Measuring device for the non-invasive determination of blood glucose concentration in the body of a mammal

Abstract

The invention relates to a measuring device for the non-invasive determination of blood glucose concentration in the body of a mammal, comprising: • A housing (G), • Measuring electronics (IC) in the housing (G), wherein the measuring electronics (IC) further comprises: • At least one transmitter (Tx) for emitting high-frequency signals with a frequency of more than 0.1 THz and less than 10 THz, • At least one receiver (Rx) for receiving high-frequency signals with a frequency of more than 0.1 THz and less than 10 THz, • wherein the at least one transmitter (Tx) is designed such that, during operation, it emits the high-frequency signal via an antenna (ANT_Tx) integrated in the measuring device. • wherein the at least one receiver (Rx) is designed such that, during operation, it receives a high-frequency signal via an antenna (ANT_Rx) integrated in the measuring device.• The measuring device is configured to be attached relative to a nail plate (NP) on a nail of a finger or toe of the mammal, • The high-frequency signals from at least one transmitter (Tx) are coupled through the nail plate (NP) into the nail bed (NB) of the mammal during operation, and the high-frequency signals backscattered from the nail bed (NB) of the mammal through the nail plate (NP) during operation are received by at least one receiver (Rx), • The measuring device further comprises an evaluation unit (CPU) configured to evaluate the backscattered high-frequency signals received by at least one receiver (Rx) in order to determine the blood glucose concentration in the body of a mammal.

