EP1062042B1 - Porte-echantillon - Google Patents

Porte-echantillon Download PDF

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Publication number
EP1062042B1
EP1062042B1 EP99911779A EP99911779A EP1062042B1 EP 1062042 B1 EP1062042 B1 EP 1062042B1 EP 99911779 A EP99911779 A EP 99911779A EP 99911779 A EP99911779 A EP 99911779A EP 1062042 B1 EP1062042 B1 EP 1062042B1
Authority
EP
European Patent Office
Prior art keywords
sample
channel
liquid
support according
sample support
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.)
Expired - Lifetime
Application number
EP99911779A
Other languages
German (de)
English (en)
Other versions
EP1062042A1 (fr
Inventor
Ralf-Peter Peters
Nezih Ünal
Dirk Klaus Osterloh
Herbert Backes
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
MERLIN Lilliput GmbH
Merlin Gesellschaft fuer Mikrobiologische Diagnostik mbH
Original Assignee
Merlin Gesellschaft fuer Mikrobiologische Diagnostik mbH
Steag 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 DE1998110499 external-priority patent/DE19810499A1/de
Application filed by Merlin Gesellschaft fuer Mikrobiologische Diagnostik mbH, Steag Microparts GmbH filed Critical Merlin Gesellschaft fuer Mikrobiologische Diagnostik mbH
Publication of EP1062042A1 publication Critical patent/EP1062042A1/fr
Application granted granted Critical
Publication of EP1062042B1 publication Critical patent/EP1062042B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502723—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 venting arrangements
    • 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
    • B01L2200/0642—Filling fluids into wells by specific techniques
    • 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
    • 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
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • 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
    • B01L2400/0677—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
    • B01L2400/0683—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers mechanically breaking a wall or membrane within a channel or chamber
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves

Definitions

  • the invention relates to a sample carrier, as for microbiological analysis of sample liquids as well as for medical and environmental analytics and Diagnostics is used.
  • sample carriers or test strips made of clear plastic with a variety of unilaterally open chambers or cup-shaped Depressions used.
  • the sample carriers or test strips have z. B. 32 or 96 chambers or wells with a reagent are occupied.
  • After inoculation with Bacterial suspension are the sample carriers or test strips if necessary sealed with a transparent foil or closed with a lid.
  • the pits have a filling volume between 60 .mu.l and 300 .mu.l and be individually filled by means of apparatus; to Are pipettes with a channel or with 8, 48 or 96 Used channels.
  • US Pat. No. 4,038,151 is a sample plate for a automated optical inspection method known, for detecting and counting suspended microorganisms and to determine their sensitivity to Antibiotics are used.
  • the plate is made of a stiffer. transparent plastic and contains z. B. 20 conical Reaction chambers. The cross-sectional area of the reaction chambers is larger on one side of the plate than on the other other plate side.
  • Next to each reaction chamber are two overflow chambers attached to each side Reaction chamber lie on which an inlet channel for the relevant reaction chamber is located.
  • the reaction chambers are via slots with the overflow chambers connected.
  • the reaction chambers, the slots and the Overflow chambers extend over the entire thickness of the Sample plate.
  • the reaction chambers are in groups over specially arranged and shaped and on a plate side located branched inlet channels with at least a sample receiving chamber connected to a septum is closed.
  • the inlet channels occur at the larger one Side of the conical reaction chamber tangentially.
  • the Shape and area of cross section of each inlet channel changes abruptly at one point. At this Places - seen in the direction of flow - a flatter and wide channel each into a deep and narrow Channel over.
  • the arranged on a plate side Inlet channels may be longer than the shortest each Connection between reaction chamber and sample receiving chamber, to the back diffusion of in the suspension complicate existing components.
  • the plate is - except for a border area - on both sides with each glued to a semipermeable film containing the reaction chambers, the overflow chambers, the slits and the on the one side of the plate attached inlet channels as well one side of the sample receiving chamber covered.
  • the Reaction chambers are with a dried layer occupied a reagent substance.
  • sample liquid in the known Sample plate are evacuated their channels and chambers, so that the sample liquid from an outside of the plate located container by means of a cannula through the Septum from the edge of the plate into the sample receiving chamber is directed and through the inlet channels in the reaction chambers and possibly in the overflow chambers flows.
  • the suspension which has flowed into the reaction chamber (Sample liquid) and the reagent layer stand in Contact with the adhesive layer applied to the foil.
  • the sample plate In the optical examination of the samples in the Reaction chambers, the sample plate is vertical in the meter. In this situation, the inlet channels in relation to the direction of gravity from above into the reaction chambers on, and the overflow chambers are above the Reaction chambers. This can be in the reaction chamber possibly existing or at. a reaction or a metabolism resulting gas bubbles in the overflow chambers collect without optically examining the samples to disturb.
  • US Pat. No. 5,670,375 discloses a sample plate whose up to 64 cavities are inoculated simultaneously. After the Air is sucked out of the cavities, this flows to examining fluid from outside the sample plate located container through a connecting pipe in the Cavities and fills them.
  • a sample carrier in which starting from a sample application area sample liquid passes through a distribution channel system in reaction chambers.
  • the reaction chambers are porous inserts, have the reagents.
  • the sample liquid is due to the resulting in the porous inserts Capillary forces "sucked" into the reaction chambers.
