EP3524982B1 - Élément d'essai rotatif - Google Patents

Élément d'essai rotatif Download PDF

Info

Publication number
EP3524982B1
EP3524982B1 EP19160587.2A EP19160587A EP3524982B1 EP 3524982 B1 EP3524982 B1 EP 3524982B1 EP 19160587 A EP19160587 A EP 19160587A EP 3524982 B1 EP3524982 B1 EP 3524982B1
Authority
EP
European Patent Office
Prior art keywords
sample
test element
capillary
axis
zone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP19160587.2A
Other languages
German (de)
English (en)
Other versions
EP3524982A1 (fr
Inventor
Christoph Boehm
Norbert Oranth
Juergen Spinke
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
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Roche Diagnostics GmbH filed Critical F Hoffmann La Roche AG
Publication of EP3524982A1 publication Critical patent/EP3524982A1/fr
Application granted granted Critical
Publication of EP3524982B1 publication Critical patent/EP3524982B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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 that is essentially disk-shaped and flat and can be rotated about a preferably central axis that is perpendicular to the disk-shaped test element plane, containing a sample application opening for application of a liquid sample, a capillary-active zone, which is a porous, absorbent matrix , and a sample channel that extends from the sample application opening to the capillary-active zone. Furthermore, the invention relates to a method for determining an analyte using the test element.
  • the systems used to analyze liquid sample materials or sample materials that can be converted into liquid form can be divided into two classes: on the one hand there are analysis systems that work exclusively with so-called wet reagents, on the other hand there are systems that work with so-called dry reagents.
  • analysis systems that work exclusively with so-called wet reagents
  • dry reagents systems that work with so-called dry reagents.
  • the former systems have prevailed in the field of permanently equipped laboratories, while the latter systems are mainly used in the field of "on-site" analysis.
  • test carriers e.g. B. offered test strips.
  • Prominent examples of this are test strips for determining blood sugar levels or test strips for urine tests.
  • Such test carriers usually integrate several functions (e.g. the storage of reagents in dried form or - albeit less frequently - in solution; the separation of unwanted sample components, in particular red blood cells from whole blood; in immunoassays, the so-called bound Free separation; the dosing of sample volumes; the transport of sample liquid from outside a device into a device; the control of the chronological sequence of individual reaction steps; etc.).
  • the function of sample transport is often accomplished by means of absorbent materials (e.g.
  • Disk-shaped test carriers so-called LabDiscs or optical BioDiscs, continue the idea of controlled sample transport using centrifugal force (centrifugal force).
  • Such disk-shaped, CompactDisc-like test carriers enable miniaturization through the use of microfluidic structures and at the same time the parallelization of processes through repeated application of identical structures for the parallel processing of similar analyzes from one sample or identical analyzes from different samples.
  • optical BioDiscs the integration of optically stored digital data for the identification of the test carrier 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 processes and measured using established evaluation technology. In the case of the chemical and biochemical components of such optical BioDiscs, it is usually possible to fall back on known chemical and biochemical components.
  • the disadvantage of the optical LabDiscs or Biodiscs based purely on centrifugal and capillary forces is that it is difficult to immobilize reagents and the accuracy of detection suffers. Especially in detection systems based on specific binding reactions such.
  • B. Immunoassays the volume component is missing compared to conventional test strip systems, especially in the so-called. Bound-free separation.
  • WO 2005/001429 (Phan et al. ) describes optical bio-disks that have pieces of membrane as reagent carriers in parts of the channel system. The reagents are dissolved by a liquid fed to the disk, 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, for separating particulate sample components, for carrying reagents and for 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.
  • the sample is then moved radially outwards again, ie away from the center of the Bio-Disk, and flows through a so-called analysis membrane.
  • the movement outwards takes place via chromatography, which is supported by the rotation of the Bio-Disk and the centrifugal force that acts on the sample as a result.
  • US 2002/0076354 A1 discloses optical bio-disks which, in addition to a channel system for transporting a liquid sample, have what is known as a “capture layer”.
  • the latter can consist of nitrocellulose, for example.
  • the "interceptor layer” is flown through with the help of centrifugal forces when the disk rotates.
  • US 2004/0265171 (Pugia et al. ) describes a test element with liquid channels in which the sample liquid is transported by means of an interplay of capillary force and centrifugal force.
  • a nitrocellulose strip can be provided within a liquid channel, which carries an agglutination reagent which reacts with the analyte and can thus lead to the formation of so-called bands which can finally be measured optically and thus serve to determine an analyte concentration in the sample.
  • the nitrocellulose strip it is possible to transport the sample liquid both parallel to the centrifugal force and in the opposite direction to the centrifugal force, especially when another absorbent material, for example an absorbent nitrocellulose paper, is used to support the suction effect.
  • WO 99/58245 (Larsson et al. ) describes microfluidic test elements in which the movement of liquids through different surfaces with different surface properties, such as e.g. B. different hydrophilicity is controlled.
  • test elements with microfluidic structures, which have, among other things, chambers for introducing the sample and chambers for introducing a dilution buffer, which are each microfluidically connected to mixing chambers, from which another channel branches off, which is connected to an analysis chamber.
  • US 5,160,702 discloses microfluidic structures that describe a sample chamber and a dilution chamber as separate substructures that open into a common mixing chamber. A channel leads from this mixing chamber to the fluidic areas in which the detection takes place.
  • the object of the invention is to eliminate the disadvantages of the prior art.
  • the subject matter of the invention is a test element according to claim 1, a system according to claim 11 and a method according to claim 7.
  • Advantageous configurations and preferred embodiments of the invention are the subject matter of the dependent patent claims.
  • test element is essentially disc-shaped and flat. It is rotatable about a preferably central axis that 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 disk, but can also be used with non-symmetrical or non-circular disks.
  • the test element initially contains a sample application opening into which a liquid sample can be pipetted or introduced in some other way.
  • the sample application port is near-axis (ie, close to the center of the disk).
  • the sample application opening can open directly into a sample channel.
  • the sample application opening it is also possible for the sample application opening to initially open into a reservoir located behind it, into which the sample flows before it continues to flow into the sample channel.
  • Appropriate dimensioning can ensure that the sample flows from the sample application opening into the downstream fluidic structures without further action. This can be done by hydrophilizing the surfaces of the fluidic structures be necessary and/or the use of structures that promote the development of capillary forces.
  • the test element contains a capillary-active zone in the form of a porous, absorbent matrix that absorbs at least part of the liquid sample.
  • the capillary-active zone has a first end remote from the axis and a second end close to the axis.
  • the test element also has a sample channel that extends from the sample application opening to the first end of the capillary-active zone, which is a porous, absorbent matrix and is remote from the axis.
  • the sample channel runs at least once through a region close to the axis which is closer to the preferably central axis than the first end of the capillary-active zone which is remote from the axis.
  • the essential feature of the test element of the present invention is that the capillary-active zone, which is a porous, absorbent matrix, has a second end close to the axis.
  • the first end of the capillary-active zone that is remote from the axis 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 positive or negative pressure.
  • the liquid sample - possibly after the absorption of reagents and/or dilution media and/or the expiry of preliminary reactions - reaches the first end of the capillary-active zone remote from the axis, it is absorbed into it and, by the capillary forces (which in the case of a porous absorbent Matrix can also be referred to as suction forces) transported through it.
  • the capillary forces which in the case of a porous absorbent Matrix can also be referred to as suction forces
  • 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 with immobilized reagents.
  • the capillary-active zone which is a porous, absorbent 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 the analyte or species derived from the analyte and related thereto from the sample flowing through the capillary-active zone.
  • These binding partners are immobilized in the form of lines, dots, patterns in or on the material of the capillary-active zone.
  • an antibody against the analyte can be immobilized on the surface of the capillary-active zone, which is a porous, absorbent matrix, which then capture the analyte (in this case an antigen or hapten) from the sample and also immobilize it in the capillary-active zone.
  • the analyte can be made detectable by further reactions, for example by further bringing it into contact with a labeled partner capable of binding, for example by a visually, optically or fluorescence-optically detectable label.
