METHOD FOR DETERMINING A SUBSTANCE CONCENTRATION AND DETECTOR DEVICE

Abstract

The invention relates to a method for determining a substance concentration in a sample comprising a liquid containing particles, in particular oxygen saturation, comprising the following steps: - Obtaining a first perfusion index based on a reflected first component of an incident first light ray with a first wavelength; - Obtaining a second perfusion index based on a reflected second component of an incident second light beam with a second wavelength; - Receiving a reflected third component of an incident third light ray with a third wavelength, wherein the third light ray is in a wavelength range that is less sensitive to oxygen saturation than the first and second light rays; - Adjust at least one of the perfusion indices in response to the third component received; - Determining the oxygen saturation or a change thereof from at least one adjusted perfusion index and the respective other perfusion index.

Description

[0001] The present application claims priority from German patent application DE 10 2023 113 575.9 dated May 24, 2023, the disclosure of which is hereby incorporated in its entirety by reference. The present invention relates to a method for determining the concentration of a substance in a sample containing particles in a liquid, in particular glucose in blood, wherein the refractive index of the liquid depends on the concentration of the substance dissolved therein. The invention also relates to a detection device. BACKGROUND

[0002] The current standard for blood glucose monitoring often uses an invasive technique involving the extraction of a small amount of blood and subsequent electrochemical analysis with a handheld device. This method is unsuitable for continuous monitoring because each measurement requires pricking the finger to obtain a fresh blood sample.

[0003] A newer technology uses a button that sits on the skin and uses a small, needle-like sensor to extract interstitial fluid from parts of the subcutaneous fat tissue. However, the needle permanently penetrates the skin.

[0004] Besides these invasive methods, there are also non-invasive methods based on optical IR measurements or Raman spectroscopy. While the selection of a suitable emitter and detector poses difficulties in the first case, an approach based on Raman spectroscopy is challenging due to its very poor signal-to-noise ratio.

[0005] In this respect, there is a need for a method that can detect a substance in a liquid in a simpler way and enables continuous measurement. SUMMARY OF THE INVENTION

[0006] These and other objectives are addressed by the subject matter of the independent claims. Features and further aspects of the proposed principles are set forth in the dependent claims.

[0007] In addition to some other ideas based on angle-dependent dispersion, the present idea relies on the evaluation of the modulation depth, also known as the perfusion index, which, according to the inventors' findings, also depends on the blood glucose concentration.

[0008] The perfusion index, or modulation depth, is a result of photoplethysmography (PPG), i.e., the optical measurement of volume changes in human blood, e.g., due to the heartbeat, at a specific location on the human body, such as the fingertip or another suitable site. These volume changes are observable as signal fluctuations during heartbeats, resulting from varying degrees of dispersion due to differing blood volumes.

[0009] Due to the scattering and absorption of light that initially strikes the skin and subsequently propagates through parts of the superficial and / or deeper tissue, which in turn contains a network of blood vessels, the amount of light exiting the skin-surface interface some distance from the point of entry varies according to the optical path length (distance) traveled in the blood. This path length is referred to as the "optical path length in the blood (BOPL)," which is directly influenced by the heartbeat. Consequently, the BOPL varies over time, while the properties of the surrounding tissue can be considered constant, at least on the timescale of the heart rate.

[0010] When the BOPL is maximal or minimal, the signal emerging after the interaction is conversely minimal or maximal. The difference between the minimum and maximum signal is called modulation, and the ratio of modulation to average signal is defined as modulation depth, AC / DC ratio, or perfusion index.

[0011] According to Beer-Lambert's law, the absorption of light in blood is largely determined by the presence of hemoglobin in the erythrocytes and by the cumulative BOPL (blood absorption per unit area). Assuming that the density of the erythrocytes does not change during the measurement period, light that propagates nominally through the more or less transparent blood plasma is scattered by the red blood cells. Therefore, the cumulative BOPL from the entry point to the detection point, both of which are determined by the instrument configuration, can depend on the scattering properties in a random pattern, i.e., it becomes a stochastic process.

[0012] Consequently, the perfusion index or modulation depth is primarily a result of the direct interaction and, in particular, the scattering between light and erythrocytes.

[0013] This principle is currently used for measuring blood oxygen saturation, also known as SpO2 measurement. SpO2 measurements are based on the ratio of the PPG signals recorded at two different wavelengths, i.e., in the red and infrared (IR) spectrum. More precisely, SpO2 measurement is performed by determining the ratio of the perfusion indices at the two different wavelengths. This is achieved with an arrangement in which, for example, a red and an IR emitter are used to illuminate tissue, e.g., by alternately transmitting short light pulses at a sufficiently high repetition rate, such as 20 Hz, 50 Hz, 200 Hz, etc., and by sampling the corresponding photocurrent generated in the photodiode. The raw current of the photodiode consists of an average signal level, referred to as direct current (DC), and a modulation of the signal due to the heartbeat, referred to as alternating current (AC).The alternating current signal can be estimated, for example, by the difference between the peaks and troughs of the raw signal. The ratio of alternating current to direct current is called the perfusion index (PI), relative modulation, or modulation percentage. See the reference "In Vivo Reflectance of Blood and Tissue as a Function of light wavelength," Weijia Cui et al., IEEE Transactions on Biomedical Engineering, Vol. 17, No. 6, June 1990.

[0014] The ratio of relative modulations is calculated to estimate oxygen saturation. This process is also known as the ratio of ratios. By properly calibrating such values ​​with a reference instrument, it is possible to detect oxygen saturation of 100% and lower values ​​at an early stage. However, the ratio of ratios for a given oxygen saturation, and thus an SpO2 measurement, depends on optical design decisions, particularly the relative distance between the light source and detector for each wavelength, the emission characteristics of each light source, the detection characteristics of the photodiode, the performance of the optical barrier between the sources and detectors, and other system aspects that influence how light propagates from a source to a detector.Nevertheless, the above-mentioned approach for optical SPO2 measurements is discussed extensively in the literature and is scientifically recognized.

[0015] It has now been observed that in a human subject under stationary conditions and constant blood glucose levels, the perfusion index remains essentially constant. When the blood glucose level rises, the properties of the blood plasma change, and in particular, the refractive index of the plasma. As a result, the difference between the refractive indices of the erythrocytes and the blood plasma decreases, leading to a reduction in light scattering. Likewise, a decrease in the glucose level leads to an increase in the difference between the refractive indices of the erythrocytes and the blood plasma, resulting in an increase in scattering. This is explained in a model where scattering is primarily caused by diffraction differences.In a transparent medium where the refractive indices of the liquid and the scattering particles are the same, no scattering would be observed, as the light would simply propagate through the medium without interaction. However, as soon as an index discrepancy exists, some of the light is scattered by the particles (e.g., backwards) and can thus be distinguished from the surroundings, i.e., the plasma.

