WO2024028469A1 - Procédé de détermination de concentration d'une substance et dispositif de détection - Google Patents

Procédé de détermination de concentration d'une substance et dispositif de détection Download PDF

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Publication number
WO2024028469A1
WO2024028469A1 PCT/EP2023/071620 EP2023071620W WO2024028469A1 WO 2024028469 A1 WO2024028469 A1 WO 2024028469A1 EP 2023071620 W EP2023071620 W EP 2023071620W WO 2024028469 A1 WO2024028469 A1 WO 2024028469A1
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WIPO (PCT)
Prior art keywords
light
component
location
sample
detecting
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PCT/EP2023/071620
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English (en)
Inventor
Klaus Flock
Timm MUELLER
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ams Sensors Germany GmbH
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Publication of WO2024028469A1 publication Critical patent/WO2024028469A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4738—Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474—Details of optical heads therefor, e.g. using optical fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/02—Mechanical
    • G01N2201/022—Casings
    • G01N2201/0221—Portable; cableless; compact; hand-held
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/066—Modifiable path; multiple paths in one sample
    • G01N2201/0668—Multiple paths; optimisable path length

Definitions

  • 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 .
  • 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 .
  • the present idea relies on the evaluation of the scattering signal , also referred to as perfusion index, which has been found by the inventors to also depend on the blood glucose concentration .
  • the path length is referred to as "blood optical path length ( BOPL ) " .
  • the BOPL is affected among other things by the beating of the heart , but essentially by the location at which the scattered light signal is measured and more precisely from the distance between the location of the incident light and the location of the scattered light .
  • the amount of scattered light is dependent on the distance between the incident position (the location on the sample at which the light enters the sample ) and the position on the sample at which the scattered light is detected . Consequently, scattered light received at two different locations behave differently . This difference is caused by the path through the liquid containing the substance whose concentration is to be determined .
  • the scattering behaviour follows a well-known principle and is merely constant , but a changing concentration over time also leads to a behaviour from which the concentration or at least a change of the concentration can be derived . It has been found that a change in concentration of glucose in blood ( or any other substance in blood) causes a measurable change of the scattering . Obtaining the amount of light at different locations from the spot of the incident light and deriving a ratio from those two obtained signals , one can obtain a value that is against any systematic error and changes directly with the substance concentration . When the time between the two measurements at the different locations is short , the effect of heartbeat causing the BOPL to change is neglectable .
  • the absorption of light in blood is largely determined by the presence of Hemoglobin within the erythrocytes , as well as the cumulative BOPL .
  • the cumulative BOPL from entry point to the two detection points 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 .
  • the detected light is primarily a result of the direct interaction and particularly the scattering between light and erythrocytes between the incident light spot and the detection location .
  • a decrease in the glucose increases the difference between the refractive indices of the erythrocytes and the blood plasma causes an increase in scattering .
  • any varying substance in blood affecting the refractive index of the blood plasma will cause a variation of scattered light in the receiving detectors .
  • an increase of the blood glucose level causes a decrease in the scattered signal and conversely, when the blood glucose level decreases , the scattering increases , resulting in a direct correlation of the optical DC/DC ratio of two scattering locations spaced apart .
  • the different glucose level also changes the BOPL during PPG measurements causing a varying AC-to-DC ratio of Photoplethysmography and blood glucose concentration . It is observed in both cases (that is for very quick measurement , in which the blood pressure due to hard beat is substantially constant and in longer measurement including the PI and the modulation depth of a PPG that an increase in the DC/DC ration at two different locations and the modulation depth due to glucose in the plasma corresponds to an effective increase in the difference between maximum and minimum BOPL .
  • the inventors propose a method for determining a substance concentration in a sample comprising liquid containing particles , in particular glucose in blood, wherein 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 , -in particular periodic- first light pulse of at least one wavelength onto a first location of the sample containing the liquid .
