Noninvasive measurement of glucose

Abstract

The present invention relates to the non-invasive measurement of glucose in blood, and more particularly to the non-invasive measurement of glucose in capillaries.

Description

[Technical field]

[0001] The present invention relates to the non-invasive measurement of glucose in blood, and in particular in capillaries, by detecting and evaluating radiation from the terahertz and infrared ranges. [Background technology]

[0002] In 2016, approximately 415 million people had diabetes. This number is expected to increase to more than 640 million by 2040. Diabetic patients need to closely monitor their blood glucose levels to allow for appropriate drug therapy. Therefore, there is a need for reliable and easy-to-use blood glucose measurement methods for patients.

[0003] Currently, the measurement of glucose in blood is mainly based on invasive methods, where a blood sample is taken from the patient and then subjected to in vitro tests or a sensor is implanted to measure glucose in vivo. The disadvantage of such invasive methods is that they cause pain and discomfort for the patient.

[0004] To circumvent this drawback, a number of approaches have already been developed to measure blood glucose concentrations non-invasively, but none of them have yet achieved commercial importance.

[0005] WO 2014 / 0206549 describes a raw data measuring device for non-invasively measuring blood parameters, such as glucose concentration, in which infrared (IR) radiation originating from an external radiation source is coupled two-dimensionally onto the body surface of a patient to be examined at multiple measuring points, and the infrared radiation emitted at the body surface is detected at multiple measuring points by a sensor device. However, this method has the disadvantage of requiring high installation costs.

[0006] WO 2018 / 122 relates to an apparatus and method for the non-invasive quantitative measurement of an analyte in blood, in particular for the non-invasive quantitative measurement of glucose in capillary blood. For this purpose, a selected body part is irradiated with infrared light, preferably in the 8-12 μm range, followed by selective evaluation of the infrared light reflected from blood vessels near the surface of the irradiated body part.

[0007] WO 2019 / 034722 likewise relates to an apparatus and method for the non-invasive quantitative measurement of an analyte in blood, in particular for the non-invasive quantitative measurement of glucose in capillary blood, in which the evaluation of infrared radiation emitted by the body is preferably carried out in the wavelength range of 8 to 12 μm without the use of an external radiation source.

[0008] Absorption maxima of glucose and other clinically relevant analytes in the terahertz range as well as in vitro spectroscopic measurements are described, for example, in Laman et al., Biophys. J. 94 (2008), 1010-1020, Upadhya et al., J. Biol. Phys. 29 (2003), 117-121, or Song et al., Scientic Report 8 (2018), Article Number 8964.

[0009] However, known non-invasive methods for measuring glucose suffer from being prone to error. Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention provides a method for the non-invasive measurement of glucose in a body fluid, and the use of a device in said method, which makes it possible to at least partially avoid the drawbacks of the prior art. [Means for solving the problem]

[0011] The present invention is based on the finding that it is possible to easily, quickly and sufficiently accurately quantitatively measure glucose in the blood of a subject by a non-invasive method. The present invention is based on detecting radiation in two different wavelength ranges from a body part of the subject to be examined and evaluating the obtained measurement signal in a composite manner. For this purpose, terahertz radiation is irradiated to a predetermined body part of the subject, for example a fingertip, and reflected terahertz radiation in a terahertz wavelength range is detected, in which the intensity of the reflected terahertz radiation varies depending on the glucose concentration in this wavelength range. Furthermore, infrared radiation specific to the body emitted from a predetermined body part of the subject, for example a fingertip, is detected separately at at least two different wavelengths or wavelength ranges in the wavelength range from about 8 μm to about 12 μm. This detection is performed at a first wavelength or a first wavelength range in which the intensity of the reflected infrared radiation is substantially independent of the glucose concentration, and separately at a second wavelength or a second wavelength range in which the intensity of the reflected infrared radiation varies depending on the glucose concentration. By combining a differential evaluation of the measurement signals at two infrared wavelengths or in the infrared wavelength range with an evaluation of the measurement signal in the terahertz range, the glucose concentration can be determined. Effect of the Invention

[0012] Surprisingly, it has been found that the non-invasive measurement of glucose in blood by combined detection and evaluation of radiation in two different spectral regions increases the accuracy of the measurement of the analyte and makes it less prone to errors. In particular, the influence of interfering substances can be reduced in this way, since interfering substances usually only exhibit an absorption behavior that interferes with glucose in one of the two spectral regions. This allows the contribution of the interfering substance in question to the measurement signal to be quantitatively determined using suitable algorithms, allowing for an accurate correction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In one embodiment of the present invention, by means of a combined measurement in the terahertz and infrared ranges, the contribution of interfering substances in the infrared measurement signal is quantitatively determined by evaluation of the terahertz signal, thereby obtaining a corrected infrared measurement signal in which the contribution of interfering substances is at least largely or completely eliminated.

[0014] In a further embodiment of the present invention, by means of a combined measurement in the terahertz and infrared ranges, the contribution of interfering substances in the terahertz measurement signal is quantitatively determined by evaluation of the infrared signal, thereby obtaining a corrected terahertz measurement signal in which the contribution of interfering substances is at least largely or completely eliminated.

[0015] In yet another embodiment of the present invention, by means of a combined measurement in the terahertz and infrared range, the contribution of a first interfering substance in the terahertz measurement signal is quantitatively determined by evaluation of the infrared signal, and the contribution of a second interfering substance in the infrared measurement signal is quantitatively determined by evaluation of the terahertz signal, thereby obtaining corrected terahertz and infrared measurement signals in which the contributions of the first interfering substance and the second interfering substance are at least largely or completely eliminated.

[0016] In the present invention, the term "terahertz range" means, unless otherwise specified, a frequency range of about 60 gigahertz (GHz) to about 3 terahertz (THz), which corresponds to a wavelength range or wavelength region of about 5 mm to about 0.1 mm, or a partial range thereof. For example, it can range from about 0.3 THz to about 3 THz (corresponding to a wavelength range or wavelength region of about 1 mm to about 0.1 mm), or from about 60 GHz to about 2.5 THz (corresponding to a wavelength range or wavelength region of about 5 mm to about 0.12 mm).

[0017] In the present invention, the term "infrared range" means, unless otherwise specified, a wavelength range or region of about 1 μm to about 20 μm, or a subrange thereof, for example, a wavelength range or region of about 5 μm to about 15 μm, particularly about 8 μm to about 12 μm.

[0018] In this case, the body part to be examined is irradiated with terahertz radiation and the reflected terahertz radiation is detected by a suitable sensor. Furthermore, infrared radiation emitted by the body is detected by a suitable sensor. In this case, the use of an external infrared source is not usually envisaged. For the evaluation of the measurement signal, advantageously a device is used which is shielded from external electrical and / or thermal radiation. This achieves a significant increase in the measurement accuracy.

[0019] In the course of the evaluation, the temperature of the body part to be examined, for example the fingertip, and the temperature of the sensor used for the detection of terahertz radiation and infrared radiation are further measured, the temperature of the sensor being kept at a value lower than the temperature of the body part to be examined. Advantageously, the temperature of the sensor is adjusted to a predetermined value, for example a value in the range of 10°C to 25°C, for example by embedding in a metal block, the temperature of which is adjusted by a temperature adjustment element, for example a Peltier element, and is measured accurately, for example with an accuracy of up to ±0.1°C or up to ±0.01°C, by a temperature measuring element. The temperature of the body part to be examined, for example the fingertip, may take on values ​​that vary depending on the subject and the external conditions. This value is measured according to the invention by the temperature measuring element accurately, for example with an accuracy of up to ±0.1°C or up to ±0.01°C.

[0020] The evaluation of the measurement signal comprises performing a temperature correction of the obtained measurement signal taking into account the value of the temperature of the body part to be examined and the value of the temperature of the sensor unit, in particular the resulting temperature difference.The invention therefore relates to a non-invasive measurement of glucose by joint evaluation of terahertz radiation and body-specific infrared radiation with temperature correction.

