Methods and apparatus for analyte measurement, including real-time quality assessment and improvement.

Abstract

1. A method for analyzing a substance (12) containing at least one analyte, wherein analyte-wavelength-specific measurements are interspersed with reference measurements (80), and response signals obtained for the reference measurements (80) are used for one or more of: calibrating an excitation radiation source (26) for generating said excitation radiation; calibrating said detection device; recognizing changes in measurement conditions by comparing results of individual reference measurements (80); adapting said analyte measurement procedure (78) with respect to one or more of the total duration of the analyte measurement procedure, the absolute or relative duration of an analyte-wavelength-specific measurement with respect to a given analyte characteristic wavelength, or termination and / or resumption of the analyte measurement procedure; and adapting the analysis performed in the analysis step.

Description

[Technical Field]

[0001] The present invention generally relates to methods and apparatus for analyzing substances, for example, as fluids, which include at least one analyte. In particular, the present invention relates to methods for non-invasive measurement of analytes in body fluids, such as the glucose concentration in human skin, especially in the interstitial fluid of human skin. [Background technology]

[0002] The present invention relates to a method for analyzing a substance comprising at least one analyte. The method comprises a measurement procedure in which the substance is brought into thermal or pressure-transfer contact with the object to be measured, and the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation in the substance to be transferred to the object to be measured. The excitation radiation is irradiated onto the substance so as to be absorbed by the substance, the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths irradiated simultaneously and sequentially or both.

[0003] As understood herein, the analyte characteristic wavelength is the wavelength that allows the presence of the analyte to be determined by wavelength-selective absorption, and thus forms the basis of the analysis. Therefore, the analyte characteristic wavelength may, in particular, include the wavelength corresponding to the maximum absorption value of the analyte. A further analyte characteristic wavelength is the wavelength corresponding to the minimum between two absorption peaks; that is, the difference between the absorption minimum and an adjacent peak is a suitable measure of the concentration of the analyte in the substance. In this specification, the term “minimum” indicates that the absorptivity of the analyte at a given wavelength is smaller than that of nearby wavelengths, but is still recognizable; otherwise, they are not characteristic of the analyte. In particular, in preferred embodiments, the absorptivity at these minimums acting as analyte characteristic wavelengths is greater than 5%, preferably greater than 10%, more preferably greater than 20%, and most preferably greater than 30% of the highest absorption peak associated with any of the analyte characteristic wavelengths on which the analyte measurement is based. While wavelengths precisely corresponding to absorption peaks or absorption minimums are usually preferred choices as analyte characteristic wavelengths, wavelengths close to the maximum / minimum value, or wavelengths between the maximum and minimum values, may also be used. Therefore, as understood herein, “analyte characteristic wavelength” is also the wavelength at which the difference in absorption with respect to the nearest absorption peak or nearest absorption minimum is less than 30%, preferably less than 20%, of the difference in absorption between the nearest absorption peak and the nearest absorption minimum. The analyte characteristic wavelength may also include wavelengths at which the absorption of other components in the substance with which the analyte is mixed is particularly low.

[0004] Furthermore, the physical response of the object being measured or a component contained within the object to the heat or pressure wave received from the substance when the excitation radiation is absorbed is detected using a detection device, the detection device generates a response signal based on the detected physical response, and the response signal indicates the degree of absorption of the excitation radiation.

[0005] The present invention is not limited to any particular physical response to heat or pressure waves received from the aforementioned substance upon absorption of excitation radiation, nor is it limited to any particular method of detecting this physical response so as to make it possible to generate a response signal indicative of the degree of absorption of the excitation radiation. Various physical responses and corresponding detection methods have been previously proposed by the present applicant for these types of analyte measurement procedures, which are briefly summarized below, each of which may be applied to the present invention.

[0006] For example, the detection device may comprise a light source for generating a detection light beam that travels through at least a part of the aforementioned measurement body or a component contained in the aforementioned measurement body, and the aforementioned physical response of the measurement body to heat or pressure waves received from the aforementioned substance upon absorption of the aforementioned excitation radiation may be a local change in the refractive index of the aforementioned measurement body or the aforementioned component. In this case, the detection device may be configured to detect one of a change in the optical path or a change in the phase of the detection light beam due to the aforementioned change in the refractive index of the substance of the measurement body or the component contained in the measurement body.

[0007] For example, in various methods and devices described in detail in two prior applications of the present applicant, published as International Publication No. 2015 / 193310 and International Publication No. 2017 / 097824, both of which are incorporated herein by reference, the measurement body is transparent to the aforementioned detection light beam, and the detection light beam is directed to be totally or partially reflected at the surface of the aforementioned measurement body that is in thermal contact with the aforementioned substance. In this case, the detection device may comprise a photodetector, in particular a position-sensitive photodetector, capable of detecting the degree of deflection, in particular the deflection angle, of the aforementioned detection light beam due to the aforementioned local change in refractive index. Thus, in this case, the physical response to the heat or pressure waves received by the measurement body is a local change in refractive index, and the response signal is the detected degree of deflection, which has been found to actually indicate the degree of absorption of the excitation radiation.

[0008] In an alternative variant proposed by the present applicant, the above detection device may comprise an interferometer device that makes it possible to evaluate the above phase change of the detection beam and generate a response signal indicative of the above phase change, as disclosed, for example, in International Application No. PCT / EP2019 / 064356, which is incorporated herein by reference. In this case, the physical response of the measurement body (or the constituent element contained in the measurement body) to the heat or pressure wave received from the substance upon absorption of the above excitation radiation is again a local change in the refractive index, and the response signal is, in this case, an interference signal that reflects the change in phase of the detection beam caused by the local change in the refractive index.

[0009] In a further alternative embodiment, the measurement body or the constituent element of the above measurement body may have an electrical property that changes in response to a local change in temperature or a change in pressure associated therewith, and the above detection device comprises an electrode for capturing an electrical signal representative of the above electrical property. Various possible setups are disclosed in International Publication No. 2019 / 110597, which is incorporated herein by reference. For example, the measurement body may comprise a section having piezoelectric properties, and the pressure change associated with the received heat results in an electrical signal that can be recorded at the electrode. In this case, the change in pressure is similar to the physical response of the measurement body or the constituent element contained in the measurement body to the heat received from the substance upon absorption of the excitation radiation, and is detected using the piezoelectric properties of the measurement body and the electrode, resulting in an electrical signal representing the above response signal that indicates the degree of absorption of the excitation radiation. In a further variant, the temperature change caused by the received heat can be directly measured using a very high-sensitivity temperature sensor.

[0010] It should be noted that the following description details the physical response of the object to the heat received from the substance. However, in various embodiments of the methods and apparatus of the present invention, the substance is in pressure-transmitting contact with the object, and it should be understood that the physical response of the object is its response to the pressure wave received from the substance. In this specification, the expression “pressure-transmitting contact” includes all relationships, in particular acoustically coupled relationships, that enable the transfer of pressure waves from the substance to the object, and the coupling may be established by a gas, liquid, or solid. All detailed descriptions given in relation to thermal contact and physical response to the heat received by the object from the substance shall be understood, where applicable, in conjunction with scenarios involving pressure-transmitting contact and physical response to pressure waves, without explicit reference.

[0011] It should be noted that the term "analyte" measurement procedure indicates that this procedure is based on the response signal obtained from excitation radiation at the characteristic wavelength of the analyte.

[0012] The method further includes an analytical step, the analysis of which is performed at least partially based on the response signal. In this case, the response signal indicates the degree of absorption of excitation radiation, including the "analyte characteristic wavelength," and is therefore directly related to the concentration of the analyte in the substance. Thus, the analytical step is at least partially based on a measure of the concentration of the analyte in the substance, and in some non-limiting applications, it may actually determine this concentration.

[0013] For example, the method described above has been employed by the applicant in a device for the non-invasive measurement of a user's glucose levels. In this particular application, the “analyte” is formed by glucose and the “substance” is the user’s skin. This method has been previously demonstrated to enable highly accurate measurement of glucose concentration in the interstitial fluid within a person’s skin, which has been found to be directly related to and thus represent the glucose content of the patient’s blood. Figure 4 of this application shows the results of a Clark error grid analysis taken from International Publication No. 2017 / 097824, demonstrating that the analytical method described above enables highly accurate prediction of a person’s actual glucose concentration.

[0014] Nevertheless, it is desirable to further improve the accuracy of the analysis results, or to obtain analysis results of the same accuracy in a shorter time. [Overview of the project] [Problems that the invention aims to solve]

[0015] The fundamental objective of the present invention is to provide a method and apparatus for analyzing the aforementioned substances that enables improvement of the accuracy or reliability of the analytical results, a reduction in the time required for the analysis, or both. [Means for solving the problem]

[0016] According to one aspect of the present invention, this problem is solved when, during the analyte measurement procedure, a series of analyte wavelength-specific measurements are performed while maintaining the thermal or pressure transmission contact between the substance and the object being measured, and in each analyte wavelength-specific measurement, excitation radiation having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. At least some of the above analyte wavelength-specific measurements are resolved by interposing a reference measurement, in which an excitation radiation having a reference wavelength is irradiated, and a corresponding response signal is obtained. Here, the reference wavelength is a wavelength different from any of the above analyte characteristic wavelengths. Preferably, the reference wavelength is a wavelength in which the absorption of the analyte is low, in particular less than 40%, preferably less than 20%, and most preferably less than 10% of the highest absorption peak of the analyte associated with one of the analyte characteristic wavelengths.

[0017] Furthermore, the above response signal obtained with respect to the reference measurement, Calibrating the excitation radiation source for generating the above excitation radiation, particularly the radiation intensity of the above excitation radiation source. Calibrating the above detection device, particularly the sensitivity of the detection device, By comparing the results of individual reference measurements, we can recognize changes in measurement conditions. Adapting the analyte measurement procedure with respect to one or more of the following: the total duration of the analyte measurement procedure, the absolute or relative duration of the wavelength-specific measurement for a given analyte characteristic wavelength, or the termination and / or resumption of the analyte measurement procedure, and To adapt the analysis performed in the analysis step, It is used for one or more of the following.

[0018] The inventors have surprisingly discovered that the accuracy of an analyte measurement procedure can be significantly improved when a reference measurement is performed during the procedure. Here, the analyte measurement procedure is a continuous measurement process in the sense that thermal or pressure-transfer contact between the substance and the object being measured is maintained throughout the measurement process. For example, if the substance is formed by a person's fingertip, this means that the fingertip is not lifted from the object being measured during the analyte measurement procedure. Furthermore, during the analyte measurement procedure, a series of analyte wavelength-specific measurements are performed, and in each analyte wavelength-specific measurement, excitation radiation having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. In this way, information on the absorption spectrum and ultimately the concentration of at least one analyte can be obtained.

[0019] However, according to this embodiment, at least some of the analyte wavelength-specific measurements are interspersed with reference measurements, in which excitation radiation having a reference wavelength is irradiated onto the substance, and a corresponding response signal is obtained. Here, the reference wavelength is a wavelength different from any of the analyte characteristic wavelengths. The reference wavelength may be a wavelength at which the absorption of the analyte is low, and / or a wavelength at which the total absorption of the substance is dominated by the absorption of a component that is present in large quantities in the substance and therefore does not change significantly in proportion (e.g., water if the substance is skin). In other words, the reference measurement is not useful for measuring the absorption of the analyte, but rather for measuring the absorption of other specific components in the substance, or the absorption of the substance background. These response signals obtained with respect to the reference measurement are then used to improve the analyte measurement procedure "on the fly," which is possible because these reference measurements are performed simultaneously with the analyte measurement procedure.

[0020] In one variant, the response signal obtained with respect to a reference measurement is used to calibrate the excitation radiation source for generating the excitation radiation. For example, in a typical analyte measurement procedure, a series of analyte wavelength-specific measurements are performed at various analyte characteristic wavelengths, yielding corresponding response signals. The inventors have noticed that even during the course of a fairly short analyte measurement procedure, which may last only a few tens of seconds, while thermal or pressure-transfer contact between the substance and the object is maintained, there may be large changes in the output of the excitation radiation source, or changes in the optical contact between the substance and the object, or both, which alter the measured absorption at different analyte characteristic wavelengths of the same analyte and thus affect the analytical results. Those skilled in the art may consider performing a calibration measurement using a reference wavelength different from the analyte characteristic wavelength before the actual analyte measurement procedure, but the inventors have found, surprisingly, that in practice, there are large changes in the output of the radiation source and the optical coupling between the substance and the object, on a much smaller timescale, which can be better and more appropriately taken into account using a reference measurement performed simultaneously with and alternately with the analyte absorption measurement. Subsequently, the reference measurement allows for the calibration of the excitation radiation source, avoiding fluctuations in its output or taking into account changes in the optical coupling between the substance and the analyte, thereby significantly improving the accuracy of the analyte measurement procedure.

[0021] Similarly, the response signal obtained with respect to a reference measurement may be used to calibrate the detection device "on the fly," thereby allowing for the taking into account variations in the detection device itself or compensating for other sources of variation that can be compensated for by the calibration of the detection device.

[0022] Alternatively, the response signals obtained with respect to a reference measurement may be used to recognize changes in measurement conditions by comparing them with the results of individual reference measurements.

[0023] As an addition or alternative, the response signal obtained with respect to a reference measurement may be used to adapt the analyte measurement procedure with respect to one or more of the following: the total duration of the analyte measurement procedure, the absolute or relative duration of the analyte wavelength-specific measurement with respect to a given analyte characteristic wavelength, and / or the end and restart of the analyte measurement procedure. For example, if the reference measurement indicates that there is significant variation in the measurement conditions, this may indicate extending the analyte measurement procedure to compensate for noisier data with a longer measurement time, in some cases. As an addition or alternative, the reference measurement may indicate a change in measurement conditions that occurs only during a specific time portion of the entire analyte measurement procedure, in which case it is sufficient to allocate more measurement time to the analyte characteristic wavelength used during that time portion. In this way, we have found that the overall quality and consistency of the measurement can be greatly improved without the need to repeat the measurement or dramatically increase the measurement time.

[0024] As an addition or alternative, the response signal obtained with respect to a reference measurement may be used to terminate, and possibly restart, the analyte measurement procedure if the reference measurement indicates that the reliability of the measurement is questionable. In the specific example of glucose measurement, this might be, for example, if the finger is not properly positioned on the measuring body and it is prudent to simply lift the finger, reposition it, and restart the measurement procedure. If this can be determined quickly, i.e., during the normal duration of the analyte measurement procedure, it is far more user-friendly than asking the patient to repeat the measurement after the entire analyte measurement procedure and the corresponding analysis have been completed. This also allows for the initiation of various trials without frustrating the user.

[0025] Instead of or in addition to calibrating the excitation radiation source or detection device, or instead of or in addition to adjusting the absolute or relative duration of analyte wavelength-specific measurements with respect to a particular analyte characteristic wavelength, it is also possible to adapt the analysis performed in the analysis step to mathematically take into account the strain and variation evaluated by the reference measurements, taking into account the timing information associated with each reference measurement. This may include, for example, normalizing at least some of the results of the analyte wavelength-specific measurements, for example, based on interpolation of various reference measurement results, at least in part on the results of one or both of the preceding or succeeding reference measurements.

[0026] In a preferred embodiment, a reference measurement is performed for at least 25%, preferably at least 50%, of each pair of consecutive analyte wavelength-specific measurements. Additionally or alternatively, the reference measurement is performed at an average rate of at least once every 5 seconds, preferably at least once every 1 second, and most preferably at least 10 times every 1 second. This detailed monitoring by reference measurements has proven to significantly improve the accuracy of the analyte measurement procedure and the corresponding analysis.

[0027] This finding is quite surprising to those skilled in the art, since the reference measurement itself does not directly contribute to information about the analyte, and the time spent on the reference measurement cannot be used for measurements specific to the analyte wavelength. In many applications, particularly with regard to non-invasive glucose measurements, measurement time is limited for practical reasons, and as a result of this limited time, much of the valuable measurement time is obviously dedicated to wavelengths that enable the detection of the analyte's absorption. However, the inventors have found that, in practice, even with respect to a given limited overall measurement time, the results become more accurate when some of the measurement time is dedicated to an interspersed reference measurement.

[0028] In an alternative embodiment, during the analyte measurement procedure, a series of analyte wavelength-specific measurements are performed while maintaining the thermal or pressure transfer contact between the substance and the object being measured, and in each analyte wavelength-specific measurement, excitation radiation having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. A quality assessment is performed based on response signals associated with one or more analyte characteristic wavelengths, and based on the above quality assessment, the measurement time allocated to the corresponding one or more analyte characteristic wavelengths in the current analyte measurement procedure or one or more future analyte measurement procedures is adjusted, or the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis are adjusted.

[0029] In a preferred embodiment, the quality evaluation is performed during the analyte measurement procedure, and the measurement time allocated to one or more corresponding analyte characteristic wavelengths is adjusted in real time during the analyte measurement procedure.

[0030] As an addition or alternative, the above quality assessment may be at least partially, - The signal-to-noise ratio of the above response signal or a quantity derived from the signal-to-noise ratio, and - Based on one or more of the results of one or more reference measurements, in a reference measurement, an excitation radiation having a reference wavelength is irradiated into the substance to obtain a corresponding response signal, wherein the reference wavelength is a wavelength at which the analyte has low absorption. For example, the reference wavelength may be a wavelength at which the absorptivity of the analyte is less than 30%, preferably less than 20%, more preferably less than 10%, and most preferably less than 5% of the absorptivity at the highest absorption peak associated with any of the analyte characteristic wavelengths on which the analyte measurement procedure is relied upon.

[0031] In a preferred embodiment, the method further includes a substance status analysis procedure, in which the current status of the substance is determined. - One or more response signals established when the substance is irradiated with excitation radiation at a wavelength different from the characteristic wavelength of the analyte mentioned above. - With respect to excitation radiation having the same analyte characteristic wavelength as used in the analyte measurement step, but with respect to the intensity modulation frequency of the excitation radiation which is at least partially different from that of the analyte measurement step, and - One or more measurements related to the status of a substance, performed using additional sensor equipment. The analysis is based on one or more of the following.

[0032] Next, based on the results of the above substance status analysis procedure, - Selection of the characteristic wavelength of the analyte used in or relied upon during the above analyte measurement procedure, - The absolute time or relative time ratio of the use of the characteristic wavelength of the analyte in the above analyte measurement procedure, or the relative weight given to the wavelength in the analysis, - Selection of analyte characteristic wavelengths to be used simultaneously during the above analyte measurement procedure, and - Selection of one or more principal frequencies of the modulation of the excitation radiation intensity to be used during the analyte measurement procedure described above, At least one of them is determined.

