WO2017153425A1

WO2017153425A1 - Analysing device, preferably for chemometric measurement of a blood sample

Info

Publication number: WO2017153425A1
Application number: PCT/EP2017/055355
Authority: WO
Inventors: Mejdi NCIRI; Eric Christian BELARBRE; Florence DROUET
Original assignee: Archimej Technology
Priority date: 2016-03-10
Filing date: 2017-03-07
Publication date: 2017-09-14
Also published as: FR3048777A1; EP3465146A1; FR3048778A1

Abstract

The present invention relates to an analysing device (100) comprising: an emitter (17) arranged to emit a light beam (18); at least one measuring zone (21) and at least one reference zone (25), which are illuminated by the light beam (18); a detector (26) of reflection, which detector is arranged, for each measuring zone (21) and at least one reference zone (25), to receive a reflection of the light beam (18) and generate an associated signal; a detector (29) of transmission, which detector is arranged, for each measuring zone (21) and reference zone (25), to receive a transmission of the light beam (18) and to generate an associated signal; and analysing means (32) arranged to deliver information on a content of the at least one measuring zone (21) depending on the signals associated with the transmissions (30, 31) and reflections (27, 28) of the various measuring and reference zones (21, 25).

Description

"Analytical device, preferably for chemometrics of a blood sample" Technical field

The present invention relates to an analysis device, and a sample holder (for example of the tongue type) to be inserted into such a device.

Such a device allows a user to analyze a sample disposed on or in the sample holder. The field of the invention is more particularly but in a non-limiting manner that of the analysis of a blood sample.

State of the art

In optical spectroscopy, spectrophotometry in particular, it is common to use the so-called "Double Beam Spectroscopy" technique in order to measure the spectral absorption of a sample.

A dual beam spectrometer according to the state of the art is conventionally provided with a splitter plate which will spatially divide a measuring beam before its divided parts are sent respectively to a reference bowl and to a bowl comprising the sample of interest.

Compared to the "Single Beam" technique, the measurement in "Double Beams" is more precise, more sensitive and above all more stable. Indeed, by the concomitant measurement of a main beam and a reference beam, this technique makes it possible to overcome (or correct) the variability of extrinsic parameters to the sample such as: the composition and / or the physico-chemical state of the bowl, the surface imperfections of the bowl, the thermal fluctuations of the environment, etc.

The purpose of the present invention is:

to improve the accuracy and / or the measurement sensitivity on the sample, and / or

to improve the compactness of the analysis or measurement device. Presentation of the invention

This objective is achieved with an analysis device, comprising: a transmitter, arranged to emit a beam of light,

a sample holder support:

arranged to receive a sample holder in a sample holder area, the sample holder area comprising at least one measurement zone and at least one reference zone, and

o arranged so that all the measurement and reference areas are illuminated by the light beam,

said device comprising at least one of:

a reflection detector:

o arranged, for each measurement zone, to receive a reflection, by this measurement zone, of the light beam, and to generate an associated signal,

o arranged, for each or a part of the at least one reference area, to receive a reflection, by reference area, of the light beam, and to generate an associated signal,

- a transmission detector:

o arranged, for each measurement zone, to receive a transmission, by this measurement zone, of the light beam, and to generate an associated signal,

o arranged, for each reference zone, to receive a transmission, by this reference zone, of the light beam, and to generate an associated signal,

said device further comprising:

analysis means arranged to provide information on a content of the at least one measurement zone according to the signals associated with the transmissions and / or reflections of the different measurement and reference zones.

The beam is preferably collimated in the sample holder region, more exactly on each measurement zone and on each reference zone. The reflection detector preferably comprises a matrix detector or a group of matrix detectors, arranged to receive the reflections of the measurement and reference zones preferably so that each reflection of a measurement or reference zone is received by several pixels. matrix detector or group of matrix detectors.

The transmission detector preferably comprises a photodiode for each measurement zone and for each reference zone. Each photodiode is preferably arranged to receive the transmission by a single measurement or reference zone.

The transmission and reflection detectors are preferably arranged to simultaneously generate their signals (possibly at different sampling frequencies).

The sample holder support is preferably arranged to receive the sample holder so that the sample holder extends in an oblique plane with respect to a propagation direction of the beam at the level of the sample. intersection between the light beam and the sample holder area.

The transmitter is preferably arranged to transmit plural wave lengths simultaneously and / or in a time-shifted manner.

According to yet another aspect of the invention, there is provided a sample holder (preferably for a device according to the invention) comprising a plurality of chambers made in a plate or tongue, characterized in that the chambers are included in FIG. the inside of a cylindrical zone having an axis perpendicular to the plate or tongue and preferably of less than or equal to 10 mm, preferably less than or equal to 5 mm.

The sample holder according to the invention may further comprise a receptacle arranged to receive a liquid, the chambers comprising:

at least one filtered measuring chamber, the sample holder further comprising, for each filtered measurement chamber, a supply channel arranged to conduct the liquid from the receptacle to the filtered measurement chamber, and means Filtration arranged on the path of the liquid between the receptacle and the filtered measuring chamber, and / or

at least one unfiltered measurement chamber, and for each unfiltered measurement chamber, a supply channel arranged to conduct the liquid from the receptacle to the unfiltered measurement chamber, and no filtration means disposed on the route liquid between the receptacle and the unfiltered measuring chamber.