  • insert parts restricts the photometric investigations of with the reagents reacting sample liquids in the Reaction chambers. It's not like that, for example possible, in such an arrangement fürlicht- and perform optical turbidity measurements.
  • the invention is therefore based on the object, a Sample carrier and a sample liquid distribution system to create a fairly high density of reaction chambers per unit area, cost-effective are manufacturable, easy to handle and have one easy to control from the outside fluid flow mechanism feature.
  • the distribution channels and inlet channels such small cross-sectional areas or have such shaped cross-sectional areas that in the liquid transport by capillary forces he follows.
  • the channels are thus formed as a capillary.
  • the reaction chambers in which the flowing over the channels Sample liquid to flow, are in cross section larger than the inlet channels. This creates the situation that the liquid from a small cross-section channel into a larger cavity, namely a reaction chamber must flow.
  • capillary force which is a flow of Sample fluid from the inlet channel into the reaction chamber enable.
  • Reaction chambers may be formed, which are the surfaces make it hydrophilic or so hydrophilic that it is for Wetting the insides of the reaction chambers and thus to completely fill the reaction chambers with Sample liquid comes.
  • the capillary force generating devices become in the junction area of the inlet channels in the reaction chambers by introducing structures, in particular by introducing an inlet channel o. realized.
  • This inlet channel has at least two Boundary surfaces passing through a transition area connected to each other. This transition area is provided with curves whose radii are so small that for flowing the sample liquid along this groove required capillary forces arise.
  • gutter is also suitable the corner area of two angles to each other Side surfaces of the reaction chamber, if the radius of curvature in the corner or transition area of both side surfaces is so small that on the sample liquid acting capillary forces arise that are so large that they sample liquid from the inlet channel "pull". What the required radii of curvature of this As far as gutters are concerned, it is generally said that they are smaller should be considered the smallest dimension of the channel to which the Connect gutters.
  • An alternative embodiment of the capillary force generating device is that the channels in an angle not equal to 90 ° from a chamber bounding area. Because of it resulting non-circular mouth opening flows the Sample liquid in the best case without additional Measures from the canal to the chamber.
  • the mechanism through which out of the sample receiving chambers the sample liquid to be examined in the distribution channels flowing may also be taking advantage of Capillary forces generating structures take place.
  • the distribution channels branch at the level of Bottom surfaces of the sample receiving chambers from these. There after filling the sample receiving chambers with sample liquid the cross sections of the distribution channels in Junction area are wetted with liquid, it comes automatically to a flow within the distribution channels. The discharge of the sample liquid from the sample receiving chambers is guaranteed.
  • An alternative consists in the cross-sectional areas of the inlet channels with increasing distance of the same from the sample receiving chamber increase to - in relation to the flow direction the sample liquid through the distribution channels-first branching inlet channels a larger throttle effect to achieve than in the later branching off Inlet channels.
  • the inlet channels both sides of the distribution channels of these branch.
  • branch inlet ducts from those opposite each other on opposite sides Branch inlet ducts, not directly opposite each other, but along the extension of the distribution channel arranged offset from each other. Because every turn of a feed channel from the distribution channel interferes, though slightly maintained by capillary forces Fluid transport. For these reasons, therefore, should Such disturbances do not simultaneously affect themselves liquid front moving along the distribution channels affect what would be the case if two opposing ones branching inlet channels at the same height of the Distribution channels and / or exactly opposite each other branch.
  • each reaction chamber is with a Provided vent opening. Will these vents when filling the reaction chambers with sample liquid wetted or even covered, so there is the Danger that the sample liquid through the vents flows out of the reaction chambers, provided the wetting and covering of the vents in cause these sufficiently large capillary forces. can. In fact, it is desirable to have the reaction chambers completely filled with sample liquid, since possibly still flowed gas the optical examination made difficult, if not impossible, by photometry impossible.
  • the further transport of the sample liquid through the vents Means for preventing the further flow of the Prevent sample liquid are advantageously based on the principle by geometric shape of the vents and the if necessary, to these subsequent venting channels for it to ensure that the resulting capillary forces such are low, that there is an interruption of the sample liquid stream comes.
  • capillary jumps ie channel widenings, in the the sample liquid due to difficult wetting conditions the walls of the channel widening by itself can not enter.
  • the Vent openings subsequent venting channels in open a cavity or channel widening wherein the Junction area within a side surface of the channel widening or cavity is located, and around the junction area no or only a few corner areas arranged are. Because each corner area in turn generates capillary forces, which in turn is determined by the degree of rounding are.
  • This Vent collection channel is with a vent provided with the venting system of the sample carrier the environment connects.
  • this second Distribution system targeted additional reagent liquids to introduce into the reaction chambers.
  • additional reagent liquids may be Sample liquids already in the reagent chambers with one introduced there in advance and for example in dried form reactant reacts have to undergo a second reaction.
  • Ventilation system via device especially in Form of channel widening features the sample liquid flow from the reaction chambers via the vents is to prevent such a Device also the transport of the reaction liquid via the ventilation channel system into the reaction chambers difficult.
  • the flow restricting device forming channel widening for it Care is taken that the flow of reagent fluid in the channel widenings by capillary forces is possible.
  • the inflow of reagent liquid into the channel widenings allow these with reagent fluid filled until the reagent liquid the confluence of the extending from the reaction chambers sections the venting channels covered. This will touch in these confluence areas the two reagent liquid and sample fluid fronts. The further The reagents are now transported by diffusion until into the reaction chambers.