[0016] Consequently, the perfusion index can be used for the so-called oral glucose tolerance test, in which a test subject begins with a baseline blood glucose level determined by several hours of fasting and then ingests a liquid or substance containing calories. Changes in the perfusion index typically become visible about 5 to 15 minutes after ingestion. The perfusion index change, which indicates a change in glucose level, can offer several advantages, as a stable state can be used as a reference value, allowing a single perfusion index measurement to be used to derive the change in blood glucose.

[0017] It was further observed that changes in the perfusion index also depend on the wavelength at which the perfusion index is measured. In other words, similar to SpO2 measurements, the ratios also change for different wavelengths. This observation has significant implications for SpO2 measurements.

[0018] In particular, this means that approximately 10 minutes after glucose intake, the SpO2 measurement based on this table configuration may indicate an oxygen level that differs from the actual oxygen saturation. Since the glucose level directly influences SpO2 measurements, these can be improved by taking the glucose level into account or at least compensating for the portion of the SpO2 measurements that may be caused by changes in glucose levels over time.

[0019] The inventor proposes several different approaches for this. In some aspects, a method for determining blood oxygen saturation is proposed. The proposed method is based on the aforementioned measurements for determining perfusion but has been adapted to compensate for possible fluctuations due to glucose uptake. For this purpose, a first perfusion index is determined based on the reflected first component of an incident first light beam with a first wavelength. Similarly, a second perfusion index is obtained based on the reflected second component of an incident second light beam with a second wavelength.

[0020] Both components can be obtained, for example, by shining the respective light beam onto human tissue and then collecting the reflected light. The emission of the respective light beams can be periodic, for example, in the form of numerous light pulses, e.g., with a frequency of more than 10 Hz and, for example, in the range between 20 Hz and 100 Hz. The high frequencies are significantly faster than the heartbeat, which allows for the determination of a large number of samples that represent the heartbeat.

[0021] The multitude of signals generated by detecting the reflected components at different wavelengths of light are used to determine the respective wavelength-dependent perfusion indices. According to the proposed principle, the perfusion indices or the detected light components are adjusted to compensate for glucose uptake or other substances.

[0022] This is achieved by additionally determining a reflected third component of an incident third light beam with a third wavelength, where the third light beam is in a wavelength range that is less sensitive to oxygen saturation than the first and second light beams.

[0023] This step exploits the fact that light of certain wavelengths is essentially insensitive with respect to blood oxygen saturation, but otherwise strongly correlates with light of other wavelengths with respect to another substance. Consequently, this correlation is used to adjust at least one of the first and second perfusion indices in response to the obtained third component or a value derived from it.

[0024] The oxygen saturation, or a change thereof, from the at least one wavelength is then determined using one adjusted perfusion index and the respective other perfusion index. In an alternative solution, the oxygen saturation, or a change thereof, from the at least one wavelength is determined based on the perfusion indices of the first and second components, as well as the resulting reflected third component. The use of the third component is particularly advantageous because it eliminates the correlation between the first and second light beams with respect to blood saturation and other substances, such as glucose, that influence the measurement of blood oxygen saturation.

[0025] In several other aspects, the results can be further improved by emitting at least one of the light beams, and especially the first and second beams, or by detecting the respective light beams in a range close to the normal angle of incidence, i.e., in a range between 0° and less than 45°, for example, less than 35° or 30°. This improvement is facilitated by the fact that signal levels for higher angles (relative to the normal angle of incidence) outweigh those for lower angles. Therefore, higher angles of incidence and detection exhibit a different correlation with glucose concentrations and could thus be particularly detrimental for SPO measurements / applications.

[0026] More specifically, it was observed that at higher illumination and acquisition angles, the response of the perfusion index to changes in blood glucose concentration can be more pronounced at red wavelengths than at IR wavelengths, such that the ratio of ratios retains a glucose signature. This signature is largely absent in the ratio of ratios when the illumination and acquisition angles are restricted to near-normal angles of incidence.

[0027] The principle described above is not limited to SpO2 or oxygen saturation measurements. Rather, the observation leads to the conclusion that the refractive index of the liquid depends not only on the concentration of the dissolved substance (the one to be determined) but also on another dissolved component. In other words, the change in the refractive index is caused by fluctuations in the concentrations of the substance and the components. Depending on the combination, the fluctuations in the refractive indices can either cancel each other out or add up, resulting in a significantly distorted overall result.

[0028] Therefore, the inventor proposes a method by which the substance concentration in a sample comprising liquid containing particles is determined more generally, wherein the refractive index of the liquid depends on the concentration of the substance dissolved therein and the density of the particles in the liquid is essentially constant.

[0029] In a first step, a light beam with a first wavelength is shone onto the sample containing the liquid, and the first component of the light beam scattered by the sample is detected. Similarly, a second light beam with a second wavelength is shone onto the sample containing the liquid, and the second component of the second light beam scattered by the sample is detected.

[0030] Subsequently, a ratio of the perfusion indices of the first and second light components is determined, adjusting the calculation to compensate for any potential distortion caused by another substance. This adjustment is performed in one or more steps. For example, the perfusion indices of at least one of the first and second light components can be adjusted by a factor derived from a third light component of a third light beam with a third wavelength, which is scattered by the sample in response to the third light beam emitted onto the sample.

[0031] Alternatively, a perfusion index can be obtained based on a third light component of a third light beam with a third wavelength, which is scattered by the sample in response to the third light beam emitted onto the sample. This perfusion index is then used to adjust the perfusion indices of the first and second scattered light components.

[0032] Alternatively or additionally, at least one of the first and second light rays can be emitted in the range between 0° and 45°, and in particular between 0° and 35°, and especially at less than 30° of the normal. Likewise, at least one of the first and second light components can be detected in the range between 0° and 45°, and in particular between 0° and 35°, and especially at less than 30° of the normal irradiance. In some aspects, the overall angle between emission and detection should be less than 60°, and in particular less than 45°, with respect to the normal irradiance.

[0033] The substance concentration, or a change in the substance concentration, is then derived from the adjusted perfusion indices.

[0034] In some further aspects, the inventor proposes using the ratio of ratios, i.e., the ratios of two perfusion beams at two different wavelengths, to obtain the glucose concentration in a liquid containing particles, particularly blood. Consequently, in some aspects, one can emit two light beams with different wavelengths and obtain the respective components scattered within the sample. The two components are then processed to determine their respective perfusion indices, and the glucose concentration can be derived from the ratio of these indices.

[0035] In some aspects, the liquid contains at least two dissolved substances, one being the substance to be measured, for example, oxygen saturation, and the other an undesired substance. The latter—as mentioned above—affects the determination of the substance concentration to be measured. In particular, the particle-containing liquid in some cases includes a component, especially glucose, that affects the refractive index of the liquid. In some aspects, the scattering of the third light beam with the third wavelength is essentially insensitive to a change in the concentration of the substance dissolved in the liquid. Therefore, there could be a correlation between the third light beam and the concentration of the undesired component, but there is essentially no or only a very weak correlation between the concentration of the substance and the third light beam.

