The present application claims priority of German patent application DE 10 2022 118 082 . 4 dated July 19 , 2022 , the disclosure of which is incorporated herein by reference in its entirety .

The present invention relates to a method for determining a substance concentration in sample containing particles in a liquid, in particular glucose in blood, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein . The invention also relates to a detector device .

BACKGROUND

The current standard for blood glucose measurement often uses an invasive technique in which a small amount of blood is drawn, and subsequent electrochemical analysis is performed using a handheld device . This method is not suitable for continuous monitoring because for each measurement , the finger must be pricked to obtain a fresh blood sample .

A more recently developed technology uses a button that sits on the skin and misses interstitial fluid in parts of the subcutaneous adipose tissue with a small , needle-like sensor . However , the needle penetrates permanently into the skin .

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

In this respect , there is a need for a method that can detect a substance in a liquid in a simpler way and allows for a continuous measurement .

SUMMARY OF THE INVENTION This and other obj ects are addressed by the subj ect matter of the independent claims . Features and further aspects of the proposed principles are outlined in the dependent claims .

Complementing some other ideas that are based on an angle dependent scattering, the present idea relies on the evaluation of the modulation depth, also referred to as perfusion index , which has been found by the inventors to also depend on the blood glucose concentration .

The perfusion index or modulation depth is a result during so-called Photoplethysmography, i . e . , the optical measurement of volume changes of human blood, e . g . , due to the beating of the heart , at a certain point of the human body, for instance the fingertip, or some other suitable location . The volume changes are observable by signal variations during the heartbeats resulting from less or more scattering based on the different blood volume .

Due to scattering and absorption of light , which is initially directed towards the skin and may subsequently propagate through portions of shallow- and/or deeper lying tissue , which in turn hosts a network of blood vessels , the amount of light that re-emerges at the skin-to- ambient interface some distance from the entry point will vary according to the optical path length ( distance ) travelled in blood . The path length is referred to as "blood optical path length ( BOPL ) , " which in turn is directly affected by the beating of the heart . Consequently, the BOPL varies with time , while the properties of surrounding portions of tissue can be considered constant , at least on the timescale of the heart rate .

When the BOPL is at a maximum or minimum, the emerging signal after interaction is conversely at a minimum or maximum. The difference between minimum and maximum signal is called modulation, and the ratio of modulation to average signal is defined as modulation depth, ac-to- dc ratio , or perfusion index .

According to Beer-Lambert ' s law, the absorption of light in blood is largely determined by the presence of Hemoglobin within the erythrocytes , as well as the cumulative BOPL . Under the assumption that the density of erythrocytes does not change during the measurement period, one can say that light propagating nominally through the more or less transparent blood plasma , undergoes scattering at the red blood cells , such that the cumulative BOPL from entry point to detection point , both of which are fixed by the device configuration, may depend on the scattering characteristics in the sense of a random walk, i . e . , it will become a stochastic process .

Consequently, the perfusion index or modulation depth is primarily a result of the direct interaction and particularly the scattering between light and erythrocytes . It has now been observed that for a human test subj ect under steady-state conditions and constant blood glucose levels , the perfusion index remains substantially constant . This characteristics may inherit some benefits , as one can use a steady state as a reference value , such that a single measurement of the perfusion index allows to derive a blood glucose change therefrom. When the blood glucose level increases , the properties of the blood plasma and more particularly the refractive index of the plasma changes . As a result , the difference between the refractive indices of the erythrocytes and the blood plasma decreases , which will cause a decreases of scattering light . Likewise , a decrease in the glucose increases the difference between the refractive indices of the erythrocytes and the blood plasma causes an increase in scattering .

This is explained in a model , in which scattering is mainly caused by diffraction differences , thus in a transparent medium, in which the refractive indices of the liquid and the scattering particles were the same , no scattering would be observable , since light would simply propagate through the medium without interaction . However , once there is an index mismatch, some light is being scattered ( e . g . , backwards ) by the particles and thus can be distinguished from the surrounding ambient , i . e . , plasma .

The effect is observable not only for glucose , but generally for any substance in a liquid containing particles , whereas the particle size is approximately in the wavelength of the light and the substance concentration influences the refractive index of the liquid . A s killed person will therefore understand that the principle disclosed herein with regards to Photoplethysmography, and glucose measurement can be applied in a more general way and implemented for various kinds of measurement determining the concentration of a substance in a particle containing liquid .