  • the targeted filling of the channel widenings, so that it can come to the diffusion transport of the reagents can Alternatively, by introducing a (opposite to the Reagents and the sample liquid) inert control fluid be achieved. For this purpose flows into the Channel expansion then a control channel over which the Control fluid enters the channel widening. On this way is a liquid controlled valve created, so to speak, the one-time operation for transfer the valve from the locked state in its füri fieschreib with a view to facilitating a Diffusion transport of the reagents allowed.
  • the Introducing the control fluid into the channel widenings can by pressurizing the control fluid or again by the use of capillary forces respectively.
  • the same mechanisms again and configurations of the sidewalls and confluence areas the channel widenings, as they are already above are described.
  • the reaction chambers are expediently characterized that this channel system with at least one reagent liquid receiving chamber fluidly connected. Out this chamber passes the reagent liquid in particular taking advantage of those mechanisms in, as related to the above Sample receiving chambers and the distribution channels described are.
  • a first Valve is arranged, preferably as a disposable valve is formed, which only once a time its blocking state in the on state transferred can be.
  • this first Valve may also be arranged in the vent channel, the associated with the group of reaction chambers with which the sample receiving chamber is connected. Because of the thus successful controlled venting of the reaction chambers is the inflow of the sample material from the Sample receiving chamber in the individual reaction chambers controlled.
  • the "interface" of the sample carrier according to the invention for controlling the first valve or the first valves should be quite simple. That requires, that the valve can be easily controlled externally. It is preferably provided, the valve hydraulically or pneumatically controlled by the valve pending liquid or by the upcoming gas.
  • the valve hydraulically or pneumatically controlled by the valve pending liquid or by the upcoming gas.
  • Another alternative of the embodiment of the first or the first valves is that this one having hydrophobic design, in the form of a corresponding surface treatment of the channel in Area of the valve or realized by an insert part becomes.
  • the fluid present at the hydrophobic valve bridges over this, for example, as a result of a particular impulsive pressurization. If the channel is in Area of the valve in this way with liquid is wetted and capillary forces to further transport the Liquid are used, so it is a disposable valve created quite simply from the outside, namely by pressurizing the sample receiving chamber can be bridged.
  • the first valve can also advantageously as Channel widening be formed, which in turn like a Capillary jump acts (see also the description above in connection with the venting channels).
  • All channels, chambers and the like structures are from preferably one side into a base body introduced by a lid body in which it is in particular is a film, liquid-tight is covered. Both body, the main body and the Cover body, but can also together the channels and Form cavities.
  • the sample carrier is preferably made of plastic, such as polystyrene or polymethylmethacrylate (PMMA), polycarbonate or ABS.
  • PMMA polymethylmethacrylate
  • the sample carrier can through Molding of a mold insert in micro-injection molding getting produced.
  • the structure of the mold insert is complementary to the structure of the sample carrier, d. H. complementary to the structure of the base body and / or the lid body.
  • Form inserts to be used are made by lithography or electroforming, by microerosion or by micromechanical processing such as diamond milling produced. Furthermore, the structured Elements of the sample holder made of a photoetchable glass or of silicon by anisotropic etching or by micromechanical machining process to be made.
  • the individual parts of the sample carrier (basic body and lid body) become together at their touch surfaces connected, in particular by ultrasonic welding. In any case, this connection must be liquid and gas tight, so that the individual Chambers and channels do not over the contact surfaces of the Elements in contact that make up the sample carrier exists (body and lid body).
  • the sample carrier according to the invention can be used for transmitted-light measurements made of transparent material and for luminescence measurements made of transparent or opaque Material exist. If the sample carrier is multi-part is constructed (body and lid body), the individual parts of the sample carrier from different Materials exist.
  • the height of the reaction chambers and thus the thickness of the Light irradiated liquid layer can be attached to the be adapted optical evaluation.
  • Within the Sample carriers can be reaction chambers with different Heights available.
  • the sample carrier according to the invention may have reaction chambers with volumes of between 0.01 ⁇ l and 10 ⁇ l.
  • the reaction chamber density can be up to 35 / cm 2 .
  • On a sample carrier handy size can thus easily accommodate 50 to 10,000 reaction chambers.
  • the individual channels have a width and depth of 10 .mu.m to 1,000 .mu.m and in particular 10 .mu.m to 500 .mu.m.
  • An inventively constructed sample carrier has, for example, a height of 4 mm, wherein in two-part construction (base body and lid body) of the base body has a thickness of about 3.5 mm and the lid body formed as a film has a thickness of 0.5 mm.
  • the possibly round, but also also angularly formable reaction chambers are about 3.0 mm deep, so that sets a bottom wall thickness of 0.5 mm.
  • the volume of these reaction chambers is 1.5 ⁇ l each.
  • the individual channels have, in particular, a rectangular cross-section, wherein the inlet channels are approximately 400 ⁇ m wide and 380 ⁇ m deep, and the distributor channels, from which the inlet channels branch off, are approximately 500 ⁇ m wide and 380 ⁇ m deep.
  • the vents are (with a rectangular cross-section) about 420 microns wide and about 380 microns deep.
  • the ventilation channels adjoining the ventilation openings have, in particular, a width and depth of 500 ⁇ m or 1,000 ⁇ m.
