NON-INVASIVE DETERMINATION OF GLUCOSE

Description

[0001] The present invention relates to the non-invasive determination of glucose in blood by detection and evaluation of radiation from the terahertz range and the IR range, in particular the non-invasive determination of glucose in capillary blood.

[0002] In 2016, approximately 415 million people suffered from diabetes. This number is expected to rise to over 640 million by 2040. For diabetes patients, precise monitoring of blood glucose levels is essential to ensure appropriate medication. Therefore, there is a significant need for reliable and user-friendly methods for measuring blood glucose.

[0003] Currently, the determination of glucose in blood is predominantly based on invasive methods. This involves either taking a blood sample from the patient and then analyzing it with a [method / analyzer]. in vitroThey undergo a test or a sensor is implanted to determine glucose levels. in vivo serves a purpose. One disadvantage of such invasive methods is that they are painful and uncomfortable for the patient.

[0004] To avoid this disadvantage, numerous approaches for the non-invasive determination of blood glucose concentration have already been developed. However, none of these approaches has yet achieved commercial significance.

[0005] 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 from an external radiation source is coupled over a surface area at several measuring points into the patient's body surface to be examined, and the IR radiation generated in the body surface is detected at several measuring points by a sensor device. A disadvantage of this method, however, is that it requires a high level of equipment complexity.

[0006] WO 2018 / 122 concerns a procedure and 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. For this purpose, a selected area of ​​the body is irradiated with IR radiation in the region of preferably 8-12 µm. Subsequently, the reflected IR radiation from near-surface blood vessels of the irradiated area is selectively evaluated.

[0007] WO 2019 / 034722 also relates to a device 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. This involves evaluating the IR radiation emitted by the body, preferably in a wavelength range of 8-12 µm, without the use of external radiation sources.

[0008] The absorption maxima of glucose and other clinically relevant analytes in the terahertz range and their spectrometric determination in vitro, are described, for example, by Laman et al., Biophys. J. 94 (2008), 1010-1020, Upadhya et al., J. Biol. Phys. 29 (2003), 117-121, or Song et al., Scientific Report 8 (2018), Article Number 8964.

[0009] Another device for determining glucose is known from US 2016 / 080665.

[0010] However, a disadvantage of known methods for the non-invasive determination of glucose is their susceptibility to error.

[0011] The present invention provides a method for the non-invasive determination of glucose in a body fluid and the use of a device in this method, with which the disadvantages of the prior art can be at least partially avoided.

[0012] The invention is based on the finding that a simple, rapid, and sufficiently accurate quantitative determination of glucose in the blood of a test subject is possible using non-invasive methods. The present invention is based on the detection of radiation from the body region of the test subject to be examined in two different wavelength regions and the combined evaluation of the resulting measurement signals. For this purpose, a predetermined body region of the test subject, e.g., a fingertip, is irradiated with terahertz radiation, and the reflected terahertz radiation is detected in a terahertz wavelength range in which the intensity of the reflected terahertz radiation changes depending on the glucose concentration. Additionally, a predetermined body region of the test subject, e.g.,The system separately detects endogenous infrared radiation (IR radiation) originating from a fingertip at at least two different wavelengths or wavelength ranges in the wavelength region of approximately 8 µm to approximately 12 µm. Detection is performed at a first wavelength or wavelength range where the intensity of the reflected IR radiation is essentially independent of the glucose concentration, and independently at a second wavelength or wavelength range where the intensity of the reflected IR radiation changes depending on the glucose concentration. The glucose concentration can be determined by differentially evaluating the measurement signals from both IR wavelengths or wavelength ranges in combination with an evaluation of the measurement signals in the terahertz range.

[0013] Surprisingly, it was found that non-invasive blood glucose measurement using combined acquisition and analysis of radiation from two different spectral ranges improves the accuracy of the analyte determination and reduces the susceptibility to errors. In particular, this method can reduce the influence of interfering substances, as such substances typically exhibit absorption characteristics that interfere with glucose in only one of the two spectral ranges. Using suitable algorithms, it is therefore possible to quantitatively determine the contribution of the interfering substance to the measurement signal, enabling precise correction.

[0014] In one embodiment of the invention, the contribution of an interfering substance to the IR measurement signal is quantitatively determined by evaluating the terahertz signal through combined determination in the terahertz and IR ranges, thereby obtaining a corrected IR measurement signal from which the contribution of the interfering substance is at least largely or completely eliminated.

[0015] In a further embodiment of the invention, the contribution of an interfering substance in the terahertz measurement signal is quantitatively determined by evaluating the IR signal through combined determination in the terahertz and IR range, thereby obtaining a corrected terahertz measurement signal from which the contribution of the interfering substance is at least largely or completely eliminated.

[0016] In yet another embodiment of the invention, the contribution of a first interfering substance in the terahertz measurement signal is quantitatively determined by combining the terahertz and IR measurements by evaluating the IR signal, and the contribution of a second interfering substance in the IR measurement signal is quantitatively determined by evaluating the terahertz signal, thereby obtaining corrected terahertz and IR measurement signals from which the contributions of the first and second interfering substances are at least largely or completely eliminated.

[0017] Unless otherwise specified, the term "terahertz range" within the scope of the present invention refers to a frequency range from approximately 60 gigahertz (GHz) to approximately 3 terahertz (THz), corresponding to a wavelength range or region of approximately 5 mm to approximately 0.1 mm, or a subrange thereof. For example, the frequency range may extend from approximately 0.3 THz to approximately 3 THz (corresponding to a wavelength range or region of approximately 1 mm to approximately 0.1 mm) or from approximately 60 GHz to approximately 2.5 THz (corresponding to a wavelength range or region of approximately 5 mm to approximately 0.12 mm).

[0018] Unless otherwise specified, the term "IR range" within the scope of the present invention refers to a wavelength range or region from approximately 1 µm to approximately 20 µm, or a subrange thereof. For example, the wavelength range or region may extend from approximately 5 µm to approximately 15 µm, and in particular from approximately 8 µm to approximately 12 µm.

[0019] The procedure involves irradiating the area of ​​the body being examined with terahertz radiation and measuring the reflected terahertz radiation using suitable sensors. Additionally, the infrared radiation emitted by the body is measured using appropriate sensors. The use of external infrared radiation sources is not typically employed. Ideally, a device shielded from external electrical and / or thermal radiation is used to evaluate the measurement signals. This significantly increases the measurement accuracy.

[0020] As part of the evaluation, the temperature of the body area under investigation, e.g., a fingertip, and the temperature of the sensors used to detect terahertz and IR radiation are measured. The temperature of the sensors is maintained at a value lower than the temperature of the body area under investigation. Advantageously, the temperature of the sensors is set to a predetermined value, e.g., in the range of 10 °C to 25 °C, e.g., by embedding them in a metal block whose temperature is regulated by a temperature control element, e.g., a Peltier element, and precisely determined by a temperature measuring element, e.g., with a precision of at most ± 0.1 °C or at most ± 0.01 °C. The temperature of the body area under investigation, e.g., a fingertip, can—depending on the test subject and the external conditions—assume a variable value, which, according to the invention, can be precisely determined by a temperature measuring element.B. with a precision of maximum ± 0.1 °C or of maximum ± 0.01 °C.

[0021] The evaluation of the measurement signal includes temperature compensation of the received measurement signals, taking into account the temperature of the body region under investigation and the temperature of the sensor unit, and in particular the resulting temperature difference. Consequently, the present invention relates to the non-invasive determination of glucose by combined evaluation of terahertz radiation and endogenous IR radiation with temperature compensation.

[0022] Furthermore, according to the present invention, a selective evaluation of endogenous IR radiation in the region of approximately 8 µm to approximately 12 µm from near-surface blood vessels of the examined body region can be performed, in particular a selective evaluation of endogenous IR radiation from the capillary blood vessels of the dermis. The inventors have now determined that endogenous IR radiation is composed of several components that can be analyzed separately. The component of endogenous IR radiation originating from near-surface blood vessels exhibits a temporal variation that depends on the arterial pulse rate 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 performed during the evaluation.

