Device for detecting an analyte via photoacoustic detection
11674931 · 2023-06-13
Assignee
Inventors
- Jean-Guillaume COUTARD (GRENOBLE, FR)
- Laurent Duraffourg (Grenoble, FR)
- Alain Gliere (Grenoble, FR)
- Alexandre Teulle (Grenoble, FR)
Cpc classification
A61B5/0095
HUMAN NECESSITIES
A61B5/14532
HUMAN NECESSITIES
G01N29/2418
PHYSICS
G01N21/1717
PHYSICS
G01N21/1702
PHYSICS
International classification
Abstract
Photoacoustic detecting device (1), intended to be applied, via a contact face (3), against a medium to be analysed, the device comprising: a hollow cavity (20) comprising a first aperture (22) produced in the contact face, the cavity being bounded by a containment shell (21) that extends around the first aperture; a pulsed or amplitude-modulated light source (10) configured to emit, in an emission spectral band (Δλ), an incident light wave (11) through the cavity (20) to the first aperture; an acoustic transducer (28) linked to the cavity and configured to detect a photoacoustic wave (12) extending through the cavity. The photoacoustic detecting device is optimized to increase the amplitude of the photoacoustic wave detected by the acoustic transducer.
Claims
1. A photoacoustic detecting device, intended to be applied, via a contact face, against a medium to be analysed, the device comprising: a hollow cavity that emerges onto a first aperture, the first aperture being produced in the contact face; a pulsed or amplitude-modulated light source configured to emit, in an emission spectral band, an incident light wave, through the cavity, to the first aperture; an acoustic transducer linked to the cavity and configured to detect a photoacoustic wave extending through the cavity; such that, under the effect of illumination of the medium, by the incident light wave, the acoustic transducer detects an acoustic wave produced by heating of the medium; wherein: the volume of the cavity is smaller than 50 μL; the device comprises an open tube extending between the cavity and air lying outside the cavity, over a length and a diameter, the length of the tube being comprised between 1 and 20 mm, the diameter of the tube being such that: when the volume of the cavity is smaller than or equal to 15 μL, the diameter of the tube is comprised between 150 μm and 300 μm; when the volume of the cavity is comprised between 15 μL and 30 μL, the diameter of the tube is comprised between 200 μm and 350 μm; when the volume of the cavity is larger than 30 μL, the diameter of the tube is comprised between 250 μm and 500 μm.
2. The device according to claim 1, wherein: the cavity is bounded by a transverse wall and a lateral wall, the lateral wall extending between the transverse wall and the contact face; the tube extends through the transverse wall or through the lateral wall.
3. The device according to claim 1, comprising an acoustic channel extending between the acoustic transducer and the cavity.
4. The device according to claim 1, comprising an optical component, configured to direct the incident light wave, emitted by the light source, to the first aperture.
5. The device according to claim 4, wherein the optical component is a reflector.
6. The device according to claim 1, wherein the light source is a laser source.
7. The device according to claim 6, the device comprising a holder extending from the contact face to the light source, the holder being configured to conduct heat emitted by the analysed medium to the light source.
8. The device according to claim 7, wherein the holder comprises a thermally conductive metal, copper or aluminium for example.
9. The device according to claim 1, wherein the volume of the cavity is smaller than 20 μL.
10. A method for estimating a concentration of analyte in a medium, comprising: a) applying a device according to claim 1 against a medium, such that the contact face is held against the medium; b) activating the light source, the light source emitting, at a wavelength corresponding to an absorption wavelength of the analyte, an incident light wave that is pulsed or amplitude-modulated at an activation or modulation frequency; c) detecting an acoustic wave emitted by the medium, under the effect of the incident light wave, at an acoustic frequency equal to the activation frequency of the light source; d) measuring an amplitude of the acoustic wave; e) detecting the presence of analyte and/or estimating the concentration of the analyte in the medium from the amplitude measured in d).
