EP1899702A2 - Dispositif et procede pour analyser un echantillon liquide - Google Patents

Dispositif et procede pour analyser un echantillon liquide

Info

Publication number
EP1899702A2
EP1899702A2 EP06742544A EP06742544A EP1899702A2 EP 1899702 A2 EP1899702 A2 EP 1899702A2 EP 06742544 A EP06742544 A EP 06742544A EP 06742544 A EP06742544 A EP 06742544A EP 1899702 A2 EP1899702 A2 EP 1899702A2
Authority
EP
European Patent Office
Prior art keywords
liquid
chambers
reaction
metering
chamber
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Withdrawn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
EP06742544A
Other languages
German (de)
English (en)
Inventor
Ilse Ballhorn
Gert Blankenstein
Ralf-Peter Peters
Birgit MÜLLER-CHORUS
Michael Schlüter
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.)
Boehringer Ingelheim Microparts GmbH
Original Assignee
Boehringer Ingelheim Microparts 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
Priority claimed from DE102005016509A external-priority patent/DE102005016509A1/de
Priority claimed from DE102005042601A external-priority patent/DE102005042601A1/de
Application filed by Boehringer Ingelheim Microparts GmbH filed Critical Boehringer Ingelheim Microparts GmbH
Publication of EP1899702A2 publication Critical patent/EP1899702A2/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Withdrawn legal-status Critical Current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
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • 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
    • 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
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0621—Control of the sequence of chambers filled or emptied
    • 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
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • 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
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • 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
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • 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
    • B01L2300/087—Multiple sequential chambers
    • 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
    • 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
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
    • 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
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/2575—Volumetric liquid transfer

Definitions

  • the present invention relates to an apparatus and a method for examining a sample liquid, in particular by means of the ELISA method.
  • the present invention is concerned with microfluidic systems or devices whose structures have a size of about 1 to 1000 ⁇ m and / or whose cavities each have a volume of about 1 to 1000 ⁇ l.
  • the following statements relate in particular to devices and methods in which capillary, pressure and / or centrifugal forces act and are crucial in particular for the function.
  • ELISA comes from the English language and means "enzyme-linked immunosorbent assay".
  • this term is to be understood as meaning a process in which an enzyme is bound to an analyte, in particular to a complex of an analyte and an antibody.
  • a substrate is modified or converted into a detection substrate, in particular a fluorescent substance or the like, in a detection reaction.
  • a detection substrate By detecting the detection substrate, a quantitative determination of the analyte in the sample liquid is possible.
  • a dilution series of the sample liquid is usually examined in this way.
  • the ELISA method is usually performed manually or automatically - for example by means of pipetting robots - on an open pipetting plate with, for example, 96 open Aufhahmehuntn.
  • a sample liquid to be examined is diluted several times in succession in the receiving chambers in order to achieve different dilution ratios.
  • the sample liquid with the different dilution ratios is pipetted into prepared Aumahmehuntn in which an analyte in the sample liquid can be bound to immobilized antibodies.
  • multiple rinsing with a washing liquid takes place. Then one is sent to a add antibody bound enzyme.
  • the detection antibody binds to the complex of analyte and immobilized antibody.
  • a substrate is added, which is converted or modified by the enzyme into a detection substrate.
  • This detection reaction is very time critical. The stopping of the detection reaction takes place, for example, by adding acid. The problem is that this can not be done simultaneously in all Aufhahmehuntn in which the detection reaction takes place, and that at higher volumes by diffusion and / or mixing processes different delays may occur.
  • the detection substrate is determined, for example, optically, in particular by fluorescence measurement or the like. From the values determined, the concentration of the analyte in the sample liquid can be determined.
  • the described method is very complicated and error-prone. In particular, inaccuracies add up due to the large number of individual steps.
  • the preparation of the receiving chambers for immobilizing the antibody is correspondingly expensive and also associated with the use of large amounts of liquid.
  • the reactions often proceed very slowly, so that the ELISA method in the hitherto customary form is very time-consuming.
  • WO 03/018198 A1 discloses microfluidic devices in which a liquid, in particular a sample liquid, can be conducted from a receiving chamber into connected chambers and divided into defined individual quantities and / or with one other liquid can be mixed and preferably react. Similar microfluidic systems are also known from US 6,706,519 Bl, US 6,719,682 B2, US 2004/0203136 A1, WO 00/78455 A1 and WO 01/87485 A2.
  • US 2004/0203136 A1 discloses a method and an apparatus for the examination and dilution of samples and reaction liquids.
  • Several dosing channels are connected via a common channel to a first receiving chamber for a sample and can be filled with the sample.
  • a second receiving chamber for a dilution liquid is connected to the common channel and thus to the metering channels.
  • the dilution liquid is conducted via the common channel into the metering channels, so that the metered sample quantities are transferred into subsequent mixing chambers, which are finally completely filled by the inflowing dilution liquid. This does not allow optimal or universal dilution.
