EP2069787B1 - Elément d'essai rotatif - Google Patents

Elément d'essai rotatif Download PDF

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Publication number
EP2069787B1
EP2069787B1 EP07818502.2A EP07818502A EP2069787B1 EP 2069787 B1 EP2069787 B1 EP 2069787B1 EP 07818502 A EP07818502 A EP 07818502A EP 2069787 B1 EP2069787 B1 EP 2069787B1
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EP
European Patent Office
Prior art keywords
sample
test element
capillary
zone
axis
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EP07818502.2A
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German (de)
English (en)
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EP2069787A1 (fr
Inventor
Christoph Boehm
Norbert Oranth
Juergen Spinke
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F Hoffmann La Roche AG
Roche Diagnostics GmbH
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F Hoffmann La Roche AG
Roche Diagnostics GmbH
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Priority to EP07818502.2A priority Critical patent/EP2069787B1/fr
Priority to EP19160587.2A priority patent/EP3524982B1/fr
Publication of EP2069787A1 publication Critical patent/EP2069787A1/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
    • B01L3/502753—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 bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
    • 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
    • B01L3/5023—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures with a sample being transported to, and subsequently stored in an absorbent for analysis
    • 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
    • B01L3/50273—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 the means or forces applied to move the fluids
    • 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
    • B01L3/502738—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 integrated valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • 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
    • B01L2300/0663—Whole sensors
    • 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
    • B01L2300/0681—Filter
    • 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
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • 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
    • B01L2300/0803—Disc shape
    • B01L2300/0806—Standardised forms, e.g. compact disc [CD] format
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/082—Active control of flow resistance, e.g. flow controllers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/11—Automated chemical analysis
    • Y10T436/110833—Utilizing a moving indicator strip or tape
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/11—Automated chemical analysis
    • Y10T436/111666—Utilizing a centrifuge or compartmented rotor

Definitions

  • the invention relates to a test element, which is substantially disc-shaped and flat and is rotatable about a central axis which is perpendicular to the disc-shaped test element plane, comprising a sample application port for discharging a liquid sample, a capillary-active zone, which is a porous, absorbent matrix and a sample channel that extends from the sample introduction port to the capillary-active zone. Furthermore, the invention relates to a method for determining an analyte with the aid of the test element.
  • test carriers eg. B. Test strips offered. Prominent examples of these are test strips for the determination of the blood glucose value or test strips for urinalysis.
  • test carriers usually integrate several functions (eg the storage of reagents in dried form or, albeit less frequently, in solution, the separation of undesired sample constituents, in particular of red blood cells from whole blood, in immunoassays, the so-called Free separation, the dosing of sample volumes, the transport of sample liquid from outside a device into a device, the control of the sequence of individual reaction steps, etc.).
  • the function of the sample transport is often accomplished by means of absorbent materials (eg papers or fleeces), by means of capillary channels or by application of external driving forces (such as pressure, suction) or by means of centrifugal force.
  • Disc-shaped test carriers so-called LabDiscs or optical BioDiscs, continue the idea of controlled sample transport by means of centrifugal force (centrifugal force).
  • Such Disc-shaped, CompactDisc-like test carriers allow miniaturization through the use of microfluidic structures and at the same time the parallelization of processes by repeated application of identical structures for the parallel processing of similar analyzes from a sample or identical analyzes from different samples.
  • optical BioDiscs the integration of optically stored digital data for the identification of the test carriers or the control of the analysis systems on the optical BioDiscs is possible.
  • BioDiscs In addition to the miniaturization and parallelization of analyzes and the integration of digital data on optical discs, BioDiscs generally have the advantage that they can be manufactured using established manufacturing methods and measured using established evaluation technology. In the chemical and biochemical components of such optical BioDiscs usually a recourse to known chemical and biochemical components is possible.
  • a disadvantage of the optical LabDiscs or Biodiscs based purely on centrifugal and capillary forces is that the immobilization of reagents is difficult and the accuracy of detection suffers. Especially in detection systems based on specific binding reactions, such.
  • As immunoassays lacks compared to conventional test strip systems, the volume component, especially in the so-called. Bound-Free separation.
  • BioDiscs with channels and channel-like structures for liquid transport on the one hand and voluminous absorbent materials in these structures (at least partially) on the other.
  • WO 2005/001429 (Phan et al. ) describes optical bio-discs which have membrane pieces as reagent carriers in parts of the channel system. The reagents are dissolved by a liquid supplied to the disc, resulting in buffered reagent solutions, which are then contacted with the sample.
  • optical bio-disks which contain absorbent membranes or papers for moving a sample liquid, separating particulate sample components, carrying reagents, and analyzing the sample.
  • the sample is first applied to a blood separation membrane near the outer edge of the bio-disk and migrates radially therethrough to a reagent paper located closer to the center of the bio-disk. Thereafter, the sample is again moved radially outward, ie away from the center of the bio-disk, and flows through a so-called Analysis membrane.
  • the outward movement takes place via chromatography, which is supported by rotation of the bio-disk and the centrifugal force acting thereon on the sample.
  • US 2002/0076354 A1 discloses bio-optical discs having, in addition to a channel system for the transport of a liquid sample, a so-called “capture layer".
