Active miniaturized sensing system and method

Abstract

The present invention relates to a non-invasive active sensing system for determining a physiological parameter in a body fluid of a subject. Further, the present invention relates to a non-invasive method for determining a physiological parameter in a body fluid of a subject.

Description

TECHNICAL FIELD

[0001] The present invention relates to a non-invasive active sensing system for determining a physiological parameter in a body fluid of a subject. Further, the present invention relates to a non-invasive method for determining a physiological parameter in a body fluid of a subject. BACKGROUND

[0002] In 2016, approximately 415 million people suffered from diabetes. By 2040, the population is expected to increase to more than 6.4 billion. Since people suffering from diabetes are at risk of complications such as blindness, kidney disease, heart disease, and stroke, it is necessary to control the disease by closely monitoring blood glucose levels.

[0003] Currently, the determination of blood glucose is mainly based on invasive systems and methods, wherein either a blood sample is taken and subsequently tested in vitro, or a sensor is implanted to determine the glucose level in the body. The disadvantage of these invasive systems and methods is that they are painful or inconvenient.

[0004] Therefore, there is a need to develop a system and method which allows for a reliable non-invasive determination of glucose and / or a physiological parameter. SUMMARY

[0005] According to the present invention, it is feasible to determine a physiological parameter simply, quickly and reliably using non-invasive systems and methods. These systems and methods involve irradiating a body part of a subject, in particular a human subject, with visual (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 detecting IR radiation emitted from the irradiated body part of the subject in the range of about 5 pm to about 12 pm. Surprisingly, the present inventors have found that irradiating a body part, such as a fingertip, earlobe, wrist or forearm, with short wavelength radiation and detecting long wavelength radiation emitted from the irradiated body part allows for the determination of a physiological parameter, such as glucose in a body fluid, such as blood.

[0006] Irradiating a body part with VIS / NIR radiation according to the present invention causes an energy absorption within the area of the irradiated body part. The energy absorption in this irradiated area, i.e. absorption area, leads to a local increase of the tissue temperature within the irradiated body part, in particular within the absorption area, which in turn causes an increased emission of IR radiation from the irradiated body part, in particular from the absorption area, including an increased emission of IR radiation in the range of about 5 pm to about 12 pm. Thus, the detection of IR radiation emitted from the irradiated body part is facilitated and significantly improved.

[0007] A first aspect of the present application relates to a non-invasive system for determining a physiological parameter, in particular glucose, in a body fluid of a subject, comprising:

[0008] (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 towards a body part of the subject, wherein the body part is in particular selected from the group consisting of a fingertip, an earlobe, a wrist, a forearm and an upper arm,

[0009] (b) a sensing unit for detecting IR radiation in the range of about 5 pm to about 12 pm emitted from the irradiated body part of the subject, wherein the sensing unit is adapted to (i) detect IR radiation having at least one wavelength or wavelength range where the intensity of the detected IR radiation depends on the concentration of the physiological parameter in the body fluid of the subject and to (ii) detect IR radiation having at least one wavelength or wavelength range where the intensity of the detected IR radiation is essentially independent of the concentration of the physiological parameter in the body fluid of the subject, and

[0010] (c) an analyzing unit for qualitatively and / or quantitatively determining the physiological parameter based on the detected IR radiation in sensing unit (b).

[0011] A further aspect of the present application relates to non-invasively determining a physiological parameter in a body fluid of a subject using the above system, in particular wherein the physiological parameter is glucose and the body fluid is blood.

[0012] Yet another aspect of the present application relates to a method for non-invasively determining a physiological parameter, in particular glucose, in a body fluid of a subject, comprising the following steps:

[0013] (a) irradiating a body part of the 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,

[0014] (b) detecting IR radiation in the range of about 5 pm to about 12 pm emitted from the irradiated body part of the subject, including separately (i) detecting IR radiation having at least one wavelength or wavelength range where the intensity of the detected IR radiation depends on the concentration of the physiological parameter in the body fluid of the subject and (ii) detecting IR radiation having at least one wavelength or wavelength range where the intensity of the detected IR radiation is essentially independent of the concentration of the physiological parameter in the body fluid of the subject, and

[0015] (c) analyzing the detected IR radiation for qualitatively and / or quantitatively determining the physiological parameter. DETAILED DESCRIPTION

[0016] The present application relates to determining a physiological parameter by detecting IR radiation from a previously irradiated body site of a subject, in particular a human subject, in a wavelength range of about 5 pm to about 12 pm, in particular in a range of about 8 pm to about 10 pm. The physiological parameter can be any compound having a characteristic absorption band in this wavelength range. For example, the physiological parameter is glucose or another clinically relevant analyte such as lactate or troponin.

[0017] In a certain embodiment of the present application, the system is adapted for non-invasively determining glucose in blood. In this embodiment, the IR radiation is detected at a glucose-specific wavelength or wavelength range in which glucose has a characteristic absorption band and the intensity of the detected IR radiation depends on the concentration of glucose in blood. More specifically, the glucose-specific wavelength or wavelength range is selected from a wavelength of about 9.2 pm, a wavelength of about 9.4 pm, a wavelength of about 9.6 pm, a wavelength range comprising at least two of the wavelengths of about 9.2 pm, about 9.4 pm and about 9.6 pm, a wavelength range comprising all three of the wavelengths of about 9.2 pm, about 9.4 pm and about 9.6 pm or any combination thereof. Furthermore, the IR radiation is detected at a reference wavelength or wavelength range in which glucose does not have a characteristic absorption band and in particular an absorption minimum and the intensity of the detected IR radiation is essentially independent of the concentration of glucose in blood. More specifically, the reference wavelength or wavelength range is selected from a wavelength or wavelength range between about 8.7 pm and about 9.0 pm, a wavelength or wavelength range between about 9.7 pm and about 10.2 pm or any combination thereof.

[0018] As mentioned above, the present application is based on irradiating body tissue with electromagnetic radiation in a wavelength range between about 500 nm and about 1500 nm (VIS / NIR radiation) and detecting electromagnetic radiation emitted from the irradiated body site in a wavelength range between about 5 pm and about 15 pm (IR radiation). Due to local energy absorption, irradiating a body site with VIS / NIR radiation leads to an enhanced spontaneous emission of IR radiation from said body site which results in a local temperature increase. Thus, the spontaneous emission of IR radiation from an irradiated body site is increased due to the previous irradiation of said body site with VIS / NIR radiation. Therefore, it is not required to irradiate the body site with an IR radiation source in a wavelength range between about 5 pm and about 15 pm. Thus, in certain embodiments, the system of the present application does not comprise an external IR radiation source, in particular in certain embodiments, the system of the present application does not comprise an external IR radiation source adapted for irradiating the body site from which the detected IR radiation is emitted.

[0019] Figure 1The penetration depth [mm] of electromagnetic radiation in human tissue is shown, depending on the wavelength [mm]. It can be seen that the penetration depth depends on the wavelength. In the visible (VIS) / near infrared (NIR) wavelength range between about 400 nm and about 1500 nm, in particular in the range of about 500 nm to about 1500 nm or in the range of about 400 nm to about 1200 nm, more particularly in the range of about 550 nm to about 1200 nm, there is a penetration depth of about 1 mm or more, in particular of about 3 mm or more. The body part irradiated with radiation will thus absorb electromagnetic energy, resulting in a local increase in tissue temperature. This in turn leads to an increased emission of longer wavelength IR radiation (e.g. IR radiation in the wavelength range of about 5 pm to about 12 pm), for which certain organic compounds present in the body fluids (i.e. physiological parameters) show an absorption band. This allows a quantitative or qualitative determination of such parameters according to the above-mentioned aspects of the present application.