  • the present invention has for its object to provide an apparatus and a method for examining a sample liquid, wherein a cost-effective, rapid and / or accurate quantitative examination, in particular by means of the ELISA method, is made possible.
  • One aspect of the present invention resides in a plurality of first metering chambers for preferably exclusively receiving sample liquid - A -
  • first, common Aufhahmehunt and a plurality of second metering chambers for preferably exclusive inclusion of a dilution liquid from a second, common Aumahmehunt provide.
  • the first and / or second metering chambers vary in their volumes.
  • the first and second metering chambers are pairwise associated with each other and each associated with an associated reaction chamber, so that by pressure and / or centrifugal forces contained in the first and second metering chambers volumes of sample liquid and dilution liquid into the respective associated reaction chambers are transferable and miscible, whereby the sample liquid is diluted with different dilution ratios.
  • This proposed dilution is also referred to below as the "parallel dilution".
  • the inaccuracies or errors arising in the prior art, such as US 2004/0203136 A1, by using common channels or the like, are avoided.
  • the metering of the first and second fluid is carried out independently of each other, so that otherwise occurring subsequent errors in the dosage can be avoided.
  • the first and second metering chambers are preferably connected via separate channels to the first and second Aumahmehunt so that no undefined premixtures, impurities or mixing errors can occur.
  • the two liquids are mixed only in the respective reaction chamber - ie quickly or selectively and / or under defined conditions, so that, for example fast reactions can take place in a defined manner.
  • the liquids from the first and second metering chambers can be transferred and mixed simultaneously or successively into the reaction chambers.
  • the volumes of the first and second metering chambers vary in opposite directions. If the metering chambers are arranged, for example, in two rows running parallel to each other or parallel, the volume of the first metering chambers increases in one direction (in particular optionally in or opposite to the filling direction), while the volume of the second metering chambers decreases in this direction.
  • a dilution series can be realized over a large dilution range.
  • the individual sums of the mating pairs of first and second metering chambers are the same.
  • This is an optimal space utilization, especially on a CD, conducive.
  • equal volumes of diluted sample liquid with different dilution ratios result, so that correspondingly the other subsequent cavities, in particular reaction chambers and the like, can all be uniformly designed for the same volumes, whereby the design is simplified and standardized.
  • a single parallel dilution suffices to cover a sufficiently large dilution range.
  • at least one further, preferably also parallel, dilution can take place after the first parallel dilution.
  • This sub-dilution can be done, for example, only for one, for example, the already diluted with the largest dilution ratio Probenfact- keitsmenge.
  • several or all of the liquid volumes of differently diluted sample liquid produced by the first parallel dilution may each be subjected to a separate further, in particular likewise parallel, dilution.
  • the dilution liquid already used or supplied for the first dilution is preferably used for the further dilution. Then a renewed supply of dilution liquid is not required, whereby the handling simplifies, in particular the required pipetting of liquids is minimized.
  • a (third) common Aumahmekanimer is provided for a plurality of reaction chambers.
  • several liquids can be supplied one after the other in the receiving chamber-that is to say sequentially-for example by pipetting or in some other way-in particular, therefore, externally or externally.
  • reaction chambers it becomes possible to prepare several or all reaction chambers in a suitable manner with minimal effort, in particular with very few pipetting operations, ie, for example, to immobilize a reagent, such as an antibody or the like, in the reaction chambers.
  • a reagent such as an antibody or the like
  • the common receiving chamber assigned to the reaction chambers allows the detection reaction to be carried out, for example by feeding corresponding liquids with the enzyme, the substrate or the like, with minimal pipetting effort.
  • reaction chambers are each assigned a detection or examination chamber and the detection reactions which preferably take place enzymatically by an immobilized enzyme in the reaction chambers can be stopped by the liquid present in the reaction chambers being introduced into the associated examination chamber - Preferably by pressure, capillary and / or centrifugal forces - is transferred.
  • This transfer takes place in particular simultaneously for several or all reaction chambers, so that the detection reactions can also be stopped simultaneously in these reaction chambers.
  • the examination in particular the detection of detection substrate or the like formed in the respective liquid, can then take place successively in the examination chambers as required.
  • a considerably greater accuracy is achieved when stopping the particular enzymatic table and accordingly time-critical detection reactions allows.
  • FIG. 1 shows a not to scale view of a part of a proposed device according to a first embodiment
  • Fig. 2 is a schematic view of part of a proposal
  • Fig. 3 is a not to scale view of a portion of a proposed device according to a third embodiment.
  • FIG. 1 shows a part of a proposed device 1 according to a first embodiment in a very schematic view, not to scale.
  • the proposed device 1 is, in particular, a microfluidic system which preferably has the shape of a round disk, for example a compact disk (CD) or the like, and accordingly has an axis of rotation 2 indicated in FIG. 1 for generating Centrifugal forces is rotatable.
  • CD compact disk
  • FIG. 1 shows a part of a proposed device 1 according to a first embodiment in a very schematic view, not to scale.