  • the capillary-active zone which is a porous, absorbent matrix, adjoins another absorbent material or an absorbent structure with the second end near the axis, so that this or this liquid can be absorbed from the zone.
  • the porous bibulous matrix and the other material overlap slightly for this purpose.
  • the additional material or the additional absorbent structure serves on the one hand to support the suction effect of the capillary-active zone, which is a porous absorbent matrix, and on the other hand as a receiving zone for liquid that has already passed through the capillary-active zone.
  • the further material can consist of the same or different materials as the matrix.
  • the matrix can be a membrane and the other absorbent material can be a fleece or paper. Other combinations are of course also possible.
  • the test element according to the invention is characterized in that the sample channel has zones of different dimensions and/or for contains different functions.
  • the sample channel can contain a zone containing sample-soluble or sample-suspendable reagents. These can be dissolved or suspended in the liquid sample as it flows in or through it and react with the analyte in the sample or with other sample components.
  • the different zones in the sample channel can also differ in that there are zones with capillary activity and zones without.
  • zones with high hydrophilicity and low hydrophilicity can be included.
  • the individual zones can pass into one another almost seamlessly 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 for reagents to be 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 base layer into which the fluidic structures are introduced and a cover layer which generally contains no further structures apart from the inlet openings for liquids and the ventilation openings.
  • the introduction of reagents during the manufacture of the test device usually takes place before the upper part of the test element (top layer) is applied to the lower part (bottom layer). At this point in time, the fluidic structures in the lower part are open, so that the reagents can easily be dosed in liquid or dried form.
  • the reagents can be introduced, 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 paper, fleece or membranes. After placing the reagents and inserting the absorbent materials, for example the porous, absorbent matrix (membrane) and optionally other absorbent materials (waste fleece, etc.), the upper and lower parts of the test element are connected to one another, for example clipped, welded, glued and the like.
  • absorbent materials such as paper, fleece or membranes.
  • the bottom layer also has the inlet openings for liquids and the ventilation openings in addition to the fluidic structures.
  • the cover layer can be formed entirely without openings, possibly with the exception of a central recess for accommodating a drive unit.
  • the upper part can simply consist of a plastic film that is glued to the lower part or welded to it.
  • the sample channel usually contains a zone for separating particulate components from the liquid sample.
  • this zone serves to separate the cellular sample components.
  • red blood cells erythrocytes
  • almost colorless plasma or serum can be obtained from blood, which is generally more suitable for subsequent visual or optical detection methods than the strongly colored blood.
  • the cellular sample components are preferably separated off by centrifugation, i. H. by rapidly rotating the test element after filling it with a liquid sample.
  • the test element according to the invention contains suitably dimensioned and geometrically designed channels and/or chambers.
  • 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 order to control the flow of the sample liquid in the test element, this can have valves, especially so-called non-closing (non-closing) or geometric valves or hydrophobic barriers. These valves serve as capillary stops. They can ensure that a targeted temporal and spatial control of the sample flow through the sample channel and the individual zone of the test element is possible.
  • the sample channel can have a sample dosing zone that allows the sample—which was initially applied in excess—to be measured precisely.
  • the sample dosing 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 application opening can initially take up an excess of sample material.
  • the sample flows either driven by capillary forces or driven by centrifugation 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.
  • the sample channel also has an inflow for other liquids apart from the sample liquid.
  • a second channel can open into the sample channel, the z. B. can be filled with a washing or reagent liquid.
  • the system according to the invention made up of a measuring device and a test element is used to determine an analyte in a liquid sample.
  • the measuring device contains, among other things, at least one drive for rotating the test element and evaluation optics for evaluating the visual or optical signal of the test element.
  • the optics of the measuring device can preferably be used for fluorescence measurement with spatially resolved detection.
  • an LED or a laser is typically used to illuminate the detection area of the test element and, if necessary, to excite optically detectable markings.
  • the optical signal is detected using CMOS or CCD (typically with 640 ⁇ 480 pixels).
  • the beam path is direct or folded (e.g. 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 take place here via a diode line.
  • the rotational movement of the test element can be used for the illumination and evaluation of the 2nd dimension in order to scan with the diode line over the flat area of the test element to be evaluated.
  • a DC motor with encoder or a stepper motor can be used as a drive for rotating and positioning the test element.
  • the temperature of the test element in the device is preferably controlled indirectly, for example by heating or cooling the plate on which the disc-shaped test element rests in the device.
  • the temperature is preferably measured 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.
  • the test element is then rotated—preferably about its preferably central axis; however, it is also possible to carry out the method according to the invention in such a way that the rotation takes place around another axis, which may also be located outside of the test element.
  • the sample is transported from the sample application opening to the end of the capillary-active zone, which is a porous, absorbent matrix, away from the axis.
  • the rotation of the test element is then slowed down or stopped to such an extent that the sample or a material obtained from the sample as it flows through the test element (e.g.
  • 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 separating the erythrocytes, etc. is transported from the end of the capillary-active zone that is remote from the axis to the end near the axis, which is a porous, absorbent matrix.
  • the analyte is detected visually or optically in the capillary-active zone, which is a porous, absorbent matrix, or in a zone downstream of it.
  • the start of the migration of the sample (or a material obtained from the sample) through the capillary-active zone can be precisely timed and controlled by deliberately 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 the counter-acting centrifugal force is it possible for the sample to move into and through the capillary-active zone.
  • the liquid transport in the capillary-active zone can be started in a targeted manner. For example, a possible pre-reaction or pre-incubation of the sample or a tempering of the sample can be awaited before the rotation of the test element is slowed down or stopped to such an extent that the sample can 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 specifically slowed down or stopped by rotating the test element again about its preferably central axis.
  • the centrifugal forces occurring during rotation counteract the capillary force, which moves the sample liquid from the end of the capillary-active zone that is remote from the axis to the end that is close to the axis.
  • a targeted Control, in particular slowing down, of the flow rate of the sample in the capillary-active zone is possible, up to and including reversing the direction of flow. In this way, for example, the dwell time of the sample in the capillary-active zone can be controlled.
  • test element and method according to the invention it is therefore possible, with the test element and method according to the invention, to reverse the direction of migration of the liquid sample and/or the other liquid through the capillary-active zone by rotating the test element, whereby this is also possible several times in order to avoid moving the to reach liquid.
  • capillary forces which transport the liquid in the capillary-active zone from the outside (i.e. from the end remote from the axis) inwards (i.e.
  • the detection can be carried out according to the sandwich assay principle or in the form of a competitive test.
  • test element after the test element has been rotated, another liquid is applied to the test element, which is transported after the sample from the end of the capillary-active zone that is remote from the axis to the end near the axis.
  • the further liquid can in particular be a buffer, preferably a washing buffer, or a reagent liquid.
  • a buffer preferably a washing buffer, or a reagent liquid.
  • the invention has the following advantages:
  • the capillary-active zone which is a porous, absorbent matrix, transports the liquid from an end remote from the axis to an end close to the axis, ie from the periphery of the disk-shaped test element in the direction of the axis of rotation.
  • the centrifugal force which can also be used to move the liquids, counteracts this direction of transport.
  • porous, absorbent matrix which essentially serves as a capture matrix for bound-free separation in immunoassays, allows sample components to be captured efficiently during the course of the immunoassay.
  • centrifugal and capillary forces makes it possible to move the sample back and forth over a reagent zone, in particular a zone with immobilized reagents (above all, a capture zone for heterogeneous immunoassays), without increased technical effort, and so on to ensure more effective dissolving of the reagents, mixing of the sample with reagents or scavenging of sample components on immobilized binding partners.