[0023] Surprisingly, the present invention allows for an accurate and reproducible determination of glucose in blood, e.g. with an accuracy of ± 2.5% compared to a reference measurement using an X-ray diffractometer.

[0024] A first aspect of the present invention thus relates to the use of a device for the non-invasive determination of glucose in the blood of a test subject, as defined in claim 1.

[0025] The device includes a radiation source (b) for generating terahertz radiation, in particular terahertz radiation in a wavelength range of approximately 0.1 mm to approximately 5 mm, approximately 0.12 mm to approximately 5 mm, or approximately 0.1 mm to approximately 1 mm, for irradiating the area of ​​the body to be examined. After irradiation of the area of ​​the body to be examined, which is placed in the receiving unit (a), terahertz radiation is reflected. The device further includes a unit (c) (ii) for detecting terahertz radiation.

[0026] The device does not necessarily contain an external IR radiation source, as it is designed to detect and evaluate endogenous IR radiation. Preferably, no external IR radiation source is present. The endogenous IR radiation is emitted by the body region to be examined, which is placed in the receiving unit (a). The device includes a unit (c) (ii) for detecting endogenous IR radiation.

[0027] The temperature, in particular the core temperature, of the body region to be examined, which is placed in the receiving unit, is precisely determined by a temperature measurement element (d) (i), e.g., a temperature sensor. Optionally, an element (d) (ii) for adjusting the body temperature of the body region to be examined in the receiving unit (a) may be provided, i.e., a heating and / or cooling element, e.g., a Peltier element.

[0028] Furthermore, the device includes means (e) (i) for determining the temperature in the unit for detecting reflected terahertz radiation (c) (i) and / or the unit for detecting self-radiated IR radiation (c) (ii), e.g., a temperature sensor, and means (e) (ii) for maintaining the temperature in the unit for detecting reflected terahertz radiation (c) (i) and / or the unit for detecting self-radiated IR radiation (c) (ii) at a substantially uniform and preferably constant temperature level. The element (e) (ii) is provided for precisely adjusting the temperature of the radiation detection unit (c) (i) and / or (c) (ii) to a value lower than the body temperature. Advantageously, the element (e) (ii) contains a body made of thermally conductive material, e.g. a metal block, and means for supplying and / or dissipating heat, e.g. a heating and / or cooling element, such as a Peltier element.

[0029] The device is designed to capture a body part of a test subject, in particular a body part of a human test subject, e.g., a fingertip, an earlobe, or a heel or parts thereof, in order to determine the endogenous IR radiation emitted therefrom. Preferably, the body part to be examined is a fingertip.

[0030] For this purpose, the device includes a unit (a) for receiving the body region to be irradiated, which may, for example, comprise a support element for the relevant body region, e.g., the fingertip. The shape of the support element is adapted to the body region on which the measurement is performed. For example, a substantially planar support element may be provided.

[0031] Advantageously, the support element (a) is partially thermally insulated from the radiation detection unit (c) (i) and / or (c) (ii), for example, by being formed at least partially from a thermally insulating material, such as a plastic like polyurethane foam. Furthermore, the support element includes one or more areas that are transparent to terahertz radiation in the region of preferably about 0.1 mm to about 5 mm or from about 0.1 mm to about 1 mm and to IR radiation in the region of preferably about 8 µm to about 12 µm, in order to allow unimpeded penetration of the terahertz and IR radiation emitted by the body region under investigation. The transparent area of ​​the support element can, for example, have a surface area of ​​about 0.5 cm² to about 1.5 cm² and be, for example, circular.Examples of suitable materials for the transparent area of ​​the support element include silicon, germanium, or organic terahertz- and IR-transparent polymers. The support element can be in any suitable shape, for example, as a disc.

[0032] Associated with the recording unit (a) is an element (d) (i) for measuring the temperature in the body region under investigation. This element comprises a temperature sensor, e.g., a bolometer or thermopile. Furthermore, a temperature setting element (d) (ii) may be provided, e.g., a heating and / or cooling element, in particular a Peltier element, to enable, if necessary, precise temperature adjustment of the body region under investigation, e.g., with a precision of at most ± 0.1 °C or at most ± 0.01 °C. For example, the temperature setting element may be configured to set a body region temperature of 25 °C or higher, e.g., approximately 28–38 °C. Furthermore, an element for measuring the pigmentation of the body region under investigation (d) (iii), e.g., a colorimetric sensor, may be present.

[0033] Preferably, the support element includes means, e.g., sensors, for detecting and / or controlling the support position and / or pressure for the body area being examined. The support position and / or pressure can be individually detected and, if necessary, adapted for each body area. This individual adaptation can, for example, involve comparing the measurement signal from the non-invasive device with a reference signal obtained conventionally, e.g., via an invasive procedure using a conventional test strip or a sensor inserted into the body. This comparison can be performed during the initial use of the device and—if necessary—repeated at intervals, e.g., daily, every other day, weekly, etc.Preferably, the calibration includes adjusting the support position and / or pressure for the body area under investigation to obtain a stable, reproducible measurement signal that corresponds as closely as possible to the reference signal. For this purpose, the device can include sensors for detecting and / or controlling the support position of the body area to be irradiated, e.g., with respect to the x, y, and z coordinates relative to the support element, and / or for detecting and / or controlling the pressure, e.g., in a range of approximately 0.5–100 N, preferably in the range of approximately 10–50 N, and particularly preferably approximately 20 N. A sensor for detecting and / or controlling the pressure can, for example, include a load cell. A sensor for detecting and / or controlling the support position can include a camera, e.g., a CCD camera, and / or a pulse sensor.

[0034] The settings for the probe position and / or pressure determined through adaptation are preferably recorded and stored by the device. During subsequent use of the device, the correct probe position or pressure can then be indicated by a signal, e.g., a visual and / or audible signal. Glucose measurement is only started once the predefined, correct settings have been verified.

[0035] The device includes a radiation source (b) for generating terahertz radiation. This radiation source can be configured to generate coherent terahertz radiation. Terahertz radiation can be generated by frequency multiplication or difference frequency generation of several laser signals, e.g., distributed feedback lasers, quantum cascade lasers, molecular gas lasers, free-electron lasers, optical parametric oscillators, and reverse-wave oscillators. Furthermore, photodiodes can be used to convert the difference frequency of two lasers into alternating current, which is emitted as terahertz radiation by a suitable photoconductive antenna. In certain embodiments of the present invention, terahertz radiation from a pulsed laser, e.g. with a wavelength in the range of 500-2,000 mm, e.g. 800 mm, can be converted into terahertz radiation by a suitable terahertz antenna.The power output of such a laser is typically about 1 mW to about 1 W.

[0036] In further embodiments, a terahertz transmit / receive chip can also be used. Such a transmit / receive chip can be made of silicon- and / or germanium-based materials. In certain embodiments, the chip includes one or more amplifiers, e.g., low-noise amplifiers (LNAs), one or more quadrature mixers, one or more multiphase filters, one or more frequency dividers, and / or an oscillator with at least one tuning input for generating terahertz radiation. Advantageously, several tuning inputs, e.g., two, three, or four, are provided to vary the bandwidth of the terahertz radiation as needed. Furthermore, transmit and / or receive antennas for radiating and / or receiving terahertz radiation can be integrated on the chip. The power output of such a chip can range from about 0.01 mW to about 100 mW, particularly from about 0.1 mW to about 1 mW.For example, the chip can have a power output of approximately 1 mW. The size of such a chip can range from approximately 100 mm² (ideally about 10 mm²) to approximately 50 mm² (for example, about 25 mm²). Such terahertz chips are available, for example, from Silicon Radar GmbH.

[0037] In another embodiment of the invention, a terahertz antenna is provided, e.g. a patch antenna or a dipole antenna.

[0038] The effective power of the terahertz radiation source, i.e. the power radiated onto the body area to be examined, is preferably about 1 mW to about 100 mW, whereby the radiation can be emitted continuously or in pulses.

[0039] Furthermore, the device includes a unit (c) for detecting radiation, namely a unit for detecting terahertz radiation (c) (i) and a unit for detecting IR radiation (c) (ii).