  • the reaction chambers in the sample carrier can by means of an adapted miniaturized device with a chemically or biologically active reagent, which is dried after introduction of the reagent fluid is and on the floor and on the walls of the reaction chambers liable.
  • reagents for example Oligopeptide ⁇ -NA derivatives, p-nitrophenyl derivatives, sugars for fermentation and other studies, organic Acids, amino acids for assimilation studies, Decarboxylase substrates, antibiotics, antimycotics, nutrient media, Marker substances, indicator substances and others Substances are used.
  • the inventive and possibly occupied with reagent Sample carrier can be used for biochemical detection and Sensitivity testing of clinically significant Microorganisms are used.
  • a fully automated and miniaturized system becomes one defined suspension of microorganisms produced with the sample carrier is loaded.
  • the inoculated sample carrier will - if necessary after further treatment - means an optical method.
  • the case obtained results are computer-aided recorded and mathematically evaluated by means of adapted methods and assessed.
  • the sample carrier according to the invention can be used in blood group serology, clinical chemistry, microbiological Detection of microorganisms, in the examination of Sensitivity of microorganisms to antibiotics, in microanalysis and in the testing of active substances be used.
  • the sample carrier 10 shown in the drawing has a two-piece construction and consists of a base plate 12, the top 14 shown in FIG a cover sheet 16 is covered (see also Figs. 2 to 4).
  • the task of the sample carrier 10 is to apply Sample liquid taking advantage of capillary forces in to conduct a variety of reaction chambers, in which there are different reagent substances. Further should be filled with sample liquid Reaction chambers can be examined photometrically. Furthermore, it is provided by different bodies from liquids targeted into the reaction chambers contribute.
  • each section 18 is the base plate 12 of the Sample carrier 10 at its top 14 structures what by introducing grooves and depressions from the top 14 is realized in the base plate 12. All Grooves and depressions form a sample liquid and a reagent liquid distribution system, that to the top of the sample carrier 10th is covered by the cover sheet 16.
  • each section 18 of the sample carrier 10 is located a sample receiving chamber 20 for receiving a sample liquid 22 (see Fig. 2).
  • a distribution channel 24 In fluid communication with the Sample receiving chamber 20 is a distribution channel 24, the at the top end of the sample receiving chamber 20 in this opens. From the distribution channel 24 extend on both sides of the same in the plan view of FIG. 1st serpentine feed channels 26, which like the distribution channel 24 by introducing grooves in the Top 14 of the base plate 12 are formed.
  • the Inlet channels 26 extend from the Distribution channel 24 to reaction chambers 28, which as of the top 14 in the base plate 12 introduced Wells are formed. From the reaction chambers 28 out (bleed) connection channels 30.
  • This Connection channels 30 terminate in groups in two Bleed collection channels 32 a, which are parallel to each other and parallel to the distribution channel 24.
  • connection channels 30th and vent collecting channels 32 are by introduction of Grooves in the top 14 of the base plate 12 is formed.
  • the bleed collection channels 32 terminate at their an end in a vent 34, which in a Outer edge side 36 (see FIG. 2) of the base plate 12th lie.
  • the these vents 34 each opposite End of the vent collection channels 32 is with a reagent fluid receiving chamber 38, on which will be discussed later. Also this chamber 38 is by introducing a recess in the top 14 of the base plate 12 realized.
  • sample liquid 22 from the sample receiving chamber 20 of a portion 18 of the sample carrier 10th into the sample receiving chamber 20 assigned Reaction chambers 28 takes place by utilizing capillary forces.
  • capillary forces arise within the channels can, these channels must be 24,26,30,32 accordingly be dimensioned.
  • it requires a surface treatment the insides of the channels to these To hydrophilize surfaces. Whether such a hydrophilization depends on the one depends Material from which the base plate 12 and the cover sheet 16 exist, and on the other by the viscosity and Nature of the liquids to be transported (Sample fluid and reagent fluid).
  • the reaction chamber 28 a square or at least rectangular cross-section on (see the illustration in Figures 1 and 5), so that between each adjacent side surfaces 56 and between the side surfaces 56 and the bottom surface 54 Corner areas 58 and 60 result. Will these corner areas with a sufficiently small rounding radius provided, so can in the transition region of the a respective corner areas forming surfaces Form fluid meniscus, due to the Tendency of the liquid, the adjacent surface areas to wet, due to capillary forces along the corner areas 58.60 moved on.
  • the corner region 58 within which the junction 52 of the inlet channel 26 is arranged, so acts as an inlet channel 62.
  • This inlet channel 62 allows the flow of the sample liquid 22 from the inlet channel 26 into the reaction chamber 28.
  • This liquid flows initially along the inlet channel 62 in the direction of the bottom surface 54 of the reaction chamber 28 to from there along the square peripheral corner regions 58 to run, until the entire bottom of the reaction chamber 28 is wetted. In this way, the reaction chamber 28 fills increasingly with sample liquid 22, and only and solely due to the use of capillary forces.
  • the filling of the plurality of reaction chambers 28 should evenly and especially simultaneously.
  • a surcharge-like filling of the reaction chambers 28 with Sample liquid 22 can cause undesirable effects lead, namely, because the sample liquid 22 optionally on the provided for the vent connection channels 30th unwanted can drain again. Therefore it is from Advantage, when the inlet of the sample liquid 22 in the Reaction chambers 28 throttled takes place. For this reason are the cross sections of the inlet channels 26 smaller Cross section of the distribution channel 24.