Description
FIGURES
(1)
(2)
(3)
(4)
(5)
(6)
(7) In
(8)
(9)
(10)
(11) In
(12)
(13)
(14)
(15) In
(16)
(17)
(18)
(19) In
(20)
(21)
DESCRIPTION OF PARTICULAR EMBODIMENTS
(22)
(23) The analyte 4 may be a molecule present in a bodily fluid. It may for example be a question of glucose, or of a bodily analyte such as cholesterol, triglycerides, urea, albumin, an alcohol (ethanol for example), or tetrahydrocannabinol.
(24) The emission spectral band preferably lies in the visible or in the infrared and for example extends between wavelengths of 3 μm and 15 μm. Preferably, the emission spectral band Δλ is narrow enough for the device 1 to be specific to a single analyte. For example, the width of the emission spectral band is of the order of 0.1 μm. When the analyte is glucose, the emission spectral band is centred on an absorption wavelength of glucose, for example a wavelength corresponding to a wavenumber of 1034 cm.sup.−1. The light source 10 may notably be a pulsed laser source and may for example be a wavelength-tunable quantum cascade laser (QCL). The emission spectral band Δλ is then located in the infrared.
(25) According to other embodiments, the light source may be a filament-based source or a light-emitting diode. According to these embodiments, it is preferable to associate the light source with a bandpass filter in order to define a sufficiently narrow emission spectral band centred on the absorption wavelength in question. However, recourse to a laser source is preferred.
(26) In the embodiment shown in
(27) The device 1 is intended to be applied against a medium to be analysed 2. It comprises a containment shell 21, which is placed in contact with the medium, and which defines a cavity 20. The cavity 20 emerges onto a first aperture 22, which is produced in the contact face 3, so as to emerge onto the medium 2. The incident light wave 11, after having been reflected by the optical component 15, propagates to the medium 2 through the cavity 20, and through the first aperture 22. The device comprises a transparent window 17, which is configured to transmit the incident light wave 11.
(28) In the device shown in
(29) Under the effect of the presence of an analyte 4 in the medium 2, a photoacoustic wave 12 is formed. The photoacoustic wave 12 is an acoustic wave formed as a result of periodic heating of the medium by the incident light wave 11, the latter being pulsed or amplitude-modulated. Some of the photoacoustic wave 12 extends through the cavity 20 so as to be detected by an acoustic transducer 28. The acoustic transducer 28 is linked to the cavity 20 by an acoustic channel 25. The acoustic transducer may be a microphone, having a detection spectral range comprising the frequency of the photoacoustic wave.
(30) As mentioned in the publication Kottmann “Mid-infrared photoacoustic detection of glucose in human skin: towards non-invasive diagnostics”, Sensors 2016, 16, 1663 (this publication will be referred to below as “Kottmann 2016”), a relationship may be established between the amplitude A of the photoacoustic wave, at the frequency f, and the volume V of the cavity 20, such that:
(31)
where: ∝ indicates proportionality; I.sub.10(λ) is the intensity of the incident light wave at the wavelength A; α(λ) is an absorption coefficient of the analysed medium at the wavelength λ; V is the volume of the cavity, including the acoustic channel where appropriate; f is the frequency of the acoustic wave.
(32) When the frequency f and the intensity I.sub.10 (λ) of the light wave are set, the amplitude of the photoacoustic wave A detected by the acoustic transducer is proportional to the absorption coefficient α(λ) of the medium. The latter may be considered to be proportional to the concentration of analyte in the medium. Thus, measuring the amplitude A with the acoustic transducer 28 allows the concentration of analyte in the medium to be estimated, via estimation of the absorption coefficient α(λ) of the medium.
(33) Expression (1) assumes that the thickness L of the medium 2 is such that:
L>>μ.sub.a(λ)>μ.sub.s(λ) (2)
where: μ.sub.a(λ) is the depth of optical penetration, μ.sub.a(λ) being such that
(34)
(35)
(36) In Expression (4), D is a coefficient of thermal diffusion, such that:
(37)
where: ρ is the density of the medium; C is the heat capacity of the medium; k is the thermal conductivity of the medium.