[0033] According to this aspect of the present invention, the method includes a specific substance status analysis procedure in which the status of a substance is analyzed. Briefly, this “substance status” analysis concerns criteria other than the analyte itself, or components other than the analyte contained in the substance, but deals with the state of the substance that may be considered in the analyte measurement procedure in order to achieve optimal measurement accuracy and / or efficiency of the analyte measurement procedure.

[0034] In particular, material status analysis procedures may include the collection of response signals established when a material is irradiated with excitation radiation at wavelengths different from the analyte characteristic wavelengths, typically wavelengths where the analyte has a low absorptivity, and even lower than all or at least most of the aforementioned minimums in the absorption spectrum, but where absorption is often still recognizable. In particular, at these wavelengths, the analyte may have an absorptivity of less than 30%, preferably less than 20%, more preferably less than 10%, and most preferably less than 5% of the absorptivity at the highest absorption peak associated with any of the analyte characteristic wavelengths on which the analyte measurement procedure relies. Thus, the presence and concentration of non-analyte components may be determined using response signals established when a material is irradiated with excitation radiation at wavelengths different from the analyte characteristic wavelength, which may correspond to one aspect of material status.

[0035] As an addition or alternative, the material status analysis procedure may include one or more response signals established with respect to excitation radiation having the same analyte characteristic wavelength as used in the analyte measurement step, but with respect to intensity modulation frequencies of the excitation radiation that are at least partially different from those in the analyte measurement step. As will become apparent from the detailed description below, in this way, for example, a suitable or optimized depth range in the material for measuring the analyte can be determined. In this specification, the expression "at least partially different intensity modulation frequencies" indicates that some of the intensity modulation frequencies employed in the material status analysis procedure with respect to a given analyte characteristic wavelength may also be used in the analyte measurement procedure, but not all of them may be used. Typically, a larger number of modulation frequencies may be tested in the material status analysis procedure, and only a subset of them may be used in the analyte measurement procedure.

[0036] As an addition or alternative, the material status analysis procedure may include one or more measurements related to the material status, performed using additional sensor equipment, i.e., sensor equipment that is essentially unrelated to the analyte measurement procedure.

[0037] Additional information regarding the material status obtained in the material status analysis procedure may then be used to improve the efficiency and / or accuracy of the analyte measurement procedure. In particular, based on the results of the material status analysis procedure, the optimal selection may be made from among the various possible analyte characteristic wavelengths actually used during the analyte measurement procedure. In this way, the analyte measurement procedure may be limited to the analyte characteristic wavelength relating to the excitation radiation that is expected to give the best, for example, the most characteristic analyte measurement result (considering the material status established by the material status analysis procedure), thereby improving the efficiency, reliability, and accuracy of the analyte measurement procedure. Instead of selecting the analyte characteristic wavelengths to be used during the analyte measurement procedure, it is also possible to select only the analyte characteristic wavelengths on which the analysis in the analysis step relies. That is, instead of omitting the analyte characteristic wavelengths that can be used during the analyte measurement procedure, it is equally possible to simply ignore measurements based on this analyte absorption wavelength during the analysis step, or to consider this analyte absorption wavelength with less weight. Nevertheless, for the purpose of reducing measurement time, it is preferable to actually make a selection regarding the possible analyte characteristic wavelengths to be used during the analyte measurement procedure.

[0038] Instead of selecting the analyte characteristic wavelength as a whole, it is also possible to select the absolute or relative time ratio of the use of the analyte characteristic wavelength during the analyte measurement procedure, or the relative weight given to the wavelength in the analysis, based on the results of the material status analysis procedure. According to this variation, more measurement time can be allocated to the analyte characteristic wavelength that is expected to contribute more significantly to accurate analytical results (in light of the results obtained from the material status analysis procedure). In this way, the efficiency of the analyte measurement procedure can also be improved.

[0039] In another variation, the results of a material status analysis procedure may suggest the selection of analyte characteristic wavelengths to be used simultaneously during the analyte measurement procedure. Thus, the efficiency of the analyte measurement procedure can be further enhanced by using two or more different analyte characteristic wavelengths simultaneously as excitation radiation.

[0040] Finally, as an addition or alternative, the results of the material status analysis procedure may suggest a preferred selection of one or more dominant frequencies for the modulation of the excitation radiation intensity to be used during the analyte measurement procedure. In this specification, the expression “dominant frequency” of modulation refers to the frequency of the dominant frequency in the Fourier spectrum of the modulation function. For example, if the modulation function is a periodic square wave function, the dominant frequency is the reciprocal of its period. Furthermore, since the modulation frequency of the excitation radiation is primarily one of the main factors determining the depth at which the analyte measurement is performed, the optimized depth for the measurement may be determined by the material status analysis step using signals provided by non-analyte components present in the material, and in some cases, whose density profile with respect to depth below the surface of the material is known in advance.

[0041] In summary, the accuracy and efficiency of the analyte measurement procedure and the analysis based thereon can be improved by combining the analyte measurement procedure with the material status analysis procedure described herein, and by further determining the optimal selection of the analyte absorption wavelength and / or modulation frequency to be used during the analyte measurement procedure based on the determined material status.

[0042] In preferred embodiments, the substance is human tissue, particularly human skin, and the analyte is glucose present in the skin, particularly in the interstitial fluid of the skin. While references to this embodiment are made in the following description and in the description of specific embodiments, it should be understood that the present invention is not limited thereto and may be applicable to other types of substances and analytes.

[0043] In preferred embodiments, the substance status analysis procedure is performed alternately or temporally superimposed on the analyte measurement procedure. In other words, in these preferred embodiments, the analyte measurement procedure relating to the same analysis step is performed intermittently or sequentially, with the substance status analysis procedure performed in between. That is, the inventors have found that the best results can be achieved when the substance status is established with the minimum time delay with respect to the analyte measurement procedure, and therefore reflects the current status of the substance applied during the analyte measurement procedure in as much detail as possible. In other embodiments, the substance status analysis procedure may be performed first, followed by the analyte measurement procedure. However, in this case, the substance status analysis procedure is preferably performed less than 5 minutes, preferably less than 3 minutes, and most preferably less than 1 minute before the start of the analyte measurement procedure.

[0044] In a preferred embodiment, thermal or pressure-transfer contact between the substance and the object being measured is maintained during a time interval that includes at least part of the substance status analysis procedure and the analyte measurement procedure. For example, if the analyte is glucose and the "substance" is the skin of a fingertip placed on the object being measured, this means that the fingertip is stably maintained on the object being measured throughout both the substance status analysis procedure and the analyte measurement procedure.

[0045] In a preferred embodiment, the substance status includes the presence and / or concentration of a perturbative component in the substance that differs from the one or more analytes but exhibits significant absorption of excitation radiation at at least one of the analyte characteristic wavelengths. An example of such a perturbative component in the measurement of glucose in the interstitial fluid of human skin is the presence of lactate, the level of which varies not only from person to person but also within each individual based on, for example, recent physical activity. The lactate absorption spectrum may overlap with the glucose absorption peak and thus perturb the measurement result. If the substance status analysis procedure then shows a sufficiently high concentration of the perturbative component, the use of at least one of the analyte characteristic wavelengths in which the perturbative component exhibits significant absorption is avoided or suppressed, or each wavelength is shifted from the maximum absorption value of the perturbative component. Other examples of perturbative components may be fatty acids, gels such as those used in cosmetics and ultrasound diagnostics, excess water, or albumin.

[0046] In a preferred embodiment relating to the measurement of glucose in human tissue, the at least one principal frequency of the modulation of the excitation radiation intensity to be used in the analyte measurement procedure includes a first principal modulation frequency and a second principal modulation frequency, wherein the first principal modulation frequency is chosen to be sufficiently low so that the response signal reflects at least partially the absorption of excitation radiation in the interstitial fluid, and the second principal modulation frequency is higher than the first principal modulation frequency, and in the analysis, the response signals corresponding to the first and second principal modulation frequencies, or quantities derived from the response signals, are mathematically combined, for example, by subtraction or division of each other, to produce information indicating absorption in the interstitial fluid. Here, the second principal modulation frequency may be at least 1.5 times, preferably at least 2.0 times, and most preferably at least 3.0 times higher than the first principal modulation frequency. In some embodiments, the first principal modulation frequency may be in the range of 20 to 30 Hz, and the second principal modulation frequency may be in the range of 150 to 300 Hz.

[0047] When excitation radiation is emitted into a substance, a portion of it is absorbed along its optical path, i.e., at various depths below the surface of the substance. In response to absorption, a thermal signal is generated, which diffuses back to the surface of the substance and is received by the object being measured. Because the intensity of the excitation radiation is modulated, the substance is heated by absorption in a time-dependent manner, changing as a function of space and time, resulting in a temperature field often called a thermal wave. The term thermal "wave" can be somewhat misleading, as the propagation of heat through the substance is governed by the diffusion equation rather than the wave equation. This also means that the maximum depth of the modulated absorption below the surface of the substance, which can be detected by the heat received by the object being measured at the surface of the substance, is the so-called diffusion length μ. t This means that it is almost limited by the diffusion length μ t ρ is the density of a substance, and C is its specific heat capacity. p , thermal conductivity k t , and depends on the modulation frequency f of the excitation radiation:

number

[0048] Furthermore, it has been found that the depth below the surface where interstitial fluid exists depends on the thickness of the stratum corneum, and the thickness of the stratum corneum not only varies from person to person, but also changes over time and across the location on the skin surface where the measurement is taken, even within the same person. For example, if a person has recently performed physical actions with their hands or practiced a stringed instrument, the stratum corneum may be thicker than usual, meaning that absorption must occur in deeper layers below the skin surface to cover the interstitial fluid. Here again, the thickness of the stratum corneum is a "material status" that can be evaluated in the material status analysis procedure described above.

[0049] Therefore, determining a first main modulation frequency that is "sufficiently low" so that the response signal at least partially reflects the absorption of excitation radiation in the interstitial fluid can be optimally done in a material status analysis procedure.

[0050] However, even when the thermal diffusion length is sufficiently long and the response signal at least partially reflects the absorption of excitation radiation by the interstitial fluid, the response signal also represents absorption in the upper layers of the skin, particularly the stratum corneum, and therefore includes a contribution not related to glucose in the interstitial fluid. In fact, this contribution from the upper layers of the skin, particularly the stratum corneum, is typically large in the response signal because the intensity of excitation radiation in the upper layers is higher than in the deeper layers of the skin, and the absorbed heat only needs to travel a shorter distance from the upper layers to reach the object. To estimate this contribution of the higher layers of the skin to the first response signal, at least one additional second response signal is recorded in response to excitation radiation having the second main modulation frequency described above, where the second main modulation frequency is higher than the first main modulation frequency, resulting in a shorter diffusion length, and therefore primarily representing absorption in the upper layers of the skin above the region where interstitial fluid is present. Then, to produce information that more specifically indicates absorption in the interstitial fluid, the response signals corresponding to the first and second main modulation frequencies, or quantities derived from the response signals, are mathematically combined. There are various ways to mathematically combine these response signals, and this aspect of the present invention is not limited to any of them. For example, the second response signal may be multiplied by a normalization coefficient obtained, for example, based on a reference measurement at an excitation wavelength where glucose absorption is negligible, and then the product may be subtracted from the first response signal.

[0051] At first glance, it might seem easy to select a first main modulation frequency that is "sufficiently low" so that the response signal at least partially reflects the absorption of excitation radiation in the interstitial fluid, by arbitrarily selecting a low modulation frequency that results in a very long diffusion length, thereby ensuring that the interstitial fluid is covered by the diffusion length. However, the inventors have found that while it is important that the diffusion length covers the depth region where the interstitial fluid is present, the quality of the response signal and the accuracy of the measurement can be greatly improved if an excessively long diffusion length is avoided. In fact, the inventors have found that particularly good results can be obtained when the thermal diffusion length is at most approximately equal to, and at least half of, the optical absorption length for excitation radiation, and the first modulation frequency is selected accordingly.

[0052] While not wishing to be bound by theory, this finding can be understood as follows: the optical absorption length μ for radiation having a wavelength λ, in a substance, particularly in human tissue α (λ) is the reciprocal of the absorption coefficient α(λ), that is, μ α (λ) = 1 / α(λ). The optical absorption length μ α (λ) corresponds to the optical path length in the substance at which the intensity of radiation having the wavelength λ is reduced to 1 / e by absorption. To detect the concentration of an analyte such as glucose, since the concentration of the analyte is proportional to the absorption coefficient α(λ), it is desirable to effectively measure a signal proportional to the absorption coefficient α(λ) at the analyte characteristic wavelength λ. However, for this purpose, the penetration depth of the excitation radiation should be longer than the thermal diffusion length. This becomes plausible by considering the opposite scenario where the optical absorption length is smaller than the thermal diffusion length: in this case, almost all of the light energy is absorbed within the depth range corresponding to the thermal diffusion length and is represented by the response signal. In other words, the response signal essentially represents the energy of the excitation beam rather than the specific absorption by the analyte. Therefore, it is necessary that only a part of the total excitation radiation is absorbed within the thickness range that contributes to the thermal signal recorded at the surface of the substance by the above response signal; in this case, the response signal actually fluctuates according to the absorption coefficient.

[0053] Accordingly, a useful response signal is expected to require μ t (f) < μ α (λ). Therefore, a reasonable lower limit f for the modulation frequency f min can be defined as the frequency at which μ t (f min ) = μ α (λ), which leads to f min = k t ·α(λ) 2 / (2·ρ·C p ). The present inventors have found that, in practice, the optimum modulation frequency f to be used as the lower first modulation frequency satisfies 4·f min > f > f min , preferably 3·f min > f > f min, more 2·f min >f>f min It was discovered that it was within the range.

[0054] The optimal first modulation frequency is k t ρ, C p While it is shown above how the modulation frequency depends on the physical parameters of the tissue, such as α(λ), this does not mean that the modulation frequency can actually be determined by determining each of these parameters individually and then calculating the modulation frequency as defined above. Rather, what this shows is how the optimal first modulation frequency depends on the parameters of the tissue, and therefore on the “material status” of the tissue or skin, which can vary from person to person and even over time in the same person. This illustrates why the accuracy and efficiency of the analyte measurement procedure can actually be improved by performing a “material status analysis procedure” and by selecting one or more dominant frequencies for modulation of excitation radiation intensity to be used during the analyte measurement procedure based on the material status analysis results.

[0055] In a preferred embodiment, the substance status includes skin water content. Preferably, skin water content is measured using a dedicated keratinometer. This keratinometer is an example of the “additional sensor equipment” mentioned above. For reasons that will be explained in more detail below, the analyte measurement procedure can be optimized in various ways to take skin water content into account.

[0056] As those skilled in the art will understand, skin water content is a substance status that tends to vary greatly not only from person to person but even within the same person, as it can depend on, for example, climatic conditions, whether an individual has recently washed their hands, or whether they have recently used moisturizing lotion. Therefore, it is advantageous to assess skin water content during or immediately before performing the analyte measurement procedure in the above substance analysis procedure. Knowledge of water content then makes it possible to select an appropriate analyte characteristic wavelength and / or an appropriate modulation frequency for modulation of excitation radiation.

[0057] In a preferred embodiment, if a higher water content is determined in the substance analysis procedure, the analyte measurement procedure preferentially uses shorter wavelengths from a given set of analyte characteristic wavelengths. “Preferentially using” shorter wavelengths may mean that shorter wavelengths from the given set of analyte characteristic wavelengths are selected for use, and one or more longer wavelengths from that set are not used. Additionally or alternatively, this may mean that all wavelengths from the given set of analyte characteristic wavelengths are used, but the relative time spent on shorter wavelengths is longer than the relative time spent on one or more longer wavelengths. In practice, such selection of wavelengths may be carried out in a variety of ways, and this embodiment is not limited to any particular one of them.

[0058] For example, in a simple embodiment, there may be a predefined threshold for water content (or another parameter related thereto), where water content above the threshold is considered "high" and water content below this threshold is considered "low". Two different subsets of the above set of given analyte characteristic wavelengths may be predefined to be used for "high" and "low" water content, respectively, where the average excitation emission wavelength in the subset associated with "high" water content is shorter than that in the subset associated with "low" water content. However, in other embodiments, there may be different subsets of analyte characteristic wavelengths to be used for different measured water content ranges. In further embodiments, a selection function may be employed that defines the selection of excitation wavelengths as a function of the determined water content value according to some mathematical rule. Any of these embodiments may be used, as long as it is guaranteed that shorter excitation wavelengths are preferred or dominant for higher water content, assuming all other properties of the material status are the same.

[0059] The rationale behind this selection of the excitation wavelength is that water has a fairly high, wavelength-independent absorption coefficient and therefore tends to attenuate excitation radiation within the relevant spectral range. Thus, even if the excitation wavelength is chosen to coincide with the absorption peak of the analyte (e.g., glucose), water contributes to the absorption coefficient α(λ), and therefore to the light absorption length μ. α This substantially reduces (λ). This is because, as explained above, the light absorption length μ α (λ) is the thermal diffusion length μ t (f) With the understanding that it should be greater than or equal to (f), the accessible depth of measurement within the material (structure) is reduced. However, in the wavelength region containing the most useful absorption peak of glucose for the purposes of the present invention, i.e., the region between approximately 8 μm and 10 μm, it has been found that the absorption coefficient of water α(λ) decreases with decreasing wavelength, and the problems associated with absorption by water are not so serious with respect to shorter excitation wavelengths. Therefore, if a higher water content is determined as part of the material status analysis procedure, this leads to the selection of shorter excitation wavelengths in the analyte measurement procedure.

[0060] As an addition or alternative, at least one of the one or more principal frequencies of the excitation radiation intensity modulation used in the analyte measurement procedure above is adapted to the water content determined in the material analysis procedure above, and assuming all other properties of the material status are the same, a higher principal frequency of the modulation is selected for higher water content. In other words, when high water content is found, at least one of the one or more principal frequencies of the excitation radiation intensity modulation is increased, and the light absorption length μ is increased as well, which is expected to decrease due to the increased absorption of water. α The thermal diffusion length μ should better match or remain below (λ). t(f) is effectively reduced. Again, there are many ways to select one or more main modulation frequencies depending on the determined water content, and this aspect of the present invention is not limited to one of them. For example, in one embodiment, a water content threshold may be defined, and a higher or lower modulation frequency may be selected depending on whether the water content is above or below this threshold. Alternatively, various water content ranges may be predefined, and for each water content range, a corresponding main modulation frequency may be predefined, with a higher modulation frequency associated with a higher water content. In further embodiments, the modulation frequency may be determined as a function of water content, and possibly further as a function of excitation emission wavelength, and a higher modulation frequency may be selected for higher water content, and possibly also for longer excitation emission frequencies, taking into account the fact that the absorption coefficient of water α(λ) decreases with wavelength. Regardless of how strictly the modulation frequency is fitted to the water content, in any case the selection is such that a higher main modulation frequency is selected for higher water content, assuming all other properties of the material status are the same.