[0036] In some cases, the scattering of the first, second, and third light beams depends on the concentration of another substance dissolved in the liquid, in particular a component that affects the measurements of the substance concentration.

[0037] Several aspects concern detection and emission. In some cases, the first component, the second first component, and optionally the third first component are detected from essentially the same location on the sample. In other aspects, the location of the first, second, and optional third light beams striking the sample may differ. In some aspects, the angle of the incident light of one of the light beams or the angle of the reflected light of one of the components relative to the normal direction of incidence may differ from the angle of the respective other light beams and / or components. However, in some cases, it may be advantageous if the angle of the incident light beam and / or the angle of the respective reflected component with the longer wavelength is also smaller, i.e., closer to the normal.This is advantageous because it has been found that light rays with longer wavelengths have a stronger dependence on glucose and other substances in the blood, which can distort the measurement of blood saturation.

[0038] In some aspects, the third wavelength lies in the range between 500 nm and 550 nm. These wavelengths are in the green region of the visible spectrum, and light of this wavelength is not very sensitive to the concentration or saturation of oxygen in the blood. However, light of this wavelength correlates with light in other regions of the spectrum with respect to other substances such as glucose. Consequently, green-range light can be used to compensate when calculating the perfusion indices of light that is sensitive to blood saturation. For example, the correlation between green light and glucose can be used to subtract this value from one of the other light amplitudes.This principle can of course be generalized and applied to all measurements where the perfusion index of light of different wavelengths for a given substance concentration is distorted by another component.

[0039] In some aspects, the first light beam lies in the range between 580 nm and 650 nm, and thus in the red spectrum. The second light beam can lie in the infrared range with a wavelength of more than 670 nm. These two spectra are suitable for human tissue because the light can penetrate deeper layers under the skin.

[0040] Surprisingly, it has turned out that it is not necessary to perform two measurements to determine the concentration or change in concentration in a liquid. This applies not only to the glucose measurements mentioned above, but also to the SpO2 measurement.

[0041] Rather, one can define a reference value and then perform a single measurement. The substance concentration or its change can be derived from the reference value. Consequently, the inventor proposes a method comprising the steps to obtain a reference value that is associated with or corresponds to at least one scattered light component or a signal derived therefrom.

[0042] For example, one of the measurements is then replaced by the reference value, which can be determined in various ways before the actual measurement. In this context, it is understood that the reference value can encompass not only the intensity signal but can also refer to any other value from which the reference concentration of a substance or a signal to be subsequently processed can be meaningfully derived.

[0043] Consequently, the term reference value is to be understood as synonymous with any value from which the substance concentration or intensity signal can be derived. According to the proposed method, the substance concentration or a change in the substance concentration is derived from the changes between the reference value and the respective other intensity value or a value derived therefrom.

[0044] The reference value and the characteristics of a curve corresponding to changes in intensity signal with respect to substance concentration, SpO2 value, or blood glucose level depend on various factors. Therefore, these factors can be used to determine substance concentration. These include, among others, age, height, weight, sex, body mass index, and skin type. In particular, skin type can be used not only to adjust the processing of the respective intensity signals but also to adjust the wavelength of the emitted signals.

[0045] In some aspects, the reference value is a statistical value obtained as a general normalized intensity signal (independent of zero) from a large number of different previous measurements. These may take into account one or more of the parameters mentioned above to obtain a small range with a specific confidence level, i.e., 2σ or 3σ.

[0046] Several other aspects concern an optoelectronic device for determining the concentration of a substance in a sample containing a liquid with particles, in particular the oxygen saturation, although many other substances are also suitable. The optoelectronic device comprises a housing with an exit window and an optional inlet window, as well as at least one emitter unit arranged below the exit window. The at least one emitter is configured to emit a first light beam and a second light beam from the exit window onto the sample during operation.

[0047] The optoelectronic device further comprises at least one photodetector arranged below the entrance window. The at least one photodetector is configured to detect a first component scattered by the sample in response to the first light beam and a second component scattered by the sample in response to the second light beam. An evaluation unit is coupled to the at least one photodetector. It is configured to receive signals from the photodetector response of the first and second components. The evaluation unit determines a modulation depth of the respective first and second components and then determines the ratio of these two modulation depths.The evaluation unit is configured to determine the oxygen concentration, or a change thereof, or more generally, a change in the substance concentration in the sample from the changes between the first and second modulation depths.

[0048] In this respect, the modulation depth or perfusion index (PI) is characterized by the ratio of an alternating current component to a direct current component of the respective detected component. The alternating current component corresponds to a varying part of the detected component, and the direct current component corresponds to a substantially constant part. By evaluating these components and calculating their ratio, information about changes in substance concentration in the sample can be derived.

[0049] As an alternative to evaluation using two or more scattering components or the modulation depth, a reference value can be used. This requires only a single measurement to determine a substance concentration or a change in substance concentration in the sample. In this alternative, the control unit is equipped with a memory that stores one or more reference values. The control unit is further configured to determine a substance concentration or a change in substance concentration in the sample using the reference value and one of the first and second scattering components, the modulation depth, or their ratio, or values ​​derived therefrom.

[0050] The reference value, as mentioned above, is associated with or can correspond to various characteristics, including the scatter component, a modulation depth, or a signal derived from it. It can correspond to a normalized level, which may be individual, derived from a statistical value, or derived over a longer period, such as a long measurement time for the respective user. Furthermore, the reference value is associated with, or can correspond to, a function that links one of the aforementioned parameters to the perfusion index, a ratio of the two scatter components, the modulation depth, or other signal characteristics. Similarly, such a function can correspond to a function that links the aforementioned signals to the glucose level, the perfusion index, or other signal characteristics.

[0051] The reference value can be derived as mentioned above, i.e., individually for each person or from a multitude of measurements as a statistically normalized value or function. At least one of the following factors can be taken into account: body mass index, age, sex, height and weight, and skin type.

[0052] In some aspects, the emitter unit is further configured to emit a third light beam with a third wavelength from the exit window onto the sample, the third wavelength being chosen such that the third light beam is scattered by the sample essentially independently of the substance concentration. The at least one photodetector located below the entrance window can be designed to detect a third component that is scattered by the sample in response to the third light beam.

[0053] Consequently, the evaluation unit is configured to adjust at least one of the modulation depths and / or the ratio of both modulation depths in response to the detected third component. In other words, the additional third component is used by the evaluation unit to compensate for any dependence of the first or second component on the second substance in the sample. The third light beam can be located in the green region of the spectrum, specifically between 510 nm and 560 nm, or the value specified here.

[0054] In some other cases, at least one of the emission angles of one of the first, second, and third light rays, and the detection angle of the first, second, and third components, lies in the range between 0° and 35° with respect to the normal incidence direction of the sample. This aspect addresses the dependence between the angle of the incident or detected light and the respective wavelength. By limiting the angle to small values ​​with respect to the normal incidence direction, this dependence can be reduced.

