EP3016590A1 - Appareil et procédé pour déterminer la concentration d'une substance dans un fluide - Google Patents

Appareil et procédé pour déterminer la concentration d'une substance dans un fluide

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Publication number
EP3016590A1
EP3016590A1 EP14748133.7A EP14748133A EP3016590A1 EP 3016590 A1 EP3016590 A1 EP 3016590A1 EP 14748133 A EP14748133 A EP 14748133A EP 3016590 A1 EP3016590 A1 EP 3016590A1
Authority
EP
European Patent Office
Prior art keywords
light
fluid
pathway
mean
determining
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14748133.7A
Other languages
German (de)
English (en)
Inventor
Panayiotis Anastasios Kyriacou
Victor Olagovich Rybynok
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City University of London
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City University of London
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Filing date
Publication date
Application filed by City University of London filed Critical City University of London
Publication of EP3016590A1 publication Critical patent/EP3016590A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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

Definitions

  • This invention relates to apparatus for measuring the concentration of a substance in a fluid. A method is also disclosed.
  • the fluid comprises blood
  • the apparatus is capable of measuring the concentration of a component of the blood, for example glucose.
  • the apparatus is operable to non-invasively measure the concentration of the substance.
  • the teaching provided below refers in detail to an apparatus that is configured for non-invasively determining the concentration of glucose in a subject's blood, but it will be appreciated and should be remembered that this is merely illustrative of the teachings of the invention and that the teachings of the invention have many other applications.
  • the apparatus disclosed herein could be used to measure the concentration of other blood components, in vitro or in vivo, or indeed components of other fluids.
  • CGM blood glucose monitors that continuously monitor the concentration of glucose in the blood are also available.
  • CGM continuous blood glucose monitors
  • These continuous blood glucose monitors (CGM) are also invasive, and typically comprise a disposable glucose sensor that is placed just under the skin, and is worn for a few days until it is replaced.
  • the sensor is linked to a non- implanted transmitter that wirelessly communicates with an electronic receiver that is worn like a pager and displays blood glucose levels on a practically continuous manner, as well as monitors rising and falling trends.
  • Such CGMs whilst providing for continuous measurement of blood glucose levels, have a number of drawbacks. For example, such CGM devices still need to be calibrated with a traditional blood glucose "fingerstick" system. Another issue is that these devices measure glucose concentration in interstitial fluid, and the level of glucose in a subject's interstitial fluid tends to lag behind the level of glucose in the subject's blood, and thus the accuracy of the measurements obtained may be compromised.
  • Non-invasive blood glucose measurement devices have previously been proposed, but a significant problem is the calibration of such devices.
  • a universal measurement method has not yet been developed.
  • These, and other, vascular tissue components render empirical calibration difficult (if not impossible), and such calibration is necessary for the accurate evaluation of blood glucose concentration using conventional spectroscopic techniques.
  • Previously proposals for addressing this calibration problem have used special empirical algorithms and large sets of experimentally obtained data, and the techniques previously proposed vary from simple curve fitting methods to regression analysis, and artificial neural networks.
  • decades of experimental research would tend to indicate that direct empirical use of information obtained from an optical sensor to predict blood glucose concentration is highly problematic, and probably impossible.
  • a blood component such as glucose
  • continuous monitoring of blood glucose would allow the close examination of how the blood glucose level reacts to insulin, exercise, food, and other factors.
  • Such a monitor would be of utility in virtually every department of a hospital.
  • Every individual diabetic could have one, allowing for better trend monitoring and also allowing their physician to see how well their diabetes has been controlled.
  • Diabetics, general practitioners, emergency and community services would all gain from such a device.
  • This device may also have economic advantages as it would not need disposables. It could be incorporated into other clinical devices and also potentially in every-day devices such as a watch or mobile phone.
  • a blood component such as glucose
  • a presently preferred embodiment of the present invention provides a method for determining the concentration of a substance in a fluid, the method comprising: operating a light emitter to illuminate a fluid; operating a light detector to determine the intensity of light that has passed through the fluid to the detector; calculating an amount of light absorbed by the fluid; determining a variation in mean light pathways through the fluid from the detector to the emitter; retrieving data concerning the absorptivity of the substance; and determining from the calculated absorbance, the determined mean light pathway variation and the retrieved absorptivity of the substance, a measure of the concentration of the substance in the fluid.
  • apparatus for determining the concentration of a substance in a fluid comprising: a light emitter for illuminating a fluid; a light detector for determining the intensity of light that has passed through the fluid to the detector; means for calculating an amount of light absorbed by the fluid; means for determining a variation in mean light pathways through the fluid from the detector to the emitter; means for retrieving data concerning the absorptivity of the substance; and means for determining from the calculated absorbance, the determined mean light pathway variation and the retrieved absorptivity of the substance, a measure of the concentration of the substance in the fluid.