Description

The invention relates to a measuring device for non-invasive determination of a blood sugar concentration in the body of a mammal.BACKGROUND OF THE INVENTIONFor diabetic humans as well as, for example, for performance sportsrs, knowledge of the current blood sugar level is important. Diabetes is an enormous problem because it is now assumed that every tenth adult human suffers diabetes worldwide.Blood glucose is often measured by invasive methods, in which one drop of blood is obtained from a blood vessel. For this purpose, the skin and an underlying venous blood vessel are normally punctured with a lancet, whereupon blood escapes. The blood drop is then placed on a test element for further evaluation. These methods include, for example, the amperometric measuring method.Such invasive procedures, however, are disadvantageous in several respects. On the one hand, even with good hygiene, there is always the risk that viruses or bacteria penetrate into the skin and / or the blood vessel system at the puncture site, and on the other hand, the repeated puncturing also provides damage to the vessel, so that after a series of puncturings at the same location the vessel can no longer be punctured. Moreover, invasive acquisition also constitutes a psychological problem. Generally, quality of life suffers.Against this background, approaches have already been sought in the past which allow a non-invasive determination of a blood sugar concentration in the body of a mammal.Exemplary methods that have been theoretically described for this are methods that are based on dielectric spectroscopy.Reference is made here by way of example to the article "Pendra goes Duty: lessons for the CE mark in Europe" by the authors I. M. E. Wentholt, J. B. L. Hoekstra, A. Scheidt and J. H. DeVries published in Diabetologia (2005) 48: 1055-1058, DOI 10.1007 / s00125-005-1754-y, "First human experiments with a novel non-invasive, non-optical continuous glucose monitoring system" by the authors A. Caduff, E. Hirt, Yu. Feldman, Z. Ali, and L. Heinemann, published in Biosensors and Bioelectronics 19 (2003) 209 / 217, as well as "Non-invasive glucose monitoring in patients with diabetes: A novel system based on impedance spectroscopy" by the authors A. Caduff, F. Dewarrat, M. Talary, G. Satlder, L. Heinemann and Yu. Feldman, published in Biosensors and Bioelectronics 22 (2006) 598-604, which describe impedance spectroscopy in the frequency range 1-200 MHz at the skin surface.Also exemplary are approaches using special stray field contact electrodes and multi-scale numerical skin models as described in the article "Sensitivity and specificity analysis of framing-field dielectric spectroscopy applied to a multilayer system modelling the human skin" by the authors Sonja Huclova, Dirk Baumann, Mark S Talary and Jurg Frohlich, published in Phys. Med. Biol. 56 (2011) 7777-7793 doi:10.1088 / 0031-9155 / 56 / 24 / 007 or "PENDRA: The Once and Future Noninvasive Continuous Glucose Monitoring Device?" of the author STUD ALAN WEINZIMER, published in DIABETES TECHNOLOGY & THERAPEUTICS, Volume 6, Number 4, 2004, pages 442-444.These approaches have been shown to be difficult to implement because the environmental variations (humidity, perspiration, etc.) of the dielectric function of the outermost skin layer (stratum corneum) are too great for a precise estimation of the blood sugar level.Further approaches, such as GHz transmission measurements, allow noninvasive glucose measurement by means of transmission and reflection measurement at frequencies around 30 GHz. The greatly varying outermost skin layers can thus be calibrated out (de-embedding) in principle. A sensor clamp for transmission measurements through the ear lobe or thumb-index finger skin fold has already been developed, see the article "Compact Non-Invasive Millimeter-Wave Glucose Sensor" by the authors Peter H. Siegel, Adrian Tang, Gabrile Viribia, Yanghyo Kim, M.C. France Chang and Victor Pikov, published in 2015 40th International Conference on Infrared, Millimeter, and Terahertz waves (IRMMW-THz), Hong Kong, China, 2015, pp. 1-3, doi: 10.1109 / IRMMW-THz.2015.7327413. and is also the subject matter of a U.S. Pat. No. 11,229,383 B2.Still further alternative approaches relate to THz transmission measurements in which, coupled with prisms, the insertion loss is measured by means of THz-TDS along the skin surface as a function of the glucose content, see, for example, the article "Noninvasive blood glucose monitoring in the terahertz frequency range" by the authors Olga Cherkasova, Maxim Nazarov, and Alexander Shkurinov, developed light in Opt Quant Electron (2016) 48:217 DOI 10.1007 / s11082-016-0490-5.A further optical approach is multi-spectral sensing by means of a portable arrangement consisting of a plurality of IR to multi-coloured LED sources with a photodetector for multi-spectral transmission measurements placed next to them on the skin surface, as is known from the article "Wearable-band type visible-near infrared optical biosensor for non-invasive blood glucose monitoring" by the authors Vega Pradana Rachim and Wan-Young Chung, published in Sensors & Actuators: B. Chemical 286 (2019) 173-180.Also known is the photo-thermal measurement of the glucose content, in which light heats the glucose molecules in the skin very specifically, followed by a temperature measurement. Such devices from DiaMon Tech AG, Berlin with various form factors (table device, pocket sensor, arm-wrist sensor) are currently in the testing phase.The problem with all approaches is the great variation in the electrical / optical behavior of the outermost skin layer. At this time, not only the large variation of the outermost skin layer itself but also the interface between a sensor and the outermost skin layer becomes adversely noticeable by, for example, sweat, moisture, etc.In the approaches based on a transmission measurement in the GHz range, a force-fit measurement clamp is also required.Other methods could in principle provide improvement, but require a considerable amount of compensation and / or computing effort.Proceeding from this situation, it is an object of the invention to provide a measuring device for non-invasively determining a blood sugar concentration in the body of a mammal, which measuring device makes it possible to measure a blood sugar concentration in the body of a mammal in a precise non-invasive manner.The object is achieved by a device according to claim 1.The invention is explained in more detail below with reference to the figures. In these, the following shows: FIG. 1 shows a basic structure of a finger with a bed of nails and a bed plate of a human being, FIG. 2 shows an exemplary schematic bistatic embodiment of the invention, FIG. 3 is an exemplary schematic monostatic embodiment of the invention; and FIG. 4 shows, by way of example, schematic functional units of a measuring device according to the invention.The invention will be illustrated in more detail below with reference to the figures. It should be noted that different aspects are described, which can be used individually or in combination. That is, any aspect may be used with various embodiments of the invention unless explicitly shown as a mere alternative.Furthermore, for the sake of simplicity, only one entity will normally be referred to below. If not explicitly stated, however, the invention can also have in each case a plurality of the entities concerned. In this respect, the use of the words "a", "an" and "an" is to be understood only as an indication that at least one entity is used in a simple embodiment.Insofar as methods are described below, the individual steps of a method can be arranged and / or combined in any order, unless the context explicitly reveals some variation. Furthermore, unless expressly stated otherwise, the methods can be combined with one another.Details with numerical values are generally not to be understood as exact values but also include a tolerance of + / - 1% up to + / - 10%.References to standards or specifications are to be understood as references to standards or specifications that apply / are considered at the time of application and / or-insofar as priority is claimed-at the time of priority application. However, this should not be understood as a general exclusion of applicability to subsequent or replacing standards or specifications.FIG. 4 schematically shows functional units of a measuring device according to the invention for non-invasive determination of a blood sugar concentration in the body of a mammal. Mammal is to be understood as human in particular, but use on the animal is likewise not excluded.The measuring device according to the invention has a housing G and a measuring electronics IC, which can consist, for example, of one or more integrated circuits or one or more photonic integrated circuits or a combination of both, in the housing G.The electronic measurement system IC furthermore has a transmitter Tx for emitting high-frequency signals with a frequency of more than 0.1 THz and less than 10 THz and a receiver Rx for receiving high-frequency signals with a frequency of more than 0.1 THz and less than 10 THz, wherein the transmitter Tx is designed such that, during