EP1337860A2 - Automatic immunoassay apparatus - Google Patents

Automatic immunoassay apparatus

Info

Publication number
EP1337860A2
EP1337860A2 EP01998838A EP01998838A EP1337860A2 EP 1337860 A2 EP1337860 A2 EP 1337860A2 EP 01998838 A EP01998838 A EP 01998838A EP 01998838 A EP01998838 A EP 01998838A EP 1337860 A2 EP1337860 A2 EP 1337860A2
Authority
EP
European Patent Office
Prior art keywords
reaction
samples
bars
supporting
wells
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Withdrawn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
EP01998838A
Other languages
German (de)
French (fr)
Inventor
Karine Bizet
Bruno Vallayer
Maurice Vattaire
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bertin Technologies SAS
Original Assignee
Bertin Technologies SAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bertin Technologies SAS filed Critical Bertin Technologies SAS
Publication of EP1337860A2 publication Critical patent/EP1337860A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/025—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations having a carousel or turntable for reaction cells or cuvettes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G01N2001/1006—Dispersed solids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N2035/00346—Heating or cooling arrangements
    • G01N2035/00356—Holding samples at elevated temperature (incubation)
    • G01N2035/00366—Several different temperatures used
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0439—Rotary sample carriers, i.e. carousels
    • G01N2035/0441—Rotary sample carriers, i.e. carousels for samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0439—Rotary sample carriers, i.e. carousels
    • G01N2035/0443—Rotary sample carriers, i.e. carousels for reagents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0439—Rotary sample carriers, i.e. carousels
    • G01N2035/0444—Rotary sample carriers, i.e. carousels for cuvettes or reaction vessels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0439—Rotary sample carriers, i.e. carousels
    • G01N2035/0446—Combinations of the above
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/24—Automatic injection systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016—Control of the volume dispensed or introduced