[0021] Furthermore, according to the present invention, it is possible to selectively evaluate the body's own infrared radiation in a region of about 8 μm to about 12 μm from the blood vessels near the surface of the body part to be examined, in particular, to selectively evaluate the body's own infrared radiation generated from the capillaries in the dermis. The inventors have found that the body's own infrared radiation is composed of a plurality of components, and these components can be analyzed separately. The body's own infrared radiation components generated from the blood vessels near the surface show a time change according to the subject's arterial pulse rate. Based on this change, it becomes possible to distinguish between signals that change with pulse frequency and signals that are independent of pulse frequency during the evaluation process.

[0022] Surprisingly, the present invention allows accurate and reproducible measurement of glucose in blood, for example with an accuracy of ±2.5% relative to a reference measurement using an X-ray diffractometer.

[0023] Thus, a first aspect of the present invention relates to the use of a device for non-invasively measuring glucose in the blood of a subject, the device comprising: (a) a unit containing the body part to be examined from the subject; (b) a radiation source that generates terahertz radiation for irradiating the body part to be examined, particularly terahertz radiation in a wavelength range of about 0.1 mm to about 5 mm, about 0.12 mm to about 5 mm, or about 0.1 mm to about 1 mm; (c) A unit for detecting radiation emanating from the part of the body to be examined, comprising: (i) a unit for detecting terahertz radiation reflected from the body part to be examined, the unit being arranged to detect terahertz radiation in a wavelength range in which the intensity of the reflected terahertz radiation varies depending on the glucose concentration; (ii) a unit for detecting body-specific infrared radiation emanating from a body part to be examined, the unit being configured to separately detect infrared radiation of at least two different wavelengths or wavelength ranges in a wavelength region of about 8 μm to about 12 μm, where at a first wavelength or first wavelength range, the intensity of the body-specific infrared radiation is substantially independent of glucose concentration, and at a second wavelength or second wavelength range, the intensity of the body-specific infrared radiation varies with glucose concentration, and the unit is optionally further configured to non-specifically detect the body-specific infrared radiation; (d) (i) an element for measuring the temperature of the body part to be examined; (ii) optionally, an element for regulating the temperature of the body part to be examined; (e) (i) an element for measuring the temperature of the detection unit (c); (ii) an element for adjusting the temperature of the detection unit (c), the element being designed so that the temperature of the detection unit (c) is lower than the temperature of the body part to be examined; (f) a unit arranged for evaluating a temperature compensated signal arising from the detection unit (c) and for determining a glucose concentration based on the evaluated signal, the unit optionally arranged for selectively evaluating body specific infrared radiation arising from capillaries in the dermis of the body part. Equipped with, relating to use.

[0024] The device comprises a radiation source (b) for generating terahertz radiation for irradiation of the body part to be examined, in particular terahertz radiation in a wavelength range of about 0.1 mm to about 5 mm, about 0.12 mm to about 5 mm, or about 0.1 mm to about 1 mm. The terahertz radiation is irradiated and then reflected from the body part to be examined introduced in the accommodation unit (a). The device further comprises a unit (c)(ii) for detecting the terahertz radiation.

[0025] The device does not necessarily comprise an external infrared source, since the external infrared source is provided for detecting and evaluating the body's own infrared radiation. Preferably, there is no external infrared source. The body part to be examined is introduced into the containment unit (a) and emits the body's own infrared radiation. The device comprises a unit (c)(ii) for detecting the body's own infrared radiation.

[0026] The temperature, in particular the core temperature, of the body part to be examined introduced into the storage unit is precisely measured by a temperature measuring element (d)(i), e.g. a temperature sensor. If necessary, an element (d)(ii) for regulating the temperature of the body part to be examined, i.e. a heating and / or cooling element, e.g. a Peltier element, may also be provided in the storage unit (a).

[0027] Furthermore, the device further comprises means (e)(i) for measuring the temperature of the unit (c)(i) for detecting reflected terahertz radiation and / or the unit (c)(ii) for detecting body-specific infrared radiation, e.g. a temperature sensor, and means (e)(ii) for maintaining the temperature of the unit (c)(i) for detecting reflected terahertz radiation and / or the unit (c)(ii) for detecting body-specific infrared radiation at a substantially equal, preferably constant, temperature level. In this case, an element (e)(ii) is provided for precisely regulating the temperature of the radiation detection units (c)(i) and / or (c)(ii) to a value lower than the value of body temperature. Advantageously, the element (e)(ii) comprises an object made of a thermally conductive material, e.g. a metal block, and means for supplying and / or extracting heat, e.g. a heating and / or cooling element, such as a Peltier element.

[0028] The device is provided for receiving a body part of a subject, in particular a body part of a human subject, such as a fingertip, an earlobe, or a heel, or a part thereof, and measuring the body-specific infrared radiation emitted therefrom. Preferably, the body part to be examined is a fingertip.

[0029] For this purpose, the device comprises a unit (a) for receiving the body part to be irradiated, which can for example comprise a support element for said body part, for example a fingertip. The shape of the support element is adapted to the body part on which the measurement is to be performed. For example, a substantially planar support element can be provided.

[0030] Advantageously, the support element (a) is partially thermally insulated from the radiation detection units (c)(i) and / or (c)(ii), for example by being at least partially formed from a thermally insulating material, for example a plastic such as polyurethane foam. Furthermore, the support element preferably comprises one or more ranges transparent for terahertz radiation in the range of about 0.1 mm to about 5 mm, or about 0.1 mm to about 1 mm, and for infrared radiation, preferably in the range of about 8 μm to about 12 μm, in order to allow the unhindered passage of terahertz radiation and infrared radiation emanating from the body part to be examined. The transparent range of the support element is, for example, about 0.5 cm. 2 ~approx. 1.5cm 2 The support element may have an area of ​​0.01 mm and may be formed, for example, as a circle. Examples of materials suitable for the transparency range of the support element are silicon, germanium, or terahertz and infrared transparent organic polymers. The support element may be formed in any suitable shape, for example as a plate.

[0031] To the accommodation unit (a) is connected an element (d)(i) for measuring the temperature of the body part to be examined. This element comprises a temperature sensor, for example a bolometer or a thermopile. Furthermore, a temperature adjustment element (d)(ii), for example a heating and / or cooling element, in particular a Peltier element, may be provided to allow for precise adjustment of the temperature of the body part to be examined, for example with an accuracy of up to ±0.1°C, or up to ±0.01°C, if necessary. For example, the temperature adjustment element may be arranged so that the temperature of the body part can be adjusted to above 25°C, for example to about 28-38°C. Furthermore, an element (d)(iii), for example a colorimetric sensor, for measuring the pigments of the body part to be examined may be provided.

[0032] Preferably, the support element comprises means, e.g. sensors, for detecting and / or controlling the support position and / or the support pressure of the body part to be examined. In this case, the support position and / or the support pressure can be detected separately for each body part and adapted as necessary. The individual adaptation can, for example, comprise one or more matchings of the measurement signal emitted by the non-invasive device with a reference signal, which is conventionally obtained, e.g. by invasive measurements using conventional test strips or sensors inserted into the body. This matching can be carried out as part of the initial use of the device and, if necessary, can be repeated at time intervals, e.g. daily, every other day, weekly, etc. Preferably, the matching comprises an adjustment of the support position and / or the support pressure of the body part to be examined in order to obtain a stable and reproducible measurement signal that corresponds as well as possible to the reference signal. For this purpose, the device can comprise sensors for detecting and / or controlling the support position of the body part to be irradiated, e.g. with respect to x, y and z coordinates relative to the support element, and / or for detecting and / or controlling a support pressure, e.g. in the range of about 0.5 to 100 N, preferably in the range of about 10 to 50 N, particularly preferably about 20 N. The sensor for detecting and / or controlling the support pressure may comprise, for example, a load cell. The sensor for detecting and / or controlling the support position may comprise a camera, for example a CCD camera and / or a pulse sensor.

[0033] The adjustment of the support position and / or the support pressure determined by the adaptation is preferably registered and stored by the device. When using the device, the correct support position or the correct support pressure can then be indicated by a signal, for example an optical and / or acoustic signal. Only if the predetermined correct adjustment is confirmed, is the glucose measurement started.