The filtration means may be common to at least two filtered measurement chambers.

The or at least one of the measuring chambers may be a reaction measuring chamber, the sample holder being equipped with reagents arranged to mix with liquid coming from the receptacle and going into this reaction chamber.

The sample holder according to the invention may comprise, for one or more or all the measuring chamber (s), pumping means arranged for pumping the liquid from the receptacle and to one or more chamber (s).

Rooms may include:

a reference chamber filled with a reference solution, and / or a reference chamber, the sample holder further comprising a reservoir pre-filled with a reference solution, and a supply channel arranged to conduct the reference solution to the reference chamber.

The chambers may include a reference chamber filled with a gas (preferably air).

Said reference chamber filled with gas may be sealed or unsealed.

Rooms may include a reference hole.

The sample holder according to the invention may comprise in the cylindrical zone opaque zones and translucent zones:

the translucent zones preferably being located solely on the chambers, and being arranged for transmission of light through each of the chambers over a range of working wavelengths (preferably between 280 nm and 980 nm), and

the opaque zones being preferably arranged to cover any channel emerging from each of the chambers, and being arranged to decrease (preferably at least 90% in luminous intensity) a transmission of light through the sample holder at the level of each zone; opaque with respect to each translucent zone over the working wavelength range and / or decrease (preferably by at least 90% in light intensity) a reflection of light on the sample holder at each opaque zone with respect to to each translucent area over the working wavelength range.

According to yet another aspect of the invention, there is provided an assembly comprising an analysis device according to the invention and a sample holder according to the invention accommodated in the sample holder support of the analysis device according to the invention. characterized in that:

each measurement or reference zone of the analysis device according to the invention corresponds respectively to one of the measurement or reference chambers of the sample holder according to the invention, and / or

the position of the light beam on the sample holder according to the invention covers or corresponds to the cylindrical zone. According to yet another aspect of the invention, there is provided a method of analysis, comprising:

an emission, by a transmitter, of a beam of light

a sample holder is accommodated in a sample holder holder in a sample holder area, the sample holder area comprising at least one measurement zone and at least one reference zone, so that all the zones measurement and reference are illuminated by the beam of light,

the method further comprising: receiving, by a reflection detector and for each measurement zone, a reflection by this light beam measuring zone, and a generation of an associated signal, and a reception, by the reflection detector and for each or a part of the at least one reference area, a reflection, by reference area, of the light beam, and a generation of an associated signal, and / or

receiving, by a transmission detector and for each measurement zone, a transmission by this measurement zone of the light beam, and a generation of an associated signal, and a reception, by the transmission detector and for each reference area, a transmission by this reference area of the light beam, and a generation of an associated signal, the method further comprising:

a supply, by means of analysis, of information on a content of the at least one measurement zone as a function of the signals associated with the transmissions and / or reflections of the different measurement and reference zones.

The reflection detector may comprise a matrix detector or a group of matrix detectors. Each reception of the measurement or reference zone reflection preferably comprises a measurement or reference zone reflection reception by several pixels of the matrix detector or the group of matrix detectors.

The transmission detector may comprise a photodiode for each measurement zone and for each reference zone. Each measurement zone or reference zone reception preferably comprises a transmission reception of a single measurement or reference zone by a photodiode.

The transmission and reflection detectors preferably simultaneously generate their signals (possibly at different sampling frequencies).

The sample holder holder accommodates the sample holder preferably so that the sample holder extends in an oblique plane with respect to a direction of propagation of the light beam at the intersection between the light beam and the sample holder area.

The transmitter preferably emits several wavelengths simultaneously and / or staggered in time.

Description of the Figures and Embodiments

Other advantages and particularities of the invention will appear on reading the detailed description of implementations and non-limiting embodiments, and the following appended drawings:

FIG. 1 is a schematic front view of a preferred embodiment of a sample holder 1 according to the invention,

FIG. 2 is a schematic sectional view of the sample holder 1 according to the invention along axis H of FIG. 1,

FIG. 3 is a schematic view of a preferred embodiment of an analysis device 100 according to the invention in which the sample holder 1 of FIG. 1 is mounted,

FIG. 4 illustrates the steps of a method according to the invention for calibrating the analysis device 100 according to the invention of FIG. 3, and

FIG. 5 illustrates the steps of a method according to the invention for using the analysis device 100 according to the invention of FIG.

These embodiments being in no way limiting, it will be possible to consider variants of the invention comprising only a selection of characteristics described or illustrated subsequently isolated from the other characteristics described or illustrated (even if this selection is isolated within a sentence including these other characteristics), if this selection of features is sufficient to confer a technical advantage or to differentiate the invention from the state of the prior art. This selection comprises at least one preferably functional characteristic without structural details, and / or with only a part of the structural details if this part alone is sufficient to confer a technical advantage or to differentiate the invention from the state of the art. earlier. Firstly, with reference to FIGS. 1 and 2, a preferred embodiment of a sample holder 1 according to the invention will be described.