In case of glucose in blood or more generally any varying substance in blood affecting the refractive index of the blood plasma will cause a variation of the perfusion index during Photoplethysmography . This is due to the different BOPL that result in different scattering , which in turn are dependent on the substance concentration in the blood . Hence , an increase of the blood glucose level causes an increase of the PI and, conversely, when the blood glucose level decreases , the PI also subsides , resulting in a direct correlation of the optical AC-to- DC ratio of Photoplethysmography and blood glucose concentration . It is observed that an increase in modulation depth due to glucose in the plasma corresponds to an effective increase in the difference between maximum and minimum BOPL .

The observation holds for different wavelength of the incident light and the correlation exists for green, red, and near-IR wavelengths . In fact , the mechanism is observable for a relatively wide range of wavelengths from the visible to NIR portions of the spectrum, in agreement with Lorenz-Mie scattering theory .

Consequently, evaluation of changes and variations of the PR or the modulation depth in Photoplethysmography over a longer period of time provides an opportunity for detecting -- non-invasively and directly - - the properties of blood only, without many of the complications arising from signals originating within the interstitial fluid and other layers or portions of tissue and skin .

In an aspect , a method for determining a substance concentration in a sample comprising liquid containing particles is proposed . A refractive index of the liquid is dependent on a concentration of the substance dissolved therein and a density of particles in the liquid is substantially constant . The method comprises the step of emitting a first light beam of at least one wavelength onto the sample containing the liquid during a first duration and detecting a first light component scattered by the sample during the first duration . A first modulation depth of the detected first light component is determined therefrom during the first duration .

Furthermore , a second light beam of the at least one wavelength is emitted onto the sample containing the liquid during a subsequent second duration . Portions of the light are scattered by the particles in the sample and detected as a second light component during the second duration . As for the first components , a second modulation depth of the detected second light component during the second duration is obtained .

The substance concentration or a change in the substance concentration is now derived from the changes between the first and the second modulation depths . Due to the possibility of a continuous measurement , concentration changes in the liquid can be observed almost instantaneously . This allows not only to act quickly in case the concentration exceeds a dedicated threshold, but also provide longterm non-invasive measurements .

It has nonetheless surprisingly found that it is not necessary to conduct two measurement to obtain the concentration change in a liquid . Rather, one can define a reference value and then conduct a single measurement . Using the reference , one is able to derive the substance concentration or changes thereof . Consequently, the inventor proposes a method comprising the steps of obtaining a reference value associated with or corresponding to at least one of a first modulation depth, a perfusion index , in particular associated with a first modulation depth, or a function linking the perfusion index with the modulation depth or linking the substance concentration to a modulation depth or a signal derived therefrom.

The first measurement is then replaced by the reference value , which can be obtained by several means prior to the actual measurement . In this regard, it is understood that the reference value may comprise not only the perfusion index or some reference glucose level ( e . g . in the range of 85 mg/cl to 115 mg/cl ) but can also refer to any value , from which the reference concentration of a substance can be derived . Consequently, the term reference value shall be understood as being equivalent to any value from which the substance concentration can be derived .

In accordance with the proposed method, the substance concentration or a change in the substance concentration is derived from the changes between the reference value and the second modulation depth or a value derived therefrom .

The reference value and also characteristics from a curve corresponding to the change of the perfusion index in relation to the substance concentration or the blood glucose level are dependent on various factors . Hence , one may utilize those factors , when obtaining the substance concentration . These include , but are not limited to the age , size , weight , gender , body mass index and skin type . Particularly skin type can be used not only to adj ust the processing of the respective modulation depths , but also adj ust the wavelength of the emitted signals .

In some aspects , the reference value is a statistical value obtained as a general normalize substance concentration ( different from zero ) form a plurality of different previous measurement . Those may take one or more of the above parameters into account to obtain a small range with certain confidence level i . e . 2o or 3o .

There are different possibilities to obtain the modulation depth or the PI when evaluating an Photoplethysmography measurement . In some instances , a fast Fourier transformation or FFT is performed on the respective detected components to obtain a frequency spectrum thereof . For this purpose , a low-pass or bandpass filter is applied to the respective detected components prior to performing the FFT . Alternatively, a low-pass or bandpass filter can also be applied on the transformed components , that is on the spectra . In this regard, the filter may comprise a cut-off frequency below 100 Hz and in particular below 50 Hz . The fundamental peak or the harmonics and their respective amplitude provide information about the PI .

In some additional aspects , a moving average from the detected first and/or second components can be calculated and used for further processing and in particular as input for filtering and the FFT , in some further aspects , the obtained moving average is subtracted from the respective detected component prior to performing an FFT . This will smooth the system and remove or at least reduce the influence of outliers .

In an alternative approach, one may normalize the respective detected first and second components in the time domain . A DC part can be subtracted from the detected components in the analogue domain to obtain a better signal to noise ratio prior to an AD conversion . Of course , the DC component can also be subtracted from the digital signal corresponding to first and second component . Alternatively, normalizing can also be achieved in the digital domain .

