EP2552587B1 - Element microfluidique pour compartiment d'analyse multifonctionnel - Google Patents

Element microfluidique pour compartiment d'analyse multifonctionnel Download PDF

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Publication number
EP2552587B1
EP2552587B1 EP11711298.7A EP11711298A EP2552587B1 EP 2552587 B1 EP2552587 B1 EP 2552587B1 EP 11711298 A EP11711298 A EP 11711298A EP 2552587 B1 EP2552587 B1 EP 2552587B1
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EP
European Patent Office
Prior art keywords
measuring
test element
level
measuring chamber
cover layer
Prior art date
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Application number
EP11711298.7A
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German (de)
English (en)
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EP2552587A1 (fr
Inventor
Valerie Winckler-Desprez
Daniel Rohleder
Christoph Klaunik
Romi Roedl
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.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
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F Hoffmann La Roche AG
Roche Diagnostics GmbH
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Publication of EP2552587A1 publication Critical patent/EP2552587A1/fr
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls

Definitions

  • the present invention relates to a test element for the optical analysis of a liquid sample with a substrate and a microfluidic channel structure which is enclosed by the substrate and a cover layer.
  • the channel structure has a measuring chamber with an inlet opening for the liquid sample.
  • microfluidic elements are used to analyze a fluid sample and to mix a fluid with a reagent.
  • Body fluids are tested for an analyte for medical purposes.
  • the liquid is mixed with a reagent, for example a liquid reagent. If the reagent is a solid, it is dissolved by the liquid and homogenized.
  • Both rotating and non-rotating test carriers or test elements each have a microfluidic channel structure for receiving a fluid sample.
  • the channel structures often comprise several chambers in order to be able to carry out complex and multi-level test procedures ("test protocols").
  • test carriers usually have at least one, often also a plurality of fluidic channel structures, so that several tests can be carried out in parallel.
  • the reagents necessary for the examination are first introduced into the reagent chamber in liquid form in dry chemical test elements where they are dried. To dissolve the reagents, it is common to dissolve them through the liquid sample. After dissolution and mixing to produce a homogeneous liquid sample, the mixed liquid is passed through further channels from the reagent and mixing chamber into an analysis or measuring chamber. Here the evaluation of the liquid sample takes place in order to detect and to determine a certain analyte in the sample.
  • the sample fluid reacts with the reagent in the test element, resulting in a change in a measurement that is uniquely related to the analyte sought.
  • This change in the measured variable is measured in the test carrier itself.
  • optical evaluation methods are used in which a color change or another optically measurable variable is detected.
  • test carriers and fluidic elements therefore consist of a carrier material, usually a substrate made of plastic material, which in the case of optical evaluation at least in the region of the measuring chamber is at least partially transparent or opaque.
  • a carrier material usually a substrate made of plastic material, which in the case of optical evaluation at least in the region of the measuring chamber is at least partially transparent or opaque.
  • Suitable materials are, for example, COC (cyclo-olefin copolymer) or plastics such as PMMA, polycarbonate, polystyrene or polyimide.
  • the test elements have a channel structure, which is enclosed by the substrate and a cover or a cover layer.
  • the channel structure which consists of a succession of several channel sections and extended chambers, is defined by structuring the substrate or carrier material.
  • the controlled movement of the sample fluid in the microfluidic test elements is accomplished by creating an external force that acts on the fluid.
  • This force can be generated by movement of the test element, for example by rotation about an axis of rotation or by a translatory movement.
  • control forces can be generated, for example, by introducing compressed air into the channel structure or by hydrostatic forces.
  • capillary forces can act, which can also be used for control depending on the structures used.
  • the detection of analytes in the liquid can be done with immunological detection methods.
  • Other detection methods for the detection of ingredients in a liquid sample may be applicable analogously.
  • the detection reaction can also take place on a solid phase at which the reagents necessary for the detection are immobilized.
  • catcher antibodies can be immobilized on the surface of the corresponding measuring chamber.
  • test carriers are based on the problem that, before the measurement, the sample liquid should be mixed as homogeneously as possible with the desired reagents.
  • test elements and used Microfluidic channel structures are becoming more compact in order to realize on a test carrier possible multiple parallel channel structures.
  • the present object is achieved by a microfluidic test element having the features of claim 1 and by an analysis system for the optical analysis of a liquid sample having the features of claim 13 and by an optical analysis method having the features of claim 15.
  • the microfluidic test element according to the invention for the optical analysis of a liquid sample comprises a substrate with a microfluidic channel structure which is enclosed by the substrate and a cover layer or a lid.
  • the substrate consists of a plastic material, which is preferably transparent or so opaque that an optical detection of an analyte in the liquid sample can take place.
  • the substrate is a moldable plastic material. This is simple and inexpensive to manufacture, allowing to manufacture the desired structures (channel structures) with high precision.
  • a suitable molding methods for example, injection molding, hot stamping or other methods are possible to produce a one-piece molding. Alternatively, material-removing methods such as milling can be used.
  • the channel structure of the test element comprises a multifunctional measuring chamber with at least one inlet opening, at which an inflow channel, which is also part of the channel structure, connects.
  • the measuring chamber is arranged in the flow direction of the liquid at the end of the channel structure.
  • the test element has a first plane that faces the cover layer.
  • the first plane extends parallel to the surface of the substrate and parallel to the cover layer.
  • the optical analysis of the liquid sample is carried out to determine an analyte contained therein.
