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EP2506959B1 - Elément micro-fluidique destiné à l'analyse d'un échantillon de liquide - Google Patents

Elément micro-fluidique destiné à l'analyse d'un échantillon de liquide Download PDF

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Publication number
EP2506959B1
EP2506959B1 EP10782320.5A EP10782320A EP2506959B1 EP 2506959 B1 EP2506959 B1 EP 2506959B1 EP 10782320 A EP10782320 A EP 10782320A EP 2506959 B1 EP2506959 B1 EP 2506959B1
Authority
EP
European Patent Office
Prior art keywords
reagent
chamber
chambers
channel
axis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP10782320.5A
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German (de)
English (en)
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EP2506959A1 (fr
Inventor
Manfred Augstein
Susanne Würl
Carlo Effenhauser
Christoph Böhm
Edwin Oosterbroek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
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Publication date
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Priority to EP10782320.5A priority Critical patent/EP2506959B1/fr
Publication of EP2506959A1 publication Critical patent/EP2506959A1/fr
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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F21/00—Dissolving
    • B01F21/20—Dissolving using flow mixing
    • B01F21/22—Dissolving using flow mixing using additional holders in conduits, containers or pools for keeping the solid material in place, e.g. supports or receptacles
    • 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
    • B01L3/502746—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 for controlling flow resistance, e.g. flow controllers, baffles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F29/00—Mixers with rotating receptacles
    • B01F29/30—Mixing the contents of individual packages or containers, e.g. by rotating tins or bottles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/10—Mixers with shaking, oscillating, or vibrating mechanisms with a mixing receptacle rotating alternately in opposite directions
    • 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
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/712—Feed mechanisms for feeding fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/71725—Feed mechanisms characterised by the means for feeding the components to the mixer using centrifugal forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions

Definitions

  • the present invention relates to a microfluidic element for determining an analyte in a fluid sample, preferably in a body fluid sample.
  • the element comprises a substrate and a channel structure which is enclosed by the substrate and a cover layer.
  • Microfluidic elements for analyzing a fluid sample and mixing a fluid with a reagent are used in diagnostic tests (in vitro diagnostics). In these tests, body fluid samples are analyzed for an analyte for medical purposes.
  • the term mixing comprises both the possibility that the reagent is in liquid form, that is, that two liquids are mixed together.
  • the term includes the possibility that the reagent is present as a solid and dissolved in a liquid and homogenized.
  • the solid dry reagent is introduced into the fluidic element in liquid form and dried in a further step before the element is used for analysis.
  • test carriers on which microfluidic elements with channel structures for receiving a liquid sample are present in order to enable the implementation of complex and multi-level test procedures ("test protocols").
  • a test carrier may comprise one or more fluidic elements.
  • Test carrier and fluidic elements consist of a carrier material, usually a substrate made of plastic material. Suitable materials are, for example, COC (cyclo-olefin copolymer) or plastics such as PMMA, polycarbonate or polystyrene.
  • the test carriers have a sample analysis channel which is enclosed by the substrate and a lid or cover layer.
  • the sample analysis channel often consists of a succession of multiple channel sections and intermediate chambers compared to the channel sections of extended chambers.
  • the structures and dimensions of the sample analysis channel with its chambers and sections are defined by a patterning of plastic parts of the substrate, which are produced, for example, by injection molding techniques or other methods for producing suitable structures. It is also possible to introduce the structure by material-removing methods such as milling.
  • Fluidic test carriers are used, for example, in immunochemical analyzes with a multi-step test procedure in which a separation of bound and free reaction components takes place.
  • a controlled liquid transport is necessary.
  • the control of the process flow can take place with internal (within the fluidic element) or with external (outside the fluidic element) measures.
  • the control can be based on the application of pressure differences or else the change of forces, for example resulting from the change in the effective direction of gravity.
  • centrifugal forces acting on a rotating test carrier a control by changing the rotational speed or the direction of rotation or by the distance from the axis of rotation can be made.
  • the US 2005/0041525 A1 describes microfluidic elements and methods for analyzing biological samples and mixing different liquids.
  • the liquids to be mixed are first added from respective containers in a first chamber to combine the liquids. Subsequently, the combined liquids from the first chamber are emptied through at least one capillary connection channel into a second chamber to mix the liquids.
  • two or more parallel capillary connection paths are used.
  • the second chamber is in flow relationship via at least one capillary connection path with at least one third mixing chamber. The transport of the liquids is effected by centrifugal forces and always takes place from the rotation axis closer chamber to the rotation axis remote chamber.
  • the sample analysis channel of the microfluidic elements contains at least one reagent which reacts with a liquid introduced into the channel.
  • the liquid and the reagent are mixed in the test carrier with each other so that a reaction of the sample liquid with the reagent leads to a change in a measured variable that is characteristic of the analyte contained in the liquid.
  • the measured variable is measured on the test carrier itself.