The sample holder 1 is of the disposable type, preferably for single use.

The sample holder 1 comprises several chambers 2, 3, 4, 5, 52,

This tab 6 is typically 30 mm long, 7 mm wide, and 300 μm thick. This tongue 6 is typically a polymer tongue (for example a cycloolefin copolymer (COC) or polydimethylsiloxane (PDMS)), in which various channels (micro-fluidics) and chambers and receptacles have been dug:

by rolling two plates 6a, 6b of 150 μm in thickness, and

by machining the channels (of diameter comprised in lpm and 100 μm, and of a typical length of 3 to 30 mm) by laser machining on one of the two plates 6a, 6b, and

by stacking and gluing the two plates 6a, 6b one on the other, and

- by digging the chambers by laser machining; for each chamber is hollowed, through the entire thickness of the tongue 6, along an axis perpendicular to the outer surface of the tongue 6, a cylinder (1 to 2 mm in diameter).

Each chamber 2, 3, 4, 5, 52, 54 is typically a cylinder about 1 mm in diameter and 300 μm thick.

The chambers 2, 3, 4, 5, 52, 54 are included inside a cylindrical zone 7:

- axis 40 perpendicular to the plate or tongue 6 and

- Of diameter 39 equal to a working diameter of preferably less than or equal to 10 mm, preferably less than or equal to 5 mm, thus giving the sample holder 1 a very compact appearance.

Each chamber 2, 3, 4, 5, 52, 54 is made by drilling a hole through the plate 6. For each of the chambers 2, 3, 4, 5, 52 (but not 54), each of the two sides is closed. hole (on both sides of the plate 6) by a film 36 plated on each of the two faces of the plate 6.

The inner face (that is to say in contact with the tongue 6) of each film 36 is plasma treated to increase the wettability thereof. The sample holder 1 further comprises a receptacle 8 arranged to receive a liquid, typically blood (for example 15 μ Ι_ of capillary blood).

The chambers 2, 3, 4, 5, 52, 54 comprise at least one measuring chamber 2, 3 filtered (two chambers 2 and 3 in FIG. 1).

The sample holder 1 further comprises, for each filtered measuring chamber respectively 2.3, a supply channel 9, 11, respectively, arranged to convey the liquid from the receptacle 8 to the filtered measuring chamber 2.3, and filtration means 10 disposed on the path of the liquid between the receptacle 8 and the filtered measuring chamber, respectively.

The sample holder 1 further comprises, for each filtered measuring chamber respectively 2.3, a discharge channel respectively 22, 23 arranged for an evacuation of air out of the chamber respectively 2 or 3 during filling of the chamber respectively 2, 3 by the liquid.

These filtration means 10 typically comprise a filtration membrane disposed on the top (10b) or the bottom (10a) of the receptacle 8, for example a membrane or a filter as described in the patent application FR2918900A1 or FR2923151A1 or FR2929135A1 or in The article "A smart pipette for free separation and delivery of plasma for on-site whole blood analysis" published in the journal "Analytical & Bioanalytical Chemistry" in February 2016 (Vol 408 Issue 5, pl391).

These filtration means 10 are preferably located at the bottom of only a portion of the receptacle 8, so as to filter to a portion of the chambers 2, 3 only (but not filter to the chamber 52 for example).

The filtration means 10 are arranged, from a drop of blood, to pass the blood plasma but block other elements, including blood cells, especially red blood cells.

The filtration means 10 are common to at least two filtered measurement chambers 2, 3. In the case of FIG. 1, the filtration means 10 are common to all the filtered measurement chambers 2, 3.

The chambers 2, 3, 4, 5, 52, 54 comprise at least one unfiltered measurement chamber 52 (only one unfiltered chamber 52 in FIG. 1). The sample holder 1 further comprises, for each unfiltered measurement chamber 52, a supply channel 59 arranged to conduct the liquid from the receptacle 8 to the unfiltered measurement chamber 52, and no filtration means disposed on the path of the liquid between the receptacle 8 and the unfiltered measurement chamber 52.

The sample holder 1 further comprises, for each unfiltered measurement chamber 52, a discharge channel 72 arranged to evacuate air from the chamber 52 during the filling of the chamber 52 with the liquid.

The or at least one of the measuring chamber (s) respectively 2, 3,

52 is a reaction measuring chamber. The sample holder 1 is equipped with chemical reagents 12, stored for each reaction chamber (according to the variant):

in liquid form in a tank 120, with pumping means 130 (of the same nature as the pumping means 13) arranged for pumping (more exactly pushing) the reagent from the tank 120 towards the chamber 3, and / or

- in dry form somewhere along the path of the liquid from the receptacle 8 to the reaction chamber respectively 2, 3, 52, preferably the supply channel respectively 9,

11, 59 of this reaction chamber to this reaction chamber respectively 2, 3, 52, said reagents 12 being arranged to mix in the liquid during contact with the liquid. In the case of Figure 1 to a single reaction chamber, there are the chemical reagents 12 stored for the reaction chamber 3:

- In liquid form in a tank 120 connected to the chamber 3 by a channel; more specifically, this tank 120 connects to the channel 11 just before a series of turns that go to the chamber 3 and ensure good mixing of the reagents with the liquid from the receptacle 8;

- In dry form in the reaction chamber 3 and arranged to mix in the liquid during contact with the liquid.