[0055] In some aspects, the optoelectronic device further includes an optical barrier arranged within the housing, extending from the exit window towards the housing base, which is located between the emitter unit and the photodetector unit. This reduces stray light and improves the signal-to-noise ratio. Additionally, several structures can be arranged on the detector or the emitter to limit the radiation and detection characteristics, thereby achieving a deviation from a typical Lambertian property. For example, these structures can include a DBR or Bragg grating structure arranged on the at least one photodetector. Similarly, an aperture can be arranged on the at least one photodetector. One or more collimator lenses can be arranged on at least one of the emitter units and the at least one photodetector.All these aspects can be combined. Additionally, the emitter type can be changed, for example by using VCSELs, which already have a more limited radiation pattern.

[0056] To achieve a specific symmetry and compensate for irregularities on the sample surface, the emitter unit can have a ring-shaped configuration in some aspects, arranged around the at least one photodetector. Alternatively or additionally, the at least one emitter unit can be arranged around the at least one photodetector. The position of the photodetector and emitter can be exchanged as needed.

[0057] In some cases, the evaluation unit is configured to perform an FFT on the acquired first and second components to obtain their frequency spectrum. Any type of analog or digital low-pass or band-pass filter (if the component is converted to the digital domain) can be applied to the acquired components before or after the FFT is performed. The optional low-pass or band-pass filter includes a cutoff frequency below 100 Hz, and specifically below 50 Hz. The fundamental frequency peak in the respective spectra and / or their harmonics are obtained to derive information about the concentration of the substance.

[0058] In some alternative embodiments, the evaluation unit is further configured to calculate a moving average from the acquired first and / or second components and then subtract the calculated moving average from the respective acquired components before performing an FFT. This reduces outliers or other errors not caused by the variance itself.

[0059] In some other alternatives, the evaluation unit is configured to normalize the respective recorded first and second components. A maximum peak of the normalized component is then identified for the given duration. Additionally, a minimum value is identified next to the respective maximum peak, either before or after the peak. From this, the amplitude between the minimum and the maximum can be determined.

[0060] In some aspects, the optoelectronic device includes an emitter that can generate light of different wavelengths, including but not limited to red, green, and infrared. During measurements, these lights are emitted sequentially. Alternatively, the detector unit also includes multiple detectors, each fitted with a filter to allow light of a specific wavelength to pass through. In this respect, each filter on the photodetector unit can be designed to block ambient light.

[0061] Several other aspects concern the implementation of the optoelectronic device according to the proposed principle. In some aspects, the optoelectronic device also includes an optical barrier arranged within the housing and extending from the exit window towards the bottom of the housing, which is located between the emitter side and the photodetector unit. Such a barrier prevents light from the emitting light source from directly reaching the respective photodetectors.

[0062] In some other aspects, the emitter side and / or the photodetector unit includes an optical system designed to create a focal point on the sample. This maximizes the light reaching the sample and improves the signal-to-noise ratio. In some aspects, the focal point of the incident light generated by the emitter side is positioned away from a point from which outgoing light can be detected at a first angle by the photodetector unit. This reduces crosstalk during the measurement.

[0063] Although the optoelectronic device presented here is described only in terms of its functionality for determining substance concentration, it should be noted that various implementations are possible. In this respect, the control unit, the evaluation unit, or parts thereof need not be implemented within the housing itself, which contains the emitter and the detector, but can be located separately. In some aspects, the control and / or evaluation unit is implemented in a separate device at some distance from the housing itself. Communication between the emitter and the detectors and the control and / or evaluation unit, as described above, is enabled, for example, by wireless communication. This allows, for instance, the implementation of a master-slave configuration in which the control unit periodically requests measurements.Furthermore, the control unit and / or evaluation unit can be largely implemented in software, for example as an app running on a mobile device, while the remaining part of the detector system is implemented in a separate housing.

[0064] In some aspects, the housing (or more generally, the optoelectronic device) is designed as a ring, earphone, watch, or other wearable device that, in some respects, blends into the user's familiar environment and can be worn continuously. The ring, earphone, watch, or any other wearable device communicates with the control unit, a mobile device, or another device that implements the control unit. The ring, earphone, watch, or any other wearable can cover a significant portion of the user's skin, for example, by being wrapped around a finger, attached to both sides of the ear, and so on. It can contain multiple emitters and detectors at different locations, allowing measurements to be taken not just at one location, but at multiple locations simultaneously or sequentially.This allows skin irregularities or other problems to be overcome and the overall measurement quality to be improved.

[0065] Besides fixtures and handheld devices, other applications are possible. For example, the optoelectronic device can be implemented in medical devices or laboratory equipment, e.g., for testing and measurement purposes. These devices can, in turn, be stationary or mobile.

[0066] Further aspects concern mobile displays in which the optoelectronic device of the proposed principle is directly implemented. In such applications, the display LEDs, e.g., for the colors red and green, can be used as emitters according to the proposed principle. A finger is placed directly on the display surface and then illuminated by the display to receive the first and / or second signal. The proposed principle can also be implemented in VR or AR glasses and devices. Another application concerns safety issues, e.g., in certain work environments, but also in driving and similar situations. It is possible to implement such detectors according to the proposed principle in a car, e.g., on the steering wheel, to receive the intensity signals and their changes while driving. This would allow, for example, warnings to be issued to the driver about potential health hazards while driving. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Further aspects and embodiments according to the proposed principle will become clear with reference to the various embodiments and examples, which are described in detail in connection with the accompanying drawings, in which the Fig. 1A-1C show a simplified model of a scattering mechanism in a particle-containing liquid; Fig. 2 shows a first embodiment of a sensor arrangement according to some aspects of the proposed principle; Fig. 3 shows a second embodiment of a sensor arrangement according to some aspects of the proposed principle; Fig. 4 illustrates a test setup of a sensor arrangement according to some aspects of the proposed principle; Fig. 5 shows the perfusion indices obtained under red and infrared light for SPO2 determination; Fig. Figure 6 shows a diagram of the alternating current values ​​obtained at a wavelength of 940 nm for a variety of different angles; Fig. 7 shows a diagram for the direct current values ​​obtained at a wavelength of 940 nm for a variety of different angles; Fig. 8 shows the corresponding perfusion index for the previously obtained respective values; Fig. Figure 9 shows the sum of all angle measurements to illustrate some dependencies that point to some aspects of the proposed principle. Fig. 10 represents the relationship between perfusion indices and a reference measurement, in order to outline some aspects of the proposed principle; Fig. Figure 11 illustrates the ratio of the perfusion indices as a function of the angles of the incident and detected light; Fig. 12 shows the different perfusion indices for red and infrared light with large incident and detected light; Fig. 13 shows the correlation between light of the green spectrum and the ratio of the perfusion indices, which is suitable for compensating for the glucose influence during SPO2 measurements. DETAILED DESCRIPTION

[0068] The following embodiments and examples reveal various aspects and their combinations according to the proposed principle. The embodiments and examples are not always to scale. Likewise, various elements may be enlarged or reduced to highlight individual aspects. It is understood that the individual aspects of the embodiments and examples shown in the figures can readily be combined without contradicting the principle of the invention. Some aspects have a regular structure or shape. It should be noted that in practice, minor differences and deviations from the ideal form may occur without contradicting the inventive concept.