  • a first light component scattered by the sample is detecting at a second location, the second location being distanced from the first location by a first distance .
  • a second light component scattered by the sample is detected at a third location .
  • the third location is distanced from the first location by a second distance different from the first distance .
  • a third light component during a duration, where no light is emitted is detected at least at one of the second and third location .
  • the detection of the third component is set to a time frame , where no artificial light is emitted .
  • the detected signals may be pre-processed, . i . e . digitized using an AD converter, in particular having a converter having at least 14 bits of resolution .
  • a first intensity signal is obtained from the first light component and the third light component .
  • the second light component is processed to obtain a second intensity signal from the second light component and the third light component .
  • the third light component can be averaged prior of being processed with the first and second light components to reduce smaller variations in the third light component .
  • the substance concentration can be derived from the first and second intensity signal , in particular from a ratio of the first and second intensity signals as indicated above .
  • the detected scattered light components correspond to different path lengths through the sample , in the previous aspect such different path length can be achieved by detecting the light components at two different location, while the incident light does not change .
  • one may emit a, -in particular periodic- first light pulse of at least one wavelength onto a first location of the sample containing the liquid .
  • a -in particular periodic- second light pulse of at least one wavelength is emitted onto a second location of the sample containing the liquid .
  • two light pulses are emitted onto the sample , but at different locations .
  • a first light component scattered by the sample is detected, the third location being distanced from the first location by a first distance .
  • a second light component scattered by the sample is detected, the third location being distanced from the second location by a second distance different from the first distance .
  • the overall path length, that is the length of the light through the sample is different .
  • a third light component may also be detected at the third location during a duration, where no light is emitted .
  • the subsequent processing is similar as previously mentioned and includes obtaining a first and second intensity signal from the first light component and the third light component and from the second light component and the third light component , respectively .
  • the substance concentration can be derived from the first and second intensity signal in the same manner , for instance from a ratio of the first and second intensity signals .
  • it may be suitable to emit the first and second light pulses at different times such that they do not interfere with each other .
  • they can be emitted with slightly different wavelength, such that their detection at the third location is distinguishable .
  • 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, or one of the first and second intensity signals or a signal derived therefrom .
  • the reference value can be obtained by several means prior to the actual measurement .
  • the reference value may comprise not only the intensity signal but can also refer to any value , from which the reference concentration of a substance or a signal to be processed subsequently can be meaningful derived . Consequently, the term reference value shall be understood as being equivalent to any value from which the substance concentration or the intensity signal can be derived .
  • 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.
  • the reference value and also characteristics from a curve corresponding to the change of the intensity signal 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 s kin type . Particularly, skin type can be used not only to adj ust the processing of the respective intensity signals , but also adj ust the wavelength of the emitted signals .
  • the reference value is a statistical value obtained as a general normalized intensity signal ( different from zero ) from 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 .
  • Some aspects concern the acquisition of data and the duration of the measurement .
  • the heartbeat will periodically change the blood volume , which then can affect the amount of scattered light .
  • the perfusion index that is the AC portion of a PPG signal over time , and the perfusion index itself may vary with a changing glucose level .
  • the detected first and second light component may contain an AC portion corresponding to the variations of obtained signal due to the external excitement ( e . g . the heartbeat ) and a DC portion .
  • the DC portion may correspond in some instances to the averaged signal obtained during the longer measurement .
  • the first and second intensity signals includes such AC and DC components .
  • a substance concentration can now be derived by either evaluating the AC portions of the two intensity signals , the DC portions of the two intensity signals or a combination thereof .
  • the substance concentration can be derived by the ratio of the AC portions of the first and second intensity signals .
  • substance concentration can be derived from a ratio of the AC/DC portions of the respective first and second intensity signals . i . e .
  • One may also utilize certain factors to adj ust to the s kin type or other parameters .
  • the first and/or second light pulse may comprise a periodicity between 20 Hz and 500 Hz , an in particular between 50 Hz and 200 Hz and particular above 75 Hz .