  • the proposed device 1 is, in particular, a microfluidic system which preferably has the shape of a round disk, for example a compact disk (CD) or the like, and accordingly has an axis of rotation 2 indicated in FIG. 1 for generating Centrifugal forces is rotatable.
  • CD compact disk
  • the proposed device 1 is used to examine a sample liquid 3, in particular by means of the ELIS A method.
  • the following description is therefore directed essentially to the application or implementation of the ELISA method, where necessary, also supplementary or alternative measures or process steps can be performed.
  • the proposed device 1 or the proposed method can in principle also be used for other examinations or methods.
  • Fig. 1 shows the sample liquid 3 immediately after filling in a first, common Aufhahmehunt 4.
  • first metering chambers 5 - in the illustrated embodiment four first metering chambers 5a to 5d - are to the first Aufhahmehunt 4 by corresponding channels or the like.
  • - In DarStellungsbeispiel by channel 18 - connected and preferably arranged in a row in the circumferential direction.
  • FIG. 1 shows the device 1 in a state immediately after the sample liquid 3 has been introduced into the first receiving chamber 4, ie before the sample liquid 3 flows into the first metering chambers 5.
  • the device 1 has a second common receiving chamber 7 for receiving a diluting liquid 8.
  • a second receiving chamber 7 for receiving a diluting liquid 8.
  • the diluting liquid 8 flows via channel 19 into the second metering chambers 9. Excess diluting liquid 8 can, if required, flow into an optionally provided second collecting chamber 10.
  • the channel 19 preferably connects the second Aufhahmehunt 7 with the second collection chamber 10.
  • the metering chambers 5 and 9 are preferably formed, for example by means not shown guide elements for the liquids 3 and 8, that the metering chambers 5, 9 and possibly the channels are completely filled without gas or air inclusion. Displaced air can escape via the preferably open collector chambers 6, 10 and / or via vent openings, not shown, which are associated in particular with the channels 18 and 19 and / or the metering chambers 5, 9.
  • the first and second metering chambers 5 and 9 are reaction chambers 11 - corresponding to the number of first and second metering chambers 5a to 5d and 9a to 9d in the illustrated embodiment, that is, four reaction chambers 11a to 11a
  • Hd - assigned which are arranged in the illustrated embodiment preferably in a row parallel to the first and second metering chambers 5, 9 and / or with respect to the rotation axis 2 radially outside the first and second metering chambers 5, 9.
  • the first and second metering chambers 5, 9 are preferably assigned in pairs to each other and each one reaction chamber 11, each pair is fluidly connected to the associated reaction chamber 11 by corresponding, in particular radially extending, preferably channel-like compounds 12, for example, the first metering chamber 5b and second metering chamber 9b with the associated reaction chamber I Ib.
  • the letters a to d thus indicate the assignment of the individual chambers 5, 9, 11 and 16 in the representation example. Accordingly, the liquid transfer takes place, in particular for dilution, mixing and / or reaction.
  • the first metering chambers 5 and 9 with the sample liquid 3 and the dilution liquid 8 preferably automatically fill themselves due to pressure and / or capillary forces, in particular when filling the liquid 3 or 8 in associated Aufhahmehuntn 4 and 7 by means of a non-illustrated Pipette o. The like. And due to the pressure exerted on the liquid 3 and 8, respectively.
  • other forces possibly even centrifugal forces, depending on the arrangement and design, alternatively or additionally be used.
  • the volumes of sample liquid 3 present in the first metering chambers 5 and the volumes of dilution liquid 8 present in the second metering chambers 9 can then be transferred into the respective associated reaction chamber 11 by appropriate centrifugal forces (caused by corresponding rotation of the device 1 about the axis of rotation 2).
  • centrifugal forces caused by corresponding rotation of the device 1 about the axis of rotation 2.
  • radial transfer takes place, the sample liquid 3 and dilution liquid 8 mixing in each case.
  • other forces for example pressure forces, capillary forces or the like, can act to convert the said volumes into the reaction chambers 11.
  • the first metering chambers 5 and / or second metering chambers 9 vary in their volumes. In fact, the volumes are selected such that different dilution ratios of the sample liquid 3 are achieved in the reaction chambers 11.
  • both the volumes of the first metering chambers 5 and the volumes of the second metering chambers 9 vary.
  • a first metering chamber 5d with a small volume is assigned a second metering chamber 9d with a large volume and vice versa.
  • this is achieved by the volume of the first metering chambers 5 increasing or decreasing in a circumferential direction and the volumes of the second metering chambers 9 decreasing or increasing inversely in this circumferential direction.
  • the sums of the volumes of the pairwise associated first and second metering chambers 5a and 9a, 5b and 9b, 5c and 9c and 5d and 9d are at least substantially equal.
  • the individual volumes of differently diluted sample liquid 3 are of equal size and the reaction chambers 11 and any other downstream chambers or the like can be made uniformly large.
  • the reaction chambers 11 and any other downstream chambers or the like can be made uniformly large.