  • the latter can for example consist of nitrocellulose.
  • the "interception layer” is traversed by means of centrifugal forces during rotation of the disk.
  • a test element with liquid channels in which sample liquid is transported by means of an interplay of capillary force and centrifugal force.
  • a nitrocellulose strip may be provided which carries an agglutination reagent which reacts with the analyte and thus can lead to the formation of so-called bands, which can be optically measured and thus used to determine an analyte concentration in the sample.
  • the nitrocellulose strip With the aid of the nitrocellulose strip it is possible to carry the sample liquid in opposite directions both in parallel to the centrifugal force and in the centrifugal force, in particular if another absorbent material, for example a nitrocellulose absorbent paper, is used to support the suction effect.
  • WO 99/58245 (Larsson et al. ) describes microfluidic test elements in which the movement of the liquids through different surfaces with different surface properties, such. B. different hydrophilicity is controlled.
  • a disadvantage of the concepts of the prior art is that just for specific binding assays, such.
  • immunoassays targeted control of the reaction and residence times of the sample liquid after receiving the reagents and after flowing into the porous, absorbent matrix is not possible.
  • the object of the invention is to eliminate the disadvantages of the prior art.
  • the invention relates to a test element according to claim 1, a system according to claim 11 and a method according to claim 7.
  • Advantageous embodiments and preferred embodiments of the invention are the subject of the dependent claims.
  • test element is essentially disc-shaped and planar. It is rotatable about a central axis which is perpendicular to the disk-shaped test element plane within the test element.
  • the test element is a circular disc, comparable to a compact disc.
  • the invention is not limited to this shape of the disc, but can readily be found in non-symmetrical or non-circular discs use.
  • the test element first contains a sample introduction opening into which a liquid sample can be pipetted or introduced in another way.
  • the sample application port is close to the axis (ie near the center of the disc).
  • the sample application opening can open directly into a sample channel.
  • the sample introduction opening can first open into a reservoir located behind it, into which the sample flows before it continues to flow into the sample channel.
  • a hydrophilization of the surfaces of the fluidic structures may be necessary and / or the use of structures that promote the formation of capillary forces.
  • the test element contains a capillary-active zone in the form of a porous, absorbent matrix, which accommodates at least a portion of the liquid sample.
  • the capillary active zone has an off-axis first end and an off-axis second end.
  • the test element further has a sample channel extending from the sample introduction port to the off-axis first end of the capillary active zone, which is a porous, bibulous matrix. At least once, the sample channel passes through an area close to the axis which is closer to the central axis than the first end of the capillary-active zone, which is remote from the axis.
  • the capillary-active zone which is a porous, absorbent matrix
  • the off-axis first end of the capillary active zone is in contact with the sample channel, in which the sample can be moved by capillary forces and / or centrifugal forces and / or other external forces, such as overpressure or underpressure.
  • capillary forces which in the case of a porous absorbent Matrix can also be referred to as suction
  • the capillary-active zone is a porous, absorbent matrix, in particular a paper, a membrane or a fleece.
  • the capillary active zone which is a porous, bibulous matrix, contains one or more zones of immobilized reagents.
  • the capillary-active zone which is a porous bibulous matrix
  • specific binding reagents for example specific binding partners, such as antigens, antibodies, (poly) haptens, streptavidin, polystreptavidin, ligands, receptors, nucleic acid strands ("capture probes") and the like, immobilized. They serve to selectively capture from the sample flowing through the capillary-active zone the analyte or analyte-derived and related species.
  • binding partners are immobilized in the form of lines, dots, patterns in or on the material of the capillary-active zone.
  • an antibody to the analyte may be immobilized on the surface of the capillary active zone, which is a porous, bibulous matrix, which will then capture the analyte (in this case, an antigen or hapten) from the sample and also in immobilize the capillary-active zone.
  • the analyte can be made detectable by further reactions, for example by further contacting with a labeled bindable partner, for example by a label which can be visually, optically or fluorescently detected.
  • the capillary-active zone which is a porous, absorbent matrix, adjoins, with the second end close to the axis, another absorbent material or an absorbent structure, so that this or this liquid can absorb from the zone.
  • the porous absorbent matrix and other material overlap slightly for this purpose.
  • the further material or the further absorbent structure serves on the one hand to support the suction effect of the capillary-active zone, which is a porous absorbent matrix, on the other hand as a receiving zone for liquid that has already passed through the capillary-active zone.
  • the further material may consist of the same or different materials as the matrix.
  • the matrix may be a membrane and the other absorbent material may be a nonwoven or a paper. Other combinations are of course possible as well.
  • the test element according to the invention is characterized in a preferred embodiment in that the sample channel contains zones of different dimensions and / or for different functions.
  • the sample channel may contain a zone containing reagents that are soluble in the sample or suspendable in the sample. These can be dissolved or suspended in the liquid sample when it flows in or through it and can react with the analyte in the sample or with other sample components.
  • the different zones in the sample channel may also differ in that there are zones with capillary activity and those without.
  • zones of high hydrophilicity and low hydrophilicity may be included.
