EP2416881A1 - Cartouche d'analyse microfluidique à usage unique pour l'analyse biologique d'analytes - Google Patents

Cartouche d'analyse microfluidique à usage unique pour l'analyse biologique d'analytes

Info

Publication number
EP2416881A1
EP2416881A1 EP10711021A EP10711021A EP2416881A1 EP 2416881 A1 EP2416881 A1 EP 2416881A1 EP 10711021 A EP10711021 A EP 10711021A EP 10711021 A EP10711021 A EP 10711021A EP 2416881 A1 EP2416881 A1 EP 2416881A1
Authority
EP
European Patent Office
Prior art keywords
chamber
test cassette
analyte
detection
reagent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10711021A
Other languages
German (de)
English (en)
Inventor
Ingmar Dorn
Andreas Schade
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.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Technology Services 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 Bayer Technology Services GmbH filed Critical Bayer Technology Services GmbH
Publication of EP2416881A1 publication Critical patent/EP2416881A1/fr
Withdrawn legal-status Critical Current

Links

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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • 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
    • B01L2200/16—Reagents, handling or storing thereof
    • 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
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions

Definitions

  • the present invention relates to a microfluidic technology-based disposable test cassette for the bioassay of analytes by means of bio and / or chemosensors, a device for bioassaying of analytes by means of bio and / or chemosensors comprising the test cassette according to the invention, a method for operating this test cassette, and their use in environmental analysis, the food sector, human and veterinary diagnostics and plant protection.
  • Bio or chemosensors are devices that can qualitatively or quantitatively detect an analyte with the aid of a signal converter and a recognition reaction.
  • the recognition reaction is generally referred to as the specific binding or reaction of a so-called analyte with a so-called recognition element.
  • recognition reactions are the binding of ligands to complexes, the complexation of ions, the binding of ligands to (biological) receptors, membrane receptors or ion channels, of antigens or haptens to antibodies, of substrates to enzymes, of DNA or RNA to specific proteins, the hybridization of DNA / RNA / PNA or the processing of substrates by enzymes.
  • Analytes may be: ions, proteins, natural or artificial antigens or haptens, hormones, cytokines, mono- and oligosaccharides, metabolites or other biochemical markers used in diagnostics, enzyme substrates, DNA, RNA, PNA, potential drugs, medications, Cells, viruses.
  • recognition elements are: natural or artificial receptors such. As complexing agents for metals / metal ions, cyclodextrins, crown ethers, antibodies, antibody fragments, anticalins enzymes, DNA, RNA, PNA, DNA / RNA-binding proteins, membrane receptors, ion channels, cell adhesion proteins or gangliosides, enzymes, mono- or oligosaccharides and haptamers.
  • bio- or chemosensors can be used in environmental analysis, the food industry, human and veterinary diagnostics and crop protection to qualitatively and / or quantitatively determine analytes.
  • the specificity of the recognition reaction also allows analytes in complex samples such. As ambient air, contaminated water or body fluids with little or no prior purification to determine qualitatively or quantitatively.
  • bio- or chemosensors can also be used in (bio-) chemical research and drug discovery to study the interaction between two different substances (eg between proteins, DNA, RNA, or biologically active substances and proteins, DNA, RNA, etc.).
  • a new class of electrical biosensors relies on the detection of analytes which are supported by metallic particles, e.g. Nanoparticles are marked. For detection, these particles are enlarged by autometallographic deposition to the extent that they short a microstructured circuit. This is demonstrated by a simple DC resistance measurement (US 4,794,089; US 5,137,827; US 5,284,748). Detection of nucleic acids by DC resistance measurement has recently been demonstrated (R. Möller, A. Csäki, J. M. Köhler, and W. Fritzsche, Langmuir 17, 5426 (2001)).
  • Field effect transistors may be used as electronic transducers e.g. for an enzymatic reaction (Zayats et al., Biosens. & Bioelectron., 15, 671 (2000)).
  • quartz crystals are described in which the change in the resonance frequency by mass occupancy takes place (Steinern et al., Biosens. & Bioelectronics 12, 787 (1997)).
  • interdigital structures are used to excite surface waves that are modified by target adsorption (Howe et al., Biosens. & Bioelectron., 15, 641 (2000)).
  • the recognition reaction can be detected by the magnetic influence of the beads on the giant magnetoresistance (GMR) of a corresponding resistor (Baselt et al., Biosens., And Bioelectron., 13, 731 (1998)).
  • GMR giant magnetoresistance
  • Integration of the recognition reaction with the signal transducer into a biosensor or chemosensor can be accomplished by immobilizing the recognition element or analyte on the surface of the transducer.
  • the recognition reaction d. H. the binding or reaction of the analyte with the recognition element, the optical properties of the medium change directly on the surface of the transducer (eg, change in optical refractive index, absorption, fluorescence, phosphorescence, luminescence, etc.) is translated by the signal converter into a measurement signal.
  • Optical (planar) waveguides are a class of signal transducers that can detect the change in optical properties of a medium that is adjacent to a waveguiding layer, typically a dielectric.
  • a medium typically a dielectric.
  • the light field at the medium / waveguide interface does not abruptly decay but decays exponentially in the so-called detection medium adjoining the waveguide.
  • This exponentially decreasing light field is called evanescent field designates.
  • waste lengths of the evanescent field intensity drops to the value 1 / e) of ⁇ 200 nm are achieved. Change the optical properties of the adjacent to the waveguide medium -.
  • the recognition element or the analyte when the recognition element or the analyte is immobilized at the interface of the waveguide, the binding to the recognition element or the reaction of the recognition element can be surface-sensitively detected, while changing the optical properties of the detection medium (liquid, solid, gaseous) at the interface to the waveguide ,
  • test cassette ready-to-use In order to simplify the operation of chemo- or biosensors, attempts have been made for some years to reduce these devices and, as far as possible, all reagents needed for the qualitative and / or quantitative determination of a sample are placed in a so-called test cassette ready-to-use.
  • microfluidics technology is being used, with the aim of providing cost-effective, storable and easy-to-use disposable cassettes that can deliver timely, reproducible results.
  • the mixing of the analyte with the detection reagent is not optimal for detection because of the uncontrollable laminar flow
  • laminar flow is affected by different surface properties which are difficult to control in the manufacture and storage of a test cartridge, such as e.g.
  • Air bubbles can form during the transport of the liquid
  • DE102005011530 describes a microfluidic device for real-time quantification of a very small amount of analyte.
  • the real-time evaluation is achieved by flowing the sample into a detection unit.
  • the detection unit consists of a flow channel in the analyte capture units for trapping the analyte z.
  • antibodies are immobilized on a variety of analyte detection units along the flow channel.
  • the quantitative determination of the analyte is z. B. by means of an optical signal.
  • the analyte sample is z. B. transported with a micropump in the flow channel.
  • the aim of the above device is to optimize the number of analytes trapped by the analyte trap unit in the direction of flow.
  • the analytes are quantitated over a wide range (the length of the flow channel) without decreasing the detection sensitivity.
  • This device consists of a variety of microscopic components based on semiconductor technologies or microscopic precision devices - micropumps, microvalves, sensors, and the like, which are miniaturized, accumulated, and integrated.
  • the manufacture and operation of this device is too complicated and too expensive for a potential use as a disposable test assay.
  • WO2005 / 070533 describes a microfluidic device for determining the concentration of an analyte in a sample fluid having a structured body which has chamber systems connected to duct systems, optionally with built-in filter units with an inlet and an outlet, and which is closed on at least one side with a sealing layer is.
  • This device comprises a reaction chamber containing reagents for binding to at least one component of the sample liquid, which are immobilized either on the lid of the chamber or on coated particles.
  • a sample chamber is filled with the sample liquid through the inlet and the inlet is closed by means of a lid.
  • the sample liquid is conveyed by means of a pump from the sample chamber through a channel system into the reaction chamber.
  • the device has further channel systems containing a label liquid and a washing liquid, and a discharge channel system for evacuating waste liquids.
  • Different parts of the complex duct systems can be closed by means of soft seals, which can be broken open under low pressure as needed.