  • the previous and in the following description is always turned off on the respective volume of the metering chambers 5 and 9 respectively.
  • well-defined volumes are required.
  • valve devices, obstacles or liquid stops are present and transferred and mixed, valve devices, obstacles or liquid stops, not shown, For example, to the connections 12 to the channels 18, 19 associated vents and / or the like. Provided.
  • first separation points T a to T le for the liquid 3 in the first channel 18 is formed, in particular between the first Aufnah- measuring chamber 4 and the first metering chamber 5 a, between the individual dosing chambers 5 and between the last dosing chamber 5d, and the first plenum 6.
  • second separation points T 2a to T 2e are formed for the liquid 8 in the second channel 19, in particular between the second receiving chamber 7 and the following second metering chamber 9a, see between the second metering chambers 9 and between the last metering chamber 9d and the second Receiving chamber 10.
  • the first and second separation points T can alternatively or additionally be formed at the transition to individual chambers and / or other suitable locations.
  • channel stops KSi and KS 2 are formed in the channel 18 and 19 between the last separation point Ti e and T 2e and the respective collection chamber 6 or 10 or at the transition to the respective collection chamber 6 and 10, respectively Such flow resistance for the respective liquid 3 and 8 to form that when filling initially the first and second metering chambers 5 and 9 are completely filled with the respective liquid 3 and 8, before this in the associated collection chamber 6 or 10 can continue to flow.
  • first liquid stops Si 3 to S d and second liquid stops S 2a to S 2d are preferably in the radially extending connections 12 between the respective first metering chambers 5 and the second metering chambers 9 and the second metering chambers 9 and the reaction chambers 11.
  • these liquid stops S can alternatively or additionally also be formed at the transitions to the respective chambers.
  • the first liquid stops Si prevent the sample liquid 3 from undesirably filling the second metering chambers 9 when the first metering chambers 5 are filled.
  • the first liquid stops S] also prevent the diluting liquid 8 from undesirably filling the first metering chambers 5 or displacing the sample liquid 3 from the first metering chambers 5 when filling the second metering chambers 9.
  • liquid stops for example, be provided at the transition of the compounds 12 in the respective second metering chambers 9.
  • the second liquid stops S 2 prevent the dilution liquid 8 from undesirably flowing into the reaction chambers 11 during the filling of the second metering chambers 9, whereby a defined metering would no longer be possible.
  • the channel stops KS and the liquid stops S are formed in such a way, or tuned to the liquids 3 and 8 or to the particular during the filling by means not shown pipettes o. The like. Occurring pressures that the first and second liquid stops S 1 and S second during the filling of the first and second metering chambers 5, 9 with the liquids 3, 8 can not be overcome, but only in the later desired transfer of the individual volumes of liquid 3 and 8 from the metering chambers 5, 9 in the reaction chambers 11, in particular only with corresponding rotation of the device 1 or only with corresponding centrifugal forces.
  • the liquid stops S are designed such that the second liquid stops S 2 can be opened or overcome before the first liquid stops S].
  • first and second liquid stops S This can also be achieved with the same or similar configuration and characteristic of the first and second liquid stops S, that greater centrifugal forces than in the first liquid stops Si occur at the second liquid stops S 2 , the S radially outward relative to the first liquid Si stops or act.
  • the separation points T and liquid stops S lead to defined volumes of liquid 3 and 8, which are mixed together.
  • the liquid 3 or 8 breaks off at the separation points T and then flows via the respective, in particular radial, connection 12 into the associated reaction chamber 11
  • the volume of liquid assigned to the second metering chamber 9b is determined or defined by the two second separation points T 2b and T 2c and the two liquid stops S 1b and 2b .
  • the to be transferred and metered volume of sample liquid 3 is, for example, for the first metering chamber 5b through the two separation points T 1 and T b] c and stop by the liquid Si b limited. This applies correspondingly to the other liquid volumes of the further metering chambers 5, 9.
  • the separation points T by corresponding, not shown ventilation o.
  • the liquid stops S and / or the channel stops KS are preferably formed by a corresponding constriction, sudden cross-sectional widening and / or modification of the wetting behavior, so that the respective liquid 3, 8, 14 can not or can not readily overcome the respective stop S, KS. Rather, in particular, a predetermined, for the individual stops S, KS, if necessary, different centrifugal force, compressive force o. The like. Required to overcome the respective stop S, KS can.
  • reaction chamber 11 a desired reaction and in particular a plurality of desired reactions can then take place or be carried out, as will be discussed in more detail later.
  • the reaction chambers 11 are preferably first prepared before the diluted sample liquid 3 is supplied. This preparation takes place in particular before the sample liquid 3 is introduced into the first receiving chamber 4 and the diluting liquid 8 into the second receiving chamber 7 and will be explained in more detail below.
  • the device 1 preferably has one, in particular only a single, common receiving chamber 13 for receiving a liquid 14, in particular a sequential receptacle of different liquids 14, such as a reaction liquid, a washing liquid, a blocking or fixing liquid, a substrate liquid or the like. on.