  • the individual zones can virtually seamlessly pass into one another or be separated from one another by certain barriers, for example valves, in particular non-closing valves, such as geometric valves or hydrophobic barriers.
  • the reagents in the sample channel are preferably in dried or lyophilized form. However, it is also possible that reagents are present in liquid form in the test element according to the invention.
  • the reagents can be introduced into the test element in a manner known per se.
  • the test element preferably contains at least two layers, a bottom layer into which the fluidic structures are introduced, and a cover layer, which as a rule contains no further structures apart from the inlet openings for liquids and the vent openings.
  • the introduction of reagents during the preparation of the test device is usually carried out before the upper part of the test element (cover layer) is applied to the lower part (bottom layer). At this time, the fluidic structures are open in the lower part, so that a dosage of the reagents in liquid or dried form is readily possible.
  • the introduction of the reagents can be done for example by printing or dispensing.
  • the reagents into the test element by placing them in the test element impregnated in absorbent materials such as papers, nonwovens or membranes. After placing the reagents and inserting the absorbent materials, such as the porous, absorbent matrix (membrane) and optionally other absorbent materials (waste nonwoven, etc.) are Upper and lower part of the test element connected to each other, for example, clipped, welded, glued and the like.
  • the bottom layer in addition to the fluidic structures also has the inlet openings for liquids and the vent openings.
  • the cover layer may be formed completely without openings, with the possible exception of a central recess for receiving a drive unit.
  • the upper part simply consist of a plastic film which is glued or welded to the lower part.
  • the sample channel contains a zone for separating particulate matter from the liquid sample.
  • that zone serves to separate the cellular sample components. From blood can be obtained by separating in particular the red blood cells (erythrocytes) nearly colorless plasma or serum, which is usually better suited for subsequent visual or optical detection methods than the heavily colored blood.
  • the separation of cellular sample components by centrifugation, d. H. by fast rotation of the test element after filling with liquid sample contains suitably dimensioned and geometrically designed channels and / or chambers for this purpose.
  • the test element for the separation of cellular blood components contains an erythrocyte collection zone (erythrocyte chamber or erythrocyte trap) and a serum or plasma collection zone (serum or plasma chamber).
  • valves In control the flow of the sample liquid in the test element, it can contain valves, in particular so-called non-closing or geometric valves or hydrophobic barriers, especially in the sample channel. These valves serve as capillary stops. It can be ensured that targeted temporal and spatial control of the sample flow through the sample channel and the individual zone of the test element becomes possible.
  • the sample channel may have a sample metering zone, which allows a precise measurement of the - initially in excess abandoned - sample.
  • the sample metering zone extends from the sample application opening via a corresponding piece of a sample channel to a valve in the fluidic structure, in particular a geometric valve or a hydrophobic barrier.
  • the Sample introduction opening can initially receive an excess of sample material. The sample, either driven by capillary forces or by centrifugation, flows from the sample application zone into the channel structure and fills it up to the valve. Excess sample initially remains in the sample application zone.
  • a sample excess chamber adjacent to the sample application zone and branching off from the sample channel is filled, for example by capillary forces or by centrifuging the test element. It must be ensured that the sample volume to be measured is initially not transported across the valve by suitably selecting the valve. As soon as excess sample is trapped in the appropriate overflow chamber, a precisely defined sample volume is located between the valve of the sample channel on one side and the inlet to the sample overflow chamber on the other side. By applying external forces, in particular by starting another centrifugation, this defined sample volume is now moved beyond the valve. All fluidic areas that lie after the valve and come into contact with the sample are now filled with a precisely defined sample volume.
  • the sample channel may also have an inflow for other liquids except the sample liquid.
  • a second channel open, the z. B. can be filled with a washing or reagent liquid.
  • the inventive system of measuring device and test element is used to determine an analyte in a liquid sample.
  • the measuring device contains at least one drive for the rotation of the test element and an evaluation optics for evaluating the visual or optical signal of the test element.
  • the optics of the measuring device can be used for fluorescence measurement with spatially resolved detection.
  • d. H. planar evaluation optics is typically used to illuminate the detection area of the test element and possibly the excitation of optically detectable markers an LED or a laser.
  • the detection of the optical signal is by CMOS or CCD (typically 640 x 480 pixels).
  • the beam path is direct or folded (eg via mirrors or prisms).
  • the illumination or excitation is typically effected by means of an illumination line which illuminates the detection area of the test element, preferably perpendicular to the detection and control lines.
  • the detection can be done here via a diode array.
  • the rotational movement of the test element can be utilized for the illumination and evaluation of the second dimension in order to scan with the diode array over the area of the test element to be evaluated.
  • a DC motor with encoder or a stepper motor can be used as drive for rotating and positioning of the test element.
  • the temperature of the test element in the device is made indirectly, for example by heating or cooling the plate on which rests the disc-shaped test element in the device.
  • the measurement of the temperature is preferably carried out without contact.
  • the method according to the invention serves to detect an analyte in a liquid sample.
  • the sample is first placed in the sample application opening of the test element. Subsequently, the test element is rotated about its central axis. In this case, the sample is transported from the sample application opening to the off-axis end of the capillary-active zone, which is a porous, absorbent matrix.