  • Commonly used are optically evaluable measuring methods in which a color change or another optically measurable variable are detected.
  • the capillary channels contain special flow obstacles.
  • the production of such obstacles, such as ribs, must be formed in the microstructure and are therefore expensive and complicate the manufacturing process of the test carrier.
  • such structures are not suitable for all mixing processes or not for all reagents and sample liquids.
  • the fluidic element should be suitable for simultaneously mixing different reagents, which are introduced separately and which, for. B. at different spatial locations, dissolve and to allow the sample liquid to react with different reagents.
  • microfluidic element having the features of claim 1.
  • test carrier for analyzing a body fluid sample for an analyte contained therein without limiting the generality of a microfluidic element.
  • other sample fluids can also be analyzed.
  • a microfluidic element is understood to mean an element with a channel structure in which the smallest dimension of the channel structure is at least 1 ⁇ m and its largest dimension (for example Length of the channel) is at most 10 cm. Due to the small dimensions and the capillary channel structures prevail in the channels or channel sections predominantly laminar flow conditions. The resulting poor conditions for thorough mixing of liquid and solid in such capillary channels are significantly improved by the microfluidic element according to the invention.
  • the microfluidic element rotates about an axis of rotation.
  • the axis of rotation preferably extends through the microfluidic element. It passes through a predetermined position, preferably z. B. by the center of gravity or the center of the element.
  • the axis of rotation extends perpendicular to the surface of the fluidic element, which preferably has a flat, disk-like shape and z. B. may be a round disc.
  • the microfluidic element is held for example in a holder of an analyzer, wherein the axis of rotation is formed by a rotary shaft of the device.
  • a channel structure which comprises a feed channel with a feed opening and a bleed channel with a bleed opening and at least two reagent chambers.
  • At least one of the reagent chambers contains a reagent which is preferably in solid form as a dry reagent and which reacts with the liquid sample introduced into the channel structure.
  • Each two adjacent reagent chambers are connected to one another via at least two connection channels such that a fluid exchange between the two reagent chambers is made possible.
  • one of the reagent chambers has an inlet opening which is in fluid communication with the feed channel so that a liquid sample can flow from the feed channel into the reagent chambers.
  • the liquid sample flows from the feed channel into the reagent chamber, which is further away from the (two) reagent chambers from the axis of rotation. The liquid thus flows into the spin axis remote reagent chamber.
  • rotational axis remote and rotational axis near do not represent absolute range indications where a structure is located, but indicate how far apart a structure is from the axis of rotation.
  • the axis of rotation is understood as the zero point of a distance scale, which extends radially outward from the axis of rotation.
  • a structure remote from the axis of rotation is, in this sense, further away from the axis of rotation than a structure near the axis of rotation.
  • a reagent chamber remote from the axis of rotation is the reagent chamber, which is further away from the axis of rotation in relation to another reagent chamber.
  • the reaction chamber remote from the axis of rotation is the chamber which, compared to other chambers, is farthest from the axis of rotation, ie the remainder of the reagent chambers.
  • rotation axis is to be understood.
  • a reagent chamber close to the axis of rotation is to be understood as meaning the reagent chamber which, in comparison to the other reagent chambers, is arranged closest to the axis of rotation.
  • connection channels between the two reagent chambers allow unhindered and rapid fluid exchange.
  • more than two connection channels are advantageous.
  • Particularly preferred three connection channels are used, the z. B. can be arranged substantially parallel to each other.
  • the reagent chambers are fluidly connected in series through the two connection channels in such a way that a fluid series connection is created.
  • the reagent chambers are geometrically independent component structures and have their own receiving volume. Fluidically, however, they are together a single fluid chamber. Thus, the positive properties of single reagent chambers are combined with the properties of a single fluid chamber.
  • the solid dry reagents are introduced into the chambers in liquid form and then dried. This drying takes place either by heating or by freezing, which preferably takes place at temperatures of below -60 ° C., particularly preferably at about -70 ° C.
  • the test carrier to improve the drying of the liquid reagent, pre-cooled. Especially with "surfactant-containing" reagents, the "cold drying" by freezing is preferred.
  • the reagent chambers are geometrically separated from one another, different reagents can be introduced into each of the reagent chambers without the reagents being mixed before or during drying. This is supported by a corresponding geometric design of the reagent chambers.
  • the chambers may be separated by sharp boundaries such as ridges or edges to prevent crosstalk due to creep effects.
  • the sharp-edged boundaries also form a barrier for transporting the fluid out of a reagent chamber. However, this can be easily overcome by the external forces (centrifugal force, hydrostatic force).
  • the arrangement of the reagent chambers of the channel structure is designed in such a way that one of the chambers is arranged to be more remote from the axis of rotation than the other chamber, ie the distance of the one reagent chamber remote from the axis of rotation from the axis of rotation is greater than the distance of the other chamber.
  • the second (and possible other rotationsachsen labre) reagent chamber is filled.