Then, minimum "peaks" and a respective maximum peak ( one or more ) adj acent to the minimum are identified in the respective duration . Minimum and maximum correspond to the heartbeats in the particular case of a PPG measurement . In some aspects , the minimum and maximum peak are adj acent to each other , i . e . each minimum peak is associated with an adj acent maximum peak and vice versa . Consequently a minimum may follow its associated maximum or vice versa . The amplitude between the associated minimum and the maximum is then derived and corresponds to the PI .

In some instances , the obtained amplitudes during the first duration are averaged to reduce possible errors in a single measurement . One may also utilize certain factors to adj ust to the skin type or other parameters . By doing so , it is assumed that the derived amplitudes do not change under the influence of substance concentration during the first duration . Hence , the first duration may be chosen to be short enough to avoid influence of substance concentration change but long enough to allow for averaging or other pre-processing step reducing the error in the measurement .

In yet another alternative , the modulation depth is characterised by a ratio of an AC portion and a DC portion, whereas the AC portion corresponds to a varying component part of the respective detected component and the DC portion corresponds to a substantially constant component part of the respective detected component .

Utilizing the ratio of AC and DC portions provides the possibility to reduce variations from the light source or other errors not caused by the scattering and the sample itself .

In some aspects , the first and second light beams are emitted onto the sample under a first angle . The first and second light component can be detected under the same angle , but also under a second angle , wherein the first and second angles are different . For example , the first angle may be rather large with regards to a reference normal to the surface of the sample , while the second angle is lower .

In some possible aspects , first angle with respect to a normal to a surface of the sample is greater than 35 ° and in particular greater than 45 ° but smaller or equal to 60 ° ; and/or wherein the second angle with respect to a normal to a surface of the sample is less than 35 ° and in particular less than 20 ° . Other typical first and second angles are in the range between 5 ° and 50 ° . In some other aspects , an angle between the emitted first and/or second light beam and the respective first and second light components generated by scattering by the particles contained in the liquid is more than 90 ° and in particular more than 120 ° .

Some other aspects concern the location on the sample' s surface at which the scattered light components are detected . In some aspects , a point of incidence of the first and/or second light beam on the sample is spaced apart from a point from which the first and/or second light component is detected . This may increase the BOPL and thus improve the signal to noise ratio . For example , in case of glucose measurements on blood a distance in the range from 1 mm to 8 mm and in particular between 2 mm and 4 mm has been found suitable . Spacing may be suitable for other measurements according to the proposed principle , because detecting light directly scattering at the surface at the point of incidence is thereby prevented .

As already mentioned, the observation on which the proposed method is based upon is not restricted to a single wavelength . Consequently, the step of emitting a first and/or second light beams may comprise emitting a first and/or second light beam at a first wavelength and emitting a first and/or second light beam at a second wavelength . For the sake of completeness it is noted that only results originating from the same measurement ( /i . e . the same wavelength) are processed together .

Some aspects relate to the timing of the different durations and the time between the first and second duration . Each duration corresponds to a certain time interval , in which one or more measurement are performed . In case of PPG measurement , the first and/or second duration can be set between 1 seconds and 10 seconds and particularly less than 45 seconds . This duration is usually long enough to obtain several heartbeats , e . g . in the range of 2 heartbeats and 100 heartbeats and particularly below 80 heartbeats and more particularly below 50 heartbeats , but short enough that a change in the concentration of the substance to be measured does not affect the measurement during said duration . The subsequent second duration is later in time , whereas it can either follow directly afterwards , resulting in a substantial continuous measurement . Alternatively, the measurements can be made periodically, e . g . every minute for 10 seconds or any other suitable period .

Some other aspects concern an optoelectronic device for determining a substance concentration in sample comprising a liquid containing particles , in particular glucose in blood . The optoelectronic device comprises a housing with an exit window and an optional entrance 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 during a first duration and a subsequent second light beams during a second duration from the exit window onto the sample . 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 subsequent 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 component . The evaluation unit determines a modulation depth of the respective first and second components ; and subsequently determines a substance concentration or a change in the substance concentration in the sample from the changes between the first and the second modulation depths .

As an alternative to an evaluation between two modulations depths , one may utilize a reference value . Hence only a single measurement is required to determine a substance concentration or a change in the substance concentration in the sample . In such alternative , the evaluation unit is configured with a memory storing one or more reference values . The evaluation unit is further configured to determine a substance concentration or a change in the substance concentration in the sample utilizing the reference value and one of the first and second modulation depths or values derived therefrom .