Definitions

  • the present invention relates to an automatic device for assaying different substances in biological or chemical samples, using known assay methods, for example of the type
  • Apparatuses of this type are known in which samples to be analyzed, reagents and reaction cuvettes are carried by different trays rotatably mounted around vertical axes and generally arranged in a triangle, the trays of samples and reagents being on the outside of the reaction cuvettes and more or less tangent or adjacent thereto. Swivel arms are arranged between the sample and reagent trays and the reaction cuvette tray for taking determined quantities of samples and reagents and for depositing them in reaction cuvettes carried by the corresponding tray.
  • the step-by-step rotation of this plate makes it possible to scroll the reaction cuvettes and successively in the stations for loading samples and reagents then in stations for heating and temperature regulation, rinsing, depositing of substrate, reading of results and optionally washing of the reaction cuvettes, the apparatus being controlled by computer to carry out previously programmed analysis cycles, corresponding to single-reactive or bi-reactive assays.
  • the invention relates to an apparatus of this type, which has a relatively small footprint, which is movable or transportable, which is adaptable to any type of dosage and which can nevertheless operate at high speed to perform a relatively large number of different dosages on a relatively small number of samples or a relatively small number of different assays on a relatively large number of samples.
  • an automatic device for dosing substances in biological or chemical samples comprising means for supporting reagents, means for supporting samples to be analyzed, means for supporting reaction cuvettes, means for taking samples to be analyzed and for reagents and for injecting these samples into the reaction cuvettes, means for rinsing the reaction cuvettes, and means for optically reading the results, characterized in that the support means d 'samples and the support means of the reaction cuvettes are coaxial rotary plates and in that the sampling and injection means are carried by a radial arm extending between the common axis of the plates and their periphery and are movable in translation along this arm, the latter being rotatable around the axis of the plates.
  • the mounting of the sample support plates and reaction cuvettes around the same axis of rotation makes it possible to significantly reduce the overall size of the dosing device.
  • the arrangement of the sampling and injection means on a radial arm which extends between the common axis of the turntables and their periphery allows samples and reagents to be taken quickly and easily to deposit them in the reaction cuvettes, without increasing the size of the device.
  • the plates and the radial arm of the withdrawal and injection means can be carried by the same central tube which defines the axis of rotation of the plates and the upper end of which supports the radial arm. cited above.
  • the displacement of the radial arm in rotation around the axis of the plates makes it possible in particular to accelerate the taking of samples and reagents and their deposit in the reaction cuvettes.
  • this radial arm it is advantageous for this radial arm to carry two withdrawal and injection units, each mounted on a carriage guided in translation on one side of the radial arm, and means for moving the two carriages independently of one of the other on the radial arm.
  • each sampling and injection unit comprises controlled means for moving a needle holder in vertical translation on the corresponding carriage.
  • the reaction cuvettes are formed by bars, each of which is formed with a determined number of aligned reaction wells in a longitudinal direction of the bar, and the support plate for these bars includes means for radial and angular positioning and immobilization of said bars relative to the common axis of the plates.
  • the bars are carried by supports in the form of a circular sector, which comprise fixing means, for example of the snap type, on the turntable or on the hub of this turntable. This facilitates the initial positioning of the bars as well as their replacement.
  • the support plate of the bars comprises means of heating and individual thermal regulation of the bars, comprising for example electrical resistances placed on the walls of the wells of the bars and controlled means of electrical supply. of these resistances.
  • the individual heating and thermal regulation of the bars makes it possible to adapt their temperature cycles to the dosages to be carried out, which may differ from one bar to another.
  • the support plate for samples to be analyzed comprises, at its radially external periphery, means for receiving tubes or the like intended to receive the samples to be analyzed, these tubes being distributed over the plate along 'at least one arc of a circle.
  • the reagent support means are fixed and arranged in an arc around the plates of support for samples to be analyzed and reaction cuvettes.
  • these support means are equipped with refrigeration means, making it possible to maintain the temperature of the reactants at an appropriate value below ambient temperature.
  • the rotational movements of the plates and of the radial arm are controlled by data processing means, of the microcomputer type, which are programmed to optimize the taking and injecting of samples and reagents according to the number and nature of the assays to be carried out and for passing the reaction cuvettes through the reading means at the end of the assay reaction, without loss of time.
  • data processing means of the microcomputer type, which are programmed to optimize the taking and injecting of samples and reagents according to the number and nature of the assays to be carried out and for passing the reaction cuvettes through the reading means at the end of the assay reaction, without loss of time.
  • the reaction cuvettes are brought to the means for reading results, not in the order in which they are on their support plate, but in the order of completion of the assay reactions carried out in these cuvettes. This increases the operating rate of the device according to one invention.
  • the means for reading the results of the assays are of the optical type and include different systems, for example one for measuring the light absorption of the contents of the reaction cuvettes at determined wavelengths, another for measuring chemiluminescence of the contents of these cuvettes, and another for the measurement of light emission, following a light excitation, of the contents of the cuvettes (fluorescence).
  • the device according to the invention can also be used in combination with other measuring devices, for example of the flow cytometry type or of the HPLC (High Performance Liquid Chro atography) type, the device according to the invention used to prepare mixtures of cells which are then analyzed by the associated devices.
  • other measuring devices for example of the flow cytometry type or of the HPLC (High Performance Liquid Chro atography) type, the device according to the invention used to prepare mixtures of cells which are then analyzed by the associated devices.
  • the reaction bars are characterized in that certain wells of each bar are sealed in a sealed manner with a removable cover and contain determined quantities of specific reagents for the determination of at least one sample in the other wells of the strip.
  • the lids sealing the wells containing the reagents it suffices to remove the lids sealing the wells containing the reagents and to place the strips on the corresponding support plate in the apparatus according to the invention.
  • the reagents are taken from the corresponding wells of the strip and deposited in the adjacent wells, with the samples to be analyzed.
  • FIG. 2 is a schematic view in axial section of this device
  • Figure 3 is a schematic perspective view of this device.
  • the metering device according to the invention shown in the drawings, comprises a chassis 10 of mechanically welded tubes, which carries a vertical central tube 12 on which two axially spaced plates 14, 16 are mounted and guided in rotation by means of bearings with bearings.
  • the upper plate 14 is intended to support sets of reaction cuvettes which are formed by bars 18 each comprising several reaction wells 20 aligned in the longitudinal direction of the bar, the number of wells per bar being eight in this example.
