Active miniaturized sensing system and method

Abstract

To provide a system and method enabling highly-reliable and non-invasive measurement of glucose and / or physiological parameters.SOLUTION: An active miniaturized sensing system includes: a radiation source adapted to emit visual (VIS) / near-infrared (NIR) radiation into a body part of a subject; a sensing unit for detecting IR radiation in a range of substantially 5 μm to substantially 12 μm emitted from the body part, the sensing unit adapted to detect IR radiation having at least one wavelength or wavelength range where the intensity of the detected IR radiation is dependent on the concentration of a physiological parameter in a bodily fluid of the subject and adapted to detect IR radiation having at least one wavelength or wavelength range where the intensity of the detected IR radiation is substantially independent of the concentration of the physiological parameter in the bodily fluid of the subject; and an analyzing unit for the qualitative and / or quantitative determination of the physiological parameter on the basis of the IR radiation detected in the sensing unit.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to a non-invasive active sensing system for measuring physiological parameters in a subject's body fluid. Further, the present invention relates to a non-invasive method for measuring physiological parameters in a subject's body fluid.

[0002] Background In 2016, approximately 415 million people suffered from diabetes. It is predicted to increase to over 640 million by 2040. Since diabetic patients are at risk of complications such as blindness, kidney disease, heart disease, and stroke, it is required to control the disease by closely monitoring blood glucose levels.

[0003] Currently, the measurement of blood glucose is mainly based on invasive systems and methods, where a blood sample is taken and subjected to in vitro tests, or a sensor is implanted to measure glucose levels in vivo. These invasive systems and methods have the disadvantages of causing pain and being inconvenient.

[0004] Therefore, there is a need to develop systems and methods that enable reliable non-invasive measurement of glucose and / or physiological parameters.

[0005] Summary of the Invention According to the present invention, a non-invasive system and method enable simple, rapid, and reliable measurement of physiological parameters. These systems and methods irradiate a body part of a subject, particularly a human subject, with visible (VIS) / near-infrared (NIR) radiation in the range of about 400 nm to about 1500 nm or about 500 nm to about 1500 nm, and detect IR radiation in the range of about 5 μm to about 12 μm emitted from the irradiated body part of the subject. Surprisingly, the inventors have found that by irradiating a body part, such as a fingertip, earlobe, wrist, or forearm, with short-wavelength radiation and detecting the long-wavelength radiation emitted from the irradiated body part, physiological parameters such as glucose in body fluids such as blood can be measured.

[0006] When the body part is irradiated with VIS / NIR radiation according to the present invention, energy absorption is caused within the region of the irradiated body part. This energy absorption in the irradiated region, i.e., the absorption region, results in a local increase in the tissue temperature within the irradiated body part, particularly within the absorption region, which in turn causes an increase in the emission of IR radiation, including an increase in the emission of IR radiation in the range of about 5 μm to about 12 μm from the irradiated body part, particularly from the absorption region. Thus, the detection of IR radiation emitted from the irradiated body part becomes easier and is substantially improved.

[0007] A first aspect of the present invention is a non-invasive system for measuring a physiological parameter, particularly glucose, in a body fluid of a subject, the system comprising (a) a radiation source adapted to emit visible (VIS) / near-infrared (NIR) radiation in the range of about 400 nm to about 1500 nm or about 500 nm to about 1500 nm to a body part of the subject, wherein the body part is particularly selected from a fingertip, earlobe, wrist, forearm, and upper arm, the radiation source; (b) a sensing unit for detecting IR radiation in the range of about 5 μm to about 12 μm emitted from the irradiated body part of the subject, (i) Detect IR radiation having at least one wavelength or wavelength range such that the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, and (ii) Detect IR radiation having at least one wavelength or wavelength range such that the intensity of the detected IR radiation does not substantially depend on the concentration of a physiological parameter in the body fluid of the subject An adapted sensing unit, and (c) An analysis unit for qualitatively and / or quantitatively measuring a physiological parameter based on the IR radiation detected by the sensing unit (b) Relates to a system comprising.

[0008] A further aspect of the present invention is the use of the above system for non-invasively measuring a physiological parameter in the body fluid of a subject, in particular, the use where the physiological parameter is glucose and the body fluid is blood.

[0009] A still further aspect of the present invention is a method for non-invasively measuring a physiological parameter, in particular glucose, in the body fluid of a subject, the method comprising (a) irradiating a body part of the subject with visible (VIS) / near-infrared (NIR) radiation in a wavelength range of about 400 nm to about 1500 nm or about 500 nm to about 1500 nm; and (b) detecting IR radiation in a wavelength range of about 5 μm to about 12 μm emitted from the irradiated body part of the subject, wherein separately, (i) detecting IR radiation having at least one wavelength or wavelength range such that the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, and (ii) detecting IR radiation having at least one wavelength or wavelength range such that the intensity of the detected IR radiation does not substantially depend on the concentration of a physiological parameter in the body fluid of the subject including steps, and (c) analyzing the detected IR radiation to qualitatively and / or quantitatively measure the physiological parameter Relates to a method including

Brief Description of Drawings

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[0011] Detailed description The present invention includes measuring physiological parameters by detecting IR radiation in the wavelength range of about 5 μm to about 12 μm, particularly in the range of about 8 μm to about 10 μm, from a previously irradiated body part of a subject, particularly a human subject. The physiological parameter can be any compound having a characteristic absorption band in this wavelength range. For example, the physiological parameter can be glucose or another clinically relevant analyte such as lactate or troponin.

[0012] In a particular embodiment of the present invention, the system is adapted to non-invasively measure glucose in the blood. In this embodiment, the IR radiation is detected at a wavelength or wavelength range specific to glucose, where glucose has a characteristic absorption band and the intensity of the detected IR radiation depends on the concentration of glucose in the blood. More particularly, the wavelength or wavelength range specific to glucose is selected from a wavelength of about 9.2 μm, a wavelength of about 9.4 μm, a wavelength of about 9.6 μm, a wavelength range including at least two of the wavelengths of about 9.2 μm, about 9.4 μm, and about 9.6 μm, a wavelength range including all three of the wavelengths of about 9.2 μm, about 9.4 μm, and about 9.6 μm, or any combination thereof. Additionally, the IR radiation is detected at a reference wavelength or wavelength range where glucose does not have a characteristic absorption band, particularly a minimum absorption value, and the intensity of the detected IR radiation does not substantially depend on the concentration of glucose in the blood. More particularly, the reference wavelength or wavelength range is selected from a wavelength or wavelength range of about 8.7 μm to about 9.0 μm, a wavelength or wavelength range of about 9.7 μm to about 10.2 μm, or any combination thereof.

[0013] As outlined above, the present invention is based on irradiating body tissue with electromagnetic radiation (VIS / NIR radiation) in the wavelength range of about 500 nm to about 1500 nm and detecting electromagnetic radiation (IR radiation) in the wavelength range of about 5 μm to about 15 μm emitted from the irradiated body site. When the body site is irradiated with VIS / NIR radiation, self-emission of IR radiation from the body site is enhanced by local energy absorption, causing a local temperature increase. Thus, the self-emission of IR radiation from the irradiated body site is increased by previous irradiation of the body site with VIS / NIR radiation. For this reason, irradiation of the body site by an external IR radiation source in the wavelength range of about 5 μm to about 15 μm is not required. Thus, in certain embodiments, the system of the present invention does not include an external IR radiation source, and in particular embodiments, the system of the present invention does not include an external IR radiation source adapted to irradiate the body site from which the detected IR radiation is emitted.

[0014] Figure 1 shows the penetration depth [mm] of electromagnetic radiation into body tissue as a function of wavelength [nm]. It can be seen that the penetration depth depends on the wavelength. In the visible (VIS) / near-infrared (NIR) wavelength range of about 400 nm to about 1500 nm, particularly in the range of about 500 nm to about 1500 nm or about 400 nm to about 1200 nm, and more particularly in the range of about 550 nm to about 1200 nm, there is a penetration depth of about 1 mm or more, particularly about 3 mm or more. Thus, the irradiated body site absorbs electromagnetic energy, resulting in a local increase in tissue temperature. This in turn results in an increase in the emission of IR radiation of longer wavelengths, for example in the wavelength range of about 5 μm to about 12 μm, by certain organic compounds present in the body fluid, i.e., physiological parameters that exhibit absorption bands. This enables quantitative or qualitative measurement of such parameters according to the above aspect of the present invention.