  • a reagent zone in particular a zone with immobilized reagents (above all, a capture zone for heterogeneous immunoassays)
  • the most efficient possible use of the small liquid volumes can be achieved not only for Reaction purposes (here the sample volume is used in particular) but also for washing purposes, for example for better discrimination of bound and free label in the capture zone. This effectively minimizes the amount of sample, liquid reagents and wash buffer.
  • the preferably central position of the axis of rotation within the test element makes it possible to design both the test element itself and the associated measuring device as compactly as possible.
  • chip-shaped test elements such as those used in figure 1 and 2 from US2004/0265171 are shown, the axis of rotation lies outside the test element.
  • An associated turntable or rotor is therefore inevitably larger than in a test element with identical dimensions, but in which the axis of rotation is preferably arranged centrally within the test element, as is the case with the test elements according to the invention.
  • figure 1 shows a schematic representation of a plan view of an embodiment of a test element that is not according to the invention. For the sake of clarity, only the layer of the test element that contains the fluidic structures is shown. The embodiment shown contains only one opening for the introduction of sample and / or washing liquid. In this embodiment, the interfering sample components are separated after the sample has been brought into contact with reagents.
  • FIG 2 shows schematically a further embodiment of a test element not according to the invention.
  • the test element there are two separate sample and wash buffer application ports.
  • the cellular sample components are already separated here before the sample is brought into contact with reagents.
  • figure 3 shows a variant of the embodiment according to the invention figure 1 in a schematic representation.
  • the cellular sample components are separated after the sample has been brought into contact with reagents.
  • the structure according to figure 3 a separate supply for washing liquid.
  • figure 4 shows a further preferred embodiment of a test element according to the invention in a schematic view analogously figure 2 .
  • figure 5 represents a minor further development of the test element according to the invention figure 3 represents.
  • figure 3 represents.
  • figure 5 a different geometric arrangement of the waste fleece and a different type of valve at the end of the sample dosing section.
  • figure 6 shows schematically a top view of a further development of the test element according to the invention according to FIG figure 5 .
  • the embodiment according to figure 5 contains the embodiment according to figure 6 a fluidic structure for taking up excess sample.
  • figure 7 is a schematic representation of a further variant of the test element according to the invention figure 3 .
  • the fluidic structures are essentially analogous to those of figure 3 . However, they are geometrically aligned and designed differently.
  • figure 8 shows schematically a further preferred embodiment of the test element according to the invention.
  • the structures in figure 8 essentially correspond to the functions provided by the test element figure 4 are already known.
  • figure 9 shows schematically a top view of an alternative to the test element according to FIG figure 6 .
  • figure 6 contains the embodiment according to figure 9 a sample application opening remote from the axis, which initially brings the sample closer to the center of the test element via a capillary, ie into an area close to the axis.
  • figure 10 shows the typical curve shape for troponin T measurements in whole blood samples (concentration of troponin T in ng/ml plotted against the signal strength (counts)). The samples were spiked with recombinant troponin T to the respective concentration.
  • Example 2 The data pertains to Example 2 and was determined using test elements according to figure 6 / Sample 1 received.
  • the Figures 3 to 8 show different preferred embodiments of a test element (1) according to the invention.
  • the figures 1 , 2 and 9 show alternative embodiments of a test element that are not according to the invention.
  • the substrate (2) containing the fluidic structures and the central recess (drive hole 3) is essentially shown in each case.
  • the disk-shaped test element (1) according to the invention also usually contains a cover layer, which is shown in the figures for clarity is not shown for the sake of it.
  • the cover layer can also have structures, but as a rule it will not have any structures apart from the openings for the samples and/or other liquids to be applied to the test element.
  • the cover layer can also be designed without any openings, for example in the form of a film which is connected to the substrate and closes off the structures located therein.
  • FIG 1 shows a first embodiment of a disc-shaped test element (1) not according to the invention.
  • the test element (1) contains a substrate (2) which contains the fluidic, microfluidic and chromatographic structures.
  • the substrate (2) is covered (not shown) by a corresponding counterpart (top layer) which contains sample application and ventilation openings which correspond 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, enables the disk-shaped test element (1) to rotate.
  • test element (according to one of Figures 1 to 9 ) has no such central recess (3) and the drive is rotated via a drive unit of the measuring device designed according to the outer contours of the test element, for example a rotating plate, in which the test element is placed in a depression corresponding to its shape.
  • Sample liquid in particular whole blood, is fed 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 dosing zone (5) can also contain the dried reagents. It is delimited by the capillary stops (6 and 8), which can be designed, for example, as a hydrophobic barrier or as a geometric/non-closing valve. The delimitation of the sample metering zone (5) by the capillary stops (6, 8) ensures that a defined sample volume is taken up and passed on to the fluidic zones that are downstream of the sample metering zone (5).
  • any excess sample is removed from the sample application opening (4) and the sample dosing zone (5) is transferred to the sample excess container (7), while the measured amount of sample is transferred from the sample dosing zone (5) to the channel (9).
  • the separation of red blood cells and other cellular sample components is started in channel (9).
  • the reagents contained in the sample dosing zone (5) are already dissolved in the sample when it enters the channel (9).
  • the entry of the sample into the channel (9) via the capillary stop (8) leads to the reagents in the sample being mixed.
  • 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).
  • sample volume can be used much more effectively with the test elements according to the invention, since there are practically no dead volumes (e.g. volume of the fiber interstices or pores) from which the sample cannot be taken again.
  • dead volumes e.g. volume of the fiber interstices or pores
  • these prior art blood-separating membranes and webs tend to be undesirable in some cases Adsorption of sample components (e.g. proteins) or destruction (lysis) of cells, which is also not observed with the test elements according to the invention.
  • the reagent-plasma mixture in which, in the case of an immunoassay, sandwich complexes of analyte and antibody conjugates have formed when the analyte is present
  • the porous-absorbent matrix (12) added to and passed through it.
  • the analyte-containing complexes are captured in the detection zone by the immobilized binding partners contained in the membrane (12) and unbound, labeled conjugate is bound in the control zone.
  • the fleece (13) adjoining the porous, absorbent matrix supports the movement of the sample through the membrane (12).
  • the fleece (13) also serves to hold the sample after it has flowed through the membrane (12).
  • the washing buffer is pipetted into the sample application opening (4) in a subsequent step.
  • the wash buffer flows through the corresponding fluidic structures of the test element (1) and washes in particular the membrane (12), where the bound analyte complexes are now located and thus removes excess reagent residues.
  • the washing step can be repeated one or more times in order to improve the signal-to-noise ratio. This allows the detection limit for the analyte to be optimized and the dynamic measuring range to be increased.
  • the sample channel in which the liquid sample in the test element (1) is transported from the sample application opening (4) to the first end of the membrane (12) remote from the axis, in the present case comprises the sample dosing zone (5), the capillary stop (8), the channel ( 9), the serum/plasma collection zone (10) and the erythrocyte chamber (11).
  • the sample channel can consist of more or fewer individual zones/areas/chambers.
  • FIG. 3 differs from figure 1 in that, on the one hand, there is no container for excess sample (7) adjoining the sample application opening (4) and there is no capillary stop at the end of the sample metering section (5) (ie metered sample application is required here) and, on the other hand, in that, according to the invention, a separate metering opening ( 16) for other liquids, e.g. B. 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 figure 5 is largely identical to the embodiment according to FIG figure 3 .
  • the two embodiments differ only in the shape of the waste fleece (13) and in that the test element according to FIG figure 5 a capillary stop (8) at the end of the sample dosing section (5).
  • the embodiment according to figure 6 is again essentially identical to the embodiment according to FIG figure 5 and differs from this by the additional presence of a container for excess sample (7) in the area between the sample dosing opening (4) and the sample dosing zone (5). No dosed application of the sample is required here (analogous to figure 1 ).
  • the embodiment of the test element (1) according to the invention figure 7 essentially corresponds to the test element (1) of figure 6 . Both embodiments have the same fluidic structures and functions. Only the arrangement and geometric design is different.
