HK1253846A1 - Apparatus and method for analyzing a material - Google Patents

Abstract

The invention relates, inter alia, to an apparatus (10) for analyzing a material (101), comprising an excitation emission device (100) for generating at least one electromagnetic excitation beam (SA), in particular an exciting light beam, having at least one excitation wavelength, further comprising a detection device (106) for detecting a reaction signal (SR), and a device (107) for analyzing the material on the basis of the detected reaction signal (SR).

Description

Device and method for analyzing materials

The intellectual property right relates to an apparatus and a method for analyzing a material. In one embodiment for measuring glucose or blood glucose, the devices described herein and the processes described herein may be used, for example, to analyze animal or human tissue.

Known methods for analyzing materials, in particular for measuring blood glucose, are described in the following publications, for example:

"Noninvasive glucose detection in human skin" by Guo et al — differential laser photothermal radiometry using wavelength modulation ", biomedical optics journal (BiomedicalOptics Express), vol 3, vol 11, 2012;

"non-invasive blood glucose measurement in the lip mucosa by fourier transform infrared spectroscopy analysis: applications of chalcogenide optical fiber systems (Non-innovative blood glucose measurement by fourier transform for detailed spectroscopic analysis by the drug of the mucous membrane of the lip: application of a chalcogenoide optical fiber System), "frontend medical Biotechnology (Front Med Biol Eng.)," 1999; 9(2) 137-;

farahi et al "Pump probe photothermal spectroscopy using a quantum cascade laser" (Pump probe spectroscopy using quaternary cascade lasers), j.phys.d.appl., 2012; and

fujinami et al, "high sensitivity detection of molecules at liquid/liquid interfaces using total internal reflection based on photothermal spectroscopy-beam deflection (high sensitivity detection of molecules at the liquid/liquid interface use)", review of scientific instruments (Rev. Sei. Instrument), Vol.74, No. 1, 2003;

-(1)von Lilienfeld-Toal,H.Weidenmüller,Xhelaj,A.w. new method of noninvasive glucose measurement by mid-infrared spectroscopy: quantum Cascade Laser (QCL) and photoacoustic detection vibration spectroscopy (ANovel Aproach to Non-active Glucose Measurement by Mid-Infrare)dSpectroscopy:The Combination of Quantum Cascade Lasers(QCL)and PhotoacousticDetection Vibrational Spectroscopy)，38:209-215,2005；

-(2)Pleitez,M.von Lilienfeld-Toal,H.W. infrared spectroscopic analysis of human interstitial fluid in vitro and in vivo using FT-IR spectroscopy and pulsed Quantum Cascade Laser (QCL): a new method for the establishment of noninvasive glucose measurements (invasive spectroscopic analysis of human interactive fluidic in vitro and in vivo using FT-IR spectroscopy and pulsed Quantitative Capsules (QCL): observing a new approach to non-invasive glucose measurement), spectrochemistry reports, part A-molecular and biomolecular spectra, 85:61-65,2012;

- (3) Pleitez, M. et al, Noninvasive Monitoring of human epidermal Glucose Concentration In Vivo by Mid-IR Pulsed Photoacoustic Spectroscopy (In Vivo nonlinear Monitoring of Glucose Concentration In human epidermal by Mid-Infrared Pulsed photonic Spectroscopy), analytical chemistry, 85:1013 + 1020, 2013;

-(4)Pleitez,M.Lieblein,T.Bauer,A.Hertzberg,O.von Lilienfeld-Toal,H.w, a windowless ultrasonic photoacoustic unit for mid-infrared spectroscopy in human epidermis: the possibility of noninvasive monitoring of glucose in interstitial fluid by Low interference of changes in air pressure, temperature and humidity caused by skin contact (Window ultrasound photosourcetive cell for in vivo-IR spectroscopy of human importance: Low interference by change of air pressure, temperature, and physiological used by skin contact for the performance of the porous for a non-invasive monitoring of glucose in the interstitial fluid), Review of scientific Instruments (Review of scientific Instruments), 84,2013;

-(5)M.A.Pleitez Rafael,O.Hertzberg,A.Bauer,M.Seeger,T.Lieblein, H.von Lilienfeld-Toal and W.Noninvasive glucose monitoring in human epidermis was achieved by total internal reflection enhanced photothermal deflection (Photo-thermal deflective enhanced by total internal reflection) analysis (the analysis), 2014 11 months.

The object of the invention is to specify a device with which a material, in particular an animal or human tissue or a component or constituent of a tissue, can be analyzed particularly simply and cost-effectively.

This object is achieved in particular by a device having the features as defined in claim 1. Embodiments of the device are specified in the dependent claims.

Reference is made to german patent DE 102014108424B 3, the contents of which are specifically incorporated and the present application extends the contents; by this express reference made herein, the entire content of german patent DE 102014108424B 3 is therefore also considered to be part of the disclosure of the present application (all details "incorporated by reference" for this disclosure). In particular, this reference relates to all features given in the issued patent claims. In addition, the reference relates specifically to the details of the excitation beam mentioned therein, for example to the numerical values of the pulse frequency and wavelength (wavelength range) cited therein, and also to details relating to the measurement of the glucose content in interstitial fluid.

In addition to the claims and the subject matter of the exemplary embodiments, which are directly and explicitly mentioned at the time of filing, the present PCT title application also relates to other aspects, which are listed at the end of this description. These aspects may be combined with the features of the claims cited at the time of filing, individually or in groups. These aspects, alone or in combination with each other or with the subject matter of the claims, represent independent inventions. Applicants reserve the right to make these inventions the subject of the claims at a later date. This may be done in the case of this application, or in the case of a subsequent divisional application, a continuation application (in the united states), a partial continuation application (in the united states), or a continuation application claiming priority to this application.

However, in the following, the subject matter of the claims mentioned at the time of filing will be discussed first.

There is provided an apparatus for analysing a material, the apparatus having: excitation transmission means for generating at least one electromagnetic excitation beam, in particular an excitation light beam having at least one excitation wavelength; detection means for detecting the response signal; and means for analyzing the material based on the detected response signal.

The main advantage of this device lies in the fact that it can be used to analyze materials in a very simple and reliable manner.

Here, the term light is understood to mean electromagnetic waves or electromagnetic radiation in the visible range, in the near and far infrared range and in the UV (ultraviolet) range.

In an exemplary embodiment of the apparatus, provided are:

the excitation delivery means is a radiation source, in one embodiment a monochromatic radiation source, in particular a polarized radiation source or light source, more particularly a laser source,

the device has an optical medium in direct contact with the material, in particular with a first region of the surface of the material,

-wherein the excitation transmission means is preferably arranged such that the emitted excitation beam penetrates the optical medium and exits the optical medium again at a predetermined point on the surface of the optical medium, and

the device comprises a system for emitting a measurement beam, in particular a measurement light beam, which system is arranged such that the emitted measurement beam penetrates into the optical medium, and wherein, in operation, the measurement beam and the excitation beam preferably overlap at an interface of the optical medium and the material surface, at which interface the measurement beam is reflected, and

the detection means are means for receiving the reflected measurement beam forming the response signal and/or means for directly or indirectly detecting a deflection of the reflected measurement beam.

Preferably, the device has an optical medium which is in direct contact with the material, in particular with a first area of the surface of the material, in an embodiment with the skin of the person, wherein for detecting the response signal the detection means detect a change of a parameter of the optical medium as a result of the response signal, in particular in an area adjacent to the first area, in particular a deformation and/or a change of density of the optical medium as a result of the local, time-dependent heating. The optical medium may comprise an optically transparent material or a material transparent to infrared or ultraviolet radiation, typically transparent to the excitation and measurement beams, such as glass, crystal, zinc sulfide (ZnS), zinc selenide (ZnSe), germanium (Ge), silicon (Si), and diamond, or a transparent plastic, which in one embodiment may comprise polyethylene. Local heating in response to the transfer or transmission of heat from the material to be analyzed or from a substance of the material to the optical medium causes a change therein, e.g., a material deformation or a local change in thermal stress or refractive index, which is detectable.

In one embodiment, the material may be a tissue of a living organism, in particular a human tissue, wherein the material surface may be skin. Thus, the substance in the tissue can be analyzed or measured.

It can also be provided that the detection device has a piezoelectric element as a detector for detecting stress, deformation and/or density changes, which piezoelectric element is connected to the optical medium or integrated into the optical medium.

It may also be provided that the detection device has at least one temperature sensor as a detector for detecting the response signal. According to measurement principles, it may be arranged directly on or around the optical medium.

Preferably, the device has a system for intensity modulation of the excitation light beam.

Preferably, the detection means are adapted to detect the time-dependent response signal in dependence on the wavelength of the excitation light and/or the intensity modulation of the excitation light.

It may also be provided that the excitation transmission means radiates at least one electromagnetic excitation beam into a volume of the material located below the first region of the material surface.

Particularly preferably, the excitation transmission means comprises two or more transmission elements, in particular in the form of a one-, two-or multi-dimensional array of transmission elements. Thus, it may be implemented as a surface array of transmission elements, or as a band of transmission elements (in one embodiment, as an array of semiconductor lasers or an array of QCLs, where QCLs represent quantum cascade lasers).