operation, it emits the high-frequency signal via an antenna ANT_Tx integrated in the measuring device on-chip or in the housing G, and wherein the receiver Rx is designed such that, during operation, it receives a high-frequency signal via an antenna ANT_Rx integrated in the measuring device on-chip or in the housing G.The measuring device, i.e. the housing G with the measuring electronics IC, is configured to be fastened to a finger or toe of the mammal relative to a nail plate NP. Attachment may be provided by gluing (e.g., with plaster), clamping (e.g., a fastener disposed on the housing G), winding (e.g., dressing, elastic tape), etc.During operation of the measuring device, the high-frequency signals from the transmitter Tx are coupled into the nail bed NB of the mammal by means of the integrated antenna ANT_Tx through the nail plate NP. The high-frequency signals backscattered from the nail bed NB of the mammal through the nail plate NP during operation are recorded by the receiver Rx by means of the integrated antenna ANT_Rx.Furthermore, the measuring device has an evaluation device CPU which is configured to evaluate the backscattered high-frequency signals received by the receiver Rx in order to determine the blood sugar concentration in the body of a mammal.Furthermore, the measuring device has an interface to an external device, e.g. to a computer or a mobile telephone or another display device (e.g. display), which can display the measured values.By means of the measuring device according to the invention, a non-invasive blood sugar determination is made possible by means of high-frequency reflection measurements and in particular THz reflection measurements of the perfused nail bed through the nail plate NP of the nail (e.g. toenail or fingernail). The method is based on the glucose-dependent reflection measurement method and allows the glucose concentrations or their changes in the well perfused nail bed NB lying underneath to be determined.The invention makes use of the fact that, unlike on the skin on the ear / ear lobe or on a skin fold, the nail bed is as a rule particularly well perfused, while no perspiration forms at the interfaces and it is moreover as a rule dimensionally stable, so that the classic problems from the prior art can be avoided. In addition, the invention permits an extremely compact and stable construction.In particular, the nail bed NB has a much simpler tissue layer structure compared to the skin (growth zone and nail bed matrix), which is much more strongly and more tightly perfused, since the nail bed is rich in blood and lymphatic vessels. Thus, the safety of encountering blood-and thus also glucose-is significantly higher.In addition, the nail bed NB is very smooth and well defined at the interface to the nail plate NP and, unlike the skin, does not have any pores, wrinkles, hurches or sweat glands. Possible modifications of the fingernail or toenail, such as nail varnish or artificial fingernails, are usually made of terahertz-transparent materials, so that this does not restrict the measuring ability, or only slightly limits it.Furthermore, the nail bed NB is naturally protected from environmental influences by the fingernail plate NP. Thus, the variations of the nail bed NB at the interface with the nail plate NP are significantly reduced compared to variations at the skin surface.In addition, a simpler construction can be provided by means of reflectometry in comparison with transmission / reflection measurement.The use of high frequencies and in particular THz frequencies is advantageous because the nail bed NB, viewed through the fingernail plate NP, has an absorption maximum in the frequency range of 0.2-0.4 THz.Likewise, at these frequencies, simple integrated antennas ANT_Tx and ANT_Rx can be integrated together with the transmitter Tx and the receiver Rx on the electronic measurement system IC, so that particularly compact measuring devices of different sizes can also be provided. The arrangement in a measurement electronics IC also allows embodiments which are permanently in moist / wet environment, so that e.g. a float / plunger can also continuously measure its blood sugar level. Unlike in the case of optical sensors, no optical window is required in this case either. Thus, the measuring device according to the invention is durable and usable all the way around.The invention makes it possible in particular also to provide very broadband and / or multi-frequency measurements for increasing the sensitivity. In this case, other parameters such as, for example, inflammation markers (leukocyte density, interleukin, etc.) can also be determined on the basis of the same measurement principle. More details on this subject can be found in the article (not yet published) "Non-invasive, easy to implement glucose sensing via the finger-like bed using THz radiation" by the authors Mandana Jalali, Andreas Prokscha, Yijun Yun, Tobias Kubiczek, Thomas Kaiser, Jan Balzer, and Daniel Ern in Biomedical Engineering / Biomedical Technology, 2023.Using known / measured dielectric functions (permittivity, conductivity) of the layers of a fingernail, a material model can be created using a multipolar Cole-Cole model for both the nail plate NP and the nail bed NB.In one embodiment of the invention, a first focusing or matching element L 1 (FIG. 2 ) or L 12 (FIG. 3 ) is arranged downstream of the antenna of the transmitter ANT_Tx, which focusing or matching element is irradiated before high-frequency signals enter the nail bed NB during operation.In a further embodiment of the invention, a second focusing or matching element L2 (FIG. 2) or L12 (FIG. 3) is arranged in front of the antenna of the receiver ANT_Rx, which element is irradiated during operation by the signals backscattered from the nail bed NB.According to one embodiment of the invention, the focusing or adapting element L 1 and / or the focusing or adapting element L 2 or L 12 (FIG. 3 ) comprises an environment-resistant plastic, in particular polymethylpentene, or a material with low absorption of the frequency range used during operation, in particular high-resistivity silicon.According to yet another embodiment of the invention - see Fig. 3 - the transmitter Tx and the receiver Rx is realized as a component Tx / Rx to emit and receive signals of more than 0.1 THz and less than 10 THz.In yet another embodiment of the invention, the antenna ANT_Tx for emitting the high-frequency signal integrated in the measuring device is at the same time also configured as an antenna ANT_Tx for reception integrated in the measuring device. In FIG. 3, this common antenna is denoted as ANT_TxRx.In yet another embodiment of the invention, the focusing or adapting element L 1 integrated in the measuring device for emitting the high-frequency signal is at the same time also configured as a focusing or adapting element L 2 for reception. In Fig. 3, this common element is denoted as L12.According to a further embodiment of the invention, the underlying measurement principle in monostatic operation is a THz reflectometry (FIG. 3 ).According to a further embodiment of the invention, the underlying measurement principle in bistatic operation is a THz ellipsometry at one or more angles (FIG. 2 ).In another embodiment of the invention, the data evaluation of the signals from the receiver Rx takes place on the basis of an electromagnetic model of the layered fingernail structure and / or by means of AI-based pattern recognition.In yet another embodiment of the invention, the measuring device is integrated into an artificial fingernail that can be applied to the fingernail.Without limiting generality, the measuring device can provide an integrated evaluation and control CPU. Under the control of the CPU-for example a microprocessor or microcontroller-the duration and the time interval of successive measurements can be determined (measurement profile), for example as a function of one or more previously measured values. The CPU can be integrated in the housing G or can be located on a separate device which communicates with the measuring device via an interface, e.g. a communication unit I / O (e.g. near field communication (NF), Bluetooth, WLAN, USB connection or the like). The CPU can also have databases and data evaluation programs or access these.Likewise, the measuring device may include an energy collection unit that collects energy by movement of the measuring device, so as to enable operation.Furthermore, the measuring device can have a communication unit I / O, with which both measured values can be made available or else measurement profiles can be programmed. The communication unit I / O can be both wired and wireless. The communication unit I / O can be configured both as a separate component in the housing G and as part of the electronic measurement system IC.References included in the specificationThis list of documents cited by the applicant has been produced in an automated manner and is only included for the better information of the reader. The list is not part of the German patent application or utility model application. The DPMA does not take any adhesion for any faults or omissions.Patent Literature citedU.S. Pat. No. 11,229,383 B2