(38) It may be seen that μ.sub.a(λ) does not depend on the frequency f, whereas μ.sub.s(λ) varies inversely with the square root of the frequency f. In “Kottman 2016”, it has been established that when the medium is a biological tissue, skin for example, the condition L>>μ.sub.a(λ)>μ.sub.s(λ) is met provided that the frequency is higher than 50 Hz.
(39) Expression (1) shows that use of low frequencies allows the amplitude of the photoacoustic wave 12 to be increased. Thus, the inventors concluded that when the medium 2 is a biological tissue, it is advantageous for the frequency of the photoacoustic wave to be lower than 1 kHz, and preferably lower than 500 Hz. It is preferably comprised between 50 Hz and 500 Hz.
(40) From Expression (4) it will be clear that decreasing the frequency f also allows the thermal diffusion length μ.sub.s(λ) to be increased. This allows the medium to be interrogated to greater depth.
(41) When the analyte 4 is glucose, or another nutrient conveyed by the blood, increasing the depth to which the concentration of the analyte is determined is an advantage. Specifically, photoacoustic detection does not allow large depths, millimeter-scale depths for example, to be reached. However, it is at these depths that the capillaries lie. With photoacoustic detection, glucose concentration is estimated indirectly, by estimating the concentration of glucose in the interstitial fluid that lies between the capillaries and the cells of the epidermis. It has been established that the glucose concentration in the interstitial fluid follows the glucose concentration in the blood, the time lag therebetween being about 20 minutes. By increasing the depth to which the medium 2 is examined, the time lag between the glucose concentration in the blood and the concentration estimated using Expression (1) is decreased.
(42) According to Expression (1), the volume of the cavity 20 must be small in order to increase the amplitude of the photoacoustic wave. However, the smaller the volume of the cavity, the higher the frequency f.
(43) On account of Expression (1), a compromise must be obtained so as to decrease volume while keeping an eye on the frequency f, the objective being to increase the amplitude of the photoacoustic wave in order to improve the sensitivity of the method.
(44) The inventors have reached a satisfactory compromise by designing a cavity 20 of small volume, comprised between 1 and 50 μL, and preferably between 5 and 30 μL. The containment shell 21 comprises a solid internal wall 23 bounding the cavity 20. The internal wall comprises: a lateral component 23.sub.1, which preferably extends parallel to a Z-axis normal to the contact face 3. a transverse component 23.sub.2, which extends parallel, or substantially parallel, to the contact face 3, facing the latter. The transverse component 23.sub.2 extends parallel, or substantially parallel, to the first aperture 22. In the embodiment shown in
(45) By substantially parallel, what is meant is parallel to within an angular tolerance of ±30° or ±20°. The lateral component 23.sub.1 extends between the contact face 3 and the transverse component 23.sub.2.
(46) The device comprises a tube 26, which extends from the cavity 20 and emerges into air outside the cavity 20. The tube 26 forms an aperture through which the cavity 20 makes contact with air, at room pressure, outside the cavity. The tube 26 extends over a length l and has a cross-section of diameter ϕ. In
(47) In the configuration shown in
(48) An important element of the invention is the observation, which the inventors made, that if the geometry of the tube 26 is varied, the spectral response of the cavity 20 varies. The inventors set themselves the objective of obtaining a spectral response that was as uniform as possible between 100 Hz and 1000 Hz. By spectral response, what is meant is the amplitude of the acoustic pressure in the cavity, as a function of frequency.
(49) The inventors considered a cavity such as shown in
(50) It is known that such a cavity may be modelled by an equivalent circuit diagram. This allows the pressure, inside the cavity, under the effect of the presence of an acoustic wave to be simulated, as described in the publication Dehé A. et al “The Infineon Silicon MEMS microphone”, AMA conferences 2013—Sensor 2013, Opto 2013.