[0069] Furthermore, the individual figures and aspects are not necessarily depicted in the correct size, nor do the proportions between individual elements need to be essentially accurate. Some aspects are emphasized through magnification. However, terms such as "above," "over," "below," "under," "larger," "smaller," and the like are correctly represented in relation to the elements within the figures. Thus, it is possible to deduce such relationships between the elements based on the figures.

[0070] The Fig. Figures 1A to 1C illustrate a model for the conceptual propagation of light in a liquid and heterogeneous medium. The medium has a refractive index of n=1, as shown in Fig. Figure 1A illustrates this. The incident light IL, propagating through the liquid medium, is scattered by a solid object BC within the liquid. The object could be, for example, a blood cell if the liquid medium is blood plasma. However, the model, as well as the proposed principle explained later, is not limited to blood plasma but also includes any other scattering objects with a refractive index greater than 1 in a liquid medium.

[0071] In the case of Fig. In case 1A, where n=1 for the liquid medium and n>1 for the scattering body, the incident light IL is partially reflected by the scattering body BS, but also scattered forward to a large extent, as shown in the figure. The magnitude of the backscattering and forward scattering is based on the difference between the refractive indices in the liquid medium and the scattering object.

[0072] In Fig. In 1B, the refractive index of the liquid medium is the same, i.e., n = 1, while the scattering object now has a different refractive index, which corresponds to the refractive index of the medium (e.g., also n = 1). According to the conceptual propagation, this means that the incident light encounters no difference in refractive index between the scattering object and the liquid medium. Consequently, the incident light propagates through the medium and is not scattered by the object BC.

[0073] In Fig. At 1C, the liquid medium has a higher refractive index, n>1. Here, the refractive index of the scattering object is equal to 1, but more importantly, the refractive index of the scattering object is lower than the refractive index of the surrounding medium. Consequently, the situation is similar to that in Fig. 1A, where the incident light is partially reflected backwards and partially scattered by the object BC. The difference between backscattering and forward scattering is based on the differences between the respective refractive indices.

[0074] According to the model, the ratio of backscatter to forward scattering changes when the difference between the refractive indices changes. Such a variation in the refractive indices and the difference between the two indices occur when the concentration of a substance dissolved in the liquid medium changes. However, a change in the refractive index can also be observed depending on the properties of the particles themselves. This is the case in oxygen measurements, where oxygen is bound to red blood cells. The blood cells to which oxygen is bound behave differently and result in a slightly different scattering compared to red blood cells to which no oxygen or carbon dioxide is bound.The dependence on the refractive index changes therefore depends on the amount of oxygen bound to the red blood cells, which is called O2 saturation, but also on the wavelength of the incident light.

[0075] In the case of blood plasma, such a substance could be glucose, for example, but it could also contain other components or substances. Often, several substances have some influence on such changes, and furthermore, the influence of the substance concentration can also depend on the wavelength of the incident light.

[0076] Therefore, the refractive index of blood plasma varies with the concentration of dissolved oxygen and glucose and can consequently be used to assess the absolute and / or relative total concentration. However, due to its similar behavior, the concentration of each other substance must be known to compensate for the effect, which is also caused by various processes that lead to a change in the refractive index.

[0077] When measuring oxygen and / or glucose concentration in blood, it is assumed that the propagation of light from the light source to a light detector through the body's tissues and blood plasma leads to scattering and absorption of the light, with the light taking a random path through the tissue. Depending on the scattering properties of the tissue, the path from the light source to the detector can vary. In particular, scattering and absorption in tissue are wavelength-dependent, with higher absorption generally occurring at shorter wavelengths. Furthermore, the extent of scattering depends on the distance between the light source and the detector, as the resulting index contrast—that is, the difference in refractive indices between the blood plasma and the red blood cells—is modulated by the oxygen and / or glucose concentration.

[0078] Various detectors can be used for such measurements. Fig. 2 and Fig. Figure 3 shows an exemplary embodiment of such measuring devices, which are not only suitable for detecting and deriving a substance concentration in the blood, such as oxygen or glucose, but also for a variety of other measurements.

[0079] The detector device 1 in Fig. Figure 2 comprises a substrate S embedded in, or forming part of, a housing 10. The housing 10 also includes three light-emitting devices 11, 14, and 15 in the form of an optoelectronic component or a light-emitting diode (LED). The LEDs are configured to emit light of a specific wavelength through an exit window 12 on the top of the housing 10. For example, diode 11 emits green light or light in the green spectrum, diode 14 emits red light, and diode 15 emits light in the infrared spectrum. Although diodes 11, 14, and 15 are shown here as spaced apart, they are in fact located close together or centered around the position of photodiode 13, such that their distance d from photodiode 13 is approximately equal.The latter ensures that the light emitted by the respective LEDs, which is scattered through the tissue, ultimately reaches the photodiode at the same angle.

[0080] A barrier 16 is arranged between the respective LEDs and the photodiode to prevent light from the diodes from hitting the photodiode directly and from being scattered through the tissue.

[0081] An entrance window with a corresponding filter element is positioned in front of each photodiode 13. The filter element is transparent to the wavelengths of the light-emitting diode 11, but otherwise exhibits high absorption or reflection for wavelengths outside the respective frequency band. The entrance windows reduce the amount of ambient light detected by the respective photodiode 13 during the measurement cycle. In an alternative embodiment, or additionally, the photodiode 13 can be sensitive to the wavelength but otherwise insensitive. The housing 10 further comprises a control and evaluation circuit 30, which is connected to the light-emitting component and the associated directional components.

[0082] Fig. Figure 3 shows a similar embodiment of a detector device according to the proposed principle. The one in Fig. However, the detector arrangement shown in Figure 3 has a first light-emitting component 11 and a second light-emitting component 14 arranged directly adjacent to each other. It can comprise a single device with a broader emission spectrum covered by two or more corresponding wavelength filters. Similar to some other embodiments, the light-emitting components can form an annular structure centered around the photodiode. The barrier 16 prevents direct light from diodes 11 and 14 from reaching the photodiode. Additionally, the surface of the photodiode 13 is covered with a DBR structure that prevents light with an angle of incidence smaller than a threshold value from the normal direction of incidence from reaching the surface of the photodiode. Consequently, only scattered light that is substantially perpendicular (or exhibits only a slight deviation from it) reaches the photodiode 13.