[0040] The detection unit (c) (i) for detecting terahertz radiation includes one or more sensors or detectors designed for detecting terahertz radiation, in particular terahertz radiation in the frequency range of about 60 gigahertz (GHz) to about 3 terahertz (THz) corresponding to a wavelength range or region of about 0.1 mm to about 5 mm or a subrange thereof, e.g. in the range of about 0.12 mm to about 5 mm, from about 0.1 mm to about 1 mm or a subrange thereof.

[0041] In a further particularly preferred embodiment, at least one focusing lens is provided in the beam path between the terahertz radiation source and the body region to be examined and / or in the beam path between the body region to be examined and the terahertz detection unit (c) (i), e.g. a spherical lens, an aspherical lens or a Fresnel lens, which consists of a material that is substantially transparent to terahertz radiation, such as polypropylene or high-density polyethylene. The lens serves to focus the terahertz radiation emitted into the body region to be examined by the terahertz radiation source to a predetermined penetration depth in the body region, e.g. of about 3-4 mm and / or to focus the terahertz radiation reflected from the body region to be examined onto the terahertz detection unit.

[0042] The terahertz radiation reflected from the body can be amplified in one or more steps before being directed to the detection unit (c) (i). Typically, the amplification in a first step is performed by an LNA. The reflected terahertz radiation can then be directed to a mixer and mixed (multiplied) with the transmitted signal. The resulting mixture can then be amplified further. For example, amplification by a factor of 10³ or higher, 10⁴ or higher, and up to 10⁶ or 10⁷ is possible. In one embodiment, the signal can be amplified in several steps, e.g., in two steps, with each step potentially increasing the signal by a factor of 10² to 10³.

[0043] The terahertz radiation detection unit is configured to detect terahertz radiation in a wavelength range where the intensity of the reflected terahertz radiation changes depending on the glucose concentration. In particular, the unit (c) (i) is configured to detect a broadband spectrum in the terahertz range, specifically comprising a frequency range from about 60 gigahertz (GHz) to about 3 terahertz (THz) corresponding to a wavelength range or region from about 0.1 mm to about 5 mm, e.g., a wavelength range from about 0.1 mm to about 0.25 mm (corresponding to a wavenumber range from about 100 cm⁻¹ to about 40 cm⁻¹ or in a subrange thereto).

[0044] The result of the terahertz measurement can be displayed separately or combined with the result of the IR measurement on a display.

[0045] Furthermore, the device includes a unit (c) (ii) for detecting endogenous IR radiation from the area of ​​the body under investigation, which is configured for the separate detection of IR radiation at at least two different wavelengths or wavelength ranges, preferably in the region of approximately 8 µm to approximately 12 µm. In a particularly preferred embodiment, this unit is configured for the separate detection of IR radiation at at least two different wavelengths or wavelength ranges in the region of approximately 8-10 µm. Additionally, a third IR sensor without a filter may be provided for comparative measurement as a reference temperature.

[0046] The detection unit (c) (ii) for detecting IR radiation contains one or more sensors designed for detecting IR radiation.

[0047] In one embodiment, the detection unit (c) (ii) includes several sensors designed for the separate detection of IR radiation with at least two different wavelengths or wavelength ranges. In another embodiment, the device may again include a sensor designed for the time-dependent, separate detection of IR radiation with at least two different wavelengths or wavelength ranges.

[0048] The detection unit (c) (ii) is configured for the separate detection of IR radiation at at least one first wavelength or wavelength range and at least one second wavelength or wavelength range. The first wavelength or wavelength range preferably lies in the region of an absorption minimum for glucose. The second wavelength or wavelength range preferably lies in the region of an absorption band of glucose, i.e., in a region where the glucose exhibits strong absorption, preferably an absorption maximum.

[0049] In one embodiment, the device comprises at least one first sensor and at least one second sensor, each configured for the separate detection of IR radiation with different wavelengths or wavelength ranges in the region of approximately 8–12 µm. A first sensor is selected such that it is configured to detect IR radiation with a first wavelength or wavelength range where the intensity of the body's own IR radiation is essentially independent of the glucose concentration. A second sensor is selected such that it is configured to detect IR radiation with a second wavelength or wavelength range where the intensity of the body's own IR radiation changes depending on the glucose concentration.

[0050] The device can contain one or more first and second IR sensors. In a specific embodiment, the device includes a first sensor configured to detect IR radiation whose intensity is independent of the glucose concentration, and two or more second sensors configured to detect IR radiation whose intensity changes depending on the glucose concentration, wherein the two or more second sensors are configured to detect IR radiation with different wavelength ranges.

[0051] The first and / or second IR sensors can be designed as wavelength-independent radiation sensors, for example, as bolometers or thermopiles, equipped with optical filter elements that are transparent to a specific wavelength or wavelength range to be detected, thus enabling wavelength-specific detection of the IR radiation. Suitable filter elements, such as bandpass, highpass, or lowpass filters, or combinations of several such filter elements, can be used for this purpose. Preferably, the optical filter elements are arranged so that they rest directly on the sensors, i.e., without any gap. In a preferred embodiment, high-precision bolometers or thermopiles are used as the first and / or second sensor.

[0052] In one embodiment, for wavelength-specific detection of IR radiation, the first and / or the second IR sensor can be equipped with narrow bandpass filter elements, which have a transmittance width of, for example, up to 0.8 µm, up to 0.6 µm, up to 0.4 µm, up to 0.3 µm or up to 0.2 µm around the first or second measurement wavelength.

[0053] In yet another embodiment, the filter elements of the first and / or the second IR sensor can comprise combinations of wide bandpass filter elements with a transmittance width of, for example, 2–12 µm, preferably 3–8 µm, high-pass filter elements, and / or low-pass filter elements. For instance, a wide bandpass filter element can be provided that is transparent to IR radiation in a region covering the entire measurement wavelength range, for example, in a region of 8–10.5 µm or 7–14 µm. This bandpass filter element can be used in combination with low-pass and / or high-pass filter elements to enable separate detection of IR radiation of different wavelengths or wavelength ranges for the first and second sensors. One of the two sensors can contain a low-pass filter element that is transparent to IR radiation down to a cutoff wavelength that lies between the first wavelength or the second wavelength.the first wavelength range and the second wavelength range. Alternatively or additionally, the other of the two sensors can contain a high-pass filter element that is transparent to IR radiation up to a second cutoff wavelength, which also lies between the first measurement wavelength range and the second measurement wavelength range.

[0054] The advantage of using wide bandpass filters in combination with a lowpass and / or highpass filter is that broader wavelength ranges can be captured. This significantly increases the efficiency of the measurement.

[0055] In one specific embodiment of this configuration, one of the two IR sensors can contain a wide bandpass filter in combination with a lowpass filter, and the other of the first or second sensors can contain a wide bandpass filter in combination with a highpass filter. In a second embodiment, one of the first or second IR sensors can optionally contain only a wide bandpass filter, and the other of the first or second sensors can contain a combination of a bandpass filter with a lowpass filter, or alternatively, a combination of a bandpass filter with a highpass filter. In the latter two embodiments, the wavelength ranges detected by the first or second sensors overlap, so this overlapping range must be subtracted during evaluation.

[0056] In yet another embodiment, the first IR sensors and / or the second IR sensors can also be designed as wavelength (range)-specific sensors, for example as quantum cascade sensors.

[0057] In another embodiment, the detection unit (c) (ii) includes at least one IR sensor configured for time-dependent separate detection of IR radiation with at least two different wavelengths or wavelength ranges in the region of about 8-12 µm, wherein at a first wavelength or a first wavelength range the intensity of the body's own IR radiation is essentially independent of the glucose concentration, and wherein at a second wavelength or a second wavelength range the intensity of the body's own IR radiation changes depending on the glucose concentration.

[0058] The sensor intended 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 approximately 3-12 µm (see e.g. Tuohinieni et al., J. Micromech. Microeng. 22 (2012), 115004; Tuohinieni et al., J. Micromech. Microeng. 23 (2013), 075011).

[0059] Additionally, the detection unit (c) (ii) may optionally include at least one further sensor, e.g., a bolometer or thermopile, which is designed for the non-specific detection of endogenous IR radiation from the irradiated body area of ​​the test subject and which can serve for referencing, e.g., for referencing body temperature. This further sensor may also perform the function of the temperature measuring element (d) (i).