  • the rotation of the test element is then slowed down so that the sample or a material recovered from the sample as it flows through the sample (for example, a mixture of the sample with reagents, a sample modified by pre-reactions with reagents from the test element, one of certain components liberated sample such as serum or plasma from whole blood after removal of the erythrocytes, etc.) from the off-axis to the proximal end of the capillary-active zone, which is a porous, absorbent matrix.
  • the analyte is finally visually or optically detected in the capillary active zone, which is a porous, bibulous matrix, or a downstream zone.
  • the initiation of migration of the sample (or material recovered from the sample) through the capillary active zone can be precisely timed and controlled by selectively slowing down or stopping the rotation of the test element. Only when the amount of capillary force (suction force) in the capillary active zone exceeds the amount of centrifugal force directed counter to it will it be possible to move the sample into and through the capillary active zone.
  • the liquid transport in the capillary-active zone can be targeted. For example, a possible pre-reaction or preincubation of the sample or a temperature control of the sample can be awaited before the rotation of the test element is slowed down or stopped so as to allow the sample to flow into the capillary-active zone.
  • the transport of the sample (or a material obtained from the sample) through the capillary-active zone can be selectively slowed or stopped by renewed rotation of the test element about its central axis.
  • the centrifugal forces occurring during the rotation counteract the capillary force which moves the sample fluid from the end of the capillary-active zone remote from the axis to the end near the axis.
  • a targeted control, in particular slowing, the flow velocity of the sample in the capillary-active zone possible, up to the reversal of the flow direction.
  • the residence time of the sample in the capillary-active zone can be controlled.
  • the detection can be carried out according to the principle of the sandwich assay or in the form of a competitive assay.
  • test element after the rotation of the test element, a further liquid is applied to the test element, which is transported after the sample from the off-axis to the near-axis end of the capillary-active zone, which is a porous, absorbent matrix.
  • the further liquid may in particular be a buffer, preferably a washing buffer, or a reagent liquid.
  • the capillary-active zone which is a porous, absorbent matrix, transports the liquid from an off-axis end to an axis-near end, ie, from the periphery of the disk-shaped test element toward the axis of rotation.
  • the centrifugal force which can also be used to move the liquids, counteracts this direction of transport exactly.
  • the use of the porous absorbent matrix which serves essentially as a scavenger matrix for bound-free separation in immunoassays, allows efficient capture of sample components during the immunoassay.
  • FIGS. 1 to 8 show different preferred embodiments of the test element (1) according to the invention.
  • each of the substrate (2) containing the fluidic structures and the central recess (drive hole 3) is shown.
  • the disk-shaped test element (1) according to the invention also generally comprises a cover layer, which in the figures provides clarity is not shown half.
  • the cover layer can also carry structures, but as a rule it will have no structures other than the openings for the samples and / or further liquids to be dispensed onto the test element.
  • the cover layer can also be designed completely without openings, for example in the form of a film, which is connected to the substrate and terminates the structures located therein.
  • FIGS. 1 to 9 show fluidic structures that perform largely the same functions, although they differ in detail from embodiment to embodiment.
  • the basic structure and the basic function will therefore be described in more detail here with reference to the embodiment according to FIG. 1 be explained.
  • the embodiments according to Figure 2 to 9 will then be explained in more detail only on the basis of the specific differences to each other in order to avoid unnecessary repetition.
  • FIG. 1 shows a first preferred embodiment of the disc-shaped test element (1) according to the invention.
  • the test element (1) contains a substrate (2) containing the fluidic and microfluidic and chromatographic structures.
  • the substrate (2) is covered by a corresponding counterpart (cover layer) (not shown) which contains sample feed and vents corresponding to the structures in the substrate (2).
  • Both the cover layer and the substrate (2) have a central recess (3) which, in cooperation with a corresponding drive unit in a measuring device, makes it possible to rotate the disk-shaped test element (1).
  • the test element (according to one of the FIGS.
  • Sample liquid in particular whole blood, is supplied to the test element (1) via the sample application opening (4). Driven by capillary forces and / or centrifugal forces, the sample liquid fills the sample dosing zone (5).
  • the sample metering zone (5) can also contain the dried reagents. It is limited by the Kapillarstopps (6 and 8), which may be formed for example as a hydrophobic barrier or as a geometric / non-closing valve.
  • the limitation of the sample dosing zone (5) by the capillary stops (6, 8) ensures that a defined sample volume is taken up and passed on into the fluidic zones which lie downstream of the sample dosing zone (5).
  • channel (9) is used to start the separation of red blood cells and other cellular sample components.
  • the reagents contained in the sample dosing zone (5) are already dissolved in the sample when the sample enters the channel (9).
  • the entry of the sample in channel (9) via the capillary stop (8) leads to a mixing of the reagents in the sample.
  • the reagent-sample mixture is directed into the fluidic structures (10) (serum / plasma collection zone) and (11) (erythrocyte collection zone). Due to the centrifugal forces acting on the reagent-sample mixture, plasma or serum is separated from red blood cells. The red blood cells collect in the erythrocyte collection zone (11), while the plasma essentially remains in the collection zone (10).