  • the reagent chamber is filled which is furthest away from the axis of rotation.
  • the (closer to the farthest reagent chamber) arranged closer to the axis of rotation chambers are filled only in one or more further steps, the order of filling depends on the distance to the axis of rotation.
  • the reagent chamber with the smallest distance to the rotation axis is filled last.
  • a release of the reagents is more reliable, more complete and faster than in only partly filled chambers.
  • a good mixing for a large number of different volumes can be achieved.
  • three or five of z. B. 12 reagent chambers are filled with the volume to be tested, with all (e.g., three or five) chambers completely filled. If all reagent chambers are filled with the same reagent or the same composition of reagents, a very good mixing with the reagents can be achieved in this way for different volumes of sample liquid.
  • the two (or more) connecting channels between two adjacent reagent chambers are arranged in parallel.
  • the spaced (separate) connection channels are preferably formed by straight channel sections.
  • the length of at least one of the connection channels is smaller than the smallest dimension of the reagent chambers in the test carrier plane.
  • the test carrier level is the level which extends perpendicular to the surface normal of the test carrier, for example, perpendicular to the axis of rotation.
  • one of the at least two connecting channels is arranged centrally between adjacent reagent chambers. He aligns with the centers of the two reagent chambers that he connects.
  • the (other) connecting channel is laterally connected to the reagent chambers such that it extends outside the central axis connecting the centers. It is particularly preferably arranged tangentially to the reagent chambers that its outer side (outer wall) is aligned with the outer walls of the reagent chambers.
  • the centric connection channel is wider (it has a larger cross-section at the same channel height) than the laterally arranged channel.
  • connection channels between two adjacent reagent chambers are designed such that, when filling the reagent chamber arrangement, the liquid can flow through the connection channels from one chamber into the second.
  • the liquid preferably flows through one of the connecting channels.
  • the air contained in the not yet filled chamber can escape through the other of the two channels, that is, the channel not wetted by the liquid, preferably through the central connecting channel.
  • a connecting channel extends along the central axis, which connects the centers of two adjacent reagent chambers.
  • the two other connection channels are preferably arranged tangentially to the reagent chambers.
  • connection channels are each arranged between two adjacent reagent chambers. Two reagent chambers are adjacent when no further reagent chamber is arranged between them and a fluid exchange between them takes place directly via the at least two connection channels, without further fluidic structures being interposed therebetween.
  • the channel structure comprises a mixing chamber in which the reagent chambers and the connection channels are integrated between the reagent chambers.
  • the reagent chambers in the mixing chamber are arranged in series in the radial direction in such a way that the row of chambers encloses an angle of at most 80 ° to the radial direction, particularly preferably of a maximum of 60 °.
  • Radial direction is to be understood as meaning a straight line that extends outward from the axis of rotation of the microfluidic element or of the test carrier. The Thus, reagent chambers need not be directly directed radially outward, but may include an angle to the radial direction that is different than 90 °.
  • the reagent chambers are designed to be filled with a liquid and to dissolve a solid dry reagent contained in the reagent chamber without the liquid flowing into the adjacent reagent chamber. As long as the amount of liquid does not exceed the volume of the reagent chamber, the liquid remains in the reagent chamber into which it flows. This is always the first time you fill the rotating axis remote reagent chamber. As a rule, therefore, it has the inlet opening, which is in fluid communication with the feed channel such that a liquid sample can flow into the rotation axis remote reagent chamber.
  • the reagent chambers have a round configuration. Their base is circular. The bottom of the individual chambers is rounded, so that the floor merges steadily into the chamber walls, ie without an edge.
  • the reagent chambers are preferably designed in the form of a hemisphere or a hemisphere segment. Between two adjacent chambers, a web is formed, which separates the two chambers. At the upper end of the chamber, an edge is provided so that a capillary stop is formed, which prevents leakage of liquid from one of the reagent chambers.
  • This web-like barrier is referred to in professional circles as a plate.
  • the edge in the transition does not have to be sharp-edged. It can also have a small radius. However, the radius should be chosen so small that the barrier function is maintained.
  • the reagent chambers which are each connected to one another by at least two connecting channels, are preferably integrated in a mixing chamber.
  • the mixing chamber consists of the reagent chambers, the connection channels, a feed opening through which liquid can enter from a feed channel into the mixing chamber, and a vent opening at the end a vent channel, which is in air exchange communication with the mixing chamber, is arranged.
  • the mixing chamber may also comprise a transport channel which is guided laterally along the reagent chambers.
  • Reagent chambers having a rounded bottom or a rounded depression as a structure are also suitable for use in rotating test carriers and Zentrifugaldevices to introduce two or more reagents individually in the structure and to mix together only when dissolved with a liquid at a later date.
  • the statements made in the figure description with respect to rotating test carrier can therefore be transferred to non-rotating test carrier in which the reagent chambers have a rounded bottom and preferably have a hemispherical shape.