  • the test element has a second plane, which is the first Level connects that the first level between the top layer and the second level is arranged.
  • the measuring chamber comprises a measuring space and a mixing space, wherein the measuring space is formed by the part of the measuring chamber which extends through the first level.
  • the mixing chamber of the measuring chamber is formed by the part of the measuring chamber which extends in the second plane.
  • the measuring space and the mixing space are arranged to each other such that they are aligned perpendicular to the cover layer with each other.
  • the arranged in the second level mixing chamber of the measuring chamber has a bottom which is structured such that it is rounded.
  • the part of the liquid which is located in the measuring chamber of the measuring chamber is optically analyzed.
  • the part of the liquid located in the mixing chamber is not analyzed. It is therefore necessary that a homogeneous mixing of the entire liquid takes place.
  • the mixing of the liquid sample takes place not only in the here geometrically defined mixing space, but also in the adjacent measuring space, which form a uniform space in relation to the mixing functionality.
  • the measuring chamber according to the invention has the advantage that not only the optical measurement takes place in it. Rather, the measuring chamber takes on even more functions that are required for the detection of ingredients in liquids. These functions can be, for example, the mixing and mixing of liquids or the dissolution of reagents in liquids.
  • the adapted geometric structure of the measuring chamber with a rounded bottom of the mixing chamber allows reliable mixing of the liquids. It is therefore not absolutely necessary to provide further chambers within the channel structure, in which reagents are dissolved or liquids are mixed with one another in such a way that they are in homogeneous form.
  • the merger of functions measuring and Mixing in the measuring chamber in the form of a multifunctional measuring chamber leads to significant space savings on the test element.
  • a reagent for detecting a desired analyte of the liquid sample is arranged in the measuring chamber.
  • the reagent is in solid form. As a rule, it is dried.
  • the cover layer is removed from the substrate or the filling of the liquid reagent takes place during production in the still open microfluidic channel structure without cover layer.
  • the mixing chamber of the measuring chamber must be designed in such a way that on the one hand the preparation and drying of the reagents is possible, on the other hand a good resuspension and homogenization of the dried reagents takes place can. In addition, the mixing of liquids must take place quickly and with high quality.
  • a measuring chamber with rounded bottom of the mixing chamber is not only advantageous for the mixing or resuspending of the reagents.
  • the avoidance of sharp edges and corners prevents the reagents presented in the liquid phase from leaving the cavity due to high capillary forces at the corners of the measuring chamber and thus in part being lost for the reaction.
  • many reagents to be dried show a strong wetting behavior.
  • the measuring space of the measuring chamber therefore has a rounded upper edge.
  • the mixing space may comprise further structural elements to accelerate mixing. These may be, for example, barriers, elevations and depressions or similar geometrical configurations. The additional barriers should also be Affix without edges to the surface of the mixing chamber, so that a uniform distribution of the reagent during the drying takes place.
  • the bottom of the mixing space is a spherical segment, preferably a hemisphere.
  • the bottom of the mixing chamber is formed spherical segment or hemispherical.
  • the bottom of the mixing chamber may have an oval, elliptical or part-circular cross-section.
  • the measuring chamber is designed such that the dried-in reagents are arranged only in the mixing chamber of the measuring chamber. Due to the shape of the measuring chamber they do not reach the measuring chamber of the measuring chamber despite their strongly wetting behavior.
  • an upper first level which is also called detection level and in which the measurement of the analyte takes place, and an underlying second level in which the structures for drying and mixing of the liquid are present, finds a clear separation between measuring on the one hand and mixing as well as drying and dissolving the reagents on the other side instead.
  • the drying structures are integrated in depressions within the measuring chamber, which are arranged outside the measuring beam path of the light for optical measurement. Disturbances of the measurement, for example due to dried-in reagents, are thus reliably avoided.
  • the inventive concept of the test element thus provides a measuring chamber in which several functions are integrated. Since the measuring chamber is preferably arranged at the end point of the flow path of the liquid, the liquid is mixed with the reagents before and / or during the measurement. Volume and reagent losses on the way through the channel structure into the measuring chamber are avoided.
  • the channel structure is very compact, as several functions are combined in the measuring chamber, allowing multiple channel structures on one test element can be integrated or parallelized. By integrating additional structures in the mixing space, the homogenization of the reagents with the liquid medium can be further accelerated and improved.
  • advantageously adapted ventilation structures can be provided in the measuring chamber.
  • the measuring chamber according to the invention allows so-called fail-safe investigations with one and the same measuring device, since the optical beam path is not disturbed.
  • a possible fail-safe feature would be, for example, the verification of the correct and complete filling of the measuring chamber by staggered determination of the absorption or other optical size before, during and after the completion of the filling process of the measuring chamber with liquid.
  • the measuring chamber according to the invention also enables a continuous or semi-continuous measurement taking place at intervals.
  • the optical measurement takes place in the first plane in the measuring chamber of the chamber along an optical axis.
  • the optical axis is understood to be a straight line along which the light beam passes for optical analysis.
  • the light beam is directed through the measuring space such that it is aligned with the longitudinal axis of the measuring space.
  • the longitudinal axis is the largest dimension of the measuring chamber of the measuring chamber perpendicular to the surface normal of the cover layer.
  • the longitudinal axis consequently runs essentially parallel to the first plane of the test element.
  • the measuring chamber is a measuring cuvette (also called detection cuvette) with two opposite parallel walls, which are aligned perpendicular to the cover layer and the optical axis.