[0020] In certain embodiments, the VIS / NIR radiation emitted into the body part is in the range of about 550 nm to about 1000 nm, in particular in the range of about 800 nm to about 820 nm, e.g. about 810 nm, and / or in the range of about 590 nm to about 660 nm, e.g. about 600 nm, and / or in the range of about 920 nm to about 980 nm, e.g. about 940 nm. In certain embodiments, the VIS / NIR radiation emitted into the body is in the range of about 450 nm to about 800 nm.

[0021] Figure 2 The relative absorption coefficients of certain compounds present in the human body are shown, depending on the wavelength in the range between 400 nm and 1100 nm. In particular, the wavelengths of about 600 nm and about 810 nm are indicated, at which radiation can be emitted into the body part. In the wavelength range of about 500 nm to about 1050 nm, the absorption of water (H20) is relatively low. In addition, the main blood components hemoglobin (Hb) and oxyhemoglobin (Hboxy) show similar absorption coefficients. The absorption coefficient of the skin pigment melamine decreases with increasing wavelength.

[0022] In embodiments of the present application, the radiation source (a) is adapted to emit VIS / NIR radiation in the range of about 920 nm to about 960 nm, e.g. about 940 nm, into the body part. This irradiation wavelength can be used alone or in combination with at least one further irradiation wavelength. As Figure 3As shown in the middle, glucose has an absorption band at a wavelength of 940 nm. Thus, illumination at about 940 nm wavelength leads to a selective excitation of glucose molecules and can lead to a stronger absorption of glucose molecules in this IR wavelength range, in particular in the wavelength range of about 5 pm to about 12 pm.

[0023] According to embodiments of the present application, the radiation source (a) is adapted to emit VIS / NIR radiation in the range of about 920 nm to about 980 nm, e.g. about 940 nm, into the 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, wherein the intensity of the detected VIS / NIR radiation depends on the concentration of glucose. As mentioned above, the measurement signal in the VIS / NIR wavelength range can be combined with the measurement signal in the IR range, e.g. by means of a comparator.

[0024] In yet another embodiment, the VIS / NIR illumination occurs in combination of at least 2 different wavelengths, in particular a combination of a first wavelength of about 800 nm to about 820 nm, e.g. about 810 nm, and a second wavelength of about 920 nm to about 980 nm, e.g. about 940 nm.

[0025] Figure 4 An embodiment of the system of the present application is shown. A body part (1), e.g. a fingertip, is placed in contact with the system, which is adapted to illuminate an absorption region (2) within the body part (1).

[0026] The system comprises a cover (3) made at least partially of an optically transparent material. For example, the cover is made at least partially of CaF2and / or BaF2or a plastic material that is transparent in the IR wavelength range of about 5 pm to about 12 pm or a sub-range thereof, e.g. about 8 pm to about 12 pm, and optionally in the VIS / NIR wavelength range of about 400 nm to about 1500 nm or a sub-range thereof. A suitable IR transparent plastic material is e.g. the PolyIR plastic material commercially available from Fresnel Technologies, Fort Worth, Texas, USA. In certain embodiments, the cover can have a thickness of about 0.2 mm to about 2 mm, in particular about 0.5 mm to about 1.5 mm, more particularly about 1 mm.

[0027] The system further comprises at least one sensor (4) which can be provided with a filter element (5) and, for example, an optional lens element (not shown) which can be arranged between the sensor (4) and the filter element (5). The sensor (4) can be mounted on a circuit board (6). In addition, the system comprises at least one radiation source (9, 9a). For example, the system can comprise a radiation source (9) which is located on the same side as the sensor (4) and / or a radiation source (9a) which is located on the opposite side of the body part (1) with respect to the sensor (4). If desired, a further sensor (4) without a filter element (5) can be provided for monitoring the exact skin temperature of the subject.

[0028] The system comprises one or more sensors (4). In Figure 4 In embodiments, the system comprises four different sensors (4). The sensors can be optical detectors, in particular optical photovoltaic detectors, for example InAsSb-based detectors, which can be used in combination with a lock-in amplifier if desired. Photovoltaic detectors, for example InAsSb-based detectors, have a rise time of only a few nanoseconds and are particularly useful in settings in which the body part is intermittently illuminated. In other embodiments, the sensors can be thermal detectors, for example thermopiles or bolometers. Suitable sensors include photovoltaic detectors (for example, Hamamatsu P13894), thermopiles (for example, Heimann FICS C21 F8-14) or other types of IR sensors (for example, Sensirion STS21 or Melexis MLX90632). If desired, the sensors (4) can be provided with a filter element (5) which is able to selectively transmit radiation of a desired wavelength or wavelength range. The filter element can have a narrow bandwidth of, for example, about 50 to 100 nm, or a wider bandwidth of, for example, about 400 nm or more. The filter can be made of germanium or other filter materials which are transparent to the respective wavelengths. In addition, the sensors can be provided with a lens element, for example a microlens which is able to focus the light falling on the sensor.

[0029] In certain embodiments, the sensor surface can be coated with a noble metal, such as Au or Ag, in particular Au, in order to increase its sensitivity. Awad (Nature Scientific Reports 9: 12197 (2019)) describes such a coating which can be shaped as a Bundt pan, the contents of which are incorporated herein by reference.

[0030] In certain embodiments, the sensor is a photovoltaic detector having a surface area of about 1 mm 2 to about 10,000 mm 2 , for example about 10 mm 2 to about 1,000 mm 2miniaturized sensors. In certain embodiments, the sensors can be even more miniaturized, e.g. ASICs (Application-Specific Integrated Circuits).

[0031] In the sensing unit of the present application, at least one sensor can be an analyte-specific 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 depends on the concentration of a physiological parameter in the body fluid of the subject, and at least one sensor can 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 is essentially independent of the concentration of a physiological parameter in the body fluid of the subject.

[0032] In certain embodiments, the sensing unit (b) is adapted to detect spontaneously emitted IR radiation from the previously irradiated body site, i.e. IR radiation generated by the body heat of the subject without irradiation by an external IR source. In addition, the sensing unit (b) can be adapted to detect IR radiation emitted from an absorption region within the previously irradiated body site, wherein the absorption region has a locally elevated temperature and exhibits an increased emission of IR radiation in the wavelength range of about 5 pm to about 12 pm.

[0033] In certain embodiments, there can be at least one further sensor, e.g. (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 certain wavelength, wherein 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 the body site.

[0034] In certain embodiments, there can be at least one further analyte-specific sensor, i.e. a sensor adapted to detect VIS / NIR radiation having at least one wavelength or wavelength range in 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 can be at least one further sensor adapted to detect VIR / NIR radiation having a wavelength of about 940 nm.

[0035] In addition, the device can comprise a circuit board (7) on which the light source (9) is mounted and an active and / or passive heat sink (8).

[0036] The VIS / NIR radiation source (9, 9a, 9b) can be adapted to emit collimated radiation, e.g. a laser-based light source, and / or 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 is used, which can be adapted to emit VIS / NIR radiation in the range of about 650 nm to about 950 nm, in particular 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. A suitable VIS / NIR emitter is for example the OSLON product from Osram, such as OSLON SFH 4763.

[0037] The radiation source is adapted to emit VIS / NIR radiation in the range of about 400 nm to about 1500 nm, in particular in the range of about 500 nm to about 1500 nm. The VIS / NIR radiation can be emitted continuously or intermittently throughout the predetermined time interval.

[0038] In certain embodiments, the radiation source is adapted to cause a local increase in temperature of the irradiated body part (e.g. a fingertip), in particular of an absorption region within the irradiated body part. The local increase in temperature can be in the range of about 1 °C to about 15 °C, in particular about 2 °C to about 10 °C, and more particularly in the range of about 3 °C to about 5 °C. The locally increased temperature of the irradiated body part (e.g. a fingertip) can be in the temperature range of up to about 45 °C, up to about 40 °C or up to about 37 °C, for example in the temperature range of about 30 °C to about 35 °C or about 30 °C to about 32 °C. This local temperature increase results in an enhanced spontaneous emission of IR radiation from the irradiated body part and in particular from an absorption region within the irradiated body part.