[0034] The device comprises a radiation source (b) for generating terahertz radiation. This radiation source may be designed to generate coherent terahertz radiation. For example, terahertz radiation can be generated by frequency doubling or difference frequency formation of a distributed feedback laser with multiple laser signals, for example quantum cascade lasers, molecular gas lasers, free electron lasers, optical parametric oscillators and backward wave oscillators. Furthermore, a photodiode can be used that converts the difference frequency of two lasers into an alternating current and radiates it in the form of terahertz radiation by a suitable photoconductive antenna. In a particular embodiment of the invention, terahertz radiation can be converted into terahertz radiation by a suitable terahertz antenna, for example by a pulsed laser having a wavelength in the range of 500 to 2000 mm, for example a wavelength of 800 mm. The power of such a laser is usually about 1 mW to about 1 W.

[0035] In further embodiments, a terahertz transceiver chip may also be used. Such a transceiver chip may be made of silicon and / or germanium based materials. In a particular embodiment, the chip comprises one or more amplifiers, for example low noise amplifiers (LNA), one or more quadrature mixers, one or more polyphase filters, one or more frequency splitters and / or an oscillator with at least one tuning input for generating terahertz radiation. Advantageously, there are multiple tuning inputs, for example two, three or four, in order to vary the bandwidth of the terahertz radiation as required. Furthermore, a transmitting and / or receiving antenna for emitting and / or receiving terahertz radiation may be integrated on the chip. The power of such a chip may be in the range of about 0.01 mW to about 100 mW, in particular in the range of about 0.1 mW to about 1 mW. For example, the chip may have a power of about 1 mW. The size of such a chip is about 100 mm. 2 up to, advantageously, about 10 mm 2 ~ approx. 50mm 2 range, for example, about 25 mm 2 Such terahertz chips are available, for example, from Silicon Radar GmbH.

[0036] In a further embodiment of the invention there is a terahertz antenna, for example a patch antenna or a dipole antenna.

[0037] The effective power of the terahertz radiation source, ie the power irradiated to the body part to be examined, is preferably from about 1 mW to about 100 mW, and the radiation can be emitted continuously or in pulses.

[0038] Further, the apparatus comprises radiation detection units (c), namely a terahertz radiation detection unit (c)(i) and an infrared radiation detection unit (c)(ii).

[0039] The terahertz radiation detection unit (c)(i) comprises one or more sensors or detectors provided for detecting terahertz radiation, in particular terahertz radiation in a frequency range of about 60 gigahertz (GHz) to about 3 terahertz (THz), which corresponds to a wavelength range or wavelength region of about 0.1 mm to about 5 mm, or a subrange thereof, for example terahertz radiation in a range of about 0.12 mm to about 5 mm, a range of about 0.1 mm to about 1 mm, or a subrange thereof.

[0040] In a further particularly preferred embodiment, in the radiation path between the terahertz radiation source and the body part to be examined and / or in the radiation path between the body part to be examined and the terahertz detection unit (c)(i), there is at least one focusing lens, e.g. a spherical lens, an aspherical lens or a Fresnel lens, made of a material that is substantially transparent to terahertz radiation, e.g. polypropylene or HD polyethylene. The lens is used to focus the terahertz radiation irradiated by the terahertz radiation source onto the body part to be examined to a predefined penetration depth into the body part, e.g. about 3-4 mm, and / or to focus the terahertz radiation reflected from the body part to be examined onto the terahertz detection unit.

[0041] 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 first step involves amplification by an LNA. The reflected terahertz radiation can then be passed through a mixer and mixed (multiplied) with the transmitted signal. The result of the mixing can then be further amplified, for example by up to 10 3 more than twice, 10 4 More than double and 10 6 Double or 10 7 In one embodiment, the signal can be amplified in multiple steps, for example two steps, with each step being 10 2 Times to 10 3 This allows for signal amplification of 100x.

[0042] A terahertz radiation detection unit is provided for detecting terahertz radiation in a wavelength range in which the intensity of the reflected terahertz radiation varies depending on the glucose concentration. In particular, the unit (c)(i) detects a broadband spectrum in the terahertz range, in particular a frequency range of about 60 gigahertz (GHz) to about 3 terahertz (THz), which corresponds to a wavelength range or wavelength region of about 0.1 mm to about 5 mm, for example a wavelength range of about 0.1 mm to about 0.25 mm (about 100 cm -1 ~about 40cm -1 The system is configured to detect a broadband spectrum in the terahertz range, including the terahertz wavenumber range, or any subrange thereof.

[0043] The terahertz measurements can be shown on a display, either alone or in combination with the infrared measurements.

[0044] The device further comprises a unit (c)(ii) for detecting body-specific infrared radiation originating from the examined body part, which is arranged for separately detecting infrared radiation in at least two different wavelengths or wavelength ranges, preferably in the region of about 8 μm to about 12 μm. In a particularly preferred embodiment, this unit is arranged for separately detecting infrared radiation in at least two different wavelengths or wavelength ranges in the region of about 8 to 10 μm. Furthermore, there may be a third infrared sensor without a filter for comparative measurement as a reference temperature.

[0045] The detection unit (c)(ii) for detecting infrared radiation comprises one or more sensors arranged to detect infrared radiation.

[0046] In one embodiment, the detection unit (c)(ii) comprises a plurality of sensors arranged for separately detecting infrared radiation having at least two different wavelengths or wavelength ranges. In another embodiment, the device may further comprise a sensor arranged for separately detecting infrared radiation having at least two different wavelengths or wavelength ranges in a time-dependent manner.

[0047] In this case, the detection unit (c)(ii) is arranged for separately detecting infrared radiation at at least one first wavelength or in a first wavelength range and at least one second wavelength or in at least one second wavelength range. The first wavelength or in a first wavelength range is preferably in the region of the absorption minimum of glucose. The second wavelength or in a second wavelength range is preferably in the region of the absorption band of glucose, i.e. in the region where glucose shows a strong absorption, preferably an absorption maximum.

[0048] In one embodiment, the device includes at least one first sensor and at least one second sensor, each configured to separately detect infrared radiation having a different wavelength or wavelength range in the region of about 8-12 μm. The first sensor is selected such that the sensor is configured to detect infrared radiation having a first wavelength or wavelength range in which the body-specific infrared radiation intensity is substantially independent of glucose concentration. The second sensor is selected such that the sensor is configured to detect infrared radiation having a second wavelength or wavelength range in which the body-specific infrared radiation intensity varies with glucose concentration.

[0049] Each of the devices can include one or more first and second infrared sensors. In certain embodiments, the devices include a first sensor arranged to detect infrared radiation whose intensity is independent of glucose concentration, and two or more second sensors arranged to detect infrared radiation whose intensity varies with glucose concentration, where each of the two or more second sensors is arranged to detect infrared radiation having a different wavelength range.

[0050] The first and / or second infrared sensor may be designed as wavelength-non-specific radiation sensors, for example bolometers or thermopiles, with optical filter elements that are transparent for the wavelength or wavelength range to be detected, respectively, in order to enable wavelength (range) specific detection of infrared radiation. For this purpose, suitable filter elements, for example band-pass, high-pass or low-pass filter elements or a combination of several such filter elements, can be used. Preferably, the optical filter elements are arranged directly, i.e. without any space therebetween, on the sensor. In a preferred embodiment, high-precision bolometers or thermopiles are used as the first and / or second sensor.

[0051] In one embodiment, for wavelength-specific detection of infrared radiation, the first and / or second infrared sensor may be provided with a narrow bandpass filter element having a transmission width around the first or second measurement wavelength, respectively, 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.

[0052] In yet another embodiment, the filter element of the first and / or second infrared sensor may include a combination of a wide bandpass filter element having a transmission width of, for example, 2 to 12 μm, preferably 3 to 8 μm, and a high-pass filter element and / or a low-pass filter element. For example, a wide bandpass filter element may be provided that transmits infrared radiation in a region covering the entire measurement wavelength range, for example, in the region of 8 to 10.5 μm or 7 to 14 μm. By using this bandpass filter element in combination with a low-pass filter element and / or a high-pass filter element, infrared radiation of different wavelengths or wavelength ranges can be detected separately for each of the first and second sensors. In this case, one of the two sensors may be provided with a low-pass filter element that transmits infrared radiation up to a cutoff wavelength between the first wavelength or first wavelength range and the second wavelength or second wavelength range. Alternatively or additionally, the other of the two sensors may be provided with a high-pass filter element that also transmits infrared light up to a second cut-off wavelength that is between the first measurement wavelength or first measurement wavelength range and the second measurement wavelength or second measurement wavelength range.