  • the light can hereby enter with as little scattering in the measuring room and on the opposite Emerge sidewall again.
  • the measuring space and the mixing space together form the measuring or detection cuvette.
  • test element according to the invention can be used in test carriers of any kind.
  • these test elements can be used in test-strip-like fluidic devices.
  • they can also be integrated into detection cassettes with channel structures.
  • the test element according to the invention is particularly preferably used as a centrifugal test carrier which rotates about an axis of rotation. By rotation of the test element is a controlled movement of the liquid. By alternately accelerating and decelerating the rotation (the so-called shake-mode, as it is known in EP 1 894 617 described) a rapid mixing and dissolution of the dry reagents is promoted.
  • the measuring chamber comprises an antechamber in which the inlet opening is arranged.
  • the vestibule is arranged in the first plane of the test element, wherein its height is at most as large as the height of the first plane perpendicular to the cover layer.
  • the vestibule is separated from the measuring space and the mixing space, ie the measuring cuvette of the measuring chamber, but there is a fluid connection between them. In this way, superfluous liquid can be collected and stored in the vestibule.
  • the liquid volume to be examined in the measuring chamber can thus be kept constant even when the measuring cuvette or the measuring chamber is "overfilled".
  • the measuring chamber has a vent opening on, which opens into a vent channel. Air can escape from the measuring chamber through the venting channel.
  • the vent opening is arranged in the antechamber of the measuring chamber.
  • the measuring chamber has a plateau between the measuring space and the inlet opening with a plateau area formed between the plateau and the covering layer.
  • the height of the plateau region perpendicular to the cover layer is less than the height of the measuring chamber of the measuring chamber.
  • the plateau is located in the first level of the test element.
  • the plateau is arranged between the antechamber and the measuring space of the measuring chamber. The plateau allows air to pass to the vent without liquid flowing back into the inlet. In this way, it is possible that formed air bubbles are passed from the measuring space in the vestibule.
  • the measuring room is thereby free of air bubbles. This ensures a reliable measurement within the measuring room.
  • a rotating test element of the vestibule is arranged so that its distance from the axis of rotation is less than the distance of the measuring chamber of the measuring chamber to the axis of rotation.
  • the liquid which has a higher density compared to the air, crowded in the measurement space remote from the rotational axis, while the "lighter” air enters the antechamber closer to the rotation axis.
  • the terms "off-axis” and “off-axis” or “near-axis” or “near-axis” have the relative position of one element relative to the other element with respect to the axis of rotation.
  • a rotation axis remote element thus has a greater distance from the axis of rotation than another element, a rotation axis nearer or rotation axis closer element a smaller distance from the axis of rotation than another element.
  • the object underlying the invention is achieved by an analysis system for the optical analysis of a liquid sample comprising an analyzer and a test element.
  • the analyzer according to the invention has a holder for holding the test element and a measuring and evaluation device. It comprises an optical transmitter for emitting light and an optical receiver for receiving light.
  • the test element according to the invention for optical analysis has a substrate and a microfluidic channel structure, which is enclosed by the substrate and a cover layer.
  • the holder of the analyzer is rotatable about an axis of rotation.
  • the test element held in the holder rotates about the axis of rotation of the analyzer holder.
  • the axis of rotation is arranged to extend through the held test element.
  • the analysis system is designed such that the optical analysis of a liquid sample takes place during the rotation of the test element.
  • the emission of light is clocked here.
  • the light transmitter of the analyzer always emits light when the test element is arranged in a position in which the emitted light passes along the optical axis through the measuring chamber of the measuring chamber until it is received at the optical receiver and evaluated by means of the measuring and evaluation unit can be.
  • a test element according to the invention is provided, preferably one with the features of claim 1.
  • the liquid sample to be examined is allowed to flow through the inlet opening into the measuring chamber.
  • the filling of the mixing chamber and the measuring chamber of the measuring chamber and a provision of a reagent, which takes place in the mixing chamber the measuring chamber is included.
  • the reagent is preferably dried.
  • the liquid sample is homogeneously mixed with the reagent.
  • no reagent is contained in the mixing space, there is a homogeneous distribution and mixing of the liquid sample in the measuring space and the mixing space.
  • a further step light is passed into the test element for optical analysis of the liquid sample.
  • the light is guided essentially parallel to the cover layer of the test element through the first plane, so that it passes through the measuring space of the measuring chamber along an optical axis.
  • the light is guided through the liquid sample contained in the measuring space.
  • the light is decoupled from the test element, so that it emerges from the test element.
  • This is followed by receiving and evaluating the light by means of a measuring and evaluation device of an analyzer.
  • the type of optical measurement in which the measuring light beam is guided through the measuring space in a plane substantially parallel to the upper side of the test element is referred to as "in-plane detection".
  • the homogeneous mixing of the liquid sample which is preferably a body fluid such as blood or plasma, with a reagent thus takes place in the same measuring chamber as the measurement and analysis of the mixed liquid. It is not necessary to transfer the liquid to another chamber after mixing. This has the advantage that the measurement can be done faster; Also, no liquid is lost by wetting additional microfluidic channel structures during liquid transport.
  • the emission of light by means of an optical transmitter is perpendicular to the cover layer of the test element instead.
  • the light is deflected so that it is guided parallel to the cover layer through the first plane.
  • the light is deflected again perpendicular to the covering layer by means of a further deflection device in such a way that the light can be received by an optical receiver of the analysis device.