[0061] In a preferred embodiment, the substance status includes the thickness of the stratum corneum above the interstitial fluid. As previously mentioned, the thickness of the stratum corneum can vary from person to person, and even in the same person, it can change significantly over time depending on the amount of recent physical activity or exercise. Therefore, the accuracy and efficiency of the analyte measurement procedure can be greatly increased if the analyte measurement procedure is adapted to the actual thickness of the stratum corneum, and the thickness of the stratum corneum is individually assessed during or before the performance of the analyte measurement procedure.

[0062] In a preferred embodiment, the thickness of the stratum corneum is evaluated directly or indirectly based on a response signal established with respect to the same wavelength of excitation radiation, but with respect to different intensity modulation frequencies of the excitation radiation, where the wavelength is selected to match the absorption bands of components present in the stratum corneum and interstitial fluid at different concentrations, respectively. As previously described, the modulation frequency of the excitation radiation governs the thermal diffusion length and, therefore, the depth range in which the absorption process can be detected by the received thermal signal. Thus, by changing the intensity modulation frequency, absorption at various depth ranges can be measured. Furthermore, since the wavelength of the excitation radiation coincides with the absorption bands of components present in the stratum corneum and interstitial fluid at different concentrations, the thickness of the stratum corneum can be estimated by depth-dependent absorption.

[0063] It should be noted that the thickness of the stratum corneum may be directly assessed in the sense that a specific thickness in millimeters is determined, or it may be assessed indirectly, for example, by simply determining the modulation frequency corresponding to the boundary region between the stratum corneum and interstitial fluid, which serves as an indirect or implicit measure of the thickness of the stratum corneum. In some embodiments, the absorbing components present in the stratum corneum and interstitial fluid at different concentrations may be the analytes themselves, such as glucose. Among the various intensity modulation frequencies, there are higher frequencies corresponding to shorter thermal diffusion lengths where glucose-induced absorption is not measured, indicating that this depth corresponds to the stratum corneum. Conversely, among the various intensity modulation frequencies, there are lower modulation frequencies corresponding to longer thermal diffusion lengths where significant glucose absorption is detected, indicating that this depth corresponds to the depth where interstitial fluid is present. Here, the glucose-induced absorption may be determined by relying on reference measurements at wavelengths low enough that local absorption is negligible, although other absorption backgrounds, particularly water, are expected to be very similar.

[0064] In a preferred embodiment, at least one of the one or more principal frequencies of the excitation radiation intensity modulation used in the analyte measurement procedure is adapted to the thickness of the stratum corneum above the interstitial fluid determined in the material analysis procedure, and a lower principal frequency of modulation is selected for higher stratum corneum thicknesses, assuming all other properties of the material status are the same. Again, there are various ways of adjusting the principal frequency of excitation radiation intensity modulation as a function of stratum corneum thickness. For example, as in the previous embodiment, there may be a predetermined threshold for stratum corneum thickness (or another parameter representing stratum corneum thickness), and the modulation frequency may be adjusted based on whether the stratum corneum thickness is less than the threshold (in which case a higher modulation frequency will be selected) or greater than the threshold (in which case a lower modulation frequency will be selected). In an alternative embodiment, there may again be several stratum corneum thickness ranges and associated modulation frequencies, with the modulation frequency for higher stratum corneum thicknesses being lower than the modulation frequency for lower stratum corneum thicknesses. In a further embodiment, the modulation frequency may be determined based on a continuous function relating the modulation frequency to be used in the analyte measurement procedure to the stratum corneum thickness determined in the material status analysis procedure. Assuming all other properties of the material status are the same, any method of selecting the modulation frequency as a function of the determined stratum corneum thickness may be employed, as long as it is guaranteed that a lower principal frequency of modulation is selected for higher stratum corneum thicknesses. Furthermore, it should be noted that instead of determining the stratum corneum thickness by measurement using various excitation radiation intensity modulation frequencies, it is equally possible to measure its thickness using a dedicated sensor or measuring device, such as an ultrasonic sensor or an OCT device.

[0065] When referring to selecting "one or more" principal frequencies of modulation with respect to the stratum corneum thickness, it should be noted that this can apply to both a first (lower) modulation frequency intended to cover the significant portion containing interstitial fluid, and a second (higher) modulation frequency intended to measure the response signal to compensate for absorption in higher layers of the skin, particularly the stratum corneum, where interstitial fluid is absent or minimal. In a preferred embodiment, at least the second modulation frequency is adapted to the determined stratum corneum thickness. However, it is also possible that only the first modulation frequency is adapted to the determined stratum corneum thickness.

[0066] In a preferred embodiment, the substance status includes the pH value of the skin, where the pH value is preferably determined using the additional sensor equipment formed in this case by a dedicated pH measuring device. If the pH value determined in the substance analysis procedure is found to be lower, the analyte characteristic wavelength superimposed on the absorption band of lactate in the analyte measurement procedure is not used as preferentially as if the pH were found to be higher, assuming all other properties of the substance status are the same.

[0067] The rationale behind this embodiment is that lower pH values ​​in the skin have often been found to indicate higher lactate concentrations in the skin. Therefore, when lower pH values, and thus higher lactate concentrations, are reasonably expected, it is preferable to avoid, or at least allocate less measurement time to, analyte characteristic wavelengths that overlap with the lactate absorption band in the analyte measurement procedure. For example, one or more thresholds for pH may be defined, and the extent to which these overlapping analyte characteristic wavelengths are used can be adapted depending on whether the pH is above or below such thresholds, including cases where the overlapping analyte characteristic wavelengths are not used at all in the analyte measurement procedure.

[0068] In a preferred embodiment, the skin forming the substance is the skin of a human subject's fingertip, and the substance status includes the average height of the skin ridges. The average height of the skin ridges is preferably estimated using the additional sensor equipment described above, which is formed by a dedicated fingerprint sensor.

[0069] Here, the output of the excitation radiation used in the analyte measurement procedure is preferably fitted as a function of the average height of the skin ridges, and the output of the excitation radiation used in the analyte measurement procedure is increased for higher average skin ridges, assuming all other properties of the material status are the same. The inventors have noticed that in the case of high skin ridges, the optical contact between the object being measured and the fingertip resting on it may be poor, and a lower proportion of the excitation radiation is actually coupled to the fingertip. This can be compensated for by detecting higher skin ridges during the material status analysis procedure and increasing the output of the excitation radiation to account for the expected loss at the interface. It should be noted that "average height of skin ridges" corresponds to the average height in this situation where the fingertip is actually pressed against the object being measured, and therefore depends on both the structure of the epidermis and the current contact pressure, which may differ from one measurement session to another, even in the same person. This is why it is advantageous to take skin ridges into account in the material status analysis procedure associated with a given analyte measurement procedure. Furthermore, the "average height of skin ridges" does not need to be determined with excessive precision, and in many cases, a qualitative assessment ("low," "normal," and "high") or estimation already serves its purpose. In some embodiments, the height of skin ridges is estimated based on the distance between adjacent skin ridges, since these two quantities are typically correlated. Fingerprints may be evaluated using capacitive measurement, for example, from fingerprint sensors in the art, using techniques known to the art itself.

[0070] The actual mapping between the additional output of the excitation radiation and the average height of the detected skin ridges can be done in many ways, and this embodiment is not limited to any particular one of them. As previously stated, in a simple variant, there is a broad classification of the detected average skin ridges, such as "low," "normal," and "high," and each of these classes is associated with a corresponding output or output correction of the excitation radiation. In other embodiments, only two or more such classes may be defined, and in yet another embodiment, the output may be a continuous function of the average skin ridge height or a parameter related thereto (such as the average distance between two adjacent skin ridges). Any of these variants are possible embodiments, as long as it is ensured that the output of the excitation radiation used in the analyte measurement procedure is generally increased with respect to higher average skin ridges (assuming all other properties of the material status are the same).

[0071] In further embodiments, the substance status includes skin temperature.

[0072] In a preferred embodiment, the time modulation of the intensity of the excitation radiation is selected such that the intensity envelope is asymmetric, and the proportion of time during which the envelope is 50% or more of the average intensity is less than 50% of the total time, preferably less than 46%, and most preferably less than 43%. However, the proportion of time during which the envelope is less than 50% should not be selected to be too low, preferably at least 20%, and more preferably at least 30%.

[0073] The obvious choice for the modulation function of the excitation radiation intensity is a square wave function alternating between zero ("off") and maximum value ("on"), with the on-interval and off-interval lengths being the same. However, the inventors have surprisingly discovered that the accuracy and efficiency of the analyte measurement procedure can be improved, for example, when the relative length of the off-interval is longer than the relative length of the on-interval, without changing the main frequency of the modulation signal or the period, which is the sum of the on-interval and off-interval.

[0074] Until now, the main focus of considerations regarding the intensity modulation of excitation radiation has been the corresponding thermal diffusion length. However, according to our theoretical understanding and practical experience, the thermal diffusion length is not affected at all, or at least not significantly, by simply increasing the relative ratio of the off-time to the on-time. Nevertheless, we have found that for the same entire frequency range, a better signal-to-noise ratio of the response signal can sometimes be obtained by making the off-interval longer and the on-interval shorter. According to our understanding, this is due to the fact that the response signal is substantially an "AC signal" in the sense that only the change in the response signal over time can be evaluated to estimate the degree of absorption. For this reason, it seems important that the physical response of the object due to the heat received from the material (such as the formation of a thermal lens that causes deflection of the detection beam) can be more completely attenuated before the next thermal pulse is received. This explains why the AC signal can be improved by increasing the off-interval, since the time for the physical response of the object to attenuate is relatively long.

[0075] It should be noted that the modulation functions considered herein are not limited to square wave functions, and similar effects may be obtained for any modulation function when the lower interval of the modulation function is longer than the higher interval. For this reason, according to this embodiment, the time modulation of the intensity of the excitation radiation is selected such that the intensity envelope is asymmetric, and the proportion of time during which the envelope is 50% or more of the average intensity is less than 50% of the total time, preferably less than 46%, most preferably less than 43%, preferably at least 20%, and more preferably at least 30%.

[0076] Alternatively, the time modulation of the intensity of the excitation radiation is selected such that the intensity envelope follows a periodically repeating pattern, the pattern comprising a high-intensity time portion including more than 80% of the intensity-time integral of the pattern and a low-intensity time portion including less than 20% of the intensity-time integral, and the ratio of the durations of the high-intensity time portion to the low-intensity time portion is less than 0.9, preferably less than 0.8, and most preferably less than 0.7. However, in a preferred embodiment, this ratio should be at least 0.4, preferably at least 0.5.

[0077] The use of a square wave modulation function with respect to excitation radiation intensity has two general advantages. The first advantage is that sharp excitation pulses with steep edges are particularly promising for generating thermal pulses, yielding good results. The second advantage is that square wave modulation is the easiest to establish in practice.

[0078] Nevertheless, despite the obvious advantages of square-wave modulation of excitation light intensity, the inventors have found that in some applications, including the non-invasive glucose measurement on the user's skin described herein, a sinusoidal modulation function may yield better results. This is a surprising finding, as the sinusoidal modulation function does not have the same sharp impulse as found with respect to square-wave modulation, which can produce particularly prominent thermal pulses in the skin that can be well detected using the apparatus of the present invention. However, the inventors have found that this drawback can be compensated for in certain circumstances, which are applicable to some of the embodiments described herein, where the analyte to be measured, e.g., glucose, is located primarily in deeper layers of the substance (e.g., skin) and is only accessible by lower modulation frequencies. When using a square-wave signal, it is necessary to distinguish between its principal frequency, which is the reciprocal of the signal's repetition period, and the harmonic contributions to the signal as seen in the Fourier series decomposition of the square-wave signal. These higher-frequency contributions result in response signals corresponding to absorption in shallower regions of the skin, which are not relevant, for example, with respect to the glucose measurement described herein.

[0079] Therefore, in a preferred embodiment, the time modulation of the intensity of the excitation radiation is chosen such that the intensity envelope is approximately harmonic, and in the Fourier decomposition of the intensity of the excitation radiation, at least 95% of the total intensity associated with the dominant frequency and the first to ninth harmonics is associated with the dominant frequency, and at least 97%, preferably at least 98%, is associated with the dominant frequency and the first harmonic. Here, the nth harmonic is usually understood to have a frequency of (n+1)·f, where f is the dominant frequency. In a sinusoidal function, i.e., a perfect harmonic function, the entire intensity is associated with the dominant frequency f. In a preferred embodiment, the time modulation function of the intensity does not need to be strictly harmonic, but it needs to be "approximately" harmonic in the sense defined above, in that at least 95% of the intensity is in the ground mode associated with the dominant frequency, and at least 97%, preferably at least 98%, is in the ground mode and the first harmonic.

[0080] In a preferred embodiment, the detection device includes a light source for generating a detection light beam that travels through the object being measured or at least a portion of the components contained in the object being measured. The physical response of the object being measured to the heat received from the substance during the absorption of the excitation radiation is a local change in the refractive index of the object being measured or its components. The above-mentioned detection device is configured to detect either a change in the optical path or a change in the phase of the detection beam due to the above-mentioned change in refractive index, and to generate a response signal indicating the above-mentioned change in the optical path or phase of the detection beam.

[0081] In a preferred embodiment, the measuring body is transparent to the detection light beam, and the detection light beam is directed so as to be fully or partially reflected by the surface of the measuring body that is in thermal pressure transfer contact with the material, and the detection device comprises a photodetector, particularly a position-sensing photodetector, capable of detecting the degree of deflection of the detection light beam due to the local change in refractive index, in particular the deflection angle.

[0082] In a preferred embodiment, the detection device includes an interferometer device that enables the evaluation of the phase change of the detection beam and the generation of a response signal indicating the phase change.

[0083] In a preferred embodiment, the measuring body or a component of the measuring body has electrical properties that change in response to a local change in temperature or a change in pressure associated therewith, and the detection device comprises electrodes for capturing an electrical signal representing the electrical properties.

[0084] In a preferred embodiment, the excitation radiation is generated using lasers, each having a dedicated wavelength, particularly semiconductor lasers, and even more specifically, quantum cascade lasers. Each laser may have its own modulation device, or the lasers may have a common modulation device and be controlled by a common or individual controller. The lasers in the array may be optically aligned to allow the use of a common optical path for the excitation beam, and can be radiated into a material, for example, through a common optical waveguide. The laser array may be combined on a single semiconductor chip.

[0085] In a preferred embodiment, the excitation radiation is generated using at least one tunable laser, in particular at least one tunable quantum cascade laser.

[0086] In preferred embodiments, some or all of the excitation wavelengths are in the range of 5 μm to 13 μm, preferably 8 μm to 11 μm. In alternative embodiments, some or all of the excitation wavelengths are in the range of 3 μm to 5 μm. This wavelength range is useful, for example, for detecting the absorption of CH2 and CH3 vibrations in fatty acids.

[0087] Further aspects of the present invention relate to an apparatus for analyzing a substance comprising at least one analyte, comprising: a measuring body having a contact surface suitable for thermal or pressure-transfer contact with the substance, wherein the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation in the substance to be transferred to the measuring body; an excitation radiation source configured to irradiate the substance with excitation radiation so as to be absorbed by the substance; a detection device for detecting the physical response of the measuring body or components contained in the measuring body to the heat or pressure waves received from the substance when the excitation radiation is absorbed, and for generating a response signal based on the detected physical response, wherein the response signal indicates the degree of absorption of the excitation radiation; and a control system.

[0088] Here, the control system is configured to control an excitation radiation source to irradiate a substance with excitation radiation so that it is absorbed by the substance, wherein the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths that are irradiated simultaneously and / or sequentially, and the control system is further configured to detect the physical response and control a detection device to generate a response signal indicating the degree of absorption of the excitation radiation.

[0089] Furthermore, the control system is further configured to control the apparatus to perform a series of analyte wavelength-specific measurements while maintaining the thermal or pressure-transfer contact between the substance and the object being measured during the analyte measurement procedure, wherein in each analyte wavelength-specific measurement, excitation radiation having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. The control system is further configured to intersperse at least some of the above-mentioned analyte wavelength-specific measurements with reference measurements, in which an excitation radiation having a reference wavelength is irradiated, a corresponding response signal is obtained, and the reference wavelength is different from any of the above-mentioned analyte characteristic wavelengths. The above control system uses the response signal obtained with respect to the reference measurement. Calibrating the excitation radiation source for generating the above excitation radiation, Calibrate the above detection device. By comparing the results of individual reference measurements, we can recognize changes in measurement conditions. Adapting the analyte measurement procedure with respect to one or more of the following: the total duration of the analyte measurement procedure, the absolute or relative duration of the analyte wavelength-specific measurement with respect to a given analyte characteristic wavelength, or the termination and / or resumption of the analyte measurement procedure, and To adapt the analysis performed in the analysis step, It is configured to be used for one or more of the following purposes.

[0090] In the relevant embodiments, a reference measurement is performed for at least 25%, preferably at least 50%, of each pair of consecutive analyte wavelength-specific measurements.

[0091] In a preferred embodiment of the apparatus, the control system is configured to control the apparatus so that the reference measurement is performed at an average rate of at least once every 5 seconds, preferably at least once every 1 second, and most preferably at least 10 times every 1 second.

[0092] In a preferred embodiment, the step of adapting the analysis performed in the analysis step based on the response signal obtained with respect to the reference measurement includes normalizing at least some of the results of analyte wavelength-specific measurements based at least in part on the results of one or both of the preceding or subsequent reference measurements.

[0093] In an alternative embodiment of the apparatus, in addition to or instead of the control system being configured to intersperse reference measurements into at least some of the analyte wavelength-specific measurements, the control system is further configured to control the apparatus during the analyte measurement procedure so that a series of analyte wavelength-specific measurements are performed while maintaining the thermal or pressure-transfer contact between the substance and the object being measured, wherein in each analyte wavelength-specific measurement, excitation radiation having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated to obtain a corresponding response signal. The control system is further configured to perform a quality assessment based on response signals associated with one or more analyte characteristic wavelengths, and, based on the quality assessment, adjust the measurement time allocated to the corresponding one or more analyte characteristic wavelengths in the current analyte measurement procedure or in one or more future analyte measurement procedures, or to adjust the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis.