  • Hemispherical reagent chambers which are preferably combined in a mixing chamber, also have a great advantage in the introduction and drying of reagents.
  • the reagents are introduced into the reagent chambers in liquid form and dried there. During the drying process, the surface tension acts, so that the metered liquid reagent wets the environment of the application point and spreads slowly. If it strikes edges or similar places, which have a higher capillarity, it dries concentrated there. The rounded bottom prevents such concentration. Since only one reagent is applied per reagent chamber, also a confluence and mixing is prevented. This is supported by the sharp-edged upper edges of the chambers. Even when the reagents are dissolved, the round bottom reagent chambers prove to be particularly advantageous.
  • FIG. 1 shows a microfluidic element 1 with three identically constructed channel structures 2, which extend substantially radially outward.
  • the smallest dimension of the channel structure 2 is at least 0.1 mm, more preferably at least 0.2 mm in size.
  • the microfluidic element 1 is a test carrier 3, which is designed as a round disc and through which a rotation axis 4 extends centrally around which the disc-shaped test carrier 3 rotates.
  • the channel structure 2 is formed by a substrate 5 and a Enclosed cover layer not shown, which covers the test carrier 3 from above.
  • the microfluidic element 1 is suitable for use in an analyzer or similar device having a support for receiving and rotating the microfluidic element.
  • the device is preferably designed such that the microfluidic element is rotated about a rotary shaft of the device, wherein the axis of the rotary shaft is aligned with the axis of rotation 4 of the microfluidic element 1.
  • the rotary shaft of the device can extend through a bore 4a of the test carrier 3.
  • the axis of rotation 4 preferably extends through the center or the center of gravity of the element 1.
  • the channel structure 2 of the microfluidic element 1 includes a feed channel 6, which comprises a U-shaped channel section 7 and a straight channel section 8.
  • a feed opening 9 is provided, through which a liquid sample, preferably, for example, a body fluid such as blood, can be entered into the feed channel 6.
  • a sample liquid can be metered by an operator manually (with a pipette) into a feed opening 9.
  • the feed channel can also be equipped with a liquid by means of a dosing station of an analytical device.
  • the channel structure 2 further comprises a vent channel 10 with a vent opening 11 and two reagent chambers 13, which are connected to each other via three connecting channels 14 so that a fluid exchange between the two reagent chambers 13 takes place.
  • the channel structure 2 is in a preferred embodiment according to FIG. 1 formed as analysis function channel 15, which comprises a measuring chamber 16, a measuring channel 17 between the measuring chamber 16 and the reagent chambers 13 and a waste chamber 18, which is connected via a disposal channel 19 with the measuring chamber 16.
  • the measuring chamber 16 is vented via its own venting channel. Trained as a reservoir 20 Waste chamber 18 has a vent passage 21 with an outlet valve at the end, can escape through the air from the channel structure 2.
  • the channel structure 2 includes a mixing chamber 22, in which the two reagent chambers 13 and the three connecting channels 14 are integrated.
  • the mixing chamber 22 has an inlet opening 23 which is in fluid communication with the feed channel 6, so that a liquid sample can flow into the rotation axis remote reagent chamber 13 a.
  • the rotation axis remote reagent chamber 13a has a greater distance to the rotation axis 4 than the other reagent chamber 13b.
  • the near-axis reagent chamber 13b (closer to the rotation axis 4 than the reagent chamber 13a) is in fluid contact with the vent passage 10 via an air outlet 33, so that air escapes from the reagent chamber assembly and the mixing chamber 22.
  • the direction of rotation and the acceleration can be an optimized solubilization of the reagents in the Reagent chambers 13 take place, which is supported by the rounded reagent chambers 13.
  • FIG. 2a shows a section along the line IIA FIG. 1 through the two reagent chambers 13a, 13b.
  • the reagent chambers 13a, 13b are preferably hemispherical in shape, wherein the open opening surface of the hemispheres 24 is closed by the cover layer.
  • the reagent chambers 13 are rounded at their bottom so that no sharp edges occur. The rounded bottom of the chamber thus ensures a uniform distribution of both the reagent and a uniform solubilization and a uniform flow rate.
  • the transitions to the connecting channels are preferably not rounded but sharp-edged, ie at the upper edge of the hemispheres 24 a sharp edge 25 is formed, wherein the edge 25 preferably includes an angle of 90 °. This creates a kind of geometric valve that provides overflow protection because the edge provides a physical barrier to the further transport of the liquid.
  • the reagents present in liquid form are introduced into the open test carrier 3 without cover layer, for example by pipetting.
  • the sharp edges then serve as boundaries that prevent creeping of the liquid reagents during drying.
  • the structure thus becomes more independent of disturbing effects during automatic processing during drying.
  • An overflow protection 26 adjoins the reagent chambers 13 at the upper edge, which prevents reagents from escaping from the mixing chamber 22.