  • the inlet channels 26 thus form a kind of throttle with increased flow resistance. This throttle effect has beyond the Advantage that, although the individual inlet channels in different Distances to the sample receiving chamber 20 from Distribute distribution channel 24, all reaction chambers 28th essentially at the same time (some delay is tolerated here) to be filled.
  • inlet channels 26 in extension of the distribution channel 24 offset from each other from this.
  • This has the Advantage that through the distribution channel 24th Moving fluid front in the area of the branch the inlet channels 26 each only through the junction of a Inlet channel 26 "is disturbed".
  • the two-sided the distribution channel 24 arranged in pairs Feed channels 26 branch each other opposite, so the liquid transport could be so disturbed that he comes to a halt. It is important to take into account that surface irregularities sometimes strongly on the can affect acting capillary forces.
  • the turnoff an inlet channel 26 from the distribution channel 24 acts as a Channel expansion, which, if it is too large, to a halt could cause the flow.
  • each connecting channel 30 opens via a prechamber space 64 in the respective reaction chamber 28 a (see also Fig. 7).
  • the pre-chamber space 64 is at the top of the Reaction chamber 28 arranged and up through the Cover sheet 16 limited. Its the cover sheet 16 opposite Bottom wall 66 extends obliquely sloping in Direction to the reaction chamber 28.
  • the design of the Vorschraum 64 is chosen such that all air or any gas that is in the reaction chamber 28th is discharged at filling the same, so that ultimately the liquid level within the Reaction chamber 28 to cover sheet 16 is sufficient and not is disturbed by gas bubbles o. The like. As in particular in Fig.
  • each Widening region 68 has on both sides of the Junction 70 of the connecting channel 30 extending Chamber areas 72, which extend into one area - Based on the gas flow direction - upstream of Junction 70 extend and to the vent collection channel 32 rejuvenate.
  • the junction 70 lies in a side surface area 74 of the widening 68, within this side surface area 74 both no laterally as well as below the confluence point 70 Corner areas are formed. The only corner area, which arises, arises laterally of the junction 70 and adjacent to the film 16.
  • each extends Vent collection channel 32 from a reagent liquid receiving chamber 38.
  • receiving chambers 38 There is an additional reagent fluid, the for triggering reactions of the sample liquid in the Reaction chambers 28 is needed.
  • the reaction chambers 28 are themselves already advantageously with reagent substances occupied, the prefabricated and in Dependence of the investigations to be carried out in the Reaction chambers 28 has been applied. Until the Entry of the sample liquid 22 are these Reaction substances in dried form in the reaction chambers 28th
  • FIGS. 5 and 9 still pointed out that in turn to Transport of the reagent fluid from the reagent receiving chambers 38 in the connected to this Venting collecting channels 32 Capillary forces exploited become.
  • the mechanism is similar to the one he uses FIGS. 1 and 6 is described.
  • Fig. 9 branches of Vent collecting channel 32 at the bottom wall 78 of the Chamber 38 facing away from the upper end.
  • the junction 80 in the sidewall boundary 82 of the chamber 38, which, as Fig. 5 shows, is rounded in this area.
  • FIG Fig. 10 A first variant of such a valve 86 is shown in FIG Fig. 10 is shown.
  • the distribution channel 24 extends through one in the Top view round duct widening 88, in which a porous hydrophobic insert body 90 is arranged. by virtue of its hydrophobic properties block the body 90 the liquid transport through the expansion 88th Will now the sample liquid in the receiving chamber 20 a Pressurized, the liquid is in the Expansion 88 and thus into the porosities of the hydrophobic Insert body 90 pushed into it. This is the porous Body 90 of sample liquid is flushed through until it is in the area adjoining the channel widening 88 the distribution channels 24, based on the flow direction behind the insert body 90 is reached.
  • FIGS. 11 and 12 show an alternative valve design 86 '.
  • the valve construction 86 ' underlying thought is as based on the Expansion regions 68 (see Figures 5 and 8).
  • 86 ' is located in Distribution channel 24 a special channel widening 88 ', the in the plan view and in the sectional view as in the FIGS. 11 and 12 is shown formed.
  • Orifice 92 of the sample receiving chamber 20 coming part of the distribution channel 24 has the Widening 88 'on a flat side surface 94, the only to the cover sheet 14 through a corner area is limited.
  • valve 86 A last embodiment of a valve 86 "is in the FIGS. 13 and 14 are shown.
  • the mechanisms and the Design of this valve are almost identical to Valve design 86 '.
  • the difference between the two is that the filling of the expansion area 88 "of the valve 86" not through the sample liquid, but by an inert to the sample liquid Control fluid 98 takes place.
  • the control fluid 98 is located in a receiving chamber 100, which has a Control channel 102 connected to the expansion region 88 ' is.
  • the introduction of the control fluid 98 in the Widening 88 " can be done by applying pressure to the Control fluid 98, on the other hand also by Maintaining a liquid flow under Exploitation of capillary forces can be realized.
  • reaction chambers of the sample carrier can in the Reaction chambers of the sample carrier already reaction substances be introduced, in particular in store dried form there. Because of the small volumes: the reaction chambers only require small amounts on reaction substances, causing the drying process is beneficial.