  • an individual measurement is taken usually in a relatively short time span, in which a change of the substance concentration but also an external slower trigger ( e . g . a heartbeat ) does not affect the individual measurement .
  • Each individual measurement is referred to as a sample , and several samples can be combined into a single value .
  • the first and/or second light pulse comprises a duty cycle in the range of 1 /20 to 1/5 of the period . This will reduce the overall power consumption but is still sufficient to obtain the necessary information .
  • the method can be implemented in a portable device , like a mobile phone , a watch or a portable medical device .
  • two light pulses are emitted onto different locations of the sample , and the back scattered light is retrieved from a single location .
  • the two light pulses may be generated time interleaved, whereas the time difference between emitting the first light pulse and emitting the second light pulse is less than 1 second and particularly between 10 ms and 250 ms and more particularly between 30 ms and 100 ms .
  • the time difference between emitting the first and second light pulse should be substantially shorter to avoid being affected by a slow varying external parameter like for example a heartbeat .
  • Some aspects concern the position of the respective emitting and detecting location .
  • a direction from the first location to the second location is different compared to a direction from the first location to the third location . This may prevent to fail in the measurement if one of the two locations is obstructed .
  • detecting light components from a plurality of different location provides the option of compensate noisy or undesired signal components , different optical behaviour on the location and the like .
  • the duration during the third light component is detected is usually longer than the duration for the detection of the first and/or second light components .
  • the third light component in this regard may represent mainly the undesired components coming from, but not limited to , ambient light signals , noise , variations in the external parameters like temperature or humidity and the like .
  • the detector device for determining a substance concentration in a sample comprising liquid containing particles .
  • the detector device comprises a housing with at least one optoelectronic component and at least one light detecting component arranged therein .
  • the housing comprises exits windows for accessing the at least one optoelectronic component and at least one light detecting component .
  • the at least one light detecting component within the housing is optically separated from the light emitting device .
  • the at least one optoelectronic component is configured to emit light through an exit window onto a sample . Accordingly, the sample is usually placed above the exit window in the beam path of the light emitted by the at least one optoelectronic component . It is useful to place the sample tight onto the exit window to reduce any ambient light from reaching the surface of the sample . Consequently, in some aspects , the housing and/or the exit is configured to follow the shape of the sample or at least adj ust such that entry of ambient light is reduced .
  • Similar configurations may be applied to the entry window in front of the at least one detector component .
  • the entry window should be tight on the sample to avoid ambient light from getting through the entry window and reaching the detector component .
  • the at least one detecting component of the detector device is configured to detect two light components corresponding to emitted light scattered through the sample , wherein said two light components correspond to different path length of light travelling through the samples .
  • one path length is longer than the second path length .
  • a control circuit is coupled to the at least one optoelectronic component and at least one light detecting component .
  • the control circuit is configured to obtain a first signal from the at least one detecting component corresponding to a detected first light component , a second signal from the at least one detecting component corresponding to a detected second light component and a third signal from the at least one detecting component corresponding to a detected third light component .
  • the third light component is detected while the at least one optoelectronic component is not emitting .
  • the third light component may include for example any ambient light , noise or other undesired component .
  • the control circuit is configured to derive a first intensity signal from the first and third signal and a second intensity signal from the second and third signal .
  • said control circuit is further configured to derive a substance concentration from the first and second intensity signal , in particular from a ratio of the first and second intensity values .
  • the detector device can be implemented in a hand-held or a mobile device . It is possible to utilize already existing setups , which are suitable for PPG measurements , blood pressure or oxygen concentration for example .
  • a distance between the at least one optoelectronic component and a first of the at least one light detecting component is different to a distance between the at least one optoelectronic component and a second of the at least one light detecting component .