  • test elements which use membranes or nonwovens to separate particulate sample components (e.g. glass fiber nonwovens or asymmetrically porous plastic membranes to separate red blood cells from whole blood, generally as blood separating membranes or nonwovens)
  • sample volume can be utilized much more effectively with the test elements according to the invention since there are practically no dead volumes (eg volume of the fiber interspaces or pores) from which the sample can not be taken again.
  • dead volumes e.g volume of the fiber interspaces or pores
  • these prior art blood separation membranes and webs tend in part to undesirably adsorb sample components (e.g., proteins) or destroy (lysate) cells, which is also not observed with the test elements of the present invention.
  • the reagent-plasma mixture (which has formed in the presence of the analyte in the case of an immunoassay, for example sandwich complexes of analyte and antibody conjugates) by the suction of the porous-absorbent matrix (12) incorporated into and passed through them.
  • the immobilized binding partners contained in the membrane (12) capture the analyte-containing complexes in the detection zone and bound unbound labeled conjugate in the control zone.
  • the nonwoven (13) adjoining the porous, absorbent matrix supports the movement of the sample through the membrane (12).
  • the fleece (13) also serves to receive the sample after flowing through the membrane (12).
  • wash buffer is pipetted into the sample application opening (4).
  • the washing buffer flows through the corresponding fluidic structures of the test element (1) and, in particular, washes the membrane (12), where the bound analyte complexes are now located, thus removing excess reagent residues.
  • the washing step may be repeated one or more times so as to improve the signal-to-background ratio. This allows an optimization of the detection limit for the analyte and an increase of the dynamic measuring range.
  • the sample channel in which the liquid sample in the test element (1) is transported from the sample application opening (4) to the first remote end of the membrane (12), comprises in the present case the sample metering zone (5), the capillary stop (8), the channel (FIG. 9), the serum / plasma collection zone (10) and the erythrocyte chamber (11).
  • the sample channel may consist of more or fewer individual zones / chambers.
  • FIG. 3 differs from FIG. 1 in that on the one hand to the Sampling opening (4) no container for sample excess (7) connects and at the end of the sample Dosierabitess (5) no capillary stop is present (ie here a metered sample application is required) and on the other hand in that a separate addition port (16) for other liquids such , As washing buffer, and an associated channel (15) are present, which can transport the buffer to the membrane (12).
  • the transport of the buffer to the membrane (12) can be based on capillary forces or centrifugal forces.
  • the embodiment according to FIG. 5 is largely identical to the embodiment according to FIG. 3 , The two embodiments differ only by the shape of the waste nonwoven fabric (13) and in that the test element according to FIG. 5 a capillary stop (8) at the end of the sample dosing (5).
  • the embodiment according to FIG. 6 again is substantially identical to the embodiment according to FIG. 5 and differs therefrom by the additional presence of a sample surplus container (7) in the region between the sample metering orifice (4) and the sample metering zone (5).
  • a sample surplus container (7) in the region between the sample metering orifice (4) and the sample metering zone (5).
  • no metered application of the sample is required (analog FIG. 1 ).
  • FIG. 7 corresponds essentially to the test element (1) of FIG. 6 , Both embodiments have the same fluidic structures and functions. Only the arrangement and geometric design is different. The embodiment according to FIG. 7 has additional vents (17), due to the different dimensions of the fluidic structures compared to FIG. 6 are necessary to allow filling of the structures with samples or washing liquid.
  • Channel (9) is designed here as a thin capillary, which is filled only during rotation of the test element (ie overcoming the capillary stop (8) is possible only by means of centrifugal force).
  • FIG. 7 possible to remove recovered plasma from the erythrocyte collection zone 11; This is done by the decanter unit 18, which finally discharges into the serum / plasma collection zone 10.
  • the embodiment of the non-inventive test element (1) according to FIG. 9 corresponds essentially to the test element (1) of FIG. 6 , Both embodiments have the same fluidic structures and functions. Only the arrangement and geometric design is different.
  • the non-inventive embodiment according to FIG. 9 basically has a further outward, that is, away from the axis, sample application opening (4). This can be advantageous if the test element (1) for filling with sample is already introduced in a measuring device. The user can in this Case, the sample application opening (4) are made more accessible than that in the inventive test elements according to Figure 1 to 8 is possible, where the sample application opening (4) in each case close to the axis (ie remote from the outer edge of the test element) is arranged.
  • the sample is transferred in a sample metering section (5), and then a serum / plasma separation from the whole blood is effected by rotation.
  • the unwanted cellular sample constituents essentially erythrocytes, accumulate in the erythrocyte trap (11), while serum or plasma accumulate in the zone (10).
  • the serum is removed from the zone (10) via a capillary and transported further into the channel structure (9), where dried reagents are accommodated and are dissolved when the sample flows in.
  • the sample-reagent mixture of channel structure (9) can overcome the capillary stop (14) and thus reach the membrane (12) via the channel (15).
  • the sample-reagent mixture is transported via the membrane (12) into the waste nonwoven (13).
  • FIG. 2 and FIG. 4 differ in that in FIG. 2 a container for sample surplus (7) is provided, while the embodiment according to FIG. 4 does not provide such a function. As in the embodiment according to FIG. 3 Here is a metered application of the sample appropriate.