It may also be provided that the two or more transmission elements each generate its own electromagnetic excitation beam and radiate its electromagnetic excitation beam into the volume below the first region. The different excitation beams may also be emitted sequentially, or at least partially simultaneously. Different transmission elements may also operate simultaneously at different modulation frequencies.

Preferably, the wavelengths of the electromagnetic excitation beams of the two or more transmission elements are different. Preferably, the wavelengths are selected such that the substance to be detected in the material to be analyzed absorbs radiation of these wavelengths particularly well. Additionally or alternatively, the wavelength or wavelength range may also be chosen such that the substance to be detected is not absorbed but is absorbed by other substances (so-called broad-tolerance wavelengths) in order to distinguish the substance to be analyzed from other substances.

In one embodiment, the excitation transmission means comprises two or more lasers, in particular in the form of a one-dimensional or two-dimensional laser array, wherein a plurality of rows of laser elements may be staggered and arranged offset one after the other to save space, in one embodiment in the form of a laser stripe and/or two or more light emitting diodes, in particular in the form of a one-dimensional or two-dimensional diode array, in one embodiment in the form of a two-dimensional array or stripe, in a depth staggered manner and arranged offset with respect to each other. The output beams of the array may have respective beam axes that are closely packed or parallel for each beam element, or the output beams of the array may have the same beam axis through a collection of already integrated optics.

With regard to the structure of the device, it may be provided that the excitation transmission means is mechanically fixedly connected to the optical medium directly or indirectly-preferably by means of the adjustment means-wherein the optical medium is in direct contact with the material, in particular with the first region of the material surface. Thus, the excitation delivery device may be aligned and fixed relative to the optical medium as early as the manufacturing stage or at least prior to deployment.

For the purpose of mounting and/or aligning or adjusting the components of the detection device and/or the excitation transmission device, the optical medium may have at least one built-in raised and/or recessed portion, such as a bridge portion, a shoulder portion, a hemispherical portion mounted thereon, a block-shaped portion mounted thereon, a tapered portion or a bore, a groove, a hollow portion or other recessed portion, on or in which the above-mentioned components (components of the detection device and/or the excitation transmission device) may be placed, may rest thereon or may be aligned or fixed therewith. It is also possible that the aligned mating surfaces are formed on the optical medium by a machining or casting process.

As regards the means for intensity modulation, it may be provided that they comprise electronic or electromechanical modulation means electrically connected to the excitation transmission means and in particular electronically controlled excitation transmission means, or that the means for intensity modulation are formed by such electronic or electromechanical modulation means. The modulation means may generate an intensity modulated excitation beam, in one embodiment a periodic intensity modulated excitation beam, also for example a rectangular pulse, a sawtooth function or a sine wave function or other periodic functional form.

Alternatively or additionally, the means for intensity modulation may comprise at least one controlled mirror arranged in the beam path, by controlling which mirror the intensity of the excitation beam can be modulated by deflection.

Alternatively or additionally, the means for intensity modulation may comprise at least one layer which is arranged in the beam path and whose transparency is controllable, or the means for intensity modulation may be formed by such a layer. The modulation element can thus be designed in the form of a transmission element, the transmission of which is controlled. The modulating element may generate a plurality of spatially separated light beams from one light beam. In one implementation, it may also be provided that the surface of the sample may be scanned using a modulating element. In one embodiment, the array of modulating elements and light/laser sources may be controlled together.

In one embodiment, the means for emitting a measuring beam (in particular a measuring beam) is arranged for emitting the measuring beam to a specific area of the optical medium in contact with the first area of the material surface.

In one embodiment, the detection means and the means for emitting the measurement beam are aligned with each other such that the detection means detects the measurement beam as a time-dependent response signal after the beam has been reflected at least once at an interface where the optical medium is in contact with the material, wherein the optical medium is in particular in contact with the first area of the surface of the material.

For ease of assembly, it is advantageous if the detection means and/or the excitation transmission means and/or the means for emitting the measurement beam are directly fixedly mechanically connected to the optical medium and/or are coupled to the optical medium by one or more fiber optic cables.

Embodiments are possible in which the optical medium directly supports the imaging optics and/or the imaging optics are integrated into the optical medium.

In addition, embodiments are conceivable in which: the surface of the optical medium has a plurality of partial surfaces inclined toward each other, at which surfaces a plurality of reflections of the measuring beam, in particular of the measuring beam, take place.

Embodiments may also be provided: one or more mirrors for reflecting the measuring beam, in particular the measuring beam, are arranged in or on the optical medium.

For a compact design, it is conceivable that the excitation transmission means and/or the detection means and/or the means for emitting the measurement beam are attached directly to each other or to a common support. In one embodiment, the various devices may be fixed to the support portion by welding or gluing or by a screw or snap connection, wherein the adjustment facility is provided by an adjustment screw or other mechanical adjustment device during assembly or at a later time. In particular, the detection device and/or the device for emitting the measurement beam should or can be easily aligned relative to one another. Thus, it is useful to attach both devices directly to the optical medium. The detection means giving a suitable guidance of the measurement beam and/or the means for emitting the measurement beam may also be arranged adjacent to each other on the same side of the optical medium or on a common support, in one embodiment they are attached to a common printed circuit board or a common semiconductor, or implemented as a common integrated semiconductor device, in one embodiment as a common integrated semiconductor component. Thus, in a particular embodiment, the support portion is adjustable with respect to the optical medium as a whole, even without further changing the relative position between the detection means and/or the means for conveying the measurement beam.

The support is preferably formed by a printed circuit board, a metal plate or a plastic plate or a housing of the device or a part of the device housing.

It may also be provided that the excitation transmission means comprise an integrated semiconductor device with one or more laser elements and at least one micro-optical component and preferably with an additional modulation element. In one embodiment, the above-mentioned elements can be etched together from one semiconductor blank or at least accommodated in a common housing.

It may also be provided that the modulation element has at least one element, in particular a mirror, which is movable relative to the remaining semiconductor device and whose position is controllable. This can be controlled by a MEMS device.

It may also be provided that the modulating element has a layer whose radiation permeability is controllable.

It may also be provided that the modulation element has an electronic control circuit for modulating one or more laser elements. In one embodiment, the modulating element may be configured such that it alters the excitation beam in a time-dependent manner by interference, phase-shift/path-shift or polarization filtering means or other known modulation mechanisms.

The one or more micro-optical components may be mirrors or lenses integrated into or made from the semiconductor component in a subtractive process, in particular by etching.

The described apparatus for analyzing a material may determine a measure of the concentration of a substance, which in one embodiment is a glucose concentration. The device may have an interface with a device for displaying the measured values and their analysis, for example by means of a colour code for the user of the device, and/or may have an interface with a dosing device for a substance dispensable into a material, in particular a tissue, or more generally a body of a living being. The device may also comprise such a dosing device directly. In this case, the device may also have a system for detecting or analyzing the surface of the material, in one embodiment the surface of the skin or in another embodiment the surface of the eye or the iris of a living being, which is capable of identifying a person or a living being based on a comparison with reference data and can thus be used to ensure that suitable reference and/or calibration values are provided for the analysis of the material and the control of the dosing means. The determined characteristic values of the material surface, which in one embodiment is the structure of a fingerprint or an iris of an eye, can be used for encrypting the communication of the state values and for controlling the encrypted or unencrypted metering device, in addition to, for example, identifying and authenticating a person in comparison with a database from which the determined characteristic values of the material surface can in principle originate. In one embodiment, the dosing device may be equipped with a sensor to determine the fill level of the substance to be dispensed, such as in one embodiment insulin and/or glucagon, and may have means for communicating the fill level to the means for material analysis and/or directly to a database.

In addition, the device may have an interface, in one embodiment a radio interface to a database to which the measured values may be sent and which may process the data. The database may be generated by means of processing and storing data from a plurality of patients, i.e. in one embodiment it also has data from a plurality of similar devices for analysing the material, and in one embodiment it also controls the respective dosing device for dispensing the substance. The database may further process the measurement data related to the material being analyzed and determine a derived analysis result, such as the amount or concentration of the material, the first and second time derivatives, the minimum deviation, the maximum deviation, the standard deviation of the blood glucose value or other physiological value of the patient, any trend of the values, compare them and derive a signal therefrom, which in one embodiment also includes an alarm signal. In one embodiment, the fill level of the dosing device may also be detected and processed by a database to determine the time frame of the fill level or the need for refilling, as well as to send a signal directly to the patient's device or service facility. For this purpose, the database may be connected to a communication device in a service facility, in one embodiment a communication device in a hospital or in medical practice. For the purpose of sending data from and/or to the database, in one embodiment the device may be connected to a mobile device or pager by a radio link, in one embodiment a bluetooth, or WLAN or Wifi or other transmission method. The device may also be directly equipped with a WLAN interface and an internet client.