[0094] In related embodiments, the control system is configured to perform a quality assessment during the analyte measurement procedure and to control the apparatus in real time during the analyte measurement procedure to adjust the measurement time allocated to one or more corresponding analyte characteristic wavelengths.

[0095] In further relevant embodiments, the above quality evaluation is at least partially, - The signal-to-noise ratio of the above response signal or a quantity derived from the signal-to-noise ratio, and - Based on one or more of the results of one or more reference measurements, in the reference measurement, excitation radiation having a reference wavelength is irradiated, a corresponding response signal is obtained, and the reference wavelength is a wavelength at which the analyte has low absorption.

[0096] In a further embodiment, the control system is configured to perform a material status analysis procedure, in which the current status of the material is determined. One or more response signals are established when a substance is irradiated with excitation radiation at a wavelength different from the characteristic wavelength of the analyte described above. With respect to excitation radiation having the same analyte characteristic wavelength as used in the analyte measurement step, but with respect to the intensity modulation frequency of the excitation radiation which is at least partially different from that of the analyte measurement step, one or more response signals established, and One or more measurements related to the material status, performed using additional sensor equipment. The analysis is based on one or more of the following.

[0097] Furthermore, the control system, based on the results of the above material status analysis procedure, - Selection of the characteristic wavelength of the analyte used in or relied upon during the above analyte measurement procedure, - The absolute time or relative time ratio of the use of the characteristic wavelength of the analyte in the above analyte measurement procedure, or the relative weight given to the wavelength in the analysis, - Selection of analyte characteristic wavelengths to be used simultaneously during the above analyte measurement procedure, and - Selection of one or more principal frequencies of the modulation of the excitation radiation intensity to be used during the analyte measurement procedure described above, It is configured to determine at least one of the following.

[0098] In a preferred embodiment of the apparatus, the control system is configured to control the apparatus for performing the method according to any one of the embodiments described above.

[0099] A control system can be embodied in hardware, software, or both. In particular, a control system may include one or more computers, processors, microcontrollers, FPGAs, ASICs, and corresponding computer programs that, when run on the corresponding hardware, provide the control functions described herein. In particular, a control system may be a distributed system, for example, comprising several control units that communicate data with one another, some of which may be provided in the device housing and others located remotely from the housing, however the control system may be formed by a single control unit.

[0100] In a preferred embodiment of the apparatus, the substance is human tissue, particularly human skin, and the analyte is glucose present in the interstitial fluid of the substance.

[0101] In a preferred embodiment of the apparatus, the control system is configured to perform the substance status analysis procedure alternately with the analyte measurement procedure, or less than 5 minutes, preferably less than 3 minutes, and most preferably less than 1 minute, before the start of the analyte measurement procedure.

[0102] In a preferred embodiment of the apparatus, the substance status includes the presence and / or concentration of a perturbative component in the substance that differs from the one or more analytes but exhibits significant absorption of excitation radiation at at least one of the analyte characteristic wavelengths, and if the substance status analysis procedure indicates a sufficiently high concentration of the perturbative component, the control system is configured to avoid or suppress the use of at least one of the analyte characteristic wavelengths in which the perturbative component exhibits significant absorption.

[0103] In a preferred embodiment of the apparatus, the at least one principal frequency of the modulation of the excitation radiation intensity to be used during the analyte measurement procedure includes a first principal modulation frequency and a second principal modulation frequency, wherein the first principal modulation frequency is low enough that the response signal reflects at least partially the absorption of excitation radiation in the interstitial fluid, and the second principal modulation frequency is higher than the first principal modulation frequency.

[0104] In a preferred embodiment, the substance status includes skin water content, and the apparatus preferably further comprises a dedicated keratinometer for measuring skin water content. In a related embodiment, if a higher water content is determined in the substance analysis procedure, the control system is configured to preferentially use shorter wavelengths from a predetermined set of analyte characteristic wavelengths in the analyte measurement procedure.

[0105] In a preferred embodiment of the apparatus, the control system is configured to match at least one of the one or more principal frequencies of the excitation radiation intensity modulation used during the analyte measurement procedure to the water content determined in the material analysis procedure, and to select a higher principal frequency of modulation for higher water content, assuming all other properties of the material status are the same.

[0106] In a preferred embodiment of the apparatus, the substance status includes the thickness of the stratum corneum above the interstitial fluid. In a related embodiment, the control system is configured to evaluate the thickness of the stratum corneum directly or indirectly based on a response signal established with respect to the same wavelength of excitation radiation, but with respect to different intensity modulation frequencies of the excitation radiation, the wavelength being selected to match the absorption bands of components present in the stratum corneum and interstitial fluid at different concentrations, respectively.

[0107] In a preferred embodiment, the control system is configured to match at least one of the one or more principal frequencies of the excitation radiation intensity modulation used during the analyte measurement procedure to the thickness of the stratum corneum above the interstitial fluid determined in the material analysis procedure, and to select a lower principal frequency of modulation for higher stratum corneum thicknesses, assuming all other properties of the material status are the same.

[0108] Preferably, the apparatus includes a dedicated pH measuring device, and the substance status includes the pH value of the skin. In a preferred embodiment, if the pH value determined in the substance analysis procedure is found to be lower, the control system is configured not to use the analyte characteristic wavelength that overlaps with the absorption band of lactate as preferentially as when the pH is found to be higher, assuming all other properties of the substance status are the same.

[0109] In a preferred embodiment of the apparatus, the skin is the skin of a human subject's fingertip, and the apparatus further comprises a dedicated fingerprint sensor configured to estimate the average height of the skin ridges of the fingertip. Here, the control system is preferably configured to fit the output of the excitation radiation used in the analyte measurement procedure as a function of the average height of the skin ridges, and to increase the output of the excitation radiation used in the analyte measurement procedure with respect to higher average skin ridges, assuming all other properties of the material status are the same.

[0110] In a preferred embodiment, the device may further include a temperature sensor for measuring skin temperature.

[0111] In a preferred embodiment of the apparatus, the control system is configured to control the apparatus to provide time modulation of the intensity of the excitation radiation such that the intensity envelope is asymmetric, and the proportion of time during which the envelope is 50% or more of the average intensity is less than 50% of the total time, preferably less than 46%, and most preferably less than 43%. However, the proportion of time during which the envelope is less than 50% should not be chosen to be too low, preferably at least 20%, and more preferably at least 30%.

[0112] In a preferred embodiment of the apparatus, the control system is configured to control the apparatus to provide time modulation of the intensity of the excitation radiation such that the intensity envelope follows a periodically repeating pattern, the pattern comprising a high-intensity time portion including more than 80% of the intensity-time integral of the pattern and a low-intensity time portion including less than 20% of the intensity-time integral, and the ratio of the durations of the high-intensity time portion to the low-intensity time portion being less than 0.9, preferably less than 0.8, and most preferably less than 0.7. However, in a preferred embodiment, this ratio should be at least 0.4, preferably at least 0.5.

[0113] In a preferred embodiment of the apparatus, the control system is configured to control the apparatus to provide time modulation of the intensity of the excitation radiation such that the intensity envelope is substantially harmonically such that, in the Fourier decomposition of the intensity of the excitation radiation, at least 95% of the total intensity associated with the dominant frequency and the first to ninth harmonics is associated with the dominant frequency, and at least 97%, preferably at least 98%, is associated with the dominant frequency and the first harmonic.

[0114] In a preferred embodiment of the apparatus, the detection device comprises a light source for generating a detection light beam that travels through at least a portion of the object being measured or components contained in the object being measured. The physical response of the object being measured to a heat or pressure wave received from the material when the excitation radiation is absorbed is a local change in the refractive index of the object being measured or components, and the detection device is configured to detect either a change in the optical path of the detection beam or a change in the phase of the detection beam by the change in the refractive index or phase of the optical path of the detection beam.

[0115] In related embodiments, the measuring body is transparent to the detection light beam, and is directed such that the detection light beam is fully or partially reflected by the surface of the measuring body that is in thermal or pressure-transmitting contact with the material, and the detection device comprises a photodetector, particularly a position-sensing photodetector, capable of detecting the degree of deflection of the detection light beam due to the local change in refractive index.

[0116] In an alternative embodiment of the apparatus, the detection device includes an interferometer device that enables the evaluation of the phase change of the detection beam and the generation of a response signal indicating the phase change.

[0117] In a preferred embodiment of the apparatus, the measuring body or a component of the measuring body has electrical properties that change in response to a local change in temperature or a change in pressure associated therewith, and the detection device comprises electrodes for capturing an electrical signal representing the electrical properties.

[0118] In a preferred embodiment of the apparatus, the excitation radiation source comprises an array of lasers, each having a dedicated wavelength, particularly a quantum cascade laser.

[0119] In a preferred embodiment of the apparatus, the excitation radiation source comprises at least one tunable laser, in particular at least one tunable quantum cascade laser.

[0120] In a preferred embodiment of the apparatus, some or all of the excitation wavelengths are in the range of 5 μm to 13 μm, preferably 8 μm to 11 μm. In an alternative embodiment, some or all of the excitation wavelengths are in the range of 3 μm to 5 μm.

[0121] In a preferred embodiment, the method includes, in addition to or instead of, the above-described substance status analysis procedure, a step of receiving user-related input, enabling optimization of either or both the analyte measurement procedure and the analysis performed in the analysis step.

[0122] Similarly, in addition to being further configured to perform the substance status analysis procedure described above, or alternatively, the device is equipped with an input interface for receiving user-related inputs, and is configured to use these inputs to optimize either or both of the analyte measurement procedure and the analysis performed in the analysis step.

[0123] In some embodiments, the above step of receiving user-related input is provided in addition to the above material status analysis procedure, based on both the results of the above material status analysis procedure and the above user-related input. - Selection of the characteristic wavelength of the analyte used in or relied upon during the above analyte measurement procedure, - The absolute time or relative time ratio of the use of the characteristic wavelength of the analyte in the above analyte measurement procedure, or the relative weight given to the wavelength in the analysis, - Selection of analyte characteristic wavelengths to be used simultaneously during the above analyte measurement procedure, and - Selection of one or more principal frequencies of the modulation of the excitation radiation intensity to be used during the analyte measurement procedure described above, At least one of them is determined.

[0124] User input can, for example, specify certain characteristics or conditions of the person undergoing glucose measurement, as described above.

[0125] For example, a person's characteristics are, - The person's skin color (for example, whether the user's skin is light or dark), - Information about a person's weight, such as body mass index, - Whether or not the person has a chronic disease, and if so, what kind of disease, especially whether or not the person has diabetes. - The person's age, - That person's occupation, - Hobbies including typical sports and exercise, - Is that person typically hypertensive or hypotensive? That's fine.

[0126] All of these characteristics can influence the optimal method by which the analyte measurement procedure is performed, and / or the optimal method by which the analysis is performed.

[0127] In addition to or instead of features, user-related inputs may also include information related to the user's state. An example related to a person's state is: - Whether that person is sweating right now, - Whether that person has a cold and / or a fever, - Whether that person is feeling cold, - Whether that person has recently drunk water or other beverages. - Whether that person is currently on a diet, - Whether that person is feeling stressed or pressed for time, It is possible.

[0128] One difference between user-related "features" and "states" is that states can change more frequently, and therefore input of user-related states may be requested more frequently, for example, every time a measurement is taken, or at least once for every measurement taken within the same time span, for example, on the same day. In contrast, features only need to be entered less frequently.

[0129] In a preferred embodiment, a protocol for performing an analyte measurement procedure may be generated or selected from several predetermined protocols based on user-related characteristics or states received by the input.

[0130] The various protocols selected or generated based on the user's characteristics / state are: - Selection of analyte characteristic wavelengths used during analyte measurement procedures or relied upon during analysis. - The absolute time or relative time ratio of the use of the characteristic wavelength of the analyte in the above analyte measurement procedure, or the relative weight given to the wavelength in the analysis, - The selection of analyte characteristic wavelengths to be used simultaneously during such analyte measurement procedures, and - Selection of one or more principal frequencies of the modulation of the excitation radiation intensity to be used during the analyte measurement procedure described above, There may be differences with respect to one or more of these.

[0131] In some embodiments, there are several predetermined protocols for performing the analyte measurement procedure, which may have been previously determined empirically to work particularly well with respect to a given characteristic and / or state. These predetermined protocols may be used instead of the substance status analysis procedure described above. In other embodiments, these protocols may be used as a starting point and then refined based on the results of the substance status analysis procedure described above.

[0132] As an addition or alternative, user-related features and / or states received by the input may be used to adapt the analysis performed in the analysis step, as described above. For example, the analysis may include one or more algorithms that convert the aforementioned response signals into estimates of glucose concentration. The inventors have found that the accuracy of such algorithms can be improved if they are specifically adapted to or take into account the aforementioned features and / or states.

[0133] Therefore, in a preferred embodiment, the analysis step is performed using one or more algorithms, the one or more algorithms being selected or adapted according to the user-related features and / or states.

[0134] For example, the analysis step may include various machine learning-based algorithms for selection, each of which is trained on data associated with a specific selection of some or all of the aforementioned features or states. Then, based on the input of user-related features / states, the appropriate one of these algorithms may be selected for use in the analysis step, and thus capable of making particularly accurate estimations based on the recorded response signals with respect to these types of features and states. In this specification, the "appropriate" (or most appropriate) of these algorithms may be the algorithm whose training data is close to (or closest to) user-related features and / or states.

[0135] In other embodiments, the algorithm used in the analysis may include one or more tunable parameters, and the method includes the step of adjusting the one or more tunable parameters based on the aforementioned features and / or states.

[0136] With respect to the apparatus, the aforementioned control system of the apparatus may be configured to perform each of the methods summarized above, relying on the input of user-related characteristics and / or states.

[0137] In particular, the control system may be configured to perform the analysis step and may be further configured to adapt this analysis step based on user-related characteristics and / or states.

[0138] Preferably, the control system includes a memory for storing various machine learning-based algorithms for selection, each of which is trained on data associated with a specific selection of some or all of the aforementioned features or states. The control system may then be further configured to select an appropriate one of these algorithms for use in the analysis step based on user-related feature / state inputs.

[0139] As an addition or alternative, the control system comprises a memory for storing one or more algorithms for use in analysis, the one or more algorithms comprising one or more tunable parameters, and the control system is further configured to adjust the one or more tunable parameters based on the aforementioned features and / or states.

[0140] In a preferred embodiment, user-related input is received by user input. The device may include a user interface for inputting such information relating to the user's characteristics or state.

[0141] In a preferred embodiment, the user interface is provided by a touch display device associated with the device.

[0142] In each of the embodiments described above, a camera may be provided to record an image of the material (particularly the skin) in the area where the excitation radiation is to be irradiated onto the material (particularly the skin). In a preferred embodiment, the camera is an infrared camera for recording infrared images. These images may be used for several purposes. For example, the camera images may be used to determine whether the device is properly positioned relative to the material, particularly the skin.

[0143] In a preferred embodiment, the method includes the step of identifying in an image the location on which the excitation radiation beam is irradiated onto the material. For example, in a specific reference to skin analysis, the method may include the step of determining, for a given position of the device relative to the skin, whether the excitation radiation is irradiated onto the skin at an appropriate location. An appropriate location is, for example, a location where the skin is relatively smooth. Further criteria for an "appropriate location" are the absence of wrinkles, hair, scars, or moles.

[0144] This is particularly important in preferred embodiments of methods in which locations other than the fingertips, especially the skin on the underside of the wrist, are used for measurement. Based on the known relative position of the camera to the excitation light source, or at least to the optical path of the excitation light beam generated by the excitation light source, the location where the excitation radiation enters the skin can be determined with high accuracy in the image. When the fingertips are used for measurement, suitable locations for the excitation radiation to be emitted into the skin are the skin ridges, where optical coupling is found better than in the grooves between two adjacent skin ridges.

[0145] With respect to the current position of the device relative to the skin, the determination of whether excitation radiation is emitted to the skin at the appropriate position may be made using a corresponding algorithm for analyzing the relevant portion of the image with respect to one or more of the above criteria. If the position is determined to be inappropriate (with respect to one or more predetermined criteria), the user may be prompted via the output interface to reposition the device relative to the skin. This may be repeated until the appropriate position is established. In a preferred embodiment, the output interface may be a display, in particular a touch display. As an addition or alternative, the output interface may include an acoustic output device.

[0146] In a preferred embodiment, the method additionally or alternatively includes a step of using camera images of the substance (particularly the skin) to monitor whether the apparatus (particularly the object being measured) is moving relative to the substance (particularly the skin) during the analyte measurement procedure. The absence of such movement is referred to herein as “positional stability”. Positional stability may be evaluated, for example, by comparing a series of recorded images of the substance (skin), where any displacement between consecutive images indicates relative motion of the object being measured relative to the substance (skin), and the absence of such displacement indicates positional stability.

[0147] In a preferred embodiment, information regarding the appropriate position and / or positional stability or relative motion of the excitation radiation may be used, and / or combined with, the “quality assessment” described above. Note that the quality assessment described above was based on the response signal rather than the camera image. However, this quality assessment may further include information regarding the appropriateness and / or positional stability of the excitation radiation.

[0148] In particular, based on detected positional stability, the measurement time allocated to one or more analyte characteristic wavelengths during the current analyte measurement procedure may be adjusted, or the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis may be adjusted. For example, if it is determined that a change in position has occurred during the measurement of a given analyte characteristic wavelength, the measurement time allocated to this wavelength may be increased to compensate for the loss of reliable measurement data during relative motion. Alternatively, the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis may be decreased to take into account the expected inaccuracy of the corresponding measurement. Additionally or alternatively, based on monitored positional stability, the measurement may be terminated and restarted. For example, if a change in position occurs immediately after the start of a measurement when not much useful measurement data has been accumulated, it may be prudent to discard the entire measurement and start anew. A similar situation may occur if it is determined that the relative motion of the device with respect to the substance (skin) results in a situation where the position of the excitation radiation is no longer appropriate. In this case, the method may include a step of terminating the measurement and prompting the user to reposition the device and start anew.

[0149] In a preferred embodiment, the user is notified when the measurement is completed due to relative movement between the object being measured and the skin, thereby increasing user awareness and ensuring positional stability in subsequent attempts of the analyte measurement procedure. In a preferred embodiment, this information is transmitted by an acoustic signal, which attracts the user's immediate attention more effectively than output by display alone.