  • the bars 18 are positioned radially on the plate 14 relative to the common axis 22 of rotation of the plates 14 and 16 and are held in position by means with spring blades.
  • the surface of the plate 14 is divided into a certain number of circular sectors which are independent of each other and which are fixed to the hub of the plate 14, for example by elastic snap-fitting or the like.
  • the bars 18 are placed and fixed ably on supports in the form of circular sectors which are positioned and removably fixed on the plate 14.
  • tools can be placed on these supports consumables, such as for example tubular sampling and injection cones, which are intended to be used each once for collecting a sample and depositing it in a well of a bar 18 and which are discarded after use.
  • These removable supports S can each carry 4, 6 or 8 bars 18 and the consumable tools correspondents, for example, and have been shown schematically in dotted lines in FIG. 1.
  • the lower plate 16 is intended for the support of samples to be analyzed, contained in liquid form in tubes 24 which are received in supports 26 arranged at the external periphery of the plate 16 and distributed in an arc of a circle, the tube supports 26 being 10 in number in the example of Figure 1.
  • the plates 14 and 16 are rotated step by step about the axis 22 independently of one another by means of belts toothed by electric motors.
  • a surface 28 for reagent support is fixedly mounted on the chassis 10 and extends in an arc of a circle over approximately 180 ° around the axis 22, radially outside the plate 16 and substantially at the level thereof.
  • This surface 28 is intended to carry a certain number of sets 30 of reagents, each corresponding to a different assay to be carried out on the samples to be analyzed.
  • the surface 28 may also include a zone 32 for receiving samples to be analyzed and a zone 34 for supporting the bottles 36 which may contain, inter alia, substrates, antibodies, sera, etc.
  • the part of the surface 28 which supports the sets of reagents 30 is equipped with refrigeration means, making it possible to maintain these reagents at a determined temperature of 4 ° C. for example.
  • the surface 38 also supports a system 44 for optical reading of the assay results by measuring the light absorption of certain wavelengths by the contents of the wells 20 of the reaction bars, this reading system 44 being followed by another system. 46 for reading the results by measuring the chemiluminescence of the liquids contained in the wells of the reaction strips 20.
  • Another system for reading results by measuring fluorescence can be provided in the apparatus according to the invention, in addition to systems 44 and 46 or in place of one of them, this other system comprising means for light excitation of the contents of the reaction cuvettes and of the means for measuring the light emission resulting from this excitation.
  • a radial arm 48 is rotatably mounted on the upper end of the central tube 12 and extends horizontally between the axis of rotation 22 and the periphery of the device.
  • This arm 48 carries two withdrawal and injection units 50 which are movable independently of one another in translation along the arm 48.
  • Each unit 50 comprises a carriage 52 guided in translation on a horizontal rail 54 of the arm 48 and driven by an electric motor.
  • Each carriage 52 comprises a vertical upright 56 carrying a rail 58 for guiding a needle holder 60 movable in translation on the rail 58 by an electric motor.
  • the arm 48 is secured to a vertical plate 62 which supports a linear actuator of the syringe pump type, as well as a syringe and a solenoid valve connected by tubes 64 to needles 60 of the aforementioned units 50 for sampling and injection.
  • a pushing liquid is contained in the syringe, the solenoid valve and part of the tubes 64, which makes it possible to withdraw and inject by means of the needles 60 small quantities of liquid, determined with precision.
  • a central well 66 allows the needles 60 to be cleaned after each use.
  • the radial arm 48 is rotated by an electric motor and a toothed belt.
  • the reaction bars 18 which are used in the apparatus according to the invention are made of glass or transparent plastic material, to allow the optical reading of the assay results. These bars can be of a reusable type, after washing and decontamination, or else disposable after a single use.
  • reaction wells 20 can undergo a treatment which makes them specific to the substances to be detected, this treatment comprising for example the deposition of an antibody coating on the inner wall of reaction wells 20.
  • reaction bars include individual heating and thermal regulation means, comprising electrical resistances, formed of wires or films deposited or glued to the external lateral surface of these wells.
  • the means provided on the plate 14 for positioning and immobilizing the bars include controlled means for supplying electrical power to the heating resistors of the wells of the bars, for a heating and individual thermal regulation of each bar.
  • each reaction strip can comprise a certain number of wells which will be used to store specific reagents for one or more determined determinations.
  • four wells of a strip comprising eight reaction wells can contain determined quantities of specific reagents of a given assay and are sealed with a removable or tear-off seal. For their use, these bars are placed on the plate 14 after removal or tearing of the aforementioned lids.
  • the reagents corresponding to the assays to be carried out are placed on the support surface 28 fixed around the plates 14 and 16.
  • Reaction bars 18, preferably new, are placed on the plate 14.
  • Samples to be analyzed are contained in the tubes 26 placed in the housings 24 of the lower plate 16.
  • the start-up of the apparatus controlled by computer, makes it possible to take, by means of the units 50, predetermined quantities of samples in the tubes 26 and of reagents in sets 30 and deposit them in the wells of the reaction bars.
  • the sample tubes 26 are identified and identified by bar code labels, readable by a reader mounted adjacent to the periphery of the plate 16.
  • the reaction bars 18 are identified by their angular position relative to a radial reference on the plate 14, these positions being numbered from 1 to 30 in the example shown.
  • the two sampling units 50 mounted on the arm 48 make it possible to accelerate the deposition of samples and reagents in the wells of the reaction bars 18, in the following manner: when a unit 50 is used to take a sample or a reagent and to deposit it in a reaction well, the other unit 50 is moved towards the axis 22 for cleaning its needle. Then, this other unit 50 is used for removal and deposition, and the first unit 50 is moved towards the axis 22 for cleaning its needle.
  • the plate 14 is rotated in one direction, then in the other, to place the wells of a bar 18 in radial alignment with the needle 60 of the unit 50 used for depositing a sample or reagent.
  • the rotations of the plates 14 and 16 allow the bars and the samples to be brought into alignment.
  • the temperatures of the bars 18 are regulated bar by bar.
  • each bar is brought, by rotation of the plate 14, to the reading means 44 or 46 in the order of completion of the reactions in the wells of the bars.
  • the apparatus according to the invention can also be used with other means for measuring results, for example with means for cytometric or chromatographic measurement. It then essentially serves as an apparatus for preparing cell mixtures and is associated by means of sampling and deposition either with a system of the HPLC type (High Performance Liquid Chromatography) or with a flow cytometry system. As is known, such a system allows the study and characterization of cells after marking with fluorescent markers and comprises fluidic means for presenting the cells one by one in front of optical detection means associated with light excitation means (for example laser), and with signal and data processing means . Three types of signals are measured:

Abstract

The invention concerns an immunoassay apparatus, comprising coaxial rotating trays (14) supporting reaction dishes (18) and (16) supporting tubes (24) containing samples to be analysed, means for driving said trays in rotation about a common axis, and means (28) supporting reagents, extending in an arc around said rotating trays.