[0015] In certain embodiments, the VIS / NIR radiation emitted to the body part is in the range of about 550 nm to about 1000 nm, particularly in the range of about 800 nm to about 820 nm, such as about 810 nm, and / or in the range of about 590 nm to about 660 nm, such as about 600 nm, and / or in the range of about 920 nm to about 980 nm, such as about 940 nm. In certain embodiments, the VIS / NIR radiation emitted to the body is in the range of about 450 nm to about 800 nm.

[0016] Figure 2 shows the relative absorption coefficients of certain compounds present in the human body as a function of wavelength in the range of 400 nm to 1100 nm. The wavelengths of about 600 nm and about 810 nm at which radiation can be emitted to the body part are specifically shown. In the wavelength range of about 500 nm to about 1050 nm, the absorption of water (H2O) is relatively low. Furthermore, hemoglobin (Hb) and oxyhemoglobin (Hboxy), which are the main blood components, exhibit similar absorption coefficients. Melanin, a skin pigment, exhibits an absorption coefficient that decreases with increasing wavelength.

[0017] In an embodiment of the present invention, the radiation source (a) is adapted to emit VIS / NIR radiation in the range of about 920 nm to about 960 nm, such as about 940 nm, to the body part. This irradiation wavelength can be used alone or in combination with at least one additional irradiation wavelength. As shown in Figure 3, glucose has an absorption band at a wavelength of 940 nm. Thus, irradiation at a wavelength of about 940 nm can cause selective excitation of glucose molecules, resulting in more absorption of glucose molecules in the IR wavelength range, particularly in the wavelength range of about 5 μm to about 12 μm.

[0018] According to an embodiment of the present invention, the radiation source (a) is adapted to emit VIS / NIR radiation in the range of about 920 nm to about 980 nm, for example about 940 nm, to a body part of the subject, and the sensing unit (b) is further adapted to detect VIS / NIR radiation having a wavelength of about 940 nm, and the intensity of the detected VIS / NIR radiation depends on the concentration of glucose. The measurement signal in the VIS / NIR wavelength range may be combined with the measurement signal in the IR range as described above, for example, by a comparator.

[0019] In yet a further embodiment, the VIS / NIR irradiation is performed with a combination of at least two different wavelengths, in particular a combination of a first wavelength in the range of about 800 nm to about 820 nm, for example about 810 nm, and a second wavelength in the range of about 920 nm to about 980 nm, for example about 940 nm.

[0020] FIG. 4 shows an embodiment of the system of the present invention. A body part (1), for example a fingertip, is placed in contact with a system adapted to perform irradiation into an absorption region (2) within the body part (1).

[0021] The system comprises a cover (3) at least partially made of an optically transparent material. For example, the cover is transparent in the IR wavelength range of about 5 μm to about 12 μm or a partial range thereof, for example about 8 μm to about 12 μm, and optionally transparent in the VIS / NIR wavelength range of about 400 nm to about 1500 nm or a partial range thereof, and is at least partially made of CaF2 and / or BaF2 or a plastic material. A suitable IR-transmissive plastic material is, for example, the PolyIR plastic material commercially available from Fresnel Technologies (Fort Worth, Texas, USA). In a particular embodiment, the cover may have a thickness of about 0.2 mm to about 2 mm, in particular about 0.5 mm to about 1.5 mm, and more particularly about 1 mm.

[0022] The system may further comprise at least one sensor (4) which may include a filter element (5) and a lens element (not shown) as an optional means, and the lens element may be arranged, for example, between the sensor (4) and the filter element (5). The sensor (4) may be mounted on a circuit board (6). Further, the system comprises at least one radiation source (9, 9a). For example, the system may include a radiation source (9) arranged on the same side as the sensor (4) and / or a radiation source (9a) located on the side of the body part (1) opposite to the sensor (4). Optionally, an additional sensor (4) without a filter element (5) may be provided to monitor the exact skin temperature of the subject.

[0023] The system includes one or more sensors (4). In the embodiment of FIG. 4, the system comprises four different sensors (4). The sensors may be optical detectors, particularly optical photovoltaic detectors, such as InAsSb-based detectors, which can be used in combination with a lock-in amplifier if desired. Photovoltaic detectors, such as InAsSb-based detectors, have a rise time of only a few nanoseconds and are particularly useful for devices in which the body part is intermittently irradiated. In other embodiments, the sensors may be thermal detectors, such as thermopiles or bolometers. Suitable sensors include photovoltaic detectors (e.g., Hamamatsu P13894), thermopiles (e.g., Heimann HCS C21 F8-14), or other types of IR sensors (e.g., Sensirion STS21 or Melexis MLX90632). Optionally, the sensor (4) may include a filter element (5) that can selectively transmit radiation of a desired wavelength or wavelength range. The filter element may have, for example, a narrow bandwidth of about 50 to 100 nm, or a wider bandwidth of, for example, about 400 nm or more. The filter may be made of germanium or other filter materials that are optically transmissive for each wavelength. Further, the sensor may include a lens element, such as a microlens, that can focus the light incident on the sensor.

[0024] In certain embodiments, the sensor surface may be coated with a noble metal such as Au or Ag, particularly Au, to enhance its sensitivity. Such coatings that can be formed as a Bundt baking-pan are described in Awad (Nature Scientific Reports 9:12197 (2019)), the content of which is incorporated herein by reference.

[0025] In certain embodiments, the sensor is about 1 mm 2 ~ about 10,000 mm 2 For example, about 10 mm 2 ~ about 1,000 mm 2 and is a miniaturized sensor having an area. In certain embodiments, the sensor may be further miniaturized and may be, for example, an ASIC (application-specific integrated circuit).

[0026] In the sensing unit of the present invention, at least one sensor may be a sensor specific to an analyte, i.e., a sensor adapted to detect IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, and at least one sensor may be a reference sensor, i.e., a sensor adapted to detect IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation does not substantially depend on the concentration of a physiological parameter in the body fluid of the subject.

[0027] In certain embodiments, the sensing unit (b) is adapted to detect IR radiation self-emitted from a previously irradiated body part, i.e., IR radiation generated by the body heat of the subject without irradiation by an external IR source. Further, the sensing unit (b) may be adapted to detect IR radiation emitted from an absorption region within a previously irradiated body part, and the absorption region shows an increase in the emission of IR radiation in the wavelength range of about 5 μm to about 12 μm with a locally increased temperature.

[0028] In certain embodiments, there may be at least one additional sensor, e.g., (i) a sensor adapted to detect unspecified IR radiation, (ii) a sensor adapted to detect unspecified VIS / NIR radiation, (iii) a sensor adapted to detect VIS / NIR radiation having wavelengths at which the intensity of the detected VIS / NIR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, and / or (iv) a temperature sensor for measuring the temperature of a body part.

[0029] In certain embodiments, there may be at least one sensor specific for at least one additional analyte, i.e., a sensor adapted to detect VIS / NIR radiation having at least one wavelength or wavelength range at which the intensity of the detected VIS / NIR radiation depends on the concentration of a physiological parameter in the body fluid of the subject. For example, there may be at least one additional sensor adapted to detect VIS / NIR radiation having a wavelength of about 940 nm.

[0030] Furthermore, the device may comprise a circuit board (7) to which a light source (9) is attached, and an active and / or passive heat sink (8).

[0031] The VIS / NIR radiation sources (9, 9a, 9b) can be adapted to emit collimated radiation (e.g., a laser-based light source) and / or can be adapted to emit non-collimated radiation (e.g., an LED-based light source). For example, the light source can be selected from an LED, a laser diode, a VCSEL (vertical-cavity surface-emitting laser), or a laser. In certain embodiments, a broadband VIS / NIR radiation emitter that can be adapted to emit VIS / NIR radiation in the range of about 650 nm to about 950 nm, particularly in the range of about 750 nm to about 850 nm, and more particularly in the range of about 780 nm to about 820 nm is used. A suitable VIS / NIR emitter is, for example, the OSLON product by Osram, OSLON SFH 4763.