[0150] In a preferred embodiment, the control system is configured to perform some or all of the described embodiments, relating to a method for identifying a suitable position for irradiation with excitation radiation and a method for monitoring the movement of the device relative to a substance (skin). In particular, the control system is configured - Controlling the camera to record an image of the material (especially the skin) within the area where the excitation radiation should irradiate the material (especially the skin), - Identifying the location where the excitation radiation beam irradiates the material within the image. - In particular, using algorithms stored in memory associated with the control system, it is determined whether excitation radiation is irradiated onto the skin at an appropriate location, based on criteria such as the absence of wrinkles, hair, scars, and moles, with respect to a given position of the device on the skin. - In particular, if the control system determines, via a display such as a touch display and / or an acoustic output device, that the position is not appropriate (with respect to one or more predetermined criteria), the user will be prompted via the output interface to reposition the device against the skin. -During the analyte measurement procedure, in particular, - Comparing continuously recorded images of a substance (skin) This allows monitoring whether the device (and especially the object being measured) has been moved relative to the substance (skin). - Based on the detected positional stability, adjust the measurement time allocated to one or more analyte characteristic wavelengths during the current analyte measurement procedure, or the relative weight associated with the corresponding analyte wavelength-specific measurement in the analysis, and / or terminate the measurement and control and restart the measurement based on the monitored positional stability. - Notify the user when the measurement is completed due to relative movement between the object being measured and the skin. It may be configured for one or more of the following purposes.

[0151] In a preferred embodiment, the measuring object is transparent to the imaging wavelength of the camera, and the camera is positioned to record an image through the measuring object.

[0152] Camera images may be used to identify skin patterns not only such as fingerprints, but also on flat skin areas such as the underside of the wrist. These images may be stored and used to ensure that the same location is used for previously selected user measurements, thereby allowing for comparison of measurement results.

[0153] A further aspect of the present invention is a method for analyzing a substance comprising at least one analyte, This includes the analyte measurement procedure, and in the analyte measurement procedure, - The substance is in thermal or pressure-transfer contact with the object to be measured, and the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation in the substance to be transferred to the object to be measured. -The excitation radiation is irradiated onto the material so as to be absorbed by the material, the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths that are irradiated simultaneously and / or sequentially. - The physical response of the object to the heat or pressure wave received from the substance when the excitation radiation is absorbed is detected using a detection device, the detection device generates a response signal based on the detected physical response, and the response signal indicates the degree of absorption of the excitation radiation. The method further includes an analysis step, the analysis of which is performed at least in part on the response signal, During the analyte measurement procedure described above, a series of analyte wavelength-specific measurements are performed while maintaining the thermal or pressure transfer contact between the substance and the object being measured. In each analyte wavelength-specific measurement, excitation radiation having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. Before or during the above analyte measurement procedure, one or more images of the substance within the area to be irradiated with excitation radiation are recorded, and the method - A step of determining, based on one or more of the above images, whether the excitation radiation is irradiated onto the substance at a position suitable for performing the analyte measurement procedure, with respect to a given position of the object to be measured relative to the substance, - A step of using camera images of the substance to monitor whether the object being measured is being moved relative to the substance during the analyte measurement procedure, Methods that include one or both of the above.

[0154] In a preferred embodiment of the above method, the substance is human tissue, particularly human skin, and the analyte is glucose present in the interstitial fluid of the substance.

[0155] In a preferred embodiment of this method, the skin is formed by the skin on the underside of the person's wrist. In a preferred embodiment, the preferred location is a location where the skin is smooth, wrinkle-free or nearly wrinkle-free, hair-free or nearly hair-free, scar-free, or mole-free.

[0156] In a preferred embodiment of this method, the skin is formed by the skin of the fingertip, and the appropriate location is the location of the skin ridge.

[0157] In a preferred embodiment of this method, if the position is determined to be inappropriate (for example, with respect to one or more predetermined criteria), the user is prompted via an output interface to reposition the object to be measured against the skin. Here, the output interface may be a display, particularly a touch display. Additionally or alternatively, the output interface may include an acoustic output device.

[0158] In a preferred embodiment of this method, the above step of using camera images of a substance, particularly skin, to monitor whether the object being measured is moving relative to the substance (skin) during the analyte measurement procedure includes comparing sequentially recorded images of the substance (skin). Here, the displacement between sequential images indicates relative motion of the object being measured relative to the substance (skin), and the absence of such displacement indicates positional stability.

[0159] In a preferred embodiment of this method, based on the detected positional stability, the measurement time allocated to one or more analyte characteristic wavelengths during the current analyte measurement procedure is adjusted, or the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis are adjusted. Additionally or alternatively, based on the monitored positional stability, measurements may be terminated and restarted.

[0160] In a preferred embodiment of this method, the user is notified when the measurement is completed due to relative movement between the object being measured and the skin, thereby increasing user awareness and ensuring positional stability in subsequent attempts of the analyte measurement procedure. In a preferred embodiment, this information is transmitted by an acoustic signal, which attracts the user's immediate attention more effectively than output by display alone.

[0161] Furthermore, a further aspect of the present invention is an apparatus for analyzing a substance comprising at least one analyte, - A measuring body having a contact surface suitable for thermal or pressure-transfer contact with the above-mentioned substance, wherein the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation in the substance to be transferred to the measuring body, - An excitation radiation source configured to irradiate a substance with excitation radiation so as to be absorbed by the substance, - A detection device for detecting the physical response of a measuring object or components contained in the measuring object to the heat or pressure wave received from the above-mentioned substance when the above-mentioned excitation radiation is absorbed, and for generating a response signal based on the detected physical response, wherein the response signal indicates the degree of absorption of the excitation radiation, -Camera and, - Control system and, Equipped with, The above control system, -The excitation radiation source (26) is configured to control the excitation radiation source (26) so as to irradiate the material (12) with excitation radiation so as to be absorbed by the material (12), wherein the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths that are irradiated simultaneously and sequentially or both. The above control system further, -The detection device is configured to detect the above physical response and to generate a response signal indicating the degree of absorption of the above excitation radiation (18), The control system described above is configured to control the apparatus so that a series of analyte wavelength-specific measurements are performed during the analyte measurement procedure (78) while maintaining the thermal or pressure transfer contact between the substance (12) and the object to be measured (16), wherein in each analyte wavelength-specific measurement, excitation radiation (18) having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. The control system described above is further configured to control the camera before or during the analyte measurement procedure to record one or more images of the substance in the area where the excitation radiation is to be irradiated onto the substance. - A step of determining, based on one or more of the above images, whether the excitation radiation is irradiated onto the substance at a position suitable for performing the analyte measurement procedure, with respect to a given position of the object to be measured relative to the substance, - A step of using camera images of the substance to monitor whether the object being measured is being moved relative to the substance during the analyte measurement procedure, The present invention relates to an apparatus further configured to perform one or both of the following.

[0162] In preferred embodiments, the control system of the apparatus according to the further embodiments described above is configured to perform some or all of the embodiments described, relating to a method for identifying a suitable position for irradiation with excitation radiation and a method for monitoring the movement of the apparatus relative to a substance (skin). In particular, the control system is configured - Controlling the camera to record an image of the material (especially the skin) within the area where the excitation radiation should irradiate the material (especially the skin), - Identifying the location where the excitation radiation beam irradiates the material within the image. - In particular, using algorithms stored in memory associated with the control system, it is determined whether excitation radiation is irradiated onto the skin at an appropriate location, based on criteria such as the absence of wrinkles, hair, scars, and moles, with respect to a given position of the device on the skin. - In particular, if the control system determines, via a display such as a touch display and / or an acoustic output device, that the position is not appropriate (with respect to one or more predetermined criteria), the user will be prompted via the output interface to reposition the device against the skin. -During the analyte measurement procedure, in particular, - Comparing continuously recorded images of a substance (skin) This allows monitoring whether the device (and especially the object being measured) has been moved relative to the substance (skin). - Based on detected positional stability, adjust the measurement time allocated to one or more analyte characteristic wavelengths during the current analyte measurement procedure, or the relative weight associated with the corresponding analyte wavelength-specific measurement in the analysis, and / or terminate the measurement based on monitored positional stability, control and restart the measurement, and / or notify the user if the measurement is terminated due to relative movement between the object being measured and the skin. It may be configured for one or more of the following purposes. [Brief explanation of the drawing]

[0163] [Figure 1] This is a schematic diagram of the measurement principle underlying one embodiment of the present invention. [Figure 2] This figure shows the absorption spectrum of glucose in water after subtracting the water background. [Figure 3] This is a schematic cross-sectional view of an apparatus suitable for carrying out an embodiment of the present invention that relies on a response signal based on the deflection of a detected light beam. [Figure 4] This figure shows the results of Clark error grid analysis obtained using the type of apparatus shown in Figure 3. [Figure 5] This is a schematic diagram of an apparatus suitable for carrying out embodiments of the present invention that rely on response signals based on the piezoelectric response to thermal or pressure waves received by a substance being analyzed. [Figure 6]This is a schematic diagram of an apparatus suitable for carrying out an embodiment of the present invention that relies on a response signal based on the phase change of a detection light beam detected by interferometry. [Figure 7] This flowchart illustrates a method according to one embodiment of the present invention, including an analyte measurement procedure, a material status analysis procedure, and a reference measurement. [Figure 8] This is a flowchart showing the detailed steps associated with the material status analysis procedure in Figure 7. [Figure 9] This is a flowchart showing the detailed steps associated with the analyte measurement procedure in Figure 7. [Figure 10] This is a flowchart showing the detailed steps associated with the reference measurement in Figure 7. [Figure 11] This is a schematic diagram of the absorption spectra of the analyte and low concentrations of interfering components, as well as the corresponding selected excitation emission wavelengths. [Figure 12] Figure 11 shows a schematic diagram of the absorption spectra of the analyte and the interfering component, but with high concentrations of interfering components, as well as the corresponding selected excitation emission wavelengths. [Figure 13] This figure shows the exponential decay of the intensity of excitation radiation with respect to penetration depth due to water absorption at two different wavelengths. [Figure 14] These are schematic diagrams of the absorption spectra of the analyte and perturbation components, as well as the synthesized absorption spectrum. [Figure 15] This is a schematic diagram of the excitation radiation modulation function formed by a square wave with equal on-intervals and off-intervals. [Figure 16] This is a schematic diagram of another excitation emission modulation function formed by a square wave with an on-interval shorter than the off-interval. [Figure 17] This is a schematic diagram of yet another excitation emission modulation function in which the envelope approximates a sine function. [Figure 18] This is a schematic diagram of a wearable device. [Figure 19] This is a schematic cross-sectional view of a device attached to the underside of a person's wrist. [Figure 20] This is an image of skin taken using the device shown in Figure 19. [Modes for carrying out the invention]

[0164] It should be understood that the above general description and the following description are for illustrative and illustrative purposes only and do not limit the methods and devices described herein. In this application, the use of singular nouns may include plural nouns unless otherwise specified. The use of “or” means “and / or” where appropriate or unless otherwise specified. Those skilled in the art will understand that the following description is illustrative and not intended to limit in any way. Other embodiments will be readily conceivable to those skilled in the art who benefit from this disclosure. The following references to various implementations of the exemplary embodiments shown in the accompanying drawings are described in detail. The same reference numerals are used throughout the drawings and the following description whenever possible to refer to the same or similar elements.

[0165] Figure 1 is a schematic diagram of the measurement principle underlying the analyte measurement procedure summarized above and described in more detail below. While the method and apparatus of the present invention are suitable for analyzing a variety of substances containing at least one analyte, the following description focuses on a specific embodiment in which the substance is a patient's skin and the analyte is glucose in the interstitial fluid of the skin. It should be understood that all details and descriptions given below by the specific reference to glucose measurement are also applicable to other substances and analytes, even if not explicitly mentioned below, where appropriate.

[0166] In the example shown in Figure 1, the user's fingertip 12 is in thermal contact with the contact surface 14 of the measuring body 16. In alternative embodiments not shown, the fingertip may be acoustically coupled to the measuring body via an acoustic cell, which may contain a hollow space filled with liquid or gas that allows for the transfer of a pressure wave to the measuring body. The excitation beam 18 is irradiated onto the measuring body 16 through air or a waveguide (not shown), and then irradiated onto the skin of the fingertip 12 through the measuring body 16. To determine the concentration of glucose in the skin, particularly in the interstitial fluid of the skin, various wavelengths of the excitation radiation 18 are selected sequentially or at least partially simultaneously for absorption measurements, and the glucose concentration can be determined from the measured absorption values. Figure 2 shows absorption spectra for various concentrations of glucose in water, where the contribution of absorption by water has been subtracted. As can be seen in this figure, glucose molecules are 993 cm⁻¹, corresponding to wavelengths in the range of 10.07 μm to 8.32 μm, respectively. -1 ~1202cm -1 Within the wavenumber range of 1140 cm², there are several characteristic absorption peaks in the mid-infrared region. Absorption minimums are observed between adjacent absorption peaks, which are indicated in Figure 2 by vertical arrows without wavenumber notations. As is evident from Figure 2, the difference in absorption, particularly between the absorption peaks and absorption minimums, is characteristic of the glucose concentration. Therefore, to determine the glucose concentration, it is preferable to measure absorption at some or all of the absorption peaks and some or all of the absorption minimums, as well as possibly at some point between the maximum and minimum values. These wavelengths are referred to herein as “analyte (glucose) characteristic wavelengths.” However, 1140 cm² -1 The absorption rate at the minimum local value is still 1035 cm⁻¹ in the important part of the spectrum. -1 Note that the maximum peak absorption rate at this wavelength is 18%. Therefore, absorption at any of these wavelengths is significantly dependent on glucose concentration, and thus these wavelengths are characteristic of glucose, i.e., "glucose characteristic wavelengths." In contrast, at approximately 1180 cm⁻¹ -1Therefore, the absorptivity is substantially zero, and thus the overall minimum rather than the minimum, and this wavelength is clearly not characteristic of glucose. While the wavelength that is just at the absorption peak or absorption minimum is a preferred choice for the glucose characteristic wavelength, wavelengths that are close to the peak / minimum but at individually defined distances from them may also be used. Thus, as understood herein, the “analyte characteristic wavelength” is also the wavelength at which the difference in absorption with respect to the wavelength at the nearest absorption peak or nearest absorption minimum is less than 30%, preferably less than 20%, of the difference in absorption between the nearest absorption peak and the nearest absorption minimum.

[0167] The intensity of the excitation beam 18 is time-modulated at a specific frequency f such that the excitation radiation, in this case the excitation light, has alternating intervals of high intensity, low intensity, or even vanishing intensity. While we do not wish to limit the modulation to any particular waveform, below, the high-intensity interval will be referred to as the "excitation light pulse." During the excitation light pulse, excitation light having a glucose characteristic wavelength is absorbed, and the radiated energy is converted into heat. A glucose molecule is approximately 10 -12 Since it relaxes from the excited state within seconds, the generation of the corresponding thermal pulse and / or pressure wave can be considered instantaneous for all practical purposes.

[0168] Therefore, along with the excitation light pulse, a localized thermal pulse is generated at the absorption site, resulting in a temperature field that changes as a function of space and time, sometimes referred to as a thermal wave. As explained above, the term thermal “wave” can be somewhat misleading, as the propagation of heat through a substance is governed by the diffusion equation rather than the wave equation. However, the concept of a “thermal wave” is appropriate, at least insofar as the thermal pulse propagates from within the skin to the surface 14 of the object 16 and into the object 16, similar to how we are accustomed to wave propagation. The thermal gradient 20 caused by such a thermal pulse is schematically shown in Figure 1.

[0169] The heat received by the measuring body 16 from the skin in Figure 12 elicits a physical response, which can be detected using one of various possible detection devices designed to generate a response signal based on that physical response, indicating the degree of absorption of excitation light. Various methods for detecting the physical response and generating an appropriate response signal are described below.

[0170] However, regardless of the exact method used to detect the physical response, the maximum depth below the skin surface where absorption can be detected by the thermal pulses traveling to the measurement body 16 is the thermal diffusion length of the skin μ t It is noteworthy that this has been found to be a good approximation by the thermal diffusion length μ t teeth,

number

[0171] Referring again to Figure 1, in the illustrated embodiment, the physical response to the absorbed heat received from the skin is a change in refractive index in a region close to the surface 14 of the measuring body 16 where a thermal gradient 20 is temporarily generated. This local change in refractive index generates what can be considered a thermal lens that can be detected by the detection light beam 22. The detection beam 22 passes through the thermal lens or thermal gradient region and is then reflected at the interface between the measuring body 16 and the skin in Figure 12. Whenever a thermal pulse is received from the skin, a local change in refractive index occurs, which results in a deflection of the detection beam 22 due to interaction with the material of the measuring body in the region of the thermal lens. In Figure 1, reference numeral 22b corresponds to the undeflected detection beam 22, and reference numeral 22a corresponds to the detection beam when deflected by the thermal lens formed in the thermal gradient region 20. This deflection can be measured to generate an example of the response signal described above. The degree of deflection indicates the amount of heat received, and therefore the degree of absorption of the excitation light 18 at the skin of the finger 12.

[0172] Figure 3 shows a more detailed cross-sectional view of the apparatus 10, which relies on the measurement principle illustrated with reference to Figure 1. The apparatus 10 comprises a housing 24 containing a measuring body 16 having an upper surface (contact surface) 14 on which a finger 12 rests. An excitation light source 26 is provided within the housing 24, which generates an excitation light beam 18. In the illustrated embodiment, the excitation light source 26 comprises an array of quantum cascade lasers, each having a dedicated wavelength. For example, the array of quantum cascade lasers may include individual quantum cascade laser elements having wavelengths corresponding to the absorption peak and minimum shown in Figure 2 (i.e., glucose characteristic wavelengths), and other wavelengths that can be used for reference measurements or to detect other components that may interfere with glucose measurements, such as lactate or albumin.

[0173] The device 10 further comprises a light source 28, such as a laser, for emitting a detection beam 22, and a position-sensing detector 30 that enables detection of the deflection of the detection beam 22. In this case, the measuring body 16 is transparent to both the excitation light beam 18 and the detection light beam 22. Furthermore, a camera 32 or another imaging device is provided that enables capturing an image of the contact surface 14 of the optical medium 16, thereby recording the fingerprint of a finger 12 resting on the contact surface 14. This fingerprint may be processed by a control unit 34 to identify the user by their fingerprint. The control unit 34 also functions to control the light sources 26 and 28 for the excitation and detection light, respectively, as well as the sensor 30. The control unit 34 also wirelessly connects to an external data processing device 36 to exchange data. For example, user-specific calibration data may be retrieved by the control unit 34 for a user identified by their fingerprint via the wireless connection. The control unit 34 and the external data processing device 36 together form an example of the “control system” mentioned above. The control system may consist of one or more processors, microcontrollers, computers, ASICs, FPGAs, etc. The control system may be distributed among various components communicating with each other, as shown in Figure 3, or it may be formed by a single control unit, such as control unit 34, designed for all the control functions described herein. The control system can generally be embodied in hardware, software, or a combination of both.