  • the method is carried out automatically by means of an analyzer, wherein first the test element is held in a holder of the analyzer.
  • the control of the movement of the liquid sample in the test element is effected by rotating the test element about an axis of rotation which corresponds to the axis of rotation of the holder of the test element.
  • the introduction of the liquid sample into the measuring chamber is thus caused by the rotation of the test element. It is also possible to operate the test element in a "shake-mode" in which it is accelerated and decelerated alternately.
  • the emission and reception of the light takes place during the rotation of the test element.
  • the optical analysis of the liquid sample is thus carried out while the test element rotates in the holder of the analyzer.
  • the light is emitted clocked, for example by means of a stroboscope.
  • the measuring chamber of the test element comprises an antechamber.
  • the control of the liquid displaces the air contained in the measuring chamber into the antechamber so that the measuring space and the mixing chamber of the measuring chamber are filled with the desired amount of liquid. Excess liquid is passed out of the measuring space and the mixing space in the vestibule according to such a method.
  • test element will be described with reference to a rotating test element, where all features and peculiarities described, unless they are explicitly related to a rotating test element, can also be applied to non-rotating, translationally moving or stationary, non-moving test elements.
  • the statements made on the basis of the example described do not constitute a restriction of the invention defined by the claims in their generality.
  • FIG. 1 shows an inventive analysis system 1 with an analyzer 2 and a test element 3.
  • the analyzer 2 comprises a holder 4, in which the test element 3 is held.
  • the holder 4 is rotatable about a shaft 5 which is driven by a motor 6.
  • the axis of rotation 7, which is aligned with the shaft 5, extends in the present case through the test element 3.
  • analysis devices 2 are conceivable in which the holder 4 is fixed for the test element 3.
  • a translatory movement could be carried out.
  • the analyzer 2 comprises an optical transmitter 8, an optical receiver 9 and a measuring and evaluation device 10.
  • the optical transmitter comprises, for example, an LED or another light source. It emits light or other electromagnetic radiation. The emitted light may be in the visible or invisible range and may include X-rays or other electromagnetic radiation. Furthermore, without limitation, the term "light" is used.
  • the light is guided so that it is passed through the test element until it finally reaches the optical receiver 9.
  • the receiver 9 may be a photodiode.
  • the signal detected at the receiver 9 is evaluated by means of the measuring and evaluation device 10, so that an analyte or its concentration in a liquid in the test element 3 can be determined.
  • FIG. 2 shows a particular embodiment of a test element 3 according to the invention with a microfluidic channel structure 11, which has a plurality of chambers and channels.
  • the test element 3 comprises a substrate 12, which consists of a transparent or opaque plastic material.
  • the substrate 12 is preferably so opaque or transparent that an optical measurement is possible. Depending on the light used for the optical measurement, the properties and the degree of transparency of the substrate are to be determined.
  • the channel structure 11 is enclosed by the substrate 12 and a lid or a cover layer, not shown in the figures.
  • a measuring chamber 13 is arranged, which comprises a measuring space 14, a mixing space 15 and a plateau 16.
  • the mixing chamber 15 and the measuring chamber 14 are formed here together in the form of a rugby ball (ellipsoid of revolution) and have an oval cross-section.
  • the measuring chamber 13 has two inlet openings 17, which are connected to channels 18, which in turn terminate in further chambers 19 of the channel structure.
  • the measuring chamber 13 comprises a vent opening 20, which is connected to a venting channel 21 and can escape through the air contained in the measuring chamber 13.
  • FIG. 3 shows an alternative embodiment of a test element 3 with a channel structure 11, at the end of a measuring chamber 13 is arranged.
  • the measuring chamber 13 likewise comprises two inlet openings 17, through which liquid from adjacent chambers 19 and channels 18 arranged therebetween can flow into the measuring chamber 13.
  • the measuring chamber 13 has a vent opening 20 through which air can escape into the venting channel 21.
  • a plateau 16 is arranged between the inlet openings 17 and the measuring space 14.
  • the measuring chamber 13 of the test element 3 is preferably designed so that its measuring space 14 is substantially cylindrical, wherein the bottom and top surfaces of the cylindrical space are substantially parallel to the top layer plane.
  • Particularly preferred is an embodiment of the measuring space 14 in the form of a double cylinder 22 with two juxtaposed cylinders 22a, 22b.
  • the cylinders 22a, 22b partially overlap ( FIG. 3 ).
  • the test element 3 comprises two optical deflection devices 23, by means of which light incident on the test element is deflected in such a way that the light passes parallel to the cover layer or surface 12a of the substrate through the measuring space 14 of the measuring chamber 13 and by means of the measuring space 14 optically downstream deflection is directed from the test element to the receiver 9.
  • the FIGS. 2 and 3 each have two deflection devices 23, which are arranged such that the measuring space 14 is positioned between the two deflection devices 23.
  • the deflection devices 23 are described in detail with reference to FIG FIG. 6 explained in more detail. Further descriptions of such deflection are also the DE 10 2005 062 174 B3 refer to.
  • the deflecting devices 42 which are optionally additionally present outside the measuring cuvette, deflect light - in contrast to the deflecting devices 23 - not through the measuring space 14 of the measuring chamber 13, but through areas outside the measuring chamber 13, for example through the substrate of the test element 3.
  • These additional deflecting devices 42 can in particular be used for reference measurements, for example, by the measured values are related to the measured values used for determining the analyte (which are obtained via the deflection means 23) in order to take into account and compensate for possible device-related fluctuations in the measuring system.