  • a distance between a first of the at least one optoelectronic component and the at least one light detecting component may be different to a distance between a second of the at least one optoelectronic component and the at least one light detecting component . Both implementations will ensure that the optical path length the signal is travelling through the sample is different , which will cause different amount of scattering thus leading to a measurable difference .
  • the control unit is configured with a memory storing one or more reference values .
  • the control 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 intensity signals 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 an intensity signal at a given distance , or a signal derived therefrom . It can correspond to a normal level at said distance , which 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 .
  • the reference value is associated with or can correspond to a function that links the intensity signal with the perfusion index, with the modulation depth or any other signal characteristics . Likewise , such function is equivalent to a function that links the intensity signal to 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 .
  • the at least one optoelectronic component and the at least one light detecting component are arranged substantially in the same plane .
  • the detecting components may detect light components that are backscattered from the light emitted onto the sample .
  • the at least one optoelectronic component and the at least one light detecting component are arranged in two different , optionally substantially parallel planes , wherein optionally, the sample is placed in a light path between the two different planes .
  • This implementation will therefore detect light components that are transmitted through the sample , although even such light components may be scattered through the sample . Combinations for both are possible , e . g . the planes of the light emitting component and the light detecting component can be inclined to each other .
  • the at least one light detecting component comprises a light filter comprising a low transmittance in a frequency spectrum different from a light spectrum emitted by the at least one light emitting component . This measure will further reduce ambient light portions in the detected component thereby improving the quality of the detected component .
  • the detector 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 .
  • the control unit or portions thereof does not need to be implemented within the housing itself containing the emitter and the detector but can be located separately therefrom.
  • the control unit is implemented in a separate device distances from the housing itself .
  • control unit Communication between the emitter and detectors and the control 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 control unit request measurement to be taken on regular basis .
  • the control unit may be implemented largely in Software , for example as an app executed on a mobile device , whereas the remaining portion of the detector device are implemented in a separate housing .
  • the housing ( or the detector 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 control unit or a mobile or any other device implementing the control 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 .
  • the detector 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 .
  • the display LEDs e . g . for the red and green colour can be used as emitter in accordance wrth 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 .
  • 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 detector devices in accordance with the proposed principle in a car, e . g . on the steering wheel to obtain the intensity signals and the changes thereof during driving . Thrs enables for example warnings to the driver of potentral health threats while driving .
  • Figure 1 shows the relation of the several intensity signals at different wavelengths and differen t path length in accordance with some aspects of the proposed principle
  • Figures 2 illustrates a first embodiment for a light emitter and detector according to some aspects of the proposed principle
  • Figure 3 shows a second embodiment for a light emitter and detector according to some aspects of the proposed principle ;
  • Figure 4 to Figure 9 illustrate several signal time-diagrams to show the influence of wavelength and other parameters in accordance with some aspects of the proposed principle .
  • Figure 1 is a diagram illustrating the relationship between the optical path length through the respective sample and the strength of the scattered light through a sample .
  • the x-axis of the diagram shows the distance of the optical path length .
  • the optical path length is defined as the distance the light travels through the sample , that is between the location of the incident spot on the sample and the location at which is backscattered light is detected .
  • Distance 0 represents a spot on the sample equal to the incident location as well as the location at which backscattered light is detected .
  • the y-axis comprises an arbitrary logarithmic value scale of the received signal .
  • the illustration in Figure 1 includes three curves referred to as KI , K2 and K3 . They represent the measurements at the respective different distances given at different wavelength .
  • curves KI illustrates the backscattered signal at a wavelength in the infrared spectrum
  • the curve K2 shows a signal of backscattered light from a red light source
  • curve K-3 illustrates the same situation for a green light source .
  • the relationship for curves KI and K2 is substantially linear and more particular both curves show a linear decrease over a distance of 5 mm starting from an initial distance at 2mm. the decrease depends on the distance between the incident spot and the detected spot and is substantially linear over the measured distance between two mm and 7 mm, respectively .