[0032] The radiation source is adapted to emit VIS / NIR radiation in the range of about 400 nm to about 1500 nm, particularly in the range of about 500 nm to about 1500 nm. The VIS / NIR radiation may be emitted continuously or intermittently over a predetermined time interval.

[0033] In certain embodiments, the radiation source is adapted to cause a local increase in the temperature of the irradiated body part, such as a fingertip, particularly the temperature of the absorption region within the irradiated body part. The local increase in temperature may be in the range of about 1 °C to about 15 °C, particularly about 2 °C to about 10 °C, and more particularly about 3 °C to about 5 °C. The local temperature increase of the irradiated body part, such as a fingertip, may be in a temperature range up to about 45 °C, up to about 40 °C, or up to about 37 °C, such as a temperature range of about 30 °C to about 35 °C or about 30 °C to about 32 °C. This local temperature increase will enhance the self-emission of IR radiation from the irradiated body part, particularly from the absorption region within the irradiated body part.

[0034] In certain embodiments, the radiation source may be adapted to emit radiation continuously at a power of about 10 mW to about 1 W, particularly about 20 mW to about 500 mW, more particularly about 50 mW to about 250 mW, still more particularly about 100 mW to about 200 mW, such as about 150 mW, over a time interval of about 0.1 to about 20 seconds, particularly about 0.2 seconds to about 5 seconds, more particularly about 0.5 seconds to about 2 seconds, such as about 1 second.

[0035] In further embodiments, the radiation source may be adapted to emit radiation intermittently at a power of about 10 mW to about 5 W, particularly about 20 mW to about 1 W, more particularly about 50 mW to about 500 mW, over a time interval of about 0.1 seconds to about 20 seconds, particularly about 0.2 seconds to about 5 seconds, more particularly about 0.5 seconds to about 2 seconds. The radiation may be adapted to be emitted intermittently at a pulse frequency of about 1 Hz to about 1 MHz.

[0036] In a further embodiment, the radiation source may be adapted to emit VIS / NIR radiation at a plurality of different wavelengths, such as 2, 3, 4, 5, 6, 7, 8 or even more different wavelengths. For example, the radiation source may be a multi-LED chip. By using a multi-wavelength radiation source, it is possible to adjust the predetermined penetration depth of the electromagnetic radiation into the tissue of the body part being irradiated according to specific characteristics of the body part, such as pigmentation, skin thickness, presence or absence of cutin, etc. As shown in FIG. 1 above, the penetration depth into body tissue varies with wavelength, and the use of VIS / NIR radiation having different wavelengths or combinations of different wavelengths can be individually adapted to each subject and / or each body part as desired.

[0037] In certain embodiments, the radiation source (a) is a multi-wavelength radiation source adapted to emit VIS / NIR radiation at at least 2, 3, 4, 6 or 8 wavelengths that can be selected from several different wavelengths or wavelength ranges, such as from about 400 nm to about 1200 nm, more particularly from about 450 nm to about 900 nm, for example wavelengths of about 470 nm, about 520 nm, about 590 nm, about 650 nm, about 750 nm and about 810 nm.

[0038] A further embodiment of the system of the present invention is shown in FIG. 5. Here, a single radiation source (9a) is provided on the side of the body part (1) opposite to a sensing unit comprising at least one sensor (4) with a filter (5) and a further sensor (4a) with a filter (5a). In certain embodiments, the sensor (4a) is an optical sensor, such as a photodiode. This is adapted to measure a reference measurement of the transmitted radiation from the radiation source (9a), for example radiation at wavelengths of about 600 nm and / or about 810 nm and / or about 940 nm. For this purpose, the filter element (5a) may be a band-pass filter of about 600 nm and / or about 810 nm and / or about 940 nm.

[0039] A further embodiment of the present invention is shown in FIG. 6. Here, direct access to the absorption region (2) within the body part (1) is provided through the skin of the body part without passing through the cover structure of the device by radiation and / or without passing through the horny structure of the body surface, such as fingernails and / or cutin, and a radiation source (9b) is provided on the side of the body part (1), for example, the fingertip. Thereby, interference, for example, interference by the cover structure, or any interference by the keratinous substance of the cutin or nail, and the manicure can be reduced or eliminated. According to this embodiment, a single radiation source (9b) or a plurality of radiation sources (9b), for example, two, three, four, six, or eight radiation sources, may be provided at positions around the body part (1), for example, the fingertip. When there are a plurality of radiation sources, they are preferably adapted to emit radiation to a single absorption region (2) within the body part, which may be about 3 mm to about 5 mm below the body surface.

[0040] A further embodiment of the present invention is shown in FIG. 7. In this embodiment, a cover (3) adapted to focus IR radiation emitted from a body part onto at least one sensor (4) of a sensing unit is provided. Thereby, the radiation intensity on the sensor, and thus the sensitivity and / or accuracy of the measurement, can be improved. The cover (3) is made of a material that is substantially transparent to IR radiation in the wavelength range detected on the sensor, in particular IR radiation in the wavelength range of about 5 μm to about 12 μm or a partial range thereof, for example in the wavelength range of about 8 μm to about 12 μm, such as plastic, metal, metal oxide or composite material. A suitable material is, for example, the aforementioned PolyIR plastic material. In this embodiment, the cover (3) may comprise an IR Fresnel lens, i.e., a lens having a large aperture and a short focal length capable of efficiently focusing the passing IR radiation, or an array comprising a plurality of, for example up to 10 or more IR Fresnel lenses. In a particular embodiment, the array may comprise IR Fresnel microlenses having a diameter in the range of about 50 nm to about 500 μm, for example up to 100 or 1000 microlenses. In a particular embodiment, the IR Fresnel lens may have a back focus length of about 3 mm to about 10 mm, for example about 5 mm, and may be manufactured from IR-transparent plastic. For example, suitable IR Fresnel lenses that are optically transparent in the wavelength range of 8 - 14 μm are commercially available from Edmund Optics (product family number 2042).

[0041] Furthermore, FIG. 7 shows a radiation source (9a) provided on the side of the body part opposite to the position of the sensing unit comprising the sensor (4). However, it should be noted that one or more radiation sources may be arranged around the body part (1), for example as shown in FIG. 6. It should be further noted that in this embodiment, there may be a plurality of different sensors, for example as shown in FIGS. 4 and 5.

[0042] As shown in FIGS. 4 and 5, the system of the present invention may comprise a plurality of different sensors (4). In certain embodiments, the system is adapted such that a first sensor detects radiation at a first wavelength or wavelength range, for example at a wavelength of about 9.2 μm, and at least another first sensor is adapted to detect IR radiation in a second wavelength range that includes the first wavelength or wavelength range and further includes another wavelength or wavelength range, a sensor specific for a plurality of analytes, such as a glucose-specific sensor. For example, another first sensor may be adapted to detect IR radiation at a wavelength of about 9.2 μm, additionally at a wavelength of about 9.4 μm and / or at a wavelength of about 9.6 μm, particularly at a wavelength of about 9.4 μm and at a wavelength of about 9.6 μm.

[0043] Furthermore, the sensing unit may comprise a plurality of reference sensors adapted to detect reference radiation at different wavelengths or wavelength ranges. For example, when measuring glucose, the reference sensor may be adapted to detect radiation having a wavelength range from about 8.6 μm to about 9.0 μm. Another reference sensor is adapted to detect radiation having a wavelength or wavelength range from about 9.8 μm to about 10.2 μm.

[0044] Yet another embodiment of the present invention is shown in FIG. 8. In this embodiment, a support (16) for a body part (1), for example a fingertip, is provided, the support (16) comprising an opening adapted to receive a part (15) of the body part (1). For example, the support may comprise an annular structure having an opening, for example a substantially circular opening, at its center. The system is adapted to press the body part (1) against the opening of the support (16) such that a part (15) of the body part (1), for example a part of the fingertip, is pushed into the opening. Thus, the tissue including the blood vessels in the part (15) is compressed, resulting in an increase in the blood volume in the capillaries in the part (15). Thereby, the signal intensity, and thus the sensitivity and / or accuracy of the measurement, can be improved.