[0060] The size of the sensors in the detection units (c) (i) and / or (c) (ii) of the device can be selected as required. For example, they can have a cross-sectional area in the range of 0.5–10 mm².

[0061] One or more sensors may be in the form of an array of several individual sensor elements such as bolometers or thermopiles, for example with 4-100 individual elements in an arrangement of e.g. 2 × 2, 3 × 3, 4 × 4 or 8 × 8 individual elements, wherein the individual sensor elements within an array may be arranged directly adjacent to each other or separated from each other by spaces.

[0062] The sensors of the device, in particular the sensors of the sensing units (c) (i) and (c) (ii), are advantageously in a state of thermal equilibration, i.e., they have a substantially similar temperature level. For example, the sensors can be in contact with a common thermally conductive support, such as a body, block, plate, or foil made of metal, e.g., copper or brass, for example, by being embedded therein. The sensors can be arranged in recesses of a body or block, with one sensor or several sensors arranged in each recess. The support or block can, in turn, be connected to an element for supplying and / or dissipating heat, e.g., a heating and / or cooling element, such as a Peltier element.

[0063] In a preferred embodiment, the sensors, in particular the sensors of the detection units (c) (i) and (c) (ii), are embedded in a metal block, e.g. in a copper block which may optionally be coated with gold.

[0064] A particularly preferred embodiment may include 3, 4, or more sensors, which are, for example, arranged together in a recess of a metal block, wherein each of these sensors may be configured as an array of several individual sensor elements, for example, 8 × 8 individual elements. One of these sensors is provided for detecting IR radiation in the region of an absorption minimum of the analyte to be determined, and one or two of these sensors are provided for detecting IR radiation in the region of an absorption band of the analyte to be determined. Optionally, a further sensor may be provided for referencing purposes.

[0065] In yet another embodiment, only the sensors of the detection unit (c) (ii), i.e. the IR sensors, are in a state of thermal equilibration, while the sensors of the detection unit (c) (i), i.e. the terahertz sensors, are uncooled.

[0066] Associated with the radiation detection unit (b) is an element (d) (i) for measuring its temperature and an element (d) (ii) for adjusting its temperature, in particular the temperature in the area of ​​the sensors. The temperature measurement element (d) (i) can, for example, be configured as a temperature sensor. An infrared calibrator or blackbody radiator, for instance, can be used as the temperature measurement element. The temperature adjustment element (d) (ii) can, for example, be configured as a heating and / or cooling element, in particular as a Peltier element.

[0067] Preferably, the temperature-setting element, e.g., the Peltier element, is oriented with its cooling side towards the radiation detection unit (c) and has a heat dissipation element, e.g., one or more heat pipes such as heat pipes or thermosiphons, on the warming side facing away from the radiation detection unit (c). The temperature-setting element is configured to provide a temperature value in the detection unit (c), and particularly in the area of ​​the terahertz and IR sensors, that is lower than the temperature value, especially the core temperature, of the body region under investigation, e.g., the fingertip. Preferably, the temperature in the detection unit is set to a value in the range of 10 °C to 25 °C and determined by a temperature-measuring element.Temperature setting and measurement in the detection unit are advantageously performed with a precision of at most ± 0.1 °C or at most ± 0.01 °C. Similarly, the measurement of the temperature of the body region under investigation is advantageously performed with a precision of at most ± 0.1 °C or at most ± 0.01 °C. The temperature difference between the terahertz and IR sensors of the detection unit and the body region under investigation can therefore be determined with high precision, e.g., at most ± 0.2 °C or at most ± 0.02 °C, and is advantageously 1 °C or more, e.g., 2 °C or more, 3 °C or more, 4 °C or more, 6 °C or more, 7 °C or more, or 8 °C or more. A temperature difference range of approximately 4 °C to approximately 40 °C is preferred, and a range of approximately 6 °C to approximately 35 °C is particularly preferred.

[0068] In one embodiment, optical focusing elements, e.g. lens elements, are arranged in the beam path between the body area to be examined and the detection unit (c) in order to enable the most point-like focusing possible of the terahertz radiation emitted into the body area to be examined, the reflected terahertz radiation and / or the body's own IR radiation on the sensor or sensors of the detection unit (c).

[0069] The sensors of the detection unit, i.e., the IR and / or terahertz sensors, e.g., the first and / or second sensor, can be equipped with optical focusing elements, e.g., plano-convex or biconvex lenses, particularly spherical lenses, made of terahertz-transparent materials such as polypropylene or IR-transparent materials such as germanium or zinc selenide, wherein the lens diameter is advantageously adapted to the diameter of the sensor. By using an optical arrangement with a focused beam path, the radiation yield and thus the sensitivity and precision of the measurement can be increased. The use of sensors, e.g., bolometers or thermopiles, equipped with biconvex lenses, particularly spherical lenses, is particularly preferred.

[0070] The device is used for the determination of glucose exhibiting characteristic absorption bands in the terahertz range, particularly in the aforementioned wavelength regions, e.g. in the regions from about 0.1 mm to about 5 mm, from about 0.12 to about 5 mm or from about 0.5 mm to about 1 mm, and in the IR range, particularly in the aforementioned wavelength regions, e.g. in the regions of about 8-12 µm.

[0071] According to the invention, the device described above is designed for the non-invasive determination of glucose in blood, in particular in the capillary blood of the dermis.

[0072] The invention thus relates to the use of the device for the non-invasive determination of glucose, in particular for the quantitative determination of glucose in the blood of a test subject.

[0073] For the determination of glucose, the terahertz wavelength region comprises, in particular, a range from approximately 0.1 mm to approximately 5 mm, from approximately 0.12 mm to approximately 5 mm, or from approximately 0.5 mm to approximately 1 mm, or a subrange thereof. Within this region, glucose exhibits several absorption bands, with three absorption bands located at approximately 0.2 mm (corresponding to a wavenumber of 50 cm⁻¹), at approximately 0.14–0.17 mm (corresponding to a wavenumber of 60–70 cm⁻¹), and at approximately 0.13 mm (corresponding to a wavenumber of 80 cm⁻¹). Preferably, the determination of glucose encompasses a broadband spectrum that includes at least two, and preferably all three, of the aforementioned absorption bands.

[0074] In the IR wavelength region, the determination of glucose comprises a first IR wavelength or wavelength range with an absorption minimum for glucose and a second wavelength or wavelength range with an absorption band of glucose or a portion thereof. For example, the first wavelength may be in the region of 8.1 ± 0.3 µm and / or 8.5 ± 0.3 µm, 8.1 ± 0.2 µm and / or 8.5 ± 0.2 µm, or 8.1 ± 0.1 µm and / or 8.5 ± 0.1 µm, or may include at least one of these regions. Glucose exhibits an absorption minimum in these wavelength regions. The second wavelength can lie in the region of 9.1 ± 0.3 µm, 9.3 ± 0.3 µm and / or 9.6 ± 0.3 µm, or of 9.1 ± 0.2 µm, 9.3 ± 0.2 µm and / or 9.6 ± 0.2 µm, or of 9.1 ± 0.1 µm, 9.3 ± 0.1 µm and / or 9.6 ± 0.1 µm, or at least encompass one of these regions. Glucose exhibits an absorption band with multiple absorption maxima in these wavelength regions.

[0075] In a preferred embodiment, the absorption of glucose is measured at two different wavelengths or wavelength ranges that comprise an absorption band of glucose or a part thereof, e.g. in the region of 9.3 µm and in the region of 9.6 µm.

[0076] Another component of the device is a unit (f) for temperature-compensated evaluation of the signals originating from the detection units (c) (i) and (c) (ii) and for determining the analyte concentration based on the evaluated signals. Advantageously, a combined evaluation of the signals from the terahertz detection unit (c) (i) and the IR detection unit (c) (ii) is performed. Several beneficial effects can be achieved by combining the evaluation of signals from the terahertz and IR ranges. On the one hand, weak signals can be amplified, thereby reducing interference during the measurement and enabling the identification and correction of any measurement inaccuracies. On the other hand, signals caused by interfering substances that exhibit absorption bands in either of the two measurement ranges that overlap with those of the analyte can be identified and eliminated.