  • measurement curve K3 comprises a stronger decrease over the same given distance . This is partially explainable by a higher absorption or scattering of the green wavelengths throughout the distance . The interaction for green light is generally stronger than for red or infrared light .
  • the incident light provided by the respective emitter is emitted onto a specific location on the sample .
  • the incident light now travels through the sample and is on its way scattered and/or partially absorbed by the particles in the sample . While the amount of absorption is mainly constant , the scattering is dependent on the substance concentration, which changes the refractive index difference between the liquid and the particles in the liquid .
  • the scattered light exiting the sample is detected .
  • the respective curves KI , K2 and K-3 correspond to the detected light at such distances .
  • each substance concentration may comprise a different decrease in the signal of the measured values over the respective distances .
  • This principle is applied to the glucose a measurement as mentioned above .
  • FIG. 2 and Figure 3 illustrate an exemplary embodiment for such measurement devices suitable not only to detect and derive a glucose concentration in blood, but also for a variety of further measurements .
  • the detector device 1 in Figure 2 comprises a substrate 5 , which is embedded in a housing 10 .
  • Housing 10 also comprises a light emitting device 11 in form of an optoelectronic component or a lighting diode , LED .
  • the lighting diode is configured to emit light of one or more wavelengths through an exit window 12 on the top surface of the housing 10 .
  • Lighting diode 11 is also spaced apart from two light detecting components or photo diodes 20 and 25 , respectively .
  • the two photo diodes 20 and 25 also spaced apart from each other .
  • the distance between lighting diode 12 and the first photo detector 20 is given by d2
  • the distance between diode 2 and second photo detector 25 is given by d3 + d2
  • the distance between the LED 11 and the two photodetectors 20 and 25 are different .
  • An entry window 13 with a respective filter element is applied in front of the respective photo diodes 20 and 25 .
  • the filter element is transparent for the wavelengths of light emitting diode 11 , but otherwise comprises a high absorption or reflection for wavelength outside that the respective frequency band .
  • the entry windows will reduce the amount of ambient light being detected by the respective photo diodes 20 and 25 during the measurement cycle .
  • the light detecting elements may be sensitive to the wavelength, but otherwise insensitive .
  • housing 10 comprises a light blocking element 32 that is provided between the light emitting diode 11 and the photo diodes 20 and 22 , respectively .
  • the lighter blocking element 32 provides an optical separation between the light emitting component and the light directing components .
  • Housing 10 further comprises a control and evaluation circuit 30 , which is connected to the light emitting component and related to directing components , respectively .
  • Figure 3 illustrates a similar embodiment of a detector device in accordance with the proposed principle .
  • the detector device illustrated in Figure 3 shows a first light emitting component 11 and a second light emitting component 15 , which are spaced apart from a single light detecting component 20 . Similar to the previous embodiment , the distance between the light emitting component and the respective light detecting components are different .
  • the difference in length does also correspond to the optical path length, which is illustrated in the Figures 2 and 3 , given the referral number DI and D2 .
  • the optical path length is the path inside the sample 2 , the light is traveling from the spot on the sample' s surface for the incident light to the location at which exiting light is detected .
  • the length of optical path DI is longer than the length of optical path D2 , there is a relation between the optical path DI and D2 and the distance between LED2 and the detector elements 20 and 25 , respectively .
  • the shape and structure of the top surface of the housing that is in the particular the exit window in front of the light emitting component and the entry window in front of the detecting components 20 and 25 should be shape such that it is substantially light tight when a sample is placed upon the respective windows .
  • the sample in which the sample is compressible , the sample should be a slightly pressed on the respective windows to further reduce any incident or ambient light from reaching the light detecting components .
  • the exit window is tightly arranged against the sample to prevent ambient light from entering the incident location at the entry sample surface .
  • FIGs 4 to Figure 9 illustrate various results of measurements for a change of the glucose concentration in blood over time after digesting a sugar containing liquid .