  • the reaction chambers 11 are connected to the third receiving chamber 13, so that in particular by pressure, capillary and / or centrifugal forces a filled into the receiving chamber 13 liquid 14 via corresponding channels or the like.
  • a channel 20 preferably extends in the circumferential direction and / or parallel to the channels 18 and 19 - in the
  • Reaction chambers 11 can flow. Excessive and / or extruded
  • Liquid 14 is preferably collected in an optionally provided, third collection chamber 15, wherein an optimal channel stop KS 3 can ensure that the liquid 14 completely fills the reaction chambers 11 before it flows into the third collection chamber 15.
  • the device 1 is embodied such that the third receiving chamber 13 is first completely emptied or emptied before another liquid 14 is supplied to the third receiving chamber 13, for example by pipetting.
  • the emptying of the third Aufhahmehunt 13 can be achieved, for example, that after filling the third receiving chamber 13 with a liquid 14 by capillary forces automatically flows through the reaction chambers 11 and possibly the third collection chamber 15 until the third Aufhahmehunt 13 fully. is constantly emptied. Additionally or alternatively, this can be achieved by centrifugal forces, in particular in the case of a radial gradient (increase in the radial distance to the pivot point 2) of the channel 20 to the third collection chamber 15, and corresponding rotations of the device 1, and / or other forces.
  • reaction chambers 11 can be emptied again, if necessary, before a new liquid 14 is introduced into the third receiving chamber 13 and this new liquid 14 flows into the reaction chambers 11.
  • the prior emptying of the reaction chamber 11 is then preferably carried out by centrifugal forces, not shown valve means or the like. To allow a controlled emptying of the reaction chambers 11.
  • a liquid 14 containing a reagent, preferably an antibody, is first of all introduced into the third receiving chamber 13 and passed into the reaction chambers 11 in order to immobilize the reagent in the reaction chambers 11, in particular To bind the antibody in the appropriately prepared reaction chambers 11 and to coat the Discussskammem 11 with the antibody.
  • reaction chambers 11 are rinsed with a washing liquid, which is filled as the next liquid 14 in the third Aumahmehunt 13, to remove unbound reagent.
  • analyte contained in the sample liquid 3 can bind in the illustrated embodiment, in particular to the immobilized reagent, in particular the immobilized antibody.
  • unbound analyte is rinsed or washed from the reaction chambers 11, in particular by a single filling of a washing liquid 14 in the third Aufhahmehunt 13 to displace the existing liquids 3, 8 from the reaction chambers 11, and / or by centrifugal forces or other forces.
  • another liquid 14, which in particular contains an enzyme bound to a detection antibody, is fed to the reaction chambers 11, in that this liquid 14 is again supplied to the third receiving chamber 13.
  • the detection antibody is designed such that it binds together with the enzyme to the complexes formed from the immobilized antibodies and the analyte in the reaction chambers 11.
  • Unbound detection antibodies and enzymes are subsequently rinsed out of the reaction chambers 11 in a washing step by preferably supplying a further washing liquid 14 once.
  • a substrate solution as further liquid 14 is preferably again supplied to the reaction chambers 11 via the third receiving chamber 13.
  • the substrate is converted or modified by the enzymes in the reaction chambers 11 in an enzymatic detection reaction, so that a later detectable detection substrate, in particular a fluorescent or other dye or the like, is formed.
  • a later detectable detection substrate in particular a fluorescent or other dye or the like
  • the supply of the various liquids 14, which preferably takes place exclusively via the common third receiving chamber 13 by sequential supply of the liquids 14, allows a very quick and easy preparation of the reaction chambers 11 and / or conducting the reactions in the reaction chambers 11, wherein the Pipettieraufwand , the required washing steps and / or the required amounts of liquid compared with the prior art - in particular over the conventional ELIS A method in an open pipetting plate - are significantly reduced.
  • the detection reactions are particularly preferably stopped by separating the liquid with the substrate and the detection substrate from the (immobilized) enzymes, reaction catalysts or other reaction partners and / or additionally provided examination chambers 16, by the liquid in the reaction chambers 11 containing the substrate and the detection substrate to stop the detection reactions in each case in an associated examination chamber 16 is transferred.
  • This transfer preferably takes place simultaneously for several or all reaction chambers 11, so that the detection reactions are stopped at the same time.
  • the said transfer or stopping by centrifugal forces by the device 1 is rotated accordingly.
  • the transfer is additionally or alternatively also possible by other forces, for example pressure or capillary forces, by means of corresponding valves or the like.
  • a sequential examination or detection of the detection substrate in the examination chambers 16 can take place-in particular optically, for example by fluorescence measurement. From the values obtained and taking into account the different dilution ratios, an extremely accurate, in particular quantitative, determination of the analyte in the sample liquid 3 can then be carried out.