  • the fluid comprises blood flowing through vascular tissue
  • the apparatus and method being operable to provide a non-invasive measure of the concentration of the substance in the blood.
  • the variation in mean light pathways through the vascular tissue may result from expansion and contraction of blood vessels within the tissue as the heart of the subject pumps blood around their body.
  • the variation in mean light pathway may be determined by measuring a Doppler frequency shift that is representative of the speed at which the vascular tissue expands and contracts.
  • the emitter may comprise a multi-wavelength monochromatic light source, such as a plurality of LEDs.
  • the Doppler frequency shift may be observed in a laser that is arranged to illuminate the vascular tissue.
  • Fig. 1 a schematically illustrates the light flux envelope between an emitter and a detector through a scattering medium, such as vascular tissue;
  • Fig. 1 b schematically illustrates the propagation delay of light traversing the scattering medium
  • Fig. 2a schematically illustrates the concept of the mean light pathway
  • Fig. 2b schematically illustrates a mean light pathway through a non- homogeneous scattering medium
  • Fig. 3a schematically illustrates vascular tissue volume changes through a subject's cardiac cycle
  • Fig. 3b schematically illustrates a PPG signal
  • Fig. 4 is a schematic representation of apparatus embodying the teachings of the present invention.
  • Fig. 5 is a functional representation of apparatus embodying the teachings of the present invention.
  • Photoplethysmography is a measurement technique that uses light to noninvasive ⁇ obtain a volumetric measurement of an organ with each cardiac cycle.
  • Pulse Oximetry is a well established empirical technique that allows the degree of arterial blood oxygen saturation (Sp0 2 ) to be evaluated from PPG signals.
  • An advantage of PO is that one can look directly into the arterial blood stream through the skin and bypass other parts of the vascular tissue (e.g. bones or muscles).
  • the apparatus disclosed herein can be used, inter alia, to non-invasively evaluate arterial blood glucose concentration from PPG signals using a technique that we call "Dynamic Pulsatile Spectroscopy" (DPS).
  • DPS Dynamic Pulsatile Spectroscopy
  • Pulse Oximetry is based on a rational model that utilises the conventional Beer- Lambert law, but neglects scattering within vascular tissue, and assumes that arterial blood chromophores consist of only oxygenated and deoxygenated haemoglobins.
  • the equations produced from that PO model enable Sp0 2 values to be estimated from PPG signals quite accurately with respect to empirical relationships established with invasive blood oxygen saturation measurements.
  • the analytical solution obtained from the rational model is not as accurate as empirically obtained results, it theoretically proves that non-invasive Sp0 2 evaluation is generally possible.
  • the analytical solution equations also reveal which parameters should be used for empirical calibration (i.e. the so-called R values).
  • the DPS technique that we have developed takes vascular tissue scattering into consideration and includes additional arterial blood analytes.
  • our DPS technique uses a method that we have named Beer-Lambert law along Non- Linear mean Light Pathways (BLNLP).
  • BLNLP light is considered to be a flux of elementary particles - namely, photons.
  • the speed of these photons is equal to the speed of light, and is defined by the electromagnetic properties of the media through which the light propagates.
  • a light photon can be emitted absorbed or scattered by an optical electron of an atom or molecule, collectively called matter particles.
  • Photon energy is proportional to the light wavelengths and the proportionality coefficient is the Plank constant. Additional postulates used in BLNLP were deduced by analysis of the following physical models: the Beer-Lambert law, Monte Carlo light scattering modelling and the light energy transport integral equation.
  • Fig. 1 demonstrates this physical concept and shows a schematic representation of the light flux envelopes 7 between an emitter 1 and detector 3 in a scattering media 5 (for example, through vascular tissue).
  • Each envelope has a characteristic "banana” shape, and represents a space area through which most photons travel from the light emitter 1 to the light detector 3.
  • Such envelopes can be obtained by light scattering modelling on the homogeneous, plain, and semi-infinite media models utilising the Monte Carlo method to solve the light radiation transfer equation.
  • time interval " during which light pulse energy travels to the light detector corresponds to light energy with the shortest pathlength in the banana envelope.
  • Time interval "II” corresponds to a longer pathlength, and so on up to the end of the light pulse propagation time interval "VI”.
  • the light energy propagation envelopes shown in Fig. 1 a can be split into a series of smaller "canoe" shaped envelopes 9 through each of which a certain fraction of light energy propagates through the matter.
  • each of these canoe shapes equates to the mean light pathway through the envelope median.
  • fractions of the light energy corresponding to each envelope are propagating along the mean light pathways, and each mean light pathway corresponds to the particular light pulse propagation delay time intervals depicted in Fig. 1 b.
  • the light intensity can be introduced for the resulting scattered light.
  • Light intensity can be computed for each point of the mean light pathway curve along its tangent and in the emitter-detector direction.