  • the various figures illustrate possible evaluation steps to be conducted by a control circuit in accordance with some aspects of the proposed principle . It has been found that the detected backscattered light shows a strong correlation between the glucose concentration and the time passed after digestion of a sugar containing liquid .
  • the measurements are taken together with a reference measurement , illustrated in the Figures 4 to 9 by curves RK.
  • the refence measurements RK are taken by conventional glucose measurement apparatus from Abbott® .
  • the measurements were taken at a resting person with a heart rate is determined to be approximately 1 . 2 Hz . Since the proposed optical measurements is purely optical and therefore non-invasive , a plurality of samples was measured and processed to obtain a plurality of data point with a frequency of one data point every 10 sec . Sampling rate was approximately 30 Hz , which is also inside the range of a typical PPG measurement . Duty cycle is approximate 10% . It should be noted in this regard that the data points will be affected by the optical path length change due to the blood level . The perfusion index is dependent on the glucose level and since the measurement points are taken at "high” or "low” blood level , the effect f the perfusion is included in the measurement . However, as this effect is present for the measurement at different distances , the overall effect may be partially compensated when evaluating as it will be explained below .
  • a background is obtained and subtracted from each sample .
  • the background is measured during the OFF period .
  • the background includes inherent dark-current of the detector as well as any ambient light , both of which may contribute to a photo-diode current , CCD-charge , voltage drop , or some other measurable quantity .
  • the background is averaged with a sample measurement in between . The result is then used for this particular sample .
  • the figures illustrate the individual evaluated data points , but also the 5 min moving average and the 15 min moving average .
  • the moving average was used to average outliers and individual measured data points in order to obtain a smoother curve .
  • the measured data points are further processed to determine different correlations and best practice .
  • Figure 4 illustrates the results after evaluating the ratio of the processed signals at 2 mm and 4 mm . Both signals are divided to compensate for ambient light and other signal portion that do not originate from the scattering . Further , forming of the ratio of the overall signal (that includes the DC portion and the AC portion originating from the perfusion ) will render the result more robust against variations .
  • the result is given by (AC/DC ) intensity signal i / (AC/DC ) intensity signal 2 -
  • the measurement is taken with green light that usually has a higher absorption and more interaction with the tissue .
  • the y-axis on the left side shows the ratio in an arbitrary scale
  • the y-axis on the right side is the glucose level derived from the reference measurement .
  • the moving average on 5 min as well as on 15 min shows a strong correlation between time the measurement results . It basically follows , although it may be slightly delayed due to process of moving average .
  • the peaks in curve K4 are an artifact resulting from the optical measurement and relate to 2n or 360 ° rotation in the measurement due to the change of the difference in the refractive index . This effect is reduced in Curve K5 with its longer moving average indicating that the peaks originate from the measurement .
  • Figure 5 illustrates a similar measurement but taken at a wavelength in the red spectrum .
  • the reference curve RK in Figure 5 is equal to the one in Figure 4 .
  • curves K4 and K5 follow the glucose concentration in blood, with curve K4 having two smaller yet recognizable maxima occurring at approximately the same time as for the curve K4 in Figure 4 .
  • Figure 6 illustrates the measurement result for a wavelength at 940 nm, whereas a ratio is firmed of the scattered signals detected at a distance of 2 mm and 4 mm, respectively .
  • the result of the moving average follows the refence curve and the corresponding glucose level .
  • the initial peak visible at around 10 . 30 is either an outlier due to the , but some measurements indicate that the initial increase in the optical signal is faster than the respective reference measurement .
  • the glucose level also strongly depends on the location at which the reference measurement takes place , while the optical measurement substantially determined in glucose level in the blood .
  • devices used for establishing the reference curve may measure the glucose level in the intermuscular tissue and/or outside larger blood vessel .
  • the any increase of the glucose in the blood stream is delayed until it may reach a similar level in the intermuscular tissue and/or outside larger blood vessel . Such delay seems to be visible particularly during the initial phase .