  • the flow direction in the device is ensured by means of valves and brush-like or valve-like flow diodes.
  • the device allows precise control of volumes and reaction times.
  • the structure of this device requires several processes in the reaction chamber before it can be measured and is correspondingly expensive.
  • Due to the fluidic elements used, the device is very complex, which is reflected in susceptibility and high production costs.
  • the use of fluidic elements also reduces the shelf life of the device.
  • the dry assay technology in which all reagents in the dry state in the cassette, if necessary, are available in separate chambers.
  • the sample liquid is usually conveyed by means of microfluidic channels from one chamber to the next.
  • WO 2005/088300 describes an integrated microfluidic test cassette for blood analysis which consists of a lower and an upper body part. Both elements are structured with chambers and channels, which are closed by the joining of the two parts.
  • the pretreatment elements are, in particular, filter elements or elements with porous properties in the form of a channel or a (micro / nano) cushion, which optionally carry dry reagents.
  • the sample is first passed through the pretreatment elements, then into the multilayer dry assay element.
  • the multilayer dry assay detection element comprises at least one functional layer bearing recognition elements for a qualitative and quantitative assay in dry and stable form.
  • This reagent layer consists of a water-absorbing layer in which stimulable recognition elements are reasonably regularly distributed in a hydrophilic polymer binder material (gelatin, agarose, etc.).
  • the detection is carried out by reflection photometry through a light-transparent window, by irradiating a detection layer in the multi-layered dry assay element in which the optically excitable liquid has diffused from the detection reaction.
  • Disadvantage of this device is that the structure of the multilayer dry assay element is expensive. Accurate control of volume, mixing and incubation times is not possible, so that the test results are quantitatively not reproducible.
  • the cassette is inserted into a device for operating the cassette, which has a light source for irradiating the reaction chamber, a filter for concentration of the signal from the reaction chamber and a detection unit.
  • Lateral flow assays have been known for many years for biochemical analysis. Lateral flow assays (LFA) exploit the effect of the antibody-antigen reaction.
  • the sample to be analyzed solution
  • capillary forces For example, to detect analytes by LFA, a direct, competitive immunoassay can be performed on a nitrocellulose strip, whereby the sample to be analyzed is pulled through the entire nitrocellulose strip due to capillary forces.
  • the zone in which the anti-analyte antibody was immobilized serves as a detection zone for the streak test.
  • An example of an LFA assay for the detection of mycotoxins is the "Reveal Assay” (test cassette) from Neogen, Lansing, MI, USA with the associated "AccuScan” reader.
  • the test cassette is inserted into the reader and the device takes a picture of the result area of the strip test.
  • the reader interprets the result image and when a line is detected, a rating is given.
  • the device eliminates the subjectivity of the interpretation and gives an objective, traceable documentation of the test result.
  • the test described is simple and relatively fast to carry out and does not require elaborate read-out devices. The disadvantage is that the method only allows a qualitative mycotoxin detection.
  • test cassette for the qualitative and / or quantitative analysis of analytes, which contains all the reagents required for carrying out the test procedure in dry form.
  • the test cassette according to the invention has a structured body in which cavities which are connected to one another by channels have been introduced.
  • the test cassette has at least one inlet for introducing an analyte-containing sample liquid, at least one reagent chamber in which one or more reagents for reaction with the analyte or for mixing with the sample liquid are housed, and at least one detection chamber in which Signal for detection or quantitative analysis of the analyte is detected, and is characterized in that:
  • the bottom or the ceiling of the detection chamber is a signal converter or a window for detecting a signal
  • the channels are designed so that the sample liquid is not drawn by capillary forces into the chamber or to the opening,
  • the reagents in the reagent chamber and optionally other reagents are housed in the detection chamber in dry form.
  • a precisely defined volume of sample liquid is conveyed in the channels and in the chambers, which is made possible by the design of the channels and the use of a suitable means for conveying the sample liquid. Reaction times can also be precisely controlled, which contributes to better reproducibility of the analysis.
  • the proper design of the chamber and channels ensures an optimal flow profile with reduced dead volume and optimal contact with any immobilized detection reagents.
  • various reaction steps e.g. Reconstitution of the reagents, mixing of the reagents with the sample liquid, reaction between reagents and analytes.
  • the detection step occurs immediately after a detection reaction without a previous wash, further simplifying the construction of the cartridge and its handling.
  • the body may be transparent or light-tight and made of various polymer materials such.
  • the bodies are made by known methods, e.g. machining (milling etc.), injection molding, embossing techniques or glass / anorg. Materials by photolithography / etching or other known methods.
  • the shape and size of the test cassette can be anything as long as the total volume of the test cassette remains low and easy to handle.
  • the chamber and the channels are incorporated into the body and closed on at least one side by means of a closure unit with the exception of the inlet and usually by optional air openings and / or a sample chamber.
  • the test cassette is constructed so that it can be tempered by contact with temperature-controllable elements.
  • the design of the test cartridge is configured such that the optional sample chamber, the reagent chamber, and the detection chamber are directed toward the underside of the body.
  • the signal converter or the window for detection then preferably form the bottom of the detection chamber.
  • this side of the cassette is closed with a thin closure unit, in particular a closure film.
  • the closure unit may be light-tight or transparent. If you place the cassette on a tempered surface, so a rapid temperature compensation between tempered pad and the sample solution can take place in the chambers.
  • the closure unit is a sealing film of 30 ⁇ m to 1000 ⁇ m, preferably 50 ⁇ m to 500 ⁇ m, thick. It is advantageous if the closure film can be fastened tightly over the body and can not bend.
  • polyolefin films or polymethylmethacrylate (PMMA) films may be used as the closure films.
  • the closure unit is applied to the upper and lower sides of the test cassette. This simplifies the production of the test cassette according to the invention.
  • the top and bottom closure foils may be the same or different thicknesses.
  • the closure units may be secured to the body by conventional bonding techniques such as, for example, U.S. Pat. B. welding or gluing, if necessary with the aid of adhesive.
  • a precisely defined volume of liquid is held up in the chambers for a certain time and forwarded after this time.
  • test cassette In the test cassette according to the invention usually from 1 to 1000 .mu.l, preferably 10 to 500 .mu.l, particularly preferably 10 to 250 ul transported.
  • the shape of the chamber can be arbitrary. Preference is given to quadrangular detection chambers and / or round reagent chambers.
  • the volumes of the chambers are usually 1 to 1000 ⁇ l, preferably 10 to 500 ⁇ l.
  • the sample chamber is typically round, preferably 5 to 15 mm, preferably 8 to 12 mm in diameter.
  • the reagent chamber is usually round with preferably 5 to 15 mm, preferably 5 to 10 mm in diameter. Both chambers can hold a fluid volume of 1 to 1000 ⁇ l.
  • the detection chamber is usually quadrangular with dimensions of preferably 5 to 15 mm wide and 5 to 15 mm long, more preferably 10 mm x 10 mm and typically absorbs a liquid volume of 1 to 1000 ul, and it must be completely filled according to the invention of the liquid.
  • sample chamber The construction of the sample chamber, reagent chamber and detection chamber should ensure an optimal flow profile with reduced dead volume and optimal contact with the immobilized detection reagents that may be present.
  • the channels may be straight or curved, preferably straight with angular turns.
  • the shape of the channel cross section is arbitrary, usually round or square, preferably round.
  • the cross-sectional sizes of the channels may be the same or different; to be favoured
  • Channels of the same size usually from 0.2 to 3 mm, preferably 0.5 to 1.5 mm in cross section or diameter.
  • the length of the channels is usually 5 mm to 1000 mm, preferably 5 mm to 500 mm.
  • liquids are conveyed by means of a means for accurately and accurately transporting the sample liquids in terms of time and volume.
  • a means for accurately and accurately transporting the sample liquids in terms of time and volume.
  • predefined fluid volumes are pushed from one to the next chamber.
  • the means for transporting the sample liquids is part of a device for operating the test cassette according to the invention, which is also the subject of the present invention.