The subject matter also relates to a method for analyzing a material, wherein in the method at least one electromagnetic excitation beam having at least one excitation wavelength is generated by a continuous operation or at least partially simultaneous operation of a plurality of laser emitters of a laser source with an excitation transport device, a response signal is detected with a detection device, and the material is analyzed based on the detected response signal. In this method, the temporal evolution or waveform of the thermal diffusivity and response signals in the material can be used to characterize the properties of the material or the spatial distribution of the substance in the material, or to characterize the depth of the absorption excitation beam.

In one embodiment, it may be provided that the response signal, in particular the instantaneous response signal waveform or pattern, may be determined continuously using different modulation frequencies of the excitation transmission means, and that a plurality of response signal waveforms or patterns at different modulation frequencies may be combined with each other, and in particular, thereby obtaining specific information of the depth range below the surface.

It may also be provided that the response signal waveform or pattern is determined at different modulation frequencies for different wavelengths of the excitation beam, and in particular specific information for each depth range below the surface is obtained therefrom. When using multiple modulation frequencies of the pump beam simultaneously, it is possible, for example, to resolve the detected signal into its frequency using a suitable analysis method (e.g., fourier transform); FT will filter out only the signal corresponding to the desired frequency.

It may also be provided that the optical medium is brought into direct contact with the material, in particular into direct contact with a first area of the surface of the material, that the emitted excitation beam is generated and in particular emitted using the excitation transmission means such that the excitation beam penetrates into the optical medium and exits from the optical medium again at a predetermined point on the surface of the optical medium, that the measurement beam, in particular the measurement beam, is generated using means for emitting a measurement beam such that the beam penetrates into the optical medium, and in particular that, in operation, the measurement beam and the excitation beam overlap at an interface of the optical medium and the surface of the material, that a reflection of the measurement beam occurs at said interface, and that the reflected measurement beam forming the response signal is measured, and/or that a deflection of the reflected beam is detected directly or indirectly using the detection means.

One aspect of the method focuses on the measurement of response signals over a selected depth range (spaced apart from the material surface) beneath the material surface. The thermal wavelength d has the greatest effect on the depth range measured using this method. It is defined as D ═ v (D/(pi ×) f), where D is the thermal diffusivity of the sample (here, for example, the skin) and f is the modulation frequency of the excitation beam.

Literature on thermal diffusivity of the skin:

U.Werner, K.Giese, B.Sennhenn, K.Piamann and K."Measurement of thermal diffusivity of the human epidermis by studying thermal wave propagation" (Measurement of the thermal diffusivity of human epidermis by catalytic thermal wave) ", Phys.Med.biol.37(1),21-35 (1992);

stock, Heat Transfer in Biotechnology (Heat Transfer in Biotechnology), volume 4 of Heat Transfer development (Advances in Heat Transfer), j.p.hartnet and t.irvin, eds. (new york, university teacher, 1967), page 117.

In one embodiment, in order to eliminate the response signal from the topmost layer of material, the change in measurement compared to the previous measurement may be used in case the measurement in the top layer changes more or less slowly compared to other deeper layers.

This may be the case in embodiments where the human skin is measured, where the topmost and lower layers of skin are not actually exchanged, and thus the physiological parameter changes very little. The measured time derivative can also be applied to provide a response signal to exclude signals from the topmost layer of the skin. Thus, the measurement or at least the evaluation may be limited or concentrated to interstitial fluid in the skin.

It may also be provided that the dosing means for dispensing the substance, in particular the dosing means for dispensing the substance into the patient, are controlled in dependence on the substance concentration identified in the material, and/or that acoustic and/or visible signals are output and/or signals are output via a wireless connection to the processing means. In this case, in addition to the currently determined measurement, the instantaneous development or evolution of the measurement value, the derivative of the measurement value, the average value of the measurement, the maximum deviation, the minimum deviation, the standard deviation and the predefined threshold value for the measurement value can be taken into account and combined with the current measurement value. In one embodiment, the processing device may be or be connected to a database that collects and processes data from a plurality of patients. The database may be directly connected to the control system of the device or remote from the control system of the device and connected to the control system of the device via a communication interface.

In order to achieve increased safety when operating a dosing device, in particular for insulin, it may be provided that this is operated locally or from a database under the control of a preset standard program, wherein the preset standard program has a preselected number of deliveries at specified times or at specifiable times, and that by means of the above-described device a meaningful deviation from a preset delivery value can be determined, which deviation serves to correct and improve the control of the dosing device. In this way, normal or emergency operation of the dosing device is ensured even in the event of a malfunction of the device.

Fig. 1-13 schematically illustrate different elements of the device and in some cases in different embodiments.

Fig. 1 shows an exemplary embodiment of an apparatus 10 for analyzing a material 101. The material 101 is preferably placed directly on the optical medium 108, wherein the optical medium 108 can be designed as an optically transparent crystal or glass body. The device for analyzing the material 101 is used, for example, for measuring glucose or blood glucose content in a fluid, such as blood in one embodiment, and for generating a glucose or blood glucose level indication BZA.

The apparatus comprises an excitation transmission device 100, the excitation transmission device 100 being adapted to emit one or more electromagnetic excitation beams SA, preferably in the form of an excitation light beam having one or more excitation wavelengths, into a volume 103, the volume 103 being positioned in the material 101 below a first region 102 of the material surface. For simplicity, the excitation delivery device 100 is also referred to hereinafter as an "excitation light source" 100. The excitation light source 100 may be a wavelength-tunable laser, specifically a tunable quantum cascade laser; as will be explained below, it is preferred to use a light source strip or an array of light sources, in particular semiconductor lasers, having at least two single emitters, each of which emits a specified independent wavelength.

In addition, means 104 for intensity modulating one or more excitation light beams SA are provided, preferably formed by modulation means for the excitation light source (in particular for controlling the excitation light source), and/or by at least one controlled mirror arranged in the beam path and/or by a layer arranged in the beam path and controllable in transparency.

In addition, the device has a system 105 for emitting an electromagnetic measuring beam 112 (in particular a measuring beam), wherein the electromagnetic measuring beam 112 is reflected, preferably totally reflected, at an interface GF between the material 101 and the optical medium 108.

The detection means 106 are arranged for detecting the reflected measurement beam 112, the reflected measurement beam 112 forming a time-dependent response signal SR; as will be explained in more detail below by way of example, the amplitude of the response signal SR is influenced by the wavelength of the excitation light SA and the intensity modulation of the excitation light SA.

The amplitude of the measurement signal depends on the wavelength of the excitation beam, the absorption and thermal properties of the sample, in particular the thermal diffusivity and thermal conductivity of the sample and the optical elements. In addition, the coupling of the thermal signal from the sample to the optical element also plays a role.

The means 107 for analysing the material evaluates the detected response signal SR and, in one embodiment, generates a glucose or blood glucose level indication BZA.

Hereinafter, the operation of the apparatus 10 according to fig. 1 in case the material 101 to be analyzed is human tissue or animal tissue and an example of a method for analyzing the material 101 in view thereof will be described in more detail and as part of the material analysis the glucose or blood glucose level indication BZA will be determined.

An electromagnetic measuring beam 112, which is preferably a beam in the visible wavelength range or an infrared beam, is radiated into the optical medium 108 by means of the device 105; the measurement beam 112 impinges on an interface GF below the first region 102 of the tissue surface. At the interface GF, the measurement beam 112 is reflected and reaches the detection device 106, and the detection device 106 measures the reflected measurement beam 112.

At the same time, the excitation light source 100 generates one or more excitation beams SA, preferably infrared beams. The wavelength of the infrared beam is preferably in the range between 3 μm and 20 μm, particularly preferably in the range between 8 μm and 11 μm.

The excitation beam SA is intensity or amplitude modulated using the means for intensity modulation 104. In one embodiment, the short light pulses are generated with the means for intensity modulation 104 preferably at a pulse frequency between 1kHz and 1MHz or with pulse bursts (double modulation or multiple modulation) preferably at an envelope frequency of l kHz to 10 kHz.

The modulated excitation beam SA is coupled into the optical medium 108 and, after passing through the interface GF, reaches the volume 103 within the tissue.

In view of the example of blood glucose measurement described herein, the wavelength of the excitation beam SA is preferably selected such that the excitation beam SA is significantly absorbed by glucose or blood glucose. The following infrared wavelengths are particularly suitable for measuring glucose or blood glucose (vacuum wavelengths): 8.1 μm, 8.3 μm, 8.5 μm, 8.8 μm, 9.2 μm, 9.4 μm and 9.7 μm. In addition, glucose-tolerant wavelengths may be used, which are not absorbed by glucose, to identify other substances present and allow their effect on the measurement to be excluded.

Due to the absorption of the excitation beam SA in the tissue in the region of the volume 103, a local temperature rise is caused, which triggers heat transfer and thus a pressure wave in the direction of the interface GF; due to the temperature and pressure fluctuations occurring at the interface GF, the refractive index and/or the deformation, the microstructure and the reflection behavior in the region 102 and/or in the reflection region of the interface GF are modulated and the beam path of the measuring beam 112 is influenced.