  • FIG. 8 shows a variant of the embodiments according to Figures 2 and 4 ,
  • the sample is transferred by centrifugation into an erythrocyte separation structure (10, 11).
  • the area denoted by (10) serves as a serum / plasma collection zone (10), from the freed of cells serum or plasma after centrifuging over a Capillary channel (21) is forwarded.
  • Chamber (20) serves as a collecting reservoir for excess serum or plasma, which after complete filling of the sample dosing section (5) possibly flows from the serum / plasma collection zone (10). All other functions and structures are analogous to FIGS. 1 to 7 ,
  • the hydrophilic or hydrophobic properties of the surfaces of the test element (1) By deliberately designing the hydrophilic or hydrophobic properties of the surfaces of the test element (1), it can be achieved that the sample liquid and / or washing liquids are moved either only with the aid of rotation and the resulting centrifugal forces or by a combination of centrifugal forces and capillary forces. The latter requires at least partially hydrophilized surfaces in the fluidic structures of the test element (1).
  • test elements according to the invention according to the FIGS. 1 . 2 . 6 . 7 . 8th and 9 an automatic functionality that allows a relatively accurate measurement of a sample aliquot from a surrendered in excess of the test element sample (so-called "metering system”). It essentially comprises the elements 4, 5, 6, and 7 of the illustrated test elements (1).
  • Sample liquid in particular whole blood, is supplied to the test element (1) via the sample application opening (4). Driven by capillary forces and / or centrifugal forces, the sample liquid fills the sample dosing zone (5).
  • the sample metering zone (5) can also contain the dried reagents.
  • Kapillarstopps (6 and 8) which may be formed for example as a hydrophobic barrier or as geometric / non-closing valves.
  • the limitation of the sample dosing zone (5) by the capillary stops (6, 8) ensures that a defined sample volume is taken up and passed on into the fluidic zones which lie downstream of the sample dosing zone (5).
  • any sample excess is transferred from the sample application port (4) and sample dosing zone (5) to the sample overflow container (7) while the measured amount of sample from the sample dosing zone (5) enters the channel (9 ) is transferred.
  • sample liquid can be applied in excess to a test element. Measuring a relatively accurate Probenaliquots, which is then further processed in the test element, this also takes place through the interaction of a metering chamber and an overflow chamber, these two zones - unlike in the present invention - by a Although narrow, but at least when filling always fluid exchange enabling contact stand.
  • Sample liquid is here directly separated during filling of the test element in a part which is passed through a wide channel in the "metering chamber", and a part which flows through a narrow channel in the "overflow chamber”. After complete filling of the "metering chamber", the test element is set in rotation and any excess sample is diverted into the "overflow chamber” so that only the desired, measured sample volume remains in the "metering chamber", which is subsequently processed further.
  • a disadvantage of the embodiment of the metering system according to US 5,061,381 is that for sample volumes that are placed on the test element and which correspond exactly to the minimum volume or only slightly larger than the minimum volume, there is a risk that the dosing is underdosed, since always a portion of the sample from the beginning unhindered in the "overflow chamber" flows.
  • a capillary stop hydrophobic barrier or a geometric or non-closing valve
  • the capillary stop prevents sample from entering the sample excess zone before the sample dosing zone is completely filled. Even with sample volumes which are applied to the test element and which correspond exactly to the minimum volume or are only slightly larger than the minimum volume, it is ensured that the sample metering zone is completely filled.
  • PC Polycarbonate
  • PS polystyrene
  • PMMA polymethyl methacrylate
  • the individual channels and zones (fluidic structures) have the following dimensions (depth of the structures (t) and possibly their volume (V); the numbers refer to FIG.
  • a transition from shallower to deeper structures is usually only possible for liquids in the fluidic structures, if external force (eg centrifugal force) acts on them.
  • Such transitions act as geometric (non-closing) valves.
  • the substrate (2) also has the sample and buffer addition openings (4, 16), ventilation openings (17) and the central recess (3).
  • the surface of the substrate (2), which has the fluidic structures, can then be cleaned by means of plasma treatment and hydrophilized.
  • reagents required for analyte detection eg biotinylated anti-analyte antibodies and anti-analyte antibodies labeled with a fluorescence label
  • sample dosing section (5) eg biotinylated anti-analyte antibodies and anti-analyte antibodies labeled with a fluorescence label
  • the reagent solutions are composed as follows: Biotinylated antibody: 50 mM Mes pH 5.6; 100 ⁇ g / ml biotinylated monoclonal anti-troponin T antibody Labeled antibodies 50 mM Hepes pH 7.4, with squaric acid derivative Fluorescent dye JG9 (embedded in polystyrene latex particles) Fluorescently labeled monoclonal anti-troponin T antibodies (0.35 percent solution)
  • the porous matrix (12) (nitrocellulose membrane on plastic carrier film 21 x 5 mm 2 ; 100 ⁇ m PE film reinforced cellulose nitrate membrane (type CN 140 of Sartorius, Germany)
  • An analyte detection line polystreptavidin
  • a control line polyhapten
  • aqueous streptavidin solution (4.75 mg / ml) is applied by line dosing to the above-described cellulose nitrate membrane.