  • reaction chambers 11 may be associated with an optionally provided, indicated in Fig. 1 by dashed lines collecting channel 17, which is connected for example via the examination chambers 16 and corresponding, preferably radial connections 12 to the reaction chambers 11 in order to empty the reaction chambers 11 liquid from the reaction chambers 11, in particular when the reaction chambers 11 are emptied by centrifugal forces by corresponding rotation of the device 1. These liquids can then be discharged through the examination chambers 16 or through not shown, direct connections or the like. Into the collecting channel 17. Such an emptying of the reaction chambers 11 can be carried out, for example, to remove liquids 3, 8 and / or 14 before feeding a new liquid 14 into the reaction chambers 11.
  • third liquid stops S 3a to S 3C i are preferably formed in the (radial) connections 12 between the reaction chambers 11 and the checking chambers 16.
  • the third liquid stops S 3 can in particular, together with the second liquid stops S 2, prevent an undesired escape of the liquid 14 into other regions, so that the liquids 14 are desirably for example only in the third collection chamber 15 or, if necessary, when the third liquid stop S is overcome 3 can be emptied or derived via the examination chambers 16 and optional fourth liquid stops S 4 into the collecting channel 17.
  • the third liquid stops S 3 ensure a defined holding of the liquid volumes of liquids 3 and 8 transferred or metered into the reaction chambers 11, thus preventing uncontrolled and undesirable outflow from the reaction chambers 11.
  • separating points or liquid stops not shown in the channel 20 or in other connections between the reaction chambers 11 and / or to the third receiving chamber 13 or third collecting chamber 15 may be provided, as required, to prevent unwanted transfer of diluted sample liquid 3 from a reaction chamber 11 in an adjacent reaction chamber 11 - for example, when mixing by accelerating and decelerating - to be able to prevent.
  • the channel 20 and, in particular, its sections extending between the individual reaction chambers 11 may also have a different course, deviating in the radial direction, from the course with an at least substantially constant distance or radius to the pivot point 2, in order to prevent unwanted transfer of dilute sample liquid 3 between individual reaction chambers 11 to prevent.
  • fourth liquid stops S 4a to S 4d are arranged in the radial connections 12 between the examination chambers 16 and the optional collection channel 17, in order to prevent an undefined outflow or discharge of liquid from the examination chambers 16.
  • the third and fourth liquid stops S 3 and S 4 can in turn also be formed, as required, at the transitions from the reaction chambers 11 and 16 to the respective connections 12.
  • the parallel dilution it should be noted that preferably in a single dilution step-that is, in a parallel dilution-3 to 20, in particular about 10, dilutions or different dilution ratios are produced. Of course, several can parallel dilutions occur simultaneously on the device 1. Accordingly, the device 1 may, if necessary, also have a plurality of arrangements, as shown in FIG.
  • the preferably provided curvature has been omitted in the preferably provided ring structure for placement on a round disk, such as a CD or the like, in order to allow a better clarity.
  • a round disk such as a CD or the like
  • the illustration of FIG. 2 is also not to scale.
  • the illustrated lengths, widths, proportions and the like do not correspond to the absolutely necessary or preferred conditions. This is also the case in the illustration according to FIG. 1.
  • a further dilution ie a lower dilution
  • This further dilution is again carried out in the illustration shown in FIG. 2 as a parallel dilution.
  • an under-dilution or further dilution for several or all reaction chambers 11 may be provided.
  • the further parallel dilution takes place substantially in accordance with the parallel dilution already explained above by means of the first and second metering chambers 5 and 9 and the downstream reaction chambers 11.
  • additional first metering chambers 5 'and additional second metering chambers 9' are provided.
  • the additional metering chambers 5 'and 9' preferably have corresponding volume ratios - in particular correspondingly reduced absolute volume - as the first and second metering chambers 5 and 9.
  • the transfer of the individual liquid volumes into the associated additional reaction chambers 11 ' is again preferably effected by centrifugal forces.
  • other forces in particular pressure and / or capillary forces may act, or valves or the like may be used.
  • another additional or additional dilution liquid can be separately supplied to the additional second metering chambers 9 'via an additional receiving chamber (not shown) for further dilution.
  • reaction chambers 11 the contents of which are not further diluted, each associated with additional reaction chambers IT, which are arranged in particular to a corresponding extent as the further dilution serving additional reaction chambers 11 'in order for all dilution stages a simultaneous examination, in particular binding of the analyte the immobilized reagent to ensure or facilitate.
  • an additional first collection chamber 6 ' may be provided, which is connected to receive additional sample liquid 3 to the additional first metering chambers 5'.
  • an additional second collection chamber 10 ' may be provided, which is arranged to receive excess dilution liquid 8 at the additional second metering chambers 9'.
  • the first metering chambers 5 are connected in parallel to a first, in particular common channel 18, which leads from the first receiving chamber 4 to the first collecting chamber 6.
  • a filling by pressure for example by attaching a pipette, not shown, or the like.
  • To the first, open receiving chamber 4, wherein thereby taking place (partial) filling of the first collection is melamine chamber 6 with appropriate dimensioning uncritical.