  • light intensity degrades along the mean pathways according to the Beer-Lambert law, apart from the fact that the Beer- Lambert integral is taken along the mean light pathways rather than a conventional straight line:
  • ⁇ ⁇ . ⁇ is the absorption for pathway p, from emitter to detector for light of wavelength ⁇ ; I D ⁇ . ⁇ is the intensity of light of wavelength ⁇ at the detector attributable to pathway ⁇ ,; ⁇ ⁇ ⁇ ' s the intensity of light of wavelength ⁇ at the emitted attributable to pathway p,; l pi is the mean light pathway for pathway p,; and ⁇ ⁇ ⁇ is the attenuation coefficient of the medium through which light of wavelength I travels.
  • the attenuation coefficient ⁇ 3 ⁇ 5 ⁇ ⁇ can be computed as follows:
  • a k 3 ⁇ 4 has the same meaning as in absorption spectroscopy— namely, a function of wavelength ⁇ , unique for each chromophore k present in the segment j of the sample; and c s k is the concentration of chromophore k within the segment j (shown in Fig. 2b).
  • Equations (1 ) to (3) above form the basis for the DPS theory that we have devised.
  • Fig. 3a there is depicted a single mean pathway 13 (i.e. one of the pathways shown in Fig. 2a) for light propagating through vascular tissue 15.
  • I E ⁇ is a light intensity at the emitter side
  • I tD 3 ⁇ 4 is a light intensity at the detector side.
  • Fig. 3b is a schematic representation of the PPG signal obtained at the detector in Fig. 3a.
  • ⁇ 3 ⁇ ⁇ ⁇ 0 be the absorption coefficient for the arterial blood as in (3);
  • B XOQ is a total mean light pathway within all arterial blood segments as in Fig. 2b;
  • ⁇ ( ⁇ ) is the total absorbance within non-arterial blood segments as in (2);
  • ⁇ ⁇ (t) 3 ⁇ AB ⁇ (0 ⁇ ⁇ AB ⁇ (0 + ⁇ (t) (5)
  • ⁇ ⁇ ( ⁇ 0 , t) ⁇ ⁇ ⁇ ( ⁇ ) ⁇ ⁇ ⁇ ⁇ ( ⁇ 0 , t) (6)
  • MLPV Mean Light Pathway Variation
  • the light intensity (/ D , Fig. 3a) used in BLNLP and the light power (P D , Fig. 3b) sensed via a photodetector are two different light energy characteristics.
  • detected light power can be computed by integrating light intensity over the photodetector's surface and over all mean light pathways leading to the photodetector (Fig. 2a).
  • AZ AB /l (t 0 , t) the Mean Light Pathway Variation
  • Indexes j in equations (9a) (9b) and (9c) identify the blood components taken into account.
  • the component with the smallest absorption coefficient (3) defines the total number of components which have to be included into equations n AB , as concentration variations of the components with the higher absorption coefficients will affect the evaluation accuracy.
  • Component absorptivities have to be different by at least one wavelength to avoid the equations being linearly dependent. The number of wavelengths at which PPGs should be monitored must be equal to or greater than the number of blood components, whose concentrations are taken into DPS equations.
  • ⁇ ⁇ . ( ⁇ 0 , t) Al AB (t 0 , t) ⁇ c AB Ck (t)
  • SPS Static Pulsatile Spectroscopy
  • the concentration of components in a fluid can be determined using the above equations if the mean light pathway variation attributable to the pulsed flow can be measured.
  • our technique is based upon the general concept that the amount the amount of light energy that is absorbed along a given pathway is the sum of the absorption that occurs over each segment of the pathway, and the absorption for each segment is the sum of the absorption due to the light-absorbing components in that segment (where the absorption for a given light- absorbing component equals the absorptivity for that component multiplied by its concentration).
  • LDF laser Doppler flowmetry
  • the technique that we have developed differs from this LDF technique in that we use the Doppler effect to measure the speed at which vascular tissue (in this particular example) expands and contracts as blood pulses through the tissue.
  • This expansion and contraction of the tissue causes a corresponding expansion and contraction of a laser beam travelling along a pathway (the Mean Light Pathway (MLP)) through the tissue.
  • MLPV Mean Light Pathway Variation
  • MLPVS Mean Light Pathway Variation Speed
  • the Doppler frequency shift of the laser light beam electromagnetic wave we can evaluate the MLPVS, and by integrating the MLPVS over time we can determine the MLPV. The determined MLPV variation can then be substituted in the abovementioned DPS equations, and the concentration of components of the blood can be calculated.
  • the Laser Wave Doppler frequency resulting from variations in the Mean Light Pathway is much lower than the Doppler Flow frequency, because blood particles move much quicker than the tissue, and hence the laser wave Doppler frequency can be separated from the Doppler flow frequency by a band pass filter.
  • Fig. 1 b As the vascular tissue expands and contracts, so the length of the Mean Light Pathway will change and the peak ⁇ ⁇ (Fig. 1 b) will move left and right as the heart of the subject beats.
  • the time variation between the ⁇ ⁇ spike and the ⁇ ⁇ peak is proportional to the MLPV with a proportionality coefficient that is equal to the speed of light in arterial blood, and hence the MLPV can be determined. Whilst this "direct" measurement is possible, in practice the equipment required is bulky and expensive and the measurement itself is complex, and hence the aforementioned Laser Wave Doppler technique is preferred.
  • the spike ⁇ ⁇ of light in Fig. 1 b can be split into Fourier spectra.
  • the light intensity can be modulated harmonically (i.e. the emitter light intensity changes in accordance with a sine function), and the intensity-modulated light beam is known as the light photon density wave.
  • the resulting wave when the light beam intensity is harmonically modulated the resulting wave is known as the Light Photon Density Wave.
  • the frequency of the intensity modulation changes with the subject's heartbeat due to the Doppler effect. This frequency change can be detected using high radio-frequency technique, and the Mean Light Pathway variation can be calculated.
  • FIG. 4 of the drawings there is a depicted an illustrative representation of apparatus 17 for determining the concentration of a component in a fluid.