[0053] The use of a wide bandpass filter in conjunction with a lowpass and / or highpass filter has the advantage that a wider wavelength range can be detected. In this way, the measurement efficiency can be significantly improved.

[0054] In one specific embodiment of this embodiment, one of the two infrared sensors may comprise a wide bandpass filter in combination with a lowpass filter, and the other of the first or second sensor may comprise a wide bandpass filter in combination with a highpass filter. In a second embodiment, one of the first or second infrared sensors may optionally comprise only a wide bandpass filter, and the other of the first or second sensor may comprise a combination of a bandpass filter and a lowpass filter, or alternatively a combination of a bandpass filter and a highpass filter. In the latter two embodiments, the wavelength ranges detected by the first or second sensor overlap, and this overlapping range must be subtracted during the evaluation.

[0055] In yet another embodiment, the first infrared sensor and / or the second infrared sensor may be designed as a wavelength (range) specific sensor, such as for example a quantum cascade sensor.

[0056] In another embodiment, the detection unit (c)(ii) comprises at least one infrared sensor arranged to detect infrared radiation having at least two different wavelengths or wavelength ranges in a time-dependent manner separately in the region of about 8-12 μm, where at a first wavelength or first wavelength range, the intensity of the body-specific infrared radiation is substantially independent of the glucose concentration and where at a second wavelength or second wavelength range, the intensity of the body-specific infrared radiation varies as a function of the glucose concentration.

[0057] Here, the sensor provided for the time-dependent separate detection of radiation having different wavelengths or wavelength ranges may be designed as a Fabry-Perot interferometer, for example as a MEMS spectrometer for the MIR / TIR range of about 3 to 12 μm (see, for example, Tuohinieni et al., J. Micromech. Microeng. 22 (2012), 115004; Tuohinieni et al., J. Micromech. Microeng. 23 (2013), 075011).

[0058] Furthermore, the detection unit (c)(ii) can optionally further comprise at least one further sensor, e.g. a bolometer or thermopile, arranged for non-specific detection of body-specific infrared radiation originating from the irradiated body part of the subject and can serve as a reference, e.g. a body temperature reference. This further sensor can also perform the function of the temperature measuring element (d)(i).

[0059] The size of the sensors of the detection units (c)(i) and / or (c)(ii) of the device can be selected as required. For example, the sensors can be 0.5 to 10 mm 2 The cross-sectional area may range from 0.01 to 0.1 mm.

[0060] The one or more sensors may optionally be in the form of an array of a plurality of individual sensor elements, such as bolometers or thermopiles, for example comprising 4 to 100 individual elements in a 2×2, 3×3, 4×4 or 8×8 individual element array, where the individual sensor elements in the array may be positioned immediately adjacent to each other or may be separated from each other by gaps.

[0061] The sensors of the device, in particular the sensors of the detection units (c)(i) and (c)(ii), are advantageously in thermal equilibrium, i.e. have substantially equal temperature levels. For example, the sensors may be in contact with a common heat-conducting support, such as an object, block, plate or foil, for example made of metal, such as copper or brass, for example by being embedded therein. For example, the sensors may be arranged in recesses in the object or block, with one sensor arranged in each recess or with several sensors arranged in each recess. The support or block may be connected to elements that supply and / or remove heat, for example heating and / or cooling elements, such as Peltier elements.

[0062] In a preferred embodiment, the sensors, in particular the sensors of detection units (c)(i) and (c)(ii), are embedded in a metal block, for example a copper block which may be gold coated.

[0063] Particularly preferred embodiments may comprise, for example, three or more sensors arranged together in one recess of a metal block, each of which may be designed as an array of a plurality of individual sensor elements, for example 8 x 8 individual elements. One of these sensors is provided for detecting infrared radiation in the range of the absorption minimum of the analyte to be measured, and one or two of these sensors are provided for detecting infrared radiation in the range of the absorption band of the analyte to be measured. If necessary, further sensors may be provided for reference.

[0064] In yet another embodiment, only the sensor of detection unit (c)(ii), i.e. the infrared sensor, is in thermal equilibrium, whereas the sensor of detection unit (c)(i), i.e. the terahertz sensor, is in an uncooled state.

[0065] Connected to the radiation detection unit (b) are 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 sensor. The temperature measuring element (d)(i) may, for example, be designed as a temperature sensor. For example, an infrared calibrator or a blackbody radiator can be used as the temperature measuring element. The temperature adjusting element (d)(ii) may, for example, be designed as a heating and / or cooling element, in particular a Peltier element.

[0066] Preferably, the temperature adjustment element, for example a Peltier element, has its cooling side facing the radiation detection unit (c) and has a heat dissipation part, for example one or more heat pipes such as a heat pipe or a thermosiphon, on the heating side opposite the radiation detection unit (c). The temperature adjustment element is arranged so as to provide a value for the temperature in the range of the detection unit (c), in particular the terahertz radiation and infrared sensor, which is lower than the value of the core temperature of the body part to be examined, for example the fingertip. Preferably, the temperature of the detection unit is adjusted to a value in the range of 10°C to 25°C and measured using a temperature measurement element. The temperature adjustment and temperature measurement in the detection unit are advantageously performed with an accuracy of up to ±0.1°C or up to ±0.01°C. The measurement of the temperature of the body part to be examined is also advantageously performed with an accuracy of up to ±0.1°C or up to ±0.01°C. Thus, the temperature difference between the terahertz radiation and infrared sensor of the detection unit and the body part to be examined can be determined with high accuracy, for example up to ±0.2° C., or up to ±0.02° C., and this temperature difference is advantageously 1° C. or more, for example 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. Preferably, the temperature difference ranges from about 4° C. to about 40° C., particularly preferably from about 6° C. to about 35° C.

[0067] In one embodiment, an optical focusing element, e.g. a lens element, is arranged in the radiation path between the body part to be examined and the detection unit (c) so that the terahertz radiation irradiated to the body part to be examined, the reflected terahertz radiation and / or the body-specific infrared rays can be focused as point-like as possible on one or more sensors of the detection unit (c).

[0068] Thus, the sensor of the detection unit, i.e. the infrared sensor and / or the terahertz sensor, for example the first sensor and / or the second sensor, can be equipped with an optical focusing element, for example a plano-convex or biconvex lens, in particular a spherical lens, made of a terahertz-transparent material, for example polypropylene, or made of an infrared-transparent material, for example germanium or zinc selenide, whereby the lens diameter can be advantageously adapted to the sensor diameter. The optical arrangement with a narrowed radiation path can increase the yield of the radiation and thus the sensitivity and accuracy of the measurement. Particular preference is given to using sensors, for example bolometers or thermopiles, with biconvex lenses, in particular spherical lenses.

[0069] The device is used to measure glucose, which has characteristic absorption bands in the terahertz range, particularly in the above-mentioned wavelength regions, for example in the region of about 0.1 mm to about 5 mm, about 0.12 to about 5 mm, or about 0.5 mm to about 1 mm, and in the infrared range, particularly in the above-mentioned wavelength regions, for example in the region of about 8 to 12 μm.

[0070] According to the invention, the device is set up for non-invasively measuring glucose in blood, particularly in the capillaries of the dermis.

[0071] The present invention therefore relates to the use of the device for the non-invasive measurement of glucose, in particular for the quantitative measurement of glucose in the blood of a subject.

[0072] When measuring glucose, the terahertz wavelength region includes, in particular, the range of about 0.1 mm to about 5 mm, about 0.12 mm to about 5 mm, or about 0.5 mm to about 1 mm, or subranges thereof. In this range, glucose exhibits multiple absorption bands, with the largest being about 0.2 mm (wavenumber 50 cm -1 0.14-0.17 mm (wave number 60-70 cm -1 ), and about 0.13 mm (equivalent to 80 cm -1 Preferably, the measurement of glucose involves the detection of a broadband spectrum that includes at least two of the above absorption bands, and advantageously all three.