For example, if it is assumed that without the excitation beam SA the alignment between the system 105 and the detection device 106 is optimal and the maximum received power is detected by the detection device 106, then the phase of the reflected measurement beam 112 can be induced or intensity modulation of the reflected measurement beam 112 can occur due to absorption of the excitation beam SA in the region of the volume 103 and due to thermal transport and pressure waves, a (at least temporary) change in amplitude or in the case of periodic modulation. The degree of intensity modulation depends on the wavelength of the excitation beam SA (because of the necessary absorption in the tissue) and the pulse frequency of the excitation beam SA (due to temperature transport and pressure waves from inside the tissue in the direction of the interface GF) and the thermal properties of the sample and the medium.

The change in reflection of the measuring beam 112 and/or the time-dependent change of the response signal SR is quantitatively acquired by the detection means 106 and the detection result D arrives at the means 107.

Based on previously performed calibration or comparison measurements, which in one embodiment are stored in the memory 107a of the device 107 in the form of a look-up table or a look-up curve, the current concentration of glucose or blood glucose in the tissue or in the volume 103 may be derived and a corresponding glucose or blood glucose indication BZA may be generated. The control table or control curve may for example have been generated based on glucose or blood glucose levels, wherein the glucose or blood glucose levels are determined based on a blood sample.

A particularly preferred embodiment and variant of the device 10 for analyzing a material 101 is described below with reference to fig. 2 to 10.

As shown in FIG. 2, the excitation delivery devices 100 for emitting one or more excitation light beams may be designed as an array. The array has at least 5, advantageously at least 10, more advantageously at least 15 or at least 50 or 100 individually controllable emitters 100a for monochromatic light in the absorption spectrum of the material to be analyzed.

The array preferably produces a beam with monochromatic light having one or more, particularly preferably all, of the following wavelengths (vacuum wavelengths): 8.1 μm, 8.3 μm, 8.5 μm, 8.8 μm, 9.2 μm, 9.4 μm and 9.7 μm, and if desired, additionally a wavelength resistant to glucose.

As shown in fig. 1, the detection means 106 and the means 105 for emitting a measuring beam 112 may be arranged separately from the optical medium 108. In view of the minimum space requirement and the minimum installation effort, it is considered advantageous if the detection means 106 and the means 105 for emitting the measuring beam 112 are directly mounted on the optical medium 108, preferably on opposite surface portions 108a and 108b of the optical medium 108, as shown in fig. 3.

It may be provided that the excitation device/excitation light source 100 is permanently mechanically connected to the optical medium 108 directly or via the adjusting device 109 to the optical medium 108. The adjustment means 109 preferably allow adjustment of the distance of the excitation light source 100 from the optical medium 108 and/or adjustment in the longitudinal direction of the beam and/or in a plane perpendicular thereto (see fig. 4).

As shown in fig. 3, 4, 6, 7 and 8, the device 105 may be arranged for emitting a measuring beam 112 into the area where the optical medium 108 is in contact with the first area 102 of the material surface. This arrangement allows the measuring beam 112 to radiate at a flat angle and allows total internal reflection at the interface of the optical medium 108 and the material 101.

By injecting radiation at a flat (small) angle (towards the sample surface), mirage deflection (similar to the known photothermal "bounce method") can be made more efficient, while deflection of the measuring beam caused by deformation can be reduced. In an embodiment, the angle between the sample surface and the measurement beam may be chosen to be less than 20 degrees, less than 10 degrees, in particular less than 5 degrees, more in particular less than 2 degrees or 1 degree, to take advantage of this effect.

Conversely, by providing radiation at a steeper (larger) angle (to the surface of the material), deflection can be made more efficient by analogy with the known photothermal "bounce" method, while mirage effects associated with deflection of the measuring beam can be reduced. In one embodiment, the angle between the surface of the material and the measuring beam may be chosen to be greater than 20 degrees, greater than 30 degrees, in particular greater than 45 degrees, more in particular greater than 60 degrees or 70 degrees, to take advantage of this effect.

See the relevant literature:

-m.bertolotti, g.l.liakhou, r.li Voti, s.paolino and c.sibilia, analysis of photothermal deflection techniques in the topic of surface reflection: theory and Experiment (Analysis of the photothermal deflective technique in the surface reconstruction the same: Theory and Experiment), Applied physical science (Journal of Applied Physics),83,966 (1998).

The means 105 for emitting the measuring beam 112 and/or the detection means 106 for detecting the measuring beam 112 and/or the response signal SR may be mechanically connected in a supporting manner to the optical medium 108, directly or via an adjustment means, and/or coupled to the optical medium 108 via one or more fiber optic cables 120.

As shown in fig. 6, it may also be provided that the optical medium 108 directly supports imaging optics 128 and/or imaging optics 129 (in each case) in the form of lenses or other reflective or refractive devices, and/or that the imaging optics are integrated into the optical medium 108. However, the imaging optics can also be integrated into the excitation transmission means or the means for generating the measurement beam, for example in the form of lenses or other reflective or diffractive elements (if these are designed as integrated components and/or semiconductor components). In one embodiment, the imaging optics can be formed from the same semiconductor component by etching subtractive forming a corresponding integrated circuit with a radiation source for the excitation beam or the measurement beam.

As shown in fig. 7, it can also be provided that the surface of the optical medium 108 has a plurality of partial surfaces 110, 111 which are inclined toward one another, at which partial surfaces 110, 111 the measuring beam 112 is reflected or refracted multiple times.

As shown in fig. 3, it may also be provided that one or more mirrors 113, 114 for reflecting the measuring beam 112 (and thus the response signal SR) are arranged in or on the optical medium 108. These mirror surfaces may be formed by inhomogenities within the optical medium 108 or by its outer surface, or by, for example, metal or metal-clad mirror elements that are integrated/assembled/cast or mounted in or on the optical medium. This extends the optical path of the measuring beam 112 in the optical medium 108 until it enters the detection device 106, so that the response signal dependent deflection of the measuring beam 112 within the optical medium 108 is increased in the case of emission at the region where the surface of the medium 108 is in contact with the first region 102 of the material surface. This deflection can therefore be detected as an absolute deflection in the detection device 106.

The detection device 106 may have a plurality of optically sensitive surfaces, such as optically sensitive semiconductor diodes, or a plurality of staggered openings 116, 117, 118 in a connector body 119 (fig. 5) at which respective fiber optic cables 120 terminate (fig. 4), into which the light of the measuring beam 112 is coupled according to its deflection. The fiber optic cable 120 is then connected to the connector body 119 and directs light to the portion of the detection device 106 disposed at the end of the fiber optic cable 120 (fig. 4), wherein the connector body 119 may be secured to the optical medium 108. Then, the connector body 119 also becomes part of the detection device 106 for detecting the measuring beam in the same manner as the optical fiber cable 120.

For the sake of completeness, it is noted that the excitation transmission means may also send excitation to the material surface as a whole or segment by segment through one or more fiber optic cables, and in one embodiment the excitation transmission means may be directly coupled to one or more fiber optic cables coupled to the optical medium.

As shown in fig. 8, it may also be provided that the excitation transmission means 100, the detection means 106 and the means 105 for emitting the measuring beam 112 are attached directly to each other or to a common support 121. The support portion, which may be formed of a plastic part, a printed circuit board, or a metal plate, is mounted in the housing 122. Thus, in one embodiment, the support portion formed to have a U-shaped cross-section in fig. 8 may at least partially surround the optical medium 108. The optical medium may be attached to and adjusted relative to the support portion.

The support may also be formed by the housing 122 itself or a housing portion.

It may also be provided that the device with the housing 122 is fastenable to a human body 123, wherein the excitation transmission means 100 for emitting one or more excitation light beams SA, the means 105 for emitting measuring light beams 112 and the detection means 106 for detecting the time-dependent response signal SR are arranged and configured to: so that the side of the device suitable for performing the measurement (with the measurement window transparent to the excitation radiation) is positioned on the side of the device facing away from the body, so that the material to be analyzed can be measured on the side 124 of the housing 122 facing away from the body 123. In connection with this, fig. 8 shows that the housing 122 is attached to the human body 123 by means of a strap 125 belonging to the housing 123, which strap 125 in one embodiment is in the form of a bracelet on the wrist. On the opposite side 124 of the wrist, the housing then has a window transparent to the excitation light beam SA, or the optical medium 108 is fitted directly to the outward side 124 of the housing, and the optical medium 108 itself forms a surface of some part of the housing.

As shown in fig. 8, a fingertip 126, schematically shown by a dashed line, may then be placed on the optical medium 108 and measured.

Optical medium 108 may be attached within housing 122 in the same manner as support 121 or directly to housing 122. The optical medium 108 may also be directly connected to the support portion 121, wherein the adjustment means 127 should be provided for the relative positioning of the support portion 121 with respect to the optical medium.

It is also contemplated that the excitation light source 100, the device 105 and the detection device 106, or even only one or two of these elements, are attached directly to the optical medium 108 and the other element or elements are attached to the support portion 121.