  • a reference measurement can also be carried out, for example, by first determining a measured value of the unfilled measuring chamber 13 before filling the measuring chamber 13, which is used as a reference value for an analyte determination with a filled measuring chamber 13.
  • the two test elements 3 according to the FIGS. 2 and 3 were used to optimize the measuring chamber 13.
  • the measuring chamber 13 has a multiple function in that it firstly serves to measure and determine an analyte in a liquid by means of an optical evaluation. On the other hand, it should take on additional functions, such as the mixing of liquids and the dissolution of reagents. As part of the investigations It has been found that a measuring chamber 13 with a cylindrical measuring chamber 14 and an adjoining mixing chamber 15 with a rounded bottom has improved properties.
  • FIG. 4 shows a section of a channel structure 11 as a plan view. Shown is the measuring chamber 13 and the two deflection means 23 of the light used for the analysis.
  • FIG. 5 shows a section along the line BB and FIG. 6 a section along the line CC FIG. 4 ,
  • the measuring chamber 13 has a measuring cuvette 28, which is formed by the measuring space 14, which extends in a first plane 24 of the test element 3, and the mixing space 15, which is arranged below the measuring space 14 in a second plane 25 of the test element.
  • the measuring chamber 14 is thus the part of the measuring cuvette 28 arranged in the first plane 24.
  • the mixing chamber 15 adjoins below the measuring chamber 14 and is the part of the measuring cuvette which extends into the second plane 25.
  • the measuring chamber 14 and the mixing chamber 15 are arranged with each other such that the common space of the measuring cell 28 is formed and a liquid can move in both rooms.
  • the measuring cuvette 28 thus has at its lower end in the second plane 25 of the test element 3 a rounded bottom 39, which is the bottom 39 of the mixing chamber 15.
  • At least two opposite side walls 41 of the measuring cuvette 28 are aligned substantially perpendicular to the upper side 12a of the substrate 12 in the region in which the light beam used for the analysis passes into the measuring cuvette and out of the cuvette again.
  • This substantially vertical region of the side walls 41 lies in the first plane 24 of the test element.
  • the side walls 41 of the measuring space 14 are aligned parallel to the surface normal of the upper side of the test element 3.
  • the cuvette 28 is in the form of a double cylinder 22 with two partially overlapping cylinders 22a, 22b.
  • the cylinders 22a, 22b overlap to form a common measurement volume.
  • the bottom 39 of the double cylinder 22 is rounded here several times. It is formed by two overlapping spherical segments 26, wherein the overlap 27 formed between the spherical segments 26 is also rounded (FIG. Fig. 5, 6 ).
  • the configuration of the measuring cuvette 28 of the measuring chamber 13 as a double cylinder 22 for mixing the liquid is particularly advantageous.
  • opposing vortex flows preferably form during rotation of the test element 3. The vortices allow very efficient and fast mixing and resuspension.
  • the two cylinders 22a, 22b are arranged in such a way that the measuring cuvette 28 formed by the double cylinder 22 has a longitudinal extent, which is aligned along a longitudinal axis 29.
  • the longitudinal axis 29 is aligned with an optical axis 30 of the measuring chamber 13.
  • the optical axis is the path through which the light passes through the measuring chamber 13.
  • the light (arrows 40) emitted by the optical transmitter 8 of the analyzer 2 is guided from the underside 33 of the test element 3 through the substrate 12 until it is deflected at a first interface 31 of the first deflecting means 23a runs parallel to the top 12a of the substrate 12 and to the cover layer of the test element 3, not shown here.
  • the light After entering through the side wall 41 and passing through the measuring space 14 in the first plane 24 of the test element 3, the light emerges on the opposite side wall 41.
  • the light is redirected at a second interface 32 of the second deflection device 23b in such a way that it exits at the underside 33 of the test element and reaches the optical receiver 9 of the analyzer 2.
  • the light beam (arrow 40) for optical analysis passes through only the measuring space 14, but not the mixing space 15, so that the optical analysis is not affected even if 15 annealed reagents should not completely solve in the mixing chamber.
  • the optical measurement parallel to the upper side 12a of the test element 3 has the advantage that a significantly longer light path can be realized.
  • the necessary length of the light path depends on the concentration range of the analyte to be measured in the liquid. If one wanted to realize this with a measurement perpendicular to the upper side 12 of the test element 3, the thickness of the test element 3 would have to be significantly greater. In the example shown, the thickness of the test element is about 4 mm. This would lead to higher material costs and poorer handling.
  • the measuring chamber 13 is designed such that the longitudinal extent of the measuring cuvette 28 along the longitudinal axis 29 is selected as a function of the concentration of the analyte to be measured.
  • a longitudinal extent of the measuring cuvette 28 in the range of at least 4 mm to 8 mm has proven to be advantageous, in particular a length of 6 mm.
  • the longitudinal extent of the measuring cuvette 28 is to be designed.
  • the measuring chamber 13 has two inlet openings 17 through which liquid enters the measuring chamber. Between the two inlet openings 17 for the liquid, a vent opening 20 is arranged through which air can escape from the measuring chamber 13.
  • the measuring chamber 13 comprises an antechamber 34, in which the inlet opening 17 is arranged.
  • the vestibule 34 is arranged in the first plane 24 of the test element 3.
  • the height of the antechamber 34 perpendicular to the upper side 12a of the substrate 12 is preferably less than the height of the first plane 24.