[0073] In the infrared wavelength region, the measurement of glucose includes a first infrared wavelength or a first wavelength range having an absorption minimum of glucose and a second wavelength or a second wavelength range having an absorption band or a part of the absorption band of glucose. 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. In these wavelength regions, glucose has an absorption minimum. The second wavelength may be in or include at least one of the following regions: 9.1±0.3 μm, 9.3±0.3 μm and / or 9.6±0.3 μm, alternatively 9.1±0.2 μm, 9.3±0.2 μm and / or 9.6±0.2 μm, alternatively 9.1±0.1 μm, 9.3±0.1 μm and / or 9.6±0.1 μm. In these wavelength regions, glucose has an absorption band with multiple absorption maxima.

[0074] In a preferred embodiment, the absorption of glucose is measured at two different wavelengths or wavelength ranges that include the absorption band of glucose or part of it, for example in the 9.3 μm region and the 9.6 μm region.

[0075] A further component of the device is a unit (f) for a temperature-compensated evaluation of the signals emitted by the detection units (c)(i) and (c)(ii) and for determining the concentration of the analyte on the basis of the evaluated signals. Advantageously, a joint evaluation of the signals originating from the terahertz detection unit (c)(i) and the infrared detection unit (c)(ii) is performed. The joint evaluation of signals from the terahertz and infrared ranges can have several advantageous effects. On the one hand, weak signals can be amplified to reduce interferences during the measurement and possible measurement errors can be identified and corrected. On the other hand, signals due to interfering substances, which have an absorption band that overlaps with the absorption band of the analyte in one of the two measurement ranges, can be identified and eliminated.

[0076] In a preferred embodiment, the detection unit (c) is arranged to sequentially detect terahertz radiation and infrared radiation, in particular by first detecting the body's inherent infrared radiation without irradiating the body part to be examined, and then irradiating the body part to be examined with terahertz radiation and detecting the reflected terahertz radiation.

[0077] The evaluation of the terahertz signal is based on the fact that a broadband spectrum of glucose is recorded over a given wavelength range in the terahertz region in which there is at least one absorption band of glucose, advantageously at least two or three absorption bands, the strength of which depends on the blood glucose concentration of the subject. The width of the wavelength range is preferably at least around 0.05 mm, or at least around 0.1 mm, and at most 0.2 mm or more.

[0078] The evaluation of the infrared signal is based on the fact that the body's own infrared radiation at a wavelength or wavelength range of the glucose absorption minimum is independent of the glucose concentration present in the subject's blood, whereas the body's own infrared radiation having a wavelength or wavelength range of the glucose absorption band is dependent on the glucose concentration in the subject's blood.

[0079] If the evaluation of the signals is performed under temperature compensation, in particular taking into account the temperature values ​​of the body part to be examined and the sensor of the radiation detection unit (c) measured by the elements (d)(i), (d)(ii), (e)(i) and / or (e)(ii) and adjusted if necessary, it is possible to perform a sufficiently accurate measurement of the glucose concentration on the basis of the difference signal arising from the first and second infrared sensors in combination with the signal of the terahertz sensor. Furthermore, a selective evaluation of infrared radiation arising from blood vessels, for example dermal and / or subcutaneous blood vessels, preferably dermal capillaries, can still be performed.

[0080] Furthermore, a further component of the device is a casing or housing that provides thermal insulation from the environment. Suitable materials for this purpose are plastics that do not or only poorly conduct heat. In this case, the casing or housing may be designed in such a way that the body part to be examined and / or the detection unit (c) introduced into the storage unit (a) are at least substantially electrically and / or thermally insulated from the environment, for example by providing an elastic cover or membrane made of a material that does not or only poorly conducts electricity and / or heat.

[0081] Additionally, the inner surface of the measurement device may be completely or partially coated with or comprise a material that does not reflect terahertz radiation and / or infrared radiation and / or that absorbs terahertz radiation and / or infrared radiation.

[0082] A further aspect of the invention is a method for non-invasively quantitatively measuring glucose in the blood of a subject, comprising the steps of: (i) irradiating a body part originating from a subject with terahertz radiation, in particular terahertz radiation in a wavelength range of about 0.1 mm to about 5 mm, about 0.12 mm to about 5 mm, or about 0.1 mm to about 1 mm, and detecting the reflected terahertz radiation by a unit for detecting terahertz radiation originating from the irradiated body part in a wavelength range in which the intensity of the reflected terahertz radiation varies depending on the glucose concentration; (ii) separately detecting body-specific infrared rays generated from a body part originating from the subject by a unit for detecting infrared rays at at least one first wavelength or a first wavelength range in a wavelength range of about 8 μm to about 12 μm, in which the intensity of the body-specific infrared rays is substantially independent of the glucose concentration, and at least one second wavelength or a second wavelength range in a wavelength range of about 8 μm to about 12 μm, in which the intensity of the body-specific infrared rays varies depending on the glucose concentration, and optionally non-specifically detecting the body-specific infrared rays from a body surface area illuminated for reference, wherein the temperature of the range of the infrared detection unit is lower than the temperature of the body part to be examined; (iii) a step of jointly evaluating the signals detected according to (i) and (ii) taking into account the temperature of the body part to be examined and the temperature in the range of the terahertz radiation unit and the infrared detection unit, optionally with selective evaluation of body-specific infrared radiation arising from capillaries in the dermis of the body part; (iv) determining a glucose concentration based on the evaluated signal. The method includes:

[0083] The method is preferably carried out without an external infrared source, by detecting inherent body infrared radiation from the subject's fingertip, for example, using the device described above, and features specifically disclosed in the context of the device apply equally to the method.

[0084] The device and method are for measuring glucose in blood.

[0085] The present invention will be described in detail below. Human skin is composed of multiple layers, from the outside to the inside, including the stratum corneum, the epidermis having a cornified layer and a germinal layer, the dermis having a papillary layer and a reticular layer, and the subcutaneous layer. There are no blood vessels in the epidermis. There are fine capillaries in the dermis, which are connected to large blood vessels subcutaneously. Arterial pulsation exists in the area of ​​the dermis where the capillaries pass, but there is no arterial pulsation in the skin layers above it, such as the epidermis.

[0086] After irradiating the skin surface with terahertz radiation, the terahertz radiation is reflected from the irradiated body part, at least part of which originates from the area of ​​the dermis where the capillaries pass. The infrared radiation emitted from the skin surface, especially the infrared radiation in the wavelength range of 8-12 μm, also originates at least partly from the area of ​​the dermis where the capillaries pass. Substances having absorption bands in the terahertz and infrared regions present in this range can absorb radiation in this absorption band range, with the degree of absorption being correlated with the concentration of the substance. The reflected terahertz radiation and the body-specific infrared radiation originate from different areas of the body part being examined, with the radiation originating from the epidermis being independent of the arterial pulsation of the subject. In contrast, the radiation originating from the area of ​​the dermis where the capillaries pass has a signal that is dependent on the arterial pulsation of the subject.

[0087] The radiation emitted by the examined body part depends on the temperature, in particular the core temperature, of the examined body part, and therefore the radiation signal measured by the sensor likewise depends on the temperature of the examined body part, but also on the temperature of the sensor itself and therefore on the difference between the temperature, in particular the core temperature, of the examined body part and the temperature of the sensor used to detect the radiation.

[0088] Thus, according to the invention, the measurement signal is evaluated with temperature correction, taking into account the temperature of the examined body part, the temperature of the sensor used for detecting terahertz radiation and infrared radiation, and the difference between the two temperatures. The measurement is carried out under conditions in which the temperature of the examined body part is, for example, at least 1° C., preferably at least 6° C. higher than the temperature of the sensor used for detecting body-specific terahertz radiation and infrared radiation. [Brief description of the drawings]

[0089] [Figure 1] FIG. 2 shows a schematic diagram illustrating the advantage that a joint evaluation of measurement signals from the terahertz and infrared ranges allows a better assignment of the measurement signals to specific analytes and thus an increased accuracy of the measurements. [Diagram 2]FIG. 1 is a schematic diagram illustrating one embodiment of an apparatus. [Diagram 3] FIG. 13 shows a further embodiment of the device. [Figure 4] FIG. 2 is a detailed view of an embodiment of an infrared detection unit. [Diagram 5] FIG. 13 illustrates an alternative embodiment for separately detecting different wavelengths of body-specific infrared radiation. [Figure 6] 4 is a schematic cross-sectional view of a further embodiment of an infrared detection unit of the device; [Figure 7] FIG. 2 shows a particularly preferred arrangement of sensors in an infrared detection unit. [Figure 8] FIG. 2 is a diagram showing a particularly preferred embodiment of a terahertz transmitting and receiving element equipped with a focusing lens. [Figure 9] FIG. 2 shows a particularly preferred embodiment of the evaluation of a terahertz measurement signal.