  • Figures 7 and 8 represent the AC potion of the measured signal obtained within red spectrum, that is at wavelength of 637 nm .
  • the overall signal will vary slightly in response to the heartbeat .
  • the difference between the maximum value and the minimum value during a single heartbeat if references as diffusion index .
  • the perfusion index is given at approximately half of the heartbeat .
  • the DC portion that is the averaged signal over a number of heartbeats .
  • the ratio between the AC portion to DC portion (AC/DC ) can be used for evaluating the substrate concentration at different distances .
  • Figures 7 and 8 represent the optical modulation, that is the AC portion and perfusion index .
  • Figure 7 is measured at a distance of 4 mm;
  • Figure 8 is measure at a distance of 2 mm.
  • the AC portion also show a correlation between the glucose concentration and the obtained results .
  • the AC portion may however contain arbitrary parts in the signal that originate from the measurement itself and not from the scattering at the substance to be detected . Hence , it is suitable to gauge the signal , by for example measuring the amount of incident light onto the sample .
  • Figure 9 finally is a measurement representing 1 /DC of a scattered signal with a wavelength of 637 nm at a distance of 4mm between the spot of incidence and the location of detection .

Abstract

L'invention concerne un procédé permettant de déterminer la concentration d'une substance dans un échantillon (2) comprenant un liquide contenant des particules, l'indice de réfraction du liquide dépendant de la concentration de la substance dissoute dans le liquide, et la densité des particules dans le liquide étant sensiblement constante. Le procédé consiste à détecter deux composantes de lumière différentes caractérisées par une longueur de trajet différente (D1, D2) à travers l'échantillon (2) et à obtenir deux signaux représentant l'intensité lumineuse de la lumière diffusée à travers l'échantillon (2). Une concentration de substance est dérivée des premier et second signaux d'intensité, en particulier d'un rapport entre les premier et second signaux d'intensité.
PCT/EP2023/071620 2022-08-04 2023-08-03 Procédé de détermination de concentration d'une substance et dispositif de détection WO2024028469A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5551422A (en) * 1992-11-09 1996-09-03 Boehringer Mannheim Gmbh Method and apparatus for analytical determination of glucose in a biological matrix
EP0536304B1 (fr) * 1990-06-27 1996-12-04 Futrex, Inc. Mesure non invasive de glycemie
EP0760091B1 (fr) * 1994-05-19 1999-11-03 Roche Diagnostics GmbH Procede et dispositif pour la determination d'un analyte dans un echantillon biologique
US20100292581A1 (en) * 2009-05-13 2010-11-18 Peter Guy Howard Dynamic Calibration of an Optical Spectrometer
US20150018646A1 (en) * 2013-07-12 2015-01-15 Sandeep Gulati Dynamic sample mapping noninvasive analyzer apparatus and method of use thereof
US20210282673A1 (en) * 2020-03-11 2021-09-16 Robert John Petcavich Wearable wireless non-invasive blood glucose measurement system

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0536304B1 (fr) * 1990-06-27 1996-12-04 Futrex, Inc. Mesure non invasive de glycemie
US5551422A (en) * 1992-11-09 1996-09-03 Boehringer Mannheim Gmbh Method and apparatus for analytical determination of glucose in a biological matrix
EP0760091B1 (fr) * 1994-05-19 1999-11-03 Roche Diagnostics GmbH Procede et dispositif pour la determination d'un analyte dans un echantillon biologique
US20100292581A1 (en) * 2009-05-13 2010-11-18 Peter Guy Howard Dynamic Calibration of an Optical Spectrometer
US20150018646A1 (en) * 2013-07-12 2015-01-15 Sandeep Gulati Dynamic sample mapping noninvasive analyzer apparatus and method of use thereof
US20210282673A1 (en) * 2020-03-11 2021-09-16 Robert John Petcavich Wearable wireless non-invasive blood glucose measurement system

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