[0174] As can be seen further in Figure 3, the excitation and detection light sources 26 and 28, as well as the position sensing detector 30, are all mounted on a common carrier structure 38. This means that these components can be strictly pre-assembled on this structure 38, and therefore, there is no need to individually adjust or calibrate these components when assembling the device 10.

[0175] Furthermore, the apparatus 10 includes a keratinometer 40 that enables the measurement of skin water content. Keratinometers for measuring water content in the upper layers of skin are known in the art and do not need to be described in detail here. For example, known keratinometers use two comb-shaped electrodes to which an AC voltage is applied to measure the impedance of the skin, particularly capacitive impedance. The keratinometer 40 in Figure 3 makes contact with the fingertip 12 when the fingertip 12 rests on the contact surface 14 of the measuring body 16. The keratinometer 40 is an example of a sensor that is essentially unrelated to the aforementioned “additional sensor equipment,” i.e., measuring devices for measuring analyte absorption.

[0176] This device also includes a pH sensor 42 for measuring the pH value of the skin. pH sensors for measuring the pH value of surfaces, including the surface of the skin, are known from the prior art and do not need to be described in detail here. pH sensors for measuring the pH value of the skin are commercially available not only for medical use but also for cosmetic purposes.

[0177] Figure 4 shows the results of Clark error grid analysis obtained with the type of apparatus shown in Figure 3, demonstrating that highly reliable blood glucose concentrations can indeed be measured purely non-invasively using the measurement procedure described with reference to Figures 1-3. The data shown in Figure 4 are taken from International Publication No. 2017 / 09782 and do not yet reflect improvements to the present invention. The present invention makes it possible to further improve the reliability of the method and reduce the measurement time required for the method.

[0178] Figure 5 schematically shows an apparatus 10 that relies on a general principle similar to that of Figures 1 and 3, including an absorbed thermal pulse received by the measuring body 16 from a substance 12, but differs in the physical response utilized and the manner in which the corresponding response signal is generated. Such apparatus 10 and numerous variations thereof are described in detail in International Publication No. 2019 / 11059782, which is incorporated herein by reference, and therefore a detailed description may be omitted herein. As before, the apparatus comprises a measuring body 16 having a surface 14 that contacts or binds to the skin of a finger 12. A light source 26 is also provided for an excitation light beam 18 having a modulated intensity, which is irradiated onto a region 44 beneath the surface of the skin 12 and absorbed therein. In this embodiment, the excitation light beam 18 passes through a hole 46 indicated by a dashed line through the measuring body 16, and therefore the measuring body 16 itself does not need to be transparent to the excitation light beam 18.

[0179] A control unit 48 is provided for modulating the intensity of the excitation light beam 18. This can generally be done in various forms, including a mechanical chopper or an element having electronically controllable transmittance or reflectance. However, in a preferred embodiment, the intensity is modulated by modulating the on / off time of the excitation light source 26 and the operating current during the on time of the excitation light source 26.

[0180] A thermal wave caused by the time-varying absorption of an intensity-modulated excitation beam 18 in a region 44 of the skin 12, symbolized by an arrow 50, enters the measuring body 16 and can be detected in a detection region 52 having piezoelectric properties. The pressure change associated with the received heat 50 or pressure wave yields an electrical signal that can be recorded by electrodes 6a-6d, which are connected via conductive leads 54 to an estimation device 56 for analyzing the material (skin of the finger 12), which may be a digital processing device, such as a microcontroller or processor or a computer. In this case, the pressure change is similar to the physical response of the measuring body 16 or other components contained in the measuring body 16 to the heat received from the material 12 when the excitation radiation is absorbed, and is detected using the piezoelectric properties of the measuring body 16 and electrodes 6a-6d, yielding an electrical signal that represents a response signal indicating the degree of absorption of the excitation radiation 18.

[0181] In alternative modifications proposed by the applicant, as disclosed, for example, in international application PCT / EP2019 / 064356, which is incorporated herein by reference, the detection device may include an interferometer device that enables evaluation of the phase change of the first portion of the detection beam relative to a second portion of the detection beam, where only one portion of the detection beam passing through the measuring arm is affected by a heat wave or pressure wave at the measuring body and generates a response signal indicating the phase change. In this case, the physical response of the measuring body 16 (or components included in the measuring body 16) to the heat received from the material 12 when the excitation radiation 18 is absorbed is again a local change in refractive index, and the response signal is, in this case, an interference signal that reflects the phase change of the detection beam due to the local change in refractive index. This is schematically shown in Figure 6, which shows the measuring body 16 in contact with a material (such as a finger, not shown in Figure 6). In this case, the measuring body 16 may be a silicon substrate provided with a light guide structure 58 forming an interference device 60. The interferometer device 60 forms a Mach-Zehnder interferometer having a measuring arm 60a and a reference arm 60b. Detect light 22 generated by the detection light source 28 is fed into a light guide structure 58 and split by a splitter 60c into a portion or part of the detection beam traveling along the measuring arm 60a and a portion or part traveling along the reference arm 60b, which are then combined by a coupler 60d. The measuring body 16 is used or positioned such that the reference arm 60a is exposed to heat received from the skin when the excitation light is absorbed, but the reference arm 60b is not exposed, or is exposed only slightly. The received heat changes the refractive index at the measuring arm 60a, and this change results in a phase shift of the detect light 22 traveling along the measuring arm 60a. Since the light traveling along the reference arm 60b is not affected by the received heat, there is a relative phase change between the two portions of light combined by the coupler 60d, and this change results in an interference pattern that can be detected using the detector 62.

[0182] Referring to Figure 7, a method for analyzing a substance comprising at least one analyte according to one embodiment of the present invention is described. In this embodiment, the analyte is glucose and the substance is human finger skin.

[0183] This method begins in step 70, in which the user places their finger 12 on the contact surface 14 of a measuring body 16 of the type shown in Figure 1, Figure 3, Figure 5, or Figure 6.

[0184] In step 72, the user is identified by their fingerprint. For this purpose, a camera or other imaging device, such as the one shown by reference numeral 32 in Figure 3, may be used. Once the user is identified, user-specific information is loaded into a control unit that will ultimately perform the analysis. This control unit may be formed, for example, by an internal control unit 34 shown in Figure 3, which is part of the portable device 10, or by an external data processing device shown by reference numeral 36 in Figure 3. The user-specific information may include specific data that enables high-precision glucose measurement, such as calibration parameters previously established for the user.

[0185] In addition to this user-specific information, a substance status analysis procedure is performed in the subsequent step 76. As described in the above summary of the invention, the substance status analysis procedure makes it possible to determine the current status of the "substance," namely the skin in this case.

[0186] The steps of the material status analysis procedure 76 are described in more detail with reference to Figure 8. As part of the material status analysis procedure, in step 90, the pH value of the skin is measured using a pH sensor 42, for example, as shown in Figure 3.

[0187] In the next step 92, the average height of the skin ridges of the user's finger 12 is determined using a dedicated sensor, also integrated with the device (not shown). The "average height of the skin ridges" corresponds to the current situation, i.e., the average height when the finger 12 is resting on the contact surface 14 of the measuring body 16. Therefore, this average height depends not only on the natural structure of the epidermis but also on the current contact pressure being applied. In particular, the region where the excitation light beam 18 enters the skin is a region where good optical coupling is required, so the average height of the skin ridges can be applied to this region.

[0188] In the next step 94, the water content of the skin is measured. Again, in the illustrated embodiment, this is done using a dedicated keratinometer sensor indicated by reference numeral 40 in Figure 3. The keratinometer sensor 40 is positioned in the apparatus 10 of Figure 3 so as to contact the finger 12 when the finger 12 is resting on the contact surface 14 of the measuring body 16. In this embodiment, the keratinometer sensor 40 measures the water content in the upper layers of the skin based on the AC impedance when an AC voltage is applied to the corresponding electrodes, particularly the comb-type electrodes.

[0189] In the subsequent step 96, “interfering components” in the skin are checked. As understood herein, “interfering components” are components that differ from one or more analytes, i.e., in this case glucose, but exhibit significant absorption of excitation radiation at at least one of a predetermined set of analyte characteristic wavelengths to be used to measure the analytes. An important example of such interfering components in glucose measurement is lactate, which can be found in the skin at various concentrations and has an absorption band that partially overlaps with the absorption band of the glucose molecule. In order to properly determine the glucose concentration, it is important to determine whether the current concentration of lactate in the skin affects the glucose measurement, and if so, to what extent.

[0190] It is emphasized that lactate concentration is a parameter that not only varies from person to person, but also changes from day to day, and even from time to time of day, within each individual. Therefore, lactate concentration cannot be described by any pre-stored user-specific information retrieved in step 74.

[0191] In the next step 98, the thickness of the stratum corneum is determined. The stratum corneum is the outermost layer of the skin and does not contain the interstitial fluid containing the glucose being measured. However, it is unavoidable that most of the excitation light is absorbed in the stratum corneum, and it is unavoidable that a considerable contribution of each response signal will reflect absorption within the stratum corneum. Instead, the response signal always takes into account the absorption of excitation light in the depth range from the surface of the skin to a depth defined by the thermal diffusion length as described above, and therefore generally including the stratum corneum. However, it is important to know the thickness of the stratum corneum, as it allows for the appropriate selection of both the maximum depth range for absorption measurements that extend well beyond the stratum corneum and an appropriate depth range for measuring absorption in the stratum corneum alone, and these depth ranges can then be used to generate a compensated signal that primarily reflects absorption in the interstitial fluid, as will be explained in more detail with reference to Figure 9.

[0192] The thickness of the stratum corneum can be estimated directly or indirectly based on the response signal established with respect to the same wavelength of excitation radiation, but with respect to different intensity modulation frequencies of the excitation radiation, where the excitation wavelength is chosen to match the absorption bands of components present in the stratum corneum and interstitial fluid at different concentrations. In fact, since glucose itself is found at higher concentrations in interstitial fluid and lower concentrations in the stratum corneum, the thickness of the stratum corneum can be assessed by performing a series of measurements at excitation wavelengths corresponding to the absorption peak of glucose, and at varying modulation frequencies, and therefore at varying depth ranges. In the depth range reaching the interstitial fluid, this becomes evident due to the increased absorption by glucose molecules present in the interstitial fluid.

[0193] Based on the information obtained in steps 90-100, in step 102, a set of glucose characteristic wavelengths to be used in the analyte measurement procedure may be selected as a subset of the complete set of all available glucose characteristic wavelengths. That is, the apparatus 10 according to the described embodiment basically provides a predefined set of glucose characteristic wavelengths that can be used, but in the actual analyte measurement procedure, only the most appropriate subset of these will be applied. For example, the excitation light source 26 shown in Figure 3 may be an array of quantum cascade lasers, each having its own dedicated excitation wavelength, and the predefined set of excitation light wavelengths corresponds to the set of wavelengths of the quantum cascade lasers in the array. In other embodiments, the excitation light source 26 may be a tunable quantum cascade laser capable of basically providing a continuum of wavelengths, but even in this case, there is typically a predefined set of predetermined analyte characteristic wavelengths to be used in the analyte measurement procedure, from which an appropriate subset is selected in step 102.

[0194] For example, depending on whether step 96 represents a high concentration of the interfering component, a selection may be made from predefined glucose characteristic wavelengths, as illustrated with reference to Figures 11 and 12. Figure 11 shows two schematic absorption spectra, namely the analyte absorption spectrum 140 and the interfering component absorption spectrum 142. Figure 12 shows the same spectrum, except that in this case the concentration of the interfering component is higher and therefore its absorption spectrum 142 is magnified. To estimate the concentration of the interfering component, in step 96 an absorption measurement is performed at the wavelength corresponding to the right-hand peak in the interfering component absorption spectrum 142, the wavelength position of which is indicated by the circle symbol "O". This is a suitable wavelength for evaluating the concentration of the interfering component because this peak in the interfering component spectrum does not overlap with any significant absorption of the analyte. As seen in Figures 11 and 12, the interfering component has a further peak on the left, however this overlaps at least partially with the left-hand peak of the analyte spectrum 140. If the measurement at the right-hand peak of the interfering component spectrum 142 performed in step 96 indicates a relatively low concentration, as in the example in Figure 11, it does not significantly interfere with the absorption measurement at the left-hand peak of the analyte spectrum 140, and therefore this left-hand analyte spectrum peak becomes the appropriate analyte characteristic wavelength to be used in the analyte measurement procedure. Accordingly, three appropriate exemplary wavelengths to be used in the analyte measurement procedure are indicated by the symbol x in Figure 11, namely the wavelengths corresponding to the two peaks and the wavelength corresponding to the minimum value between them.

[0195] However, if the measurement in step 96 indicates a high concentration of interfering components, as schematically shown in Figure 12, the analyte characteristic wavelength corresponding to the left-hand peak of the analyte spectrum 140 is no longer a good choice because it is superimposed by significant absorption due to the interfering components. Instead, as shown in Figure 12, it may be preferable in this case to use two analyte-specific wavelengths close to the right-hand (main) peak of the analyte spectrum, and, as before, dedicate another one to the minimum, thereby enabling a more accurate measurement of the right-hand absorption peak of the analyte. This type of selection is made in step 102.

[0196] Figure 14 shows a more complex situation, where the substance includes one analyte (solid line) and two perturbation components represented by long and short dashed lines in the absorption spectrum illustrated in Figure 14. The total absorption spectrum is represented by a vertical line. The analyte absorption spectrum has two peaks; however, it can be seen that the left peak is superimposed with perturbation component 1, and the right peak is superimposed with perturbation component 2.

[0197] To determine the concentration of the analyte, a simple procedure is to measure all six peaks in the total spectrum, indicated by vertical arrows with corresponding numbers 1-6 representing the measurement steps, along with the background, which is subtracted in the spectrum shown in Figure 14 but is naturally present in the actual measurement and is determined by a seventh measurement at the wavelength indicated by the corresponding arrow. Then, the approximate shapes of three spectra can be determined from the seven measurements, and the relative heights can be calculated to determine the concentration of the analyte. However, according to a preferred embodiment of the present invention, measurements using different excitation wavelengths are performed simultaneously, meaning that only four measurements are required. These four measurements are indicated in Figure 14 by numbers 1-4 circled.

[0198] Specifically, in the first measurement, an absorption measurement is performed while simultaneously irradiating with two absorption frequencies of the first perturbation component, corresponding to measurements 1 and 5 in the simple procedure. Then, in the second measurement, two separated excitation peaks of the second interfering component, corresponding to measurements 2 and 6 in the standard procedure, are measured by simultaneously irradiating the substance with two corresponding excitation light frequencies in a single step. Since these measurements relate to the interfering component, they are performed in step 96 of the flowchart in Figure 8. Subsequently, as a third measurement during the analyte measurement procedure, an absorption measurement can be performed by simultaneously irradiating with wavelengths corresponding to measurements 3 and 4 in the normal procedure. These wavelengths used in the third measurement are analyte-specific wavelengths, i.e., wavelengths corresponding to, or at least close to, the maximum absorption value of the analyte. Furthermore, the background is measured as a fourth measurement.

[0199] Therefore, step 102, selecting a set of glucose characteristic wavelengths, may also include selecting specific glucose characteristic wavelengths to be irradiated simultaneously to obtain a response signal showing simultaneous absorption of both analyte characteristic wavelengths, such as the wavelengths corresponding to the third measurement described above (the third and fourth measurements according to the standard procedure). In some cases, two excitation radiation beams having two different wavelengths to be irradiated simultaneously may be modulated at different modulation frequencies so as to be positioned to separate their respective measurement signals. Knowing the schematic shapes of the individual spectra of the analyte and the two interfering components, the relative height and ultimately the concentration of the analyte can also be determined from a signal representing the sum of the two absorption peaks. When two or more excitation wavelengths are used simultaneously, more information may be obtained per unit of measurement time, thereby improving the efficiency of the analyte measurement procedure. Furthermore, the results of measurements 1 and 2 performed during step 96 of the substance status analysis procedure, “checking for interfering components,” may be such that in step 102, it is determined that the superposition with these two interfering components is too large, and the analyte characteristic wavelengths associated with the two absorption peaks in the analyte spectrum (third and fourth measurements according to the standard procedure shown in Figure 14) are not selected, and instead other analyte characteristic wavelengths (not shown in Figure 14) are selected.

[0200] Based on the information obtained from the measurements in steps 90-100, further examples of how a set of glucose characteristic wavelengths may be selected in step 102 are illustrated with reference to Figure 13. Figure 13 shows the typical exponential decay of excitation light with increasing depth when penetrating the skin. Thus, the intensity I(d) as a function of penetration depth d is given as I(d) = I(d=0)·exp(-α(λ)·d), where α(λ) is the wavelength-dependent absorption coefficient. In practice, a considerable portion of the absorption is due to the water content of the skin. In the wavelength range containing the most useful absorption peak of glucose for the purposes of this invention, i.e., the range between approximately 8 μm and 11 μm, the absorption coefficient α(λ) of water has been found to be lower with respect to shorter wavelengths than with respect to longer wavelengths. Thus, although not shown on a uniform scale and exaggerated for illustrative purposes, the upper curve in Figure 13 corresponds to shorter wavelengths among the possible analyte characteristic wavelengths, and the lower curve in Figure 13 corresponds to longer wavelengths. Therefore, if high water content is found in the skin in step 94, this indicates that water absorption is intense and it is difficult to obtain sufficient intensity of excitation light in the deeper regions of the skin where interstitial fluid is present. As explained above, the problem with a large absorption coefficient α(λ) is not only that the intensity of excitation light is low in the target depth range and therefore the contribution of absorption in this depth range to the response signal is small, but this problem seems to be something that can be basically overcome by longer measurement times and proper data processing. Rather, for the reasons given above, the light absorption length μ is the reciprocal of the wavelength-dependent absorption coefficient α(λ). α (λ) is the thermal diffusion length μ t When it is lower than (f), there is a fundamental problem. Therefore, with respect to the high water content determined in step 94, a lower absorption coefficient α(λ) and therefore a longer light absorption length μ is required. α To benefit from (λ), a shorter glucose characteristic wavelength is preferred in the selection in step 102.

[0201] Further step 104 of the material status analysis procedure 76 determines the absolute or relative measurement time for the selected glucose characteristic wavelength. In other words, rather than simply selecting which of the predefined glucose characteristic wavelengths should be used and which should be excluded in the analyte measurement procedure, as in step 102, step 104 may allocate relative or absolute measurement times to the selected glucose characteristic wavelength, thereby allocating valuable measurement time to the selected wavelength in a manner in which measurement accuracy is expected to be maximized based on the results of steps 90-100.