[0083] The in the Fig. 2 and Fig. The length of the beam path D1, D2 shown in Figure 3 results from the path the light travels from the point on the sample surface where the incident light strikes to the point where the exiting light is detected. For accurate measurements, the shape and structure of the top of the housing, particularly the exit window in front of the light-emitting components 11 and 14 and the entrance window in front of the detection component 13, should be designed to be essentially opaque when a sample is placed on the respective windows. If the sample is compressible, it should be pressed lightly onto the respective windows to further reduce the penetration of incident or ambient light into the light-detecting components. Similarly, the exit window is positioned close to the sample to prevent ambient light from entering the entrance area on the sample surface.

[0084] It is suitable if the difference between photodiode 13 and light emitters 11 and 14 is essentially the same, in order to avoid possible effects due to different optical path lengths through the tissue. Alternatively, a different length can be taken into account when calculating the respective ratios for the perfusion indices.

[0085] It should be noted that the positions of the photodiode and the LEDs can be interchanged and that more than one photodiode can be positioned on the sensor. Since the proposed principle evaluates light intensity ratios and not absolute light intensities, it is sufficient to consider the known and measurable distances between the LED and the photodiode that receives the light from the LED.

[0086] Fig. Figure 4 shows a test setup to illustrate various aspects of the proposed principle, including the dependence of the perfusion index on the angle of incidence. The in Fig. The test setup 1A shown is applied to the skin surface of a person to be diagnosed. The essential components of the detector setup are listed again here by way of example. The skin surface is marked with the reference symbol 6 and is, for example, part of a finger or another area of ​​skin. For this purpose, the test setup includes a frame 3 with a window 7, which is placed on the skin surface as close to the light as possible and pressed lightly against it. The seal with the skin prevents (or at least reduces) stray light from entering the measuring detector during the measurement process and thus leading to a poorer signal-to-noise ratio.

[0087] As explained above, the test setup comprises a measuring transmitter ME in the form of several LEDs and a reference transmitter RE in the form of several LEDs. These LEDs for the reference and measuring transmitters can be controlled separately and are configured to emit light in the green, red, and infrared spectrum. Optics O1, each comprising an aperture and a downstream focusing optic, are positioned in front of both the measuring transmitter ME and the reference transmitter RE. The optics O1 are designed to project a substantially common focal point onto the skin surface 6 within an area SE that can be illuminated by both the measuring transmitter and the reference transmitter RE. A common focal point is not strictly necessary but is useful to avoid measurement differences due to irregularities at different measurement sites.

[0088] On the receiver side, a measuring detector MD and a reference detector RD are arranged. Each of these two detectors is also preceded by a second optical system O2, which in turn comprises an aperture and one or more focusing lenses. The arrangement of the two detectors MD and RD and the preceded optical system O2 is chosen such that their respective detection points on the surface of skin 6 are located in the region SD. The three detectors comprise one or more photodiodes that are sensitive to the light emitted by the reference and measuring detectors.

[0089] Depending on the angle, the light emitted from this area strikes either detector MD or detector RD. Areas SE and SD are spatially separated by a slight distance of a few millimeters. Additionally, an optical barrier 4 is provided within the detector assembly between the emitter side and the detector side. This barrier extends from window 7 into detector assembly 1A and serves to prevent crosstalk of light from the measuring emitter or the reference emitter to the respective detectors.

[0090] The arrangement on the emitter side, with the measuring emitter ME and the reference emitter RE, is designed such that a measuring light beam generated by the measuring emitter strikes the measuring area SE of the skin s on the skin surface 6 at an angle α. The angle α is measured relative to the skin surface or the surface of the window 7 placed on the skin. Thus, the angle of incidence is 90° - α to the normal. For the reference emitter RE, the angle α is much larger and close to 90°, so the angle to the normal is small, in the range between 5° and 15°. Consequently, the reference emitter RE emits a reference light beam that strikes the area SE at a relatively steep angle of over 80° and approximately 90° (relative to the skin surface). In other words, the reference emitter is positioned so that the light it generates strikes the area SE to be illuminated essentially perpendicularly.

[0091] Similarly, the measuring detector MD and the reference detector RD are positioned at different angles to the normal. The measuring detector MD is arranged such that the light scattered from the area SD enters the measuring detector MD at a shallow angle α' in the range between 25° and 45°. In contrast, the reference detector RD primarily detects light that is backscattered substantially perpendicular to the skin surface and the surface of window 7. In a particular embodiment, the emitters and detectors are arranged symmetrically around an axis through the optical barrier, which in turn lies along a normal to the window and the skin surface, respectively. This means that the measuring emitter and the measuring detector each have the same angle to the normal as the reference emitter and the reference detector.

[0092] Since the light rays penetrate the sample and the substance to be measured may be located within the sample and not on the surface, such an approach seems appropriate. Indeed, for glucose measurements in body parts, it has been shown that a certain distance between the SE and SD regions improves the measurement result. This effect can be explained, in part, by the effective suppression of light reflected from the surface, thus improving the signal-to-noise ratio. The light emitted by emitters ME and RE penetrates the SE region and interacts with the blood there in the manner described here. The light entering the detectors with this wavelength has thus propagated through the tissue, significantly increasing the probability of interaction with blood.

[0093] The test equipment according to Fig. Device 3 is used to perform SpO2 measurements, but can also be used for oral glucose tolerance tests. The light emitted into the tissue comprises three main wavelengths: 520 nm, 637 nm, and 940 nm. The signals are pulsed at a frequency between 20 Hz and 50 Hz and processed accordingly. The different wavelengths of light are emitted sequentially.

[0094] The determination of oxygen saturation, referred to as SpO2 measurement, is based on the ratio of the PPG signals recorded at red and IR wavelengths, in this case at 637 nm and 940 nm. Specifically, the ratio of the perfusion indices at the two wavelengths is determined by illuminating the tissue with short light pulses at a sufficiently high repetition rate, in this case 200 Hz, and then sampling the corresponding photocurrent generated in the photodiode.

[0095] The raw current of the photodiode consists of an average signal level, the so-called DC level, and a modulation of the signal due to the heartbeat, the so-called AC level. The AC signal can be estimated, for example, by the difference between the peaks and troughs of the raw signal. The perfusion index (PI), or relative modulation, or modulation percentage, is derived from the ratio of AC to DC current. Fig. Figure 5 illustrates the two different signals over time. The relative modulation for red light is approximately 0.75%, measured at the fingertip.

[0096] Similarly, the relative modulation for IR light is approximately 2%. To estimate oxygen saturation, the ratio of the relative modulations is calculated, which is referred to as the ratio of ratios; in this example, the result is approximately 0.375. An oxygen concentration level is assigned to this value by calibration with a reference device. In the embodiments, 0.375 is assumed to correspond to nearly 100% oxygen saturation for the present arrangement.