  • the embodiment according to figure 7 has additional ventilation openings (17), which due to the different dimensions of the fluidic structures compared to figure 6 are necessary to fill the To allow structures with samples or washing liquid.
  • Channel (9) is designed here as a thin capillary which is only filled when the test element rotates (ie overcoming the capillary stop (8) is only possible by means of centrifugal force). It is already in accordance with the test element (1) during the rotation figure 7 possible to discharge collected plasma from the erythrocyte collection zone 11; the decanting unit 18, which finally opens into the serum/plasma collection zone 10, is used for this purpose.
  • test element (1) according to the invention figure 9 essentially corresponds to the test element (1) of figure 6 . Both embodiments have the same fluidic structures and functions. Only the arrangement and geometric design is different.
  • the non-inventive embodiment according to figure 9 basically has a sample application opening (4) further to the outside, i.e. away from the axis. This can be advantageous if the test element (1) has already been placed in a measuring device for filling with sample. In this case, the sample application opening (4) can be made accessible to the user more easily than is the case with test elements according to FIG Figure 1 to 8 is possible where the sample application opening (4) is arranged close to the axis (ie away from the outer edge of the test element).
  • the separation of the cellular sample components from the sample liquid takes place before the sample comes into contact with reagents.
  • This has the advantage that the use of whole blood or plasma or serum as sample material does not lead to different measurement results, since plasma or serum always comes into contact with the reagents first and the dissolution/incubation/reaction behavior should therefore be practically the same .
  • the liquid sample is first applied to the test element (1) via the sample application opening (4). The sample is then transported further from the sample application opening (4) into the channel structures by capillary forces and/or centrifugal forces.
  • the sample after transferred to the sample application opening (4) in a sample dosing section (5) and then causes a serum/plasma separation from the whole blood by rotation.
  • the undesired cellular sample components essentially erythrocytes, collect in the erythrocyte trap (11), while serum or plasma collect in 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 housed and are dissolved when the sample flows in.
  • the sample-reagent mixture from the 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 across the membrane (12) into the waste fleece (13).
  • the embodiments according to figure 2 and figure 4 differ in that in figure 2 a container for excess sample (7) is provided, while the embodiment according to figure 4 does not provide such a function. As in the embodiment according to figure 3 a dosed application of the sample is advisable here.
  • FIG 8 shows a variant of the embodiments according to FIG figures 2 and 4 .
  • the sample is transferred by centrifugation into an erythrocyte separation structure (10, 11) immediately after the sample application opening (4) after passing through a first geometric valve (19).
  • the area marked (10) serves as a serum/plasma collection zone (10) from which serum or plasma freed from cells is passed on via a capillary channel (21) after centrifugation.
  • Chamber (20) serves as a collection reservoir for excess serum or plasma, which may flow out of the serum/plasma collection zone (10) after the sample metering section (5) has been completely filled. All other functions and structures are analogous to the Figures 1 to 7 .
  • the hydrophilic or hydrophobic properties of the surfaces of the test element (1) By specifically 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 either only with the help 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 figures 6 , 7 and, 8th an automatic functionality that allows a relatively accurate measurement of a sample aliquot from a sample applied in excess to the test element (so-called "metering system"). It essentially comprises the elements 4, 5, 6 and 7 of the test elements (1) shown.
  • Sample liquid in particular whole blood, is fed 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 dosing zone (5) can also contain the dried reagents.
  • the capillary stops (6 and 8) can be designed, for example, as a hydrophobic barrier or as geometric/non-closing valves.
  • the delimitation of the sample metering zone (5) by the capillary stops (6, 8) ensures that a defined sample volume is taken up and passed on to the fluidic zones that are downstream of the sample metering zone (5).
  • any excess sample is transferred from the sample application opening (4) and the sample dosing zone (5) into the container for excess sample (7), while the measured amount of sample from the sample dosing zone (5) flows into the channel (9 ) is transferred.
  • it is also possible to use other forces instead of the force generated by rotation that moves the sample e.g. B. by applying an overpressure on the sample inlet side or a negative pressure on the sample outlet side. Consequently, the metering system shown is not necessarily tied to rotatable test elements, but can also be used in other test elements.
  • a disadvantage of the design of the metering system according to U.S. 5,061,381 is that with sample volumes that are applied to the test element and that correspond exactly to the minimum volume or are only slightly larger than the minimum volume, there is a risk that the dosing zone will be underdosed, since a proportion of the sample always flows unhindered into the "overflow chamber" flows.
  • a capillary stop hydrophobic barrier or a geometric or non-closing valve
  • the capillary stop prevents the sample from flowing into the zone for sample excess before the sample dosing zone is completely filled. Even with sample volumes that are applied to the test element and which correspond exactly to the minimum volume or are only slightly larger than the minimum volume, this ensures that the sample dosing zone is completely filled.
  • a transition from less deep to deeper structures is generally only possible for liquids in the fluidic structures if an external force (e.g. centrifugal force) acts.
  • Such transitions act as geometric (non-closing) valves.
  • the substrate (2) also has the sample and buffer feed 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 and rendered hydrophilic by means of plasma treatment.
  • Some of the reagents required for analyte detection e.g. biotinylated anti-analyte antibodies and anti-analyte antibodies marked with a fluorescent label
  • the reagent solutions are composed as follows: Biotinylated Antibody: 50mM Mes pH 5.6; 100 ⁇ g/ml biotinylated monoclonal anti-troponin T antibodies Labeled antibodies 50 mM Hepes pH 7.4, with squaric acid derivative fluorescent dye JG9 (embedded in polystyrene latex particles) fluorescently labeled anti-troponin T monoclonal antibody (0.35 percent solution)
  • the porous matrix (12) (nitrocellulose membrane on plastic carrier film; 21 ⁇ 5 mm 2 ; reinforced with 100 micron PE film cellulose nitrate membrane (type CN 140 from Sartorius, Germany)), in which an analyte detection line (polystreptavidin) and a control line (polyhapten) were introduced by means of line impregnation (see below), inserted and, if necessary, fixed with double-sided adhesive tape.
  • aqueous streptavidin solution (4.75 mg/ml) is applied by line dosing to the cellulose nitrate membrane described above.
  • the dosing is selected (dosing quantity 0.12 ml/min, web speed 3 m/min) that a line with a width of approx. 0.4 mm arises.
  • This line serves to identify the analyte to be determined and contains approx. 0.95 ⁇ g streptavidin per membrane.
  • an aqueous 0.3 mg/ml troponin T polyhapten solution is applied under identical dosing conditions.
  • This line serves as a function control of the test element and contains approx. 0.06 ⁇ g polyhapten per test.
  • the cover (foil or injection-molded part without fluidic structures, which can optionally be made hydrophilic) is then applied and optionally permanently connected to the substrate (2), preferably glued, welded or clipped.
  • the substrate is turned and the waste fleece (13) (13 ⁇ 7 ⁇ 1.5 mm 3 fleece made of 100 parts glass fiber (diameter 0.49 to 0.58 ⁇ m, length 1000 ⁇ m) and 5 Parts of polyvinyl alcohol fibers (Kuralon VPB 105-2 from Kuraray) with a basis weight of about 180 g/m 2 ) are inserted, which is then fixed in the substrate (2) by means of an adhesive tape.
  • the waste fleece (13) 13 ⁇ 7 ⁇ 1.5 mm 3 fleece made of 100 parts glass fiber (diameter 0.49 to 0.58 ⁇ m, length 1000 ⁇ m) and 5 Parts of polyvinyl alcohol fibers (Kuralon VPB 105-2 from Kuraray) with a basis weight of about 180 g/m 2 ) are inserted, which is then fixed in the substrate (2) by means of an adhesive tape.
  • the quasi-self-dosing sample receiving unit (comprising the sample application opening (4), the sample dosing section (5) and the structures delimiting it (capillary stop (8) and container for excess sample (7)) ensures that, regardless of the amount applied to the test element (1). sample amount (if it exceeds a minimum volume (in this example 27 ⁇ l)) when using different test elements, the same sample amounts can be used reproducibly.
  • reagents By distributing the reagents throughout the sample dosing section (5), preferably in the form of alternating reagent spots (i.e. small, almost punctiform reagent areas), in combination with rapid filling of the sample dosing 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.
  • the reagents are practically completely dissolved, so that here again an increased reproducibility compared to conventional test elements based on absorbent materials (test strips, bio-disks with reagent pads, etc.) is observed.
  • the measurement data are in figure 10 played back.
  • 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 "Roche Diagnostics Elecsys Troponin T Test" reference method.
  • the detection limit for the quantitatively evaluable measuring range with the test element according to the invention is shifted down (cardiac troponin T: 0.1 ng / ml; invention: 0.02 ng / ml) and the dynamic measuring range extended upwards (cardiac troponin T: 2.0 ng/ml; invention: 20 ng/ml).
  • the test elements according to the invention show improved precision.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Claims (11)