  • the introduction of the sample liquid is carried out by the user. If the cover sheet 16 is not up in the Areas of the upper side 14 of the base plate 12 extends, in where the sample receiving chambers 20 are located these freely accessible, so that the sample liquid on conventional manner be introduced by pipetting can. The same applies if the cover sheet over the entire top and extends with the sample chambers (and the reagent fluid receiving chambers 38) aligned Has openings. For the sake of an improved Evaporation protection, it is advantageous if the cover sheet the chambers 20 and 38 covered. In such a Case, the sample liquid can be by puncture of Insert cover sheet. An alternative is that the cover sheet slotted in the region of the chambers 20 and 38 is and thus in the manner of a septum for the Proben beaukeitseinbringung can be opened.

Claims (38)

  1. Porte-échantillon comprenant
    au moins un compartiment de prélèvement d'échantillon (20) pour un liquide d'échantillon,
    un conduit de distribution (24) pour liquide d'échantillon, qui est relié avec le au moins un compartiment de prélèvement d'échantillon, au moins un conduit de distribution s'étendant à partir de chaque compartiment de prélèvement d'échantillon,
    au moins un compartiment de réaction (28) qui présente une cavité limitée par des surfaces, dans lequel débouche un conduit d'alimentation dérivant du au moins un conduit de distribution et
    un orifice de purge d'air pour chaque compartiment de réaction,
    le dimensionnement de chaque conduit de distribution et de chaque conduit d'alimentation étant prévu pour que le transport de liquide par les conduits de distribution et d'alimentation s'effectue sous l'effet de forces capillaires, caractérisé en ce que
    dans chaque compartiment de réaction, les surfaces limitant la cavité sont conçues, dans la zone d'embouchure (52, 62) du conduit d'alimentation, de manière à former un dispositif permettant de produire une force capillaire pour l'écoulement du liquide d'échantillon du conduit d'alimentation dans le compartiment de réaction.
  2. Porte-échantillon selon la revendication 1, caractérisé en ce que chaque compartiment de réaction présente une surface de fond avec deux surfaces latérales formant un angle avec celle-ci et que le dispositif de production de force capillaire est réalisé par formation d'un petit rayon d'arrondi dans la zone de transition entre les surfaces latérales et la surface de fond, de sorte que le liquide d'échantillon s'écoule le long des zones de transition par des forces capillaires.
  3. Porte-échantillon selon la revendication 2, caractérisé en ce que le conduit d'alimentation débouche dans la zone de transition entre les surfaces latérales et la surface de fond d'un compartiment de réaction.
  4. Porte-échantillon selon la revendication 2, caractérisé en ce que le conduit d'alimentation débouche dans un compartiment de réaction, au-dessus de la surface de fond de celui-ci, et qu'une goulotte d'entrée présentant une aire et une forme de section produisant l'écoulement du liquide d'échantillon par force capillaire s'étend entre l'embouchure du conduit d'alimentation et la zone de transition entre la surface de fond et les surfaces latérales.
  5. Porte-échantillon selon la revendication 4, caractérisé en ce que la goulotte d'entrée est formée .par le rayon d'arrondi dans la zone de transition entre deux surfaces latérales du compartiment de réaction, voisines et formant un angle l'une avec l'autre.
  6. Porte-échantillon selon l'une quelconque des revendications 1 à 5, caractérisé en ce que chaque compartiment de prélèvement d'échantillons présente une surface de fond et des surfaces latérales formant un angle avec celle-ci et que chaque conduit de distribution débouche dans le compartiment de prélèvement d'échantillon qui lui est associé, dans la zone de transition entre la surface de fond et les surfaces latérales.
  7. Porte-échantillon selon l'une quelconque dés revendications 1 à 5, caractérisé en ce que chaque compartiment de prélèvement d'échantillons présente une surface de fond et des surfaces latérales formant un angle avec celle-ci, que chaque conduit de distribution débouche dans le compartiment de prélèvement d'échantillon qui lui est associé, au-dessus de la zone de transition entre la surface de fond et les surfaces latérales, et qu'une goulotte de sortie, dont l'aire et la forme de section transversale permettent un écoulement du liquide d'échantillon par force capillaire, s'étend à partir de l'embouchure en direction de la surface de fond.
  8. Porte-échantillon selon la revendication 7, caractérisé en ce que la goulotte de sortie est formée par deux surfaces latérales formant un angle entre elles, dont la zone de transition présente un petit rayon d'arrondi, de façon que des forces capillaires soient produites pour l'écoulement du liquide d'échantillon le long de la zone de transition.
  9. Porte-échantillon selon l'une quelconque des revendications 1 à 8, caractérisé en ce que tous les conduits d'alimentation dérivant d'un conduit de distribution présentent une aire de section inférieure à celle du conduit de distribution.
  10. Porte-échantillon selon la revendication 9, caractérisé en ce que des conduits d'alimentation dérivent des deux côtés de chaque conduit de distribution, et que les points de dérivation des conduits d'alimentation opposés les uns aux autres sont disposés décalés les uns par rapport aux autres.
  11. Porte-échantillon selon l'une quelconque des revendications 1 à 10, caractérisé en ce qu'un conduit de liaison s'étend à partir de chaque orifice de purge d'air de chaque compartiment de réaction et que plusieurs conduits de liaison débouchent dans un conduit collecteur de purge d'air qui présente un orifice collecteur de purge d'air.