  • the surface enlargement by the overflow protection 26 can also have an elongating effect on the mixing time during mixing or dissolution of the dry reagents.
  • FIG. 2b shows the section through the channel structure 2 FIG. 2a
  • the reagent chambers 13 and the mixing chamber 22 is here designed so that the depth t of the overflow protection 26 is about one third of the depth T of the mixing channel 22.
  • the Depth t of the overflow protection 26 is about 400 microns.
  • Two-thirds of the depth T of the mixing channel 22 is formed by the reagent chambers 13.
  • the dried reagent 35 covers the bottom and the inner surfaces of the hemispheres 24, wherein the filling height h of the dry reagent 35 at the bottom corresponds approximately to half the height H of the hemisphere 24.
  • the reagent 35 continues to flow up during the drying; However, it is prevented by the physical barrier and the edge 25 from crawling over the web 27 formed between the two chambers 13a, 13b.
  • the web 27 preferably extends between two adjacent reagent chambers 13 in the direction of the cover layer 34 and thus separates the two reagent chambers 13a, 13b of the mixing chamber 22.
  • Figure 2c shows a three-dimensional view in the area of the line IIc FIG. 1 through the connecting channels 14 of the channel structure 2.
  • the feed channel 6 has a backstop 28, which is designed as a microfluidic valve 29.
  • the depth of the feed channel 6 from the surface 30 of the microfluidic element 1 is of the same order of magnitude as the depth of the connecting channels 14. However, it is significantly larger than the depth of the rotation axis remote reagent chamber 13a.
  • the depth of the feed channel 6 is therefore also about 400 microns.
  • a liquid flowing into the overflow protection 26 of the mixing chamber 22 by rotational force from the feed channel 6 flows via the edge 25 into the hemispherical reagent chamber 13a. By rotation of the test carrier 3, the liquid that has flowed in is moved in the reagent chamber 13a and thus dissolves the dry reagent (not shown here).
  • connection channels 14a, 14b and 14c When another liquid flows in, it is also conducted through the connection channels 14a, 14b and 14c into the further reagent chambers 13 (not shown).
  • the transitions into the capillary connection channels 14a, 14b, 14c, which are formed by the hemisphere 24, are preferably not smaller than 0.4 ⁇ 0.4 mm in cross section (or their diameter is not smaller than 0.4 mm) and may later taper gradually.
  • connection channels 14 with a smaller cross section the applied capillary force is so great that an overflow (“crosstalk”), in particular the liquid reagents before drying, is formed.
  • the channel structure 2 with bottomed reagent chambers 13 can also be used in non-rotating test carriers.
  • a fluid driven by an (external) force first flows in a non-rotating microfluidic element 1 into the first reagent chamber 13a, fills it completely and dissolves the contained reagent.
  • the rounded bottom of the chamber not only ensures even distribution of the reagent.
  • the dissolution of the reagent is also optimized. Only the influx of additional (force-driven) liquid allows it to overcome the edge 25, so that it can flow through the connection channels 14 in the adjacent reagent chamber. Consequently, the reagent contained here is first dissolved in a second step.
  • FIG. 3 shows by way of example a further embodiment of a test carrier 3, with five identical channel structures 2.
  • the feed channel 6 also has a U-shaped channel section 7 and a straight channel section 8.
  • the mixing chamber 22 also has a venting channel 10 with a vent 11 at its end close to the axis of rotation.
  • the channel structure 2 is designed as an analysis function channel 15 and comprises a measuring chamber 16.
  • FIG. 4 shows a detailed drawing of the mixing chamber 22 from FIG. 3 with the three series-connected reagent chambers 13a, b, c and in each case two connecting channels 14, namely in each case a central connecting channel 14a and a lateral (near the axis of rotation) connecting channel 14b.
  • the mixing chamber 22 preferably has a rotational axis-near inlet opening 23, through which liquid from the feed channel 6 enters the mixing chamber 22.
  • a capillary transport channel 31 is preferably arranged on the long axis 36 of the mixing chamber 22 remote from the axis of rotation.
  • the transport channel 31 extends laterally and radially outward on the series-arranged reagent chambers 13. Its depth (viewed from the surface 30 of the test carrier 3) is about 150 to 2000 microns less than the depth of the connecting channels.
  • the incoming liquid is passed through the transport channel 31 into the reagent chamber 13a.
  • the venting channel 10 is wider than the feed channel 8 and as the connecting channels 14 between the reagent chambers 13. In this way, a smaller capillary force is generated by the venting channel 10, so that no liquid penetrates into the venting channel 10.
  • the venting channel 10 is always arranged close to the axis of rotation so that the liquid can not pass from the reagent chambers 13 into the venting channel 10 during rotation.
  • the air contained therein escapes through the connection channels 14a and 14b into the next reagent chamber 13c.
  • liquid flows through the two connection channels 14a and 14b into the reagent chamber 13c.