[0039] In certain embodiments, the radiation source can be adapted to emit radiation continuously at a power of about 10 mW to about 1 W, in particular about 20 mW to about 500 mW, more particularly about 50 mW to about 250 mW, even more particularly about 100 mW to about 200 mW, for example about 150 mW, for a duration of about 0.1 to about 20 s, in particular about 0.2 s to about 5 s, more particularly about 0.5 s to about 2 s, for example about 1 s.

[0040] In further embodiments, the radiation source can be adapted to intermittently emit radiation at a power of about 10 mW to about 5 W, in particular about 20 mW to about 1 W and more particularly about 50 mW to about 500 mW for a time interval of about 0.1 s to about 20 s, in particular about 0.2 s to about 5 s and more particularly about 0.5 s to about 2 s. The radiation can be intermittently emitted at a pulse frequency of about 1 Hz to about 1 MHz.

[0041] In further embodiments, the radiation source can be adapted to emit VIS / NIR radiation of a plurality of different wavelengths, for example, 2, 3, 4, 5, 6, 7, 8 or even more different wavelengths. For example, the radiation source can be a multi-LED chip. The use of a multi-wavelength radiation source allows to adjust the predetermined penetration depth of the electromagnetic radiation into the tissue of the body part being irradiated according to the specific characteristics of the body part, for example, pigmentation, skin thickness, presence or absence of stratum corneum. As shown in the above Figure 1 penetration depth into the body tissue varies with the wavelength and, if desired, the use of VIS / NIR radiation having different wavelengths or combinations of different wavelengths can be individually adjusted for each subject and / or each body part.

[0042] In certain embodiments, the radiation source (a) is a multi-wavelength radiation source adapted to emit VIS / NIR radiation at several different wavelengths or wavelength ranges, for example, between about 400 nm to about 1200 nm, more particularly between about 450 nm and about 900 nm, for example, at least 2, 3, 4, 6 or 8 wavelengths can be selected from about 470 nm, about 520 nm, about 590 nm, about 650 nm, about 750 nm and about 810 nm.

[0043] Further embodiments of the system of the present application are shown in Figure 5 Here, a single radiation source (9a) is provided on the side of the body part (1) opposite to the sensing unit comprising at least one sensor (4) provided with a filter (5) and a further sensor (4a) provided with a filter (5a). In certain embodiments, the sensor (4a) is an optical sensor, for example, a photodiode. It is adapted for reference measurements of the transmitted radiation from the radiation source (9a), for example, for measuring radiation at a wavelength of about 600 nm and / or about 810 nm and / or about 940 nm. For this purpose, the filter element (5a) can be a bandpass filter at about 600 nm and / or 810 nm and / or 940 nm.

[0044] Yet another embodiment of the present application is shown in Figure 6is shown in Fig. 2. Here, the radiation source (9b) is provided on one side of the body part (1) (e.g. a fingertip), wherein direct access to the absorption region (2) within the body part (1) is provided through the skin of the body part without the need for the radiation to pass through a cover structure of the device and / or without the need for the radiation to pass through a keratinous structure on the body surface (e.g. a nail and / or keratinous skin). Thereby, interferences, e.g. from the cover structure or from the keratinous keratinous skin or nail material and optionally nail polish, can be reduced or eliminated. According to this embodiment, a single radiation source (9b) or a plurality of radiation sources (9b), e.g. 2, 3, 4, 6 or 8 radiation sources, can be provided at positions around the circumference of the body part (1) (e.g. a fingertip). If a plurality of radiation sources is present, they are preferably adapted to emit radiation into a single absorption region (2) within the body part, which can be about 3 mm to about 5 mm below the body surface.

[0045] Yet another embodiment of the present application is shown in Figure 7 is shown in Fig. 2. Here, the radiation source (9b) is provided on one side of the body part (1) (e.g. a fingertip), wherein direct access to the absorption region (2) within the body part (1) is provided through the skin of the body part without the need for the radiation to pass through a cover structure of the device and / or without the need for the radiation to pass through a keratinous structure on the body surface (e.g. a nail and / or keratinous skin). Thereby, interferences, e.g. from the cover structure or from the keratinous keratinous skin or nail material and optionally nail polish, can be reduced or eliminated. According to this embodiment, a single radiation source (9b) or a plurality of radiation sources (9b), e.g. 2, 3, 4, 6 or 8 radiation sources, can be provided at positions around the circumference of the body part (1) (e.g. a fingertip). If a plurality of radiation sources is present, they are preferably adapted to emit radiation into a single absorption region (2) within the body part, which can be about 3 mm to about 5 mm below the body surface.

[0046] Additionally, Figure 7 is shown in Fig. 2. Here, the radiation source (9b) is provided on one side of the body part (1) (e.g. a fingertip), wherein direct access to the absorption region (2) within the body part (1) is provided through the skin of the body part without the need for the radiation to pass through a cover structure of the device and / or without the need for the radiation to pass through a keratinous structure on the body surface (e.g. a nail and / or keratinous skin). Thereby, interferences, e.g. from the cover structure or from the keratinous keratinous skin or nail material and optionally nail polish, can be reduced or eliminated. According to this embodiment, a single radiation source (9b) or a plurality of radiation sources (9b), e.g. 2, 3, 4, 6 or 8 radiation sources, can be provided at positions around the circumference of the body part (1) (e.g. a fingertip). If a plurality of radiation sources is present, they are preferably adapted to emit radiation into a single absorption region (2) within the body part, which can be about 3 mm to about 5 mm below the body surface. Figure 6as shown in Figure 4 and 5 as shown in

[0047] As shown in Figure 4 and 5 The system of the present application can comprise a plurality of different sensors (4), as shown in

[0048] Additionally, the sensing unit can comprise a plurality of reference sensors, which are adapted to detect reference radiation at different wavelengths or wavelength ranges. For example, when determining glucose, a reference sensor can be adapted to detect radiation having a wavelength range between about 8.6 pm and about 9.0 pm. Another reference sensor is adapted to detect radiation at a wavelength or wavelength range between about 9.8 pm and about 10.2 pm.

[0049] Yet another embodiment of the present application is shown in Figure 8 In this embodiment, a support (16) for a body part (1), e.g. a fingertip, is provided, wherein the support (16) comprises an opening adapted to receive a portion (15) of the body part (1). For example, the support can comprise a ring-shaped structure having an opening in its center, e.g. a substantially circular opening. The system is adapted to press the body part (1) onto the opening in the support (16) such that a portion (15) of the body part (1), e.g. a portion of a fingertip, is pressed into the opening. Thus, tissue comprising blood vessels within the portion (15) is compressed, resulting in an increased blood volume of the capillaries within the portion (15). Thereby, the signal strength can be increased and thus the sensitivity and / or accuracy of the measurement.

[0050] Additionally, Figure 8 The system of the present application comprises a cover (3), which can be formed as an IR-Fresnel lens, as outlined above in Figure 7described in the context of Fig. 1. However, it should be noted that other caps are suitable as well. Furthermore, a radiation source (9a) is shown which is provided on the opposite side of the body part with respect to the position of the sensing unit comprising the sensor (4). However, it should be noted that one or more radiation sources can also be arranged in a circumferential arrangement around the body part (1), for example as shown in Figure 6 Figure 4 and 5

[0051] In Fig. 1, measurements at a plurality of analyte-specific wavelengths / wavelength ranges and a reference wavelength / wavelength range are shown. Figure 9 The absorption signal of glucose (24) has three different peaks at about 9.2 pm, about 9.4 pm and about 9.6 pm. A first glucose-specific sensor can be adapted to measure only the peak at 9.2 pm. Such a sensor would be fitted with a filter element that can only transmit radiation within a narrow range (22). Thus, the sensor is able to selectively detect radiation within this narrow range. Another glucose-specific sensor can be adapted to measure radiation within a wider range between about 9.1 pm and about 9.7 pm, thereby encompassing the peaks at about 9.2 pm, 9.4 pm and 9.6 pm. This sensor can be fitted with a filter element that can transmit radiation within a wider range (21).