  • the dosage is selected (dosage 0.12 ml / min, web speed 3 m / min), that a line with a width of about 0.4 mm is formed. This line is used to detect the analyte to be determined and contains about 0.95 ⁇ g streptavidin per membrane.
  • an aqueous troponin T polyhapten solution of 0.3 mg / ml is applied under identical dosing conditions. This line serves as a functional check of the test element and contains approx. 0.06 ⁇ g polyhapten per test.
  • the cover (film or injection molded part without Fluidik Modellen, which may or may be hydrophilized) is applied and optionally permanently connected to the substrate (2), preferably glued, welded or clipped.
  • the substrate is turned and in the corresponding recess the waste nonwoven fabric (13) (13 x 7 x 1.5 mm 3 fleece 100 parts of glass fiber (diameter 0.49 to 0.58 microns, length 1000 microns) and 5 Divide polyvinyl alcohol fibers (Kuralon VPB 105-2 from Kuraray) with a basis weight of about 180 g / m 2 ), which is then fixed by means of an adhesive tape in the substrate (2).
  • the waste nonwoven fabric 13 x 7 x 1.5 mm 3 fleece 100 parts of glass fiber (diameter 0.49 to 0.58 microns, length 1000 microns) and 5 Divide polyvinyl alcohol fibers (Kuralon VPB 105-2 from Kuraray) with a basis weight of about 180 g / m 2 ), which is then fixed by means of an adhesive tape in the substrate (2).
  • the quasi self-dosing sample receiving unit (comprising the sample application opening (4), the sample dosing (5) and the structures limiting it (capillary stop (8) and container for excess sample (7)) ensures that regardless of the on the test element (1) discontinued Amount of sample (if it exceeds a minimum volume (in this example 27 ⁇ l)) if different test elements are used, reproducibly the same amount of samples.
  • the reagents in the entire sample metering section (5) preferably in the form of alternating reagent spots (ie smaller, almost punctiform reagent areas), in combination with a rapid filling of the sample metering section (5) with sample, a homogeneous dissolution of the reagents in the entire sample volume is achieved , Especially if the filling is much faster than the release.
  • a virtually complete dissolution of the reagents so that here again an increased reproducibility compared to conventional, based on absorbent materials test elements (test strips, bio-discs with reagent pads, etc.) is observed.
  • test element On the test element according to Example 1, 27 .mu.l of whole blood to which different amounts of recombinant troponin T were added, abandoned. The test element is then further treated on the basis of the procedure given in Table 1 and finally measured the fluorescence signals for different concentrations.
  • Table 1 Measurement procedure Time (min: sec) Duration (min: sec) Rotation at revolutions per minute action 00:00 01:00 0 Add 27 ⁇ l sample; Dissolve the reagents 01:00 02:00 5000 Erythrocyte separation and incubation 03:00 01:00 800 Chromatography (generate signal) 04:00 12:10 0 Add 12 ⁇ l washing buffer 1) 04:10 02:00 800 Wash buffer transport and chromatography 06:10 12:10 0 Add 12 ⁇ l washing buffer 1) 06:20 02:00 800 Wash buffer transport and chromatography 08:20 12:10 0 Add 12 ⁇ l washing buffer 1) 08:30 02:00 800 Wash buffer transport and chromatography 10:30 0 measure up 1) 100 mM Hepes, pH 8.0; 150 mM NaCl; 0.095% sodium azide.
  • the measured data are in FIG. 10 played.
  • the respective measurement signals (in counts) are plotted against the concentration of recombinant troponin T (c (TnT)) in [ng / ml].
  • the actual troponin T concentration in the whole blood samples was determined using the reference method "Roche Diagnostics Elecsys Troponin T Test".
  • the detection limit for the quantitatively evaluable measuring range with the test element according to the invention is shifted downwards (Cardiac Troponin T: 0.1 ng / ml, invention: 0.02 ng / ml) and the dynamic measuring range after dilated at the top (Cardiac Troponin T: 2.0 ng / ml, invention: 20 ng / ml).
  • the test elements according to the invention show improved precision.

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Claims (11)

  1. Élément d'essai (1) pour la détection d'un analyte dans un échantillon liquide, qui est sensiblement discoïde, comprenant
    - un axe central à l'intérieur de l'élément d'essai, qui est disposé perpendiculairement au plan de l'élément d'essai et autour duquel l'élément d'essai (1) est rotatif,
    - un orifice de distribution d'échantillons (4), pour l'introduction d'un échantillon liquide,
    - une zone à activité capillaire (12), qui est une matrice poreuse absorbante (12), la zone à activité capillaire (12) contenant une ou plusieurs zones pourvues d'agents réactifs immobilisés, les réactifs immobilisés étant des agents réactifs liants spécifiques, qui sont aptes à capturer de manière ciblée, à partir de l'échantillon s'écoulant à travers la zone à activité capillaire (12) l'analyte ou des espèces dérivées de l'analyte et qui sont en relation avec celui-ci et qui sont présents en étant immobilisés sous forme de lignes, de points, de motifs dans ou sur la matière de la zone à activité capillaire (12), avec une première extrémité éloignée de l'axe et une seconde proche de l'axe, et
    - un canal à échantillons (9), qui mène de l'orifice de distribution d'échantillons (4) via une zone proche de l'axe jusqu'à la première extrémité éloignée de l'axe de la zone à activité capillaire (12) et qui comporte une zone pour la séparation des composants particulaires hors de l'échantillon liquide (10, 11),
    caractérisé en ce que
    la première extrémité éloignée de l'axe de la zone à activité capillaire (12) est en contact avec le canal à échantillons (9) et
    l'orifice de distribution d'échantillons (4) est proche de l'axe et le canal à échantillons (9) mène de l'orifice de distribution d'échantillons (4) jusqu'à la première extrémité éloignée de l'axe de la zone à activité capillaire (12).