Other parameters of the material surface or placed fingertip 126, such as a fingerprint in one embodiment, may be measured through the optical medium 108 and/or through an optical window in the housing 122. For this purpose, in the housing, a light detector 130, for example in the form of a camera, may be fastened to the support 121, which light detector 130 records a digital image of the surface of the material through the optical medium 108. The image is processed in a processing unit 107, so that the processing unit 107 can be connected directly to the detection means and also to the excitation transmission means, as well as measuring information by the detection means 106. The processing means may also perform control tasks for the measurements. It may also be at least partially separate and remote from the rest of the device and communicate with them via a wireless connection.

Thus, image data from the camera 130 may also be processed within the housing, or even via a radio link external to the housing, and compared to a personal identity database to retrieve calibration data for the identified person.

This type of calibration data may also be stored in a database for remote retrieval, in one embodiment a cloud. The measurement data from the detection device 106 may be further processed both within the housing and externally.

If the data is processed outside the housing, the generated data should preferably be transmitted by radio back to the device within the housing for display there.

In both cases, a display may be provided on the housing 122, wherein the display is advantageously readable through the optical window and, in one embodiment, to some extent also through the optical medium. The display may also project an optical indicator through an optical window onto a display surface and may have a projection means for this purpose. In one embodiment, the display may be used to display measurement or analysis results, in particular glucose concentration. In one embodiment, this information may be output via a symbol or color code. By means of a display or a signal transmission device similar to a display, in one embodiment, a recommendation of an insulin dose may be made in dependence of other patient parameters (e.g. an insulin correction factor), or a signal may be automatically transmitted to a dosing device in the form of an insulin pump.

The connection of the device to the external data processing device 131 can be implemented using all conventional standards, such as fiber optic cable, wireless (e.g., bluetooth, WiFi), or ultrasonic or infrared signals.

Fig. 9 shows a modulation device with a controller 132 that activates the excitation transmission means in a modulated manner. Both the controller 132 and the detection device 106 for the measuring beam are connected to the evaluation device 107.

Fig. 10 shows an excitation light source 100, in front of which a mirror arrangement driven by MEMS (micro-electro-mechanical system) 135 is arranged, which mirror arrangement has one or more micro mirrors 133, 134, such as those known from optical image projection technology, for occasional deflection of the excitation light beam in a deflection direction 136.

Fig. 11 shows an excitation light source 100, in front of which an optical layer 138 with a transmission section controllable by a control device 137 is arranged in the excitation beam, which optical layer 138 in one embodiment has an LCD unit.

The present title application (as already mentioned above) relates to the following aspects in addition to the subject matter of the claims and the exemplary embodiments as described above. These aspects can be combined in each case individually or in groups with the features of the claims. Additionally, these aspects represent independent inventions, either alone, in combination with each other, or in combination with the subject matter of the claims. Applicants reserve the right to make these inventions the subject of the claims at a later date. This may be done in the context of this application or in the context of a subsequent divisional application or a continuation application claiming priority to this application.

1) A method for analysing a material in a body, the method comprising:

emitting an excitation light beam having one or more specific excitation wavelengths through a first region of the body surface,

-intensity modulating, in particular continuously modulating, the excitation light beam at one or more frequencies, modulating by means other than a mechanical chopper wheel, in particular by electronic activation of the excitation light source, adjusting means for a resonator of the excitation laser serving as the excitation light source, or movable mirror means, a controllable diffraction means, a shutter or mirror means coupled to a motor (such as a stepping motor) or MEMS, or a layer in the beam path, wherein the transport of the layer in the beam path is controllable,

-detecting in a time-resolved manner, by means of a detector located outside the body, a response signal, which response signal is attributable to the effect of the wavelength-dependent absorption of the excitation light beam within the body.

In one embodiment, the modulation may be performed by interference or by influencing the phase or polarization of the radiation exciting the transmission means, in particular if it comprises laser means.

2) The method according to aspect 1, characterized in that the excitation light beam is generated by a plurality of emitters or multi-emitters, in particular in the form of laser arrays, which emit light with different wavelengths simultaneously or sequentially, or in an arbitrary pulse pattern.

3) The method according to aspect 1 or 2, characterized in that on the first area of the surface of the body, the acoustic response signal is detected by an acoustic sensor.

4) The method according to any of the aspects 1 to 3, characterized in that the response signal is detected on the first area of the body surface by an infrared radiation sensor, in particular a thermocouple, a bolometer or a semiconductor detector (e.g. a quantum cascade detector).

5) The method according to any one of aspects 1 to 4, comprising the steps of:

-bringing the optical medium into contact with the surface of the material such that at least one region of the surface of the optical medium is in contact with the first region of the surface of the body;

emitting an excitation beam having an excitation wavelength into a volume in the material positioned below the first region of the surface, in particular through a region of the surface of the optical medium in contact with the first region of the surface of the material,

measuring the temperature in a first region of the surface of the optical medium using an optical thermometry method,

-analyzing the material based on the temperature increase detected according to the wavelength of the excitation light beam.

6) The method of aspect 5,

emitting a measuring beam through the optical medium onto a region of the surface of the optical medium in direct contact with the surface of the material such that the measuring beam and the excitation beam overlap at an interface of the optical medium and the surface of the material, the measuring beam being reflected at the interface of the optical medium and the surface of the material;

detecting, directly or indirectly, the deflection of the reflected measuring beam depending on the wavelength of the excitation beam; and

the material is analyzed based on the deflection of the measuring beam detected according to the wavelength of the excitation beam.

7) The method according to one of the aspects 5 or 6, characterized in that the measuring beam is generated by the same light source that generates the excitation light beam.

8) The method according to any of aspects 5, 6 or 7, characterized in that after deflection and before detection within the optical medium, one or more reflections of the measuring beam occur outside the optical medium or inside and outside parts of the optical medium.

9) The method according to aspect 1 or any of the other preceding or following aspects, characterized in that the measuring beam is an intensity modulated, in particular pulsed, excitation beam in the infrared spectral range, wherein in particular the modulation rate is between 1Hz and 10kHz, preferably between 10Hz and 3000 Hz.

10) The method of aspect 1 or any of the other preceding or following aspects, wherein the light of the one or more excitation light beams is generated simultaneously or sequentially or partially simultaneously and partially sequentially by an integrated arrangement having a plurality of individual lasers (in particular, laser arrays).

11) The method of aspect 1 or any of the other preceding or following aspects, wherein an intensity distribution of the response signal is determined from the response signals acquired at different modulation frequencies of the excitation beam according to a depth below the surface at which the response signal is generated.

12) The method of aspect 1 or any of the other preceding or following aspects, wherein the intensity distribution of the response signal is determined from a phase position of the response signal with respect to the excitation beam modulated at one modulation frequency or a different modulation frequency of the excitation beam, according to a depth below the surface at which the response signal is generated.

13) The method according to aspect 11 or 12, characterized in that in order to determine the intensity distribution of the response signal from the depth below the surface, the measurements at different modulation frequencies are weighted and combined with each other.

14) The method according to aspect 11, 12 or 13, characterized in that the material density of the material is determined from an intensity distribution taken in a depth below the surface of the body, wherein the material absorbs the excitation light beam in a specific depth or in a specific wavelength range within the depth range.

15) The method according to aspect 1 or any of the other preceding or following aspects, characterized in that immediately before, during or after detection of the one or more response signals, at least one biometric measurement, in particular a fingerprint measurement, is made on an ontology in or directly adjacent to the first area of the surface, and the ontology is identified, in particular a person is identified, and in particular a reference value (calibration value) can be assigned to detect the response signal.

16) A device for the analysis of a material, comprising,

having means for emitting one or more excitation light beams each having an excitation wavelength, the one or more excitation light beams being emitted into a volume positioned in the material below the first area of the surface of the material, having means for modulating the excitation light beam, the means being formed by modulation means of the radiation source, in particular by its controller, interference means, phase or polarization modulation means and/or at least one controlled mirror arranged in the beam path, and/or a layer arranged in the beam path, the transparency of which is controllable; and having detection means for detecting a time-dependent response signal in dependence on the wavelength of the excitation light and the intensity modulation of the excitation light; and means for analyzing the material based on the detected response signal.

17) The apparatus according to aspect 16, having means for determining the response signals independently from different intensity modulation frequencies and/or having means for determining the response signals from the phase position of the respective response signals with respect to the modulation phase of the excitation light beam, in particular from the modulation frequency of the excitation light beam.

18) The apparatus for analyzing a material according to aspect 16 or 17, having an optical medium to establish contact of a surface of the optical medium with a first area of a surface of the material, and having

Means for emitting an excitation light beam with one or more excitation wavelengths into a volume positioned in the material below a first region of the surface, in particular a region where the excitation light beam passes through the surface of the optical medium in contact with the surface of the material, and means for measuring the temperature in the region where the surface of the optical medium is in contact with the surface of the material using optical methods, and means for analyzing the material based on the temperature increase detected from the wavelength of the excitation light beam and the intensity modulation of the excitation light beam.

19) The apparatus of claim 18 wherein the excitation light source is directly fixedly mechanically coupled to the optical medium.