[0052] Two reference sensors can be provided, wherein the reference sensors are each provided with a filter element that can transmit radiation within a range of about 8.6 pm and about 9.0 pm, in particular about 8.8 pm - 8.9 pm (20) and / or radiation within a range of about 9.8 pm and about 10.2 pm, in particular about 9.9 pm - 10.1 pm (23).

[0053] Parallel and separate measurements at a wavelength of about 9.2 pm and within a wavelength range that encompasses the peak at 9.2 pm and also at least one of the other peaks, in particular the peak at about 9.6 pm, have the further advantage that they allow to determine whether the blood of the subject contains ethanol. Since ethanol and other alcohols have an absorption band at a wavelength of about 9.6 pm, but not at a wavelength of about 9.2 pm, the ratio of the peak at 9.2 pm to the peak at 9.6 pm can be used to calculate a determination and optionally a correction of the interference caused by blood alcohol.

[0054]

[0055] ​​​In an alternative embodiment, the first glucose specific sensor can be adapted to measure only the peak at 9.6 pm. Such a sensor would be provided with a filter element that can only transmit radiation within a narrow range. A further glucose specific sensor can be adapted to measure radiation within a broader range between about 9.4 pm and about 9.6 pm, thereby encompassing the peaks at about 9.4 pm and about 9.6 pm and not encompassing the peak at 9.2 pm. This sensor can be provided with a filter element that can transmit radiation within a broader range.

[0056] In a further alternative embodiment, a reference sensor can be provided that is provided with a filter element that can transmit radiation within a range of wavelengths of about 7.8 pm and about 8.2 pm, in particular about 7.9 pm - 8.1 pm, optionally in combination with at least one further reference sensor that is provided with a filter element that can transmit radiation within a range of wavelengths of about 8.8 pm - 9.2 pm and / or radiation of wavelengths of about 9.8 pm - 10.2 pm, respectively.

[0057] In yet another embodiment of the present application, the system can comprise a sensor that is adapted for time-dependent detection of IR radiation having different wavelengths or wavelength ranges. In this embodiment, the system can be provided with a sensor that comprises a plurality of filters that are adapted to transmit IR radiation having different wavelengths or wavelength ranges, wherein said filters can be placed on the sensor during different phases of a measurement cycle, thereby allowing detection of different wavelengths or wavelength ranges within the measurement cycle. Such an embodiment is shown in Figure 10 In this regard, a system is provided that comprises a filter wheel (10) that can be rotated about an axis (11) and a shutter wheel (13) that can be rotated about an axis. The filter wheel and the shutter wheel are provided with an illumination aperture (15) through which light from a radiation source (not shown) can enter a body part of a subject (not shown). Reflected light from the illuminated body part can pass through different apertures (14) of the filter wheel (10), which can be provided with analyte specific filter elements and / or reference filter elements as described above. The positions of the filter wheel (10) and the shutter wheel (13) can be monitored with magnets (12) in combination with magnetic sensors. In operation, they can be rotated at a predetermined frequency, thereby allowing radiation from the radiation source to be delivered to the body part in time- dependence and allowing radiation emitted from the body part to be delivered to a sensor (not shown) through different apertures (14) of the filter wheel (10) in time- dependence at predetermined time intervals.

[0058] In an alternative embodiment (not shown), the sensor adapted for time-dependent detection of IR radiation having different wavelengths or wavelength ranges can be a Fabry-Perot interferometer, e.g. a MEMS spectrometer for a desired IR wavelength range (cf. Tuohinieni et al., J. Micromech. Microeng. 22 (2012), 115004; Tuohinieni et al., J. Micromech. Microeng. 23 (2013), 075011).

[0059] In certain embodiments, the system comprises a single sensor adapted for time-dependent detection of IR radiation having different wavelengths or wavelength ranges. This sensor can be provided with different filters, e.g. with a filter wheel, or be a Fabry-Perot interferometer as described above.

[0060] The system of the present application further comprises an analysis unit (c) for qualitatively and / or quantitatively determining a physiological parameter based on the IR radiation detected in the sensing unit (b). The analysis unit can comprise e.g. an A / D converter and a microcontroller. The analysis of the measured signal can be based on the intensity and / or the decay time.

[0061] A further embodiment of the present application is shown in Figure 11 . The system of this embodiment is adapted to be permanently fixed to the body of a subject. This system is particularly 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 a body part (33), e.g. a wrist or a forearm. In addition, the system comprises a radiation source for emitting VIS / NIR light into an absorption region (34) of the body part (33) and a sensor for detecting IR radiation emitted from the irradiated body part.

[0062] A further embodiment of the present application is shown in Figure 12 . The system of this embodiment is adapted to be permanently fixed to the body of a subject and is particularly 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 a body part (33), e.g. a wrist or a forearm. In addition, the system comprises a plurality of radiation sources, e.g. 2 radiation sources, for emitting VIS / NIR light into an absorption region (34) of the body part (33) and a sensor for detecting IR radiation emitted from the irradiated body part. The light emitted from the sources can fall on the surface of the body part (33) at an angle of e.g. about 30° to about 75°.

[0063] In Figure 13 , a schematic diagram of the system of Figure 4 is shown.

[0064] Figure 14 A heat map of a fingertip is shown after a time period of 2 s of illumination with 810 nm light.

[0065] Figure 15 is a plot showing the time-dependent thermal power output during intermittent illumination with 810 nm light at a power of 2 mW and a frequency of 0.1 Hz, in addition to the spontaneous emission of the fingertip.

[0066] Figure 16a A block diagram of an embodiment of the sensing unit of the present application is shown. The region of interest (ROI), i.e. the skin tissue of a subject, in particular a human subject, is illuminated with 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 about 810 nm and, optionally, a third light source emitting VIS / NIR radiation having a wavelength of about 600 nm. The radiation transmitted through or reflected from the region of interest is analyzed by the sensing unit. In addition, the device comprises a temperature sensor.

[0067] The sensing unit comprises a plurality of sensors, e.g. analyte-specific IR sensors (1) and (2) and a reference sensor (e.g. IR sensor (4)). For the determination of glucose, IR sensor (1) can be provided with a first optical filter which is transmissive for a wavelength of about 9.2 pm and IR sensor (2) can be provided with a second optical filter which is transmissive for a wavelength range between about 9.2 pm and about 9.6 pm. Reference sensor (4) can be provided with a fourth optical filter which is transmissive for a wavelength or wavelength range between about 8.6 pm and about 9.0 pm and / or a wavelength or wavelength range between about 9.8 pm and about 10.2 pm. In addition, the sensing unit comprises a NIR sensor for detecting VIS / NIR radiation with a wavelength of about 940 pm where glucose has a strong absorption band. The NIR sensor is provided with a suitable optical filter which is transmissive for this wavelength. In addition, the sensing unit can comprise a temperature sensor for measuring the temperature of the skin tissue in the region of interest. The respective sensors can be coupled to an amplifier (AMP) for a first signal amplification. The signals from the individual sensors can be referenced with the signals from the other sensors by means of a comparator, thereby improving the measurement accuracy and / or the signal quality. For example, the measurement signal from the NIR sensor at 940 nm can be referenced with the measurement signal from the analyte-specific IR sensor (1). Alternatively or additionally, the measurement signal from the NIR sensor at 940 nm can be referenced with the measurement signals from the analyte-specific IR sensor (1) and / or the analyte-specific IR sensor (2) and / or the reference IR sensor (4). The measured and optionally referenced signals are further amplified by a lock-in amplifier unit and transmitted to a microcontroller unit. A feedback control from the lock-in amplifier to the light source can be provided. From the microcontroller unit, the signals and / or the results of internal algorithms can be transmitted to a display unit and / or another device, e.g. by a direct connection or via Bluetooth and / or WLAN.