[0010] Cited Non-Patent LiteratureI.M.E. Wentholt, J.B.L. Hoekstra, A. Schiedt and J.H. DeVries, published in Diabetologia (2005) 48:1055-1058, DOI 10.1007 / s00125-005-1754-y

[0007] First human experiments with a novel non-invasive, non-optical continuous glucose monitoring system" by the authors A. Caduff, E. Hirt, Yu. Feldman, Z. Ali, and L. Heinemann, published in Biosensors and Bioelectronics 19 (2003) 209 / 217

[0007] Non-invasive glucose monitoring in patients with diabetes: A novel system based on impedance spectroscopy" by the authors A. Caduff, F. Dewarrat, M. Talarary, G. Stalder, L. Heinemann and Yu. Feldman, published in Biosensors and Bioelectronics 22 (2006) 598-604

[0007] Sensitivity and specificity analysis of flying-field dielectric spectroscopy applied to a multilayer system modelling the human skin" of the authors Sonja Huclova, Dirk Baumann, Mark S Talary and Jurg Frohlich, published in Phys. Med. Biol. 56 (2011) 7777-7793 doi:10.1088 / 0031-9155 / 56 / 24 / 007

[0008] PENDRA: The One and Future Noninvasive Continuous Glucose Monitoring Device?", authored by STUDART ALAN WEINZIMER, published in DIABETES TECHNOLOGY & THERAPEUTICS, volume 6, number 4, 2004, pages 442-444