  • the height of the first plane 24 is the extension of the first plane 24 perpendicular to the upper side 12a of the substrate 12.
  • the vestibule 34 is positioned outside the optical axis 30.
  • a light beam 40 for the optical detection of an analyte in a liquid sample is not passed through the vestibule 34. The optical analysis is thus independent of an amount of liquid collected in the antechamber 34.
  • a plateau 16 is arranged in the measuring chamber 13 between the inlet opening 17 and the measuring space 14. Between the plateau 16 and the cover layer not shown in the figures, a plateau region 36 is formed whose height perpendicular to the upper side 12a of the test element 3 is less than the height of the measuring space 14 and thus also less than the height of the first plane 24 of the test element 3. Preferably, the height of the plateau region 36 is also less than the height of the antechamber 34.
  • an inclined ramp 37 is arranged between the plateau 16 and the measuring space 14, one end of which faces the measuring space 14 being arranged at the interface between the first level 24 and the second level 25 at the measuring space 14.
  • one end of the ramp 37 is arranged at the transition between the measuring chamber 14 and the mixing chamber 15.
  • the transitions from the measuring cuvette 28 to the ramp 37 and the transition from the ramp 37 to the platform 16 are preferably rounded. Liquid can not escape from the measuring cuvette 28 by capillary force.
  • the measuring chamber 13, in particular the cuvette 28, only rounded shapes. Also, an upper edge 35 of the measuring space 14, which forms a transition to the plateau 16, is rounded.
  • the ramp 37 extends between the plateau 16 and the radially inner cylinder 22a of the measuring cuvette 28. It is arranged such that the plateau 16 is L-shaped. In the present embodiment the measuring chamber 13, the plateau 16 has a maximum length of about 6.6 mm and a maximum width at the transition to the vestibule 34 of about 3.3 mm.
  • the arrangement of the ramp 37 and the rounding off of the ends of the ramp 37 ensures that air bubbles formed during the resuspension of dry reagents in the mixing chamber 15 escape from the measuring cuvette 28, ie from the mixing chamber 15 and the measuring chamber 14, and into the antechamber 34 of the measuring chamber 13 are moved.
  • the rounded transitions of the ramp 37 enhance the transport of air bubbles or foam to ensure that the sample cuvette 28 is free of air bubbles. An influence on the measurement or a falsification of the measurement results due to bubble formation in the beam path is avoided.
  • the filling level within the measuring cell 28 is constant. Due to the complex fluidic system of the channel structure 11 of the rotating test element 3, the volume to be examined can not be kept completely constant. In the context of investigations, isolated fluctuations of the filling level within the measuring cuvette 28 occurred. In the preferred embodiment, excess fluid volume may escape from the cuvette 28. The excess liquid passes via the ramp 37 on the plateau 16 and is collected in the antechamber 34. However, the liquid remains in the measuring chamber 13. In this way, a slight overfilling of the measuring cell 28 can be compensated. In addition, the antechamber 34 allows a filling of the measuring chamber 13 such that air within the measuring chamber 13 remains. As a result, mixing of the liquids is improved. At the same time, however, the measuring cell 28 is completely filled.
  • the liquid flowing into the measuring chamber 13 is forced into the measuring cuvette 28, which is further away from the axis of rotation 7 in comparison to the inlet opening 17. Since the inlet openings 17 are arranged at the upper edge of the first plane 24, the liquid flows over the antechamber 34 away directly into the measuring cuvette 28. Due to its lower density, air is forced out of the measuring cuvette 28 in the direction of the antechamber 34 and can escape through the vent opening 20.
  • the plateau 16 extends in the direction of the radial component 38 of the test element 3.
  • the radial component 38 is the direction of the rotation axis 7 to the outer edge of the test element 3 direction.
  • the measuring chamber 13 is formed such that the longitudinal axis 29, which is aligned with the optical axis 30, with the radial component 38 of the rotatable test element 3 forms an angle which is between 20 degrees and 40 degrees.
  • an angle of at least 25 degrees and at most 35 degrees is provided, more preferably the angle is 30 degrees.
  • the cover layer of the test element 3 is arranged on the upper side 12 a of the substrate 12. However, it is not shown in the present figures.
  • the cover layer like the substrate 12 itself, may also be transparent or opaque. It can also be opaque, since the coupling in and out of the light takes place through the underside 33 of the test element 3.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Optical Measuring Cells (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Claims (17)

  1. Elément d'essai destiné à l'utilisation dans un appareil d'analyse comportant un émetteur optique permettant d'émettre de la lumière pour l'analyse optique d'un échantillon liquide, comprenant un substrat et une structure à canaux microfluidique entourée dudit substrat et d'une couche de couverture,
    dans lequel
    - la structure à canaux (11) comprend une chambre de mesure (13) comportant au moins une entrée (17),
    - l'élément d'essai (3) comporte un premier niveau (24) faisant face à ladite couche de couverture et servant à réaliser l'analyse optique dudit échantillon liquide, et comporte un deuxième niveau (25) prolongeant le premier niveau (24) de manière à ce que le premier niveau (24) soit disposé entre la couche de couverture et le deuxième niveau (25),
    - une partie de la chambre de mesure (13) s'étend à travers le premier niveau (24) pour y former une enceinte de mesure (14), la chambre de mesure (13) se prolongeant par une partie s'étendant au moins partiellement dans le deuxième niveau (25) et constituant une enceinte de mélange (15),
    - l'enceinte de mélange (15), disposé dans le deuxième niveau (25), comporte un fond (39) arrondi,
    - deux dispositifs optiques de renvoi (23, 23a, 23b) sont disposés dans le premier niveau (24) et permettent de renvoyer de la lumière incidente, laquelle est envoyée sur l'élément d'essai (3) pour soumettre l'échantillon liquide à une analyse optique, de manière à ce que ladite lumière soit dirigée à travers le premier niveau (24) selon une direction sensiblement parallèle à la couche de couverture pour traverser l'enceinte de mesure (14) de la chambre de mesure (13) le long d'un axe optique (30), caractérisés en ce que
    - la lumière incidente est renvoyée par le premier dispositif de renvoi (23a) selon une direction parallèle à la couche de couverture et renvoyée par le deuxième dispositif de renvoi (23b) de manière à ce qu'elle quitte l'élément d'essai (3)
  2. Elément d'essai selon la revendication 1, caractérisé en ce que l'enceinte de mélange (15) de la chambre de mesure (13) contient un réactif qui est destiné à détecter un analyte dans l'échantillon liquide, qui réagit avec ledit échantillon liquide et qui se présente préférentiellement sous une forme solide, avec une préférence particulière solidifiée par séchage.