The chemical reagents may comprise a reagent intended to interact with blood in particular in order to perform a dosage of colorimetry and / or turbidimetry on the sample, for example a reference Arsenazo III reagent A92775 Sigma-Aldrich for performing the colorimetric determination of calcium.

The sample holder 1 comprises, for one or more or all the measuring chamber (s) (only for all the filtered chambers 2 and 3 in the case of FIG. 1), pumping means 13 arranged for pumping the liquid in from the receptacle 8 and to each measuring chamber 2, 3 equipped with these pumping means 13.

These pumping means 13 typically comprise pumping means arranged to push the liquid from the receptacle 8 and to each measuring chamber 2, 3 equipped with these pumping means 13, and have typically been manufactured as described in the article " A smart pipette for equipment-free separation and delivery of plasma for on-site whole blood analysis "published in the journal" Analytical & Bioanalytical Chemistry "in February 2016 (Vol 408 Issue 5, pl391).

The chambers 2, 3, 4, 5, 52, 54 also include one or more reference chambers, typically:

a reference chamber pre-filled with a reference solution, and / or

a reference chamber 4, the sample holder 1 further comprising a reservoir 14 pre-filled with a reference solution, a supply channel 15 arranged to conduct the reference solution to the reference chamber 4, and pumping means 16 (of the same nature as the pumping means 13) arranged to pump (more exactly push) the reference solution from the reservoir 14 to the reference chamber 4.

The sample holder 1 further comprises, for the reference chamber 4, a discharge channel 24 arranged for an evacuation of air from the chamber 4 during filling of the chamber 4 with the reference solution. The reference solution is typically a solution of 0.9% NaCl ("physiological saline") or distilled water.

The chambers 2, 3, 4, 5, 52, 54 comprise a reference chamber 5 filled with a gas (preferably air). Said reference chamber filled with gas can be: - sealed, if the gas is a specific gas that must not escape into the ambient air, or

advantageously unsealed (in particular if the gas is air) so that air can circulate between the chamber 5 and the outside of the sample holder 1, which makes it possible to avoid that the sample holder 1 deforms in case of pressure difference (caused for example by a variation in temperature) between the inside of the chamber 5 and the outside of the sample holder 1.

The reference chambers comprise a reference hole 54. This hole 54 is arranged so that, when the sample holder 1 is placed in air, a ray of light passing through the hole 54 passes through the sample holder 1 passing only by air.

The sample holder 1 comprises on its outer surfaces (preferably more exactly on each of the films 36), in the cylindrical zone 7, opaque zones 37 and translucent zones 38.

The translucent areas 38 are located only on the chambers 2, 3, 4, 5, 52, 54. The opaque areas 37 are everywhere else.

The translucent areas 38 all have the same properties of reflection and light transmission.

The translucent areas 38 are arranged to allow light transmission through each of the chambers 2, 3, 4, 5, 52, 54 (by passing through the sample holder 1 over a working wavelength range preferably between 280 nm and 980 nm.

The opaque areas 37 all have the same properties of reflection and light transmission.

The opaque areas 37 are arranged to cover any channel 9, 11, 15, 59, 22, 23, 24, 72 emerging from each of the chambers 2, 3, 4, 5, 52, 54.

The opaque zones 37 are arranged, over the working wavelength range, for:

prevent light transmission through the sample holder 1 at each opaque zone 37 and / or

prevent light reflection on the sample holder 1 at each opaque zone 37, or at least for:

decreasing (by at least 90% in light intensity) a light transmission through the sample holder 1 at each opaque zone 37 with respect to each translucent zone 38 over the working wavelength range and / or

decreasing (by at least 90% in light intensity) a reflection of light on the sample holder 1 at each opaque zone 37 with respect to each translucent zone 38 over the working wavelength range.

In a first variant, these translucent and opaque zones 37 are obtained respectively by:

translucent zones of the films 36 for the chambers 2, 3, 4, 5, 52 and a hole in the films 36 for the chamber 54

- opaque areas of the films 36.

Each film 36 is a polymer film (for example a cycloolefin copolymer (COC)), alone (for the translucent zones 38) or covered with a carbon layer (for the opaque zones 37).

In a second variant, these translucent 38 and opaque areas 37 are obtained by directly tinting the tongue 6 in the mass.

3, an embodiment of an analysis device 100 according to the invention accommodating the sample holder 1 in its sample-holder support 19 will now be described with reference to FIG.

The analysis device 100 comprises a transmitter 17, arranged to emit a collimated light beam 18 preferably having a uniform and substantially uniform (at 1%) energy and spectral distribution at least over the working diameter (ie over a diameter at least 5 or 10 millimeters) in the plane 33. The emitter 17 is for example a device for emitting a collimated light beam as described in the application WO2013 / 167824 and / or WO2015 / 018844.