Description

Appareil automatique de dosage immunologique Automatic immunoassay device
La présente invention concerne un appareil automatique de dosage de différentes substances dans des échantillons biologiques ou chimiques, au moyen de méthodes de dosages connues, par exemple du typeThe present invention relates to an automatic device for assaying different substances in biological or chemical samples, using known assay methods, for example of the type
ELISA.ELISA.
On connaît des appareils de ce type dans lesquels des échantillons à analyser, des réactifs et des cuvettes de réaction sont portés par des plateaux différents montés à rotation autour d'axes verticaux et disposés en général en triangle, les plateaux d'échantillons et de réactifs étant à l'extérieur du plateau des cuvettes de réaction et plus ou moins tangents ou adjacents à celui-ci. Des bras pivotants sont agencés entre les plateaux d'échantillons et de réactifs et le plateau des cuvettes de réaction pour prélever des quantités déterminées d'échantillons et de réactifs et pour les déposer dans des cuvettes de réaction portées par le plateau correspondant. La rotation pas à pas de ce plateau permet de faire défiler les cuvettes de réaction et successivement dans les postes de chargement d'échantillons et de réactifs puis dans des postes de chauffage et de régulation de température, de rinçage, de dépôt de substrat, de lecture de résultats et éventuellement de lavage des cuvettes de réaction, l'appareil étant piloté par ordinateur pour effectuer des cycles d'analyse préalablement programmés, correspondant à des dosages mono-réactifs ou bi-réactifs.Apparatuses of this type are known in which samples to be analyzed, reagents and reaction cuvettes are carried by different trays rotatably mounted around vertical axes and generally arranged in a triangle, the trays of samples and reagents being on the outside of the reaction cuvettes and more or less tangent or adjacent thereto. Swivel arms are arranged between the sample and reagent trays and the reaction cuvette tray for taking determined quantities of samples and reagents and for depositing them in reaction cuvettes carried by the corresponding tray. The step-by-step rotation of this plate makes it possible to scroll the reaction cuvettes and successively in the stations for loading samples and reagents then in stations for heating and temperature regulation, rinsing, depositing of substrate, reading of results and optionally washing of the reaction cuvettes, the apparatus being controlled by computer to carry out previously programmed analysis cycles, corresponding to single-reactive or bi-reactive assays.
Ces appareils connus sont complexes et encombrants et sont en général conçus pour réaliser de façon répétitive un petit nombre de dosages différents à cadence élevée sur un grand nombre d'échantillons. Du fait de leur encombrement et de leur complexité, ils sont installés à poste fixe et il n'est pas envisageable de les transporter ou de les déplacer, sauf de façon tout à fait exceptionnelle .These known devices are complex and bulky and are generally designed to repeatedly perform a small number of different assays at a high rate on a large number of samples. Due to their size and their complexity, they are installed in a fixed position and it is not possible to transport or move them, except in quite exceptional cases.
L'invention a pour objet un appareil de ce type, qui ait un encombrement relativement faible, qui soit déplaçable ou transportable, qui soit adaptable à tout type de dosage et qui puisse néanmoins fonctionner à cadence élevée pour effectuer un nombre relativement important de dosages différents sur un nombre relativement petit d'échantillons ou un nombre relativement petit de dosages différents sur un nombre relativement grand d'échantillons.The invention relates to an apparatus of this type, which has a relatively small footprint, which is movable or transportable, which is adaptable to any type of dosage and which can nevertheless operate at high speed to perform a relatively large number of different dosages on a relatively small number of samples or a relatively small number of different assays on a relatively large number of samples.
Elle propose, à cet effet, un appareil automatique de dosage de substances dans des échantillons biologiques ou chimiques, comprenant des moyens de support de réactifs, des moyens de support d'échantillons à analyser, des moyens de support de cuvettes de réaction, des moyens de prélèvement d'échantillons à analyser et de réactifs et d'injection de ces prélèvements dans les cuvettes de réaction, des moyens de rinçage des cuvettes de réaction, et des moyens de lecture optique des résultats, caractérisé en ce que les moyens de support d'échantillons et les moyens de support des cuvettes de réaction sont des plateaux tournants coaxiaux et en ce que les moyens de prélèvement et d'injection sont portés par un bras radial s 'étendant entre l'axe commun des plateaux et leur périphérie et sont déplaçables en translation le long de ce bras, ce dernier étant déplaçable en rotation autour de l'axe des plateaux. Le montage des plateaux supports d'échantillons et de cuvettes de réaction autour d'un même axe de rotation permet de réduire sensiblement l'encombrement général de l'appareil de dosage. La disposition des moyens de prélèvement et d'injection sur un bras radial qui s'étend entre l'axe commun des plateaux tournants et leur périphérie, permet de prélever facilement et rapidement les échantillons et les réactifs pour les déposer dans les cuvettes de réaction, sans augmenter l'encombrement de l'appareil. En outre, du fait de ce montage, les plateaux et le bras radial des moyens de prélèvement et d'injection peuvent être portés par un même tube central qui définit l'axe de rotation des plateaux et dont l'extrémité supérieure supporte le bras radial précité .To this end, it proposes an automatic device for dosing substances in biological or chemical samples, comprising means for supporting reagents, means for supporting samples to be analyzed, means for supporting reaction cuvettes, means for taking samples to be analyzed and for reagents and for injecting these samples into the reaction cuvettes, means for rinsing the reaction cuvettes, and means for optically reading the results, characterized in that the support means d 'samples and the support means of the reaction cuvettes are coaxial rotary plates and in that the sampling and injection means are carried by a radial arm extending between the common axis of the plates and their periphery and are movable in translation along this arm, the latter being rotatable around the axis of the plates. The mounting of the sample support plates and reaction cuvettes around the same axis of rotation makes it possible to significantly reduce the overall size of the dosing device. The arrangement of the sampling and injection means on a radial arm which extends between the common axis of the turntables and their periphery, allows samples and reagents to be taken quickly and easily to deposit them in the reaction cuvettes, without increasing the size of the device. In addition, due to this arrangement, the plates and the radial arm of the withdrawal and injection means can be carried by the same central tube which defines the axis of rotation of the plates and the upper end of which supports the radial arm. cited above.
Le déplacement du bras radial en rotation autour de l'axe des plateaux permet notamment d'accélérer les prélèvements d'échantillons et de réactifs et leur dépôt dans les cuvettes de réaction.The displacement of the radial arm in rotation around the axis of the plates makes it possible in particular to accelerate the taking of samples and reagents and their deposit in the reaction cuvettes.
Aux mêmes fins, il est avantageux que ce bras radial porte deux unités de prélèvement et d'injection, montées chacune sur un chariot guidé en translation sur un côté du bras radial, et des moyens pour déplacer les deux chariots indépendamment l'un de l'autre sur le bras radial.For the same purposes, it is advantageous for this radial arm to carry two withdrawal and injection units, each mounted on a carriage guided in translation on one side of the radial arm, and means for moving the two carriages independently of one of the other on the radial arm.
Pour le prélèvement des échantillons et des réactifs, chaque unité de prélèvement et d'injection comprend des moyens commandés de déplacement d'un porte-aiguille en translation verticale sur le chariot correspondant.For the sampling of samples and reagents, each sampling and injection unit comprises controlled means for moving a needle holder in vertical translation on the corresponding carriage.
Dans un mode de réalisation préféré de l'invention, les cuvettes de réaction sont constituées par des barrettes dont chacune est formée avec un nombre déterminé de puits de réaction alignés dans une direction longitudinale de la barrette, et le plateau de support de ces barrettes comporte des moyens de positionnement radial et angulaire et d'immobilisation desdites barrettes par rapport à l'axe commun des plateaux.In a preferred embodiment of the invention, the reaction cuvettes are formed by bars, each of which is formed with a determined number of aligned reaction wells in a longitudinal direction of the bar, and the support plate for these bars includes means for radial and angular positioning and immobilization of said bars relative to the common axis of the plates.