[0097] However, it should be noted that the ratios for a given oxygen saturation generally depend on decisions regarding the optical design, in particular the relative distance between the light source and the detector for each wavelength, the emission characteristics of each light source, the detection characteristics of the photodiode, and the performance of the optical barrier between sources and detectors, as well as other system aspects that influence how light can propagate from a source to a detector. Therefore, with a given device, such as the sensor described in the figures above, the sensor can be calibrated before subsequent measurements.

[0098] Fig. Figure 6 shows the result of an oral glucose tolerance test (OGTT) at different angles of incidence and detection compared to a reference glucose measurement. The reference curve, labeled "reference" in Figure 6, represents the glucose measurement. Fig. Test 8 is performed after several hours without food intake. The baseline value in this example is 88 mg / dL, as determined using an Abbott Freestyle Libre 3® reference device. The reference device is read once per minute during the OGTT.

[0099] At 9:58 a.m., the test subject consumes a glucose-containing meal. These meals can vary but generally contain a high amount of glucose to illustrate the effect. In previous measurements, particularly regarding the reference measurement, it was observed that fluctuations in the baseline value can occur shortly after food intake. Therefore, the drop in the reference value between 10:00 and 10:15 a.m. could be a natural fluctuation of the reference device or a phenomenon caused by the digestion of the glucose-containing food. For example, the human body must first use some of the glucose available in the blood to obtain the digested glucose. Approximately 15 minutes after food intake, the reference glucose level begins to rise, with the peak glucose concentration being reached about 35 minutes after food intake, reaching a maximum value of 128 mg / dL at 10:33 a.m.After reaching its peak, the glucose concentration gradually decreases over the next 45 minutes and stabilizes near the baseline value of 86 mg / dL. In addition to the reference measurement, our benchtop device was used to measure [the parameters listed in the original text]. Fig. A PPG measurement was performed over 10 seconds using the test equipment shown in Figure 4. The setup allows for different angles between the emitted incident light and the detected light. These are designated E5° and E65°, corresponding to the angular arrangement of the reference emitter RE (E5°) and the measuring emitter (E65°) with an incidence angle of 5° and 65°, respectively, measured relative to the surface normal. The detectors RD and MD are designated D35° and D65°, respectively. The measurements were performed at a sampling rate of 200 Hz, with interleaved measurements using emitters ME and RE for the different wavelengths and a pulse width of <100 µs for each illumination event. The light is detected by a photodiode located at the position of detectors RD and ED.

[0100] As described above, all four permutations of the reference and measurement channels are performed for the three available wavelengths. This provides data over the emission and detection angle range described above.

[0101] The DC and AC components are then separated from the raw signal. Fig. Figure 6 shows the AC coefficients of the raw signal in counting units for the wavelength 940 nm (IR) along with the glucose reference measurements (the corresponding y-scale is on the right axis). The AC signal increases with increasing glucose concentration for all channel permutations. However, the signal levels differ for the various angles, with higher emission angles producing larger AC signals.

[0102] In Fig. Figure 7 shows the corresponding DC levels, demonstrating that the E65° / D65° channel combination generates a signal approximately three times stronger than the E5° channels. In other words, incident light produces weaker DC signals when it is closer to the normal value. This behavior is not only observed in the Fig. The phenomenon is observed not only at the infrared wavelength shown in Figure 7, but also at other wavelengths, albeit to a lesser extent. According to the scattering model, this behavior can be attributed to the (forward) scattering property of tissue. The Fig. The results shown in Figure 7 also demonstrate that when integrating over a Lambertian emitter, higher angles relative to the normal case (e.g., 90° - α > 45°) lead to a higher weighting for these angles.

[0103] The larger angles also point to another phenomenon. It appears that as blood glucose levels rise (and the scattering decreases as a result), the DC value also decreases, and vice versa.

[0104] To obtain the perfusion index for the respective measurements at different angles and for a wavelength of 940 nm, the ratio of the AC values ​​to the DC values ​​is calculated. The result is in Fig. Figure 8 shows the perfusion index for each of the four angle combinations. At low angles of incidence, e.g., the E5° channels on RD, the correlation is somewhat stronger than at higher angles. The AC component, as seen in the previous figure, increases with increasing glucose concentration, while the DC component decreases. Compared to the reference measurement, the sensitivity of such a measurement for the E5° channels on RD is approximately a factor of 3; that is, a 50% change in glucose leads to a change in the perfusion index, determined using the proposed method, by a factor of 3. In contrast, the correlation is weakest for the E65° / D65 combination, which corresponds to an angle of 65° to the normal.

[0105] In typical measurement systems, it can be assumed that both the emitter and the detector exhibit Lambertian radiation and detection characteristics. Therefore, the angle measurements obtained during an OGTT, as shown in the preceding figures, can be used to approximately emulate such a measurement system by summing all AC coefficients or all DC coefficients, and then dividing the sum of AC coefficients by the sum of DC coefficients for red and IR wavelengths. The results are shown in Fig. 9 shown.

[0106] The perfusion index for the red and infrared spectrum shows a strong correlation with the glucose reference value, which can also potentially influence SpO2 measurement. Therefore, it is useful to consider the ratio of the two curves and determine whether the glucose correlation cancels out. At the beginning of the measurement, the perfusion index measured with infrared light (IR) is approximately 50% higher than with red light (RED), while at the peak of the glucose test, around 10:35 AM, the difference has decreased to about 20%. Consequently, the glucose correlation does not completely cancel out of the perfusion index at different wavelengths, and therefore not out of the ratio used for SpO2 measurement.

[0107] In other words, an SpO2 measurement using a Lambertian emission or detection property at red and infrared light will be distorted if glucose is ingested during the measurement. This result can also apply to non-Lambertian properties or other wavelengths. Therefore, some form of compensation must be considered when determining oxygen saturation. These results are also discussed in Fig. 10 clearly.

[0108] The figure shows the ratio of the perfusion indices PI_RED / PI_IR. Before glucose intake and the oral glucose tolerance test, the ratio is approximately 0.6. After feeding, however, the ratio increases to approximately 0.95, which is much closer to ~1. Such a change in the ratio during an SpO2 measurement would normally indicate a significant drop in oxygen saturation. Given the measurement approximately 35 minutes after feeding, the SpO2 measurement, based on this table configuration, would indicate a falsely low oxygen saturation, even though the oxygen saturation was not altered by external means, such as increasing the pressure of the test environment or decreasing the oxygen concentration of the ambient air, or by internal means, i.e., different respiration.

[0109] Fig. Figure 11 illustrates a possible reason for this. The figure shows the ratios for different angle combinations. It appears that the PI_RED / PI_IR ratio for the E65° / D65° and E65° / D35° combinations exhibits a strong glucose signature compared to the other settings. Combined with the observation that signal levels for higher angles outweigh those for lower angles, it can be concluded that higher angles of incidence and acquisition correlate more strongly with glucose concentrations. They distort all SpO2 measurements if not accounted for or compensated for. As a solution to this problem, it is proposed to restrict the illumination and acquisition angles to suitable ranges closer to the normal angle of incidence. Suitable ranges lie between 0° and 35°.