(51)
(52) If P.sub.0 is the pressure of the acoustic wave in the cavity, the current I.sub.0 depends on the power of the laser according to the expression:
(53)
where γ is an adiabatic coefficient of air and P.sub.laser is the power of the laser.
μ.sub.s is the thermal diffusion length described with respect to Expression (4);
α is a coefficient of absorption per unit length.
(54) The effect of the cavity is modelled by a capacitor C.sub.2, such that:
(55)
where V is the volume of the cavity 20, including the acoustic channel 25 where appropriate.
(56) The effect of the tube 26 is modelled by a capacitor C.sub.1 connected in parallel to the capacitor C.sub.2, and an inductor L.sub.1 connected in series with a resistor R.sub.1, which are such that:
(57)
where l and S correspond to the length and to the cross-sectional area of the tube 26, respectively.
(58)
where ρ.sub.0 corresponds to the density of air.
(59)
where μ corresponds to the viscosity of air.
(60) The inventors have used the model schematically shown in
(61) The inventors have successively considered 4 different cavity volumes, equal to 5 μL, 10 μL, 20 μL and 50 μL, respectively. For each volume, they studied the effect of varying the diameter of the tube and its length, on the spectral response in the cavity. The performance of each modelled configuration was examined considering: a relative pressure variation ΔP.sub.0 in the spectral band 100 Hz-1 kHz: It corresponds to the following expression:
(62)
(63)
(64) To determine ΔP.sub.0 and
(65)
(66) The analysis of
(67)
(68)
(69)
(70) It may be deduced from
(71)
(72) Generally, whatever the volume in question, when the diameter of the tube is small, the spectral response is close to that of a closed cavity. When the diameter of the tube is large, the spectral response of the cavity approaches that of a resonant cavity, with the appearance of a resonant peak. The aforementioned diameter and length ranges corresponding to a relatively flat spectral response, between the spectral response of a closed cavity and the spectral response of a resonant cavity.
(73) Based on the modelling performed, the inventors have determined, for various cavity-volume ranges, the optimal dimensions of the tube: When the volume of the cavity is smaller than or equal to 15 μL, the diameter of the tube may be comprised between 150 μm and 300 μm. When the volume of the cavity is comprised between 15 μL and 30 μL, the diameter of the tube may be comprised between 200 μm and 350 μm. When the volume of the cavity is larger than 30 μL, the diameter of the tube may be comprised between 250 μm and 500 μm.
(74) Whatever the volume, the length of the tube is preferably greater than 1 mm or than 3 mm. It is preferably less than 20 mm.
(75) In the embodiment shown in
(76) The optimal operating temperature of QCL laser sources is generally comprised between 30° C. and 40° C. When the device is applied against the skin of a living user, the body heat of the user may be used by way of heat source of the QCL laser source. The device then comprises a holder 16, against which the laser source 10 is placed. The holder 16 is configured to make contact with the skin of the user. The holder is made of a material having good properties as regards thermal conduction, of a metal for example, and notably of copper or of aluminium. The holder 16 extends between the contact face 3 and the light source 10. The thickness of the holder 16, along the Z-axis, is for example comprised between 1 mm and 10 mm. The holder 16 thus acts as thermal buffer, between the skin of the user and the light source.
(77) The invention will possibly be employed to detect the presence of an analyte in a medium, the latter possibly being the skin of the user. To do this, the following steps will be applied: applying the device against a medium, such that the contact face is held against the medium; activating the light source at an activation frequency or a modulation frequency; detecting a photoacoustic wave emitted by the medium, under the effect of the incident light wave, at an acoustic frequency equal to the activation or modulation frequency of the light source; measuring an amplitude of the acoustic wave, this amounting to estimating the amplitude A described with reference to Expression (1); detecting the presence of the analyte and/or estimating the concentration of the analyte in the medium from the measured amplitude. This step is carried out by estimating the absorption coefficient α described with reference to Expression (1), the relationship between the analyte concentration and the absorption coefficient being known.