  1. Élément d'essai (1) destiné à la détection d'un analyte dans un échantillon liquide, lequel est essentiellement en forme de disque et peut tourner autour d'un axe, lequel est perpendiculaire à un plan de l'élément d'essai en forme de disque, comprenant
    - un orifice d'introduction d'échantillons (4) destiné à l'introduction d'un échantillon liquide,
    - une zone (12) à activité capillaire, laquelle est une matrice (12) poreuse absorbante, où la zone (12) à activité capillaire comporte au moins une zone comportant des réactifs immobilisés, où les réactifs immobilisés sont des agents liants spécifiques, lesquels sont appropriés pour capturer de manière ciblée un analyte ou des espèces dérivées de l'analyte et en relation avec celui-ci dans l'échantillon s'écoulant dans la zone (12) à activité capillaire et lesquels sont présents immobilisés sous forme de lignes, de points, de motifs, dans ou sur la matière de la zone (12) à activité capillaire, comportant une première extrémité éloignée de l'axe et une seconde extrémité proche de l'axe, et
    - un canal à échantillons (9), lequel s'étend depuis l'orifice d'introduction d'échantillons (4) par l'intermédiaire d'une zone proche de l'axe jusqu'à la première extrémité éloignée de l'axe de la zone (12) à activité capillaire,
    caractérisé en ce que,
    la première extrémité éloignée de l'axe de la zone (12) à activité capillaire est en contact avec le canal à échantillons (9) et
    l'orifice d'introduction d'échantillons (4) est proche de l'axe et le canal à échantillons (9) s'étend de l'orifice d'introduction d'échantillons (4) jusqu'à la première extrémité éloignée de l'axe de la zone (12) à activité capillaire et
    le canal à échantillons comporte une entrée pour d'autres liquides en dehors du liquide d'échantillonnage et
    où ladite entrée comporte un orifice d'addition (16) séparé pour d'autres liquides, de préférence un tampon de lavage, et un canal (15) associé, lequel peut transporter le tampon vers la zone (12) à activité capillaire, où
    l'orifice d'addition (16) séparé est agencé plus proche de l'axe, autour duquel l'élément d'essai peut tourner, que la zone du canal à échantillons (9), laquelle est directement reliée à la première extrémité éloignée de l'axe de la zone (12) à activité capillaire et
    le canal (15) associé relie directement l'orifice d'addition (16) séparée à la zone du canal à échantillons (9), laquelle est directement reliée à la première extrémité éloignée de l'axe de la zone (12) à activité capillaire.
  2. Élément d'essai (1) selon la revendication 1, caractérisé en ce que la matrice (12) poreuse absorbante 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 (12) à activité capillaire est en contact, au moyen de la seconde extrémité proche de l'axe, avec une autre matière (13) absorbante ou une structure absorbante, laquelle peut respectivement capturer le liquide de la zone (12) à activité capillaire.
  4. Élément d'essai (1) selon l'une des revendications précédentes, caractérisé en ce que le canal à échantillons (9) comporte des zones présentant des dimensions différentes et/ou pour des fonctions différentes, en particulier une zone comportant des réactifs solubles et/ou une zone de dosage d'échantillon (5) et/ou une zone de séparation des constituants particulaires de l'échantillon liquide.
  5. Élément d'essai (1) selon l'une des revendications précédentes, caractérisé en ce que le canal à échantillons (9) comporte des valves ou des barrières hydrophobes (6, 8, 14, 19) géométriques.
  6. Élément d'essai (1) selon l'une des revendications 1 à 5, caractérisé en ce que l'orifice d'introduction d'échantillons (4) est en contact avec une zone de dosage d'échantillon (5) et une zone (7) pour l'excès d'échantillon, où, entre la zone de dosage d'échantillon (5) et la zone (7) pour l'excès d'échantillon, un arrêt capillaire (6) est disposé.
  7. Procédé de détection d'un analyte dans un échantillon liquide, où
    - l'échantillon est introduit dans l'orifice d'introduction d'échantillons (4) de l'élément d'essai (1) selon l'une des revendications 1 à 6,
    - l'élément d'essai (1) est entraîné en rotation de telle sorte que l'échantillon est transporté vers l'extrémité éloignée de l'axe de la zone (12) à activité capillaire,
    - la rotation de l'élément d'essai (1) est ralentie ou arrêtée de telle sorte que l'échantillon ou une matière extrait de l'échantillon lors de la traversée de l'élément d'essai (1) est aspiré de l'extrémité éloignée de l'axe jusqu'à l'extrémité proche de l'axe de la zone (12) à activité capillaire, et
    - l'analyte dans la zone (12) à activité capillaire ou dans une zone en aval de celle-ci est détecté visuellement ou optiquement.
  8. Procédé selon la revendication 7, caractérisé en ce que
    après la rotation de l'élément d'essai (1), un autre liquide est introduit sur l'élément d'essai (1), lequel est aspiré, après l'échantillon, de l'extrémité éloignée de l'axe jusqu'à l'extrémité proche de l'axe de la zone (12) à activité capillaire.
  9. Procédé selon la revendication 7 ou 8, caractérisé en ce que la migration de l'échantillon liquide et/ou de l'autre liquide à travers la zone (12) à activité capillaire est ralentie ou arrêtée de manière ciblée au moyen de la rotation de l'élément d'essai (1).
  10. Procédé selon l'une des revendications 7 à 9, caractérisé en ce que la direction de la migration de l'échantillon liquide et/ou de l'autre liquide à travers la zone (12) à activité capillaire est inversée au moyen de la rotation de l'élément d'essai (1).
  11. Système de détermination d'un analyte dans un échantillon liquide comportant un élément d'essai (1) selon l'une des revendications 1 à 6 et un appareil de mesure, où l'appareil de mesure comporte
    - au moins un entraînement pour la rotation de l'élément d'essai (1) et
    - une optique d'évaluation permettant d'évaluer le signal visuel ou optique de l'élément d'essai (1).
EP19160587.2A 2006-09-27 2007-09-27 Élément d'essai rotatif Active EP3524982B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06020219A EP1916524A1 (fr) 2006-09-27 2006-09-27 Elément d'essai rotatif
EP07818502.2A EP2069787B1 (fr) 2006-09-27 2007-09-27 Elément d'essai rotatif
PCT/EP2007/008419 WO2008037469A1 (fr) 2006-09-27 2007-09-27 Élément d'essai rotatif