De préférence, les barrettes sont portées par des supports en forme de secteur circulaire, qui comprennent des moyens de fixation, par exemple du type à encliquetage, sur le plateau tournant ou sur le moyeu de ce plateau tournant. Cela facilite la mise en place initiale des barrettes ainsi que leur remplacement.Preferably, the bars are carried by supports in the form of a circular sector, which comprise fixing means, for example of the snap type, on the turntable or on the hub of this turntable. This facilitates the initial positioning of the bars as well as their replacement.
Selon une autre caractéristique de l'invention, le plateau de support des barrettes comprend des moyens de chauffage et de régulation thermique individuels des barrettes, comprenant par exemple des résistances électriques posées sur les parois des puits des barrettes et des moyens commandés d'alimentation électrique de ces résistances. Le chauffage et la régulation thermique individuels des barrettes permettent d'adapter leurs cycles de température aux dosages à effectuer, qui peuvent différer d'une barrette à l'autre.According to another characteristic of the invention, the support plate of the bars comprises means of heating and individual thermal regulation of the bars, comprising for example electrical resistances placed on the walls of the wells of the bars and controlled means of electrical supply. of these resistances. The individual heating and thermal regulation of the bars makes it possible to adapt their temperature cycles to the dosages to be carried out, which may differ from one bar to another.
Selon encore une autre caractéristique de l'invention, le plateau support d'échantillons à analyser comporte à sa périphérie radialement externe des moyens de réception de tubes ou analogues destinés à recevoir les échantillons à analyser, ces tubes étant répartis sur le plateau le long d'au moins un arc de cercle.According to yet another characteristic of the invention, the support plate for samples to be analyzed comprises, at its radially external periphery, means for receiving tubes or the like intended to receive the samples to be analyzed, these tubes being distributed over the plate along 'at least one arc of a circle.
Ces tubes sont, par rapport à l'axe commun des plateaux, radialement à l'extérieur des barrettes de réaction.These tubes are, with respect to the common axis of the plates, radially outside the reaction bars.
Les moyens de support de réactifs sont fixes et disposés en arc de cercle autour des plateaux de support des échantillons à analyser et des cuvettes de réaction.The reagent support means are fixed and arranged in an arc around the plates of support for samples to be analyzed and reaction cuvettes.
Compte-tenu de la nature des réactifs, ces moyens de support sont équipés de moyens de réfrigération, permettant de maintenir la température des réactifs à une valeur appropriée inférieure à la température ambiante.Given the nature of the reagents, these support means are equipped with refrigeration means, making it possible to maintain the temperature of the reactants at an appropriate value below ambient temperature.
Les mouvements de rotation des plateaux et du bras radial sont commandés par des moyens de traitement de l'information, du type microordinateur, qui sont programmés pour optimiser les prélèvements et les injections d'échantillons et de réactifs en fonction du nombre et de la nature des dosages à effectuer et pour faire passer les cuvettes de réaction par les moyens de lecture en fin de réaction de dosage, sans perte de temps. Ainsi, les cuvettes de réaction sont amenées aux moyens de lecture de résultats, non pas dans l'ordre dans lequel elles se trouvent sur leur plateau de support, mais dans l'ordre d'achèvement des réactions de dosage réalisées dans ces cuvettes. On augmente ainsi la cadence de fonctionnement du dispositif selon 1 ' invention.The rotational movements of the plates and of the radial arm are controlled by data processing means, of the microcomputer type, which are programmed to optimize the taking and injecting of samples and reagents according to the number and nature of the assays to be carried out and for passing the reaction cuvettes through the reading means at the end of the assay reaction, without loss of time. Thus, the reaction cuvettes are brought to the means for reading results, not in the order in which they are on their support plate, but in the order of completion of the assay reactions carried out in these cuvettes. This increases the operating rate of the device according to one invention.
Les moyens de lecture des résultats des dosages sont du type optique et comprennent des systèmes différents, par exemple l'un pour la mesure de l'absorption lumineuse des contenus des cuvettes de réaction à des longueurs d'onde déterminées, un autre pour la mesure de la chimiluminescence des contenus de ces cuvettes, et un autre pour la mesure de l'émission de lumière, consécutive à une excitation lumineuse, des contenus des cuvettes (fluorescence) .The means for reading the results of the assays are of the optical type and include different systems, for example one for measuring the light absorption of the contents of the reaction cuvettes at determined wavelengths, another for measuring chemiluminescence of the contents of these cuvettes, and another for the measurement of light emission, following a light excitation, of the contents of the cuvettes (fluorescence).
L'un ou l'autre de ces systèmes de lecture est utilisé, en fonction de la nature des dosages dont on veut lire les résultats. De plus, l'appareil selon l'invention est également utilisable en association avec d'autres appareils de mesure, par exemple du type à cytométrie de flux ou du type HPLC (High Performance Liquid Chro atography) , l'appareil selon l'invention servant à la préparation de mélanges de cellules qui sont ensuite analysés par les appareils associés.Either of these reading systems is used, depending on the nature of the assays for which the results are to be read. In addition, the device according to the invention can also be used in combination with other measuring devices, for example of the flow cytometry type or of the HPLC (High Performance Liquid Chro atography) type, the device according to the invention used to prepare mixtures of cells which are then analyzed by the associated devices.
Selon un autre aspect particulièrement intéressant de l'invention, les barrettes de réaction sont caractérisées en ce que certains puits de chaque barrette sont obturés de façon étanche par un opercule amovible et contiennent des quantités déterminées de réactifs spécifiques pour le dosage d'au moins un échantillon dans les autres puits de la barrette. Pour utiliser ces barrettes, il suffit de retirer les opercules obturant les puits contenant les réactifs et de placer les barrettes sur le plateau support correspondant dans l'appareil selon 1 ' invention. Pour chaque dosage, les réactifs sont prélevés dans les puits correspondants de la barrette et déposés dans les puits adjacents, avec les échantillons à analyser.According to another particularly interesting aspect of the invention, the reaction bars are characterized in that certain wells of each bar are sealed in a sealed manner with a removable cover and contain determined quantities of specific reagents for the determination of at least one sample in the other wells of the strip. To use these strips, it suffices to remove the lids sealing the wells containing the reagents and to place the strips on the corresponding support plate in the apparatus according to the invention. For each assay, the reagents are taken from the corresponding wells of the strip and deposited in the adjacent wells, with the samples to be analyzed.
L'invention sera mieux comprise et d'autres détails, caractéristiques et avantages de celle-ci apparaîtront plus clairement à la lecture de la description qui suit, faite à titre d'exemple en référence aux dessins annexés dans lesquels : - la figure 1 est une vue schématique de dessus d'un appareil selon l'invention ;The invention will be better understood and other details, characteristics and advantages thereof will appear more clearly on reading the description which follows, given by way of example with reference to the appended drawings in which: - Figure 1 is a schematic top view of an apparatus according to the invention;
- la figure 2 est une vue schématique en coupe axiale de cet appareil ; la figure 3 est une vue schématique en perspective de cet appareil. L'appareil de dosage selon l'invention, représenté aux dessins, comprend un châssis 10 en tubes mécano-soudés, qui porte un tube central vertical 12 sur lequel deux plateaux 14, 16 axialement espacés sont montés et guidés en rotation au moyen de paliers à roulements.- Figure 2 is a schematic view in axial section of this device; Figure 3 is a schematic perspective view of this device. The metering device according to the invention, shown in the drawings, comprises a chassis 10 of mechanically welded tubes, which carries a vertical central tube 12 on which two axially spaced plates 14, 16 are mounted and guided in rotation by means of bearings with bearings.
Le plateau supérieur 14 est destiné à supporter des ensembles de cuvettes de réaction qui sont formés par des barrettes 18 comportant chacune plusieurs puits de réaction 20 alignés dans la direction longitudinale de la barrette, le nombre de puits par barrette étant de huit dans cet exemple.The upper plate 14 is intended to support sets of reaction cuvettes which are formed by bars 18 each comprising several reaction wells 20 aligned in the longitudinal direction of the bar, the number of wells per bar being eight in this example.