  • the filling of the second reagent chamber 13c thus initially also takes place at least partially through the connection channels 14a, 1-4b and through the transport channel 31.
  • the air contained in the second reagent chamber 13c escapes through the connection capillaries 14a and 14b which form the connection to the rotational axis-nominal reagent chamber 13b. In this way it is ensured that no air is trapped in the reagent chambers 13a, 13b and 13c. From the reagent chamber 13b, the air escapes through the vent passage 110. In this way, a preferred filling of the reagent chambers 13 from radially outside to radially inside is made possible.
  • the arrangement according to the invention allows the liquids to be mixed even when the reagents are being dissolved, in particular when the reagents in the second and further reagent chambers 13 are dissolved.
  • the degree of solubilization is therefore particularly high and effective.
  • the filling of the reagent chambers 13a, b, c of the mixing chamber 22 is based on or FIGS. 5a to 5c explained in more detail.
  • Entering the mixing chamber 22 Liquid is conducted past the capillary-active transport channel 31, which is adjacent to the inlet opening 23, past the two reagent chamber 13b, 13c near the axis of rotation and flows into the reagent chamber 13a remote from the axis of rotation (arrow direction F).
  • the inflowing liquid is held by capillary action in the transport channel 31.
  • the rotational axis near reagent chamber 13b is filled by the liquid first flows through the central and tangential connection channels 14a, b and also through the transport channel 31 and later directly into the chamber 13b.
  • the air contained in the reagent chambers 13 finally escapes through the air outlet 33 and the venting channel 10.
  • the reagent chambers 13 a single volume of 3 ul, so that the three reagent chambers together have a volume of about 9 ul.
  • the volumes of the individual reagent chambers 13 are preferably between 3 ⁇ l and 10 ⁇ l.
  • Reagent chambers with a volume of 2 ⁇ l or only 1 ⁇ l are also conceivable, as well as reagent chambers 13 with a volume of 20 ⁇ l, 50 ⁇ l, 100 ⁇ l or 500 ⁇ l.
  • FIG. 6 shows a further preferred embodiment with a mixing chamber 22, in which two reagent chambers 13a, 13b are integrated.
  • a capillary transport channel 31 is provided through which into the mixing chamber 22 entering liquid is guided to the rotation axis remote reagent chamber 13a, which is the two reagent chambers 13a, 13b the farthest from the axis of rotation reagent chamber.
  • the reagent chambers 13 are preferably arranged adjacent to one another such that their distance is smaller than the smallest dimension of the reagent chambers 13 in the test carrier plane, rapid fluid transport from one chamber 13 to the other is also possible.
  • the smallest distance is defined in the context of the invention as the smallest distance between the reagent chambers 13 and between the Reagenzhuntau touchcardn.
  • At least the centrally located connecting channel 14a between two reagent chambers 13 is therefore shorter than the smallest dimension of the reagent chambers 13.
  • the central connecting channel 14a is about 0.2 mm long. Its width and depth are each 0.4 mm.
  • the reagent chambers, 13 have a height of 1.4 mm.
  • the diameter of the reagent chambers is 1.95 mm.
  • test carrier 3 Due to the modular design with small reagent chambers 13, it is possible to provide test carrier 3, which are based on this principle arbitrarily expandable. So not only two or three, but also several chambers can be connected in series.
  • reagent chambers In addition to the round hemispherical reagent chambers, other forms of the reagent chambers are possible, for example, drop-shaped reagent chamber forms or when using two reagent chambers, which are integrated in a mixing chamber 22 z. B. so-called “yin-yang formations". Preferably, these reagent chambers are rounded at the bottom. Above all, oval and round chamber shapes prove advantageous.
  • FIG. 7 shows a star-shaped arrangement of three reagent chambers 13 in a mixing chamber 22. Also in this arrangement, the rotation axis remote mixing chamber 13a is filled via the transport channel 31 first. If further liquid flows in, then the two reagent chambers 13b, 13c closer to the axis of rotation are filled together. Between the reagent chambers 13a and 13b, only a central connection channel 14a is provided, since the capillary transport channel 31 as a second connection channel see, since the capillary transport channel 31 serves as a second connection channel 14b.
  • FIGS. 8a and 8b Three-dimensional views of such a star-shaped reagent chamber arrangement are shown. Clearly visible are the rounded connection channels 14 between the reagent chambers 13 and the rounded hemispherical reagent chambers 13 themselves. In this embodiment, it can be seen that the transport channel 31 also functions fluidically as a connection channel 14.
  • FIG. 9 shows that even a star-shaped or circular arrangement of reagent chambers 13 can be extended.
  • six reagent chambers 13 can be interconnected fluidically, whereby the principle is maintained that the rotor axis furthest reagent chamber 13a is filled first. A filling of the other chambers then starts from the rotation axis remote chamber 13 a, which is farthest from the axis of rotation 4.