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP07818502.2A Division EP2069787B1 (fr) 2006-09-27 2007-09-27 Elément d'essai rotatif

Publications (2)

Publication Number Publication Date
EP3524982A1 EP3524982A1 (fr) 2019-08-14
EP3524982B1 true EP3524982B1 (fr) 2022-10-19

Family

ID=37719401

Family Applications (3)

Application Number Title Priority Date Filing Date
EP06020219A Ceased EP1916524A1 (fr) 2006-09-27 2006-09-27 Elément d'essai rotatif
EP19160587.2A Active EP3524982B1 (fr) 2006-09-27 2007-09-27 Élément d'essai rotatif
EP07818502.2A Active EP2069787B1 (fr) 2006-09-27 2007-09-27 Elément d'essai rotatif

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP06020219A Ceased EP1916524A1 (fr) 2006-09-27 2006-09-27 Elément d'essai rotatif

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP07818502.2A Active EP2069787B1 (fr) 2006-09-27 2007-09-27 Elément d'essai rotatif

Country Status (8)

Country Link
US (1) US8470588B2 (fr)
EP (3) EP1916524A1 (fr)
JP (1) JP5502482B2 (fr)
CN (1) CN101517413B (fr)
CA (1) CA2664565C (fr)
ES (2) ES2933349T3 (fr)
HK (1) HK1136626A1 (fr)
WO (1) WO2008037469A1 (fr)

Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8632243B2 (en) * 2008-03-10 2014-01-21 The Hong Kong Polytechnic University Microfluidic mixing using continuous acceleration/deceleration methodology
EP2133149A1 (fr) * 2008-06-13 2009-12-16 F.Hoffmann-La Roche Ag Dispositif d'étiquetage sur disque
EP2145682A1 (fr) * 2008-07-18 2010-01-20 Roche Diagnostics GmbH Elément de test destiné à l'analyse d'un analyte contenu dans un échantillon de liquide corporel, système d'analyse et procédé de commande du mouvement d'un liquide contenu dans un canal d'un élément de test
EP2198964B8 (fr) 2008-11-06 2013-04-24 F. Hoffmann-La Roche AG Procédé destiné à la préparation d'un réactif séché dans un système microfluidique
EP2194381B1 (fr) * 2008-12-03 2015-12-02 Roche Diagnostics GmbH Elément de test doté d'une zone de contrôle et de calibrage combinée
GB2473425A (en) * 2009-09-03 2011-03-16 Vivacta Ltd Fluid Sample Collection Device
EP2329877A1 (fr) * 2009-12-04 2011-06-08 Roche Diagnostics GmbH Elément micro-fluidique destiné à l'analyse d'un échantillon de liquide
KR101722548B1 (ko) * 2010-01-29 2017-04-03 삼성전자주식회사 원심력기반의 미세유동장치 및 이를 이용한 유체시료 내 분석대상물질 검출방법
EP2369324A1 (fr) 2010-03-23 2011-09-28 F. Hoffmann-La Roche AG Procédé de fabrication d'un élément de test analytique, élément de test analytique, utilisation d'un élément de test analytique ainsi que système de test analytique
DE102010013752A1 (de) 2010-03-31 2011-10-06 Roche Diagnostics Gmbh Multifunktionelle Detektionsküvette
JP5728217B2 (ja) 2010-12-14 2015-06-03 ローム株式会社 マイクロチップおよびそれを用いた検査または分析方法
US11485968B2 (en) 2012-02-13 2022-11-01 Neumodx Molecular, Inc. Microfluidic cartridge for processing and detecting nucleic acids
CN114134029A (zh) 2012-02-13 2022-03-04 纽莫德克斯莫勒库拉尔公司 用于处理和检测核酸的微流体盒
US11648561B2 (en) 2012-02-13 2023-05-16 Neumodx Molecular, Inc. System and method for processing and detecting nucleic acids
US9637775B2 (en) 2012-02-13 2017-05-02 Neumodx Molecular, Inc. System and method for processing biological samples
US9604213B2 (en) 2012-02-13 2017-03-28 Neumodx Molecular, Inc. System and method for processing and detecting nucleic acids
US10668622B2 (en) * 2012-10-11 2020-06-02 Siemens Healthcare Diagnostics Inc. Automation maintenance carrier
EP2912174B1 (fr) 2012-10-25 2019-06-19 Neumodx Molecular, Inc. Procédé et matériaux pour isoler des matériaux d'acide nucléique
EP2777499B1 (fr) 2013-03-15 2015-09-16 Ortho-Clinical Diagnostics Inc Dispositif de collecte d'échantillon de fluide rotatif
WO2014172238A1 (fr) 2013-04-15 2014-10-23 Becton, Dickinson And Company Dispositif de prélèvement de fluide biologique et système d'analyse et de séparation de fluide biologique
ES2755490T3 (es) * 2013-04-15 2020-04-22 Becton Dickinson Co Dispositivo de extracción de fluidos biológicos y sistema de separación de fluidos biológicos
SG11201601039XA (en) * 2013-08-23 2016-03-30 Daktari Diagnostics Inc Microfluidic metering of fluids
EP3077806B1 (fr) * 2013-12-06 2019-09-11 Ortho Clinical Diagnostics, Inc. Dispositif d'analyse doté d'un orifice de nettoyage
EP2944965A1 (fr) 2014-05-13 2015-11-18 Roche Diagnostics GmbH Cartouche rotative pour mesurer une propriété d'un échantillon biologique
EP3151963B1 (fr) 2014-06-06 2018-03-14 Roche Diagnostics GmbH Cartouche rotative avec une chambre de dosage permettant d'analyser un échantillon biologique
EP2952257A1 (fr) 2014-06-06 2015-12-09 Roche Diagnostics GmbH Cartouche rotative pour le traitement et l'analyse d'un échantillon biologique
EP2952258A1 (fr) * 2014-06-06 2015-12-09 Roche Diagnostics GmbH Cartouche rotative pour analyser un échantillon biologique
EP2957890A1 (fr) * 2014-06-16 2015-12-23 Roche Diagnostics GmbH Cartouche avec couvercle rotatif
WO2016066591A1 (fr) 2014-10-30 2016-05-06 Ge Healthcare Bio-Sciences Ab Procédé pour déterminer des courbes de correction de solvant
JP6600861B2 (ja) * 2015-04-08 2019-11-06 株式会社パートナーファーム 固相反応チップ及びこれを用いた測定方法
WO2017044732A1 (fr) * 2015-09-09 2017-03-16 Northwestern University Dispositifs, systèmes, et procédés de préparation de spécimens faisant appel à des forces capillaires et centrifuges
EP3173149A1 (fr) 2015-11-26 2017-05-31 Roche Diagnostics GmbH Détermination d'une quantité d'un analyte dans un échantillon de sang
EP3184158B1 (fr) 2015-12-21 2019-01-16 Roche Diagniostics GmbH Collecteur de sang avec structure capillaire
CN107192819A (zh) * 2016-03-14 2017-09-22 北京康华源科技发展有限公司 一种离心分离检测方法
JP2019507887A (ja) * 2016-03-14 2019-03-22 北京康華源科技発展有限公司 遠心分離検出方法および装置
EP3231513B1 (fr) * 2016-04-14 2022-03-02 Roche Diagnostics GmbH Cartouche et mesure optique d'un analyte avec cette cartouche
KR101868961B1 (ko) 2016-06-21 2018-06-19 울산과학기술원 미세 유체 장치
ES2857735T3 (es) 2016-11-16 2021-09-29 Hoffmann La Roche Cartucho giratorio con múltiples cámaras medidoras
EP3571510B1 (fr) * 2017-01-20 2021-05-19 Université Libre de Bruxelles Procédés et dispositifs de dosage immunologique centrifugique
JP7004732B2 (ja) * 2017-02-09 2022-01-21 エッセンリックス コーポレーション 異なる間隔の高さを使用するアッセイ法
WO2018165440A1 (fr) * 2017-03-08 2018-09-13 Northwestern University Dispositifs, systèmes, et procédés de préparation et d'analyse d'échantillons faisant appel à des forces capillaires et centrifuges
CN107525923A (zh) * 2017-04-01 2017-12-29 北京康华源科技发展有限公司 一种离心分离免疫层析检测方法及装置
WO2018177445A1 (fr) * 2017-04-01 2018-10-04 北京康华源科技发展有限公司 Procédé et appareil de détection par immunochromatographie à centrifugation
KR102140370B1 (ko) 2017-11-20 2020-07-31 주식회사 엘지화학 회전식 디스크 시스템을 활용한 중금속 정성 및 정량 분석 디바이스 및 분석 방법
US11433390B2 (en) * 2017-12-07 2022-09-06 Ion Llc Methods and systems for a capillary device
JP6846388B2 (ja) * 2018-06-26 2021-03-24 シスメックス株式会社 測定用カートリッジおよび送液方法
CN110614126B (zh) * 2018-06-28 2021-04-09 北京中科生仪科技有限公司 一种实现光学检测的微流控芯片及其制作方法
SE542462C2 (en) * 2018-09-20 2020-05-12 Astrego Diagnostics Ab Sample loading cartridge for a microfluidic device
CN111207242B (zh) * 2020-04-18 2020-09-01 博奥生物集团有限公司 流体驱动控制阀及使用方法
KR102433675B1 (ko) * 2020-07-02 2022-08-18 주식회사 클리노믹스 입자 여과 장치 및 입자 여과 방법
BE1029228B1 (fr) * 2021-03-22 2022-10-18 Unisensor Dispositif microfluidique