Les barrettes 18 sont positionnées radialement sur le plateau 14 par rapport à l'axe commun 22 de rotation des plateaux 14 et 16 et sont maintenues en position par des moyens à lames de ressort.The bars 18 are positioned radially on the plate 14 relative to the common axis 22 of rotation of the plates 14 and 16 and are held in position by means with spring blades.
De préférence, la surface du plateau 14 est partagée en un certain nombre de secteurs circulaires qui sont indépendants les uns des autres et qui sont fixés sur le moyeu du plateau 14, par exemple par encliquetage élastique ou analogue.Preferably, the surface of the plate 14 is divided into a certain number of circular sectors which are independent of each other and which are fixed to the hub of the plate 14, for example by elastic snap-fitting or the like.
Dans une variante, les barrettes 18 sont posées et fixées a oviblement sur des supports en forme de secteurs circulaires qui sont positionnés et fixés de façon amovible sur le plateau 14. En même temps que les barrettes 18, on peut placer sur ces supports des outils consommables, tels par exemple que des cônes tubulaires de prélèvement et d'injection, qui sont destinés à être utilisés chacun une fois pour le prélèvement d'un échantillon et son dépôt dans un puits d'une barrette 18 et qui sont jetés après usage. Ces supports amovibles S peuvent porter chacun 4, 6 ou 8 barrettes 18 et les outils consommables correspondants, par exemple, et ont été représentés schématiquement en pointillés en figure 1.In a variant, the bars 18 are placed and fixed ably on supports in the form of circular sectors which are positioned and removably fixed on the plate 14. At the same time as the bars 18, tools can be placed on these supports consumables, such as for example tubular sampling and injection cones, which are intended to be used each once for collecting a sample and depositing it in a well of a bar 18 and which are discarded after use. These removable supports S can each carry 4, 6 or 8 bars 18 and the consumable tools correspondents, for example, and have been shown schematically in dotted lines in FIG. 1.
Le plateau inférieur 16 est destiné au support d'échantillons à analyser, contenus sous forme liquide dans des tubes 24 qui sont reçus dans des supports 26 agencés à la périphérie externe du plateau 16 et répartis en arc de cercle, les supports de tube 26 étant au nombre de 10 dans l'exemple de la figure 1. Les plateaux 14 et 16 sont entraînés en rotation pas à pas autour de l'axe 22 indépendamment l'un de l'autre au moyen de courroies crantées par des moteurs électriques.The lower plate 16 is intended for the support of samples to be analyzed, contained in liquid form in tubes 24 which are received in supports 26 arranged at the external periphery of the plate 16 and distributed in an arc of a circle, the tube supports 26 being 10 in number in the example of Figure 1. The plates 14 and 16 are rotated step by step about the axis 22 independently of one another by means of belts toothed by electric motors.
Une surface 28 de support de réactifs est montée fixement sur le châssis 10 et s'étend en arc de cercle sur environ 180° autour de l'axe 22, radialement à l'extérieur du plateau 16 et sensiblement au niveau de celui-ci. Cette surface 28 est destinée à porter un certain nombre d'ensembles 30 de réactifs, correspondant chacun à un dosage différent à effectuer sur les échantillons à analyser. La surface 28 peut également comporter une zone 32 de réception d'échantillons à analyser et une zone 34 de support de flacons 36 pouvant contenir, entre autres, des substrats, des anticorps, des sérums, etc.A surface 28 for reagent support is fixedly mounted on the chassis 10 and extends in an arc of a circle over approximately 180 ° around the axis 22, radially outside the plate 16 and substantially at the level thereof. This surface 28 is intended to carry a certain number of sets 30 of reagents, each corresponding to a different assay to be carried out on the samples to be analyzed. The surface 28 may also include a zone 32 for receiving samples to be analyzed and a zone 34 for supporting the bottles 36 which may contain, inter alia, substrates, antibodies, sera, etc.
La partie de la surface 28 qui supporte les ensembles 30 de réactifs est équipée de moyens de réfrigération, permettant de maintenir ces réactifs à une température déterminée de 4°C par exemple.The part of the surface 28 which supports the sets of reagents 30 is equipped with refrigeration means, making it possible to maintain these reagents at a determined temperature of 4 ° C. for example.
A une extrémité de la surface 28, se trouve une autre surface de support 38 portée par le châssis 10 et sur laquelle on peut déposer des flacons 40 de liquide de rinçage ou de lavage, destinés à l'alimentation d'une tête de rinçage 42 qui s'étend de façon fixe radialement au-dessus du trajet des barrettes de réaction portées par le plateau 14.At one end of the surface 28, there is another support surface 38 carried by the frame 10 and on which can be placed bottles 40 of rinsing or washing liquid, intended for supplying a rinsing head 42 extending fixedly radially above the path of the reaction bars carried by the plate 14.
La surface 38 supporte également un système 44 de lecture optique des résultats de dosage par mesure de l'absorption lumineuse de certaines longueurs d'onde par les contenus des puits 20 des barrettes de réaction, ce système de lecture 44 étant suivi par un autre système 46 de lecture de résultats par mesure de la chimiluminescence des liquides contenus dans les puits des barrettes de réaction 20.The surface 38 also supports a system 44 for optical reading of the assay results by measuring the light absorption of certain wavelengths by the contents of the wells 20 of the reaction bars, this reading system 44 being followed by another system. 46 for reading the results by measuring the chemiluminescence of the liquids contained in the wells of the reaction strips 20.
Un autre système de lecture de résultats par mesure de fluorescence peut être prévu dans l'appareil selon l'invention, en plus des systèmes 44 et 46 ou à la place de l'un d'eux, cet autre système comprenant des moyens d'excitation lumineuse des contenus des cuvettes de réaction et des moyens de mesure de l'émission lumineuse résultant de cette excitation.Another system for reading results by measuring fluorescence can be provided in the apparatus according to the invention, in addition to systems 44 and 46 or in place of one of them, this other system comprising means for light excitation of the contents of the reaction cuvettes and of the means for measuring the light emission resulting from this excitation.
Un bras radial 48 est monté à rotation sur l'extrémité supérieure du tube central 12 et s'étend horizontalement entre l'axe de rotation 22 et la périphérie de l'appareil. Ce bras 48 porte deux unités 50 de prélèvement et d'injection qui sont déplaçables indépendamment l'une de l'autre en translation le long du bras 48. Chaque unité 50 comporte un chariot 52 guidé en translation sur un rail horizontal 54 du bras 48 et entraîné par un moteur électrique. Chaque chariot 52 comprend un montant vertical 56 portant un rail 58 de guidage d'un porte-aiguille 60 déplaçable en translation sur le rail 58 par un moteur électrique.A radial arm 48 is rotatably mounted on the upper end of the central tube 12 and extends horizontally between the axis of rotation 22 and the periphery of the device. This arm 48 carries two withdrawal and injection units 50 which are movable independently of one another in translation along the arm 48. Each unit 50 comprises a carriage 52 guided in translation on a horizontal rail 54 of the arm 48 and driven by an electric motor. Each carriage 52 comprises a vertical upright 56 carrying a rail 58 for guiding a needle holder 60 movable in translation on the rail 58 by an electric motor.
A son extrémité située au niveau de l'axe de rotation 22, le bras 48 est solidaire d'une plaque verticale 62 qui supporte un actionneur linéaire du type pousse-seringue, ainsi qu'une seringue et une électrovanne reliée par des tubes 64 aux aiguilles 60 des unités précitées 50 de prélèvement et d'injection. De façon classique, un liquide pousseur est contenu dans la seringue, 1 ' électro-vanne et une partie des tubes 64, ce qui permet de prélever et d'injecter au moyen des aiguilles 60 de faibles quantités de liquide, déterminées avec précision. Un puits central 66 permet le nettoyage des aiguilles 60 après chaque utilisation. Le bras radial 48 est entraîné en rotation par un moteur électrique et une courroie crantée.At its end located at the axis of rotation 22, the arm 48 is secured to a vertical plate 62 which supports a linear actuator of the syringe pump type, as well as a syringe and a solenoid valve connected by tubes 64 to needles 60 of the aforementioned units 50 for sampling and injection. Conventionally, a pushing liquid is contained in the syringe, the solenoid valve and part of the tubes 64, which makes it possible to withdraw and inject by means of the needles 60 small quantities of liquid, determined with precision. A central well 66 allows the needles 60 to be cleaned after each use. The radial arm 48 is rotated by an electric motor and a toothed belt.