[0090] FIG. 1 shows a schematic diagram illustrating the advantage that a joint evaluation of measurement signals from the terahertz and infrared ranges allows a better assignment of the measurement signals to specific analytes and thus an increased measurement accuracy.

[0091] Figure 1a shows the absorption spectra in the infrared wavelength range (approximately 8 μm to approximately 10 μm) of alcohol (red), glucose (green), fructose (blue), and an unknown substance (yellow). When using an infrared sensor (e.g., a thermopile) with wavelengths of 8.5 μm (reference wavelength) and 9.6 μm (specific wavelength of the analyte), it is possible to reliably distinguish between glucose and the unknown substance. In contrast, distinguishing between glucose and fructose is problematic. Figure 1b shows the absorption spectra in the terahertz wavelength range of 400 μm to 100 μm (corresponding to 0.5 to 4.0 THz) of glucose (black), fructose (red, dotted line), and an unknown substance (yellow). In the terahertz range, a reliable distinction between glucose and fructose is possible, whereas the absorption spectra of glucose and the unknown substance overlap. Combining the absorption spectra in the infrared and terahertz ranges allows for improved discrimination of the individual substances, thus increasing the measurement accuracy.

[0092] 2 is a schematic diagram of an embodiment of the device. The device comprises a terahertz radiation source (100), for example a femtosecond laser with a wavelength of 800 nm, whose radiation first passes through a semi-transparent beam splitter (102) where it is split into partial beams (104a) and (104b). The partial beam (104a) is converted in a mixer (106), for example a gallium arsenide crystal, into terahertz radiation (108), which is directed through an optical device (110), for example a prism, to the body part (112) to be examined, for example a fingertip. The radiation reflected from the body part is directed through the optical element (110), a further mixer (114), for example a gallium arsenide crystal, and possibly a further semi-transparent beam splitter (116), to a terahertz sensor (118), for example a photodiode arranged to detect the spectrum in the terahertz range. The partial beam (104b) emerging from the beam splitter (102) can be directed, if necessary via a delay element (120), to a mixer (114) and from there to a photodiode (118) for reference. Furthermore, the device comprises an infrared detection unit (120) with one or more infrared sensors arranged to detect body-specific infrared radiation emerging from the body part (112) to be examined. The measurement signals emerging from the infrared sensor (120) are sent to an evaluation unit (124), for example a CPU. In this unit (124), evaluation is carried out in combination with the measurement signal emerging from the terahertz sensor (118), after a fast Fourier transformation, if necessary, in a unit (128). In the evaluation unit (124), a value (126) of the concentration of an analyte, for example glucose, is determined from the combination of the terahertz measurement signal and the infrared measurement signal, which can then be appropriately displayed, for example by means of a display (not shown).

[0093] Furthermore, the device comprises a support element (130), e.g. a metal support, e.g. copper, provided for housing at least the infrared detection unit (120) and possibly further 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 in order to allow a temperature-compensated measurement of the infrared signal and possibly the terahertz signal.

[0094] 3 shows a further embodiment of the device. The device comprises a terahertz transceiver chip (200), which is arranged to emit terahertz radiation (202) towards a body part (204) to be examined, for example a fingertip, and to detect terahertz radiation (206) reflected therefrom. Measurement signals originating from the chip (200) are sent via a fast Fourier transform unit (210) to an evaluation unit (212), for example a CPU. The device further comprises at least one infrared sensor (214) for detecting body-specific infrared radiation (216) originating from the body part (204) to be examined. The measurement signals detected by the at least one infrared sensor (214) are sent to the evaluation unit (212) where they are evaluated in combination with the terahertz measurement signals.

[0095] A detailed view of one embodiment of the infrared detection unit is shown in Figure 4. The body part (14) of the subject to be examined is introduced into the device.

[0096] Here, preferably a body part with good circulation is selected, for example a fingertip. The body part (14) rests on a support element (16), which is thermally insulated and comprises an area (16a) that is at least partially optically transparent to the infrared radiation (20) emitted by the body part (14), i.e. at least in the range of the measuring wavelengths. The support element (16) comprises means (16b) for measuring the temperature of the body part (14) to be examined, for example a fingertip, for example a temperature sensor. Furthermore, means for detecting and / or controlling the support position and / or the support pressure of the body part to be irradiated, for example a sensor, may be present (not shown). Furthermore, the support element can comprise a temperature regulating element (not shown).

[0097] The infrared radiation (20) emanating from the body part (14) to be examined originates, at least in part, from the near-surface capillaries in the region of the dermis (18) at a distance of about 2.5-3 mm from the body surface. Analytes present in the capillaries, or possibly in adjacent tissue, absorb radiation within their specific absorption bands, with the degree 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 body-specific infrared radiation (20) of different wavelengths or wavelength ranges, preferably in the region of 8-12 μm. The first and second sensors may be designed as bolometers or thermopiles. If appropriate, the first and second sensors may also consist of an array of, for example, 8×8 individual sensor elements.

[0099] The first sensor (22a) is arranged to selectively detect body-specific radiation having a first wavelength or a first wavelength range in the absorption minimum of glucose, with a first filter element (24a) selectively transmitting radiation having the first wavelength or the first wavelength range. That is, the signal measured by the first sensor is substantially independent of the glucose concentration. The second sensor (22b) is also arranged to selectively detect body-specific radiation (20) having a second wavelength or a second wavelength range in the absorption band in the range of the absorption maximum of glucose, with a second filter element (24b) selectively transmitting radiation having the second wavelength or the second wavelength range. That is, the signal detected by the second sensor depends on the glucose concentration. If necessary, there may be two or more second sensors capable of detecting radiation having different wavelengths or wavelength ranges. For example, two second sensors can be used for measuring glucose, which separately detect infrared radiation in the ranges of 9.1 μm and 9.6 μm, respectively.

[0100] The filter elements (24a, 24b) are advantageously arranged to be mounted directly on the respective sensors (22a, 22b).

[0101] Optionally, the device further comprises a third sensor (22c) arranged to non-specifically detect the body's own infrared radiation (20) and used for reference, for example, to reference the body temperature of the body part (14) to be examined.

[0102] To enable focusing of the resulting body-specific infrared radiation, the sensors (22a, 22b and, optionally, 22c) may optionally be equipped with optical lens elements, for example biconvex lenses, in particular spherical lenses.

[0103] The sensors (22a, 22b, and optionally 22c) are in thermal equilibrium, whereby they are in contact with or embedded in a block (32) made of conductive material, e.g. metal, e.g. by being placed in a recess in the block, or the thermally conductive material may be formed as a plate or foil.

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

[0105] The signals arising from the sensors (22a, 22b, and optionally 22c) and the temperatures measured by the elements (16b) and (26) are sent to a CPU unit (30), whereupon the temperatures of the sensors (22a, 22b, and 22c) are adjusted, if necessary, to a value lower than the temperature of the body part to be examined and a temperature-compensated evaluation of the signals is carried out. On the basis of this evaluation the glucose concentration is determined. The results can then be displayed on a display (32).

[0106] The inner surface (34) of the measurement system may be completely or partially covered with or provided with a surface made of a material that does not reflect infrared radiation (20) emanating from the body part (14) and / or that absorbs infrared radiation (20) emanating from the body part (14).

[0107] The measurement system may further comprise a casing or housing that provides electrical and / or thermal insulation from the environment.