The transmitter 17 comprises an electroluminescent diode (LED) or several electroluminescent diodes arranged to emit different wavelengths. The analysis device 100 comprises a support 19 of the sample holder.

The support 19 (typically a tongue slide) is arranged to receive the sample holder 1 in a sample holder zone 20, the sample holder zone 20 comprising at least one measurement zone 21 and at least one reference zone 25.

All the measurement zones 21 and 25 are inside the cylindrical zone 7:

of axis 40 perpendicular to plane 33, and

- 39 diameter equal to the working diameter preferably less than or equal to 10mm, preferably less than or equal to 5 mm.

The support 19 is arranged so that all the measurement zones 21 and 25 are illuminated by the single collimated light beam 18 (and not by several beams of light, even from the division (by separating blade (s) (s) or other) of a single initial beam).

The holder 19 of the sample holder is arranged to receive the sample holder 1 so that the sample holder 1 extends in an oblique plane (that is to say neither perpendicular nor parallel) with respect to a direction propagation 34 of the collimated light beam 18 at the intersection between the collimated light beam 18 and the sample holder area 20.

The oblique plane 33 forms an angle 60 less than 90 ° (preferably between 70 ° and 80 °, preferably 75 °) with the direction of propagation 34.

When the sample holder 1 is received in the support 19, each measuring zone 21 or reference 25 of the analysis device 100 corresponds respectively to one of the measuring chambers 2, 3, 52 or 4, 5, 54 of the sample holder 1.

When the sample holder 1 is received in the support 19, the position of the collimated light beam 18 (in particular its uniform energy distribution zone) encompasses the entire cylindrical zone 7.

The transmitter 17 is arranged to emit several wavelengths (in the previously described working wavelength interval) simultaneously and / or in a time-shifted manner. Thus, one can obtain signals of transmissions and reflections for several wavelengths. The transmitter 17 is thus arranged to control the spectrum of the beam 18 (via a monochromator, for example).

The analysis device 100 comprises a reflection detector 26.

The reflection detector 26 is arranged, for each measurement zone 21, to receive a reflection 27, by this measurement zone 21, of the collimated light beam 18, and to generate an associated signal.

In the present description, the term "generated signal" means an electrical signal.

The reflection detector 26 is arranged, for at least one of the so-called "reflected" reference zones (preferably for each reference zone 25, in the case of FIG. 3 for each reference zone except one corresponding to the reference hole 54) to receive reflection 28, by reflected reference area 25, of the collimated light beam 18, and to generate an associated signal.

The analysis device 100 comprises a transmission detector 29.

The transmission detector 29 is arranged, for each measuring zone 21, to receive a transmission 30, by this measurement zone 21, of the collimated light beam 18, and to generate an associated signal.

The transmission detector 29 is arranged, for each reference zone 25, to receive a transmission 31, by this reference zone 25, the collimated light beam 18, and generate an associated signal.

Thus, the optical spectroscopy device 100, for characterizing a blood sample or the like placed in the receptacle 8 of the sample holder 1, is designed to measure its spectral transmission on the one hand and also its spectral reflection on the other hand, which amounts to characterizing the complex refractive index of the sample.

As many transmitted beams are obtained as there are optical chambers 2, 3, 4, 5, 52, 54 (measurement or reference) from a single incident beam 18.

As many reflected beams are obtained as there are optical measuring chambers 2, 3, 52 from a single incident beam 18. At least one beam reflected by reference optical chambers 4, 5, 54 is obtained from a single incident beam 18 (only for chambers 4 and 5 in the case it shines in the figures).

By measuring the intensity of these different transmitted and reflected beams, it is then possible to determine the spectral absorption and reflection properties of samples with the same benefits as conventional dual beam spectroscopy; but in a lesser flight, and at a lower cost.

From measurements of the spectral transmission factors and spectral reflections of the reference chamber (s) 4, 5, 54 and the measuring chamber (s) 2, 3, 52, it is possible to calculate the spectral complex refractive ind ective of a sample independently of that of the sample holder windows 1.

Typically, in a simple case not with six chambers but with only the measuring chamber and the reference chamber shown in FIG. 3, the absorption of the sample with respect to the reference to the length of the wave λ is A _x = log (-) and the reflection factor

^ B

of the sample relative to the reference to the wavelength λ is

R _x = - or R _x = - with the correction of a background noise D _ark with: the ^~ D _ark

I _has the signal corresponding to the transmission 31,

I _B the signal corresponding to the transmission 30,

I _c the signal corresponding to the reflection 28, and

I _D the signal corresponding to reflection 27.

The transmission detector 29 comprises a photodiode 35 for measuring zone 21 and for reference zone 25, each photodiode 35 being arranged to receive the transmission 30, 31 by a single measurement or reference zone 21, 25.

The transmission detector 29 may thus comprise a plurality of photodiodes (s), some photodiodes of which may for example be grouped together in a detector of the PSD type (for "Position Sensing").