[0008] Compact Non-Invasive Millimeter Wave Glucose Sensor" from the authors Peter H. Siegel, Adrian Tang, Gabreli Vibria, Yanghyo Kim, M. C. Frank Chang and Victor Pikov, published in 2015 40th International Conference on Infrared, Millimeter, and Terahertz waves (IRMMW-THz), Hong Kong, China, 2015, pp. 1-3, doi: 10.1109 / IRMMW-THz.2015.7327413

[0010] Noninvasive blood glucose monitoring in the terahertz frequency range" of the authors Olga Cherkasova, Maxim Nazarov, and Alexander Shkurinov, developed in Opt Quant Electron (2016) 48:217 DOI 10.1007 / s11082-016-0490-5

[0011] Wearable-band type visible-near infrared optical biosensor for non-invasive blood glucose monitoring" by the authors Vega Pradana Rachim and Wan-Young Chung, published in Sensors & Actuators: B. Chemical 286 (2019) 173-180

[0012] Non-invasive easy to implement glucose sensing via the finger-like using THz radiation" of the authors Mandana Jalali, Andreas Prokscha, Yijun Yun, Tobias Kubiczek, Thomas Kaiser, Jan Balzer, and Daniel Ern in Biomedical Engineering / Biomedical Technique, 2023

[0040]

Claims

A measuring device for non-invasive determination of a blood sugar concentration in the body of a mammal, comprising • a housing (G), • measuring electronics (IC) in the housing (G), wherein the measuring electronics (IC) further comprises: • at least one transmitter (Tx) for emitting high-frequency signals having a frequency of more than 0.1 THz and less than 10 THz, • at least one (Rx) for receiving high-frequency signals having a frequency of more than 0.1 THz and less than 10 THz, • wherein the at least one transmitter (Tx) is designed such that, during operation, it emits the high-frequency signal via an antenna (ANT_Tx) integrated in the measuring device. • wherein the at least one receiver (Rx) is designed such that, in operation, it receives a high-frequency signal via an antenna (ANT_Rx) integrated in the measuring device. • wherein the measuring device is configured to be fastened relative to a nail plate (NP) to a nail of a finger or toe of the mammal, • wherein the high-frequency signals from the at least one transmitter (Tx) are coupled into the nail bed (NB) of the mammal in operation through the nail plate (NP) and wherein the high-frequency signals backscattered from the nail bed (NB) of the mammal through the nail plate (NP) are received by the receiver (Rx). • wherein the measuring device further comprises an evaluation device (CPU) configured to, evaluating the backscattered high frequency signals received from at least one receiver (Rx) in order to determine the blood sugar concentration in the body of a mammal.Measuring device according to claim 1, characterised in that arranged downstream of the antenna of the at least one transmitter (ANT_Tx) is a first focusing or adjusting element (L1), which is irradiated before high-frequency signals enter the nail bed (NB) during operation.Measuring device according to claim 1 or 2, characterised in that a second focusing or adjusting element (L2) is arranged in front of the antenna of the at least one receiver (ANT_Rx), which element is irradiated during operation by signals backscattered from the nail bed (NB).Measuring device according to claim 2 or 3, characterised in that the focusing or adapting element (L1, L2) comprises an environment-resistant plastic, in particular polymethylpentene, or a material with low absorption in the frequency range used during operation, in particular highly resistive silicon.Measuring device according to one of the preceding claims, characterized in that the at least one transmitter (Tx) and the at least one receiver (Rx) are realized as a component (Tx / Rx) for emitting and receiving signals of more than 0.1 THz and less than 10 THz.Measuring device according to one of the preceding claims, characterized in that the antenna (ANT_Tx) for emitting the high-frequency signal, which antenna is integrated in the measuring device, is also configured at the same time as an antenna (ANT_Tx) for reception, which antenna is integrated in the measuring device.Measuring device according to one of the preceding claims, characterized in that the focusing or adjusting element (L1) integrated in the measuring device for emitting the high-frequency signal is also configured at the same time as a focusing or adjusting element (L2) for reception. This element is referred to as L12.Measuring device according to one of the preceding claims, characterized in that the underlying measuring principle in monostatic operation is a THz reflectometry.Measuring device according to one of the preceding claims, characterized in that the underlying measuring principle in bistatic operation is a THz ellipsometry.Measuring device according to one of the preceding claims, characterized in that the data evaluation of the signals from at least one receiver (Rx) takes place on the basis of an electromagnetic model of the layered fingernail structure and / or by means of AI-based pattern recognition.Measuring device according to one of the preceding claims, characterized in that it can be integrated into an artificial fingernail which can be applied to the fingernail.

Images