  • the means for transporting the sample fluids into a docking station for introducing the test cartridge into the o. G. Integrated device.
  • the handling of liquids preferably takes place only in the test cassette according to the invention, so that the above-mentioned device does not come into contact with sample liquid or reagents.
  • precisely defined air bursts are given in the test cassette over time and volume via the means for transporting the sample liquids. These jets of air guide the sample fluid through the various channels and cavities.
  • the sample liquid to be analyzed is introduced into the test cassette through the inlet, preferably into a sample chamber.
  • the test cassette is then usually hermetically sealed by means of one or more lids.
  • the lids may be made of polymeric or inorganic materials which may be obtained by various techniques, e.g. Gluing, welding, laminating, etc. are connected to the body airtight.
  • the reagents in the reagent chamber in a fibrous or porous material for. B. fine particles or tissue, in the form of a reagent pad, in the reagents (adsorbed on, fixed on, dispersed in, dried in) were housed.
  • the reagent pad is selected to meet the requirements of the detection chamber with respect to the required liquid volume of the supernatant solution and the concentration of the individual components in this solution.
  • a preferred reagent pad is made of glass or polymers such. Cellulose. Reagent pads that are also used in so-called lateral flow tests and are commercially available in various forms are suitable.
  • the "extra thick glass filter” from Paill Corporation pore size 1 ⁇ m, typical thickness 1270 ⁇ m (50 mils), typical water flow rate 210 mL / min / cm 2 at 30 kPa is selected, with two circular Filter pieces with a suitable diameter are stacked on top of each other.
  • the reagents of the reagent chamber are typically:
  • recognition elements that are used in recognition reaction, in particular natural or artificial receptors such.
  • Anticalins enzymes DNA, RNA, PNA, DNA / RNA binding proteins, membrane receptors, ion channels, cell adhesion proteins or gangliosides, enzymes, mono- or oligosaccharides and haptamers and / or
  • analytes such as ions, proteins, natural or artificial antigens or haptens, hormones, cytokines, mono- and oligosaccharides,
  • Metabolites or other biochemical markers used in diagnostics be, enzyme substrates, DNA, RNA, PNA, potential drugs, drugs, cells, viruses.
  • labeled antibodies are used as recognition elements.
  • cofactors or other chemicals that are required or advantageous for reacting a recognition element with an analyte are also accommodated in the reagent chamber.
  • the reagent chamber also contains adjuvants to suppress nonspecific interactions between the reagents, to assist in impregnating or triggering the reagents from the reagent pad, such as, for example.
  • adjuvants such as surfactants, lipids, biopolymers, polyethylene glycol, biomolecules, proteins, peptides.
  • the reagents are applied in predefined concentrations and ensures the reproducibility of their release during operation of the cassette.
  • the reagent pad is usually impregnated with about 50 to 500 .mu.l of a solution containing the reagents in concentrations of 10 "3 M to 10 " 15 M, preferably nanomolar concentrations, and usually auxiliaries in amounts of 15 wt.% To 0, Contains 1 ppb.
  • the impregnation is carried out, for example, by drying or lyophilization.
  • the sample fluid delivery means displaces the sample fluid so that it flows into the reagent chamber and completely wets the reagent pad.
  • the reagents are dissolved and react with the analytes or are perfectly mixed with the sample liquid.
  • the reagents are both dissolved (usually by 1 ms to 10 s, preferably about 500 ms to 5, particularly preferably 1 sec) wetting of the reagent pad with a defined sample volume (by the defined air burst) ( reconstituted) and optimally mixed with the sample liquid, and the concentration of the reagents in the sample liquid is set very reproducible. This makes it possible to carry out a quantitative determination of the analytes in the sample volume.
  • a defined time pre-incubation time
  • the sample volume with the dissolved reagents is transported via a channel further into the detection chamber.
  • the sample liquid is filtered in the test cassette in front of the reagent chamber and freed from cells, blood components or other biological, organic or inorganic particles.
  • one or more filter units z.
  • the filter unit may preferably separate particles of 0.2 to 100 ⁇ m, preferably 0.5 to 15 ⁇ m, from the sample liquid.
  • vent (s) takes place.
  • the detection via a signal converter (sensor platform, biochip), which is installed in the detection chamber as a floor.
  • the closure unit is applied over the entire lower side of the cassette, with the exception of the detection chamber.
  • one or more separate measuring ranges are defined, in which one or more further binding partners for detecting the analyte are immobilized in the sample.
  • a biochemical reaction between immobilized binding partner and analyte takes place on the surface of the biochip.
  • the labeled reactants are excited in the detection chamber, the generated signal is detected and used to quantify the analytes.
  • biochips such as e.g. Surface Plasmon Resonance, Planar Waveguides, Quartz Micro Weighing, Electroluminescence, are used and various procedures, eg. As measurement of the refractive index changes by the binding to the surface of the biochip, can be used (see, for example, WO02 / 20873 and EP1316594).
  • Reactions in the detection chamber are for example:
  • a planar thin-film waveguide is used as a biochip, which is a first optically transparent
  • the excitation light is coupled in the thin-film waveguide via the one or more coupling elements and optionally coupled via one or more decoupling elements.
  • lattice structures of the same period and / or modulation depth are preferably used as coupling elements.
  • one or more reactants are immobilized on the surface of the sensor platform for the detection of the analytes directly by physical absorption or electrostatic interaction alternatively by means of an optical transparent primer layer.
  • the binding partners are selectively applied to spatially separated measurement areas on the surface of the sensor platform and the area passivated between the measurement areas to suppress non-specific binding.
  • one or more methods can be used from the group formed by ink jet spotting, mechanical spotting by means of pen or spring, micro contact printing, fluidic contacting of the measuring ranges with the biological or Biochemical or synthetic recognition elements by their supply in parallel or crossed microchannels, under the influence of pressure differences or electrical or electromagnetic potentials.
  • binding-specific detectable recognition elements for one or more analytes of the sample liquid are provided in predefined concentrations in the reagent chamber.
  • the recognition elements are dissolved and enter into the analyte with a specific binding (analyte-recognition element conjugate).
  • the free binding sites of the recognition elements are increasingly saturated with increasing amount of analytes in the sample liquid.
  • analyte-recognition element conjugates and optionally recognition elements with free binding sites to immobilized binding partners By another air blast the analyte-recognition element conjugates and optionally recognition elements with free binding sites to immobilized binding partners, z.
  • analyte-protein conjugates in particular analyte-BSA conjugates, on the signal converter.
  • Free-binding site recognition elements specifically bind with the corresponding immobilized analyte-protein conjugates.
  • the more detectable recognition elements with free binding sites are present in the solution, that is, the lower the proportion of the corresponding analyte in the sample liquid, the more detectable recognition elements are bound on the chip.
  • the analyte-saturated recognition elements from the sample liquid remain in the solution.
  • the recognition elements bound and labeled on the immobilized analyte-protein conjugates can be excited in the evanescent field of the waveguide.
  • the labeled recognition elements present in the solution are not excited in this case. In this way, an indirect quantification of the analytes contained in the sample liquid is possible.
  • the detection chamber has as bottom a transparent window, by which the biochemical reaction taking place in the detection chamber can be detected.
  • the transparent window can through the sealing film, which must be transparent in this case, and z. B. from polymethylmethacrylate (PMMA), are formed or constitute an independent element.
  • the window is preferably made of glass or of a plastic which is transparent to the light used, and is fastened on the side of the test cassette by means of the closure unit, with the exception of the detection chamber.
  • reagents are preferably placed only in the reagent chamber in which mixing with the sample liquid takes place prior to transport into the detection chamber.
  • a reagent in the solution is reacted, depending on the concentration of the analyte to be determined, in such a way that it alters its spectral properties, for example absorption, luminescence, fluorescence, etc., which can be optically detected.
  • a detection reagent is bound in the solution depending on the concentration of the analyte to be determined to another reagent or to the analyte itself, so that the detection reagent changes its spectral properties - eg absorption, luminescence, fluorescence, electroluminescence, electrical capacitance, etc. that can be optically detected.