[0077] In a preferred embodiment, the detection unit (c) is configured for sequential detection of terahertz radiation and IR radiation, wherein in particular, first detection of endogenous IR radiation without irradiation of the body area to be examined is carried out, followed by irradiation of the body area to be examined with terahertz radiation and detection of the reflected terahertz radiation.

[0078] The evaluation of terahertz signals is based on recording a broadband spectrum of glucose over a predetermined wavelength range in the terahertz region, containing at least one, and preferably at least two or three, absorption bands of glucose. The intensity of these absorption band(s) depends on the glucose concentration in the test subject's blood. The width of the wavelength range is preferably at least 0.05 mm or at least 0.1 mm and up to 0.2 mm or more.

[0079] The evaluation of IR signals is based on the fact that the body's own IR radiation at a wavelength or wavelength range from an absorption minimum of glucose is independent of the glucose concentration present in the test subject's blood. Conversely, the body's own IR radiation with a wavelength or wavelength range from an absorption band of glucose is dependent on the glucose concentration in the test subject's blood.

[0080] Based on the differential signal from the first and second IR sensors, and in conjunction with the signal from the terahertz sensor, a sufficiently accurate determination of the glucose concentration can be performed if the signal evaluation is carried out under temperature compensation, in particular taking into account the temperature values ​​measured and, if necessary, set by elements (d) (i), (d) (ii), (e) (i) and / or (e) (ii) for the body region under investigation and for the sensors of the radiation detection unit (c). Furthermore, selective evaluation of IR radiation originating from blood vessels, e.g., from blood vessels of the dermis and / or subcutis, preferably from capillary blood vessels of the dermis, can also be performed.

[0081] Another component of the device is a casing or housing that provides thermal insulation from the environment. Suitable materials for this purpose are thermally non-conductive or only slightly conductive plastics. The casing or housing can be designed such that the body area to be examined, which is placed in the receiving unit (a), and / or the detection unit (c) are at least substantially electrically and / or thermally isolated from the environment, for example, by providing a flexible sheath or membrane made of a material that is electrically and / or thermally non-conductive or only slightly conductive.

[0082] The inner surface of the measuring device may also be fully or partially coated or equipped with a material that does not reflect terahertz and / or IR radiation and / or absorbs terahertz and / or IR radiation.

[0083] Another aspect of the invention is a method for the non-invasive quantitative determination of glucose in the blood of a test subject, comprising the steps of: (i) Irradiating a body region originating from the test subject with terahertz radiation, in particular in a wavelength region of about 0.1 mm to about 5 mm, of about 0.12 mm to about 5 mm or of about 0.1 mm to about 1 mm, and detecting reflected terahertz radiation from the irradiated body region by a terahertz radiation detection unit in a wavelength range in which the intensity of the reflected terahertz radiation changes depending on the glucose concentration; (ii) separately detecting endogenous IR radiation from a body region originating from the test subject by an IR radiation detection unit at at least a first wavelength or a first wavelength range in the wavelength region of about 8 µm to about 12 µm, where the intensity of the endogenous IR radiation is essentially independent of the glucose concentration.and at least one second wavelength or second wavelength range in the wavelength region of approximately 8 µm to approximately 12 µm, where the intensity of endogenous IR radiation changes depending on the glucose concentration, and optionally non-specific detection of endogenous IR radiation from the irradiated body surface area for reference, wherein the temperature in the area of ​​the IR radiation detection unit is lower than the temperature of the body area under investigation, (iii) combined evaluation of the signals detected according to (i) and (ii) taking into account the temperature of the body area under investigation and the temperature in the area of ​​the terahertz radiation and IR radiation detection units, and wherein optionally a selective evaluation of endogenous IR radiation from capillary blood vessels of the dermis of the body area is carried out, and (iv) determination of the glucose concentration based on the evaluated signals.

[0084] The method is preferably carried out by capturing endogenous IR radiation from a fingertip of the test subject without using an external source of IR radiation, e.g., using the device described above. The features specifically disclosed in connection with the device also relate to the method.

[0085] The device and method are intended for the determination of glucose in blood.

[0086] The present invention will now be explained in more detail. Human skin consists of several layers from the outside in: the epidermis, comprising the stratum corneum, stratum keratinization, and stratum germinativum; the dermis, comprising the papillary layer and reticular layer; and the subcutaneous tissue. The epidermis contains no blood vessels. The dermis contains fine capillary blood vessels that connect with larger blood vessels in the subcutaneous tissue. An arterial pulse is present in the capillary-rich area of ​​the dermis, but not in overlying skin layers, such as the epidermis.

[0087] Following irradiation of the skin surface with terahertz radiation, terahertz radiation is reflected from the irradiated body area, originating at least partially from the capillary-rich region of the dermis. Infrared radiation emitted from the skin surface, particularly infrared radiation in the 8–12 µm wavelength range, also originates at least partially from the capillary-rich region of the dermis. Substances in this region with absorption bands in the terahertz and infrared regions can absorb radiation in these absorption bands, with the extent of absorption correlating with the concentration of the substance in question. The reflected terahertz radiation and the body's own infrared radiation originate from different regions of the examined body area, with radiation originating from the epidermis showing no dependence on the test subject's arterial pulse.In contrast, radiation originating from the capillary-rich area of ​​the dermis exhibits a signal dependent on the arterial pulse of the test subject.

[0088] The radiation emitted by the body region under investigation depends on the temperature, particularly the core temperature of the area being examined. The radiation signal measured by a sensor therefore also depends on the temperature of the body region being examined, but also on the temperature of the sensor itself, and thus on the temperature difference between the temperature, especially the core temperature of the body region being examined, and the temperature of the sensor used to detect the radiation.

[0089] According to the present invention, the measurement signal is therefore evaluated in a temperature-compensated manner, taking into account the temperature of the body region under investigation, the temperature of the sensors used to detect the terahertz and IR radiation, and the difference between these two temperatures. The measurement is carried out under conditions in which the temperature of the body region under investigation is higher, for example at least 1 °C and preferably at least 6 °C higher, than the temperature of the sensors used to detect the body's own terahertz and IR radiation.

[0090] Figure 1 The diagram schematically shows the advantages of a combined evaluation of measurement signals from the terahertz range and the IR range, which can increase the accuracy of the measurement by improving the assignment of the measurement signals to a specific analyte.

[0091] In Figure 1aThe absorption spectra of alcohol (red), glucose (green), fructose (blue), and an unknown substance (yellow) are shown in the IR wavelength range of approximately 8 µm to approximately 10 µm. Using IR sensors (e.g., thermopiles) with wavelengths of 8.5 µm (reference wavelength) and 9.6 µm (analyte-specific wavelength), a reliable distinction between glucose and the unknown substance is possible. However, differentiating between glucose and fructose is problematic. Figure 1bAn absorption spectrum in the terahertz wavelength range from 400 µm to 100 µm (corresponding to a frequency of 0.5 to 4.0 THz) of glucose (black), fructose (red; dotted line), and the unknown substance (yellow) is shown. In the terahertz range, glucose and fructose can be reliably distinguished, whereas the absorption spectra of glucose and the unknown substance overlap. Combining the absorption spectra in the IR and terahertz ranges allows for improved differentiation of the individual substances, thereby increasing measurement accuracy.