  • This apparatus utilises the aforementioned Laser Wave Doppler technique to determine the MLPV.
  • the apparatus 17 comprises a light emitter 19 that is coupled by means of an optic fibre to a fibre splitter 21 which splits the incident light from the emitter 19 into a first beam that is directed via an optic fibre to vascular tissue 25 (that comprises, in this illustrative example, a subject's finger), and a second reference beam that is directed to a laser wave Doppler module 23 by an optic fibre.
  • vascular tissue 25 that comprises, in this illustrative example, a subject's finger
  • a second reference beam that is directed to a laser wave Doppler module 23 by an optic fibre.
  • Part of the light of the first beam from the splitter 21 travels through the vascular tissue (the remainder being absorbed) to a fibre splitter 27 that is coupled by respective optic fibres to a light detector 29 and the aforementioned laser wave Doppler module 23.
  • a control and data processing system 31 receives data from both the light detector 27 and the laser wave Doppler module 23.
  • the light emitter comprises a multi-wavelength monochromatic source of light, such as a plurality of light emitting diodes.
  • the light emitter 19 could comprise, in an illustrative implementation, a single-wavelength laser light source (for example, a 100 mW, 980 nm fibre laser), although it is envisaged that the laser could be tunable to enhance the measurement of the mean light pathway variation.
  • the laser Doppler module comprises a band pass filter (to filter low frequency amplitude modulation and high frequency noise), and logic for determining - in the manner aforementioned - the mean light pathway variation speed.
  • Light detector 29 comprises, in a preferred implementation, a multichannel photodetector.
  • Light from fibre splitter 21 is modulated by the pulsating vascular tissue and the resulting modulated laser light is split by fibre splitter 27 and passed to the detector 29 and the laser wave Doppler module 23.
  • the light detector outputs data representing the intensity of light received, and from this information the control and data processing system can compute the amount of light absorbed as the light traverses the vascular tissue.
  • the laser wave Doppler module 23 filters out frequency shifts attributable to the speed of the blood flowing through the tissue, leaving the frequency shifts attributable to the speed at which the vascular tissue expands and contracts.
  • the Laser Wave Doppler module computes the mean light pathway variation speed and outputs this data to the control and data processing system for processing.
  • the control and data processing system calculates, from the mean light pathway variation speed, the mean light pathway variation. Given the observed absorbance, the calculated mean light pathway variation and data concerning the absorptivity of a given blood constituent (which data may be preprogrammed into the control and data processing system or retrieved from a data store), the control and data processing system can calculate the concentration of that constituent in the blood using the DPS equations set out above.
  • Fig. 4 can be operated to noninvasive ⁇ determine the concentration of absorbers (such as glucose, for example) in the blood of a subject.
  • absorbers such as glucose, for example
  • the laser wave Doppler module 23 of Fig 4 comprises an acousto-optic modulator module 35 that is configured to shift the frequency of the reference laser beam output from the first fibre splitter 21 by a small amount (typically a few kilohertz), a light detector 41 , an attenuator 37 that is configured to attenuate the reference beam so that it does not saturate the detector, and a fibre mixer 39 that is configured to generate interference fringes from the light from the second fibre splitter (i.e. light that has travelled through the sample 25) and the attenuated reference beam.
  • acousto-optic modulator module 35 that is configured to shift the frequency of the reference laser beam output from the first fibre splitter 21 by a small amount (typically a few kilohertz)
  • a light detector 41 typically a few kilohertz
  • an attenuator 37 that is configured to attenuate the reference beam so that it does not saturate the detector
  • a fibre mixer 39 that
  • fringes provide a frequency signal that is proportional to the Doppler shift imparted by the pulsating sample, but frequency shifted (by the acousto-optic module) so that it does not overly the signal representative of intensity variation caused by the pulsatile flow (i.e. the output of fibre splitter 27).
  • the acousto-optic module comprises a first acousto- optic modulator that is configured to shift the frequency (for example, increase) of the reference beam by an amount X, and a second acousto-optic modulator that is configured to shift the frequency of the reference beam in an opposite direction (for example, reduce) by the same amount X.
  • the beam output by the acousto- optic module should have the same frequency as the reference beam, but in practice as the two modulators are not exactly identical, the beam has a slightly different frequency from the reference beam.
  • the scope of the present invention is not limited to in-vivo concentration measurement.
  • the techniques described herein are of use wherever one can introduce a mean light pathway variation between two beams of laser light travelling through a sample.
  • the teachings of the invention could be implemented with a cuvette that includes an internal step so that the cuvette has a region with a first diameter and a region with a second larger diameter.
  • Light beams shone through each of the two regions would have a known mean light pathway variation, and by observing the absorbance of each beam one it is possible to calculate the concentration of given components using the observed absorbance, the known mean light pathway variation and the absorptivity for the component of interest.
  • a conical flask could be employed as an alternative to a stepped cuvette.