  3. Elément d'essai selon les revendications 1 ou 2, caractérisé en ce que la chambre de mesure (13) comprend une antichambre (34) dans laquelle l'entrée (17) est disposée, l'antichambre (34) étant disposée dans le premier niveau (24) de l'élément d'essai (3), et l'antichambre (34) ayant une hauteur, dans une direction perpendiculaire à la couche de couverture, qui est inférieure ou égale à la hauteur du premier niveau (24).
  4. Elément d'essai selon la revendication 3, caractérisé en ce que l'antichambre (34) est positionnée de manière à ce qu'elle se situe en dehors de la trajectoire du rayon lumineux destiné à l'analyse optique de l'échantillon liquide dans la chambre de mesure (13).
  5. Elément d'essai selon l'une des revendications précédentes, caractérisé en ce qu'un plateau (16) est disposé entre l'enceinte de mesure (14) de la chambre de mesure (13) et l'entrée (17) vers la chambre de mesure (13) et que celui-ci comporte une zone sur plateau (36) qui est formée entre le plateau (16) et la couche de couverture et qui présente, perpendiculairement au plan de la couche de couverture, une hauteur inférieure à la hauteur de l'enceinte de mesure (14) de la chambre de mesure (13).
  6. Elément d'essai selon la revendication précédente, caractérisé en ce qu'une rampe (37) inclinée est disposée entre l'enceinte de mesure (13) et le plateau (16) et présente une extrémité qui fait face à l'enceinte de mesure (14) et qui est disposée préférentiellement dans la zone de transition entre l'enceinte de mesure (14) et l'enceinte de mélange (15).
  7. Elément d'essai selon l'une des revendications précédentes, caractérisé en ce que le fond (39) de l'enceinte de mélange (15) de la chambre de mesure (13) présente la forme d'un segment de sphère (26) et qu'il est réalisé préférentiellement sous forme d'un hémisphère.
  8. Elément d'essai selon l'une des revendications précédentes, caractérisé en ce que la chambre de mesure (13) est disposée à la sortie de la structure à canaux (11), selon le sens d'écoulement d'un liquide.
  9. Elément d'essai selon l'une des revendications précédentes, caractérisé en ce que la chambre de mesure (13) renferme une cuvette de mesure (28) comprenant l'enceinte de mesure (14) et l'enceinte de mélange (15), les parois latérales (41) de la cuvette de mesure (28), situées l'une en face de l'autre, présentant dans la zone de l'enceinte de mesure (14) une orientation sensiblement perpendiculaire à la couche de couverture.
  10. Elément d'essai selon la revendication précédente, caractérisé en ce que la cuvette de mesure (28) de la chambre de mesure (13) est réalisée sous une forme cylindrique.
  11. Elément d'essai selon la revendication précédente, caractérisé en ce que la cuvette de mesure (28) est réalisée sous forme d'un double cylindre (22) comportant deux cylindres (22a, 22b) disposés l'un à côté de l'autre et se chevauchant de préférence partiellement, chacun des cylindres (22a, 22b) comportant dans le deuxième niveau (25) de l'élément d'essai (3) un fond (39) arrondi.
  12. Elément d'essai selon l'une des revendications précédentes, caractérisé en ce que la chambre de mesure (13) comprend un évent (20) relié à un canal d'évacuation (21) permettant d'évacuer de l'air contenu dans la chambre de mesure (13).
  13. Système d'analyse destiné à l'analyse optique d'un échantillon liquide, comprenant un appareil d'analyse (2) et un élément d'essai (3) selon l'une des revendications précédentes,
    dans lequel
    l'appareil d'analyse (2) comprend un organe de fixation (4) permettant de fixer l'élément d'essai (3), un dispositif de mesure et de traitement (10), un récepteur optique (9) et un émetteur optique (8) pour émettre de la lumière,
    l'élément d'essai (3) destiné à l'analyse optique comporte un substrat (12) et une structure à canaux microfluidique (11) entourée du substrat (12) et de la couche de couverture,
    - la structure à canaux (11) comprenant une chambre de mesure (13) pourvue d'au moins une entrée (17),
    - l'élément d'essai (3) comportant un premier niveau (24) lequel fait face à ladite couche de couverture et dans lequel est réalisée l'analyse optique dudit échantillon liquide, et comportant un deuxième niveau (25) qui prolonge le premier niveau (24) de manière à ce que le premier niveau (24) soit disposé entre la couche de couverture et le deuxième niveau (25),
    - une partie de la chambre de mesure (13) s'étendant à travers le premier niveau (24) et formant une enceinte de mesure (14), la chambre de mesure (13) se prolongeant par une partie qui s'étend au moins partiellement dans le deuxième niveau (25) et forme une enceinte de mélange (15),
    - la lumière mise en oeuvre pour l'analyse optique de l'échantillon liquide étant guidée à travers le premier niveau (24) selon une direction sensiblement parallèle à la couche de couverture, faisant en sorte que la lumière traverse l'enceinte de mesure (14) de la chambre de mesure (13) le long d'un axe optique (30), et
    - l'enceinte de mélange (15), disposé dans le deuxième niveau (25), comportant un fond (39) structuré tel que le fond (39) est arrondi.