Said reference value is associated with or can correspond to -as previously mentioned above- different characteristics including, but not limited to a first modulation depth, a perfusion index , in particular a normalized perfusion index , that is with normal glucose level for example i . e . in the range between 85 mg/cl and 110 mg/cl . Such normal level may be individual or obtained from statistical value or derived over a longer period of time , e . g . a long measurement time of the respective user . Furthermore , the reference value is associated with or can correspond to a function that links the perfusion index with the modulation depth or any other signal characteristics . Likewise , such function is equivalent to a function that links the glucose level to the perfusion index or any other signal characteristics . The reference value can be derived as mentioned above , i . e . individually for each person or from a plurality of measurements as a statistical normalized value or function . This can take at least one of body mass index , age , gender , height and weight and s kin type into account .

In this regard, the modulation depth or the PI is characterised by a ratio of an AC portion and a DC portion of the respective detected component . The AC portion thereof corresponds to a varying component part of the respective detected components and the DC portion corresponds to a substantially constant component part of the respective detected components . By evaluating these components and calculating the ratio thereof , one can derive information about a change in the substance concentration in the sample .

In some instances , the evaluation unit is configured to perform an FFT on the detected first and second components to obtain a frequency spectrum thereof . Any kind of analogue or digital low-pass or bandpass filter ( if the component is converted to the digital domain ) can be applied on the detected components prior to performing the FFT or on the frequency spectrum ( that is after performing the FFT ) . The optional low-pass or band-pass filter comprises a cut-off frequency below 100Hz and in particular below 50Hz . The fundamental peak in the respective spectra and/or the harmonics thereof are obtained to derive information about the concentration substance .

In some alternative aspects , the evaluation unit is further configured to obtain a moving average from the detected first and/or second components ; and subsequently subtract the obtained moving average from the respective detected components prior to performing an FFT . This will reduce outliers or other errors not caused by the scattering itself .

In some further alternatives , the evaluation unit is configured to normalize the respective detected first and second components . Then, a maximum peak of the normalized component in the respective duration . Also a minimum adj acent to the respective maximum peak, either prior to the peak or following it is identified . The amplitude between the minimum and the maximum can be obtained therefrom .

In some aspects , the optoelectronic device contains an emitter unit capable of producing light of different wavelength, including , but not limited to red, green, and infrared . During measurements those lights are emitted sequentially . Alternatively, the detector unit also comprises several detectors having respective filter attached to it such that they pass light of dedicated wavelength . In this regard, any filter on the photodetector unit may be suitable to block ambient light .

Some other aspects concern the implementation of the optoelectronic device according to the proposed principle . In some aspects , the optoelectronic device also comprises an optical barrier arranged in the housing and extending from the exit window towards the housing bottom arranged between the emitter unit and the photodetector unit . Such barrier will prevent light from the emitting light source to directly reach the respective photo detectors .

In some further aspects , the emitter unit and/or the photodetector unit comprises an optical system, which is designed to generate a focal point on the sample . This will maximize the light on the sample and improve the signal to noise ratio . In some aspects , a focal point of the incident light , which is light generated by the emitter unit is spaced apart from a point from which outgoing light at a first angle is detectable by the photodetector unit . This will reduce cross talk during the measurement .

Although the optoelectronic device presented herein is only illustrated with regards to its functionality concerning the determination of substance concentration, one may note that various implementations are possible . In this respect , the evaluation unit does not need to be implemented within the housing itself containing the emitter and the detector but can be located separately therefrom. In some aspects , the evaluation unit is implemented in a separate device distances from the housing itself . Communication between the emitter and detectors and the evaluation unit as described above is facilitated for example by a wireless communication . This will allow for example to realize a master slave configuration, in which the evaluation unit request measurement to be taken on regular basis . Furthermore , the evaluation unit may be implemented largely in Software , for example as an app executed on a mobile device , whereas the remaining portion of the optoelectronic device are implemented in a separate housing .

In some aspects , the housing ( or optoelectronic device in more general terms ) is implemented as a ring , earbud, watch or any other wearable , that may fit in some aspects into a user' s usual environment and can be carried continuously . Said ring, earbud, watch or any other wearable is in communicative connection with the evaluation unit or a mobile or any other device implementing the evaluation unit . The ring, earbud, watch or any other wearable may cover a larger portion of the user' s s kin, e . g . wrap around the finger, clipped to the ear from both sides and the like . They may contain several emitters and detectors at various location, thus allowing not only to measure at one spot but at several at once or subsequently . As a result thereof , skin irregularity or other issue can be overcome and the overall measurement quality improved .

Apart from devices and handheld devices , other applications are possible . For example the optoelectronic device can be implemented in medical devices or laboratory equipment , e . g . for test and measurement purposes . Those devices again can be stationary or mobile .

