of the device according to the invention.
  • the device contains a plurality of excitation sources (60a, 60b) for IR radiation (62), which are preferably designed as diffused broadband heat sources, eg in the form of a plurality of individual heating resistors or attenuators or multiple arrays of a plurality of heating resistors or attenuators.
  • the excitation sources (60a, 60b) can be provided with optical lens elements, eg plano-convex Lens elements, upstream, which allow a focused emission of the IR radiation in the body region.
  • the focusing of the radiation to a predetermined penetration depth of about 2.5 to 3 mm in the body region to be irradiated takes place.
  • the excitation sources (60a, 60b) are arranged annularly on a cooling element (64), for example in the form of a Peltier element. Diffused or focused IR radiation (62) emitted by the excitation sources (60a, 60b) irradiates a body region of the test subject (not shown).
  • the irradiated body region can be arranged on a support element (66) which is at least partially optically transparent to the IR radiation (62) originating from the excitation sources (60a, 60b).
  • the support element is an Si or Ge disc.
  • the support element (66) is preferably provided with a cooling element (68), which preferably comprises a Peltier element.
  • the support element (60) includes means, such as sensors, for detecting and / or controlling the contact pressure, such as a load cell, and optionally sensors for detecting and / or controlling the support position.
  • a contact pressure of about 1 -5 N, for example, about 2 N is set.
  • the device further includes a first sensor (70a) and a second sensor (70b) for detecting the reflected IR radiation (72) having different wavelengths in the region of 0.7-20 ⁇ , preferably 3-20 ⁇ from the irradiated body area.
  • the first and the second sensor can each be designed as a bolometer.
  • the first sensor (70a) may be adapted to selectively detect reflected IR radiation having a first wavelength from an absorbance minimum of the analyte, for example, wherein a first filter element (74a), eg a narrow pass bandpass filter, is provided for radiation the first wavelength is selectively permeable, wherein the signal is substantially independent of the concentration of the analyte to be determined.
  • the first wavelength is preferably 8, 1 ⁇ 0.3 ⁇ and / or 8.5 ⁇ 0.3 ⁇ or at 8.1 ⁇ 0.2 ⁇ and / or 8.5 ⁇ 0.2 ⁇ , more preferably at 8.1 ⁇ 0.1 ⁇ and / or 8.5 ⁇ 0.1 ⁇ .
  • the second sensor (74b) is in turn for selective detection of reflected IR radiation (72) having a second wavelength from an absorption band, preferably in the region of Absorbance maximum of the analyte to be determined, furnished, wherein a second filter element (74b), for example, a bandpass filter with a narrow transmittance, is provided, which is selectively transparent to radiation having the second wavelength.
  • the second wavelength is preferably in the range of 9.1 ⁇ 0.3 ⁇ , 9.3 ⁇ 0.3 ⁇ and / or 9.6 ⁇ 0.3 ⁇ or at 9.1 ⁇ 0.2 ⁇ , 9.3 ⁇ 0.2 ⁇ and / or 9.6 ⁇ 0.2 ⁇ , more preferably in the range of 9.1 ⁇ 0.1 ⁇ , 9.3 ⁇ 0.1 ⁇ and / or 9.6 ⁇ 0.1 ⁇ .
  • bandpass filters with narrow transmission instead of bandpass filters with narrow transmission, the combination of a bandpass filter with wide transmission and a high-pass and / or a low-pass filter shown in FIG. 4 may also be used.
  • the sensors (70a, 70b) may optionally be equipped with optical lens elements, e.g. Biconvex lenses to allow focusing of the incident reflected IR radiation.
  • optical lens elements e.g. Biconvex lenses to allow focusing of the incident reflected IR radiation.
  • the device according to the invention further includes a third sensor (70c) adapted for nonspecifically detecting reflected IR radiation (72) and for referencing, e.g. for referencing the energy output of the excitation sources (60a, 60b).
  • the third sensor (70c) may be designed as a bolometer.
  • an intermediate wall (78) may be arranged between the first sensor (70a) and the second sensor (70b).
  • the signals from the sensors (70a, 70b and optionally 70c) are transmitted to a CPU unit (80) for evaluating the signals. Based on this evaluation, the concentration of the analyte is determined, the result can then be shown in a display (82).
  • the CPU unit may also be used to control the excitation sources (60a, 60b) and / or the cooling elements (64, 68).
  • the sensors (70a, 70b and optionally 70c) are in thermal equilibrium by being in contact with a thermally conductive material, eg a body, plate or foil of metal.
  • a thermally conductive material eg a body, plate or foil of metal.
  • the inner surface of the measuring system may be coated with a material that does not reflect IR radiation.
  • the measuring system may have a thermal insulation from the environment.