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3445816C1 (de) 1984-12-15 1986-06-12 Behringwerke Ag, 3550 Marburg Flaechenfoermiges diagnostisches Mittel
US5160702A (en) * 1989-01-17 1992-11-03 Molecular Devices Corporation Analyzer with improved rotor structure
US5242606A (en) * 1990-06-04 1993-09-07 Abaxis, Incorporated Sample metering port for analytical rotor having overflow chamber
US5061381A (en) 1990-06-04 1991-10-29 Abaxis, Inc. Apparatus and method for separating cells from biological fluids
US6235531B1 (en) * 1993-09-01 2001-05-22 Abaxis, Inc. Modified siphons for improved metering precision
US5591643A (en) * 1993-09-01 1997-01-07 Abaxis, Inc. Simplified inlet channels
IL108159A (en) * 1993-12-23 1998-02-08 Orgenics Ltd Apparatus for separation, concentration and detection of target molecules in liquid sample
GB9809943D0 (en) * 1998-05-08 1998-07-08 Amersham Pharm Biotech Ab Microfluidic device
AU2002219979A1 (en) 2000-12-01 2002-06-11 Burstein Technologies, Inc. Apparatus and methods for separating components of particulate suspension
EP1390144A2 (fr) * 2001-03-19 2004-02-25 Gyros AB Unites structurelles definissant des fonctions fluidiques
AU2003293399A1 (en) * 2002-12-04 2004-06-23 Spinx, Inc. Devices and methods for programmable microscale manipulation of fluids
US20050014249A1 (en) 2003-02-21 2005-01-20 Norbert Staimer Chromatographic analysis on optical bio-discs and methods relating thereto
US20050037484A1 (en) 2003-04-23 2005-02-17 Norbert Staimer Optical bio-discs including spiral fluidic circuits for performing assays
US7390464B2 (en) * 2003-06-19 2008-06-24 Burstein Technologies, Inc. Fluidic circuits for sample preparation including bio-discs and methods relating thereto
US20040265171A1 (en) * 2003-06-27 2004-12-30 Pugia Michael J. Method for uniform application of fluid into a reactive reagent area
EP1644184A2 (fr) 2003-06-27 2006-04-12 Nagaoka & Co., Ltd. Circuits de fluides et procedes et appareil d'utilisation d'echantillons de sang entier dans des analyses colorimetriques
WO2005009581A2 (fr) * 2003-07-15 2005-02-03 Nagaoka & Co. Ltd. Procedes et appareil de separation et d'analyse du sang utilisant des membranes sur un biodisque optique
JP4646204B2 (ja) * 2005-01-27 2011-03-09 ブラザー工業株式会社 検査対象受体、分取装置、及び分取方法

Also Published As

Publication number Publication date
JP2010505096A (ja) 2010-02-18
US20090191643A1 (en) 2009-07-30
EP3524982A1 (fr) 2019-08-14
US8470588B2 (en) 2013-06-25
EP2069787B1 (fr) 2019-03-06
CN101517413A (zh) 2009-08-26
EP1916524A1 (fr) 2008-04-30
HK1136626A1 (en) 2010-07-02
ES2933349T3 (es) 2023-02-06
ES2724734T3 (es) 2019-09-13
CA2664565A1 (fr) 2008-04-03
JP5502482B2 (ja) 2014-05-28
CA2664565C (fr) 2014-04-01
WO2008037469A1 (fr) 2008-04-03
CN101517413B (zh) 2013-11-06
EP2069787A1 (fr) 2009-06-17

Similar Documents

Publication Publication Date Title
EP3524982B1 (fr) Élément d'essai rotatif
DE602005005485T2 (de) Assayvorrichtung und verfahren mit gesteuertem fluss
EP0989407B1 (fr) Méthode pour la détermination de l'hémoglobine glycosylée
EP0073513B2 (fr) Méthode d'exécution d'une détermination analytique et moyen approprié
EP1944078B1 (fr) Dispositif destiné à la détermination d'un analyte dans un liquide et procédé
DE69906986T2 (de) Analytisches testgerät und verfahren
DE60037268T2 (de) Verfahren zur durchführung magnetischer chromatographischer assays
DE60218695T2 (de) Biosensoren und messverfahren
US10983119B2 (en) Device for rapid diagnostic tests to detect antigens with improved sensitivity
EP0167171B1 (fr) Méthode et dispositif pour l'exécution de déterminations analytiques
EP0052769A1 (fr) Méthode de détermination analytique et élément de rotor pour la mise en oeuvre de la méthode
EP1495799A2 (fr) Dispositif pour le traitement d'une portion limitée de liquide
EP3829767B1 (fr) Dispositif et procédé destinés à conduire un liquide à travers un milieu poreux
DE2332760B2 (de) Material fuer die quantitative spektrophotometrische analyse einer fluessigkeit
EP1808696A1 (fr) Elément de test immunologique doté d'une zone de contrôle améliorée
EP1522343B1 (fr) Dispositif de test analytique comprenant une matrice hydrophile pour former un canal capillaire, son utilisation et procédé pour déterminer un analyte dans un liquide.
DE102007019695B4 (de) Küvette für die optische Analyse kleiner Volumina
US20030190690A1 (en) Biosensor and method for analyzing blood components using it
EP2194381B1 (fr) Elément de test doté d'une zone de contrôle et de calibrage combinée
DE10001116C2 (de) Vorrichtung und Verfahren zur optischen oder elektrochemischen quantitativen Bestimmung chemischer oder biochemischer Substanzen in flüssigen Proben
DE3912901A1 (de) Gefaess zur agglutinationsanalyse
DE102005010096B3 (de) Assay mit osmotisch induzierter Abtrennung und Anreicherung hochmolekularer nachzuweisender Substanzen und fluidisches Mikrosystem zu seiner Durchführung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN PUBLISHED

AC Divisional application: reference to earlier application

Ref document number: 2069787

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200214

RBV Designated contracting states (corrected)

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20200707

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 502007016985

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: G01N0033543000

Ipc: B01L0003000000

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

RIC1 Information provided on ipc code assigned before grant

Ipc: G01N 33/543 20060101ALN20220425BHEP

Ipc: B01L 3/00 20060101AFI20220425BHEP

INTG Intention to grant announced

Effective date: 20220520

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AC Divisional application: reference to earlier application

Ref document number: 2069787

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 502007016985

Country of ref document: DE

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1525232

Country of ref document: AT

Kind code of ref document: T

Effective date: 20221115

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2933349

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20230206

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20221019

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20230220

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20230219

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20230120

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230524

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 502007016985

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

26N No opposition filed

Effective date: 20230720

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20230822

Year of fee payment: 17

Ref country code: GB

Payment date: 20230823

Year of fee payment: 17

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221019

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20230822

Year of fee payment: 17

Ref country code: DE

Payment date: 20230822

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20231002

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20231001

Year of fee payment: 17

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230927