Some more aspects concern mobile displays in which the detectors are directly implemented . In such applications , the display LEDs e . g . for the red and green colour can be used as emitter in accordance with the proposed principle . A finger is placed directly on the display surface and then illuminated by the display for obtaining the first and/or second signal . Likewise , the proposed principle can be implemented in VR or AR glasses and devices . Another application concerns safety issued, e . g . during certain labour work but also during driving and the like . It is possible to implement such optoelectronic devices in accordance with the proposed principle in a car, e . g . on the steering wheel to obtain the perfusion index and the changes thereof during driving . This enables for example to warn drives of potential health threats while driving .

SHORT DESCRIPTION OF THE DRAWINGS

Further aspects and embodiments in accordance with the proposed principle will become apparent in relation to the various embodiments and examples described in detail in connection with the accompanying drawings in which

Figure 1 shows a first embodiment of a setup illustrating several aspects of the proposed principle ;

Figures 2 illustrates a second embodiment of a setup illustrating several aspects of the proposed principle ;

Figure 3 shows a time diagram illustrating the two different durations in accordance with some aspects of the proposed principle ;

Figure 4 illustrates an exemplary result of two measurements and the perfusion index at two different durations in accordance with some aspects of the proposed principle ;

Figures 5 and 6 show a time perfusion index diagram also illustrating the corresponding glucose value at two different wavelengths in accordance with some aspects of the proposed principle ;

Figures 7A to 7C illustrate several embodiments of method for processing the signal in accordance with some aspects of the proposed principle .

DETAILED DESCRIPTION

The following embodiments and examples disclose various aspects and their combinations according to the proposed principle . The embodiments and examples are not always to scale . Likewise , different elements can be displayed enlarged or reduced in size to emphasize individual aspects . It goes without saying that the individual aspects of the embodiments and examples shown in the figures can be combined with each other without further ado , without this contradicting the principle according to the invention . Some aspects show a regular structure or form. It should be noted that in practice slight differences and deviations from the ideal form may occur without , however, contradicting the inventive idea .

In addition, the individual figures and aspects are not necessarily shown in the correct size , nor do the proportions between individual elements have to be essentially correct . Some aspects are highlighted by showing them enlarged . However , terms such as "above" , "over" , "below" , "under" "larger" , "smaller" and the like are correctly represented with regard to the elements in the figures . So it is possible to deduce such relations between the elements based on the figures .

Figures 1 and 2 show a detector arrangement according to the proposed principle as well as the envisaged non-intensive measuring method for determining a substance concentration in a liquid containing particles . In the present case , the glucose concentration is determined in a biological sample , in particular a human tissue .

Thereby, the detector arrangement la shown in Figure 1 is placed on the skin surface of a person, whose glucose concentration is to be determined . The essential components of the detector arrangement are listed here again by way of example . The s kin surface is marked with the reference sign 6 and is , for example , a part of the finger or another skin area . It should be noted that the area in which the glucose concentration is to be determined may affect the result , so multiple measurements should take place at roughly the same location 5 , the interaction area to reduce a potential error margin .

The detector arrangement comprises a frame 3 with a transparent window 7 , which is placed as light tight as possible on the skin surface and is lightly pressed against it . The closure with the s kin prevents ( or at least reduces ) stray light from entering the measurement detector during the measurement process , thus leading to a poorer signal-to- noise ratio . The detector arrangement la comprises a first measurement emitter ME , and a second emitter RE . The measurement emitters are configured to emit light of different wavelength, for example red and infrared light or green and red or infrared light . Of course those two emitters can also be implemented in a single device or , one of the two emitters can be left out , thus only emitting light of one wavelength . In front of the first measurement emitter ME and the second measurement emitter RE , optics 01 are arranged, respectively, which have an aperture and a downstream focusing optics . The optics 01 are designed to proj ect a substantially common focal point on the s kin surface 6 in an area SE that can be illuminated by the first measurement emitter and the second measurement emitter . A common focal point is not fundamentally required, but is useful to avoid measurement differences due to irregularities at different measurement locations .

The receiver side includes a first detector MD and a second detector RD . These two detectors are also each preceded by a second optical system 02 , which in turn comprises an aperture and one or more focusing lenses . The arrangement of the two detectors MD and RD and the upstream optics 02 is such that their respective detection point is located on the surface of the skin 6 within the area 5 of interaction and more precisely at SD . Light emitted from this area thus strikes the first detector MD and/or the second detector RD, depending on the angle . In this regard, the detector also may contain a colour filter , such that each detector is particularly sensitive to only one of the emitted light beams . As such, the measurement could be done simultaneously at different wavelength .