[0068] Figure 16b A block diagram showing a further embodiment of the sensing unit of the present application is shown, which is similar to the sensing unit shown in Figure 16a herein. Here, additionally or alternatively, a multi-wavelength light source is provided, e.g. a multi-wavelength LED comprising a plurality of individual diodes. The multi-wavelength light source can e.g. have a wavelength range from 400 nm to about 700 nm and can be operated by the microcontroller unit. In addition, there is a temperature sensor coupled to an amplifier (AMP). This temperature sensor can also be operated by the microcontroller unit.

[0069] In yet another embodiment of the present application, the system can include a spectral or line sensor or a spectral or line sensor array, typically a bolometer or thermopile array, adapted to detect the IR spectrum in a wavelength range of interest, e.g., including a range of about 7 μιη to about 12 μιη, in particular a range of about 8 μιη to about 10 μιη. The IR spectrum can be generated by passing the IR radiation from the illuminated body part through a spectral splitting or diffracting device and then to the sensor or sensor array. Such an embodiment is shown in Figure 17 IR radiation 70 emitted from the illuminated body part (71), e.g., a fingertip, is optionally focused by a focusing element 72, e.g., a lens or a concave mirror element, adapted to focus the IR radiation, and then passed through a spectral splitting or diffracting element (73), e.g., a prism or a transmissive or reflective grating, where the IR radiation is split according to its wavelength. From there, the diffracted radiation is passed to a spectral sensor or line sensor or sensor array (74), typically a bolometer or thermopile array, where the IR spectrum in the wavelength range of interest, e.g., between 8 μιη and about 20 μιη, including the analyte-specific wavelength or wavelength range and the reference wavelength or wavelength range, e.g., as described above, is detected. The amount of the physiological parameter of interest, e.g., glucose, can be determined from the predetermined relative intensities of the analyte-specific and reference wavelengths by spectral analysis.

[0070] The systems and methods of the present application allow for qualitative and / or quantitative determination of the physiological parameter to be measured, in particular qualitative and / or quantitative determination of glucose in blood.

[0071] In certain embodiments, the concentration of the physiological parameter, e.g., glucose in blood, is determined quantitatively. In certain embodiments, the rate of change of the amount of the measured physiological parameter, e.g., glucose, is determined. These embodiments can involve non-quantitative measurements, e.g., a relative measurement of the change in analyte amount per time unit, i.e., an increase in analyte amount per time unit or a decrease in analyte amount per time unit. If the change in analyte amount in a single direction, i.e., increase or decrease, exceeds a predetermined level and / or time period, then the system will provide an alert. This embodiment is particularly useful for systems as shown in Figure 11 and Figure 12 which can be permanently fixed on the subject's body, e.g., around the wrist, forearm or upper arm. This embodiment can be adapted for stable glucose level monitoring.

[0072] In certain embodiments, the system of the present application is adapted to perform non-quantitative measurements and quantitative measurements. For example, the system can be adapted to perform non-quantitative measurements, e.g. qualitative measurements, analyzing changes in the amount of the analyte over time, e.g. an increase or decrease, during standard operation. For example, non-quantitative measurements can be performed as continuous and / or intermittent monitoring measurements as required. In case the changes in the amount of the analyte exceed a predetermined level and / or time period, the system is adapted to switch to quantitative measurements to provide more detailed information. In these embodiments, the system can be used which is adapted to be permanently fixed to the body, e.g. to the wrist of the arm or to the ankle. Specific embodiments of such systems are shown in Figure 11 and Figure 12 .

[0073] In certain embodiments, the system is adapted to perform non-quantitative measurements, e.g. continuous and / or intermittent monitoring measurements, and quantitative measurements on several different body sites. For example, the system can be adapted to perform non-quantitative measurements on a first body site, e.g. a body site to which the system can be permanently fixed, such as the wrist of the arm or the ankle, and quantitative measurements on a second body site, e.g. a body site where capillaries are more easily accessible, such as the earlobe or the fingertip. For performing measurements on the second body site, the system is removed from the first body site and brought into contact with the second body site, in particular direct contact. After performing measurements on the second body site, the system can be removed therefrom and brought into contact with the first body site again, e.g. by fixing the system to the first body site. In particular embodiments, the first body site is the wrist of the arm and / or the second body site is the fingertip.

[0074] Yet another aspect of the present application is a non-invasive system for determining glucose in blood which allows to identify and optionally correct for interference by blood alcohol, the system comprising a sensing unit for detecting IR radiation emitted from a body site of said subject in the range of about 5 pm to about 12 pm,

[0075] wherein the sensing unit is adapted to (i) detect IR radiation at a wavelength of about 9.2 pm and separately therefrom to detect IR radiation at a wavelength of at least about 9.2 pm and about 9.6 pm, in particular at a wavelength range encompassing wavelengths of about 9.2 pm, about 9.4 pm and about 9.6 pm, and an analysis unit for determining glucose from the above sensing unit individually.

[0076] Yet another aspect of the present application is a method of non-invasively determining glucose in blood of a subject using this system.

[0077] Preferred features of these aspects are as indicated above in the description.

[0078] Yet another aspect of the present invention is the use of an InAsSb sensor, optionally in combination with a lock-in amplifier, for measuring IR radiation emitted from a body part.

[0079] Preferred features of this aspect are as previously indicated in the description above.

[0080] Yet another aspect of the present invention is a system and method for non-quantitative measurement of glucose, involving a plurality of measurements during a predetermined time interval, and determining a change in the measured signal indicative of a change in the amount of the analyte, and providing an alarm if the change in the amount of glucose in one direction (i.e. increase or decrease) exceeds a certain level within a predetermined time period. This system and method can be suitable for stable glucose level monitoring.

[0081] Preferred features of this aspect are as previously indicated in the description above.

[0082] In the following, certain aspects and embodiments of the present invention are described as part of the description.

[0083] Embodiments of the specification

[0084] 1. A non-invasive system for determining a physiological parameter in a body fluid of a subject, comprising:

[0085] (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 into a body part of the subject, wherein the irradiated body part absorbs electromagnetic energy, thereby causing a local increase in tissue temperature and causing an increase in emission of IR radiation in the wavelength range of about 5 pm to about 12 pm,

[0086] (b) a sensing unit for detecting IR radiation in the range of about 5 pm to about 12 pm emitted from the previously irradiated body part of the subject,

[0087] wherein the sensing unit is adapted to (i) 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 the physiological parameter in the body fluid of the subject,

[0088] and to (ii) 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 the physiological parameter in the body fluid of the subject, and

[0089] (c) an analysis unit for qualitatively and / or quantitatively determining the physiological parameter based on the IR radiation detected in sensing unit (b).

[0090] 2. The system of embodiment 1, which does not comprise an external radiation source for emitting IR radiation in the wavelength range of about 5 pm to about 12 pm.

[0091] 3. The system of embodiment 1 or 2, wherein the physiological parameter is selected from a compound having at least one characteristic absorption band in the IR range of about 5 pm to about 12 pm, in particular in the range of about 8 pm to about 10 pm.

[0092] 4. The system of any of the preceding embodiments, wherein the physiological parameter is glucose.

[0093] 5. The system of any of the preceding embodiments, wherein the body fluid is blood.