20) The device according to aspect 18 is characterized in that means are provided for emitting a measuring beam into the region of the optical medium in contact with the first region of the material surface, and that the device and/or the detection means are directly fixedly mechanically connected to the optical medium and/or are coupled to the optical medium by means of a fiber optic cable for detecting the measuring beam.

21) The apparatus according to aspect 18, 19 or 20, characterized in that the optical medium directly supports the imaging optics and/or the imaging optics are integrated into the optical medium.

22) The apparatus of aspect 18 or any of the other preceding or following aspects, wherein the surface of the optical medium has a plurality of partial faces inclined toward each other, at which the measuring beam is reflected multiple times.

23) The apparatus of aspect 18 or any other preceding or following aspect wherein one or more mirrors are disposed in or on the optical medium to reflect the measuring beam.

24) The device according to aspect 16 or 17, characterized in that, for detecting the time-dependent response signal, the detection device has an acoustic detector, in particular a resonator, more particularly a helmholtz resonator, for detecting the acoustic wave on the surface of the material. Since a quartz fork is used as a detector of the sound source, it preferably has the same resonance frequency as the resonator. The resonator may be open or closed. The quartz prongs are preferably located in or on the neck of the resonator (off-beam) or inside or outside the resonator (in-beam).

25) The device according to aspect 16, 17 or 18, characterized in that for detecting the time-dependent response signal the detection device has a thermal radiation detector, in particular an infrared detector, more particularly a thermocouple, a bolometer or a semiconductor detector, for detecting thermal radiation at the surface of the material.

26) The device according to any of the aspects 16 to 25, characterized in that the excitation light source and the detection device are directly attached to each other or to a common support, wherein the common support is in particular formed by a housing or a housing part of the device.

27) The device according to any of the aspects 16 to 26, characterized in that the device has a wearable housing which is fastenable to a human body, wherein the means for emitting one or more excitation light beams and the detection means for detecting the time-dependent response signal are arranged and configured such that the material to be analyzed is measured on the side of the housing facing away from the body.

28) A device according to any of the aspects 16 to 26, characterized in that the device has a wearable housing which can be fastened to a human body, and that the housing of the device has a window which, in a position intended to be worn, is transparent to the excitation light beam on its side facing away from the body.

29. Apparatus for analysing a material, the apparatus having: excitation transmission means for generating at least one electromagnetic excitation beam (in particular an excitation light beam) having at least one excitation wavelength; detection means for detecting the response signal; and means for analyzing the material based on the detected response signal.

30. The apparatus according to any of the preceding aspects 16 to 29, characterized in that the detection means are configured for measuring the deformation of the crystal.

By analogy with photothermal "bouncing", the deformation can be measured more effectively by choosing a steeper (larger) angle of incidence of the measuring beam on the sample surface, and the effect of the measuring beam mirage-related deflection can be minimized.

The literature:

analysis of photothermal deflection techniques in the m.bertolotti, g.l.liakhou, r.li Voti, s.paolino and c.sibilia. surface reflection topics: theory and Experiment (Analysis of the photothermal deflective technique with the surface reconstruction the. A physical Journal (Journal of Applied Physics),83,966(1998) is Applied.

The cantilever can be placed directly on the sample or on a sufficiently thin optical medium where the sample is placed on one side and the cantilever is placed on the other side. Due to thermal expansion of the sample or the optical element, the cantilever is set into vibration by thermal expansion caused by the absorption modulated pumped beam. The measuring beam is emitted on the upper side of the cantilever tip and is deflected by the vibrations, wherein the amount of deflection depends on the modulation frequency, the wavelength radiated and the thermal properties of the sample. The deflection is detected.

31. A device according to any of the preceding aspects 16 to 30, characterised in that the excitation transmission means comprises an interrogating laser or LED, such as a NIR (near infrared) LED.

32. The apparatus of any of the preceding aspects 16 to 31, wherein the excitation delivery means comprises a detection laser having a smaller diameter than the additional pump laser.

33. The device according to any of the preceding aspects 16 to 32, characterized in that, in order to achieve a more favorable signal-to-noise ratio, a special coating is provided, in particular the optical emitter, such as IRE, so that the heat dissipation is better (e.g. "thermal grease").

The optical element may be coated on the contact surface such that an improved conduction of the thermal signal to the optical medium may be provided. In addition, the coating can also serve as a protection against scratches, and a reflective surface for the measuring beam can also be realized by intelligent selection of the material. In this case, transparency to the excitation light must be maintained.

34. The device according to any of the preceding aspects 16 to 33, characterized in that it has a system for:

i. pulse sequence/double modulation;

ii, swinging the mirror;

mems interferometers.

35. The device according to any of the preceding aspects 16 to 34, characterized in that the device is designed to be permanently wearable on the body by a person, in one embodiment by a stopping device connected to the housing, such as a belt, a belt or a chain or a clasp, and/or that the detection device has a detection surface which can also be used as a display surface for information, such as measured values, clock time and/or text information.

36. The device according to the preceding aspect 35, characterized in that it has a pull-off membrane in the area of the detection surface, preferably the area against the detection surface, for the pre-treatment of the material surface and to ensure a clean surface, which in one embodiment is provided specifically for skin cleansing purposes in the case of glucose measurements.

37. Device according to any of the preceding aspects 16 to 36, characterized in that the detection means are configured to read and recognize fingerprints to retrieve certain values/calibrations of the person and/or to detect the position of the finger, preferably to detect and determine unintentional movements during the measurement.

38. The device according to any of the preceding aspects 16 to 37, characterized in that the detection device has a result display, preferably implemented as an analog display using color coding, which in one embodiment comprises an error indication (e.g. "100 mg/dl +/-5 mg/dl"); acoustically and/or as a measurement result display with steps greater than the accuracy allowed by the device. This means that small fluctuations, which may for example cause the user to be restless, are not conveyed.

39. The device according to any of the preceding aspects 16 to 38, characterized in that the device comprises a data interface for communicating measurement data and retrieving calibration data or other data from other devices or cloud systems, wherein the device is preferably configured such that the data can be transmitted in encrypted form, in particular encrypted by a fingerprint or other biometric data of an operator.

40. A device according to any of the preceding aspects 16 to 39, characterized in that the device is configured such that the suggested insulin dose to be administered to the person can be determined by the device in combination with other data (e.g. insulin correction factors), and/or that the weight, body fat can be measured, and/or that the weight, body fat can be simultaneously manually specified or can be transferred to the device from other devices.

41. The apparatus according to any of the preceding aspects 16 to 40, characterized in that it is configured to identify other parameters to increase the measurement accuracy, in one embodiment sensors for determining skin temperature, diffusivity of skin, conductivity/moisture content, sensors for measuring polarization of light (secretion of water/sweat on finger surface) or the like are used to identify other parameters.

Water and sweat on the surface of human skin, which can influence glucose measurements, can be detected by a test stimulus with excitation radiation using a stimulus transmission means, wherein the specific wavelength band of water is 1640cm^-1(6.1 μm) and 690cm^-1(15 μm). If the absorption exceeds a certain value, the measurement site/material surface/skin surface is too wet for a reliable measurement. Alternatively, the measurement site may be measured nearby or directlyThe conductivity of the material at the site of measurement is measured to determine the moisture content. Thus, an error message and an instruction to dry the surface may be output.

42. The device according to one of the preceding aspects 16 to 41, characterized in that it has a cover in the beam path of the pump laser and/or the measuring beam laser. This ensures that mandatory human eye safety is provided.

43. The device according to any of the preceding aspects 16 to 42, characterized in that the device has a replaceable detection surface.

44. The device according to any of the preceding aspects 16 to 43, characterized in that it is provided with grooved or rough crystals as optical medium in some areas, which allows better conditioning of the sample (e.g. a finger). The measuring point of the surface on which the material to be analyzed is placed is preferably designed to be free of grooves and smooth.

45. The device according to any of the preceding aspects 16 to 44, characterized in that for the measurement beam a cylindrical TEMpl TEM00 mode can be used, or other modes can be used instead of the cylindrical TEMpl TEM00 mode, such as TEM01 (ring), TEM02 or TEM 03. In particular, the latter mode has the following advantages: their intensity can be matched to the sensitivity distribution of the quadrant diodes which form the detector for the deflected measuring beam (see the figure). In addition, rectangular mode TEMmn, such as TEM30 or TEM03 or higher temn may be used. This allows sampling/measurement of less interfering beams to be used in either the horizontal or vertical direction.

46. The device according to any of the preceding aspects 16 to 45, characterized in that the device is measured not only at points but also in a grid. This can be done by moving the pump laser or the probe laser or the detection unit. Instead of moving, one or more pump laser arrays or probe laser arrays are possible.

Other detection methods for detecting the response signal after emitting the excitation beam may include:

-photoacoustic detection using a tuning fork or other vibrating element, or: slightly modified photoacoustics (quartz enhanced photoacoustic spectroscopy) with open QePAS cells. These methods can be used to detect pressure fluctuations/vibrations on the surface and evaluate them for measured beam deflection in the manner described above.