The areas SE and SD are spatially separated from each other, with the distance being in the range of a few millimetres . Consequently, emitted light will travel a certain distance during blood vessels under the skin prior to exiting the s kin again at location SD and reaching the two detectors RD and MD . In addition, an optical barrier 4 is provided between the emitter side and the detector side within the detector arrangement , which extends from the window 7 into the detector arrangement la and is intended to prevent crosstalk of light emitted by the first and/or the second measurement emitter to the respective detectors .

The arrangement on the emitter side with the first measurement emitter ME and the second measurement emitter RE is configured such that a measurement light beam generated by the measurement emitter is incident on the measurement area SE on the skin surface 6 at an angle a . As illustrated in the current examples this angle is different . It has been found in previous experiments that the angle of the incident light as well as the angle of the exiting light influence the signal strength and the signal-to noise ratio .

However , this can be taken into account either utilized or compensated for in the proposed principle . In the latter case , one may change the configuration such that all light emitted and detected comprises substantially the same incident angle . In the former case , the dependence on the measurement angle is "superimposed" to the dependence of the glucose concentration during the Photoplethysmography measurement , which may improve the overall signal quantity .

This is particularly the case if light from a single emitter is received at both detectors , thus being influenced by the different angles . It can be subsequently evaluated . If it received only by a single detector, the effect is still there , but may no longer be identifiable . In some embodiments , light from emitter ME is received by detector MD and light of a different wavelength by emitter RE is detected at detector RD .

In the present embodiment , the second emitter RE emit light of a first wavelength during a certain period of time . The emitted light penetrates partially the surface at location SE and interact with the blood vessel and the bloods plasma beneath the surface . Some of the light is scattered at the erythrocytes in the plasma in a characteristic way . This stochastic process of scattering , absorption and/or rescattering is repeated . Some of the light exits the surface of the tissue again at location SD and is received by the detector RD . Figure 2 illustrates a similar example using the same arrangement . However in this case , light emitter ME emits light of a certain wavelength that again interacts with the blood cells in the blood plasma and exits the surface of the sample 6 under different angles . The receiver optics 02 comprise light filters that block light at certain wavelength . In the present case only light from emitter ME will reach the detector MD . Likewise , light with a different wavelength from emitter RD can transmit through the optics 02 in front of detector RD, but is blocked by the other optics in front of detector MD .

The BOPL, that is the blood optical path length changes in dependence of the heartbeat . As already indicated and in accordance with the Beer- Lambert ' s law, the absorption of light in blood is largely determined by the presence of Hemoglobin within the erythrocytes , as well as the cumulative BOPL . When one assumes constant concentration of erythrocytes , the incident light propagating nominally through the more or less transparent blood plasma undergoes scattering at the red blood cells . This scattering effect increases when the optical path increases . The cumulative BOPL from entry point SE to detection point SD, both of which are fixed by the setup configuration specified by the arrangement la , may depend on the scattering characteristics in the sense of a random walk, i . e . , it will become a stochastic process .

Due to heart beats , the blood vessels increase and decrease slightly in size . The blood optical path length is directly affected by the beating of the heart and is therefore varying with time , while the properties of surrounding portions of tissue can be considered constant , at least on the timescale of the heart rate . This particularly applies to the concentration of the substance , which shall be determined by the proposed principle . Consequently, measurements taken at the same wavelength over a certain short time duration of a few seconds will show the heart beats resulting in a maximum signal (when the scattering is lowest and the BOPL is small ) and a minimum signal when scattering is largest and the BOPL is also high . In other words , a large BOPL results in a small signal and vice versa . Figure 3 illustrates the various measurements as well as the respective transmitted and received signals Tx and Rx . The measurements are taken for a certain short duration between two -longer spaced apart- time periods . The first duration is between times tl and t2 , the second duration is between times t3 and t4 , respectively .

The duration between tl and t2 as well as t3 and t4 for the measurements is relatively small compared to the timely distance between the measurements . Consequently, a change or variation of the substrate to be measured during the respective durations is very small and may be neglectable . However, it may become large between the two measurements . A comparison of the perfusion index and/or the modulation index as explained further below, is used to determine any change of substrate concentration over a longer period of time .

In the present case , the duration for measurements between the time tl and t2 as well as t3 and t4 is about a couple of seconds corresponding to a few heartbeats . Such measurements are similar to Photoplethysmography . In fact by proper PPG measurement one may use the PPG signal for its intended purpose , but also obtain further information out of it , like the glucose or other substrate concentration in accordance with the proposed principle .