[0092] Figure 2Figure 1 shows a schematic representation of an embodiment of the device. The device contains a source of terahertz radiation (100), e.g. a femtosecond laser with a wavelength of 800 nm, whose radiation is first passed through a semipermeable beam splitter (102) and split there into partial beams (104a) and (104b). A partial beam (104a) is converted into terahertz radiation (108) in a mixer (106), e.g., a gallium arsenide crystal. This terahertz radiation is directed through an optical device (110), e.g., a prism, onto a body area (112) to be examined, e.g., a fingertip. The radiation reflected from the body area is directed via the optical element (110), another mixer (114), e.g., a gallium arsenide crystal, and optionally another semipermeable beam splitter (116) into a terahertz sensor (118), e.g., a photodiode, which is configured to detect a spectrum in the terahertz range.The partial beam (104b) from the beam splitter (102) can optionally be directed via a delay element (120) into the mixer (114) for referencing and from there into the photodiode (118). Furthermore, the device includes an IR detection unit (120) with one or more IR sensors configured to detect endogenous IR radiation from the body region (112) under investigation. The measurement signal from the IR sensor (120) is routed to an evaluation unit (124), e.g., a CPU. Evaluation takes place in the unit (124) in combination with the measurement signal from the terahertz sensor (118), optionally after a fast Fourier transform in the unit (128). In the evaluation unit (124) a value (126) for the concentration of the analyte, e.g. glucose, is determined from the combined terahertz and IR measurement signals, which can then be displayed in a suitable way, e.g. by means of a display (not shown).

[0093] Furthermore, the device includes a support element (130), e.g., a metal support such as copper, which is designed to accommodate at least the IR detection unit (120) and optionally other elements such as the optical device (110) and / or the terahertz sensor (118). The temperature of the support element (130) can be stabilized by suitable means to enable temperature-compensated measurement of the IR signal and, optionally, the terahertz signal.

[0094] Figure 3Figure 1 shows another embodiment of the device. The device includes a terahertz transmit-receive chip (200) that emits terahertz radiation (202) into the body area (204) to be examined, e.g., a fingertip, and is configured to detect the terahertz radiation (206) reflected therefrom. The measurement signal from the chip (200) is routed via a Fast Fourier Transform unit (210) to the evaluation unit (212), e.g., a CPU. Furthermore, the device includes at least one IR sensor (214) for detecting endogenous IR radiation (216) from the body area (204) to be examined. The measurement signal detected by the at least one IR sensor (214) is routed to the evaluation unit (212) and evaluated there in combination with the terahertz measurement signal.

[0095] A detailed description of one embodiment of the IR detection unit is provided in Figure 4shown. A body region (14) of a test subject to be examined is placed into the device.

[0096] Preferably, a well-vascularized area of ​​the body, such as a fingertip, is selected. The body area (14) rests on a support element (16) which is thermally insulated and contains a region (16a) that is at least partially optically transparent to the IR radiation (20) originating from the body area (14), i.e., at least in the range of the measurement wavelengths. The support element (16) contains means (16b) for determining the temperature of the body area under investigation, such as a fingertip (14), e.g., a temperature sensor. Furthermore, means, e.g., sensors, for detecting and / or controlling the support position and / or the pressure of the body area to be irradiated may be present (not shown). The support element may also contain a temperature setting element (not shown).

[0097] IR radiation (20) from the body region (14) under investigation originates at least partially from the superficial blood capillaries in the dermis (18), which are located approximately 2.5 to 3 mm from the body surface. An analyte located in the blood capillaries or, if applicable, 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.

[0098] The device further comprises a first sensor (22a) and a second sensor (22b) for separately detecting the body's own IR radiation at different wavelengths or wavelength ranges (20) in the region of preferably 8-12 µm. The first and second sensors can be configured as bolometers or thermopiles. Optionally, the first and second sensors can also consist of arrays of individual sensor elements, e.g., 8 × 8 individual sensor elements.

[0099] The first sensor (22a) is configured for the selective detection of endogenous radiation with a first wavelength or a first wavelength range from an absorption minimum of glucose, wherein a first filter element (24a) is provided which is selectively transparent to radiation with the first wavelength or with the first wavelength range. That is, the signal measured by the first sensor is essentially independent of the glucose concentration. The second sensor (22b) is again configured for the selective detection of endogenous radiation (20) with a second wavelength or a second wavelength range from an absorption band, preferably in the region of an absorption maximum of glucose, wherein a second filter element (24b) is provided which is selectively transparent to radiation with the second wavelength or with the second wavelength range.This means that the signal detected by the second sensor depends on the glucose concentration. Optionally, two or more second sensors can be used, capable of detecting radiation with different wavelengths or wavelength ranges. For example, to determine glucose, two second sensors can be used, each separately detecting IR radiation in the range of 9.1 µm and 9.6 µm.

[0100] The filter elements (24a, 24b) are advantageously arranged so that they rest directly on the respective sensors (22a, 22b).

[0101] Optionally, the device may also include a third sensor (22c) which is designed for the non-specific detection of endogenous IR radiation (20) and serves for referencing, e.g., for referencing the body temperature in the body area (14) to be examined.

[0102] The sensors (22a, 22b and optionally 22c) may optionally be equipped with optical lens elements, e.g. biconvex lenses, in particular spherical lenses, to enable focusing of the incident endogenous IR radiation.

[0103] The sensors (22a, 22b and optionally 22c) are in thermal equilibration by being in contact with or embedded in a block (32) made of conductive material, e.g., metal, for example, by being arranged in a recess of the block. Alternatively, the thermally conductive material can also be in the form of a plate or film.

[0104] Furthermore, means (26) for determining the temperature of the block (24) containing the sensors (22a, 22b and optionally 22c), e.g. a temperature sensor, and means (28) for adjusting the temperature of the block (24) containing the sensors (22a, 22b and optionally 22c), e.g. cooling and / or heating elements, are provided.

[0105] The signals from the sensors (22a, 22b and, if applicable, 22c) and the temperatures determined by the elements (16b) and (26) are transmitted to a CPU unit (30). If necessary, the temperature of the sensors (22a, 22b and 22c) is adjusted to a value lower than the temperature of the body region being examined, and the signals are temperature-compensated for evaluation. Based on this evaluation, the glucose concentration is determined. The result can then be displayed on a display (32).

[0106] The inside (34) of the measuring system can be fully or partially coated or equipped with a surface made of a material which does not reflect and / or absorbs the IR radiation (20) originating from the body area (14).

[0107] The measuring system may also include a casing or housing that provides electrical and / or thermal insulation from the environment.

[0108] An alternative embodiment for the separate detection of endogenous IR radiation at different wavelengths is described in Figure 5The absorption curve of glucose in the region between 8 and 14 µm is shown as a bold line (G). Two sensors are used to separately detect IR radiation with two different wavelengths from this region, each comprising different combinations of bandpass, highpass, and / or lowpass filter elements. In one embodiment, both sensors include a wide bandpass filter (C) with a transmittance in the region between 8 and 14 µm. In the first sensor, filter (C) is combined with a highpass filter (A) that is transmittable to IR radiation with a wavelength of approximately 8.5 µm or less. A sensor equipped with filters (A) and (C) will therefore detect a signal from the 8–8.5 µm region that is essentially independent of the glucose concentration.The second sensor is equipped with a combination of a bandpass filter (C) and a lowpass filter (B) that is transparent to IR radiation with a wavelength of 8.5 µm or higher. The signal detected by this sensor includes an absorption band of glucose localized in the region of approximately 9–10 µm and is therefore dependent on the glucose concentration. The glucose concentration can be determined by differentially evaluating the signals detected by both sensors.

[0109] In another embodiment, a first sensor can be equipped with the bandpass filter (C) and the highpass 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.

[0110] Figure 6Figure 1 shows a schematic cross-sectional view of another embodiment of the IR detection unit of the device. The body region of the test subject to be examined (not shown) is arranged on a thermally insulating support element (66) which contains a region (66a) that is at least partially optically transparent to IR radiation. For example, the optically transparent region (66a) is a silicon or germanium disc. The support element (66) is provided with a temperature sensor (66b) and optionally with a temperature setting element (not shown), which preferably comprises a Peltier element. The temperature of the body region can be set, for example, to a range of approximately 28–38 °C. Preferably, the support element (66) includes means, e.g.,Sensors (68) for detecting and / or controlling the contact pressure, such as a load cell, and optionally sensors for detecting and / or controlling the contact position, such as a camera and / or a pulse sensor. A contact pressure of approximately 1-50 N, e.g., approximately 20 N, is preferably set.

[0111] The device further comprises a first IR sensor (70a) and a second IR sensor (70b) for detecting the body's own IR radiation (72) with different wavelengths in the region of 0.7–20 µm, preferably 3–20 µm, from the area of ​​the body being examined. The first and second sensors can each be configured as bolometers or thermopiles. Optionally, the first and second sensors can also consist of arrays of individual sensor elements.