[0202] Finally, in step 106, the excitation light modulation frequency with respect to the selected glucose characteristic wavelength is determined. As explained above, the frequency of the excitation light intensity modulation is the thermal diffusion length μ t (f) Thus, the depth range covered by the measurement is determined. If the determination of the stratum corneum thickness in step 98 indicates, for example, a large stratum corneum thickness, this requires a lower modulation frequency to allow for a longer thermal diffusion length. In step 106, the selection of the modulation frequency is made such that a lower principal frequency of modulation is chosen with respect to a higher stratum corneum thickness, assuming all other properties of the material status are the same.

[0203] For example, as described above, step 104 may rely on a predetermined threshold of stratum corneum thickness (or another parameter representing stratum corneum thickness), and the modulation frequency may be adjusted based on whether the stratum corneum thickness is less than the threshold (in which case a higher modulation frequency will be selected) or greater than the threshold (in which case a lower modulation frequency will be selected). In alternative embodiments, there may be several stratum corneum thickness ranges and associated modulation frequencies, where the modulation frequency for greater stratum corneum thicknesses is lower than the modulation frequency for smaller stratum corneum thicknesses, or the modulation frequency may be determined based on a continuous function that defines the modulation frequency as a function of the determined stratum corneum thickness. Any method of determining the modulation frequency as a function of the determined stratum corneum thickness may be employed, as long as it is guaranteed that a lower principal frequency of modulation is selected for greater stratum corneum thicknesses, assuming all other properties of the material status are the same.

[0204] It should be noted that in step 106, generally, at least two excitation light modulation frequencies are determined for several or each selected glucose characteristic wavelength, namely, a first (lower) modulation frequency intended to cover a significant portion including interstitial fluid, and a second (higher) modulation frequency intended to measure the response signal to compensate for absorption in higher layers of the skin, particularly the stratum corneum, where interstitial fluid is absent or present in little or no form. In some embodiments, in step 106, at least the second modulation frequency is determined according to the determined thickness of the stratum corneum.

[0205] Furthermore, in some embodiments, the selection or determination of the excitation light modulation frequency in step 106 also depends on the water content determined in step 94. A high water content is determined, and therefore a short light absorption length μ α If (λ) must be expected, this is the thermal diffusion length μ t (f) is the light absorption length μ α To ensure that it is less than or equal to (λ), we do not choose an excitation light modulation frequency that is too low.

[0206] Referring again to Figure 7, after the completion of the material status analysis procedure 76, the analyte measurement procedure 78 is performed. Referring to the flowchart in Figure 9, the analyte measurement procedure is described. In step 110 of Figure 9, the skin is irradiated with a first selected glucose characteristic wavelength at a first modulation frequency, and the corresponding response signal is detected. In the next step 112, the skin is irradiated with the same first selected glucose characteristic wavelength but at a second modulation frequency that is higher than the first modulation frequency, and the corresponding response signal is detected. The first modulation frequency is selected to be low enough that the response signal reflects at least part of the absorption of the excitation light in the interstitial fluid. In some embodiments, the first modulation frequency f is 4·f min >f>f min Preferably 3·f min >f>f min , most preferably 2·f min >f>f min It is selected within the range. Here, as derived above, f min is, f min =k t ·α(λ) 2 / (2·ρ·C p ) is defined as, k t ρ, and C p Here again, α(λ) represents the thermal conductivity, density, and specific heat capacity of the tissue, respectively, and α(λ) is the absorption coefficient with respect to the first selected glucose characteristic wavelength λ in the above tissue.

[0207] Simply put, the second modulation frequency is chosen to cover a shallower depth range of the skin that is not the target, i.e., a range that does not contain a recognizable amount of interstitial fluid, and therefore the glucose concentration in that range does not reflect the current glucose concentration in the interstitial fluid. It is primarily recorded so that it is subtracted from the response signal associated with the first modulation frequency after appropriate normalization in order to obtain a corrected signal that reflects the absorption of glucose in the interstitial fluid in as much detail as possible. An appropriate normalization factor is, for example, 1180 cm⁻¹ at the wavelength where the glucose absorption rate disappears. -1This can be the ratio of the response signals corresponding to measurements using the first and second modulation frequencies (see Figure 2). Using this normalization factor, if there is no glucose absorption, the difference in the response signals between the first and second modulation frequencies will be zero. Then, using the same normalization factor for measurements using the first and second modulation frequencies at the glucose characteristic wavelength, the difference between the two measurements will be a measure of glucose absorption in deeper layers of the skin that are accessible only by the first modulation frequency and not by the second modulation frequency.

[0208] In step 114, it is checked whether the data acquired in steps 110 and 112 is of sufficient quality. For this purpose, for example, the signal-to-noise ratio of the response signal or a quantity derived from the signal-to-noise ratio is determined. If it is found that the data quality is still insufficient, the procedure returns to step 110 to collect more data. In this way, it is ensured that sufficient measurement time is allocated to the first selected glucose characteristic wavelength in order to obtain measurement results of sufficient quality.

[0209] If the data quality is found to be sufficient, the process proceeds to step 116, and the procedures of steps 110-114 are repeated in steps 116-124 with respect to a second selected glucose characteristic wavelength. This procedure is continued with respect to some or all of the selected glucose characteristic wavelengths, as well as the corresponding first and second modulation frequencies. In fact, as can be seen in Figure 7, several instances of the analyte measurement procedure 78 are provided, interspersed with reference measurement 80 and possibly further material status analysis procedures 76, so that not all selected glucose characteristic wavelengths need to be covered in each instance of the analyte measurement procedure 78.

[0210] Importantly, both the glucose characteristic wavelength used in the analyte measurement procedure 78 and the corresponding first and second modulation frequencies are optimally selected to take into account the substance (skin) status determined in the substance status analysis procedure 76, which was performed immediately before the analyte measurement procedure without requiring the finger 12 to be lifted and removed or even moved from the contact surface 14 of the object being measured 16.

[0211] Referring again to Figure 7, in the next step 80, a reference measurement is performed. The reference measurement 80 is described with reference to the flowchart in Figure 10. In step 130, the skin is irradiated with one or more reference excitation wavelengths, and in step 132, the corresponding response signal is detected. The reference wavelength is a wavelength different from any analyte characteristic wavelength and is a wavelength at which glucose absorption is low. In step 134, the response signal is compared to the response signal of a previous reference measurement. The previous reference measurement may be, for example, a reference measurement performed as step 100 in the material status analysis procedure 76. Furthermore, several instances of the reference measurement 80 may be alternated with analyte measurement procedures for different wavelengths, and generally, earlier reference measurements 80 may exist and be used for comparison of response signals.

[0212] Based on the comparison, the calibration of the excitation light source 26 or the detection device can be determined so that drift of the light source, drift of the detection device, or other fluctuations, such as changes in the optical or thermal coupling between the finger 12 and the measuring body 16, can be taken into account in real time and compensated for by recalibrating one or both of the excitation light source 26 and the detection device.

[0213] Referring again to Figure 7, one result of the reference measurement could be that the analyte measurement procedure is defective, for example, because the position of the finger 12 on the object 16 has changed, resulting in insufficient thermal or optical bonding. Therefore, in step 82, it is determined whether the result of the reference measurement 80 is such that the procedure should be terminated. If the procedure should be terminated, the process jumps to step 86, which outputs terminated as a result. This may include, for example, a notification to the user that the finger 12 should be repositioned on the object 16 and the procedure should be resumed.

[0214] If reference measurement 80 does not indicate that the measurement should be terminated, step 84 checks whether reference measurement 80 indicates that the analyte measurement procedure 78 should be repeated. If this is the case, the procedure returns to step 78.

[0215] As can be seen further in Figure 7, various instances of the analyte measurement procedure 78 and the reference measurement 80 are repeated. This essentially means that the analyte wavelength-specific measurements performed in the analyte measurement procedure 78 are interspersed with the reference measurement 80, so that the analyte measurement procedure is accompanied by the reference measurement in real time, thereby enabling real-time monitoring of the analyte wavelength-specific measurements and, accordingly, real-time recalibration of the instrument 10.

[0216] As can be seen further in Figure 7, the analyte measurement procedure 78 may be interspersed with one or more further instances of the material status analysis procedure 76. Importantly, throughout all instances of the analyte measurement procedure 78, the material status analysis procedure 76, and the reference measurement 80, the finger 12 remains in contact with the contact surface 14 of the body being measured 16.

[0217] In step 84, the glucose content is determined based on the response signals measured in various instances of the analyte measurement procedure 78, and the result is output in step 86.

[0218] Figure 15 shows an exemplary modulation function related to the intensity of excitation light. The modulation function of the excitation radiation intensity is a square wave function alternating between zero ("off") and a maximum value ("on"), and the lengths of the on-interval and the off-interval are the same. The on-interval may also be referred to as a pulse, and the pulse length suitable for the application described in the present specification, that is, glucose measurement in the skin, is in the range of 2 to 50 ms.

[0219] It should be noted that the modulation function may be obtained in various manners, for example using a chopper or a selectively transmissive element, or corresponding control of the excitation light source 26. In a preferred embodiment, the excitation light source 26 is formed by an array of quantum cascade lasers, and the intensity modulation within the relevant frequency range is controlled by its electronic control. In this case, the quantum cascade laser is controlled to emit a pulse signal composed of "micro-pulses" that typically have a frequency 10,000 to 100,000 times higher than the modulation frequency. Therefore, these micro-pulses are on a much higher time scale than any of the thermal processes on which the measurement relies, and their fine structure can be completely ignored. Thus, in this case, the intensity modulation becomes the envelope of the plurality of micro-pulses.

[0220] The present inventors have surprisingly discovered that, as shown in Figure 16, the accuracy and efficiency of the analyte measurement procedure can be improved without changing the frequency of the modulation signal or the period which is the sum of the on-interval and the off-interval, for example, when the relative length of the off-interval is longer than the relative length of the on-interval.

[0221] It can be seen that using the modulation of Figure 16 instead of the modulation of Figure 15 may result in a better signal-to-noise ratio of the response signal. As explained above, according to the present understanding of the present inventors, this is due to the fact that the response signal is an "AC signal" in the sense that only changes in the response signal over time can be evaluated to estimate the degree of absorption. For this reason, it appears to be important that the physical response of the measurement body due to the heat received from the substance can attenuate as much as possible before the next heat pulse is received. By increasing the off-time, the time for the physical response of the measurement body to attenuate is extended, which leads to a better signal-to-noise ratio.

[0222] It should be noted that the square wave modulation function is an obvious choice for at least two reasons. The first reason is that a sharp excitation pulse with steep edges is promising for producing the best results for generating heat pulses, which is indeed true in many applications. The second reason is that square wave modulation is practically the easiest to establish.

[0223] Nevertheless, the present inventors have discovered that despite the apparent advantages of square wave modulation of excitation light intensity, a sinusoidal modulation function may yield better results in several applications, including the glucose measurement described herein. This is a surprising finding, as the sinusoidal modulation function does not have the same sharp impulses found with square wave modulation that result in particularly pronounced thermal pulses in the skin that can be well detected using the device of the present invention. However, the present inventors have found that this drawback can be compensated for in the particular situation under consideration, where the analyte to be measured, i.e., glucose, is located primarily in deeper layers of the material (skin) and is only accessible by lower modulation frequencies. When using a square wave signal, a distinction must be made between its fundamental frequency, which is the reciprocal of the repetition period of the signal, and the harmonic contributions to the signal that are found in the Fourier series decomposition of the square wave signal. These higher frequency contributions again result in response signals corresponding to absorption in shallower regions of the skin that are not of interest for glucose measurement.

[0224] Therefore, in a preferred embodiment, the time modulation of the intensity of the excitation radiation is chosen such that the intensity envelope is approximately harmonic, i.e., similar to a sine function, and in the Fourier decomposition of the intensity of the excitation radiation, of the total intensity associated with the dominant frequency and the first to ninth harmonics, at least 95% is associated with the dominant frequency, and at least 97%, preferably at least 98%, is associated with the dominant frequency and the first harmonic.

[0225] Figure 17 is a schematic diagram of the time-dependent intensity of excitation radiation having an envelope that coincides with a sine function. The excitation light itself may again consist of pulses having different durations, different pulse densities, or pulse amplitudes, as is commonly known from PWM, PDM, or PAM, and these techniques may be used to generate an envelope that is "approximately harmonic" as defined above.

[0226] Figure 17 is a schematic representation only, and it should be noted that in many applications, each period of the modulated intensity of the excitation radiation may consist of a number of “micropulses” as mentioned above, which may be provided, for example, by a quantum cascade laser or a quantum cascade laser element in a laser array. In a preferred embodiment, these micropulses are modulated with respect to one or both of their length and / or their amplitude, and the amplitude may be changed within a certain range by changing the operating current, thereby producing an intensity envelope that is at least “approximately harmonic.” However, it is also possible to generate “macropulses” while keeping the micropulses constant with respect to one or both of their amplitude and frequency, each macropulse being formed by a series of multiple micropulses, where the duration of each macropulse is still considerably shorter than the period of the excitation radiation intensity envelope. The desired envelope of the excitation radiation may then be obtained by adjusting one or more of the length, frequency, and amplitude of the macropulses accordingly, as is commonly known from PWM, PDM, or PAM.

[0227] Figure 18 shows a wearable device 150 incorporating an apparatus for measuring a person's glucose levels. Figure 18 shows a top view of the wearable device 150, which is provided with a touch display 154, and the apparatus's measuring body is provided on the bottom of the device (not shown in Figure 18) to make contact with the skin when the device 150 is worn around the user's wrist using a wristband 152. All of the aforementioned components of the apparatus, including an excitation radiation source, a detection device for detecting the physical response of the measuring body to a heat or pressure wave received by the skin when the excitation radiation is absorbed, and a control system (not shown), may be provided to the wearable device 150. In the illustrated embodiment, the touch display 154 prompts the user to provide user-related inputs that enable the optimization of one or both of the analyte measurement procedure and the analysis performed in the analysis step. Such user-related inputs may include characteristics or conditions of the person using the wearable device 150 for glucose measurement. For example, in the scenario shown in Figure 18, the user is asked to declare whether they are currently sweating (see reference numeral 156). The user is prompted to answer "yes" or "no" by checking boxes 158 and 106 on the touch display 154, respectively. Sweating is one example of a user's condition. Further examples of conditions may include whether the person has a cold and / or a fever, or is feeling chills, is currently on a diet, has recently drunk water, or is feeling stressed. This information may be entered via a smartphone or another device communicating with the wearable device 150, via a graphical user interface, or via voice and microphone in combination with voice recognition.

[0228] In addition to querying the user's state, the device may also be configured to query the user's characteristics. While there may be debate as to the clear distinction between a user's characteristics and their state, as understood herein, “state” refers to a condition or quality that is expected to change, for example, within a few hours or at least a few days, whereas characteristics change only on longer time scales and therefore do not need to be evaluated as frequently as the state. Examples of characteristics include, for example, a person’s skin color, e.g., whether their skin color is light or dark; information related to their weight, e.g., body mass index; whether they have a chronic disease, and if so, what disease it is (e.g., whether they have diabetes, or whether glucose measurements are taken for general health or nutritional monitoring); and their age.

[0229] Features can also be queryed via the touch display 154, but not as frequently as the status. Queries regarding user-related information may be performed by the device (its control system), for example, before step 70 in Figure 7. At least some of the information regarding features may be obtained using sensors. For example, skin color may be determined using a camera and its respective image analysis.

[0230] In addition to the information established in the material state analysis procedure 76, user-related information may be used. That is, all selections and decisions made in steps 102, 104, and 106 based on the results of the material status analysis procedure may be based on both the results of the material analysis procedure and the user-related input received. However, in other cases, user input may be used instead of the information established in the material state analysis procedure.

[0231] In some embodiments, the protocol for performing the analyte measurement procedure may be generated or selected from several predetermined protocols based on user-related states / characteristics received through user input. Different protocols selected or generated based on user states / characteristics may include, for example, - Selection of the characteristic wavelength of the analyte used in or relied upon during the above analyte measurement procedure, - The absolute time or relative time ratio of the use of the characteristic wavelength of the analyte in the above analyte measurement procedure, or the relative weight given to the wavelength in the analysis, - Selection of analyte characteristic wavelengths to be used simultaneously during the above analyte measurement procedure, and - Selection of one or more principal frequencies of the modulation of the excitation radiation intensity to be used during the analyte measurement procedure described above, There may be differences with respect to one or more of these.

[0232] The protocol may have been previously determined empirically to work particularly well with respect to a given characteristic and / or state. These predetermined protocols may be used instead of the material status analysis procedures described with reference to Figure 7 or 8. However, in a particularly preferred embodiment, these protocols may be used as a starting point and then refined based on the results of the material status analysis procedures of Figures 7 and 8.

[0233] Furthermore, user-related inputs may be used, either additionally or alternatively, to adapt the analysis performed in the analysis step. In the illustrated embodiment, the control system includes a memory for storing various algorithms that convert response signals into estimates of glucose concentration.

[0234] In a preferred embodiment, the memory stores various machine learning-based algorithms trained on training data associated with different features and states. Then, based on user input, one of these machine learning-based algorithms trained on features / states most similar to those received by the user input may be selected. Instead of selecting from alternative algorithms for use in analysis, it may also be possible to simply adjust specific parameters of an algorithm based on features or states.

[0235] Figure 19 shows a cross-sectional view of apparatus 162 similar to the apparatus in Figure 3. Identical or similar components in Figure 19 are denoted by the same reference numerals as in Figure 3 and are not mentioned again. Apparatus 162 includes a wrist band 164 for attaching the device, which is strapped to the wrist 166. In the illustrated embodiment, apparatus 162 is a dedicated device to be worn on the underside of the wrist 166, and the surface of the skin on the underside of the wrist 166 is schematically indicated by a dashed line 168. The inventors have found that the skin on the underside of the wrist 166 is particularly suitable for high-precision glucose measurement. Alternatively, the same type of apparatus 162 may be incorporated into a wearable device, such as the one shown in Figure 18 by reference numeral 150, in which case the measurement may be performed on the upper side of the wrist 166, which is the normal position of the wearable device 150. However, it is also possible to simply temporarily orient the wearable device 150 to the underside of the wrist 166 when performing glucose measurement.

[0236] Figure 19 again shows the camera 32 used to record fingerprints for user identification in the embodiment of Figure 3. However, in the embodiment shown in Figure 19, the camera 32 is specifically configured to record an image of the area of ​​skin 168 from which excitation radiation 18 is to be emitted.