  • the very compact and small arrangement obtained has the advantage that a plurality of cascaded channel structures 2 can be arranged on a test carrier 3.
  • FIGS. 10a to 10c Based on FIGS. 10a to 10c the drying process of two reagents in a microfluidic element 1 is explained at different times, wherein in each figure both a top view and a section is shown.
  • connection channels 14 Starting from two reagent chambers 13, which are separated from each other and in fluid communication with each other via connection channels 14, is the drying of the initially liquid reagents explained.
  • the two reagent chambers 13a, 13b are integrated in a mixing chamber 22. Between the two reagent chambers 13a, 13b, a web 27 is arranged, so that the two chambers 13 are spatially spaced from each other. In the web 27, the connecting channels 14 are embedded.
  • the embodiment shown here has three connection channels 14a, 14b and 14c, wherein the connection channel 14a is a central channel and the two further connection channels 14b and 14c are each arranged laterally.
  • FIG. 10a shows that a liquid reagent is introduced into the hemispherical reagent chambers 13a, 13b.
  • a reagent chamber 13 is used, which is referred to as “pearl” due to their shape. Overall, therefore, a “pearl chain structure" is present in the mixing chamber 22.
  • the reagent is in each case applied to the middle of the reagent chamber 13a, 13b. During the following drying process, the reagent wets the environment of the dosing point, forming a uniform film. Since the reagent chambers are free of edges or corners where the reagent might concentrate, a very even distribution occurs. When the liquid reagent reaches the connection channels 14, it enters it.
  • connection channels 14 due to the flow resistance of the connection channels 14, it is slowed down and does not flow until it has passed into the adjacent reagent chamber 13. If the liquid reagent reaches the upper edge of the reagent chamber 13, which forms the end to the surface of the microfluidic element 1, the reagent stops at the Edge and does not continue to flow. The resulting cross-sectional increase thus has a capillary stop effect.
  • the connecting channels 14 preferably have such a cross section that the liquid in the connecting channels 14 is braked and is not transported into the adjacent reagent chamber 13 due to capillary forces. Consequently, on the one hand, the cross-section must be large enough so that the resulting capillary forces are small enough so that the connection channels are not completely filled with the reagent and the reagents in the connection channels mix. On the other hand, the must Cross-section of the connecting channels should be small enough so that the flow resistance is sufficient to decelerate inflowing reagent in the connecting channels 14.
  • connection channels 14 not only affects the drying process when only capillary forces act.
  • the cross sections also have an influence on the mixing efficiency and the exchange of liquids between two reagent chambers 13.
  • the cross section of the connection channels is at least 0.1 mm 2 , preferably 0.4 x 0.4 mm 2 large. Cross sections of less than 0.05 mm 2 have proved to be unsuitable.
  • the hemispherical or bottom-rounded reagent chambers 13 show that when filled with a liquid reagent with a maximum volume of 70% of the chamber volume, a trouble-free drying of the reagents is possible. A mixing of two reagents in two adjacent chambers 13 is reliably prevented.
  • the volume of the liquid reagent to be applied is preferably less than 60% of the chamber volume, particularly preferably less than 55%.
  • FIG. 10c shows the two reagent chambers 13, after the liquid reagent is spread.
  • the connecting channels 14 are wetted with liquid only at their beginning. The largest distance of the respective connection channels 14 is free of liquid, so that a mixing of the two reagents is reliably prevented.
  • the reagent chambers 13 with a rounded bottom, in particular if they are preferably integrated in a mixing chamber 22, are not only particularly suitable for drying two different reagents, but that such reagent chambers 13 are in non-rotating microfluidic Elements 1 can be used.
  • required force is generated by an external force.
  • pressure forces can be generated, which are caused for example by an external pump.
  • this force can be based on a hydrostatic pressure.
  • the statements made in the context of this invention for rotating test carriers therefore also apply to non-rotating microfluidic elements.
  • the basis of the FIGS. 2 to 9 corresponding features can also be used accordingly in non-rotating arrangements and channel structures.

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  • Health & Medical Sciences (AREA)
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Claims (15)

  1. Élément microfluidique destiné à l'analyse d'un échantillon de liquide, comportant
    un substrat (5) et une structure de canaux (2) entourée par le substrat (5) et une couche de couverture,
    l'élément microfluidique (1) pouvant tourner autour d'un axe de rotation (4) ;
    la structure de canaux (2) incluant un canal d'amenée (6) pourvu d'un orifice d'amenée (9), un canal de dégazage (10) pourvu d'un orifice de dégazage (11) et au moins deux chambres de réactif (13) ;
    les chambres de réactif (13) étant reliées entre elles de manière telle, via deux canaux de liaison (14), qu'un échange de fluide entre les chambres de réactif (13) est possible ;
    l'une des chambres de réactif (13) étant une chambre de réactif (13a) distante de l'axe de rotation et celle des chambres de réactif (13) qui est la plus éloignée de l'axe de rotation ;
    la chambre de réactif (13a) distante de l'axe de rotation contenant un réactif (35) qui réagit avec l'échantillon de liquide ;
    l'une des chambres de réactif (13) présentant un orifice d'admission (23) qui est en communication fluidique avec le canal d'amenée (6), de sorte que, du fait de la rotation de l'élément microfluidique, l'échantillon de liquide introduit dans la structure de canaux (2) est acheminé tout d'abord vers la chambre de réactif (13a) distante de l'axe de rotation, de sorte que cette chambre de réactif (13a) distante de l'axe de rotation est remplie la première et que le réactif déposé dans cette chambre de réactif (13a) distante de l'axe de rotation est dissout.