[0045] Furthermore, the system of FIG. 8 includes a cover (3) that can be formed as an IR Fresnel lens as described above in the context of FIG. 7. However, it should be noted that other covers are also suitable. Furthermore, a radiation source (9a) is shown provided on the side of the body part opposite to the position of the sensing unit comprising the sensor (4). However, it should be noted that one or more radiation sources may also be arranged around the body part (1), for example as shown in FIG. 6. Furthermore, in this embodiment, it should be noted that a plurality of different sensors may be present, for example as shown in FIGS. 4 and 5.

[0046] FIG. 9 shows measurements at wavelengths / wavelength ranges specific to a plurality of analytes and reference wavelengths / wavelength ranges.

[0047] The absorption signal (24) of glucose has three different peaks at approximately 9.2 μm, approximately 9.4 μm, and approximately 9.6 μm. A first glucose-specific sensor can be adapted to measure only the peak at 9.2 μm. Such a sensor is adapted by a filter element that can transmit radiation only in a narrow range (22). Thus, the sensor can selectively detect radiation within this narrow range. A further glucose-specific sensor may be adapted to measure radiation in a wider range from approximately 9.1 μm to approximately 9.7 μm and thereby include the peaks at approximately 9.2 μm, 9.4 μm, and 9.6 μm. This sensor may be adapted by a filter element that can transmit radiation in a wider range (21).

[0048] Two reference sensors may be provided, where each said reference sensor comprises a filter element that can transmit radiation (20) at wavelengths in the range from approximately 8.6 μm to approximately 9.0 μm, in particular from approximately 8.8 μm to 8.9 μm, and / or radiation (23) at wavelengths in the range from approximately 9.8 μm to approximately 10.2 μm, in particular from approximately 9.9 μm to 10.1 μm.

[0049] When measurements at a wavelength of approximately 9.2 μm and measurements in a wavelength range including a peak at 9.2 μm and at least one other peak, particularly a peak at approximately 9.6 μm, are performed separately and in parallel, it is possible to determine whether ethanol is contained in the blood of a subject, thus obtaining an additional advantage. Ethanol and other alcohols have an absorption band at a wavelength of approximately 9.6 μm but not at a wavelength of approximately 9.2 μm. Therefore, the ratio between the peak at 9.2 μm and the peak at 9.6 μm can be used to measure and, as an optional means, correct for disturbances caused by blood alcohol.

[0050] In an alternative embodiment, the first glucose-specific sensor may be adapted to measure only the peak at 9.6 μm. Such a sensor comprises a filter element that can transmit radiation only in a narrow range. A further glucose-specific sensor may be adapted to measure radiation in a wider range from approximately 9.4 μm to approximately 9.6 μm, thereby including peaks at approximately 9.4 μm and approximately 9.6 μm but not including the peak at 9.2 μm. This sensor may comprise a filter element that can transmit radiation in a wider range.

[0051] In a further alternative embodiment, a reference sensor comprising a filter element that can transmit radiation having a wavelength in the range from approximately 7.8 μm to approximately 8.2 μm, particularly in the range from approximately 7.9 μm to approximately 8.1 μm, may be provided in combination with at least one further reference sensor each comprising a filter element that can transmit radiation having a wavelength in the range from approximately 8.8 μm to 9.2 μm and / or radiation having a wavelength in the range from approximately 9.8 μm to 10.2 μm as optional means.

[0052] In yet a further embodiment of the present invention, the system may comprise a sensor adapted to detect IR radiation having different wavelengths or wavelength ranges in a time-dependent manner. In this embodiment, the system may comprise a sensor comprising a plurality of filters adapted to transmit IR radiation having different wavelengths or wavelength ranges, said filters being arranged on the sensor during different stages of a measurement cycle, thereby enabling detection of different wavelengths or wavelength ranges within the measurement cycle. Such an embodiment is shown in FIG. 10. Here, a system is provided comprising a filter wheel (10) rotatable about an axis (11) and a shutter wheel (13) rotatable about the axis. The filter wheel and the shutter wheel comprise an illumination aperture (15) through which light from a radiation source (not shown) can pass to a body part of a subject (not shown). The reflected light from the illuminated body part can pass through different apertures (14) of the filter wheel (10) which may comprise filter elements specific to an analyte as described above and / or reference filter elements. The positions of the filter wheel (10) and the shutter wheel (13) can be monitored using magnets (12) in combination with magnetic sensors. During operation, these are rotated at a predetermined frequency, thereby passing the radiation from the radiation source to the body part in a time-dependent manner at predetermined time intervals and passing the radiation emitted from the body part to a sensor (not shown) through different apertures (14) of the filter wheel (10) in a time-dependent manner.

[0053] In an alternative embodiment (not shown), the sensor adapted to detect IR radiation having different wavelengths or wavelength ranges in a time-dependent manner may be a Fabry-Perot interferometer, for example, a MEMS spectrometer for a desired IR wavelength range (see: Tuohinieni et al., J. Micromech. Microeng. 22 (2012), 115004; Tuohinieni et al., J. Micromech. Microeng. 23 (2013), 075011).

[0054] In certain embodiments, the system comprises a single sensor adapted to detect IR radiation having different wavelengths or wavelength ranges in a time-dependent manner. This sensor may comprise different filters, such as a filter wheel, or may be a Fabry-Perot interferometer as described above.

[0055] The system of the present invention further comprises an analysis unit (c) for qualitatively and / or quantitatively measuring physiological parameters based on the IR radiation detected in the sensing unit (b). The analysis unit may comprise, for example, an A / D converter and a microcontroller. The analysis of the measured signal may be based on intensity and / or decay time.

[0056] A further embodiment of the present invention is shown in FIG. 11. The system of this embodiment is adapted to be permanently fixed to the body of a subject. In particular, the system is adapted to perform a plurality of measurements at predetermined time intervals. The system comprises a housing (30) and a strap (31) for fixing the housing around the body (33), such as the wrist or forearm. Furthermore, the system comprises a radiation source for emitting VIS / NIR light into the absorption region (34) of the body part (33) and a sensor for detecting the IR radiation emitted from the irradiated body part.

[0057] A further embodiment of the present invention is shown in FIG. 12. The system of this embodiment is adapted to be permanently fixed to the body of a subject and, in particular, is adapted to perform a plurality of measurements at predetermined time intervals. The system comprises a housing (30) and a strap (31) for fixing the housing around the body (33), such as the wrist or forearm. Furthermore, the system comprises a plurality of radiation sources, for example two radiation sources, for emitting VIS / NIR light into the absorption region (34) of the body part (33) and a sensor for detecting the IR radiation emitted from the irradiated body part. The light emitted from these radiation sources may be incident obliquely on the surface of the body part (33), for example at an angle of about 30° to about 75°.

[0058] FIG. 13 shows a schematic diagram of the system of FIG. 4.

[0059] FIG. 14 shows a heat map of the fingertip after irradiation with 810 nm light for 2 seconds.

[0060] FIG. 15 shows the time-dependent thermal power output during intermittent irradiation with 810 nm light at a power of 2 mW and a frequency of 0.1 Hz, in addition to the self-emission of the fingertip.

[0061] FIG. 16a shows a block diagram of an embodiment of the sensing unit of the present invention. A region of interest (ROI), i.e., the skin tissue of a subject, particularly a human subject, is irradiated by a first light source emitting VIS / NIR radiation having a wavelength of 940 nm, a second light source emitting VIS / NIR radiation having a wavelength of approximately 810 nm, and a third light source emitting VIS / NIR radiation having a wavelength of approximately 600 nm as an optional means. The radiation transmitted through or reflected from the region of interest is analyzed by the sensing unit. Further, the device comprises a temperature sensor.