The measurements are illustrated in the Tx and Rx lines , respectively . In the Tx line a plurality of small light pulses is emitted by the respective emitter towards the tissue and the blood vessel to be measured . Some of the light is scattered back and received by the detector causing a signal on the RX line . The received signal comprises alternating minima and maxima over its duration corresponding to the heartbeats .

Figure 4 illustrates in curve Cl obtained at 12 : 19 PM the heartbeat during a measurement duration of a few seconds . The difference between a minimum in the signal ( local minimum) and an adj acent local maximum corresponds to the modulation depth and the perfusion index . Assuming no blood pressure increase , or any other external parameter influences the measurement during the duration from tl to t2, the difference between adjacent extreme points is substantially equal.

The results of such first measurement are stored in a memory and the measurement repeated during the second duration at times t3 and t4, resulting in curve C2 obtained at 12:49, so 30 minutes later. Similar to the previous measurement, a pulse train is emitted towards the tissue and the blood vessel. The backscattered light exiting the surface of the tissue is detected and the signals evaluated.

Similar as in the first curve, the signal curve C2 shows several minima as well as maxima values corresponding to respective heartbeats during the measurement. However, in the meantime, a substrate concentration in the liquid has changed, i.e. the glucose level in the blood is different now. Consequently, the perfusion index has changed, namely increased from 0.2 arbitrary units in curve Cl to about 0.35 units in curve C2. Several observations in this regard have been made and experimentally verified. For a human test subject under steady-state conditions and a constant blood glucose level, the perfusion index remains substantially constant over the measurement duration and also for a longer period of time.

When the blood glucose level increases, the perfusion index also increases. Likewise, when the blood glucose level subsides, the perfusion index also decreases . The reason for it can be explained by the above-mentioned scattering model. Scattering depends on the difference between the refractive indices of the object and its surrounding liquid. If the index of scattering object and the object surrounding liquid were the same (assuming a transparent liquid) , no scattering (or only very low almost non-observable ) on the objects in the liquid takes place, since light would simply propagate through the medium without interaction. Due to the refractive index mismatch, some light is being scattered (e.g. , backwards) by the red blood cells, and they start to be visible and can be distinguished from the surrounding ambient, i.e. , plasma.

Under the assumption on an increase of the blood glucose concentration, the index contrast between the plasma and the red blood cells (the particles at which scattering takes place ) decreases . Consequently, propagation through the erythrocyte containing the light absorbing Hemoglobin increases while scattering of light back into the transparent plasma is reduced, leading to an overall increase in the effective BOPL in the presence of elevated glucose concentrations . This will result in a direct correlation of the optical AC-to-DC ratio of Photoplethysmography and blood glucose concentration; one can surmise that an increase in modulation depth due to glucose corresponds to an effective increase in the difference between maximum and minimum BOPL .

This behaviour is illustrated when comparing curves Cl and C2 in Figure 4 , in which the first curve Cl is taken at 12 : 19 PM and the second curve C2 is taken at 12 : 49 after some sugar containing liquid has been consumed at 12 : 10 . The overall perfusion index in both curves differ and in particular the perfusion index or modulation depth in C2 is larger indicating an increase in the glucose level .

Figure 5 in this regard illustrates a measurement of the perfusion indices at different times in accordance with the proposed principle as well as the corresponding glucose level obtained by a different reference measurement . The reference measurement and the reference curve are obtained by a state-of-the-art glucose meter that measures the glucose content directly with a blood sample .

The sugar containing liquid was consumed at around 12 : 10 P . M . and the measurements are taken shortly thereafter . Over a course of about 30 minutes , the glucose level in the blood increases reaching a maximum at around 12 : 55 and dropping shortly thereafter until about 90 minutes later reaching a minimum again .

There is a strong observable correlation between the measurement points in the curve MC obtained in accordance with the present invention and the reference curve RC . Each measurement point was obtained using a plurality of measurements over several heartbeats followed by some averaging . The overall duration of each of those measurements was shorter compared to the overall timeframe . Furthermore , outliers and glitches as well as artifacts have been removed from the curve MC . It is observed that the points obtained in accordance with the present invention strongly correlates with the reference curve RC indicating the glucose level between approximately 100 and its maximum of 160 . The optical values corresponding to the modulation depth and the PI also show a strong correlation between 0 . 0085 arbitrary and 0 . 0245 in the respective maximum.

The correlation and the behaviours are also observable for different wavelength, namely for red, green as well as for infrared light . Figure 5 illustrates the measurement using an emitter configured to emit green light . Figure 6 corresponds to a measurement obtained for red light . Red and green light as well as infrared light have different properties penetrating the skin as well as different scattering properties . However , s kin variations render it suitable to change the emission wavelength to obtain a good signal-to-noise ratio .