Detectors ") or a photodiode array. The photodiodes can for example be grouped up to a number of sixteen in a reference detector U DT-4x4D of OSI-Optoelectronic.

In FIG. 3, it can be seen for example that the detector 29 comprises in particular two photodiodes 35 for the pair of zones comprising:

the measuring zone 21 corresponding to the chamber 52, and

the reference zone 25 corresponding to the chamber 5.

Each photodiode 35 thus allows a detection of light signals and a generation of high frequency transmission electrical signals (typically 14 bits and between 10 and 500 MHz).

The reflection detector 26 comprises a matrix detector or a group of matrix detectors (for example of the CCD type), arranged to receive the reflections 27, 28 of the measurement zones 21 and preferably 25 so that each reflection 27, 28 a measurement or reference zone is received by several pixels of the matrix detector or the group of matrix detectors.

Sensors of this type have several advantages for beams reflected with respect to photodiodes:

- they are more sensitive because they integrate over a long time (which is good for reflection intensities typically 10 to 100 times lower than the transmission intensities)

they allow a tolerance on an inaccuracy of the inclination of the sample holder 1 in its support 19 by different possible pixels that can be struck (with respect to a fixed photodiode 35)

Typically, the reflection detector 26 comprises a single Omnivision reference detector OV16825-2A for all the measurement zones 21 and 25.

The transmission and reflection detectors 26, 29 are arranged to simultaneously generate their signals (possibly at different sampling frequencies). Thus, the device 100 is arranged to simultaneously detect the reflections 27, 28 and the transmissions 30, 31. The analysis device 100 comprises analysis means 32 arranged to provide information on a content of the at least one measurement zone 21 as a function of the signals associated with the transmissions 30, 31 and reflections 27, 28 of the different zones of the transmission. measure 21 and reference 25.

The means 32 comprise only technical means, for example a computer, and / or a central or computing unit, and / or an analog electronic circuit (preferably dedicated), and / or a digital electronic circuit (preferably dedicated), and / or a microprocessor (preferably dedicated), and / or software means. These analysis means 32 comprise for example:

for each photodiode 35: a transimpedance 41 (current transformation in voltage with gain and impedance matching) an amplifier 42, and an analog / digital converter 43,

downstream of each photodiode 35 (after the means 41, 42, 43 described above): a programmable logic circuit 44 (FPGA or "field-programmable grating array")

a processor 45 (CPU or "central processing unit") located downstream of the detectors 26 and 29.

With reference to FIG. 4, the device 100 (and more specifically the means 32) are calibrated or calibrated according to the method according to the invention: for each reference sample from a reference sample bank, measurements are made X signal reflections and transmissions by the sensors 26 and 29 of the device 100 and further determination of relevant variables Y by other analyzes (typically chemical or otherwise). Relevant variables include, for example, a value (within a restricted range) of a concentration of a particular chemical compound. A predictor is then constructed which correlates the measured signals X and the relevant variables by an automatic learning method (or "machine learning" in English) or otherwise. For example, a non-exhaustive list could be used: a correspondence table, a method random forests, principal component analysis, multiple linear regression or artificial neural network with cross-validation on subsamples (K-fold cross validation), etc.

We will now describe steps of a preferred embodiment of the method according to the invention.

First, the sample holder 1 in the sample holder area 20 is accommodated in the sample holder holder 19, the sample holder area 20 comprising the at least one measurement zone 21 and the at least one reference zone 25, so that all the measurement zones 21 and 25 are illuminated by the collimated light beam 18.

The holder 19 of the sample holder accommodates the sample holder 1 so that the sample holder 1 extends in the plane 33 oblique with respect to the direction of propagation 34 of the collimated light beam 18 at the intersection between the collimated light beam 18 and the sample holder area 20.

Each respectively measuring zone 21 or reference 25 of the analysis device 100 corresponds respectively to one of the measuring chambers 2, 3, 52 or reference 4, 5, 54 of the sample holder 1. This correspondence or this good optical alignment is made by adjusting the position of the sample holder 1 in its support 19. The beam 18 is fixed in the device 100.

Then, the sample (typically a drop of blood) is placed in the sample holder, more exactly in the receptacle 8. It is expected, typically a few minutes, that the blood is filtered by the filtration means and / or that the liquid ( the blood without filtration or the result of the filtration) is conveyed to each chamber 2, 3, 52 connected to the receptacle 8, possibly mixing with the reagent 12.

Next, this embodiment of the method according to the invention comprises an emission, by the transmitter 17, of the collimated light beam 18.