[0062] The sensing unit comprises a plurality of sensors, for example IR sensors (1) and (2) specific to the analyte, and a reference sensor, for example IR sensor (4). For the measurement of glucose, IR sensor (1) may comprise a first optical filter that is transmissive to wavelengths of about 9.2 μm, and IR sensor (2) may comprise a second optical filter that is transmissive to a wavelength range of about 9.2 μm to about 9.6 μm. The reference sensor (4) may comprise a fourth optical filter that is transmissive to a wavelength or wavelength range of about 8.6 μm to about 9.0 μm and / or a wavelength or wavelength range of about 9.8 μm to about 10.2 μm. Further, the sensing unit comprises a NIR sensor for detecting VIS / NIR radiation having a wavelength of about 940 μm at which glucose has a strong absorption band. The NIR sensor comprises a suitable optical filter that is transmissive to this wavelength. Further, the sensing unit may comprise a temperature sensor for measuring the temperature of the skin tissue in the region of interest. Each sensor may be coupled to an amplifier (amp) for initial signal amplification. Signals from the individual sensors may be referenced by signals from other sensors using a comparator, thereby improving the measurement accuracy and / or signal quality. For example, the measurement signal from the 940 nm NIR sensor may be referenced by the measurement signal from the IR sensor (1) specific to the analyte. Alternatively or additionally, the measurement signal from the 940 nm NIR sensor may be referenced by the measurement signals from the IR sensor (1) specific to the analyte and / or the IR sensor (2) specific to the analyte and / or the reference IR sensor (4). The measured signal, and the reference signal as an optional means, are further amplified by a lock-in amplifier unit and transmitted to a microcontroller unit. Feedback control from the lock-in amplifier to the light source may also be provided. The signal and / or the result of the internal algorithm may be transmitted from the microcontroller unit to a display unit and / or another device, for example by a direct connection or via Bluetooth and / or WLAN.

[0063] FIG. 16b shows a block diagram of a further embodiment of the sensing unit of the present invention, similar to the sensing unit shown in FIG. 16a. Here, additionally or alternatively, a multi-wavelength light source, for example, a multi-wavelength LED comprising a plurality of individual diodes, is provided. The multi-wavelength light source may have a wavelength range of, for example, 400 nm to about 700 nm and may be operated by a microcontroller unit. Further, there is a temperature sensor coupled to an amplifier (AMP). This temperature sensor may also be operated by the microcontroller unit.

[0064] In yet a further embodiment of the present invention, the system is adapted to detect an IR spectrum within a wavelength range of interest, including, for example, a range from about 7 μm to about 12 μm, particularly a range from about 8 μm to about 10 μm, and may comprise a spectral or line sensor or a spectral or line sensor array, typically a bolometer or a thermopile array. The IR spectrum can be generated by passing the IR radiation from the irradiated body part through a spectral splitting or diffracting device and then through the sensor or sensor array. Such an embodiment is shown in FIG. 17. The IR radiation (70) emitted from the irradiated body part (71), for example, a fingertip, is focused by a focusing element (72), for example, a lens or a concave mirror element, adapted to focus the IR radiation, as an optional means, and then proceeds to a spectral splitting or diffracting element (73), for example, a prism or a transmissive or reflective optical grating, where the IR radiation is split according to its wavelength. The diffracted radiation then proceeds from there to a spectral sensor or line sensor or sensor array (74), typically a bolometer or a thermopile array, where an IR spectrum in the wavelength range of interest, for example, as described above, including, for example, a wavelength or wavelength range specific to an analyte and a reference wavelength or wavelength range, from 8 μm to about 20 μm, is detected. The physiological parameter of interest, for example, the amount of glucose, may be measured by spectral analysis according to the relative intensities of a wavelength specific to a given analyte and a reference wavelength.

[0065] The systems and methods of the present invention enable the qualitative and / or quantitative measurement of physiological parameters to be measured, particularly the qualitative and / or quantitative measurement of glucose in the blood.

[0066] In certain embodiments, the concentration of a physiological parameter, such as the concentration of glucose in the blood, is measured quantitatively. In certain embodiments, the rate of change of the measured amount of a physiological parameter, such as glucose, is measured. These embodiments may include non-quantitative measurements, such as the relative measurement of the change in the amount of analyte per unit time, i.e., an increase or decrease in the amount of analyte per unit time. When the change in the amount of analyte in one direction, i.e., an increase or decrease, exceeds a predetermined level and / or time, the system generates a warning. This embodiment is particularly useful for systems such as those shown in FIGS. 11 and 12 that can be continuously secured around a subject's body, such as the wrist, forearm, or upper arm. This embodiment may be adapted for continuous monitoring of glucose levels.

[0067] In certain embodiments, the systems of the present invention are adapted to perform both non-quantitative and quantitative measurements. For example, the system may be adapted to perform non-quantitative measurements, such as qualitatively measuring the change in the amount of analyte over time, such as an increase or decrease, during standard operation. Non-quantitative measurements may be performed, for example, as continuous and / or intermittent monitoring measurements as needed. When the change in the amount of analyte exceeds a predetermined level and / or time, the system is adapted to switch to quantitative measurements to provide more detailed information. In these embodiments, systems adapted to be continuously secured to the body, such as the wrist or ankle, may be used. Specific embodiments of such systems are shown in FIGS. 11 and 12.

[0068] In certain embodiments, the system is adapted to perform non-quantitative measurements, such as continuous and / or intermittent monitoring measurements, and quantitative measurements of several different body parts. For example, the system performs non-quantitative measurements of a first body part, such as a body part like the wrist or ankle where the system can be continuously fixed, and is adapted to perform quantitative measurements of a second body part, such as a body part like the earlobe or fingertip that is easily accessible by capillaries. To perform the measurement of the second body part, the system is removed from the first body part and brought into direct contact specifically with the second body part. After performing the measurement of the second body part, the system is removed therefrom and may be brought back into contact with the first body part, for example, by fixing it to the first body part. In a specific embodiment, the first body part is the wrist and / or the second body part is the fingertip.

[0069] A further aspect of the invention is a non-invasive system for measuring glucose in blood that enables the identification and optional correction of disturbances caused by blood alcohol, (i) a sensing unit adapted to detect IR radiation in the range of about 5 μm to about 12 μm emitted from a body part of the subject, detecting IR radiation at a wavelength of about 9.2 μm and separately detecting IR radiation at wavelengths of at least about 9.2 μm and about 9.6 μm, in particular IR radiation in a wavelength range including wavelengths of about 9.2 μm, about 9.4 μm, and about 9.6 μm, an analysis unit for measuring glucose, separate from the above sensing unit and a system comprising the same.

[0070] A further aspect of the invention is a method for non-invasively measuring glucose in a subject's blood using this system.

[0071] Preferred features of these aspects are as previously indicated in the above specification.

[0072] Yet a further aspect of the present invention is the use of an InAsSb sensor in combination with a lock-in amplifier as optional means for measuring IR radiation emitted from a body part.

[0073] Preferred features of this aspect are as previously indicated in the above specification.

[0074] Yet a further aspect of the present invention is a system and method for non-quantitatively measuring glucose, including a plurality of measurements during a predetermined time interval, measuring a change in a measurement signal indicating a change in the amount of analyte, and generating a warning when a unidirectional change in the amount of glucose, i.e., an increase or decrease, exceeds a specific level within a predetermined time. This system and method may be adapted for continuous monitoring of glucose levels.

[0075] Preferred features of this aspect are as previously indicated in the above specification.

[0076] Hereinafter, specific aspects and embodiments of the present invention are described as part of the specification.

[0077] Embodiments of this specification 1. A non-invasive system for measuring physiological parameters in a subject's body fluid, the system comprising (a) a radiation source adapted to emit visible (VIS) / near-infrared (NIR) radiation in the range of about 400 nm to about 1500 nm or about 500 nm to about 1500 nm to a body part of the subject, wherein the irradiated body part absorbs electromagnetic energy to cause a local increase in tissue temperature and an increase in the emission of IR radiation in the wavelength range of about 5 μm to about 12 μm; (b) a sensing unit for detecting IR radiation in the range of about 5 μm to about 12 μm emitted from a previously irradiated body part of the subject, wherein (i) the intensity of the detected IR radiation is detected to have at least one wavelength or wavelength range that depends on the concentration of a physiological parameter in the subject's body fluid, and (ii) Detect IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation does not substantially depend on the concentration of the physiological parameter in the body fluid of the subject. The adapted sensing unit, and (c) An analysis unit for qualitatively and / or quantitatively measuring a physiological parameter based on the IR radiation detected in the sensing unit (b). A system comprising.