  • one or more signal transducers are located in the detection chamber, by means of which the biochemical reaction taking place in the detection chamber can be detected.
  • the window may be transparent or light-tight.
  • the reagents are also preferably placed here only in the reagent chamber, in which the mixing with the sample liquid takes place before being transported into the detection chamber.
  • a reagent in the solution can be reacted depending on the concentration of the analyte to be determined so as to maintain its material properties - e.g.
  • each test cassette carries a bar code which preferably includes the following information for describing the test cassette:
  • this information is contained by the device for the bioassay of analytes by means of bio and / or chemosensors the inventive test cassette, which is also the subject of the present invention, read and used.
  • test cassette has a plurality of adjacent channel and chamber systems, so that different detection reactions could be performed simultaneously in a test cassette.
  • the present invention further provides an apparatus for bioassaying analytes by means of bio- and / or chemosensors comprising the test cassette according to the invention, at least one docking station for the positioning of the test cassette according to the invention, at least one means for conveying the sample liquids in the test cassette.
  • the device according to the invention for controlling the operating temperature in the test cassette also has at least one temperature regulating unit.
  • the temperature regulating unit has at least one flat temperature-controllable element on which the thin side of the test cassette according to the invention is placed, so that a rapid temperature compensation between tempered support and sample solution can take place in the chambers.
  • Peltier or cartridge elements can be used to control the temperature of the overlay.
  • the temperature control unit is computer controlled and the temperature is kept constant during operation of the test cartridge.
  • the test cassette is operated at a temperature of 20 to 37 0 C, preferably around 25 0 C.
  • Fig. 13 Dew point temperature diagram
  • the coupling point has a mechanical trigger on which the reaction, that is to say the first air blast, starts with the aid of the means for conveying the sample liquid and / or the tempering by means of the tempering unit in the test cassette.
  • the device according to the invention also comprises at least one optical unit which has at least one source for an excitation light, in particular a laser and at least one read-out unit for detecting the biochemical reaction in the detection chamber of the test cassette according to the invention.
  • the readout unit is a location-resolving detector, for example from the group formed by CCD cameras, CCD chips, photodiode arrays, avalanche diode arrays, multi-channel plates and multi-channel photomultipliers.
  • the optical unit usually also has mirrors, prisms and / or lenses for shaping - in particular focus, graduation, redirection and orientation - of the excitation light.
  • a goniometer for controlling and regulating the excitation path, in particular for optimizing the coupling parameters by positioning the laser beam with respect to angle of incidence and position to the lattice structure in the optical unit. Precise adjustment of the laser beam maximizes the intensity of the light scattered from the PWG sensor platform.
  • test cassette is also held precisely by means of a fixing unit in the coupling point.
  • a precision of 100 ⁇ m parallel to the grating and 200 ⁇ m normal to the surface of the PWG chip is preferred.
  • the second positioning is set in the course of the coupling-in setting with a resolution of 50 ⁇ m. It is noted that the quality of the signal depends on the exact positioning of the sensor platform to the laser beam so that tolerance limits should be considered.
  • the test cassette z. B sealed with a silicone lid and the means for transporting the sample liquid, for.
  • a syringe, a stamp or a pump presses a first volume of air in the test cartridge.
  • the air pressure transports the sample fluid from the sample chamber into the reagent chamber and cross-links the reagent pad.
  • the toxins of the sample reacts with the fluorescent antibody.
  • the preincubation time is from 1 to 20 minutes, preferably from 3 to 7 minutes, depending on the reactants. Usually, a longer preincubation time produces a stronger signal. It is preferred to control the preincubation time with a precision of 3 seconds.
  • the means for conveying the sample liquid pushes a second predefined volume of air into the test cassette, which leads to the further transport of the sample liquid - possibly through a filter - into the channel into the reaction chamber.
  • the main incubation takes place, which usually lasts from 1 to 100 minutes.
  • the detection is preferably carried out after 1 to 30 minutes, preferably 5 to 15 minutes with a precision of ⁇ 5 seconds.
  • a laser beam is directed into the detection chamber on the surface of the sensor platform and the fluorescence generated is registered by the readout unit.
  • the reaction has not reached equilibrium. It is therefore preferred to precisely observe the duration of the respective steps in order to ensure the reproducibility of the measurement.
  • the device according to the invention has a control unit for automatically controlling the means for conveying the sample liquid and / or the temperature regulation unit and / or the optical unit and corresponding positioning of the test cassette in the coupling site by means of a fastening unit, control and adjustment of the biochemical reaction parameters, such. Incubation time / temperature, reaction time / temperature, etc.
  • the control unit also has a calculator element for calculating the analyte values by reference to a calibration curve and display of the analyte values.
  • the user inserts the test cassette into the docking station.
  • the device according to the invention carries out the following steps independently with the aid of the control unit:
  • the temperature control unit heats the test cassette until a temperature of e.g. B. 25 ° C and maintained.
  • the sample liquid conveying means conveys the sample liquid into the reagent chamber. The preincubation is started.
  • the sample liquid conveying means conveys the sample liquid into the reaction chamber. The main incubation is started.
  • the coupling conditions are finely optimized. An angle compensation of 1 ° is taken into account because of the change in the refractive index (air in step 5, water solution now). 8.
  • the laser beam is switched on and the resulting signal is registered by the readout unit.
  • the rate of wetting is controlled and is preferably 1 ms to 10 s,
  • a precisely defined volume of sample liquid is preferably conveyed. It is also advantageous to control the temperature of the cassette in the reagent chamber and in the detection chamber by means of the temperature regulating unit during operation.
  • a great advantage of the invention is that the person performing an analysis with the new microfluidic test cassette does not have to perform any quantitative process steps of the analysis, such as exact metering of the sample volume and exact metering of the reagents.
  • the biochemical test procedure can also be carried out by persons who are not analyst experts.
  • Another advantage is that no liquids are stored in the test cassette before starting the test, only dry reagents.
  • a major advantage of the system is that no additional liquids need to be added except for the sample solution, which makes the process easy to carry out. At the end of the analysis, the sample liquid remains in the test cassette, so that no risk to the environment from toxic or infectious substances can occur. This use of the test cassette as a disposable cassette is made economically possible by a simple structure and correspondingly low production costs.
  • test cassette a device for operating the test cassette and methods for operating the test cassette in environmental analysis, the food sector, human and veterinary diagnostics and crop protection in order to qualitatively and / or quantitatively determine analytes is likewise an object of the present invention.
  • Examples of this use are the quantitative and / or qualitative determination of chemical, biochemical or biological analytes in screening methods in pharmaceutical research, combinatorial chemistry, clinical and preclinical development, for real-time binding studies and for the determination of kinetic parameters in affinity screening and in research, for qualitative and quantitative analyte determinations, in particular for DNA and RNA analysis and the determination of genomic or proteomic differences in the genome, such as single nucleotide polymorphisms, for the measurement of protein-DNA interactions, for the determination of control mechanisms for mRNA expression and for the protein (bio) synthesis, for the preparation of toxicity studies and for the determination of expression profiles, in particular for the determination of biological and chemical marker substances, such as mRNA, proteins, peptides or low-molecular organic (messenger) substances n, and for the detection of antibodies, antigens, pathogens or bacteria in pharmaceutical product research and development, human and veterinary diagnostics, agrochemical product research and development, symptomatic and presymptomatic plant diagnostics, for patient stratification in pharmaceutical product