  • the first channel 18 is emptied after filling the first metering chamber 5 - in particular by capillary and / or centrifugal forces - before transferring the sample liquid 3 from the first metering chambers 5 into the associated reaction chambers 11 into the first collecting chamber 6.
  • This allows particularly accurate dosages, which then lead to correspondingly precise dilution series in the subsequent mixing with dilution liquid 8 and in particular in the ELISA method to very accurate quantitative results.
  • the second metering chambers 9 are preferably connected in a corresponding manner parallel to a second, in particular common, channel 19, which connects the second receiving chamber 7 to the second collecting chamber 10. Accordingly, the second metering chambers 9 can be filled faster with the diluting liquid 8.
  • the filling with the diluting liquid 8 also follows by pressure, in particular by applying a pipette, not shown, or the like.
  • the second channel 19 is preferably completely emptied into the second collection chamber 10 after filling the second metering chambers 9, in particular by capillary and / or centrifugal forces, before the dilution liquid 8 is transferred from the second metering chambers 9 into the associated reaction chambers 11 becomes.
  • This results in a very accurate dosage, since the dilution liquid 8 defined at the transitions (separation points T 2 ) from the channel 19 to the metering chambers 9 and corresponding connections tears off, as already explained above for the sample liquid 3 and the first metering chambers 5. Accordingly, this allows particularly accurate dilution series and in particular very accurate quantitative investigations according to the ELISA method or in any other way.
  • the first and second channels 18, 19 are preferably emptied simultaneously.
  • the separation points T are formed in particular by corresponding constrictions and / or kinks to ensure the desired defined tearing of the liquid.
  • the parallel connection provided in the third embodiment of the first metering chambers 5 to the first channel 18 and / or the second metering chambers 9 to the second channel 19 allows, as already explained, a particularly fast and parallel filling of the chambers 5 and 9 and is required Also, independently of other aspects and features of the present Ausruhrungsformen feasible.
  • the channels 18 and 19 preferably have in turn channel stops KS 1 and KS 2 to the respective collection chamber 6 and 10 down to ensure that first the respective metering chambers 5 and 9 are completely filled before the corresponding liquid 3 and 8 in the associated collection chamber 6 and 10 can continue to flow.
  • the channel stops KS are designed such that they are supplied by the respective liquid 3 or 8 of the pressure for feeding - for example, by a pipette, not shown, with which the respective liquid is supplied to the associated Aumahmehunt 4 and 7 - (first) can be overcome after complete filling of the associated metering chambers 5 and 9 respectively.
  • complete filling of the metering chambers 5 and 9 with the respective liquid 3 or 8 can be ensured.
  • the channels 18 and 19 are preferably substantially rectilinear or with only minor dislocations or kinks and / or preferably without V or U-shaped arcs.
  • the channels 18 and 19 alternatively or additionally preferably have a radial gradient, in particular between the respective start and end or the respective Aumahmehunt 4 and 7 and 6 and 10 collecting chamber, so that the centrifugal forces increasing with increasing radius lead, with appropriate rotation of the device 1, to the desired emptying of the channels 18, 19.
  • the associated first metering chambers 5 and second metering chambers 9 are not connected in series as in the first or second embodiment (the order being freely selectable) or connected in series to the associated reaction chambers 11, but preferably in parallel or quasi connected in parallel to the associated reaction chambers 11. Particularly preferred is the "quasi-parallel" connection, which is explained in more detail below with reference to FIG. 3.
  • the second metering chambers 9 are connected via connections 12, which preferably extend at least substantially radially, to the associated reaction chambers 11.
  • the second liquid stops S 2 prevent an uncontrolled flow of the diluting liquid 8 from the second metering chambers 9 via the connections 12 into the reaction chambers 11.
  • the first metering chambers 5 are now in turn - preferably via first liquid stops Si - connected to the associated compounds 12, in particular after each of the second liquid stops S 2 .
  • the first liquid stops Si are each formed, for example, by a corresponding constriction or sudden cross-sectional widening, so that the sample liquid 3 from the first metering chambers 5 - preferably even upon reaching an angular velocity or centrifugal force, which leads to a transfer of the diluting liquid 8 from the second metering chambers 9 leads into the associated reaction chambers 11 - not or not readily transferred to the associated reaction chambers 11 via the connections 12. Rather, preferably a downstream wetting - in particular the liquid stops Si - by the dilution liquid 8 is required.
  • the feed can also be reversed, ie the dilution liquid 8 can be introduced into sample liquid streams in the connections 12.
  • the third embodiment it is not decisive whether the first liquid stops S 1 or the second liquid stops S 2 are first overcome by the respective liquid 3 or 8, since in both cases thorough mixing of the two liquids 3 and 8 - At least in the reaction chambers 11 - can be reached. Accordingly, the third embodiment is a very robust system.