[0078] 2. The system according to embodiment 1, which does not comprise an external radiation source for emitting IR radiation in the wavelength range of about 5 μm to about 12 μm.

[0079] 3. The system according to embodiment 1 or 2, wherein the physiological parameter is selected from compounds having at least one characteristic absorption band in the IR range of about 5 μm to about 12 μm, particularly in the range of about 8 μm to about 10 μm.

[0080] 4. The system according to any one of embodiments 1 to 3, wherein the physiological parameter is glucose.

[0081] 5. The system according to any one of embodiments 1 to 4, wherein the body fluid is blood.

[0082] 6. The system is adapted to measure glucose in blood, and the sensing unit is adapted to detect IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation depends on the concentration of glucose in the blood of the subject. The at least one wavelength or wavelength range is particularly selected from a wavelength of about 9.2 μm, a wavelength of about 9.4 μm, a wavelength of about 9.6 μm, a wavelength range including at least two of the wavelengths of about 9.2 μm, about 9.4 μm and about 9.6 μm, a wavelength range including all three wavelengths of about 9.2 μm, about 9.4 μm and about 9.6 μm, or any combination thereof. The system according to any one of embodiments 1 to 5.

[0083] 7. The system is adapted to measure glucose in blood, and the sensing unit is adapted to detect IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation is substantially independent of the concentration of glucose in the blood of the subject, and the at least one wavelength or wavelength range is particularly selected from a wavelength or wavelength range of about 8.7 μm to about 9.0 μm, a wavelength or wavelength range of about 9.7 μm to about 10.2 μm, or any combination thereof. The system according to any one of Embodiments 1 to 6.

[0084] 8. The system according to any one of Embodiments 1 to 7, wherein the system comprises a single radiation source (a).

[0085] 9. The system according to any one of Embodiments 1 to 7, wherein the system comprises a plurality of radiation sources (a), for example, 2, 3, 4 or more, for example up to 10 individual radiation sources (a).

[0086] 10. The radiation source (a) is adapted to emit VIS / NIR radiation in the range of about 400 nm to about 1200 nm, particularly in the range of about 550 nm to about 1100 nm, particularly in the range of about 800 nm to about 820 nm, for example about 810 nm, and / or in the range of about 590 nm to about 660 nm, for example about 600 nm, and / or in the range of about 920 nm to about 980 nm, for example about 940 nm. The system according to any one of Embodiments 1 to 9.

[0087] 11. The radiation source (a) is adapted to emit collimated radiation and / or is adapted to emit non-collimated radiation. The system according to any one of Embodiments 1 to 10.

[0088] 12. The radiation source (a) is an LED, a laser diode, a vcsel (vertical cavity surface emitting laser), or a laser. The system according to any one of Embodiments 1 to 11.

[0089] 13. The system according to any one of embodiments 1 to 12, wherein the radiation source (a) is adapted to emit VIS / NIR radiation continuously or intermittently over a predetermined time interval.

[0090] 14. The system according to any one of embodiments 1 to 13, wherein the radiation source (a) is adapted to emit VIS / NIR radiation to obtain a local temperature rise in the range of about 2 °C to about 10 °C, particularly in the range of about 3 °C to about 5 °C, in the irradiated body part, especially in the absorption region within the irradiated body part.

[0091] 15. The system according to embodiment 13 or 14, wherein the radiation source (a) is adapted to continuously emit VIS / NIR radiation at a power of about 10 mW to about 1 W, particularly about 20 mW to about 500 mW, and more particularly about 50 mW to about 250 mW.

[0092] 16. The system according to embodiment 13, 14 or 15, wherein the radiation source (a) is adapted to continuously emit VIS / NIR radiation over a time interval of about 0.1 second to 20 seconds, particularly about 1 second to about 5 seconds, and more particularly about 0.5 second to about 2 seconds.

[0093] 17. The system according to embodiment 13 or 14, wherein the radiation source (a) is adapted to intermittently emit VIS / NIR radiation at a power of about 10 mW to about 5 W, particularly about 20 mW to about 1 W, and more particularly about 50 mW to about 500 mW.

[0094] 18. The system according to embodiment 13, 14 or 17, wherein the radiation source (a) is adapted to intermittently emit VIS / NIR radiation over a time interval of about 0.1 second to about 20 seconds, particularly about 0.2 second to about 5 seconds, and more particularly about 0.5 second to about 2 seconds.

[0095] 19. The system according to embodiment 13, 14, 17 or 18, wherein the radiation source (a) is adapted to intermittently emit VIS / NIR radiation at a pulse frequency of about 1 Hz to about 1 MHz.

[0096] 20. The system according to any one of embodiments 1 to 19, wherein the radiation source (a) is a multi-wavelength radiation source, and in particular, the radiation source emits VIS / NIR radiation of several, for example, 2, 3, 4, 6, 8, 10 or more different wavelengths or wavelength ranges, for example, from about 400 nm to about 1200 nm, and more particularly from about 450 nm to about 900 nm, which can be selected from, for example, about 470 nm, about 520 nm, about 590 nm, about 650 nm, about 750 nm and about 810 nm.

[0097] 21. The system according to any one of embodiments 1 to 20, wherein the radiation source (a) is provided on the side of the body part opposite to the sensing unit (b).

[0098] 22. The system according to any one of embodiments 1 to 21, wherein at least one radiation source (a) is provided on the side of the body part such that the radiation can be directly emitted to the body part without passing through a part of the system.

[0099] 23. The system according to any one of embodiments 1 to 22, wherein at least one radiation source (a) is provided on the side of the body part such that the radiation can be directly emitted into the body part without passing through the horny part of the body surface, for example, a fingernail.

[0100] 24. The system according to any one of embodiments 1 to 23, wherein the sensing unit (b) is adapted to detect IR radiation self-emitted from the previously irradiated body part.

[0101] 25. The system according to any one of embodiments 1 to 24, wherein the sensing unit (b) is adapted to detect IR radiation emitted from an absorption region within the previously irradiated body part, and the absorption region shows an increase in the emission of IR radiation in the wavelength range of about 5 μm to about 12 μm with a locally increased temperature.

[0102] 26. The sensing unit (b) comprises at least one first sensor, at least one second sensor, and optionally at least one third sensor, wherein the at least one first sensor is adapted to detect IR radiation having at least one wavelength or wavelength range such that the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, the at least one second sensor is adapted to detect IR radiation having at least one wavelength or wavelength range such that the intensity of the detected IR radiation does not substantially depend on the concentration of a physiological parameter in the body fluid of the subject, and the at least one third sensor, when present, is (i) adapted to detect unspecified IR radiation, (ii) adapted to detect unspecified VIS / NIR radiation, (iii) adapted to detect VIS / NIR radiation having a wavelength such that the intensity of the detected VIS / NIR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, and / or (iv) a temperature sensor for measuring the temperature of a body part. The system according to any one of embodiments 1 to 25.

[0103] 27. The system according to embodiment 26, wherein the at least one first sensor and the at least one second sensor each comprise a filter element that is optically transparent at a predetermined wavelength or wavelength range, and optionally a lens element.

[0104] 28. The system according to embodiment 26 or 27, comprising at least two different first sensors adapted to detect IR radiation having at least two different wavelengths or wavelength ranges.

[0105] 29. The system according to embodiment 26, 27 or 28, wherein at least one first sensor is adapted to detect IR radiation having a first wavelength or wavelength range, and at least one other first sensor is adapted to detect IR radiation having a second wavelength range, the second wavelength range including the first wavelength or wavelength range and further including another wavelength or wavelength range.