[0112] The first sensor (70a) can be configured for the selective detection of endogenous IR radiation with a first wavelength from an absorption minimum of the analyte, for example, wherein a first filter element (74a), e.g., a narrow-pass bandpass filter, is provided which is selectively transparent to radiation with the first wavelength at which the signal is essentially independent of the concentration of the analyte to be determined. For the determination of glucose, the first wavelength is, for example, 8.1 ± 0.3 µm and / or 8.5 ± 0.3 µm, preferably 8.1 ± 0.2 µm and / or 8.5 ± 0.2 µm, and particularly preferably 8.1 ± 0.2 µm and / or 8.5 ± 0.1 µm. The second sensor (74b) is again configured for the selective detection of endogenous IR radiation (72) with a second wavelength from an absorption band, preferably in the region of an absorption maximum of the analyte to be determined, wherein a second filter element (74b), e.g.A narrow bandpass filter is provided, which is selectively transparent to radiation with the second wavelength. For example, in the determination of glucose, the second wavelength is 9.1 ± 0.3 µm, 9.3 ± 0.3 µm, and / or 9.6 ± 0.3 µm, preferably 9.1 ± 0.2 µm, 9.3 ± 0.2 µm, and / or 9.6 ± 0.2 µm, and particularly preferably in the range of 9.1 ± 0.1 µm, 9.3 ± 0.1 µm, and / or 9.6 ± 0.1 µm. Optionally, two or more secondary sensors may be provided, capable of detecting radiation with different wavelengths or wavelength ranges. For the determination of glucose, for example, two second sensors can be used, which separately detect IR radiation in the range of 9.1 µm or 9.3 µm and 9.6 µm.

[0113] The filter elements (74a, 74b) are conveniently in direct contact with the sensors (70a, 70b).

[0114] Alternatively, instead of narrow bandpass filters, the following can also be used: Figure 5 The illustrated combination of a wide-pass bandpass filter and a high-pass and / or low-pass filter can be used.

[0115] Optical focusing elements, e.g., lens elements, can be arranged in the beam path of the body's own IR radiation (72) between the body part to be examined and the sensors (70a, 70b and optionally 70c). The sensors (70a, 70b) can optionally be equipped with optical lens elements, e.g., biconvex lenses, in particular spherical lenses, to enable focusing of the incident body's own IR radiation.

[0116] Optionally, the device further includes a third sensor (70c) configured for the non-specific detection of endogenous IR radiation (72) and for reference purposes, e.g., for reference to the body temperature of the body region under investigation. The third sensor (70c) may be configured as a bolometer or thermopile.

[0117] An intermediate wall (78) may optionally be arranged between the first sensor (70a) and the second sensor (70b).

[0118] The sensors (70a, 70b and optionally 70c) are in thermal equilibration by being in contact with thermally conductive material, e.g. a block (76), a plate or a foil of metal.

[0119] Furthermore, an element (80) is provided for determining the temperature of the block (76) containing the sensors (70a, 70b and 70c), e.g. a temperature sensor. Furthermore, an element (82) is provided for adjusting the temperature of the block (76) containing the sensors (70a, 70b and 70c), e.g. a cooling and / or heating element.

[0120] The signals from the sensors (70a, 70b and, if applicable, 70c), as well as the temperatures determined by the elements (66b) and (80), are transmitted to a CPU unit (84) for temperature-compensated evaluation of the signals. Based on this evaluation, the analyte concentration is determined, and the result can then be displayed on a display (86). The CPU unit can also be used to control the elements (68, 82).

[0121] Optionally, the inner surface of the measuring system can be coated with a material that does not reflect IR radiation and / or absorbs IR radiation. Furthermore, the measuring system can have thermal insulation from the environment.

[0122] A particularly preferred arrangement of sensors in the IR detection unit is described in Figure 7The instrument shows four IR sensors (90a, 90b, 90c, and 90d) arranged together in a recess of a metal block (not shown) and thus thermally equilibrated. Preferably, each sensor consists of an array of several, e.g., 8 × 8, individual sensor elements. The sensors (90a, 90b) are designed for the selective detection of IR radiation with a wavelength from an absorption band of the analytes to be determined and are therefore equipped with corresponding filter elements. For the determination of glucose, the sensor (90a) can be provided for the selective detection of IR radiation with a wavelength of about 9.6 µm, e.g. 9.6 ± 0.1 µm, and the sensor (90b) can be provided for the selective detection of IR radiation with a wavelength of about 9.1 µm, e.g. 9.1 ± 0.1 µm or about 9.3 µm, e.g. 9.3 ± 0.1 µm.The sensor (90c) is designed for the selective detection of IR radiation with a wavelength corresponding to an absorption minimum of the analytes to be determined and is therefore equipped with appropriate filter elements. For the determination of glucose, the sensor (90c) can be configured for the selective detection of IR radiation with a wavelength of approximately 8.5 µm, e.g., 8.5 ± 0.1 µm. The sensor (90d) does not contain a filter element and serves for reference purposes.

[0123] A particularly preferred embodiment of a terahertz transmit / receive element with a focusing lens is described in Figure 8 shown. A terahertz transmit / receive element (100) contains a terahertz radiation source (102), e.g. an antenna, and a terahertz detection unit (104).

[0124] Terahertz radiation (106) emitted from the radiation source (102) is guided through a focusing lens (108), e.g., a spherical lens. The lens is made of a material transparent to terahertz radiation, such as polypropylene.

[0125] The radiation (106) is focused by the lens (108) onto a predetermined zone (112) of the body area (110) to be examined, e.g., a finger (capillary blood area or saturated tissue). Preferably, the focusing is performed to a predetermined penetration depth, e.g., a penetration depth of 3-4 mm. The radiation (114) reflected from the focusing zone (112) is again guided through the lens (108), focusing onto the terahertz detection unit (104).

[0126] In Figure 9A particularly preferred embodiment for evaluating a terahertz measurement signal is shown. The frequency of a terahertz signal is modulated over a range (f0...f1) containing an absorption band of glucose, the analyte to be determined. The modulation can be continuous, e.g., by changing the voltage with a voltage-controlled oscillator (VCO), or discontinuous.

[0127] The frequency-modulated terahertz signal is directed to an antenna, e.g., a patch antenna (PA), and then projected onto the body area (K) to be examined, e.g., a finger. This can be done via a lens (see, e.g., Figure 8 ) or a waveguide. There, the terahertz radiation is reflected and reaches a sensor (S), e.g., a patch antenna or a dipole, and from there a preamplifier, e.g., an LNA.

[0128] The signal is then routed to a mixer (X), which multiplies the received signal with the transmitted signal. Due to the distance the signal travels to and from the target area, the received signal has a different path length than the transmitted signal. Because of the frequency modulation and the different path lengths and propagation times of the received and transmitted signals, a frequency difference proportional to the propagation time difference (e.g., a path length difference of approximately 50 mm corresponds to a propagation time difference of 166 psec) is generated at the mixer. This results in a mixed signal (sin(fa)*(fb) = sin(fa+fb) and sin(fa-fb), where the difference is the desired signal, which is further amplified by an amplifier (AMP). One or more phases of the signal are then routed to an analog-to-digital converter (ADC) and processed by a CPU.

[0129] The evaluation preferably includes a continuously performed Fast Fourier Transform (FFT) to filter out unwanted interference signals. Thus, as the frequency (f0...f1) increases, a different spectrum is generated at the THz transmitter, controlled by the voltage input. The signal corresponding to the beam path to the capillary layer and back can be identified and measured via its characteristic time-of-flight difference. This yields a characteristic curve that corresponds to the reflection and absorption spectrum of glucose in capillary blood. A comparative measurement at the absorption maxima and minima of glucose provides the glucose concentration in the capillary blood.

[0130] As an alternative to frequency modulation, the terahertz signal can also be radiated as a pulse-modulated signal onto the area of ​​the body to be examined, whereby signal pulses, in particular discrete signal pulses with different frequencies, are radiated at predetermined time intervals.