The transmitter 17 emits several wavelengths, simultaneously and / or preferably being shifted in time. Next, this embodiment of the method according to the invention comprises, for each transmission shifted in time by the transmitter 17 (and therefore preferably for each emitted wavelength):

a reception, by the reflection detector 26 and for each measurement zone 21, of a reflection 27 by this measurement zone 21 of the collimated light beam 18, and a generation of an associated signal,

receiving, by the reflection detector 26 and for each or a part of the at least one reference area 25, a reflection 28, by reference area 25, of the collimated light beam 18, and a generation of an associated signal,

the reflection detector 26 comprises the matrix detector or the group of matrix detectors, and each reception of the reflection 27, 28 of measurement or reference zone comprises a reflection reception 27, 28 of measurement or reference zone by several pixels the matrix detector or the group of matrix detectors,

a reception, by the transmission detector 29 and for each measuring zone 21, of a transmission 30 by this measuring zone 21 of the collimated light beam 18, and a generation of an associated signal,

a reception, by the transmission detector 29 and for each reference zone 25, of a transmission 31 by this reference zone 25 of the collimated light beam 18, and a generation of an associated signal,

the transmission detector 29 comprises a photodiode 35 per measurement zone 21 and by reference zone 25, and each transmission reception 30, 31 of measurement or reference zone comprises a transmission reception of a single zone 21, 25 of measurement or reference by a photodiode 35.

The transmission and reflection detectors 26, 29 simultaneously generate their signals (possibly at different sampling frequencies). Next, this embodiment of the method according to the invention comprises a supply, by the analysis means 32, of information on a content of the at least one measurement zone 21 as a function of the various signals associated with the transmissions 30. , 31 and reflections 27, 28 of the different measurement zones 21 and 25 and possibly for different wavelengths. With reference to FIG. 5, these different signals are input data of the predictor whose calibration has been described with reference to FIG. 4. The analysis means 32 implement a prediction calculation based on this predictor. , and thus estimate Y variables representative of information on a content of the at least one measurement zone 21, comprising, for example: absorption property and / or spectral reflection of the content of the at least one measurement zone 21, optical index, pH, chemical concentration, etc.

Of course, the invention is not limited to the examples that have just been described and many adjustments can be made to these examples without departing from the scope of the invention.

Of course, the various features, shapes, variants and embodiments of the invention can be associated with each other in various combinations to the extent that they are not incompatible or exclusive of each other. In particular all the variants and embodiments described above are combinable with each other.

Claims

An analyzing device (100), comprising:

a transmitter (17) arranged to emit a light beam (18), - a sample holder support (19):

arranged to accommodate a sample holder (1) in a sample holder area (20), the sample holder area (20) comprising at least one measuring area (21) and at least one reference area (25). ), and

arranged so that all the measurement (21) and reference (25) zones are illuminated by the light beam (18), said device comprising at least one of:

a reflection detector (26):

o arranged, for each measurement zone (21), to receive a reflection (27), by this measurement zone (21), of the light beam (18), and to generate an associated signal,

arranged for each or a portion of the at least one reference area (25) to receive a reflection (28), by reference area (25), of the light beam (18), and to generate an associated signal ,

a transmission detector (29):

o arranged, for each measurement zone (21), to receive a transmission (30), by this measurement zone (21), of the light beam (18), and to generate an associated signal,

o arranged, for each reference area (25), to receive a transmission (31), by this reference area (25), of the light beam (18), and to generate an associated signal,

said device further comprising:

analysis means (32) arranged to provide information on a content of the at least one measurement zone (21) as a function of the signals associated with the transmissions (30, 31) and / or reflections (27, 28) of the different measurement (21) and reference (25) zones.

Device according to Claim 1, characterized in that it comprises the reflection detector and in that the reflection detector (26) comprises a matrix detector or a group of matrix detectors, arranged to receive the reflections (27, 28) of the measurement (21) and reference (25) zones so that each measurement or reference area reflection (27, 28) is received by several pixels of the matrix detector or matrix detector group.

Device according to Claim 1 or 2, characterized in that it comprises the transmission detector and in that the transmission detector (29) comprises a photodiode (35) for each measurement zone (21) and for each reference zone (25). ), each photodiode (35) being arranged to receive the transmission (30, 31) by a single zone (21, 25) measurement or reference.

Device according to any one of the preceding claims, characterized in that it comprises the reflection detector and the transmission detector and in that the transmission and reflection detectors (26, 29) are arranged to simultaneously generate their signals.

Device according to any one of the preceding claims, characterized in that the holder (19) of the sample holder is arranged to receive the sample holder (1) so that the sample holder (1) extends in a plane (33) oblique with respect to a propagation direction (34) of the light beam (18) at the intersection of the light beam (18) and the sample holder area (20).

Device according to any one of the preceding claims, characterized in that the transmitter (17) is arranged to emit several wavelengths simultaneously and / or shifted in time.

7. An assembly comprising an analysis device (100) according to any one of claims 1 to 6 and a sample holder (1) accommodated in the sample holder holder (19) of the analysis device (100), characterized in that

the sample holder (1) comprises a plurality of chambers (2, 3, 4, 5,

52, 54) made in a plate or tongue (6), the chambers (2, 3, 4, 5, 52, 54) being included inside a cylindrical zone (7) with an axis perpendicular to the plate or tongue (6) and of diameter less than or equal to 10 mm.

each measurement zone (21) or reference zone (25) of the analysis device corresponds respectively to one of the measuring chambers (2, 3, 52) or to reference chambers (4, 5) of the sample holder (1), and or

the position of the light beam (18) on the sample holder (1) covers or corresponds to the cylindrical zone (7).