  14. Système d'analyse selon la revendication précédente, caractérisé en ce que l'organe de fixation (4) de l'appareil d'analyse (2) peut effectuer une rotation autour d'un axe de rotation (7), permettant ainsi à un élément d'essai (3) supporté dans l'organe de fixation (4) d'effectuer une rotation autour de l'axe de rotation (7) de l'organe de fixation (4), l'axe de rotation (7) s'étendant préférentiellement à travers l'élément d'essai (3) fixé.
  15. Procédé d'analyse optique d'un échantillon liquide, comprenant les étapes suivantes :
    - mise à disposition d'un élément d'essai (3) selon l'une des revendications 1 à 12 comportant un substrat (12) et une structure à canaux microfluidique (11) qui est entourée du substrat (12) et d'une couche de couverture et qui comprend une chambre de mesure (13) pourvue d'au moins une entrée (17), l'élément d'essai (3) comportant un premier niveau (24) qui fait face à ladite couche de couverture, et comportant un deuxième niveau (25) qui prolonge le premier niveau (24) de manière à ce que le premier niveau (24) soit disposé entre la couche de couverture et le deuxième niveau (25), et une partie de la chambre de mesure (13) s'étendant à travers le premier niveau (24) pour y former une enceinte de mesure (14), la chambre de mesure (13) se prolongeant par une partie qui s'étend au moins partiellement dans le deuxième niveau (25), qui constitue une enceinte de mélange (15) et qui présente un fond (39) arrondi,
    - introduction de l'échantillon liquide par l'entrée (17) dans la chambre de mesure (13),
    - remplissage de l'enceinte de mélange (15) et de l'enceinte de mesure (14) avec l'échantillon liquide ;
    - mise en oeuvre d'un réactif qui est contenu dans l'enceinte de mélange (15) et se présente préférentiellement sous une forme solidifiée par séchage ;
    - réalisation d'un mélange homogène entre l'échantillon liquide et ledit réactif au sein de l'enceinte de mesure (14) et de l'enceinte de mélange (15) ;
    - injection de lumière dans l'élément d'essai (3) pour réaliser une analyse optique de l'échantillon liquide de manière à ce que ladite lumière soit dirigée à travers le premier niveau (24) selon une direction sensiblement parallèle à la couche de couverture et que la lumière traverse l'enceinte de mesure (14) de la chambre de mesure (13) le long d'un axe optique (30),
    - extraction de la lumière de manière à ce qu'elle quitte l'élément d'essai (3) ;
    - réception et traitement de la lumière par un récepteur optique d'un dispositif de mesure et de traitement (10) d'un appareil d'analyse (2).
  16. Procédé selon la revendication précédente, caractérisé par les étapes supplémentaires suivantes :
    - émission de lumière au moyen d'un émetteur optique (8), selon une direction perpendiculaire à la couche de couverture de l'élément d'essai (3) ;
    - renvoi de la lumière au moyen d'un dispositif de renvoi (23), de manière à ce que la lumière soit dirigée à travers le premier niveau (24) de l'élément d'essai selon une direction sensiblement parallèle à la couche de couverture ;
    - suite à la traversée de l'enceinte de mesure (14), renvoi de la lumière perpendiculairement à la couche de couverture, de manière à envoyer la lumière sur un récepteur optique (9) d'un appareil d'analyse (2).
  17. Procédé selon les deux revendications de procédé précédentes 15 ou 16, caractérisé par les étapes supplémentaires suivantes :
    - fixation de l'élément d'essai (3) dans un organe de fixation (4) de l'appareil d'analyse (2) ;
    - rotation de l'élément d'essai autour d'un axe de rotation (7) pour commander le déplacement de l'échantillon liquide et pour introduire l'échantillon liquide dans la chambre de mesure (13) ;
    - émission et réception cadencées de la lumière pendant la rotation de l'élément d'essai (3).
EP11711298.7A 2010-03-31 2011-03-17 Element microfluidique pour compartiment d'analyse multifonctionnel Active EP2552587B1 (fr)

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DE102010013752A DE102010013752A1 (de) 2010-03-31 2010-03-31 Multifunktionelle Detektionsküvette
PCT/EP2011/054069 WO2011120819A1 (fr) 2010-03-31 2011-03-17 Élément microfluidique comprenant une chambre de mesure multifonctionnelle

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EP2552587A1 (fr) 2013-02-06
JP5767693B2 (ja) 2015-08-19
JP2013524184A (ja) 2013-06-17
WO2011120819A1 (fr) 2011-10-06
DE102010013752A1 (de) 2011-10-06

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