In principle, a measure of the phase drift of the response signal with respect to the periodically modulated excitation beam can be used for depth profiling. (for this reason, the temperature change/cooling phase of the material surface should be evaluated more accurately with respect to their wave shape or pattern.)

The described device can be associated with the supply of adhesive tape for removing dead skin layers, to allow maximally distortion-free measurement of the human body and of a paste with a thermally conductive paste, which can be applied to the optical medium periodically. The optical medium may be replaceable, giving the remaining parts suitable fastening and adjustment.

To perform the measurement, the device may be arranged and configured not only on the fingers of the person, but also on the lips or earlobes.

In some embodiments, measurements may be taken even without direct contact and placement on a finger or other part of the body (at a distance), resulting in a contactless measurement.

By combining a plurality of measurement systems described and illustrated with similar sensitivity to errors, the accuracy and reliability of the measurements can be improved.

The DAQ and lock-in amplifier under evaluation may be combined in one device and the overall evaluation may be digitized.

The measuring device can also be performed on a moving surface, so that during grid measurement: the excitation light source and/or the measurement light source are moved over the skin during the measurement in a grid pattern, which allows irregularities of the skin to be compensated for or even eliminated.

By adjusting/altering the wavelength of the probe beam/measuring light source, the sensitivity of the detection device/deflection unit can be optimized. For this purpose, the measuring light source may vary with wavelength, or include a plurality of laser light sources of different wavelengths, to be selected or combined.

For the deflection of the pump laser/probe laser, the ideal transverse mode (TEM) can be selected.

The excitation transmission means, measurement light source and detector may be configured in a common array and the beams may be suitably deflected in the optical medium to concentrate the emission and reception of all beams at one point.

A lens on or in the crystal of the optical medium may help to deflect the measuring beam more strongly in dependence of the response signal.

In addition, it is contemplated that a gapless photodiode is used for detection, and then a lens can focus the measuring beam after it exits, thereby enabling more accurate measurements.

Additional variants of the invention according to the patent claims are described in the following concepts. This concept, whether used alone or in combination with the above aspects or with the subject matter of the claims, also constitutes at least one independent invention. The applicants reserve the right to make this invention or these inventions the subject of the claims at a later date. This may be done in the context of this application or in the context of a subsequent divisional application or a continuation application claiming priority to this application.

A concept of non-invasive blood glucose measurement, determining glucose in the skin by thermal wave measurement using excitation of quantum cascade lasers and radiant heat. Based on fig. 12 and 13, a method of determining the concentration of glucose or another material in interstitial fluid (ISF) in the skin is described. Glucose in ISF represents blood glucose and in the event of a change, it will quickly follow the blood glucose change. The method comprises at least a single step or group of the following steps or the whole sequence:

1. a spot on the skin 102 (in this case, a first area of the material surface) is irradiated with a beam of a quantum cascade laser, which is focused and possibly reflected at a mirror or parabolic mirror 140 and is tuned incrementally or continuously over a specific infrared range in which glucose is specifically absorbed. It is also possible to use a laser array having multiple lasers radiating at a single wavelength instead of the quantum cascade laser 100. The spectral range (or individual wavelengths, typically 5 or more wavelengths) may specifically be at about 900cm^-1And about 1300cm^-1In this range, glucose has an absorption fingerprint, i.e. typical and representative absorption lines.

2. The excitation beam denoted SA (CW laser) is used continuously, or in a pulsed mode with a high pulse repetition rate or in a modulated manner. In addition, the excitation beam is low frequency modulated, in particular in a frequency range between 10Hz and 1000 Hz. The low frequency modulation may be performed using various periodic functions, such as a sine wave, a rectangular wave, or a sawtooth wave, among others, in various embodiments.

3. Due to the radiation of the skin and depending on the wavelength of the specific vibrations excited in the glucose molecules, the IR radiation penetrates deep into the skin to a depth of approximately 50 to 100 μm. These excitations from vibration level v0 to v1 return to the initial state in a very short time; in this step, heat is released.

4. As a result of the heat generated according to (3), a thermal wave is formed, which propagates isotropically from the position of absorption. The thermal wave periodically reaches the surface of the skin at a modulation frequency according to the thermal diffusion length defined by the low frequency modulation described in (2) above.

5. The periodic appearance of the thermal wave on the surface corresponds to a periodic modulation of the thermal radiation properties of the skin (material surface of the sample). The skin can be described herein generally as a black body radiator, the overall emission of which is proportional to the fourth power of the surface temperature according to Stefan-Boltzmann law.

6. The periodic temperature increase described according to (5) is recorded with a detector 139 for thermal radiation, i.e. an infrared detector, i.e. a thermocouple, bolometer, semiconductor detector or similar device, which is directed at the point of the irradiated skin. This depends on the irradiation of infrared light as described according to (1) and (2), the absorption as described according to (3) and thus on the concentration of glucose. The thermal radiation SR (in this case the response signal) is collected by an optical element, which in one embodiment is an infrared lens or mirror, in particular a parabolic concave mirror 141, and in one embodiment is directed onto the detector 139 via a convex mirror 141 a. For this purpose, the collecting mirror used in one embodiment may have an opening 142, through which opening 142 the collected beam is directed. A filter 143 may be arranged in the beam path, which filter 143 only allows infrared radiation of a certain wavelength range to pass.

7. In processing the response signal, the modulation frequency may be considered in particular, for which the response signal may be processed in the lock-in amplifier 144. By analyzing the phase angle between the excitation signal and the thermal radiation signal (response signal) using the control and processing unit 147, depth information about the depth below the surface can be acquired, wherein the response signal is mainly acquired from the depth information.

8. The depth information may also be obtained by: the various low frequency modulation frequencies as described in (2) for the excitation beam are selected and analyzed, and the results of the different modulation frequencies are combined (where the results may also be weighted differently for the different modulation frequencies). For this purpose, a differential method or other calculation method can be used to compensate for the absorption of the uppermost skin layer.

9. In order to maximize the sensitivity of the thermal radiation detection according to point (6), it is used over a wide spectral band for the entire available infrared range. As many regions of the planck radiation curve as possible should be used. In order to make the detection insensitive to the intensified excitation radiation, blocking filters (notch filters) 143 for these excitation wavelengths are provided for the detection of thermal radiation. The wavelength range 148 transmitted by the blocking filter 143 is also apparent in the illustration of fig. 13. Where the intensity of the response signals are shown both as a function of wavelength, there is no excitation beam or only excitation radiation of a wavelength which is not specific for the material to be identified (i.e. the wavelength of the specific absorption band of the material is not present) in a first (solid) curve 145, and then a similar curve is shown in a second (dashed) curve 146, where the radiation comprises an excitation beam of an absorption wavelength which is specific for the material to be identified.

10. If glucose is to be identified, then in one embodiment, from the thermal signal measured according to (6-9) as a function of the excitation wavelength, the background is determined first using the non-glucose related (or excluded) wavelengths of the excitation beam (curve 145) and then the difference from the background signal is determined using (or including) the glucose related wavelengths. This results in a glucose concentration in one or more skin layers, which glucose concentration is defined by the phase position selected according to (7) or the different modulation frequencies according to (8) or a combination thereof.

Although the invention has been illustrated and described in more detail by means of preferred exemplary embodiments, the invention is not limited by the disclosed examples and other variants can be derived therefrom by the person skilled in the art without departing from the scope of protection of the invention.

List of reference numerals

10 device

100 excitation transmission device/excitation light source

100a transmitter/transmission element

101 material

102 first region

103 volume

104 device

105 device

106 detection device

107 processing means/evaluation means

107a memory

108 optical medium

108a surface portion

108b surface portion

109 adjustment device

110 part surface

111 part surface

112 measuring beam/measuring beam

113 mirror surface

114 mirror surface

116 open mouth

117 opening

118 opening

119 connector body

120 optical fiber cable

121 supporting part

122 shell

123 body

124 side part

125 strip-shaped piece

126 finger tip

127 regulating device

128 imaging optics

129 imaging optics

130 optical detector/camera

131 data processing device

132 controller

133 micro mirror

134 micro mirror

135 micro-electro-mechanical system

136 deflection arrangement

137 control device

138 layer

139 infrared detector

140 mirror

141 parabolic mirror

142141 opening

143 wavelength filter

144 lock-in amplifier

145 signal curve of response signal (solid line)

146 Signal curve of response signal (dotted line)

147 control and processing device

148 wavelength range

BZA blood glucose level indication

D test results

GF interface

SA excitation beam

SR response signal

Claims (34)

1. Device (10) for analyzing a material (101), having:

-excitation transmission means (100) for generating at least one electromagnetic excitation beam (SA), in particular an excitation light beam having at least one excitation wavelength;

-detection means (106, 139) for detecting the response Signal (SR); and

-means (107, 147) for analyzing the material based on the detected response Signal (SR).