8. The assembly of claim 7, characterized in that the sample holder (1) further comprises a receptacle (8) arranged to receive a liquid, the chambers comprising:

at least one measuring chamber (2, 3) filtered, the sample holder

(1) further comprising for each filtered measuring chamber (2, 3) a feed channel (9, 11) arranged to convey the liquid from the receptacle (8) to the filtered measuring chamber (2, 3) , and filtration means (10) disposed on the path of the liquid between the receptacle (8) and the filtered measuring chamber (2,3), and / or

at least one unfiltered measurement chamber (52), and for each unfiltered measurement chamber (52), a supply channel (59) arranged to conduct the liquid from the receptacle (8) to the measuring chamber unfiltered (52), and no filtration means disposed on the path of the liquid between the receptacle (8) and the unfiltered measuring chamber (52).

9. The assembly of claim 8, characterized in that the filtering means (10) are common to at least two filtered measuring chambers (2, 3).

10. The assembly of claim 8 or 9, characterized in that the or at least one of the measuring chambers (2, 3, 52) is a reaction measuring chamber, the sample holder (1) being equipped with chemical reagents. (12) arranged to mix with liquid from the receptacle (8) and into this reaction chamber (2, 3, 52).

11. Assembly according to any one of claims 8 to 10, characterized in that the sample holder (1) comprises, for one or more or all the measuring chamber (2, 3, 52), means pumping station (13) arranged to pump the liquid from the receptacle (8) and to one or more chambers (s).

12. Assembly according to any one of claims 7 to 11, characterized in that the chambers comprise:

a reference chamber filled with a reference solution, and / or

a reference chamber (4), the sample holder (1) further comprising a reservoir (14) pre-filled with a reference solution, and a supply channel (15) arranged to conduct the reference solution to the reference chamber (4).

13. An assembly according to any one of claims 7 to 12, characterized in that the chambers comprise a reference chamber (5) filled with a gas.

14. Assembly according to any one of claims 7 to 13, characterized in that the chambers comprise a reference hole (54).

15. An assembly according to any one of claims 7 to 14, characterized in that the sample holder (1) comprises in the cylindrical zone (7) opaque zones and translucent zones:

the translucent zones being situated only on the chambers (2, 3, 4, 5, 52, 54), and being arranged for transmission of light through each of the chambers (2, 3, 4, 5, 52, 54) over a range of working wavelengths, and

the opaque zones being arranged to cover any channel (9, 11, 15, 59, 22, 23, 42, 72) emerging from each of the chambers (2, 3, 4, 5, 52, 54), and being arranged to decreasing a light transmission through the sample holder at each opaque zone with respect to each translucent zone over the working wavelength range and / or reducing a reflection of light on the sample holder at each opaque zone relative to each translucent area over the working wavelength range.

16. An analysis method (100), comprising:

emitting, by a transmitter (17), a light beam (18) - a sample holder (1) is accommodated in a sample holder holder (19) in a sample holder area (20). ), the sample holder region (20) comprising at least one measurement zone (21) and at least one reference zone (25), so that all the measurement (21) and reference (25) zones are illuminated by the light beam (18),

the method further comprising:

receiving, by a reflection detector (26) and for each measurement zone (21), a reflection (27) by this measurement zone (21) of the light beam (18), and a generation of a associated signal, and a reception, by the reflection detector

(26) and for each or a part of the at least one reference area (25), a reflection (28), by reference area (25), the light beam (18), and a generation of an associated signal, and / or receiving, by a transmission detector (29) and for each measurement zone (21), a transmission (30) through this measurement zone (21) of the light beam (18), and generating a signal, and a reception, by the transmission detector (29) and for each reference area (25), of a transmission (31) by this reference area (25) of the light beam (18), and a generating an associated signal, the method further comprising:

a supply, by analysis means (32), of information on a content of the at least one measurement zone (21) as a function of the signals associated with the transmissions (30, 31) and / or reflections (27). , 28) of the different measuring (21) and reference (25) zones.

Method according to claim 16, characterized in that the reflection detector (26) comprises a matrix detector or a group of matrix detectors, and in that each reception of the reflection (27, 28) of the measuring zone or reference comprises a reflection zone reception (27, 28) by a plurality of pixels of the matrix detector or matrix detector group.

Method according to claim 16 or 17, characterized in that the transmission detector (29) comprises a photodiode (35) for each measurement area (21) and reference area (25), and that each reception of measurement or reference zone transmission (30, 31) comprises a transmission reception of a single measurement or reference zone (21, 25) by a photodiode (35).

19. Method according to any one of claims 16 to 18, characterized in that the transmitters and reflection detectors (26, 29) simultaneously generate their signals.

20. Process according to any one of claims 16 to 19, characterized in that the holder (19) of the sample holder accommodates the sample holder (1) so that the sample holder (1) extends in a plane (33) oblique to a propagation direction (34) of the light beam (18) at the intersection of the light beam (18) and the sample holder region (20).

21. Method according to any one of claims 16 to 20, characterized in that the transmitter (17) emits several wavelengths simultaneously and / or staggered in time.