  • Another aspect of the third embodiment is that, for example, the channels 18, 19, but also other cavities, connections 12 or the like., Not always on a flat side of the carrier - especially not on the flat side, in which the chambers 4 to 7, 9 to 11, 13, 15 and 16 - must be formed, in which the cavities, channels or the like. Are formed. Rather, in the illustration according to FIG. 3, the sections indicated by dashed lines are preferably formed on the underside, while the solid cavities, channels and the like are preferably formed on the upper side or from the upper side. The upper and lower side cavities, channels and the like are then connected to one another by means of corresponding apertures, bores or the like. This allows much greater freedom in the design of the device 1, in particular with regard to the arrangement, configuration and connection of the chambers.
  • the cavities, channels and the like which are preferably formed by the flat sides (upper and lower sides), are then covered on each flat side, preferably by a cover (not shown), for example a foil or disk, so that an at least quasi-closed system is formed , Only the required openings, for example for filling the chambers 4, 7, 13 and for venting or the like. Then then, possibly even closable, openings to the environment.
  • reaction chambers 11 are not shown to scale. It should also be noted that the volumes of individual NEN chambers can also vary greatly depending on the depth of the chambers. Furthermore, examination chambers 16 according to the first or second embodiment can of course also be connected to the reaction chambers 11 if required.
  • the device 1 according to a feasible also independent of the present embodiment aspect of the present invention of several, preferably segmental modules M constructed, which can be arranged for example by means of an adapter or holder, not shown, in a disc-shaped configuration.
  • This modular design allows the combination of different examinations as needed. In Fig. 3, only a single module M is shown schematically.
  • first, second and third embodiments can also be combined as desired. Furthermore, individual aspects can also be used independently of the present embodiments in other embodiments or applications.
  • the mixing of the sample liquid 3 with the dilution liquid 8 - especially in the reaction chambers 11 - can be required or achieved by braking and accelerating the rotation of the device 1.
  • the diameter of the device 1 or the CD is preferably about 50 to 250 mm, in particular about 125 mm.
  • the thickness is preferably 1 to 6 mm, in particular about 3 mm.
  • the device 1 is preferably made of a suitable plastic.
  • the depth or width of the microstructures is preferably 20 to 1000 ⁇ m, in particular approximately 200 ⁇ m, in the illustrated embodiment.
  • All microstructures are preferably covered by a suitable, not shown or transparent cover. Only the receiving chambers 4, 7 and 13, possibly the collecting chambers 6, 10, 15, if necessary, the collecting channel 17 and / or other not shown vent openings or the like are formed open to the outside. Thus, the evaporation losses can be minimized and accordingly work with high accuracy with low volumes of liquid.
  • the volumes of liquids to be used are about 10 to 2,000 ⁇ l per liquid, preferably only about 50 to 200 ⁇ l.
  • the sum of the volumes of the paired first and second metering chambers 5, 9 is preferably 1 to 100 .mu.l, in particular about 10 ul.
  • the said sum and the respective volumes of the reaction chambers 11 and the examination chambers 16 are the same.
  • sample liquid and dilution liquid 8 are preferably also very generally understood as different liquids.
  • the ELISA method or another method can be very easily and very quickly and in particular with the use of very small amounts of liquid and thus cost-effective. Furthermore, a minimization of the required pipetting steps or other processes for the supply of liquids is made possible. In particular, a very precise examination in the form of a precise quantitative determination of an analyte in the sample liquid is made possible.

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Abstract

La présente invention concerne un dispositif et un procédé pour analyser un échantillon liquide, selon lesquels il est possible de mettre en oeuvre en particulier le procédé ELISA de manière très simple, rapide et plus précise. A cette fin, un échantillon liquide et un liquide de dilution sont respectivement amenés à plusieurs chambres de dosage de volumes différents, de manière que l'échantillon liquide puisse être dilué à différents taux de dilution, dans des chambres de réaction associées, lors d'une étape de dilution. Il est possible d'amener différents liquides successivement dans les chambres de réaction au moyen d'une chambre de réception commune. Afin d'arrêter la réaction d'identification, les liquides sont transférés depuis les chambres de réaction jusque dans des chambres d'analyse associées.
EP06742544A 2005-04-09 2006-04-07 Dispositif et procede pour analyser un echantillon liquide Withdrawn EP1899702A2 (fr)

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DE102005016503 2005-04-09
DE102005016509A DE102005016509A1 (de) 2005-04-09 2005-04-09 Vorrichtung und Verfahren zur Untersuchung einer Probenflüssigkeit
DE102005042601A DE102005042601A1 (de) 2005-04-09 2005-09-07 Vorrichtung und Verfahren zur Untersuchung einer Probenflüssigkeit
PCT/EP2006/003156 WO2006108559A2 (fr) 2005-04-09 2006-04-07 Dispositif et procede pour analyser un echantillon liquide

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JP2008534972A (ja) 2008-08-28
US7731907B2 (en) 2010-06-08
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WO2006108559A3 (fr) 2007-03-22
US20070189927A1 (en) 2007-08-16

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