[0106] 30. The system according to embodiment 29, wherein the system is for measuring glucose in blood, a first sensor is adapted to detect IR radiation having a wavelength of about 9.2 μm, and another first sensor is adapted to detect IR radiation having a wavelength range from about 9.2 μm to about 9.6 μm.

[0107] 31. The system according to embodiment 29, wherein the system is for measuring glucose in blood, a first sensor is adapted to detect IR radiation having a wavelength of about 9.6 μm, and another first sensor is adapted to detect IR radiation having a wavelength range from about 9.4 μm to about 9.6 μm.

[0108] 32. The system according to any one of embodiments 26 to 31, comprising at least two different second sensors adapted to detect IR radiation having at least two different wavelengths or wavelength ranges.

[0109] 33. The system according to embodiment 32, wherein the system is for measuring glucose in blood, a second sensor is adapted to detect IR radiation having a wavelength or wavelength range from about 8.6 μm to 9.0 μm, and another second sensor is adapted to detect IR radiation having a wavelength or wavelength range from about 9.8 μm to about 10.2 μm.

[0110] 34. The system is for measuring glucose in blood, a second sensor is adapted to detect IR radiation having a wavelength or wavelength range of about 7.8 μm to about 8.2 μm, and at least one additional second sensor as an optional means is adapted to detect IR radiation having a wavelength or wavelength range of about 8.6 μm to 9.0 μm and / or to detect IR radiation having a wavelength or wavelength range of about 9.8 μm to about 10.2 μm, the system according to any one of embodiments 26 to 32.

[0111] 35. The system is for measuring glucose in blood and comprises at least one third sensor adapted to detect VIS / NIR radiation, particularly VIS / NIR radiation having a wavelength of about 940 nm, the system according to any one of embodiments 26 to 34.

[0112] 36. The sensing unit (b) comprises at least one sensor adapted to detect IR radiation having different wavelengths or wavelength ranges separately in a time-dependent manner, in at least one first time interval, the sensor is adapted to detect IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, in at least one second time interval, the sensor is adapted to detect IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation does not substantially depend on the concentration of a physiological parameter in the body fluid of the subject, the system according to any one of embodiments 1 to 35.

[0113] 37. The sensing unit (b) comprises at least one sensor comprising a plurality of filters adapted to transmit IR radiation having different wavelengths or wavelength ranges, the system according to embodiment 36.

[0114] 38. The system according to embodiment 36 or 37, wherein the sensor comprises a shutter wheel and / or a filter wheel.

[0115] 39. The system according to embodiment 38, wherein the shutter wheel comprises a plurality of openings, and at least some of the openings comprise a filter element that is optically transparent at a predetermined wavelength or wavelength range, and a lens element as an optional means.

[0116] 40. The system according to embodiment 36, wherein the sensing unit (b) comprises at least one sensor that is a Fabry - Perot interferometer.

[0117] 41. The system according to any one of embodiments 1 to 40, wherein the sensing unit (b) comprises at least one spectral sensor or line sensor, or an array of spectral or line sensors.

[0118] 42. The system according to any one of embodiments 36 to 41, wherein the sensing unit (b) comprises a single sensor.

[0119] 43. The system according to any one of embodiments 1 to 42, wherein the sensing unit (b) comprises at least one sensor that is an optical detector, particularly an optical photovoltaic detector, and more particularly an InAsSb - based detector.

[0120] 44. The system according to any one of embodiments 1 to 43, wherein the sensing unit (b) comprises at least one sensor that is a thermopile or a bolometer.

[0121] 45. The system according to any one of embodiments 1 to 44, wherein the analysis unit (c) comprises a microcontroller adapted to quantitatively measure the concentration of a physiological parameter and / or non - quantitatively measure the rate of change of a physiological parameter.

[0122] 46. The system according to any one of embodiments 1 to 45, adapted to detect IR radiation from a body part selected from fingertip, earlobe, wrist, forearm and upper arm.

[0123] 47. The system according to any one of embodiments 1 to 46, wherein the radiation source (a) and the sensing unit (b) are arranged on the same side of the body part.

[0124] 48. The system according to any one of embodiments 1 to 47, wherein the radiation source (a) and the sensing unit (b) are arranged on different sides of the body part, particularly opposite sides.

[0125] 49. The system according to any one of embodiments 1 to 48, wherein the first radiation source (a) is arranged on the same side of the body part as the sensing unit (b), and a further radiation source (a) is arranged on a different side, particularly on the side of the body part opposite to the sensing unit.

[0126] 50. The system according to any one of embodiments 1 to 49, further comprising a cover at least partially made of a material optically transparent to the VIS / NIR radiation emitted by the radiation source (a) and / or the IR radiation detected by the sensing unit (b).

[0127] 51. The cover of the system according to embodiment 50 is at least partially made of CaF2 and / or BaF2 and / or at least partially made of a plastic material transparent to IR radiation and optionally also transparent to VIS / NIR radiation by any means.

[0128] 52. The optically transparent material of the cover has a thickness of about 0.2 mm to about 2 mm, particularly about 0.5 mm to about 1.5 mm, and more particularly about 1 mm, of the system according to embodiment 50 or 51.

[0129] 53. The system according to any one of embodiments 1 to 52, further comprising an optically transparent cover for IR radiation detected by the sensing unit, particularly in the IR wavelength range from about 5 μm to about 12 μm or a partial range thereof, wherein the material is at least partially made of a material that is substantially optically impermeable to VIS / NIR radiation emitted by a radiation source (a) as an optional means.

[0130] 54. The system according to any one of embodiments 1 to 53, further comprising a cover for focusing IR radiation from a body part onto the sensing unit (b), particularly onto at least one sensor of the sensing unit (b).

[0131] 55. The system according to embodiment 54, wherein the cover comprises an IR Fresnel lens or an array comprising a plurality of IR Fresnel lenses.

[0132] 56. Use of the system according to any one of embodiments 1 to 55 for non-invasively measuring a physiological parameter in a subject's body fluid.

[0133] 57. The use according to embodiment 56, wherein the physiological parameter is glucose and the body fluid is blood.

[0134] 58. The use according to embodiment 56 or 57, wherein the physiological parameter is measured quantitatively.

[0135] 59. The use according to embodiment 56, 57 or 58, wherein the rate of change of the physiological parameter rate is measured non-quantitatively.

[0136] 60. A method for non-invasively measuring a physiological parameter in a subject's body fluid, the method comprising (a) Irradiating a body part of the subject with visible (VIS) / near-infrared (NIR) radiation in a wavelength range of about 500 nm to about 1500 nm or about 500 nm to about 1500 nm, wherein the irradiated body part absorbs electromagnetic energy, resulting in a local increase in tissue temperature and an increase in the emission of IR radiation in a wavelength range of about 5 μm to about 12 μm; (b) Detecting IR radiation in a wavelength range of about 5 μm to about 12 μm emitted from a previously irradiated body part of the subject, separately, (i) detecting IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, and (ii) detecting IR radiation having at least one wavelength or wavelength range in which the intensity of the detected IR radiation does not substantially depend on the concentration of a physiological parameter in the body fluid of the subject comprising the steps of; (c) Analyzing the detected IR radiation to qualitatively and / or quantitatively measure a physiological parameter A method comprising.

[0137] 61. The method according to embodiment 60, wherein the body part is not irradiated by an external IR radiation source in a wavelength range of about 5 μm to about 12 μm.

[0138] 62. The method according to embodiment 60 or 61, wherein the physiological parameter is glucose and the body fluid is blood.

[0139] 63. The method according to embodiment 60, 61 or 62, wherein the physiological parameter is measured quantitatively.

[0140] 64. The method according to any one of embodiments 60 to 63, wherein the rate of change of the physiological parameter rate is measured non-quantitatively.