[0108] An alternative embodiment for separately detecting body-specific infrared radiation of different wavelengths is shown in FIG. 5. The absorption curve of glucose in the 8-14 μm region is shown by the thick line (G). To separately detect infrared radiation with two different wavelengths from this region, two sensors are used that include different combinations of band-pass, high-pass and / or low-pass filter elements. In one embodiment, both sensors include a wide band-pass filter (C) that is transparent in the 8-14 μm region. In the first sensor, the filter (C) is combined with a high-pass filter (A) that transmits infrared radiation with wavelengths of approximately 8.5 μm or less. Thus, the sensor with filters (A) and (C) detects a signal from the 8-8.5 μm region that is substantially independent of the glucose concentration. The second sensor includes a combination of a band-pass filter (C) and a low-pass filter (B) that transmits infrared radiation with wavelengths of 8.5 μm or more. The signal detected by this sensor includes the absorption band of glucose localized in the region of approximately 9-10 μm and therefore depends on the glucose concentration. The glucose concentration can be determined by differentially evaluating the signals detected by both sensors.

[0109] In another embodiment, the first sensor may also be equipped with a band-pass filter (C) and a high-pass filter (A), while the second sensor is equipped with only a band-pass filter (C). The signal detected by the first sensor is independent of the glucose concentration, while the signal detected by the second sensor varies with the glucose concentration.

[0110] FIG. 6 shows a schematic cross-sectional view of a further embodiment of the infrared detection unit of the device. Here, the body part of the subject to be examined (not shown) is arranged on a thermally insulating support element (66) which comprises an area (66a) which is at least partially optically transparent to infrared radiation. For example, the optically transparent area (66a) is a plate of Si or Ge. The support element (66) comprises a temperature sensor (66b) and optionally a temperature adjustment element (not shown), preferably comprising a Peltier element. In that case, for example, the temperature of the body part can be adjusted to a range of about 28-38°C. Preferably, the support element (66) comprises a means for detecting and / or controlling the support pressure, for example a sensor (68) such as a load cell, and optionally a sensor for detecting and / or controlling the support position, for example a camera and / or a pulse sensor. Advantageously, the support pressure is adjusted to about 1-50 N, for example to about 20 N.

[0111] The device further comprises a first infrared sensor (70a) and a second infrared sensor (70b) for detecting body-specific infrared radiation (72) having different wavelengths in the range of 0.7 to 20 μm, preferably 3 to 20 μm, originating from the examined body part. The first and second sensors may each be designed as a bolometer or a thermopile. If appropriate, the first and second sensors may consist of an array of individual sensor elements.

[0112] The first sensor (70a) may, for example, be arranged to selectively detect body-specific infrared radiation having a first wavelength at which the analyte has an absorption minimum, with a first filter element (74a), for example a band-pass filter with a narrow transmission, being provided which selectively transmits radiation having a first wavelength whose signal is substantially independent of the concentration of the analyte to be measured. In the case of the measurement 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, particularly preferably 8.1±0.2 μm and / or 8.5±0.1 μm. The second sensor (74b) is also arranged for selectively detecting body-specific infrared radiation (72) having a second wavelength in an absorption band preferably in the range of the absorption maximum of the analyte to be measured, with a second filter element (74b), for example a band-pass filter with narrow transmission, being provided, which selectively transmits radiation having the second wavelength. In the case of the measurement of glucose, the second wavelength is, for example, in the range of 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, particularly preferably 9.1±0.1 μm, 9.3±0.1 μm and / or 9.6±0.1 μm. If necessary, there may be two or more second sensors capable of detecting radiation having different wavelengths or wavelength ranges. For glucose measurements, two second sensors may be used that separately detect infrared radiation in the ranges of, for example, 9.1 μm or 9.3 μm and 9.6 μm, respectively.

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

[0114] It is also possible to use, instead of narrow bandpass filters, a combination of wide bandpass filters and high-pass and / or low-pass filters, as shown in FIG.

[0115] An optical focusing element, e.g. a lens element, may be arranged in the radiation path of the body-specific infrared radiation (72) between the body part to be examined and the sensors (70a, 70b, and optionally 70c). For example, in order to enable focusing of the resulting body-specific infrared radiation, the sensors (70a, 70b) may, if desired, be equipped with an optical lens element, e.g. a biconvex lens, in particular a spherical lens.

[0116] Optionally, the device further comprises a third sensor (70c), which is arranged for non-specific detection of body-specific infrared radiation (72) and is used for reference, for example to reference the body temperature of the body part to be examined. The third sensor (70c) may be designed as a bolometer or a thermopile.

[0117] If necessary, an intermediate wall (78) may be disposed between the first sensor (70a) and the second sensor (70b).

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

[0119] Additionally, there are elements (80), e.g., temperature sensors, for measuring the temperature of the block (76) containing the sensors (70a, 70b, and 70c), and elements (82), e.g., cooling and / or heating elements, for regulating the temperature of the block (76) containing the sensors (70a, 70b, and 70c).

[0120] The signals arising from the sensors (70a, 70b, and optionally 70c) and the temperatures measured by the elements (66b) and (80) are sent to a CPU unit (84) for a temperature-compensated evaluation of the signals. Based on this evaluation, the concentration of the analyte is determined and the results can then be displayed on a display (86). Furthermore, the CPU unit can also be used for controlling the elements (68, 82).

[0121] If appropriate, the inner surfaces of the measurement system may be coated with a material that does not reflect infrared radiation and / or absorbs infrared radiation. Furthermore, the measurement system may exhibit thermal insulation from the environment.

[0122] A particularly preferred arrangement of sensors in the infrared detection unit is shown in FIG. 7. Here, there are four infrared sensors (90a, 90b, 90c, 90d), which are arranged together in a recess in a metal block (not shown) and are therefore in thermal equilibrium. Preferably, each sensor consists of a plurality, for example an 8×8 array of individual sensor elements. The sensors (90a, 90b) are provided for selectively detecting infrared radiation having a wavelength in the absorption band of the analyte to be measured and are therefore provided with corresponding filter elements. For the measurement of glucose, a sensor (90a) may be provided for selectively detecting infrared radiation having a wavelength of about 9.6 μm, for example 9.6±0.1 μm, and a sensor (90b) for selectively detecting infrared radiation having a wavelength of about 9.1 μm, for example 9.1±0.1 μm or about 9.3 μm, for example 9.3±0.1 μm. The sensor (90c) is provided for selectively detecting infrared radiation having a wavelength in the absorption minimum of the analyte to be measured and is therefore provided with corresponding filter elements. For the measurement of glucose, a sensor (90c) may be provided that selectively detects infrared radiation having a wavelength of about 8.5 μm, for example 8.5±0.1 μm. Sensor (90d) has no filter element and is used for reference.

[0123] A particularly preferred embodiment of a terahertz transceiver element with a focusing lens is shown in Figure 8. The terahertz transceiver element (100) comprises a terahertz radiation source (102), for example an antenna, and a terahertz detection unit (104).

[0124] Terahertz radiation (106) emitted from the radiation source (102) is directed through a focusing lens (108), for example a spherical lens, which is made of a material that is transparent to terahertz radiation, for example polypropylene.

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

[0126] A particularly preferred embodiment of the evaluation of the terahertz measurement signal is shown in figure 9. The terahertz signal is modulated in frequency in a range (f0...f1) which includes the absorption band of glucose as the analyte to be measured. The modulation can be continuous, for example by a voltage change by a voltage controlled oscillator (VCO), or discontinuous.

[0127] The frequency modulated terahertz signal reaches an antenna, for example a patch antenna (PA), where it is radiated towards the body part (K) to be examined, for example a finger. This can be done through a lens (see for example Fig. 8) or a waveguide. There the terahertz radiation is reflected and reaches a sensor (S), for example a patch antenna or a dipole, and from there to a preamplifier, for example an LNA.

[0128] The signal is then sent to a mixer (X), where the received and transmitted signals are multiplied. The received signal has a different path length than the transmitted signal, based on the path it takes to the body part and back. In addition to the frequency modulation, the received and transmitted signals have different path lengths and travel times, resulting in a frequency difference in the mixer that is proportional to the difference in travel times (e.g., a path length difference of about 50 mm corresponds to a time difference of 166 psec). This results in a mixed signal (sin(fa)*(fb)=sin(fa+fb) and sin(fa-fb)), the difference of which is the useful signal, which is further amplified by the amplifier (AMP). One or more phases of the signal are sent to an A / D converter and evaluated by the CPU.