[0094] 6. The system of any of the preceding embodiments, which is adapted to determine glucose in blood, wherein the sensing unit is adapted to detect IR radiation having at least one wavelength or wavelength range, wherein the intensity of the detected IR radiation depends on the concentration of glucose in the blood of the subject, in particular selected from a wavelength of about 9.2 pm, a wavelength of about 9.4 pm, a wavelength of about 9.6 pm, a wavelength range comprising at least two of the wavelengths of about 9.2 pm, about 9.4 pm and about 9.6 pm, a wavelength range comprising all three of the wavelengths of about 9.2 pm, about 9.4 pm and about 9.6 pm, or any combination thereof.

[0095] 7. The system of any of the preceding embodiments, which is adapted to determine glucose in blood, wherein the sensing unit is adapted to detect IR radiation having at least one wavelength or wavelength range, wherein the intensity of the detected IR radiation is substantially independent of the concentration of glucose in the blood of the subject, in particular selected from a wavelength or wavelength range between about 8.7 pm and about 9.0 pm, a wavelength or wavelength range between about 9.7 pm and about 10.2 pm, or any combination thereof.

[0096] 8. The system of any of the preceding embodiments, which comprises a single radiation source (a).

[0097] 9. The system of any of embodiments 1 to 7, which comprises a plurality of radiation sources (a), e.g. 2, 3, 4 or more, and e.g. up to 10 individual radiation sources (a).

[0098] 10. The system of any of the preceding embodiments, wherein the radiation source (a) is adapted to emit VIS / NIR radiation in the range of about 400 nm to about 1200 nm, in particular in the range of about 550 nm to about 1100 nm, in particular in the range of about 800 nm to about 820 nm (e.g. at about 810 nm) and / or in the range of about 590 nm to about 660 nm (e.g. at about 600 nm) and / or in the range of about 920 nm to about 980 nm (e.g. at about 940 nm).

[0099] 11. The system of any of the preceding embodiments, wherein the radiation source (a) is adapted to emit collimated radiation and / or is adapted to emit non-collimated radiation.

[0100] 12. The system of any of the preceding embodiments, wherein the radiation source (a) is a LED, a laser diode, a vcsel (vertical-cavity surface-emitting laser) or a laser.

[0101] 13. The system of any of the preceding embodiments, wherein the radiation source (a) is adapted to emit the VIS / NIR radiation continuously or intermittently throughout a predetermined time interval.

[0102] 14. The system of any of the preceding embodiments, wherein the radiation source (a) is adapted to emit the VIS / NIR radiation to obtain a local temperature increase in the irradiated body part, in particular in the range of about 2 °C to about 10 °C, in particular in the range of about 3 °C to about 5 °C in an absorption region within the irradiated body part.

[0103] 15. The system of embodiment 13 or 14, wherein the radiation source (a) is adapted to emit the VIS / NIR radiation continuously with a power of about 10 mW to about 1 W, in particular about 20 mW to about 500 mW and more particularly about 50 mW to about 250 mW.

[0104] 16. The system of embodiment 13, 14 or 15, wherein the radiation source (a) is adapted to emit the VIS / NIR radiation continuously for a time interval of about 0.1 s to 20 s, in particular about 1 s to about 5 s and more particularly about 0.5 s to about 2 s.

[0105] 17. The system of embodiment 13 or 14, wherein the radiation source (a) is adapted to emit the VIS / NIR radiation intermittently with a power of about 10 mW to about 5 W, in particular about 20 mW to about 1 W and more particularly about 50 mW to about 500 mW.

[0106] 18. The system of embodiment 13, 14 or 17, wherein the radiation source (a) is adapted to intermittently emit VIS / NIR radiation for a time interval of about 0.1 s to about 20 s, in particular about 0.2 s to about 5 s and more particularly about 0.5 s to about 2 s.

[0107] 19. The system of 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.

[0108] 20. The system of any of the preceding embodiments, wherein the radiation source (a) is a multi-wavelength radiation source, in particular wherein the radiation source is adapted to emit VIS / NIR radiation at several (e.g., 2, 3, 4, 6, 8, 10 or more) different wavelengths or wavelength ranges (e.g., at least 2, 3, 4, 6 or 8 wavelengths, which can be selected from about 470 nm, about 520 nm, about 590 nm, about 650 nm, about 750 nm and about 810 nm) between about 400 nm to about 1200 nm, more specifically between about 450 nm and about 900 nm.

[0109] 21. The system of any of the preceding embodiments, wherein the radiation source (a) is provided on a side of the body part opposite to the sensing unit (b).

[0110] 22. The system of any of the preceding embodiments, wherein the at least one radiation source (a) is provided on a side of the body part which allows for direct emission of radiation into the body part without passing through a part of the system.

[0111] 23. The system of any of the preceding embodiments, wherein the at least one radiation source (a) is provided on a side of the body part which allows for direct emission of radiation into the body part without passing through a keratinous part of the body surface (e.g., a nail).

[0112] 24. The system of any of the preceding embodiments, wherein the sensing unit (b) is adapted to detect spontaneously emitted IR radiation from the previously irradiated body part.

[0113] 25. The system of any of the preceding embodiments, wherein the sensing unit (b) is adapted to detect IR radiation emitted from an absorption region within the previously irradiated body part, wherein the absorption region has a locally elevated temperature and exhibits increased IR radiation emission in a wavelength range of about 5 pm to about 12 pm.

[0114] 26. The system of any of the preceding embodiments, wherein the sensing unit (b) comprises at least one first sensor, at least one second sensor and optionally at least one third sensor,

[0115] wherein the at least one first sensor is adapted to detect IR radiation having at least one wavelength or wavelength range where the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject,

[0116] wherein the at least one second sensor is 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 a physiological parameter in the body fluid of the subject, and

[0117] wherein 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 wavelengths where 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 the body part.

[0118] 27. The system of embodiment 26, wherein the at least one first sensor and the at least one second sensor are each provided with filter elements and optionally lens elements which are optically transparent in the predetermined wavelength or wavelength range.

[0119] 28. The system of embodiment 26 or 27, comprising at least two different first sensors which are adapted to detect IR radiation having at least two different wavelengths or wavelength ranges.

[0120] 29. The system of embodiment 26, 27 or 28, wherein the 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, wherein the second wavelength range comprises the first wavelength or wavelength range and further comprises another wavelength or wavelength range.

[0121] 30. The system of embodiment 29 for determining glucose in blood, wherein the first sensor is adapted to detect IR radiation having a wavelength of about 9.2 pm, and the other first sensor is adapted to detect IR radiation having a wavelength range between about 9.2 pm and about 9.6 pm.

[0122] 31. The system of embodiment 29 for determining glucose in blood, wherein the first sensor is adapted to detect IR radiation having a wavelength of about 9.6 pm, and the other first sensor is adapted to detect IR radiation having a wavelength range between about 9.4 pm and about 9.6 pm.

[0123] 32. The system of any one of embodiments 26-31, comprising at least two different second sensors adapted to detect IR radiation having at least two different wavelengths or wavelength ranges.

[0124] 33. The system of embodiment 32 for determining glucose in blood, wherein the second sensor is adapted to detect IR radiation having a wavelength or wavelength range between about 8.6 pm and 9.0 pm and the other second sensor is adapted to detect IR radiation having a wavelength or wavelength range between about 9.8 pm and about 10.2 pm.

[0125] 34. The system of any one of embodiments 26-32 for determining glucose in blood, wherein the second sensor is adapted to detect IR radiation having a wavelength or wavelength range between about 7.8 pm and about 8.2 pm and optionally at least one further second sensor is adapted to detect IR radiation having a wavelength or wavelength range between about 8.6 pm and 9.0 pm and / or for detecting IR radiation having a wavelength or wavelength range between about 9.8 pm and about 10.2 pm.