  • the apparatus includes a plurality of excitation sources (100a, 100b) for IR radiation (102), e.g. in the form of several individual heating resistors or attenuators or multiple arrays, each containing a plurality of heating resistors or attenuators.
  • the IR excitation sources (100a, 100b) are provided with a first filter element (104a) or a second filter element (104b), which may be formed, for example, as a narrow pass bandpass filter.
  • the first filter element (104a) is selectively permeable to radiation having a first wavelength from an absorption minimum of the analyte.
  • the second filter element (104b) is selectively transmissive to radiation having a second wavelength from an absorption band, preferably in the region of an absorption maximum of the analyte to be determined.
  • the aforementioned first and second wavelengths are used.
  • a combination of a wide-pass bandpass filter and a high-pass and / or low-pass filter may be used to generate different wavelength IR radiation.
  • the excitation sources (100a, 100b) are provided with a cooling element (106), which preferably comprises a Peltier element. Diffused IR radiation (102) emitted by the excitation sources (100a, 100b) irradiates a body region of the test subject (not shown). Alternatively, the excitation sources (110a, 100b) can be equipped with lens elements as described above. In this case, the irradiated body region may be in contact with a support element (108) which is substantially optically transparent to the IR radiation (102) originating from the excitation sources (100a, 100b). Preferred embodiments of the support element are as previously described. The support element (108) is in Connection with a cooling element (1 10), which preferably comprises a Peltier element. The support element preferably contains sensors for detecting and / or checking the contact pressure of the examining body region and optionally sensors for detecting and / or checking the contact position of the body region to be examined.
  • the device further includes a sensor (1 12), which allows a time-dependent measurement at two different measurement wavelengths.
  • this sensor is designed as an IR-MEMS sensor, which can preferably detect IR radiation in the range of 8-14 ⁇ .
  • the sensor (1 12) may be in connection with another cooling element (1 14), which may for example comprise a Peltier element.
  • the sensor (12) may optionally be equipped with a lens element as described above.
  • the signals from the sensor (1 12) are preferably transmitted via an A / D converter to a CPU unit (1 16) for evaluating the signals. Based on this evaluation, the concentration of the analyte is determined. The result can then be shown in a display (1 18).
  • the CPU unit (16) may be further configured to control the excitation sources (100a, 100b) and / or the cooling elements (106, 110, 14).
  • the inner surface of the measuring system may be provided with a coating which does not reflect IR radiation.
  • the measuring system may have a thermal insulation from the environment.
  • FIG 7 shows a detailed representation of the excitation sources in the device according to Figure 5.
  • the unit for generating IR radiation consists of a plurality of different units (A, B), which are arranged on an annular Peltier element (106).
  • Each of the units A and B comprises an IR radiation source (100a, 100b), which in each case is a resistor, for example a heating resistor or an attenuator and in particular in each case an array consisting of a multiplicity of resistors, in particular heating resistors or attenuators, is.
  • the units A and B have first filter elements (104a) and second filter elements (104b) which are selective for IR radiation having a first wavelength or a first wavelength Wavelength range or for IR radiation having a second wavelength or a second wavelength range, as described above, are permeable.
  • the excitation sources may include lens elements as described above.

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Abstract

La présente invention concerne un dispositif et un procédé de détermination quantitative non invasive d'un analyte dans le sang, en particulier de détermination quantitative non invasive de glucose dans le sang capillaire.
PCT/EP2017/084729 2016-12-30 2017-12-28 Dispositif et procédé de détermination non-invasive d'analytes WO2018122319A1 (fr)

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WO2022090503A1 (fr) * 2020-11-02 2022-05-05 Glucomat Gmbh Système de détection miniaturisé actif

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EP0160768A1 (fr) * 1984-05-04 1985-11-13 Kurabo Industries Ltd. Dispositif spectrophotométrique pour la détermination, par voie non-invasive, de glucose dans les tissus vivants
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WO2022090503A1 (fr) * 2020-11-02 2022-05-05 Glucomat Gmbh Système de détection miniaturisé actif

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