2. The apparatus of claim 1,

-the excitation transmission means is a radiation source, in one embodiment a monochromatic radiation source, in particular a polarized radiation source, more particularly a laser light source;

-the device (10) comprises an optical medium (108), the optical medium (108) being in direct contact with the material (101), in particular the optical medium (108) being in direct contact with a first region (102) of the surface of the material;

-wherein the excitation transmission device (100) is preferably arranged such that the emitted excitation beam (SA) penetrates the optical medium (108) and exits the optical medium (108) again at a predetermined point on the surface (12) of the optical medium, and

-the apparatus comprises a system (105) for emitting a measurement beam (112), in particular a measurement beam, the system (105) being arranged such that the emitted measurement beam (112) penetrates the optical medium (108), and wherein, preferably, in operation, the measurement beam (112) and the excitation beam (SA) overlap at an interface (GF) of the optical medium (108) with a surface of the material (101), wherein a reflection of the measurement beam (112) occurs at the interface (GF), and

-the detection device (106) is a device for receiving the reflected measurement beam (112) and/or for directly or indirectly detecting a deflection of the reflected measurement beam (112), wherein the reflected measurement beam (112) forms the response Signal (SR).

3. The device according to any one of the preceding claims,

the device (10) comprises an optical medium (108), the optical medium (108) being in direct contact with the material (101), in particular the optical medium (108) being in direct contact with a first region (102) of the surface of the material, and the detection means (106) detect a change of a parameter of the optical medium to detect a response Signal (SR), in particular a change of a parameter of the optical medium caused by the response signal, in particular a deformation and/or a density change of the optical medium, in a region adjacent to the first region.

4. The device according to any one of the preceding claims,

the detection means comprise a piezoelectric element connected to or integrated in the optical medium as a detector for detecting deformations and/or density changes.

5. The device according to any one of the preceding claims,

the detection means comprise a temperature sensor as a detector for detecting the response signal.

6. The device according to any one of the preceding claims,

-the device comprises means (104) for intensity modulating the excitation light beam (SA), and

-said detection means (106) is adapted for detecting a time-dependent response Signal (SR) depending on said wavelength of said excitation light and/or an intensity modulation of said excitation light.

7. The device according to any one of the preceding claims,

the excitation transmission device (100) radiates the at least one electromagnetic excitation beam (SA) into a material volume (103), the material volume (103) being positioned below a first region (102) of a surface of the material (101).

8. The device according to any one of the preceding claims,

the excitation transmission arrangement (100) comprises two or more transmission elements (100a), the transmission elements (100a) being in particular transmission elements in the form of one-, two-or multi-dimensional transmission element arrays.

9. The device according to any one of the preceding claims,

the two or more transmission elements (100a) each generate its own electromagnetic excitation beam and radiate the electromagnetic excitation beam into a volume below the first region (102).

10. The device according to any one of the preceding claims,

the wavelengths of the electromagnetic excitation beams of the two or more transmission elements (100a) are different.

11. The device according to any one of the preceding claims,

the excitation transmission means comprises two or more lasers, in particular in the form of a one-dimensional, two-dimensional or multi-dimensional laser array, and/or two or more light emitting diodes, in particular in the form of a one-dimensional, two-dimensional or multi-dimensional diode array.

12. The device according to any one of the preceding claims,

the excitation transmission means is mechanically fixedly connected to an optical medium (108) directly or indirectly through adjustment means (109), the optical medium (108) being in direct contact with the material (101), in particular the optical medium (108) being in direct contact with the first region (102) of the surface of the material (101).

13. The device according to any one of the preceding claims,

the means (104) for intensity modulation comprise or are formed by electrical modulation means, which are electrically connected to the excitation transmission means (100) and which electrically control the excitation transmission means (100).

14. The device according to any one of the preceding claims,

the device (104) for intensity modulation comprises at least one controlled mirror (133, 134), the at least one controlled mirror (133, 134) being arranged in the beam path.

15. The device according to any one of the preceding claims,

the means (104) for intensity modulation comprises or is formed by at least one layer which is arranged in the beam path (138) and whose transparency is controllable.

16. The device according to any one of the preceding claims,

means (105) are provided for emitting a measuring beam (112), in particular a measuring beam, the measuring beam (112) being emitted into a region of the optical medium (108) which is in contact with the first region (102) of the surface of the material.

17. The device according to any one of the preceding claims,

the detection device and the device for emitting a measurement beam are mutually aligned with each other such that the detection device detects the measurement beam as the time-dependent response signal after at least one reflection of the measurement beam at the interface (GF) of the optical medium (108), wherein the interface (GF) of the optical medium (108) is in contact with the material, in particular the interface (GF) of the optical medium (108) is in contact with the first area (102) of the surface of the material (101).

18. The device according to any one of the preceding claims,

the detection means and/or the excitation transmission means and/or the means for emitting a measurement beam are mechanically fixedly connected directly to the optical medium and/or are coupled to the optical medium by a fiber optic cable (120).

19. The device according to any one of the preceding claims,

the optical medium directly supports imaging optics (128, 129), and/or imaging optics (128, 129) are integrated in the optical medium.

20. The device according to any one of the preceding claims,

the surface of the optical medium has a plurality of partial surfaces (110, 111) which are inclined toward one another, and the measuring beam (112) is reflected multiple times at the plurality of partial surfaces (110, 111), in particular the measuring beam is reflected multiple times at the plurality of partial surfaces (110, 111).

21. The device according to any one of the preceding claims,

one or more reflection surfaces (113, 114) are provided on or in the optical medium (108) for reflecting the measurement beam (112), in particular the measurement beam.

22. The device according to any one of the preceding claims,

the excitation transmission means (100) and/or the detection means (106) and/or the means (105) for emitting a measurement beam are attached directly to each other or to a common support (121).

23. The device according to any one of the preceding claims,

the support (121) is formed by a printed circuit board, a metal or plastic plate or a housing (122) or a housing part of the device.

24. The device according to any one of the preceding claims,

the excitation transmission means has an integrated semiconductor component comprising one or more laser elements and at least one micro-optical component and preferably an additional modulation element.

25. The device according to any one of the preceding claims,

the modulating element comprises at least one element, in particular a mirror, which is movable with respect to the rest of the semiconductor device and whose position is controllable.

26. The device according to any one of the preceding claims,

the modulating element comprises a layer having a controllable radiation permeability.

27. The device according to any one of the preceding claims,

the modulation element comprises electronic control circuitry for modulating the one or more laser elements.

28. Method for analyzing a material (101), wherein, in the method,

-generating at least one electromagnetic excitation beam (SA) having at least one excitation wavelength by at least partially simultaneously or continuously operating a plurality of laser emitters of a laser light source with an excitation transmission device (100);

-detecting the response Signal (SR) with the detection means (106); and

-analyzing the material based on the detected response Signal (SR).

29. The method of claim 28,

using different modulation frequencies of the excitation transmission means, continuously determining a response signal, in particular an instantaneous response signal waveform or pattern, and combining a plurality of response signal waveforms or patterns at different modulation frequencies with each other, and in particular obtaining specific information of a depth range of the subsurface from the combined response signal waveforms or patterns.

30. The method of claim 29,

for the excitation beams of different wavelengths, response signal waveforms or patterns at different modulation frequencies are determined, in particular, specific information for each depth range of the subsurface is obtained from the response signal waveforms or patterns.

31. The method of claim 30,

when a plurality of modulation frequencies of the pump beam are used simultaneously, the detected signal is resolved into signal frequencies by an analytical process, preferably by a fourier transformation, and

only the part of the signal corresponding to the desired frequency is filtered out.

32. The method according to any of the preceding claims 28 to 31,

-bringing an optical medium (108) in direct contact with the material (101), in particular bringing the optical medium (108) in direct contact with a first region (102) of the surface of the material (101);

-generating said emitted excitation beam (SA) with said excitation transmission device (100), and in particular said excitation beam (SA) being irradiated such that said excitation beam (SA) penetrates into said optical medium (108) and exits said optical medium (108) again at a predetermined point on the surface of said optical medium (108);

-generating a measurement beam (112), in particular a measurement beam, with a device (105) for emitting a measurement beam (112), such that the measurement beam (112) penetrates the optical medium (108), and in particular, that, in operation, the measurement beam (112) and the excitation beam (SA) overlap at an interface (GF) of the optical medium (108) with the surface of the material (101), wherein a reflection of the measurement beam (112) occurs at the interface (GF); and

-measuring the reflected measurement beam (112) with the detection device (106), wherein the reflected measurement beam (112) forms the response Signal (SR); and/or

-detecting directly or indirectly the deflection of the reflected measuring beam.

33. The method according to any of the preceding claims 28 to 32,

the method comprises the steps of periodically amplitude modulating the excitation beam at a first frequency, and determining a frequency offset of the response signal relative to the first frequency, and determining a velocity of movement of the measured material based on the doppler effect.

34. The method according to any of the preceding claims 28 to 33,

depending on the concentration of the substance identified in the material, a dosing means for delivering the substance into the material is activated, in particular a dosing means for delivering the substance into the patient's body is activated, and/or an acoustic and/or visible signal is output, and/or the signal is transmitted via a wireless connection to a processing means.