Les barrettes de réaction 18 qui sont utilisées dans l'appareil selon l'invention sont réalisées en verre ou en matériau plastique transparent, pour permettre la lecture optique des résultats de dosage. Ces barrettes peuvent être d'un type réutilisable, après lavage et décontamination, ou bien jetables après un usage unique.The reaction bars 18 which are used in the apparatus according to the invention are made of glass or transparent plastic material, to allow the optical reading of the assay results. These bars can be of a reusable type, after washing and decontamination, or else disposable after a single use.
Pour faciliter et simplifier l'utilisation de l'appareil selon l'invention, les puits de réaction 20 peuvent subir un traitement qui les rend spécifiques des substances à détecter, ce traitement comprenant par exemple le dépôt d'un revêtement d'anticorps sur la paroi interne des puits de réaction 20.To facilitate and simplify the use of the apparatus according to the invention, the reaction wells 20 can undergo a treatment which makes them specific to the substances to be detected, this treatment comprising for example the deposition of an antibody coating on the inner wall of reaction wells 20.
En outre, les barrettes de réaction comportent des moyens individuels de chauffage et de régulation thermique, comprenant des résistances électriques, formées de fils ou de films déposés ou collés sur la surface latérale extérieure de ces puits. Les moyens prévus sur le plateau 14 pour le positionnement et l'immobilisation des barrettes comprennent des moyens commandés d'alimentation électrique des résistances de chauffage des puits des barrettes, pour un chauffage et une régulation thermique individuels de chaque barrette.In addition, the reaction bars include individual heating and thermal regulation means, comprising electrical resistances, formed of wires or films deposited or glued to the external lateral surface of these wells. The means provided on the plate 14 for positioning and immobilizing the bars include controlled means for supplying electrical power to the heating resistors of the wells of the bars, for a heating and individual thermal regulation of each bar.
Dans un mode de réalisation particulier, chaque barrette de réaction peut comprendre un certain nombre de puits qui vont servir au stockage de réactifs spécifiques à un ou des dosages déterminés. Par exemple, quatre puits d'une barrette comprenant huit puits de réaction peuvent contenir des quantités déterminées de réactifs spécifiques d'un dosage donné et sont obturés à étanchéité par un opercule amovible ou déchirable. Pour leur utilisation, ces barrettes sont placées sur le plateau 14 après retrait ou déchirure des opercules précités.In a particular embodiment, each reaction strip can comprise a certain number of wells which will be used to store specific reagents for one or more determined determinations. For example, four wells of a strip comprising eight reaction wells can contain determined quantities of specific reagents of a given assay and are sealed with a removable or tear-off seal. For their use, these bars are placed on the plate 14 after removal or tearing of the aforementioned lids.
L'appareil qui vient d'être décrit fonctionne de la façon suivante :The apparatus which has just been described operates as follows:
Les réactifs correspondant aux dosages à réaliser sont mis en place sur la surface de support 28 fixe autour des plateaux 14 et 16. Des barrettes de réaction 18, de préférence neuves, sont mises en place sur le plateau 14. Des échantillons à analyser sont contenus dans les tubes 26 placés dans les logements 24 du plateau inférieur 16. La mise en route de l'appareil, piloté par ordinateur, permet de prélever, au moyen des unités 50, des quantités prédéterminées d'échantillons dans les tubes 26 et de réactifs dans les ensembles 30 et de les déposer dans les puits des barrettes de réaction. Les tubes d'échantillons 26 sont repérés et identifiés par des étiquettes à code à barres, lisibles par un lecteur monté adjacent à la périphérie du plateau 16. Les barrettes de réaction 18 sont repérées par leur position angulaire par rapport à une référence radiale sur le plateau 14, ces positions étant numérotées de 1 à 30 dans l'exemple représenté. Les deux unités de prélèvement 50 montées sur le bras 48 permettent d'accélérer le dépôt des échantillons et des réactifs dans les puits des barrettes de réaction 18, de la façon suivante : quand une unité 50 est utilisée pour prélever un échantillon ou un réactif et pour le déposer dans un puits de réaction, l'autre unité 50 est déplacée vers l'axe 22 pour le nettoyage de son aiguille. Ensuite, cette autre unité 50 est utilisée pour un prélèvement et un dépôt, et la première unité 50 est déplacée vers l'axe 22 pour le nettoyage de son aiguille. A chaque inversion des tâches des unités 50, le plateau 14 est déplacé en rotation dans un sens, puis dans l'autre, pour placer les puits d'une barrette 18 en alignement radial avec l'aiguille 60 de l'unité 50 utilisée pour le dépôt d'un échantillon ou d'un réactif. Les rotations des plateaux 14 et 16 permettent d'amener les barrettes et les échantillons en alignement. Pendant les réactions de dosage, les températures des barrettes 18 sont régulées barrette par barrette.The reagents corresponding to the assays to be carried out are placed on the support surface 28 fixed around the plates 14 and 16. Reaction bars 18, preferably new, are placed on the plate 14. Samples to be analyzed are contained in the tubes 26 placed in the housings 24 of the lower plate 16. The start-up of the apparatus, controlled by computer, makes it possible to take, by means of the units 50, predetermined quantities of samples in the tubes 26 and of reagents in sets 30 and deposit them in the wells of the reaction bars. The sample tubes 26 are identified and identified by bar code labels, readable by a reader mounted adjacent to the periphery of the plate 16. The reaction bars 18 are identified by their angular position relative to a radial reference on the plate 14, these positions being numbered from 1 to 30 in the example shown. The two sampling units 50 mounted on the arm 48 make it possible to accelerate the deposition of samples and reagents in the wells of the reaction bars 18, in the following manner: when a unit 50 is used to take a sample or a reagent and to deposit it in a reaction well, the other unit 50 is moved towards the axis 22 for cleaning its needle. Then, this other unit 50 is used for removal and deposition, and the first unit 50 is moved towards the axis 22 for cleaning its needle. Each time the tasks of the units 50 are inverted, the plate 14 is rotated in one direction, then in the other, to place the wells of a bar 18 in radial alignment with the needle 60 of the unit 50 used for depositing a sample or reagent. The rotations of the plates 14 and 16 allow the bars and the samples to be brought into alignment. During the dosing reactions, the temperatures of the bars 18 are regulated bar by bar.
En fin de réaction, chaque barrette est amenée, par rotation du plateau 14, devant les moyens de lecture 44 ou 46 dans l'ordre d'achèvement des réactions dans les puits des barrettes.At the end of the reaction, each bar is brought, by rotation of the plate 14, to the reading means 44 or 46 in the order of completion of the reactions in the wells of the bars.
L'appareil selon l'invention est également utilisable avec d'autres moyens de mesure de résultats, par exemple avec des moyens de mesure cytométrique ou chromatographique. Il sert alors essentiellement d'appareil de préparation de mélanges de cellules et est associé par des moyens de prélèvement et de dépôt soit à un système du type HPLC (High Performance Liquid Chromatography) soit à un système de cytométrie en flux. De façon connue, un tel système permet l'étude et la caractérisation de cellules après marquage par des marqueurs fluorescents et comprend des moyens fluidiques de présentation des cellules une par une devant des moyens de détection optique associés à des moyens d'excitation lumineuse (par exemple laser), et à des moyens de traitement de signaux et de données. Trois types de signaux sont mesurés :The apparatus according to the invention can also be used with other means for measuring results, for example with means for cytometric or chromatographic measurement. It then essentially serves as an apparatus for preparing cell mixtures and is associated by means of sampling and deposition either with a system of the HPLC type (High Performance Liquid Chromatography) or with a flow cytometry system. As is known, such a system allows the study and characterization of cells after marking with fluorescent markers and comprises fluidic means for presenting the cells one by one in front of optical detection means associated with light excitation means (for example laser), and with signal and data processing means . Three types of signals are measured:
- la diffraction de la lumière aux petits angles (1 à 20°), donnant des informations sur les tailles des cellules et leur réfringence (cellules vivantes ou mortes) ,- the diffraction of light at small angles (1 to 20 °), giving information on the sizes of the cells and their refraction (living or dead cells),
- la diffraction de la lumière à 90°, donnant des informations sur le contenu interne des cellules,- 90 ° light diffraction, giving information on the internal content of the cells,
- la fluorescence émise spontanément et/ou après fixation d'une sonde fluorescente. - fluorescence emitted spontaneously and / or after fixation of a fluorescent probe.