[0129] The evaluation preferably includes a Fast Fourier Transform (FFT) performed successively to eliminate unwanted interfering signals. Thus, at higher frequencies (f0...f1), different spectra are generated by the input voltage controlled by the THz transmitter. The signals corresponding to the round trip radiation path to the capillary layer can be identified and measured by their characteristic time difference. In this way, a characteristic curve corresponding to the reflection and absorption spectrum of glucose in the capillaries is obtained. By comparative measurement of the absorption maximum and minimum of glucose, the glucose content in the capillaries is obtained.

[0130] As an alternative to frequency modulation, it is also possible to irradiate the terahertz signal as a pulse-modulated signal to the body part to be examined, with signal pulses, in particular individual signal pulses each having a different frequency, being irradiated at defined time intervals.

Claims

1. 1. A method for non-invasively quantitatively measuring glucose in the blood of a subject, comprising: (i) irradiating a body part originating from a subject with terahertz radiation, in particular terahertz radiation in a wavelength range of about 0.1 mm to about 5 mm, about 0.12 mm to about 5 mm, or about 0.1 mm to about 1 mm, and detecting the reflected terahertz radiation by a unit for detecting terahertz radiation originating from the irradiated body part in a wavelength range in which the intensity of the reflected terahertz radiation varies depending on the glucose concentration; (ii) separately detecting body-specific infrared rays generated from a body part originating from the subject by a unit for detecting infrared rays at at least one first wavelength or a first wavelength range in the wavelength range of about 8 μm to about 12 μm, in which the intensity of the body-specific infrared rays is substantially independent of the glucose concentration, and at least one second wavelength or a second wavelength range in the wavelength range of about 8 μm to about 12 μm, in which the intensity of the body-specific infrared rays varies depending on the glucose concentration, and optionally non-specifically detecting body-specific infrared rays from a body surface area illuminated for reference, wherein the temperature of the range of the infrared detection unit is lower than the temperature of the body part to be examined; (iii) a step of jointly evaluating the signals detected according to (i) and (ii) taking into account the temperature of the body part to be examined and the temperature in the area of ​​the terahertz radiation unit and the infrared detection unit, optionally with selective evaluation of body-specific infrared radiation originating from capillaries in the dermis of the body part; (iv) determining a glucose concentration based on the evaluated signal; wherein said glucose measurement is preferably performed by detecting the body's inherent infrared radiation emanating from the subject's fingertip without excitation by an external infrared source.

2. The steps (i) and (ii) (a) a unit for containing a body part to be examined from said subject; (b) a radiation source generating terahertz radiation for irradiating the examined body part, in particular terahertz radiation in a wavelength range of about 0.1 mm to about 5 mm, about 0.12 mm to about 5 mm, or about 0.1 mm to about 1 mm; (c) a unit for detecting radiation emanating from said body part to be examined, comprising: (i) a unit for detecting terahertz radiation reflected from the body part to be examined, the unit being arranged to detect terahertz radiation in a wavelength range in which the intensity of the reflected terahertz radiation varies depending on the glucose concentration; (ii) a unit for detecting body-specific infrared radiation emanating from the body site to be examined, the unit being configured for separately detecting infrared radiation of at least two different wavelengths or wavelength ranges in a wavelength region of about 8 μm to about 12 μm, where at a first wavelength or first wavelength range, the intensity of the body-specific infrared radiation is substantially independent of glucose concentration, and at a second wavelength or second wavelength range, the intensity of the body-specific infrared radiation varies with glucose concentration, the unit being optionally further configured for non-specific detection of the body-specific infrared radiation; (d) (i) an element for measuring the temperature of the body part to be examined; (ii) optionally an element for regulating the temperature of the body part to be examined; (e) (i) an element for measuring the temperature of said detection unit (c); (ii) an element for adjusting the temperature of the detection unit (c), the element being designed so that the temperature of the detection unit (c) is lower than the temperature of the body part to be examined; (f) a unit arranged for temperature-compensated evaluation of a signal arising from said detection unit (c) and for determining a glucose concentration based on the evaluated signal, said unit optionally arranged for selectively evaluating body-specific infrared radiation arising from capillaries in the dermis of said body part. The method of claim 1 , wherein the method is performed using an apparatus comprising:

3. The method described in claim 2, wherein the radiation source (b) generating the terahertz radiation comprises an antenna, in particular a patch antenna or a dipole antenna, and is preferably arranged to emit frequency-modulated or pulse-modulated terahertz radiation.

4. A method as described in claim 2 or 3, wherein a focusing lens, such as a spherical lens, an aspherical lens or a Fresnel lens, is arranged in a radiation path between a radiation source (b) generating the terahertz radiation and the body part to be examined, the focusing lens being made of a material that is substantially transparent to the terahertz radiation, and the focusing lens is preferably installed to focus the radiation generated by the terahertz radiation (b) into a predetermined zone of the body part to be examined, in particular a zone containing capillaries.

5. A method as described in any one of claims 2 to 4, wherein the unit (c)(i) is arranged for detecting a broadband spectrum in the terahertz range, in particular in a frequency range of about 0.12 mm to about 5 mm (corresponding to 60 GHz to about 2.5 THz), and / or the unit (c)(i) is arranged for producing a single-stage or multi-stage amplification, in particular a two-stage amplification, of the terahertz radiation reflected from the body part to be examined.

6. A method as described in any one of claims 2 to 5, wherein the unit (c)(i) is arranged for combined detection of terahertz radiation reflected from the body part to be examined and terahertz radiation irradiated to the body part to be examined, in which the unit (c)(i) is arranged in particular for detecting a frequency modulated or pulse modulated signal.

7. A method as described in any one of claims 2 to 6, wherein the apparatus does not have an external infrared generating source.

8. A method as described in any one of claims 2 to 7, wherein the unit (a) for accommodating the body part to be examined comprises an element supporting the body part to be examined which is at least partially thermally insulating with respect to the radiation detection unit (c), the element including a range which is transparent to terahertz radiation, in particular terahertz radiation of about 0.12 mm to about 5 mm (corresponding to about 60 GHz to about 2 THz) or any sub-range thereof, and which is transparent to infrared radiation, in particular in the wavelength region of about 8 μm to 12 μm or any sub-range thereof.

9. A method as described in any one of claims 2 to 8, wherein the unit (a) accommodating the body surface area to be examined is provided with means, e.g. a sensor, for detecting and / or controlling the support position and / or support pressure of the body part to be examined, in particular with means for detecting and / or controlling a support pressure in the range of approximately 0.5 to 100 N, preferably in the range of approximately 1 to 50 N, particularly preferably approximately 20 N.

10. The method of any one of claims 2 to 9, wherein the unit (c)(ii) for detecting the body-specific infrared rays comprises at least one first sensor, at least one second sensor, and optionally at least one third sensor, the first sensor being arranged to detect infrared rays having a first wavelength or wavelength range in a region of about 8 μm to about 12 μm, in which the intensity of the body-specific infrared rays is substantially independent of glucose concentration, the second sensor being arranged to detect infrared rays having a second wavelength or second wavelength range in a region of about 8 μm to about 12 μm, in which the intensity of the body-specific infrared rays varies depending on the glucose concentration, and the third sensor being arranged to refer to the body-specific infrared rays, and the unit (c)(ii) for detecting the body-specific infrared rays preferably comprises two or more second sensors arranged to detect infrared rays of different wavelengths or wavelength ranges in which the intensity of the body-specific infrared rays varies depending on the glucose concentration.

11. The method described in any one of claims 2 to 10, wherein the radiation detection unit (c) is in contact with a thermally conductive support, and in particular, the terahertz radiation detection unit (c)(i) and the infrared detection unit (c)(ii) are in contact with the same thermally conductive support.

12. A method described in any one of claims 2 to 11, wherein a temperature within the detection unit (c) is provided that 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 part to be examined.

13. A method as described in any one of claims 2 to 12, wherein the apparatus is provided for sequentially detecting terahertz radiation and infrared radiation, in particular by first detecting body-specific infrared radiation without irradiating the body part to be examined, and then irradiating the body part to be examined with terahertz radiation and detecting reflected terahertz radiation.

14. The method according to any one of claims 2 to 13, wherein the unit (f) is provided for a temperature-compensated evaluation of signals based on temperature values ​​measured by the elements (d) and / or (e) and adjusted as necessary, and / or the unit (f) is provided for a combined evaluation of signals arising from the terahertz detection unit (c)(i) and the infrared detection unit (c)(ii).

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