[0126] 35. The system of any one of embodiments 26-34 for determining glucose in blood, comprising at least one third sensor adapted to detect VIS / NIR radiation, in particular VIS / NIR radiation having a wavelength of about 940 nm.

[0127] 36. The system of any one of the preceding embodiments, wherein the sensing unit (b) comprises at least one sensor adapted to detect IR radiation having different wavelengths or wavelength ranges time-dependently and individually,

[0128] wherein in at least one first time interval the sensor is adapted to detect IR radiation having at least one wavelength or wavelength range, wherein the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the body fluid of the subject, and

[0129] wherein in at least one second time interval the sensor is adapted to detect IR radiation having at least one wavelength or wavelength range, wherein the intensity of the detected IR radiation is essentially independent of the concentration of a physiological parameter in the body fluid of the subject.

[0130] 37. The system of embodiment 36, wherein the sensing unit (b) comprises at least one sensor provided with a plurality of filters, the filters being adapted to transmit IR radiation having different wavelengths or wavelength ranges.

[0131] 38. The system of embodiment 36 or 37, wherein the sensor is provided with a shutter wheel and / or a filter wheel.

[0132] 39. The system of embodiment 38, wherein the shutter wheel comprises a plurality of openings, wherein at least some of the openings are provided with a filter element and optionally a lens element, the lens element being optically transparent in a predetermined wavelength or wavelength range.

[0133] 40. The system of embodiment 36, wherein the sensing unit (b) comprises at least one sensor which is a Fabry-Perot interferometer.

[0134] 41. The system of any of the preceding embodiments, wherein the sensing unit (b) comprises at least one spectral sensor or line sensor or an array of spectral or line sensors.

[0135] 42. The system of any of embodiments 36-41, wherein the sensing unit (b) comprises a single sensor.

[0136] 43. The system of any of the preceding embodiments, wherein the sensing unit (b) comprises at least one sensor which is an optical detector, in particular an optical photovoltaic detector, more particularly an InAsSb-based detector.

[0137] 44. The system of any of the preceding embodiments, wherein the sensing unit (b) comprises at least one sensor which is a thermopile or bolometer.

[0138] 45. The system of any of the preceding embodiments, wherein the analysis unit (c) comprises a microcontroller which is adapted to quantitatively determine the concentration of the physiological parameter and / or non-quantitatively determine the rate of change of the physiological parameter.

[0139] 46. The system of any of the preceding embodiments, which is adapted to detect IR radiation from a body site selected from the group consisting of fingertip, earlobe, wrist, forearm, and upper arm.

[0140] 47. The system of any of the preceding embodiments, wherein the radiation source (a) and the sensing unit (b) are arranged on the same side of the body site.

[0141] 48. The system of any of the preceding embodiments, wherein the radiation source (a) and the sensing unit (b) are arranged on different sides of the body site, in particular on opposite sides.

[0142] 49. The system of any of the preceding embodiments, wherein a first radiation source (a) and the sensing unit (b) are arranged on the same side of the body site, and another radiation source (a) and the sensing unit are arranged on different sides of the body site, in particular on opposite sides.

[0143] 50. The system of any of the preceding embodiments, further comprising a cover, wherein the cover is at least partially made of a material that is optically transparent for VIS / NIR radiation emitted by the radiation source (a) and / or for IR radiation detected by the sensing unit (b).

[0144] 51. The system of embodiment 50, wherein the cover is at least partially made of CaF2and / or BaF2and / or a plastic material, which is transparent for IR radiation and optionally transparent for VIS / NIR radiation.

[0145] 52. The system of embodiment 50 or 51, wherein the optically transparent material of the cover has a thickness of about 0.2 mm to about 2 mm, in particular about 0.5 mm to about 1.5 mm, more particularly about 1 mm.

[0146] 53. The system of any of the preceding embodiments, further comprising a cover, wherein the cover is at least partially made of a material that is optically transparent for IR radiation to be detected by the sensing unit, in particular in the IR wavelength range between about 5 pm to about 12 pm or a sub-range thereof, and wherein the material is optionally substantially non-transparent for VIS / NIR radiation emitted by the radiation source (a).

[0147] 54. The system of any of the preceding embodiments, further comprising a cover focusing IR radiation from the body part to the sensing unit (b), in particular to at least one sensor of the sensing unit (b).

[0148] 55. The system of embodiment 54, wherein the cover comprises an IR Fresnel lens or an array comprising a plurality of IR Fresnel lenses.

[0149] 56. Use of the system of any of the preceding embodiments for non-invasively determining a physiological parameter in a body fluid of a subject.

[0150] 57. The use of embodiment 56, wherein the physiological parameter is glucose and the body fluid is blood.

[0151] 58. The use of embodiment 56 or 57, wherein the physiological parameter is quantitatively determined.

[0152] 59. The use of embodiment 56, 57 or 58, wherein a rate of change of the physiological parameter rate is non-quantitatively determined.

[0153] 60. A method for non-invasively determining a physiological parameter in a body fluid of a subject, comprising the following steps:

[0154] (a) irradiating a body site 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 site absorbs electromagnetic energy, resulting in a local increase in tissue temperature and resulting in an increase in emission of IR radiation in a wavelength range of about 5 μιη to about 12 μιη,

[0155] (b) detecting IR radiation in the range of about 5 μιη to about 12 μιη emitted from the previously irradiated body site of the subject,

[0156] including 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 a bodily fluid of the subject, and

[0157] (ii) detecting 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 a physiological parameter in a bodily fluid of the subject, and

[0158] (c) analyzing the detected IR radiation to qualitatively and / or quantitatively determine the physiological parameter.

[0159] 61. The method of Example 60, wherein the body site is not irradiated by an external IR radiation source having a wavelength range of about 5 μιη to about 12 μιη.

[0160] 62. The method of Example 60 or 61, wherein the physiological parameter is glucose and the bodily fluid is blood.

[0161] 63. The method of Example 60, 61, or 62, wherein the physiological parameter is quantitatively determined.

[0162] 64. The method of any one of Examples 60-63, wherein the rate of change of the physiological parameter rate is non-quantitatively determined.

Claims

1. A non-invasive system for determining physiological parameters in a subject's body fluids, comprising: (a) A radiation source adapted to emit visible (VIS) / near-infrared (NIR) radiation in the range of 400 nm to 1500 nm or 500 nm to 1500 nm onto a body part of the subject, wherein the irradiated body part absorbs electromagnetic energy, thereby causing a local increase in tissue temperature and resulting in an increase in the emission of IR radiation in the wavelength range of 5 μm to 12 μm. (b) A sensing unit for detecting IR radiation in the range of 5 μm to 12 μm emitted from a previously irradiated body part of the subject. The previously irradiated body parts showed a localized increase in tissue temperature and an increase in the emission of IR radiation in the wavelength range of 5 μm to 12 μm. The sensing unit is adapted to (i) detect IR radiation of at least one wavelength or wavelength range, the intensity of which depends on the concentration of a physiological parameter in the subject's body fluids. And suitable for (ii) detecting IR radiation of at least one wavelength or wavelength range having an intensity of IR radiation that is substantially independent of the concentration of physiological parameters in the body fluids of the subject, and (c) An analysis unit for qualitatively and / or quantitatively determining physiological parameters based on IR radiation detected in the sensing unit (b); The non-invasive system is adapted to determine glucose in the blood, and the sensing unit is adapted to detect IR radiation having an intensity that depends on the concentration of glucose in the subject's blood of at least one wavelength or wavelength range, wherein the at least one wavelength or wavelength range includes one or more of a wavelength of 9.2 μm, a wavelength of 9.4 μm, and a wavelength of 9.6 μm.