  2. Élément d'essai (1) selon la revendication 1, caractérisé en ce que la matrice poreuse absorbante (12) est un papier, une membrane ou un non-tissé.
  3. Élément d'essai (1) selon l'une des revendications précédentes, caractérisé en ce que la zone à activité capillaire (12) est en contact par la seconde extrémité proche de l'axe avec une autre matière absorbante (13) ou une structure absorbante, qui est susceptible, le cas échéant de capturer le liquide dans la zone à activité capillaire (12).
  4. Élément d'essai (1) selon l'une des revendications précédentes, caractérisé en ce que le canal à échantillons (9) comporte des zones de dimensions différentes et/ou destinées à des fonctions différentes, en particulier une zone contenant des agents réactifs solubles et/ou une zone de dosage d'échantillons (5) et/ou une arrivée pour d'autres liquides (16), hormis le liquide échantillon.
  5. Élément d'essai (1) selon l'une des revendications précédentes, caractérisé en ce que le canal à échantillons (9) comporte des valves géométriques ou des barrières hydrophobes (6, 8, 14, 19).
  6. Élément d'essai (1) selon l'une des revendications 1 à 5, caractérisé en ce que l'orifice de distribution d'échantillons (4) est en contact avec une zone de dosage d'échantillons (5) et une zone (7) destinée à l'excédent d'échantillon, entre la zone de dosage d'échantillons (5) et la zone (7) destinée à l'excédent d'échantillon étant présente une butée capillaire (6).
  7. Procédé de détection d'un analyte dans un échantillon liquide, lors duquel
    - on introduit l'échantillon dans l'orifice de distribution d'échantillons (4) de l'élément d'essai (1) selon l'une des revendications 1 à 6,
    - on fait tourner l'élément d'essai (1), de manière à transporter l'échantillon vers l'extrémité éloignée de l'axe de la zone à activité capillaire (12),
    - on ralentit ou on arrête la rotation de l'élément d'essai (1), de manière à ce que l'échantillon ou une matière obtenue à partir de l'échantillon lors de la traversée de l'élément d'essai (1) soit aspiré(e) de l'extrémité éloignée de l'axe vers l'extrémité proche de l'axe de la zone à activité capillaire (12), et
    - on détecte par voie visuelle ou optique l'analyte dans la zone à activité capillaire (12) ou dans une zone située en aval de celle-ci.
  8. Procédé selon la revendication 7, caractérisé en ce qu'après la rotation de l'élément d'essai (1), on distribue sur l'élément d'essai (1) un autre liquide qui est aspiré après l'échantillon de l'extrémité éloignée de l'axe jusqu'à l'extrémité proche de l'axe de la zone à activité capillaire (12).
  9. Procédé selon la revendication 7 ou 8, caractérisé en ce qu'on ralentit ou on arrête de manière ciblée la migration de l'échantillon liquide et/ou de l'autre liquide à travers la zone à activité capillaire (12) par la rotation de l'élément d'essai (1).
  10. Procédé selon l'une des revendications 7 à 9, caractérisé en ce qu'on inverse la direction de la migration de l'échantillon liquide et/ou de l'autre liquide à travers la zone à activité capillaire (12) par la rotation de l'élément d'essai (1).
  11. Système, destiné à déterminer un analyte dans un échantillon liquide, comportant un élément d'essai (1) selon l'une des revendications 1 à 6 et un instrument de mesure, l'instrument de mesure
    - présentant au moins un entraînement pour la rotation de l'élément d'essai (1) et
    - une optique d'évaluation pour évaluer le signal visuel ou optique de l'élément d'essai (1).
EP07818502.2A 2006-09-27 2007-09-27 Elément d'essai rotatif Active EP2069787B1 (fr)

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EP1916524A1 (fr) 2008-04-30
CA2664565C (fr) 2014-04-01
HK1136626A1 (en) 2010-07-02
US20090191643A1 (en) 2009-07-30
ES2933349T3 (es) 2023-02-06
ES2724734T3 (es) 2019-09-13
WO2008037469A1 (fr) 2008-04-03
EP2069787A1 (fr) 2009-06-17
EP3524982A1 (fr) 2019-08-14
EP3524982B1 (fr) 2022-10-19
JP2010505096A (ja) 2010-02-18
JP5502482B2 (ja) 2014-05-28
CA2664565A1 (fr) 2008-04-03
CN101517413A (zh) 2009-08-26
US8470588B2 (en) 2013-06-25
CN101517413B (zh) 2013-11-06

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