Claims

1. Use of a device for the non-invasive determination of glucose in the blood of a test subject, wherein the device comprises: (a) a unit (16) for receiving a body region (14) originating from the test subject and that is to be investigated, (b) a radiation source (100) for generating terahertz radiation, in particular terahertz radiation in a wavelength region from about 0.1 mm to about 5 mm, from about 0.12 mm to about 5 mm or from about 0.1 mm to about 1 mm, for irradiating the body region to be investigated, (c) a unit for detecting radiation from the body region to be investigated, comprising: (i) a unit (118) for detecting reflected terahertz radiation from the body region to be investigated, which is adapted to detect terahertz radiation in a wavelength range in which the intensity of the reflected terahertz radiation changes depending on the glucose concentration, (ii) a unit (120) for detecting the body's own IR radiation from the body region to be investigated, which is adapted for the separate detection of IR radiation at at least two different wavelengths or wavelength ranges in the wavelength region from about 8 µm to about 12 µm, wherein at a first wavelength or a first wavelength range the intensity of the body's own IR radiation is substantially independent of the glucose concentration, and wherein at a second wavelength or a second wavelength range the intensity of the body's own IR radiation changes depending on the glucose concentration and wherein the unit is optionally additionally adapted for the non-specific detection of the body's own IR radiation, and (d) (i) an element (16b) for measuring the temperature in the body region to be investigated, (ii) optionally an element for setting the temperature in the body region to be investigated, (e) (i) an element (26) for measuring the temperature in the detection unit (c), (ii) an element (28) for setting the temperature in the detection unit (c), wherein it is provided that the temperature in the detection unit (c) is lower than the temperature in the body region to be investigated, and (f) a unit (124) which is adapted for the temperature-compensated evaluation of the terahertz signals originating from the detection unit (c) (i) and the body's own IR signals originating from the detection unit (c) (ii) and for the determination of the glucose concentration on the basis of the evaluated terahertz signals and the body's own IR signals, wherein the unit is optionally adapted for the selective evaluation of the body's own IR radiation originating from capillary blood vessels of the dermis of the body region.

2. Use according to claim 1, characterised in that the radiation source for generating terahertz radiation (b) comprises an antenna, in particular a patch or a dipole antenna, and is preferably designed to emit frequency-modulated or pulse-modulated terahertz radiation.

3. Use according to claim 1 or 2, characterised in that a focusing lens, e.g. a spherical lens, an aspherical lens or a Fresnel lens, is arranged in the beam path between the radiation source for generating terahertz radiation (b) and the body region to be investigated, wherein the focusing lens is made of a material that is substantially transparent to terahertz radiation, wherein the focusing lens is preferably designed to focus the radiation generated by the terahertz radiation source (b) onto a predetermined zone of the body region to be investigated, in particular onto a zone containing capillary blood.

4. Use according to one of claims 1-3, characterised in that the unit (c) (i) is adapted to detect a broadband spectrum in the terahertz range, in particular within a frequency range from about 0.12 mm to about 5 mm (corresponding to 60 GHz to about 2.5 THz), and / or that the unit (c) (i) is adapted to perform a single-stage or multi-stage amplification, in particular a two-stage amplification, of the terahertz radiation reflected from the body region to be investigated.

5. Use according to one of claims 1-4, characterised in that the unit (c) (i) is adapted for the combined detection of reflected terahertz radiation from the body region to be investigated and terahertz radiation radiated into the body region to be investigated, and wherein the unit (c) (i) is adapted in particular for the detection of frequency-modulated or pulse-modulated signals.

6. Use according to one of claims 1-5, characterised in that the device does not contain an external source for generating IR radiation.

7. Use according to one of claims 1-6, characterised in that that the unit for recording the body region to be investigated (a) comprises an element for supporting the body region to be investigated that is at least partially thermally insulating with respect to the unit (c) for detecting radiation, and that contains a region that is transparent to terahertz radiation, in particular from about 0.12 mm to about 5 mm (corresponding from about 60 GHz to about 2.5 THz) or in a sub-range thereof and to IR radiation in the wavelength region in particular from about 8 µm to 12 µm or in a sub-range thereof.

8. Use according to one of claims 1-7, characterised in that the unit for recording the body surface area to be investigated (a) comprises means, e.g. sensors, for detecting and / or monitoring the support position and / or contact pressure of the body area to be investigated, wherein in particular means are provided for detecting and / or monitoring a contact pressure in the range of approximately 0.5-100 N, preferably in the range of approximately 1-50 N and particularly preferably of approximately 20 N are provided.

9. Use according to one of claims 1-8, characterised in that the unit for detecting the body's own IR radiation (c) (ii) comprises at least one first sensor, at least one second sensor and optionally at least one third sensor, wherein the first sensor is designed to detect IR radiation with a first wavelength or a first wavelength range in the region from about 8 µm to about 12 µm, where the intensity of the body's own IR radiation is substantially independent of the glucose concentration, wherein the second sensor is designed to detect IR radiation with a second wavelength or a second wavelength range in the region from about 8 µm to about 12 µm, where the intensity of the body's own IR radiation changes depending on the glucose concentration, and wherein the third sensor is designed to reference the body's own IR radiation, wherein the unit for detecting the body's own IR radiation (c) (ii) comprises two or more second sensors that are designed to detect IR radiation at different wavelengths or wavelength ranges, where the intensity of the body's own IR radiation changes depending on the glucose concentration.

10. Use according to one of claims 1-9, characterised in that the unit for detecting radiation (c) is in contact with a thermally conductive carrier, wherein in particular the unit for detecting terahertz radiation (c) (i) and the unit for detecting IR radiation (c) (ii) are in contact with the same thermally conductive carrier.

11. Use according to one of claims 1-10, characterised in that a temperature is provided in the detection unit (c) which is at least 5°C, at least 6°C or at least 7°C and up to 15°C lower than the temperature of the body region to be investigated.

12. Use according to one of claims 1-11, characterised in that the device is provided for a sequential detection of terahertz radiation and IR radiation, wherein in particular the body's own IR radiation is first of all detected without irradiating the body area to be investigated and then the body area to be investigated is irradiated with terahertz radiation and the reflected terahertz radiation is detected.

13. Use according to one of claims 1-12, characterised in that the unit (f) is provided for the temperature-compensated evaluation of the signals on the basis of the temperature values measured and optionally set by the elements (d) and / or (e), and / or that the unit (f) is provided for the combined evaluation of the signals from the terahertz detection unit (c) (i) and the IR detection unit (c) (ii).

14. Use according to any one of claims 1-13 for the non-invasive quantitative determination of glucose in the blood of a test subject.

15. Method for the non-invasive quantitative determination of glucose in the blood of a test subject, comprising the steps: (i) irradiating a body region originating from the test subject with terahertz radiation, in particular in a wavelength region from about 0.1 mm to about 5 mm, from about 0.12 mm to about 5 mm or from about 0.1 mm to about 1 mm, and detecting reflected terahertz radiation by a unit for detecting terahertz radiation from the irradiated body region in a wavelength range in which the intensity of the reflected terahertz radiation changes depending on the glucose concentration, (ii) separately detecting the body's own IR radiation from a body region originating from the test subject by a unit for detecting IR radiation at at least a first wavelength or a first wavelength range in the wavelength region from about 8 µm to about 12 µm, where the intensity of the body's own IR radiation is substantially independent of the glucose concentration, and at least a second wavelength or a second wavelength range in the wavelength region from about 8 µm to about 12 µm, where the intensity of the body's own IR radiation changes depending on the glucose concentration, and optionally non-specific detection of the body's own IR radiation from the irradiated body surface area for referencing, wherein the temperature in the region of the unit for detecting IR radiation is lower than the temperature of the body area to be investigated, (iii) combined evaluation of the signals detected according to (i) and (ii) taking account of the temperature of the body area to be investigated and the temperature in the region of the units for detecting terahertz radiation and IR radiation, and wherein optionally a selective evaluation of the body's own IR radiation from capillary blood vessels of the dermis of the body area is performed and (iv) determining the glucose concentration on the basis of the evaluated signals, wherein the determination of glucose is preferably carried out by detecting the body's own IR radiation from a fingertip of the test subject without stimulation by an external source of IR radiation.