2. The system of claim 1, wherein the body part is one or more of the following: fingertip, earlobe, wrist, forearm, and upper arm.

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

4. The system of claim 1, wherein the at least one wavelength or wavelength range includes: a wavelength range including at least two of a wavelength of 9.2 μm, a wavelength of 9.4 μm, and a wavelength of 9.6 μm, and / or a wavelength range including all wavelengths of 9.2 μm, a wavelength of 9.4 μm, and a wavelength of 9.6 μm.

5. The system of claim 1, wherein the radiation source (a) is adapted to emit VIS / NIR radiation in the range of 550 nm to 1200 nm.

6. The system of claim 5, wherein the radiation source (a) is adapted to emit NIR radiation in the range of 800 nm to 820 nm, and / or VIS radiation in the range of 590 nm to 610 nm, and / or NIR radiation in the range of 920 nm to 980 nm.

7. The system of claim 1, wherein the radiation source (a) is a laser.

8. The system of claim 1, wherein the radiation source (a) is an LED or a laser diode.

9. The system of claim 1, wherein the radiation source (a) is a vertical cavity surface-emitting laser (VCSEL).

10. The system of claim 1, wherein the radiation source (a) is a multi-wavelength radiation source.

11. The system of claim 1, wherein the sensing unit (b) comprises at least one first sensor and at least one second sensor. The at least one first sensor is adapted to detect IR radiation of at least one wavelength or wavelength range, wherein the intensity of the detected IR radiation depends on the concentration of a physiological parameter in the subject's body fluids. The at least one second sensor is adapted to detect IR radiation of at least one wavelength or wavelength range, wherein the intensity of the detected IR radiation is substantially independent of the concentration of physiological parameters in the subject's body fluids.

12. The system of claim 11, wherein the sensing unit (b) further comprises at least one third sensor. The at least one third sensor is (i) adapted to detect nonspecific IR radiation, (ii) adapted to detect nonspecific VIS / NIR radiation, (iii) adapted to detect VIS / NIR radiation having a wavelength in 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) is a temperature sensor for measuring the temperature of a body part.

13. The system of claim 11, 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 includes the first wavelength or wavelength range and also includes another wavelength or wavelength range.

14. The system of claim 13, wherein the first sensor is adapted to detect IR radiation having a wavelength of 9.2 μm, and another first sensor is adapted to detect IR radiation having a wavelength range between 9.2 μm and 9.6 μm, the wavelength range between 9.2 μm and 9.6 μm including the first wavelength of 9.2 μm and also including wavelengths of 9.4 μm and 9.6 μm.

15. The system of claim 11, comprising at least two different second sensors adapted to detect IR radiation having at least two different wavelengths or wavelength ranges.

16. The system of claim 15, wherein the second sensor is adapted to detect IR radiation having a wavelength or wavelength range between 8.6 μm and 9.0 μm, and another second sensor is adapted to detect IR radiation having a wavelength or wavelength range between 9.8 μm and 10.2 μm.

17. The system of claim 1, wherein the sensing unit (b) comprises at least one sensor adapted to detect IR radiation of different wavelengths or wavelength ranges in a time-dependent and individual manner. During at least one first time interval, the sensor is adapted to detect IR radiation of at least one wavelength or wavelength range, the intensity of which depends on the concentration of physiological parameters in the subject's body fluids. During at least one second time interval, the sensor is adapted to detect IR radiation of at least one wavelength or wavelength range having an intensity of IR radiation that is substantially independent of the concentration of physiological parameters in the subject's body fluids.

18. The system of claim 1, wherein the sensing unit (b) comprises a single sensor.

19. The system of claim 1, wherein the sensing unit (b) includes at least one sensor, said at least one sensor being an optical detector.

20. The system of claim 19, wherein the at least one sensor is an optical photovoltaic detector.

21. The system of claim 19, wherein the at least one sensor is an InAsSb-based detector.

22. The system of claim 1, further comprising a lid, wherein the lid is at least partially made of a material that is optically transparent to IR / VIS radiation emitted by the radiation source (a) and to IR radiation detected by the sensing unit (b). The lid is made at least partially of CaF2 and / or BaF2 and / or of a plastic material that is transparent to IR radiation. The optically transparent material of the lid has a thickness of 0.2 mm to 2 mm.

23. The system of claim 22, wherein the optically transparent material of the cover has a thickness of 0.5 mm to 1.5 mm.

24. The system of claim 22, wherein the plastic material is transparent to IR radiation and transparent to VIS / NIR radiation.

25. The system of claim 1, further comprising a cover that focuses IR radiation from the body part onto the sensing unit (b).

26. The system of claim 25, wherein the cover focuses IR radiation from the body part onto at least one sensor of the sensing unit (b).

27. The system of claim 25, wherein the cover comprises an IR Fresnel lens or an array comprising a plurality of IR Fresnel lenses.

28. The use of the system as described in any of the preceding claims for noninvasively determining a physiological parameter in a subject's body fluids, wherein the physiological parameter is glucose and the body fluid is blood, and wherein the rate of change of the amount of glucose in the blood is determined.

29. A method for non-invasively determining physiological parameters in the body fluids of a subject, comprising the following steps: (a) Irradiating a body part of the subject with visible (VIS) / near-infrared (NIR) radiation in the wavelength range of 400 nm to 1500 nm or 500 nm to 1500 nm, wherein the irradiated body part absorbs electromagnetic energy, thereby causing a local increase in tissue temperature and resulting in an increase in the emission of IR radiation in the wavelength range of 5 μm to 12 μm. (b) Detect IR radiation emitted from previously irradiated body parts of the subject in the wavelength range of 5 μm to 12 μm. The previously irradiated body parts showed a localized increase in tissue temperature and an increase in the emission of IR radiation in the wavelength range of 5 μm to 12 μm. This includes individually (i) detecting IR radiation having an intensity that depends on the concentration of a physiological parameter in the subject's body fluids, and (ii) detecting IR radiation having an intensity that is substantially independent of the concentration of a physiological parameter in the subject's body fluids, and (c) Analyze the detected IR radiation to qualitatively and / or quantitatively determine physiological parameters; The physiological parameter is glucose, and the body fluid is blood, and the step of (b) detecting IR radiation emitted from a previously irradiated body part of the subject in the wavelength range of 5 μm to 12 μm includes detecting IR radiation having an intensity of at least one wavelength or wavelength range in which the intensity of the detected IR radiation depends on the concentration of glucose in the subject's blood, and wherein the at least one wavelength or wavelength range includes one or more of a wavelength of 9.2 μm, a wavelength of 9.4 μm, and a wavelength of 9.6 μm.

30. The method of claim 29, wherein the body parts are not irradiated by an external IR radiation source in the wavelength range of 5 μm to 12 μm.

31. The method of claim 29, wherein the concentration of the physiological parameter is quantitatively determined, and / or wherein the rate of change of the amount of the physiological parameter is determined.

32. The method of claim 31, wherein the rate of change of the physiological parameter is non-quantitatively determined.

33. The method of claim 29, wherein, (b) The step of detecting IR radiation emitted from previously irradiated body parts of the subject in the wavelength range of 5 μm to 12 μm includes performing the following operations individually: (i) Detecting IR radiation having an intensity dependent on the concentration of glucose in the subject's body fluids of at least two wavelengths or wavelength ranges, including detecting IR radiation with a wavelength of 9.2 μm and detecting IR radiation with a wavelength range between 9.2 μm and 9.6 μm, wherein the wavelength range between 9.2 μm and 9.6 μm includes a wavelength of 9.2 μm and also includes wavelengths of 9.4 μm and 9.6 μm. (ii) Detecting IR radiation of at least one wavelength or wavelength range, wherein the intensity of the detected IR radiation is substantially independent of the concentration of glucose in the subject's body fluids.

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