[0110] This aspect is also addressed by the in Fig. Figure 12 confirms the result shown, which displays the perfusion index for red and infrared light at an emission angle of 65° (E65°) and a detection angle of 65° (D65°). The infrared perfusion index does not appear to respond as strongly to changes in glucose concentration as the red perfusion index. As a solution, the setup for SpO2 or other measurements is configured to eliminate only the higher angles of light in the infrared spectrum. For example, an infrared VCSEL with a narrow emission characteristic can be used and combined with an illumination diode in a single measurement system. Alternatively, red and infrared VCSELs, both with narrow emission characteristics, can be used for SpO2 measurements.Similarly, as described in the embodiments above, the detector can use distributed Bragg gratings, suitable apertures at a distance above the PD, lenses, or other elements to limit the angle of the detected light. Another alternative or addition is to place collimating lenses over the LEDs.

[0111] In addition to mechanical compensations, it has been observed that green light is not sensitive to blood oxygen saturation. Fig. Figure 13 shows the perfusion index for green light during the oral glucose tolerance test and shows a fairly good correlation with the ratio of the perfusion indices for red and infrared light. Consequently, light of a third wavelength, which is not sensitive to blood oxygen but correlates with blood glucose concentration, can be used to break and compensate for the correlation for red and infrared wavelengths. REFERENCE MARK LIST 2 fingers 4 Locking barrier 5, 6 Skin surface 7 windows 10 substrate 11 emitter LEDs 13 Detector, photodiode 14,15 transmitters, LED 16 barrier 20 Detector, photodiode 30 Control circuit RE, ME Emitter RD, MD Detector O1, O2 optical elements D1, D2 optical path BC blood cell S substrate SE, SD area QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] DE 10 2023 113

[0001] Zitierte Nicht-Patent Literature

[0000] In Vivo Reflectance of Blood and Tissue as a Function of Light Wavelength“, Weijia Cui et al., IEEE Transactions on Biomedical Engineering, Band 17, No. 6. June 1990

[0013] .

Claims

[1] Method for determining a substance concentration in a sample comprising liquid containing particles, in particular oxygen in blood, wherein a refractive index of the liquid depends on a concentration of the substance dissolved therein and a density of particles in the liquid is essentially constant, comprising the steps: - Emitting a first light beam with a first wavelength onto the sample containing the liquid and detecting a first light component of the first light beam that is scattered by the sample; - Emitting a second light beam with a second wavelength onto the sample containing the liquid and detecting a second light component of the second light beam that is scattered by the sample; - Determining the ratio of the refractive indices of the first light component and the second light component - where the step of determining includes the following step: - Adjusting the perfusion indices of at least one of the first light component and the second light component by a factor derived from at least one of the following factors: - a third light component of a third light beam with a third wavelength, which is scattered by the sample in response to the third light beam emitted onto the sample; - a perfusion index obtained by a third light component of a third light beam with a third wavelength, which is scattered by the sample in response to the third light beam emitted onto the sample; - Emit at least one of the first and second light rays and / or detect at least one of the first and second light components in the range between 0° and 45° and in particular between 0° and 35° and in particular less than 30° of the normal; - Deriving the substance concentration or a change in substance concentration from the adjusted perfusion indices. [2] Method according to claim 1, wherein the liquid containing particles comprises a component, in particular glucose, which affects the refractive index of the liquid. [3] Method according to one of the preceding claims, wherein the scattering of the third light beam with the third wavelength is essentially insensitive to a change in the concentration of the substance dissolved in the liquid. [4] Method according to any of the preceding claims, wherein the scattering of the first light beam, the second light beam and the third light beam depends on a concentration of another substance dissolved in the liquid. [5] Method according to any of the preceding claims, wherein the first component, the second first component and the third first component are detected at substantially the same location on the sample. [6] Method for determining the oxygen saturation in the blood, comprising the following steps: - Obtaining a first perfusion index based on a reflected first component of an incident first light ray with a first wavelength; - Obtaining a second perfusion index based on a reflected second component of an incident second light beam with a second wavelength; - Obtaining a reflected third component of an incident third light beam with a third wavelength, wherein the third light beam is in a wavelength range that is less sensitive to oxygen saturation than the first and second light beams; - Adjust at least one of the first and second perfusion indices in response to the obtained third component or a value derived from it; - Determining the oxygen saturation or a change thereof from at least one adjusted perfusion index and the other perfusion index. [7] Method according to one of the preceding claims, wherein the third wavelength is in the range between 500 nm and 550 nm. [8] Method according to one of the preceding claims, wherein the first light beam is in the range between 580 nm and 650 nm. [9] Method according to one of the preceding claims, wherein the second light beam is in the infrared range with a wavelength of more than 670 nm. [10] Optoelectronic device for determining a substance concentration in a sample containing a liquid with particles, in particular the oxygen saturation, comprising: - a housing with an exit window and an optional entry window; - at least one emitter unit arranged below the exit window and designed to emit a first beam of light with a first wavelength and at least one second beam of light with a second wavelength from the exit window onto the sample; - at least one photodetector arranged below the entrance window, designed to detect a first component scattered by the sample in response to the first light beam and a second component scattered by the sample in response to the second light beam; - an evaluation unit that is coupled to the at least one photodetector and is designed to, - to determine a modulation depth for the respective first and second components; and - Determination of a substance concentration or a change in the substance concentration in the sample from changes in the ratio of the first and second modulation depths. [11] The optoelectronic device according to claim 10, wherein the emitter side is further configured to emit a third light beam with a third wavelength from the exit window onto the sample, wherein the third wavelength is selected such that the third light beam is scattered by the sample substantially independently of the substance concentration; and optionally, the at least one photodetector arranged below the entrance window is configured to detect a third component that is scattered by the sample in response to the third light beam. [12] Optoelectronic device according to claim 11, wherein the third light beam is in the green region of the spectrum, in particular between 510 nm and 560 nm. [13] Optoelectronic device according to one of claims 10 to 12, wherein at least one of the emission angles of one of the first, second and third light rays and the detection angle of the first, second and third component is in the range between 0° and 35° with respect to the normal direction of incidence of the sample. [14] The optoelectronic device according to any one of claims 10 to 13, further comprising at least one of the following elements: - an optical barrier arranged in the housing and extending from the exit window towards the bottom of the housing, which is located between the emitter unit and the photodetector unit; - a DBR structure arranged on the at least one photodetector; - an aperture arranged on the at least one photodetector; - one or more collimator lenses arranged on at least one of the emitter unit and the at least one photodetector; - one or more VCSELs as part of the emitter unit. [15] The optoelectronic device according to any one of claims 10 to 13, wherein the emitter unit has a ring-shaped form arranged around the at least one photodetector; or wherein the at least one emitter unit is arranged around the at least one photodetector.

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