  • Fig. 4 Construction of the test cassette - view from above at the side Fig. 5: Structure of the test cassette - view from below at the side Fig. 6: PWG biochip Fig. 7: PWG biochip side view Fig. 8: Dimensions of the PWG biochip.
  • the test cassette 1 consists of a structured body 2, in which channels and cavities are introduced. This body is at the top and bottom with a sealing film. 5 whereby it is achieved that the various cavities and channels of the structured body are sealed airtight (with the exception of the openings 3, 19 and 20).
  • test cassette according to the invention was produced in an injection molding process.
  • the body consists of a plate of black polyoxymethylene (POM), in which the channels and chambers were drilled and milled.
  • POM polyoxymethylene
  • the test cassette 1 comprises an inlet 2 for introducing a sample liquid containing the analyte to be detected into the test cassette 1, a reagent chamber 7 into which the sample liquid is conveyed via a channel 6, and a detection chamber 9 into which the analyte is conveyed via a further channel 6 is conveyed and which includes a PWG biochip 10.
  • the sample chamber 4 is round with 10 mm diameter.
  • the reagent chamber 7 is round with 8 mm diameter.
  • the detection chamber 9 is quadrangular with dimensions of 10 mm x 10 mm.
  • the channels 6 have a round cross section with a diameter of 1 mm.
  • reagent chamber 7 there are antibodies labeled with a fluorescent dye, which are specific for an analyte from the sample liquid, impregnated on a reagent pad 8.
  • the reagent pad 8 consists of "extra thick glass filter” PaIl Corporation (pore size 1 micron, typical thickness 1270 microns (50 mils), typical water flow rate 210 mL / min / cm 2 at 30 kPa), with two circular filter pieces 8 mm diameter stacked on top of each other.
  • Both the PWG biochip 10 and the reagent pad 8 are held in place between two polyolefin films in the POM plate 2, which also serve as sealing foils 5 for sealing the test cassette.
  • the foil In the region of the PWG biochip 10, the foil has a window 21 which grants free access to the measuring region of the PWG biochip 10.
  • the upper sealing foil 5 is 180 ⁇ m thick and the lower sealing foil 5 is 80 ⁇ m thick.
  • the sample liquid is introduced into the sample chamber 4 at the beginning of the test and sealed airtight with a suitable silicone lid.
  • the liquid is distributed in the sample chamber 4 and in the adjacent channels 6, which are designed such that the liquid is not drawn by capillary forces into the reagent chamber 7 or to the inlet 3.
  • a defined volume of air is introduced into the sample chamber 4 via the channel 6 at the inlet. This volume of air displaces the sample liquid so that it flows into the reagent chamber 7 and completely wets the reagent pad 8.
  • the antibodies are dissolved and enter into a specific binding with the analytes contained in the sample liquid (analyte-antibody conjugate).
  • the free binding sites of the antibodies are increasingly saturated with increasing amount of analytes in the sample liquid.
  • the sample liquid is conveyed with containing analyte antibody conjugates in a next step with a further defined puff of air into the detection chamber. 9
  • the detection chamber 9 is completely filled by the sample liquid.
  • venting of the complete duct system takes place via the vent opening (s) 20, which are applied in the upper closure film.
  • the detection chamber 9 comprises a PWG biochip 10.
  • the PWG biochip 10 is shown schematically in plan view in FIG. 6 and schematically in a side view in FIG.
  • the course or the end point of the biochemical detection reaction is detected.
  • the PWG biochip 10 in the detection chamber 9 consists for example of a 10 mm x 12 mm glass plate with a thickness of 0.7 mm (12.0 +/- 0.05 mm x 10.0 +/- 0.05 mm x 0.70 +/- 0.05 mm).
  • On one side of the chip is a 155 nm thin waveguiding layer 12 of Ta 2 O 5 (Tantalum pentoxide).
  • the measuring region of the chip comprises a central 10 mm x 6 mm square detection area. Parallel to this detection area is a 500 ⁇ m wide crescent-shaped band: the grating 11 for coupling the excitation light.
  • the positional accuracy of the grating 11 to the edges of the PWG biochip 10 is +/- 0.05 mm.
  • the grating depth is 18 nm and the grating period is 318 nm with a duty cycle of 0.5.
  • analyte-BSA conjugates are adsorptively applied / immobilized in the form of an array 15. The free areas between the analyte-BSA conjugate spots 16 and reference spots 17 are blocked with BSA 14 (passivation).
  • the analyte-antibody conjugates and optionally antibodies with free binding sites reach the immobilized analyte-BSA conjugate spots 16 on the PWG biochip 10.
  • Antibodies with free binding sites make a specific binding with the corresponding immobilized analyte BSA Conjugates.
  • the antibodies saturated with analytes in the sample liquid remain in the solution.
  • the antibodies bound to the immobilized analyte-BSA conjugates and labeled with a fluorescent dye in the evanescent field of the thin-film waveguide 12 can be excited to fluoresce.
  • the antibodies present in the solution and labeled with a fluorescent dye are not excited in this case. In this way, an indirect quantification of the analytes contained in the sample liquid is possible.
  • FIG. 9 Particular embodiments of the device according to the invention for operating the test cassette are shown in FIG. 9 without being limited thereto.
  • Fig. 9 Schematic representation of the inventive device for operating the
  • the device for operating the test cassette according to the invention has a coupling point with a support 30 for positioning the test cassette 1 according to the invention. Below the PWG biochip 10 is a window 31 in the support 30.
  • the device also has the means for conveying the sample liquid 32 in the test cassette 1 and the tempering element 33. In FIG. 9, the tempering element 33 tempered the support 30 by contact, which in turn forwards the temperature control to the test cassette 1.
  • the device according to the invention in the optical unit has a movable laser 37, and at least one CCD camera 35 for detecting the biochemical reaction in the detection chamber of the test cassette 1.
  • the optical unit also includes a movable mirror 36 and a lens with filters 34.
  • Further prisms and / or lenses for Design - in particular focus, division, redirection and orientation - of the excitation light, and a goniometer for controlling and regulating the excitation path, in particular for optimizing the coupling parameters by positioning the laser beam with respect to angle of incidence and position to the lattice structure of the PWG biochip 10, are also possible (not shown in FIG. 9). By precisely adjusting the laser beam, the intensity of the light scattered from the PWG biochip 10 is maximized.
  • the laser beam (see FIG. 9) is reflected on the PWG chip 10 of the test cartridge 1.
  • Fluorescence photons obtained by the light excitation are registered by the CCD camera 35 through the optical window 31.
  • the docking station also has a mechanical trigger that starts the reaction in the test cartridge.
  • the temperature regulation unit 33 regulates the operating temperature in the test cassette 1. It is typically turned on by the actuation of the trigger to start the cassette.
  • the test cartridge is operated at a temperature of 25 0 C +/- 2K.
  • Fig. 10 shows the influence of temperature on the dose response curve of an assay.
  • Fig. 11 shows the experimental setup for the measurement of temperature by means of "Peltier" elements, and
  • Fig. 12 shows a simulation of the cooling rate of the test cassette.
  • the means for transporting the sample liquid 32 delivers precisely defined puffs of air to the sealed test cassette. These bursts of air direct the sample liquid through the various channels 6 and cavities and perform various reaction steps there, e.g. Reconstitution of the reagents, mixing of the reagents with the sample etc.
  • test cassette 1 is sealed with a silicone lid 21, and the sample liquid conveying means 32 (a pump) presses a first volume of air into the test cassette 1
  • Air pressure conveys the sample liquid from the sample chamber 4 into the reagent chamber 7 and crosslinks the reagent pad 8. This starts the preincubation phase, during which, for B. the toxin of the sample reacts with the fluorescent antibody.
  • the preincubation time is from 2 to 5 minutes ⁇ 3 seconds depending on the reactants. Usually, a longer preincubation time produces a stronger signal.
  • FIG. 14 shows the influence of the incubation time on the dose-response curve of the assay on the basis of the mycotoxin fumonisin.
  • the means of transportation pushes the sample liquid 32, a second predefined volume of air into the test cassette 1, which leads to further transport of the sample liquid - possibly through a filter - into the channel 6 to the detection chamber 9.
  • the detection is preferably after ten minutes with a precision of ⁇ 5 seconds.
  • a laser beam is directed into the detection chamber 9 on the surface of the PWG biochip 10 and the generated fluorescence is registered by the CCD camera 35. Usually, the reaction has not reached equilibrium. The duration of each step is precisely met.
  • the analyte values are calculated and displayed by reference to a calibration curve by means of an accounting element of the control unit 38.
  • the parameters in particular volumes, times (transport and incubation times) and / or temperature are determined and the respective elements of the device are automatically controlled by the control unit 38.