[0237] Figure 20 shows a schematic diagram of an image 170 taken through the measurement body 14 using the camera 32 of Figure 19. In image 170, the circle 172 represents the position where the excitation light beam 18 is emitted into the skin 168. This position 172 in image 170 is known in advance (i.e., before irradiation with the excitation light beam 18), for example, by the known relative positions of the camera 32 and the excitation light source 26. This position 172 may be determined in a calibration procedure.

[0238] This position 172 within the image 170 can be known, and an appropriate algorithm can then be used to determine, for a given position of the device 162 relative to the skin 168, whether the excitation radiation irradiates the skin at a "suitable position". A "suitable position" is a position where the skin quality is such that reliable measurement results can be expected. Reliable measurements are usually obtained when the skin is smooth, clean, and free of wrinkles (schematically indicated by reference numeral 178), scars 176, or moles 174. From the image 170 shown in Figure 20, the algorithm can determine that the radiation position 172 overlaps with the mole 174 identified in the image 170, which means that for this relative position of the device 162 relative to the skin 168, the excitation beam 18 is not actually directed at a "suitable position".

[0239] This is determined using an image analysis algorithm, and in response to this determination, the user is prompted via the output interface to reposition the device 162 relative to the skin 168. The user interface may again be a touch display. Additionally or alternatively, the output interface may comprise an acoustic output device.

[0240] In this way, it can be ensured that the measurement is performed at a suitable position on the skin 168, thereby eliminating one cause of inaccurate measurement results.

[0241] A further cause of inaccurate measurements is a lack of positional stability, i.e. when the device 162 is moved relative to the skin 168 during measurement. In the illustrated embodiment, images of the skin are not only captured before taking a measurement, but also periodically during the analyte measurement procedure. Successively recorded images of the skin are compared, and if the images are offset from one another, this indicates that the device 162 has moved. If it is determined that the device 162 has moved, this may indicate that the analyte measurement procedure is terminated and restarted anew.

[0242] In some cases, even if it is determined that the device 162 has moved relative to the skin 168, it may be advantageous not to terminate the analyte measurement procedure, and possibly to repeat a portion of it, or to extend the measurement time allocated for a given wavelength that is likely to be affected by the change in position. Similarly, relative motion of the device 162 relative to the skin 168 may result in a situation where the position 172 at which the excitation light beam 18 strikes the skin 168 is no longer in a suitable position according to one of the applicable criteria. In this case as well, it may be decided to terminate the measurement or to adapt the measurement protocol.

[0243] It should be noted that information regarding the appropriate position and / or positional stability of excitation radiation may be used in the same way as the aforementioned "quality assessment," except that the aforementioned assessment was based on response signals rather than camera images.

[0244] In particular, based on the detected positional stability, the measurement time allocated to one or more analyte characteristic wavelengths during the current analyte measurement procedure may be adjusted. Alternatively, the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis may be adjusted as described above with reference to quality assessment. Additionally or alternatively, based on the monitored positional stability, the measurement may be terminated and restarted.

[0245] Regarding the aforementioned applications of cameras, it should be noted that, generally, any camera or imaging device that is highly sensitive within the visual range of light, i.e., within the range perceptible to humans, may be used. However, it should also be noted that using infrared cameras, or cameras of a type that is highly sensitive within a specific range or segment of the optical, infrared, or UV spectrum, may also be advantageous. The realization of the sensitivity range may be implemented, for example, by inserting filters.

[0246] In the illustrated embodiment, the device is configured to notify the user when the measurement is complete due to relative movement between the device 162 (or its measuring body 16) and the skin 168. The user does not need to do anything proactive to restart the analyte measurement procedure, but this enhances user awareness and thus ensures positional stability in subsequent attempts of the analyte measurement procedure. Preferably, this information is transmitted to the user via an acoustic signal.

[0247] Although the present invention has been described in relation to specific embodiments, those skilled in the art will understand that variations and modifications will be conceivable, and that all of them are intended as aspects of the present invention. Therefore, only the limitations expressed in the claims should be imposed on the present invention.

Claims

1. A method for analyzing a substance (12) containing at least one analyte, The procedure includes an analyte measurement procedure (78), and in the analyte measurement procedure (78), The substance (12) is in thermal or pressure-transfer contact with the measuring body (16), and the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation (18) in the substance to be transferred to the measuring body. Excitation radiation (18) is irradiated onto the substance (12) such that it is absorbed by the substance (12), the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths that are irradiated simultaneously and / or sequentially. The physical response of the measuring body (16) or components contained in the measuring body (16) to the heat or pressure wave received from the substance (12) when the excitation radiation (18) is absorbed is detected using a detection device, the detection device generates a response signal based on the detected physical response, and the response signal indicates the degree of absorption of the excitation radiation. The method further includes an analysis step, the analysis being performed at least in part based on the response signal, In the analyte measurement procedure (78), a series of analyte wavelength-specific measurements are performed while maintaining the thermal or pressure transfer contact between the substance (12) and the measuring body (16), and in each analyte wavelength-specific measurement, excitation radiation (18) having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. At least some of the analyte wavelength-specific measurements are interspersed with reference measurements (80), in which an excitation radiation (18) having a reference wavelength is irradiated, and a corresponding response signal is obtained, wherein the reference wavelength is different from any of the analyte characteristic wavelengths. A method wherein the response signal obtained with respect to the reference measurement (80) is used to adapt the analyte measurement procedure (78) with respect to the total duration of the analyte measurement procedure and / or the absolute or relative duration of the analyte wavelength-specific measurement with respect to a given analyte characteristic wavelength.

2. The method according to claim 1, wherein a reference measurement (80) is performed for at least 25% of each pair of consecutive analyte wavelength-specific measurements.

3. The method according to claim 1 or 2, wherein the reference measurement (80) is performed at an average rate at least once every 5 seconds.

4. The method according to any one of claims 1 to 3, wherein the step of adapting the analysis performed in the analysis step based on the response signal obtained with respect to the reference measurement (80) includes normalizing at least some of the results of the analyte wavelength-specific measurements based at least in part on the results of one or both of the preceding or subsequent reference measurements.

5. A method for analyzing a substance (12) containing at least one analyte, The procedure includes an analyte measurement procedure (78), and in the analyte measurement procedure (78), The substance (12) is in thermal or pressure-transfer contact with the measuring body (16), and the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation (18) in the substance to be transferred to the measuring body. Excitation radiation (18) is irradiated onto the substance (12) such that it is absorbed by the substance (12), the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths that are irradiated simultaneously and / or sequentially. The physical response of the measuring body (16) or components contained in the measuring body (16) to the heat or pressure wave received from the substance (12) when the excitation radiation (18) is absorbed is detected using a detection device, the detection device generates a response signal based on the detected physical response, and the response signal indicates the degree of absorption of the excitation radiation. The method further includes an analysis step, the analysis being performed at least in part based on the response signal, In the analyte measurement procedure (78), a series of analyte wavelength-specific measurements are performed while maintaining the thermal or pressure transfer contact between the substance (12) and the measuring body (16), and in each analyte wavelength-specific measurement, excitation radiation (18) having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. A quality assessment is performed based on the response signals associated with one or more characteristic wavelengths of the analyte, and based on the quality assessment, the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis are adjusted. method.

6. The method according to claim 5, wherein the quality evaluation is performed during the analyte measurement procedure (78), and the measurement time allocated to the corresponding one or more analyte characteristic wavelengths is adjusted in real time during the analyte measurement procedure.

7. The aforementioned quality evaluation is at least partially, The signal-to-noise ratio of the response signal or a quantity derived from the signal-to-noise ratio, and Based on one or more of the results of one or more reference measurements (80), in the reference measurement (80), excitation radiation (18) having a reference wavelength is irradiated, a corresponding response signal is obtained, and the reference wavelength is the wavelength at which the absorption of the analyte is low. The method according to claim 5 or 6.

8. The method according to any one of claims 1 to 7, wherein the substance (12) is human tissue and the analyte is glucose present in the interstitial fluid of the substance (12).

9. The procedure further includes a substance status analysis procedure (76), wherein in the substance status analysis procedure (76), the current status of the substance is One or more response signals established when the substance (12) is irradiated with excitation radiation (18) at a wavelength different from the characteristic wavelength of the analyte, With respect to excitation radiation (18) having the same analyte characteristic wavelength as used in the analyte measurement procedure, however, one or more response signals established with respect to the intensity modulation frequency of the excitation radiation which is at least partially different from that of the analyte measurement procedure, and One or more measurements related to the material status, performed using additional sensor equipment. The analysis is based on one or more of the following: Based on the results of the aforementioned substance status analysis procedure (76), Selection of analyte characteristic wavelengths used in or relied upon during the analyte measurement procedure (78), The absolute time or relative time ratio of the use of the analyte characteristic wavelength in the aforementioned analyte measurement procedure (78), the individual excitation radiation intensity, or the relative weight given to the wavelength in the aforementioned analysis, Selection of analyte characteristic wavelengths to be used simultaneously during the analyte measurement procedure (78), and Selection of one or more principal frequencies of the modulation of the excitation radiation (18) intensity to be used in the analyte measurement procedure (78), The method according to any one of claims 1 to 8, wherein at least one of the following is determined.

10. The method according to claim 9, wherein the substance status analysis procedure (76) is performed alternately with the analyte measurement procedure (78), or less than 5 minutes before the start of the analyte measurement procedure.

11. The method according to claim 9, wherein the substance status includes the water content of human skin (12).

12. The method according to claim 11, wherein if a higher water content is determined in the substance (12) analysis procedure, a shorter wavelength from a predetermined set of analyte characteristic wavelengths is preferentially used in the analyte measurement procedure (78).

13. The method according to claim 11 or 12, wherein at least one of the one or more principal frequencies of the modulation of the excitation radiation (18) intensity used in the analyte measurement procedure (78) is selected for higher water content, such that the water content is matched to the water content determined in the substance (12) analysis procedure, and all other properties of the substance status are the same.

14. The method according to any one of claims 1 to 13, wherein the excitation radiation (18) is generated using an array of lasers, each having a dedicated wavelength.

15. The method according to any one of claims 1 to 14, wherein the excitation radiation (18) is generated using at least one tunable laser.

16. The method according to any one of claims 1 to 15, wherein some or all of the wavelengths of the excitation radiation (18) are in the range of 6 μm to 13 μm.

17. An apparatus (10) for analyzing a substance (12) containing at least one analyte, A measuring body (16) having a contact surface (14) suitable for thermal or pressure-transfer contact with the substance (12), wherein the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation (18) in the substance to be transferred to the measuring body, An excitation radiation source (26) configured to irradiate the substance (12) with excitation radiation so as to be absorbed by the substance (12), A detection device for detecting the physical response of the measuring body (16) or components contained in the measuring body (16) to the heat or pressure wave received from the substance (12) when the excitation radiation (18) is absorbed, and for generating a response signal based on the detected physical response, wherein the response signal indicates the degree of absorption of the excitation radiation. Equipped with a control system, The control system, The excitation radiation source (26) is configured to control the excitation radiation source (26) so as to irradiate the substance (12) with excitation radiation so as to be absorbed by the substance (12), wherein the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths that are irradiated simultaneously and / or sequentially. The control system further, The detection device is configured to detect the physical response and to control the detection device to generate a response signal indicating the degree of absorption of the excitation radiation (18). The control system is further configured to control the apparatus so that, during the analyte measurement procedure (78), a series of analyte wavelength-specific measurements are performed while the thermal or pressure-transfer contact between the substance (12) and the measuring body (16) is maintained, wherein in each analyte wavelength-specific measurement, excitation radiation (18) having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated to obtain a corresponding response signal. The control system is further configured to intersperse reference measurements (80) with at least some of the analyte wavelength-specific measurements, wherein in the reference measurement (80), an excitation radiation (18) having a reference wavelength is irradiated, a corresponding response signal is obtained, and the reference wavelength is different from any of the analyte characteristic wavelengths. Apparatus (10) wherein the control system is configured to use the response signal obtained with respect to the reference measurement (80) to adapt the analyte measurement procedure (78) with respect to the total duration of the analyte measurement procedure and / or the absolute or relative duration of the analyte wavelength-specific measurement with respect to a given analyte characteristic wavelength.

18. The apparatus (10) according to claim 17, wherein a reference measurement (80) is performed for at least 25% of each pair of consecutive analyte wavelength-specific measurements.

19. The apparatus (10) according to claim 17 or 18, wherein the control system is configured to control the apparatus such that the reference measurement (80) is performed at an average rate of at least once every 5 seconds.

20. Apparatus (10) according to any one of claims 17 to 19, wherein the step of adapting the analysis performed in the analysis step based on the response signal obtained with respect to the reference measurement (80) includes normalizing at least some of the results of the analyte wavelength-specific measurements based at least in part on the results of one or both of the preceding or subsequent reference measurements.

21. An apparatus (10) for analyzing a substance (12) containing at least one analyte, A measuring body (16) having a contact surface (14) suitable for thermal or pressure-transfer contact with the substance (12), wherein the thermal or pressure-transfer contact allows heat or pressure waves generated by the absorption of excitation radiation (18) in the substance to be transferred to the measuring body, An excitation radiation source (26) configured to irradiate the substance (12) with excitation radiation so as to be absorbed by the substance (12), A detection device for detecting the physical response of the measuring body (16) or components contained in the measuring body (16) to the heat or pressure wave received from the substance (12) when the excitation radiation (18) is absorbed, and for generating a response signal based on the detected physical response, wherein the response signal indicates the degree of absorption of the excitation radiation. Equipped with a control system, The control system, The excitation radiation source (26) is configured to control the excitation radiation source (26) so as to irradiate the substance (12) with excitation radiation so as to be absorbed by the substance (12), wherein the intensity of the excitation radiation is time-modulated, and the excitation radiation includes radiation of different analyte characteristic wavelengths that are irradiated simultaneously and / or sequentially. The control system further, The detection device is configured to detect the physical response and to control the detection device to generate a response signal indicating the degree of absorption of the excitation radiation (18). The control system is configured to control the apparatus so that, during the analyte measurement procedure (78), a series of analyte wavelength-specific measurements are performed while maintaining the thermal or pressure transfer contact between the substance (12) and the measuring object (16), and in each analyte wavelength-specific measurement, excitation radiation (18) having an analyte characteristic wavelength selected from a predetermined set of analyte characteristic wavelengths is irradiated, and a corresponding response signal is obtained. Apparatus (10) wherein the control system is further configured to perform a quality evaluation based on the response signal associated with one or more analyte characteristic wavelengths, and to adjust the relative weights associated with the corresponding analyte wavelength-specific measurements in the analysis based on the quality evaluation.

22. The apparatus (10) according to claim 21, wherein the control system is configured to perform the quality evaluation during the analyte measurement procedure (78) and to control the apparatus in real time during the analyte measurement procedure to adjust the measurement time allocated to the corresponding one or more analyte characteristic wavelengths.

23. The aforementioned quality evaluation is at least partially, The signal-to-noise ratio of the response signal or a quantity derived from the signal-to-noise ratio, and Based on one or more of the results of one or more reference measurements (80), in the reference measurement (80), excitation radiation (18) having a reference wavelength is irradiated, a corresponding response signal is obtained, and the reference wavelength is the wavelength at which the absorption of the analyte is low. The apparatus (10) according to claim 21 or 22.

24. The apparatus (10) according to any one of claims 17 to 23, wherein the substance (12) is human tissue and the analyte is glucose present in the interstitial fluid of the substance (12).

25. The control system is further configured to perform a material status analysis procedure (76), in which the current status of the material is determined. One or more response signals established when the substance (12) is irradiated with excitation radiation (18) at a wavelength different from the characteristic wavelength of the analyte, With respect to excitation radiation (18) having the same analyte characteristic wavelength as used in the analyte measurement procedure, however, one or more response signals established with respect to the intensity modulation frequency of the excitation radiation which is at least partially different from that of the analyte measurement procedure, and One or more measurements related to the material status, performed using additional sensor equipment. The analysis is based on one or more of the following: Based on the results of the material status analysis procedure (76), the control system controls the material status analysis procedure. Selection of analyte characteristic wavelengths used in or relied upon during the analyte measurement procedure (78), The absolute time or relative time ratio of the use of the analyte characteristic wavelength in the aforementioned analyte measurement procedure (78), the individual excitation radiation intensity, or the relative weight given to the wavelength in the aforementioned analysis, Selection of analyte characteristic wavelengths to be used simultaneously during the analyte measurement procedure (78), and Selection of one or more principal frequencies of the modulation of the excitation radiation (18) intensity to be used in the analyte measurement procedure (78), The apparatus according to any one of claims 17 to 24, configured to determine at least one of the following.

26. The apparatus (10) according to claim 25, wherein the substance status includes the water content of human skin (12).

27. If a higher water content is determined in the substance (12) analysis procedure, the control system is configured to preferentially use shorter wavelengths from a predetermined set of analyte characteristic wavelengths in the analyte measurement procedure (78), the apparatus (10) according to claim 26.

28. The apparatus (10) according to claim 26 or 27, wherein the control system is configured to match at least one of the one or more principal frequencies of the modulation of the excitation radiation (18) intensity used in the analyte measurement procedure (78) to the water content determined in the substance (12) analysis procedure, and such that a higher principal frequency of the modulation is selected for a higher water content, assuming all other characteristics of the substance status are the same.

29. The detection device includes a light source (28) for generating a detection light beam (22) that travels through the measuring body (16) or at least a portion of the components included in the measuring body, The physical response of the measuring body (16) to the heat or pressure wave received from the substance (12) at the time of absorption of the excitation radiation (18) is a local change in the refractive index of the measuring body or its components. The detection device is configured to detect either a change in the optical path or a change in the phase of the detection light beam (22) based on a change in the refractive index or phase of the optical path of the detection light beam. The apparatus (10) according to any one of claims 17 to 28.

30. The apparatus (10) according to claim 29, wherein the measuring body (16) is transparent to the detection light beam (22), the detection light beam is directed so as to be fully or partially reflected by the surface (14) of the measuring body which is in thermal or pressure-transfer contact with the substance (12), and the detection device comprises a photodetector capable of detecting the degree of deflection of the detection light beam due to the local change in refractive index.

31. The apparatus (10) according to any one of claims 17 to 30, wherein the excitation radiation source (26) comprises lasers each having a dedicated wavelength.

32. The apparatus (10) according to any one of claims 17 to 31, wherein the excitation radiation source (26) comprises at least one tunable laser.

33. The apparatus (10) according to any one of claims 17 to 32, wherein some or all of the wavelengths of the excitation radiation (18) are in the range of 6 μm to 13 μm.

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