  12. Porte-échantillon selon la revendication 11, caractérisé en ce qu'un dispositif pour arrêter la poursuite de l'écoulement du liquide d'échantillon résultant des forces capillaires est disposé dans chaque conduit de liaison et/ou dans chaque orifice de purge d'air.
  13. Porte-échantillon selon la revendication 12, caractérisé en ce que les dispositifs d'arrêt des forces capillaires sont disposés dans les zones d'embouchure des conduits de liaison dans les conduits collecteurs de purge d'air.
  14. Porte-échantillon selon la revendication 12 ou 13, caractérisé en ce que chaque dispositif d'arrêt des forces capillaires est conçu comme un élargissement du conduit de liaison ou de l'orifice de purge d'air, qui présentent chacun une surface latérale dans laquelle débouche un conduit de liaison, la zone d'embouchure du tronçon du conduit de liaison s'étendant à partir du compartiment de réaction n'étant limitée, dans l'élargissement, par aucune zone d'angle ou limitée par un nombre si faible de zones d'angle avec des rayons d'arrondi produisant la force capillaire, que l'écoulement du liquide d'échantillon est arrêté dans la zone d'élargissement.
  15. Porte-échantillon selon la revendication 14, caractérisé en ce que chaque conduit collecteur de purge d'air s'étend à partir d'un compartiment à réactifs destiné à recevoir un liquide réactif, l'écoulement du liquide réactif par les conduits de purge d'air s'effectuant par les forces capillaires produites dans ceux-ci et que, dans la zone d'embouchure de chaque conduit collecteur de purge d'air dans les élargissements et/ou dans les zones d'embouchure des tronçons des conduits de liaison s'étendant à partir des conduits de purge d'air dans les élargissements, un dispositif pour produire une force capillaire afin de remplir les élargissements est disposé.
  16. Porte-échantillon selon la revendication 15, caractérisé en ce que chaque compartiment de réactif présente une surface de fond et des surfaces latérales formant un angle avec celle-ci et que le conduit collecteur de purge d'air associé à un compartiment de réactifs débouche au-dessus de la surface de fond dans le compartiment de réactifs, un dispositif pour produire une force capillaire pour l'écoulement du liquide réactif du compartiment de réactifs dans le conduit collecteur de purge d'air étant disposé entre l'embouchure et la surface de fond.
  17. Porte-échantillon selon la revendication 16, caractérisé en ce que le dispositif de production de force capillaire est conçu comme une goulotte de sortie dont la forme et l'aire de section permettent un écoulement du liquide réactif par la force capillaire.
  18. Porte-échantillon selon la revendication 17, caractérisé en ce que la goulotte de sortie est conçue comme une rainure formée dans une surface latérale.
  19. Porte-échantillon selon la revendication 17, caractérisé en ce que la goulotte de sortie est conçue comme une zone de transition entre deux surfaces latérales voisines et formant un angle entre elles, la zone de transition présentant un petit rayon d'arrondi de façon à produire des forces capillaires provoquant un écoulement du liquide réactif.
  20. Porte-échantillon selon la revendication 14, caractérisé en ce que chaque conduit collecteur de purge d'air s'étend à partir d'un compartiment de réactifs destiné à recevoir un liquide réactif et que, dans la zone d'embouchure de chaque conduit collecteur de purge d'air dans les élargissements et/ou dans les zones d'embouchure des tronçons des conduits de liaison s'étendant à partir des conduits de purge d'air dans les élargissements, un dispositif pour produire une force capillaire est disposé afin de remplir les élargissements.
  21. Porte-échantillon selon l'un quelconque des revendications 1 à 20, caractérisé en ce qu'il est prévu des dispositifs pour l'écoulement contrôlé du liquide d'échantillon par les conduits de distribution dans le compartiment de réaction.
  22. Porte-échantillon selon la revendication 21, caractérisé en ce que les dispositifs de contrôle de l'écoulement présentent des vannes qui sont disposées dans chaque conduit de distribution et/ou les orifices de ventilation des compartiments de réaction ou montées en aval de ceux-ci.
  23. Porte-échantillon selon la revendication 22, caractérisé en ce que chaque vanne peut être passée d'une position de barrage à une position de passage de manière hydraulique ou pneumatique par commande externe et/ou par admission de la pression du liquide d'échantillon s'exerçant sur elle ou du gaz s'exerçant sur elle.
  24. Porte-échantillon selon la revendication 23, caractérisé en ce que chaque vanne présente un film d'éclatement et/ou une pièce d'insertion poreuse hydrophobe et/ou une paroi intérieure hydrophobe.
  25. Porte-échantillon selon la revendication 23, caractérisé en ce que chaque vanne est conçue comme un élargissement de conduit disposé dans un conduit de distribution, dans lequel débouche le premier tronçon d'un conduit de vanne s'étendant à partir d'un compartiment de prélèvement d'échantillon et à partir duquel s'étend le deuxième tronçon du conduit de distribution orienté vers les conduits d'alimentation, la zone d'embouchure du premier tronçon du conduit de distribution dans l'élargissement n'étant limité par aucune zone d'angle ou limité par un nombre si réduit de zones d'angle avec des rayons d'arrondi produisant des forces capillaires, que le flux du liquide d'échantillon est interrompu dans la zone d'embouchure.