Abstract

La présente invention concerne une cartouche d'analyse à usage unique pour l'analyse qualitative et/ou quantitative d'analytes. Ladite cartouche contient un corps structuré dans lequel sont ménagées des cavités reliées entre elles par des canaux. Cette cartouche d'analyse présente au moins un orifice d'entrée pour introduire un échantillon liquide contenant l'analyte, au moins une chambre à réactifs dans laquelle sont introduits un ou plusieurs réactifs destinés à réagir avec l'analyte ou à être mélangés avec l'échantillon liquide, et au moins une chambre de détection dans laquelle est détecté un signal pour faire la preuve de la présence ou pour l'analyse quantitative de l'analyte. Cette cartouche d'analyse est caractérisée en ce que le fond ou le couvercle de la chambre de détection est constitué d'un convertisseur de signaux ou d'une fenêtre pour la détection d'un signal, les canaux étant disposés de manière à ce que le liquide ne puisse pas être aspiré par capillarité jusque dans la chambre à réactifs ou jusqu'à l'ouverture et à ce que les réactifs soient logés dans la chambre à réactifs et, le cas échéant, que d'autres réactifs sous forme sèche soient logés dans la chambre de détection. L'invention concerne en outre un dispositif pour l'analyse biologique d'analytes au moyen de capteurs biologiques et/ou chimiques. Ce dispositif comprend la cartouche d'analyse selon l'invention, au moins un point d'accouplement pour la mise en place de la cartouche d'analyse, au moins un moyen pour introduire les échantillons liquides dans la cartouche d'analyse et au moins une unité de régulation de la température. L'invention concerne de plus un procédé pour faire fonctionner ce dispositif. La cartouche d'analyse, le dispositif et le procédé selon l'invention peuvent être employés dans les domaines de l'analyse environnementale, de l'alimentaire, du diagnostic humain et vétérinaire et de la protection des végétaux et permettent d'opérer une détermination qualitative et/ou quantitative d'analytes.
EP10711021A 2009-04-09 2010-03-27 Cartouche d'analyse microfluidique à usage unique pour l'analyse biologique d'analytes Withdrawn EP2416881A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009016712A DE102009016712A1 (de) 2009-04-09 2009-04-09 Einweg-Mikrofluidik-Testkassette zur Bioassay von Analyten
PCT/EP2010/001949 WO2010115531A1 (fr) 2009-04-09 2010-03-27 Cartouche d'analyse microfluidique à usage unique pour l'analyse biologique d'analytes

Publications (1)

Publication Number Publication Date
EP2416881A1 true EP2416881A1 (fr) 2012-02-15

Family

ID=42226071

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10711021A Withdrawn EP2416881A1 (fr) 2009-04-09 2010-03-27 Cartouche d'analyse microfluidique à usage unique pour l'analyse biologique d'analytes

Country Status (13)

Country Link
US (1) US20120040470A1 (fr)
EP (1) EP2416881A1 (fr)
JP (1) JP2012523550A (fr)
KR (1) KR20120013316A (fr)
CN (1) CN102387863A (fr)
AU (1) AU2010234064A1 (fr)
BR (1) BRPI1015211A2 (fr)
CA (1) CA2758083A1 (fr)
DE (1) DE102009016712A1 (fr)
EA (1) EA201190244A1 (fr)
MX (1) MX2011010589A (fr)
WO (1) WO2010115531A1 (fr)
ZA (1) ZA201107240B (fr)

Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9182353B2 (en) 2010-07-22 2015-11-10 Hach Company Lab-on-a-chip for alkalinity analysis
WO2012068499A2 (fr) * 2010-11-19 2012-05-24 The Regents Of The University Of California Intégration optofluidique planar hybride
US9289764B2 (en) 2010-12-20 2016-03-22 Boehringer Ingelheim Microparts Gmbh Method for mixing at least one sample solution having at least one reagent, and device
US9180449B2 (en) 2012-06-12 2015-11-10 Hach Company Mobile water analysis
TWI630385B (zh) * 2012-07-16 2018-07-21 昌和生物醫學科技（揚州）有限公司 增強疾病檢測與鑒定的器件與方法
USD768872S1 (en) 2012-12-12 2016-10-11 Hach Company Cuvette for a water analysis instrument
WO2014187488A1 (fr) * 2013-05-23 2014-11-27 Tecan Trading Ag Système microfluidique numérique doté de cartes de circuit imprimé échangeables
TWI498166B (zh) * 2013-07-02 2015-09-01 Univ Nat Taiwan 以表面電漿共振定量分析之自動操作檢測程序的多孔性薄膜微流體裝置
US20150185207A1 (en) * 2013-07-30 2015-07-02 Gordon Black Quantifying Neutrophil Concentration in Blood
GB201318814D0 (en) * 2013-10-24 2013-12-11 Petroleum & Chemical Corp Microfluidic devices and arrangements for supplying such devices with reagents and biological samples
BR112016009958B1 (pt) * 2013-11-06 2021-08-03 Becton, Dickinson And Company Dispositivo microfluídico, método, sistema e kit
JP6518245B2 (ja) 2013-11-13 2019-05-22 ベクトン・ディキンソン・アンド・カンパニーＢｅｃｔｏｎ， Ｄｉｃｋｉｎｓｏｎ Ａｎｄ Ｃｏｍｐａｎｙ 光学撮像システム及びそれを用いた方法
CN104374930B (zh) * 2014-02-28 2016-06-29 深圳市第二人民医院 人类免疫缺陷病毒检测装置及其检测方法
GB201403790D0 (en) * 2014-03-04 2014-04-16 Ge Healthcare Ltd Microfluidic devices and arrangements for introducing reagents and biological samples to such devices
EP2916125A1 (fr) * 2014-03-07 2015-09-09 One Drop Diagnostics Sàrl Dosages par détection de fluorescence sur des puces microfluidiques
BR112016029490B1 (pt) 2014-06-18 2021-06-15 Scandinavian Micro Biodevices Aps Sistema de detecção microfluídica
US20160067709A1 (en) * 2014-09-05 2016-03-10 Htc Corporation Micro-channel module
US20180059004A1 (en) * 2015-04-10 2018-03-01 Mycartis Nv Analysis system with spacing means
KR101982330B1 (ko) * 2015-09-14 2019-05-24 에센릭스 코프. 증기 응축액 특히 입김 응축액을 수집 및 분석하기 위한 장치 및 시스템 그리고 이 장치 및 시스템을 사용하는 방법
JP2017058243A (ja) * 2015-09-16 2017-03-23 積水化学工業株式会社 マイクロチップ
DE102016204234A1 (de) * 2016-03-15 2017-09-21 Robert Bosch Gmbh Mikrofluidische Vorrichtung und Verfahren zur Durchführung von chemischen, biochemischen und/oder biologischen Untersuchungen
CN105866450A (zh) * 2016-04-12 2016-08-17 东莞博识生物科技有限公司 一种微流体测试卡
US11209394B2 (en) 2016-07-26 2021-12-28 Qorvo Us, Inc. Cartridges for integrated BAW biosensors and methods for using the same
WO2018022757A1 (fr) * 2016-07-29 2018-02-01 Qorvo Us, Inc. Biocapteur d'ondes acoustiques de volume comprenant un dispositif de chauffage et un capteur de température et procédés d'utilisation de celui-ci
US10773255B2 (en) * 2016-10-07 2020-09-15 Boehringer Ingelheim Vetmedica Gmbh Cartridge and method for testing a sample
CA3035143A1 (fr) * 2016-10-07 2018-04-12 Boehringer Ingelheim Vetmedica Gmbh Systeme d'analyse et procede permettant de tester un echantillon
CN109803762B (zh) * 2016-10-07 2022-04-01 勃林格殷格翰维特梅迪卡有限公司 用于控制分析装置和分析系统的方法
EP3535056A4 (fr) * 2016-11-07 2020-07-01 Cytochip Inc. Cartouche fluidique pour cytométrie et analyse supplémentaire
US10883978B2 (en) * 2017-01-31 2021-01-05 Agilent Technologies, Inc. Method and device for calibration of biological flux
CN111183350A (zh) * 2017-08-17 2020-05-19 雅培医护站股份有限公司 用于对血细胞成像的单次使用测试设备
CN110869745B (zh) * 2017-08-17 2023-08-11 雅培医护站股份有限公司 用于执行光学测定的设备、系统和方法
US20190056384A1 (en) * 2017-08-17 2019-02-21 Abbott Point Of Care Inc. Single-use test device for imaging assay beads
CN107543934B (zh) * 2017-09-01 2020-01-14 中国电子科技集团公司第三十八研究所 一种硅基生物传感芯片的封装结构
CN111201326A (zh) * 2017-10-05 2020-05-26 勃林格殷格翰维特梅迪卡有限公司 用于测试样品的试剂盒、分析系统和方法
CN111183343A (zh) * 2017-10-06 2020-05-19 生物辐射实验室股份有限公司 蛋白质定量设备
US11491487B2 (en) * 2017-10-23 2022-11-08 Cytochip Inc. Devices and methods for measuring analytes and target particles
US20210101143A1 (en) * 2017-11-13 2021-04-08 Indian Institute Of Science Clinical sample storage cassettes
SE541514C2 (en) * 2017-12-28 2019-10-22 Delaval Holding Ab A cassette
GB201801019D0 (en) 2018-01-22 2018-03-07 Q Linea Ab Sample holder
DE102018000965A1 (de) 2018-02-07 2019-08-08 Lilian Labs GmbH Vorrichtung und Verfahren zur Flüssigkeitsanalyse
JP2021518259A (ja) * 2018-03-22 2021-08-02 株式会社ニコン 流体デバイス
US20210008564A1 (en) * 2018-04-06 2021-01-14 Boehringer Ingelheim Vetmedica Gmbh Analysis device, cartridge, analysis system and method for testing a sample
US11007526B2 (en) * 2018-07-06 2021-05-18 Qorvo Us, Inc. Capless sample well port for a cartridge
CA3114522A1 (fr) * 2018-09-28 2020-04-02 Siemens Healthcare Diagnostics Inc. Procedes de detection d'effet(s) crochet associe(s) a un (des) analytes d'interet pendant la conductance de dosage(s) diagnostique(s) ou resultant de cette conductance
GB201902810D0 (en) * 2019-03-01 2019-04-17 Vidya Holdings Ltd Disposition of reagents in assay device
WO2020185200A1 (fr) * 2019-03-08 2020-09-17 Hewlett-Packard Development Company, L.P. Cassettes microfluidiques jetables
KR102276639B1 (ko) * 2019-08-06 2021-07-12 연세대학교 산학협력단 미세유체 디바이스 및 이를 포함하는 플레이트
CN113164110A (zh) * 2019-09-17 2021-07-23 诺尔生物医药有限公司 用于测量血液中肝酶水平的系统和方法
CA3160946A1 (fr) * 2019-12-09 2021-06-17 Claudio Oliveira Egalon Systemes et procedes d'eclairage lateral de guides d'ondes
CN115151346A (zh) * 2020-01-24 2022-10-04 科锐丽亚生物系统公司 自动分析物测定系统及与其一起使用的试剂盒
DE102020107918B4 (de) * 2020-03-23 2021-11-18 Digital Diagnostics AG Detektion von viren
US20220002795A1 (en) * 2020-07-06 2022-01-06 Wuhan University Of Science And Technology Nano-pen sequencing: an integrated nanotube and tunnel gap platform for polymer sequencing
CN113418898B (zh) * 2021-06-18 2022-10-28 贵州医科大学 一种pifo平台的由微流控芯片和荧光传感器组成的集成装置
BE1029778B1 (fr) 2021-09-21 2023-04-17 Univ Liege Cassette destinée à contenir une puce microfluidique
CN113952993B (zh) * 2021-11-23 2022-09-20 中北大学 集成微混合器与Tesla阀的多级惯性微流控血样处理芯片