Claims

1. 1. A non-invasive system for measuring a physiological parameter in a bodily fluid of a subject, the system comprising: (a) a radiation source adapted to emit visible (VIS) / near infrared (NIR) radiation in the range of about 400 nm to about 1500 nm or 500 nm to about 1500 nm to a body part of the subject, the body part being selected from, inter alia, a fingertip, an earlobe, a wrist, a forearm and an upper arm, the irradiated body part absorbing electromagnetic energy resulting in a local increase in tissue temperature and an increased emission of IR radiation in the wavelength range of about 5 μm to about 12 μm; (b) a sensing unit for detecting IR radiation in the range of about 5 μm to about 12 μm emitted from the previously irradiated body part of the subject, (i) detecting IR radiation having at least one wavelength or range of wavelengths, the intensity of the detected IR radiation being dependent on the concentration of said physiological parameter in said body fluid of said subject; and (ii) detecting IR radiation having at least one wavelength or range of wavelengths, the intensity of the detected IR radiation being substantially independent of the concentration of said physiological parameter in said body fluid of said subject. an adapted sensing unit; (c) an analysis unit for qualitatively and / or quantitatively measuring the physiological parameter based on the IR radiation detected in the sensing unit (b); A system comprising:

2. The system of claim 1 , wherein the system does not include an external radiation source for emitting IR radiation in the wavelength range of about 5 μm to about 12 μm.

3. The system of claim 1 or 2, wherein the physiological parameter is glucose and the body fluid is glucose.

4. 4. The system according to claim 1, wherein the system is adapted to measure glucose in blood, and the sensing unit is adapted to detect IR radiation having at least one wavelength or wavelength range, the intensity of the detected IR radiation being dependent on the concentration of glucose in the blood of the subject, and the at least one wavelength or wavelength range is selected from, in particular, a wavelength of about 9.2 μm, a wavelength of about 9.4 μm, a wavelength of about 9.6 μm, a wavelength range including at least two of the wavelengths of about 9.2 μm, about 9.4 μm and about 9.6 μm, a wavelength range including the wavelengths of about 9.2 μm, about 9.4 μm and about 9.6 μm, or any combination thereof.

5. 5. The system according to claim 1, wherein the radiation source (a) is adapted to emit VIS / NIR radiation in the range of about 550 nm to about 1200 nm, in particular in the range of about 800 nm to about 820 nm, such as about 810 nm, and / or in the range of about 590 nm to about 610 nm, such as about 600 nm, and / or in the range of about 920 nm to about 980 nm, such as about 940 nm.

6. The system of claim 1 , wherein the radiation source (a) is an LED, a laser diode, a vcsel (Vertical Cavity Surface Emitting Laser), or a laser.

7. The system according to any one of claims 1 to 6, wherein the radiation source (a) is a multi-wavelength radiation source.

8. the sensing unit (b) comprises at least one first sensor, at least one second sensor, and optionally at least one third sensor; the at least one first sensor is adapted to detect IR radiation having at least one wavelength or range of wavelengths, wherein an intensity of the detected IR radiation is dependent on a concentration of the physiological parameter in the body fluid of the subject; the at least one second sensor is adapted to detect IR radiation having at least one wavelength or range of wavelengths in which an intensity of the detected IR radiation is substantially independent of a concentration of the physiological parameter in the body fluid of the subject; The at least one third sensor, if present, is: (i) adapted to detect non-specific IR radiation; (ii) adapted to detect non-specific VIS / NIR radiation; (iii) adapted to detect VIS / NIR radiation having a wavelength where the intensity of the detected VIS / NIR radiation depends on the concentration of the physiological parameter in the body fluid of the subject; and / or (iv) a temperature sensor for measuring the temperature of the body part. A system according to any one of claims 1 to 7.

9. At least one first sensor is adapted to detect IR radiation having a first wavelength or range of wavelengths and at least one other first sensor is adapted to detect IR radiation having a second range of wavelengths; the second wavelength range includes the first wavelength or wavelength range and a further wavelength or wavelength range; The system is particularly adapted to measure glucose in blood, the first sensor being adapted to detect IR radiation having a wavelength of about 9.2 μm, and the other first sensor being adapted to detect IR radiation having a wavelength range of about 9.2 μm to about 9.6 μm, the wavelength range of about 9.2 μm to about 9.6 μm further comprising a first wavelength of about 9.2 μm and at least one wavelength of about 9.4 μm and about 9.6 μm, in particular further comprising wavelengths of about 9.4 μm and about 9.6 μm. The system of claim 8.

10. the system comprising at least two different second sensors adapted to detect IR radiation having at least two different wavelengths or wavelength ranges; The system is particularly adapted to measure glucose in blood, the second sensor being adapted to detect IR radiation having a wavelength or range of wavelengths from about 8.6 μm to 9.0 μm, and the other second sensor being adapted to detect IR radiation having a wavelength or range of wavelengths from about 9.8 μm to about 10.2 μm.

10. A system according to claim 8 or 9.

11. the sensing unit (b) comprises at least one sensor adapted to separately detect IR radiation having different wavelengths or wavelength ranges in a time-dependent manner, during at least one first time interval, the sensor is adapted to detect IR radiation having at least one wavelength or range of wavelengths, the intensity of the detected IR radiation being dependent on a concentration of the physiological parameter in the body fluid of the subject; during at least one second time interval, the sensor is adapted to detect IR radiation having at least one wavelength or range of wavelengths, wherein an intensity of the detected IR radiation is substantially independent of a concentration of the physiological parameter in the body fluid of the subject. A system according to any one of claims 1 to 10.

12. The system according to claim 1 , wherein the sensing unit (b) comprises a single sensor.

13. The system according to any one of claims 1 to 12, wherein the sensing unit (b) comprises at least one sensor which is an optical detector, in particular an optical photovoltaic detector, more in particular an InAsSb-based detector.

14. the system further comprising a cover at least partially made from a material that is optically transparent to the IR / VIS radiation emitted by the radiation source (a) and the IR radiation detected by the sensing unit (b); The cover is made of CaF ２ and / or BaF ２ and / or at least partially made from a plastic material transparent to IR radiation and optionally transparent to VIS / NIR radiation, The optically transparent material of the cover has a thickness of about 0.2 mm to about 2 mm, particularly about 0.5 mm to about 1.5 mm, and more particularly about 1 mm. A system according to any one of claims 1 to 13.

15. 15. The system of claim 1, further comprising a cover for focusing IR radiation from the body part onto the sensing unit (b), in particular onto the at least one sensor of the sensing unit (b), in particular the cover comprising an IR Fresnel lens or an array comprising a plurality of IR Fresnel lenses.

16. 16. Use of a system according to any one of claims 1 to 15 for non-invasively measuring a physiological parameter in a body fluid of a subject, wherein the physiological parameter is glucose, the body fluid is blood and the rate of change of the amount of glucose in the blood is measured.

17. 1. A method for non-invasively measuring a physiological parameter in a body fluid of a subject, said method comprising: (a) irradiating a body part of the subject with visible (VIS) / near infrared (NIR) radiation in the wavelength range of about 400 nm to about 1500 nm or about 500 nm to about 1500 nm, wherein the irradiated body part absorbs electromagnetic energy resulting in a local increase in tissue temperature and an increase in emission of IR radiation in the wavelength range of about 5 μm to about 12 μm; (b) detecting IR radiation in the wavelength range of about 5 μm to about 12 μm emitted from the previously irradiated body part of the subject; Separately, (i) detecting IR radiation having at least one wavelength or range of wavelengths, wherein the intensity of the detected IR radiation is dependent on the concentration of said physiological parameter in said body fluid of said subject; and (ii) detecting IR radiation having at least one wavelength or range of wavelengths, wherein the intensity of the detected IR radiation is substantially independent of the concentration of said physiological parameter in said body fluid of said subject. and (c) analyzing the detected IR radiation to qualitatively and / or quantitatively measure said physiological parameter; A method comprising:

18. 20. The method of claim 17, wherein the body site is not illuminated by an external source of IR radiation in the wavelength range of about 5 μm to about 12 μm.

19. 19. The method of claim 17 or 18, wherein the physiological parameter is glucose and the body fluid is blood.

20. 20. The method according to any one of claims 17 to 19, wherein the concentration of the physiological parameter is measured quantitatively and / or the rate of change of the amount of the physiological parameter is measured, in particular non-quantitatively.

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