  26. Porte-échantillon selon la revendication 25, caractérisé en ce que les élargissements de conduits peuvent être remplis du liquide d'échantillon par admission de pression du liquide d'échantillon présent dans les premiers tronçons des conduits de distribution, et les tronçons des conduits de distribution peuvent ainsi être court-circuités par le liquide d'échantillon.
  27. Porte-échantillon selon la revendication 25, caractérisé en ce que, dans chaque élargissement de conduit, débouche un conduit de contrôle pour un liquide de contrôle, dont l'élargissement de conduit peut être rempli et les tronçons des conduits de distribution peuvent ainsi être court-circuités par le liquide de contrôle.
  28. Porte-échantillon selon la revendication 27 caractérisé en ce que l'écoulement du liquide de contrôle par les conduits de contrôle s'effectue par des forces capillaires.
  29. Porte-échantillon, selon la revendication 28, caractérisé en ce que l'écoulement du liquide de contrôle à partir des conduits de contrôle dans les élargissements de conduits s'effectue également par des forces capillaires et/ou par une admission de pression du liquide de contrôle.
  30. Porte-échantillon selon l'une quelconque des revendications 27 à 29, caractérisé en ce que chaque conduit de contrôle s'étend à partir d'un compartiment de réception du liquide de contrôle jusqu'à l'élargissement de conduit concerné.
  31. Porte-échantillon selon la revendication 30, caractérisé en ce que chaque compartiment de réception du liquide de contrôle présente une surface de fond et des surfaces latérales formant un angle avec celle-ci et que le conduit collecteur de purge d'air associé à un compartiment de réception de liquide de contrôle débouche au-dessus de la surface de fond dans le compartiment de réception de liquide de contrôle, un dispositif pour produire une force capillaire pour l'écoulement de liquide de contrôle depuis le compartiment de réception de liquide de contrôle dans le conduit collecteur de purge d'air étant disposé entre l'embouchure et la surface de fond.
  32. Porte-échantillon selon la revendication 31, caractérisé en ce que le dispositif de production de force capillaire est conçu comme une goulotte de sortie dont la forme et l'aire de section permettent un écoulement du liquide de contrôle par force capillaire.
  33. Porte-échantillon selon la revendication 32, caractérisé en ce que la goulotte de sortie est conçue comme une rainure formée dans une surface latérale.
  34. Porté-échantillon selon l'une quelconque des revendications 1 à 33, caractérisé en ce que les compartiments, conduits et autres structures sont logés dans un corps de base à partir d'au moins un côté de celui-ci et que ce côté au moins unique du corps de base est recouvert de manière étanche aux liquides par un corps de couvercle.
  35. Porte-échantillon selon la revendication 34, caractérisé en ce que le corps de base et le corps de couvercle sont en matière plastique, en verre, en métal ou en silicium.
  36. Porte-échantillon selon la revendication 34 ou 35, caractérisé en ce que le corps de couvercle est un film.
  37. Porte-échantillon selon l'une quelconque des revendications 1 à 36, caractérisé en ce que le compartiment de réaction au moins unique contient des réactifs desséchés.
  38. Utilisation d'un porte-échantillon selon l'une quelconque des revendications précédentes dans le diagnostic micro-biologique, la sérologie des groupes sanguins, la chimie clinique, la micro-analytique et le contrôle d'agents actifs, chaque compartiment de prélèvement d'échantillon contenant des réactifs différents.
EP99911779A 1998-03-11 1999-03-11 Porte-echantillon Expired - Lifetime EP1062042B1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE19810499 1998-03-11
DE1998110499 DE19810499A1 (de) 1998-03-11 1998-03-11 Mikrotiterplatte
DE19902309 1999-01-21
DE19902309 1999-01-21
PCT/EP1999/001607 WO1999046045A1 (fr) 1998-03-11 1999-03-11 Porte-echantillon

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EP1062042A1 EP1062042A1 (fr) 2000-12-27
EP1062042B1 true EP1062042B1 (fr) 2003-05-28

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EP (1) EP1062042B1 (fr)
JP (1) JP4350897B2 (fr)
AT (1) ATE241430T1 (fr)
AU (1) AU739563B2 (fr)
BR (1) BR9909249B1 (fr)
CA (1) CA2323424C (fr)
DE (1) DE59905743D1 (fr)
ES (1) ES2203093T3 (fr)
HK (1) HK1035683A1 (fr)
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US7560073B1 (en) 2009-07-14
BR9909249B1 (pt) 2009-12-01
HK1035683A1 (en) 2001-12-07
DE59905743D1 (de) 2003-07-03
US20090155128A1 (en) 2009-06-18
AU739563B2 (en) 2001-10-18
ATE241430T1 (de) 2003-06-15
AU3034099A (en) 1999-09-27
ES2203093T3 (es) 2004-04-01
IL138286A (en) 2004-02-19
JP4350897B2 (ja) 2009-10-21
BR9909249A (pt) 2000-11-28
JP2002505946A (ja) 2002-02-26
EP1062042A1 (fr) 2000-12-27
WO1999046045A1 (fr) 1999-09-16
CA2323424C (fr) 2005-03-08
US20070025875A1 (en) 2007-02-01
IL138286A0 (en) 2001-10-31

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