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4815843A (en) 1985-05-29 1989-03-28 Oerlikon-Buhrle Holding Ag Optical sensor for selective detection of substances and/or for the detection of refractive index changes in gaseous, liquid, solid and porous samples
US5137827A (en) 1986-03-25 1992-08-11 Midwest Research Technologies, Inc. Diagnostic element for electrical detection of a binding reaction
US4794089A (en) 1986-03-25 1988-12-27 Midwest Research Microscopy, Inc. Method for electronic detection of a binding reaction
CA2031108A1 (fr) * 1989-12-26 1991-06-27 Thomas William Glanville Trousse jetable de reactifs chimiques; mode d'emploi
ATE145725T1 (de) 1991-04-26 1996-12-15 Scherrer Inst Paul Verfahren und vorrichtung zur bestimmung einer messgrösse mittels eines integriert-optischen sensormoduls
US6953676B1 (en) * 1992-05-01 2005-10-11 Trustees Of The University Of Pennsylvania Mesoscale polynucleotide amplification device and method
DE69319427T2 (de) * 1992-05-01 1998-12-10 Univ Pennsylvania Analyse bei messung des durchflusswiderstandes
JP3645907B2 (ja) 1994-05-27 2005-05-11 ノバルティス アクチエンゲゼルシャフト 漸減励起された発光を検出する方法
EP0824684B1 (fr) 1995-05-12 2007-11-07 Novartis AG Procede de detection parallele d'une pluralite d'analytes a l'aide de la luminescence excitee par evanescence
EP0890095B1 (fr) 1996-03-30 2007-11-21 Novartis AG Capteur optique de luminescence integre
US5869828A (en) 1996-04-02 1999-02-09 Braginsky; Philip Yale Color and shape system for encoding and decoding data
JP5006494B2 (ja) 1999-08-13 2012-08-22 バイエル・テクノロジー・サービシーズ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 複数の分析物を測定するためのデバイス及び方法
ES2300358T3 (es) 2000-09-05 2008-06-16 Bayer Technology Services Gmbh Procedimiento para la precipitacion de monocapas y capas multiples de acidos organofosforicos y organofosfonicos y sus sales, asi como su uso.
DE10111457B4 (de) * 2001-03-09 2006-12-14 Siemens Ag Diagnoseeinrichtung
DE10158149A1 (de) 2001-11-28 2003-06-18 Bayer Ag Silangruppen enthaltende Polymere
DE10305050A1 (de) * 2003-02-07 2004-08-19 Roche Diagnostics Gmbh Analytisches Testelement und Verfahren für Blutuntersuchungen
EP1561507A1 (fr) 2004-01-27 2005-08-10 Future Diagnostics B.V. Système pour caractériser un fluide, dispositif microfluidique pour caractériser ou analyser les composants de concentrations, une méthode de caractériser ou d'analyser de telles concentrations et un dispositif de mesure
US20070178521A1 (en) 2004-03-16 2007-08-02 Yoshiki Sakaino Assay chip
US7169617B2 (en) 2004-08-19 2007-01-30 Fujitsu Limited Device and method for quantitatively determining an analyte, a method for determining an effective size of a molecule, a method for attaching molecules to a substrate, and a device for detecting molecules
PL1883474T3 (pl) * 2005-05-25 2021-10-18 Boehringer Ingelheim Vetmedica Gmbh System do zintegrowanej i zautomatyzowanej analizy dna lub białka oraz sposób działania takiego systemu
DE102006024149B4 (de) * 2005-05-25 2020-04-02 Boehringer Ingelheim Vetmedica Gmbh System zur integrierten und automatisierten DNA- oder Protein-Analyse
JP4770382B2 (ja) * 2005-10-17 2011-09-14 凸版印刷株式会社 液体移送装置
DE102005062377A1 (de) 2005-12-23 2007-06-28 Bayer Technology Services Gmbh Vorrichtung und Verfahren zum Nachweis von Mykotoxinen
JP2008151772A (ja) * 2006-11-22 2008-07-03 Fujifilm Corp マイクロ流体チップの温調方法及び検体分析システム並びにマイクロ流体チップ
WO2009037784A1 (fr) * 2007-09-21 2009-03-26 Tya K. K. Instrument analytique pour composant de fluide corporel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010115531A1 *

Also Published As

Publication number Publication date
ZA201107240B (en) 2012-12-27
EA201190244A1 (ru) 2012-04-30
JP2012523550A (ja) 2012-10-04
KR20120013316A (ko) 2012-02-14
DE102009016712A1 (de) 2010-10-14
WO2010115531A1 (fr) 2010-10-14
BRPI1015211A2 (pt) 2016-05-03
CN102387863A (zh) 2012-03-21
MX2011010589A (es) 2011-10-19
AU2010234064A1 (en) 2011-10-27
US20120040470A1 (en) 2012-02-16
CA2758083A1 (fr) 2010-10-14

Similar Documents

Publication Publication Date Title
EP2416881A1 (fr) Cartouche d'analyse microfluidique à usage unique pour l'analyse biologique d'analytes
US7598091B2 (en) Micromachined diagnostic device with controlled flow of fluid and reaction
US7258837B2 (en) Microfluidic device and surface decoration process for solid phase affinity binding assays
US20110124130A1 (en) Device and method for analysis of samples with depletion of analyte content
US7931868B2 (en) Device for the manipulation of limited quantities of liquids
EP3385713B1 (fr) Dispositif de dosage à écoulement latéral
Pinger et al. A printed equilibrium dialysis device with integrated membranes for improved binding affinity measurements
JP2009501908A (ja) マイクロ流体装置およびその作製方法ならびに利用方法
JP2018522206A (ja) マイクロ流体バルブおよびマイクロ流体デバイス
DE102018212930B3 (de) Vorrichtung und Verfahren zum Leiten einer Flüssigkeit durch ein poröses Medium
CN102357352A (zh) 流体递送系统和方法
US20090087925A1 (en) Devices and methods for analysis of samples with depletion of analyte content
EP2783747B1 (fr) Procédé et dispositif destinés au mélange sans contact de liquides
EP2417436A1 (fr) Dispositif et procédé pour la détection et pour l'analyse quantitative d'analytes, notamment de mycotoxines
US20020127740A1 (en) Quantitative microfluidic biochip and method of use
Aoyama et al. Enhanced immunoadsorption on imprinted polymeric microstructures with nanoengineered surface topography for lateral flow immunoassay systems
DE202008001277U1 (de) Mobiles Microarray-Messgerät mit automatischer Reagenzienzufuhr und Chemilumineszenz-Ausleseeinheit
WO2023026820A1 (fr) Dispositif d'alimentation en solution, ensemble de détection et procédé de détection
DE102016015171B4 (de) Analysevorrichtung mit funktionalisierten Kryogelen
AT505854A1 (de) Mikrofluidische vorrichtung

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

17P Request for examination filed

Effective date: 20111109

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 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER INTELLECTUAL PROPERTY GMBH

17Q First examination report despatched

Effective date: 20140606

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

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20141001