Abstract

L'invention concerne un procédé pour déterminer la concentration d'une substance dans un fluide, le procédé comprenant : (i) l'actionnement d'un émetteur de lumière pour éclairer un fluide; (ii) l'actionnement d'un détecteur de lumière pour déterminer l'intensité d'une lumière qui a traversé le fluide jusqu'au détecteur; (iii) le calcul d'une quantité de lumière absorbée par le fluide; (iv) la détermination d'un trajet de lumière moyen à travers le fluide, à partir du détecteur jusqu'à l'émetteur; (v) la récupération de données concernant le pouvoir d'absorption optique de la substance; et (vi) la détermination, à partir de l'absorbance calculée, du trajet de lumière moyen déterminé et du pouvoir d'absorption récupéré de la substance, d'une mesure de la concentration de la substance dans le fluide. L'invention concerne également un appareil pour déterminer la concentration d'une substance dans un fluide.
EP14748133.7A 2013-07-02 2014-07-02 Appareil et procédé pour déterminer la concentration d'une substance dans un fluide Withdrawn EP3016590A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB201311859A GB201311859D0 (en) 2013-07-02 2013-07-02 Apparatus & method for determining the concentration of a substance in a fluid
PCT/EP2014/064125 WO2015000997A1 (fr) 2013-07-02 2014-07-02 Appareil et procédé pour déterminer la concentration d'une substance dans un fluide

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EP3016590A1 true EP3016590A1 (fr) 2016-05-11

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US10271745B2 (en) 2016-06-17 2019-04-30 Qualcomm Incorporated Monolithic integrated emitter-detector array in a flexible substrate for biometric sensing

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JP3944448B2 (ja) * 2002-12-18 2007-07-11 浜松ホトニクス株式会社 血液測定装置
GB0523832D0 (en) 2005-11-23 2006-01-04 Univ City Non-invasive optical monitoring of glucose using an adaptive modelling scheme
WO2007126389A1 (fr) * 2006-05-02 2007-11-08 Asensor Pte Ltd Système de détection optique pour analyse d'échantillon comprenant au moins deux longueurs de chemin optique différentes
US20120310062A1 (en) * 2011-05-31 2012-12-06 Nellcor Puritan Bennett Llc Photon density wave based determination of physiological blood parameters

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