The overall optical value and the PI is the difference between the measurements for green and red light , respectively . This is explainable due to different absorption and the like and the different DC portions in the perfusion index . On the other hand the same behaviour is observable including a strong corelation between the reference curve RC and the measurements MC over time .

In addition, there is an observable peak identified at approximately 12 : 31 that is about 20 minutes after consumption of the sugar containing liquid . This small peak is not directly observable in the reference measurement RC . It should be noted though that the number of measurement points in the reference curve RC is substantially lower than the number of obtained measurement points with the method in accordance with the proposed principle and the identified peak in the measurement curve MC may therefore simply not visible in the reference curve RC . Nevertheless , the strong correlation between the different wavelengths supports the conclusion that the mechanism indicated herein is observable for a relatively wide range of different wavelengths from visible light to near infrared portions of the spectrum. This is in agreement with the underlying the Lorenz-Mie scattering theory . Figure 7A illustrates several embodiments of method for processing the signal and particularly a method for obtaining the concentration of a substance in a liquid containing particle .

The sample is prepared in the step SI , wherein the sample contains the substance to be measured dissolved in a liquid . In step S2 , a first light beam is emitted into the sample containing the liquid, said light beam having a first wavelength . This step is performed during a first duration or a first duration . The first light beam is scattered within the sample in accordance with the principles disclosed herein . In step S3 , a first light component is detected, wherein the first light component is scattered by the sample during first duration .

The process of emitting a light beam and subsequently detecting the scattered light can be either performed periodically or continuously during the first duration to obtain a plurality of signals corresponding to the scattered first light component . Some preprocessing of the obtained signals can be performed including but not limited to averaging, AD conversion, outlier detection and removal filtering and the like .

In step S4 , a first modulation depth then derived from the first light component detected during the first duration . The results may be stored in a memory for later use .

Then, after a certain period of time , a second light beam is emitted having the same wavelength onto the sample during a subsequent second duration in step S5 . Similar to the previous steps the emitted light beam will interact with the sample , thereby being partially scattered . Light components scattered by the sample are detected during said second duration . The steps and also any pre-processing step during the second duration should follow the one performed during the first duration to avoid influencing the results by different pre-processing . In step S 6 , the detected signals are evaluated, and a modulation depth and perfusion index , PI are derived therefrom. The substance concentration can then be calculated in step S7 by evaluating the changes between the first and second modulation depths over time . A plurality of different approaches is possible for the purpose of obtaining the respective modulation .

Figure 7B illustrates some steps of obtaining the modulation depth of the detected backscattered components during the respective durations . In step S41 are Fast Fourier Transformation or FFT is performed on the respective detected components to obtain the frequency spectrum thereof . A low-pass or bandpass filter can be applied to the detected spectrum to remove any spurious or higher frequency components . The step of applying a low-pass or bandpass filter in the step S41 can either be performed on the spectrum or on the original detected component itself that is prior to performing the step S41 .

The low-pass or bandpass filter comprises a cut-off frequency below 100 Hz and in particular below 50 Hz to include only components linked to the lower beating of the heart , from which the perfusion index and modulation depth is derived . In addition, such a low cut-off frequency may block incident light components , which are flickering with the power supply frequency .

Furthermore to these steps , a moving average from the detected first and second components can be obtained . The obtained moving average is subtracted from the respective detected component prior to performing the FFT . This will reduce a DC component in the overall signal , leaving the varying AC component intact .

As a result , the modulation depth that is used to evaluate any changes in the substance concentration is characterized by the ratio of an AC portion and the DC portion of the detected light signals . The AC portion corresponds to a varying component part of the respective detected components that includes for example the heartbeat in the blood vessel of a potential human or any other living body . The DC component corresponds to a substantially constant part of the respective detected component and can be pre-processed to be subtracted from the overall signal to improve the signal-to-noise ratio . Yet another possibility for evaluating and obtaining of the modulation depth is illustrated in Figure 7C .

In this embodiment , the respective first and second components are normalized in step S41 ' . After normalization, one or more minima are identified in the respective normalized component detected during the duration for which the measurement took place . Likewise , one or more maximum peaks in the normalized components are identified . Minima and maxima are alternating , which allow to associate one minimum with an adj acent maximum or vice versa .

A maximum peak can thereby follow the adj acent detected and identified minimum but also precede the identified minimum . Pairs of minima and adj acent maxima are formed and the amplitude -that is the difference between the minimum and maximum value- is obtained . Said difference corresponds to the modulation depth .

LIST OF REFERENCES la detector arrangement

3 frame 4 optical barrier

5 Area of interaction

6 sample area

7 window

ME first measurement emitter RE second measurement emitter

MD first detector

RD second detector

01 emitter optics

02 detector optics