Claims

REVENDICATIONS
1 - Appareil de dosage de substances dans des échantillons biologiques ou chimiques, comprenant des moyens (28) de support de réactifs, des moyens (16) de support d'échantillons à analyser, des moyens (14) de support de cuvettes de réaction, des moyens (50) de prélèvement d'échantillons à analyser et de réactifs et d'injection de ces prélèvements dans les cuvettes de réaction (18), et des moyens (44, 46) de lecture optique des résultats, caractérisé en ce que les moyens (16) de support d'échantillons et les moyens (14) de support des cuvettes de réaction sont des plateaux tournants coaxiaux et en ce que les moyens (50) de prélèvement et d'injection sont portés par un bras radial (48) s ' étendant entre l'axe commun1 - apparatus for dosing substances in biological or chemical samples, comprising means (28) for supporting reagents, means (16) for supporting samples to be analyzed, means (14) for supporting reaction cuvettes, means (50) for taking samples to be analyzed and reagents and for injecting these samples into the reaction cuvettes (18), and means (44, 46) for optical reading of the results, characterized in that the means (16) for supporting samples and the means (14) for supporting the reaction cuvettes are coaxial turntables and in that the means (50) for sampling and injection are carried by a radial arm (48) extending between the common axis
(22) des plateaux (14, 16) et leur périphérie et sont déplaçables en translation le long de ce bras, ce dernier étant déplaçable en rotation autour de l'axe commun (22) des plateaux.(22) of the plates (14, 16) and their periphery and are movable in translation along this arm, the latter being movable in rotation around the common axis (22) of the plates.
2 - Appareil selon la revendication 1, caractérisé en ce que le bras radial (48) porte deux unités (50) de prélèvement et d'injection, montées chacune sur un chariot guidé en translation sur un côté du bras radial (48), et des moyens pour déplacer les deux chariots indépendamment de l'autre sur le bras radial.2 - Apparatus according to claim 1, characterized in that the radial arm (48) carries two units (50) for sampling and injection, each mounted on a carriage guided in translation on one side of the radial arm (48), and means for moving the two carriages independently of the other on the radial arm.
3 - Appareil selon la revendication 2, caractérisé en ce que chaque unité (50) de prélèvement et d'injection comprend des moyens commandés de déplacement en translation verticale sur le chariot correspondant. 4 - Appareil selon l'une des revendications 1 à 3, caractérisé en ce que les cuvettes de réaction comprennent des barrettes (18) formées chacune avec un nombre déterminé de puits de réaction (20) qui sont alignés dans une direction longitudinale de la barrette, et en ce que le plateau (14) de support de ces barrettes comporte des moyens de positionnement radial et angulaire et d'immobilisation desdites barrettes (18) .3 - Apparatus according to claim 2, characterized in that each unit (50) of sampling and injection comprises controlled means of displacement in vertical translation on the corresponding carriage. 4 - Apparatus according to one of claims 1 to 3, characterized in that the reaction cuvettes comprise bars (18) each formed with a determined number of reaction wells (20) which are aligned in a longitudinal direction of the bar , and in that the plate (14) for supporting these bars includes means for radial and angular positioning and immobilization of said bars (18).
5 - Appareil selon la revendication 4, caractérisé en ce que les barrettes (18) sont portées par des supports en forme de secteur circulaire comprenant des moyens de fixation, par exemple du type à encliquetage, sur le plateau tournant (14) ou sur un moyeu de ce plateau et portant éventuellement des outils consommables.5 - Apparatus according to claim 4, characterized in that the bars (18) are carried by supports in the form of a circular sector comprising fixing means, for example of the snap-on type, on the turntable (14) or on a hub of this plate and possibly carrying consumable tools.
6 - Appareil selon la revendication 4 ou 5, caractérisé en ce que le plateau (14) de support des barrettes de réaction comprend des moyens de chauffage et de régulation thermique individuels des barrettes, constitués par des résistances électriques posées sur les parois des puits (20) des barrettes et par des moyens commandés d'alimentation électrique de ces résistances.6 - Apparatus according to claim 4 or 5, characterized in that the plate (14) for supporting the reaction bars comprises means of heating and individual thermal regulation of the bars, constituted by electrical resistances placed on the walls of the wells ( 20) of the bars and by controlled means of electrical supply of these resistors.
7 - Appareil selon l'une des revendications précédentes, caractérisé en ce que les mouvements de rotation des plateaux (14, 16) et du bras radial (48) sont commandés par des moyens de traitement de l'information, programmés pour optimiser les prélèvements et dépôts d'échantillons et de réactifs et pour amener les cuvettes de réaction devant les moyens (44 ou 46) de lecture optique des résultats dans l'ordre d'achèvement des réactions de dosage.7 - Apparatus according to one of the preceding claims, characterized in that the rotational movements of the plates (14, 16) and the radial arm (48) are controlled by information processing means, programmed to optimize the samples and sample and reagent depots and to bring the reaction cuvettes in front of the means (44 or 46) for optical reading of the results in the order of completion of the assay reactions.
8 - Appareil selon l'une des revendications précédentes, caractérisé en ce que le plateau (16) de support d'échantillons comprend à sa périphérie radialement externe des moyens (26) de réception de tubes destinés à recevoir les échantillons à analyser, ces tubes étant répartis en arc de cercle sur le plateau (16) radialement à l'extérieur du plateau (14) portant les cuvettes de réaction.8 - Apparatus according to one of the preceding claims, characterized in that the plate (16) for sample support comprises at its radially outer periphery means (26) for receiving tubes intended to receive the samples to be analyzed, these tubes being distributed in an arc on the plate (16) radially outside the plate (14) carrying the reaction cuvettes.
9 - Appareil selon la revendication 8, caractérisé en ce que les plateaux (14, 16) de support des barrettes de réaction et des échantillons à analyser sont axialement décalés sur leur axe commun .9 - Apparatus according to claim 8, characterized in that the plates (14, 16) for supporting the reaction bars and samples to be analyzed are axially offset on their common axis.
10 - Appareil selon l'une des revendications précédentes, caractérisé en ce que les moyens (28) de support de réactifs sont fixes et disposés en arc de cercle radialement à l'extérieur des plateaux (14, 16) de support des cuvettes de réaction et des échantillons à analyser.10 - Apparatus according to one of the preceding claims, characterized in that the means (28) for reagent support are fixed and arranged in an arc of a circle radially outside the plates (14, 16) for supporting the reaction cuvettes and samples to be analyzed.
11 - Appareil selon la revendication 10, caractérisé en ce que les moyens (28) de support de réactifs comprennent des moyens de réfrigération des réactifs.11 - Apparatus according to claim 10, characterized in that the means (28) for reagent support comprises means for refrigerating the reagents.
12 - Appareil selon l'une des revendications précédentes, caractérisé en ce qu'il comprend plusieurs systèmes (44, 46) de lecture optique des résultats, par mesure de l'absorption lumineuse des contenus des cuvettes ou des puits de réaction à des longueurs d'onde déterminées, par mesure de la chimiluminescence de ces contenus et/ou par mesure de l'émission lumineuse de ces contenus en réponse à une excitation lumineuse.12 - Apparatus according to one of the preceding claims, characterized in that it comprises several systems (44, 46) for optical reading of the results, by measuring the light absorption of the contents of the cuvettes or reaction wells to wavelengths determined by measuring the chemiluminescence of these contents and / or by measuring the light emission of these contents in response to a light excitation.
13 - Appareil selon l'une des revendications précédentes, caractérisé en ce qu'il est associé à un appareil de cytométrie en flux ou de chromatographie du type HPLC.13 - Device according to one of the preceding claims, characterized in that it is associated with a flow cytometry or HPLC type chromatography device.
14 - Barrette de réaction pour un appareil du type décrit dans l'une des revendications précédentes, caractérisée en ce que certains puits (20) de la barrette sont obturés de façon étanche par un opercule amovible et contiennent des réactifs spécifiques pour le dosage d'au moins un échantillon dans les autres puits de la barrette. 14 - Reaction strip for an apparatus of the type described in one of the preceding claims, characterized in that certain wells (20) of the strip are sealed in a sealed manner by a removable cover and contain specific reagents for the determination of at least one sample in the other wells of the strip.
EP01998838A 2000-11-29 2001-11-21 Automatic immunoassay apparatus Withdrawn EP1337860A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0015701A FR2817350B1 (en) 2000-11-29 2000-11-29 AUTOMATIC IMMUNOLOGICAL DOSING APPARATUS
FR0015701 2000-11-29
PCT/FR2001/003686 WO2002044740A2 (en) 2000-11-29 2001-11-21 Automatic immunoassay apparatus

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EP1337860A2 true EP1337860A2 (en) 2003-08-27

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EP01998838A Withdrawn EP1337860A2 (en) 2000-11-29 2001-11-21 Automatic immunoassay apparatus

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US (1) US20040009099A1 (en)
EP (1) EP1337860A2 (en)
AU (1) AU2002222020A1 (en)
FR (1) FR2817350B1 (en)
WO (1) WO2002044740A2 (en)

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Also Published As

Publication number Publication date
AU2002222020A1 (en) 2002-06-11
FR2817350B1 (en) 2008-01-04
US20040009099A1 (en) 2004-01-15
WO2002044740A3 (en) 2003-01-03
WO2002044740A2 (en) 2002-06-06
FR2817350A1 (en) 2002-05-31

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