  2. Élément microfluidique selon la revendication 1, caractérisé en ce que l'élément microfluidique (1) est un support de test (3) traversé par l'axe de rotation (4).
  3. Élément microfluidique selon la revendication 1 ou 2, caractérisé en ce que la structure de canaux (2) est un canal fonctionnel d'analyse (15) qui comprend une chambre de mesure (16).
  4. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que la chambre de réactif (13a) distante de l'axe de rotation comporte l'orifice d'admission (23).
  5. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que la structure de canaux (2) comprend une chambre de mélange (22) qui inclut les chambres de réactif (13) et les canaux de liaison (14) entre les chambres de réactif (13).
  6. Élément microfluidique selon la revendication 5, caractérisé en ce que :
    - la chambre de mélange (22) présente un orifice d'admission (23) proche de l'axe de rotation et
    - est réalisé, dans la chambre de mélange (22), latéralement et radialement extérieurement sur les chambres de réactif (13), un canal de transport capillaire (31) dont la section transversale est inférieure à la section transversale des canaux de liaison (14), de sorte que du liquide traverse le canal de transport (31) de l'orifice d'admission (23) proche de l'axe de rotation vers la chambre de réactif (13a) distante de l'axe de rotation et située vis-à-vis de l'orifice d'admission (23).
  7. Élément microfluidique selon la revendication 5 ou 6, caractérisé en ce que sont réalisés, entre deux chambres de réactif (13) voisines dans la chambre de mélange (22), des éléments traversants (27) qui s'étendent verticalement en direction de la couche de couverture (34) et qui séparent les chambres de réactif (13) dans la chambre de mélange (22).
  8. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que les chambres de réactif (13) sont agencées de manière telle en rangée en direction radiale que la rangée des chambres de réactif (13) forme un angle de 80° au maximum par rapport à la direction radiale.
  9. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que les chambres de réactif (13) sont de forme sensiblement semi-sphérique, la surface d'ouverture de la demi-sphère (24) étant fermée par la couche de couverture (34) de l'élément microfluidique (1).
  10. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que la chambre de réactif (13) voisine de l'axe de rotation (4) présente l'orifice d'admission (23) et possède une admission d'air (33) qui relie la chambre de réactif (13) à un canal de dégazage (10).
  11. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que l'un canal de liaison (14a) est agencé de manière telle, entre deux chambres de réactif voisines (13), qu'il est en alignement avec les centres des deux chambres de réactif (13).
  12. Élément microfluidique selon la revendication 11, caractérisé en ce que le deuxième canal de liaison (14b) est relié latéralement aux deux chambres de réactif (13) de manière telle qu'il passe en dehors d'un axe central qui relie les centres de deux chambres de réactif voisines (13).
  13. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que deux chambres de réactif voisines (13) sont agencées de manière telle que la distance entre elles est inférieure à la plus petite dimension des chambres de réactif (13) dans le plan du support de test.
  14. Élément microfluidique selon l'une des revendications précédentes,
    caractérisé en ce que les chambres de réactif (13) sont réalisées de manière telle qu'un remplissage avec un liquide et la dissolution d'un réactif (35) contenu dans la chambre de réactif (13) s'effectuent sans que du liquide passe dans la chambre de réactif voisine (13).
  15. Élément microfluidique selon l'une des revendications précédentes, caractérisé en ce que le canal de liaison (14) présente une section transversale telle que la plus petite dimension de la section transversale est d'au moins 150 µm.
EP10782320.5A 2009-12-04 2010-11-30 Elément micro-fluidique destiné à l'analyse d'un échantillon de liquide Active EP2506959B1 (fr)

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EP10782320.5A EP2506959B1 (fr) 2009-12-04 2010-11-30 Elément micro-fluidique destiné à l'analyse d'un échantillon de liquide

Applications Claiming Priority (3)

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EP09015031A EP2329877A1 (fr) 2009-12-04 2009-12-04 Elément micro-fluidique destiné à l'analyse d'un échantillon de liquide
PCT/EP2010/068499 WO2011067241A1 (fr) 2009-12-04 2010-11-30 Élément microfluidique pour l'analyse d'un échantillon liquide
EP10782320.5A EP2506959B1 (fr) 2009-12-04 2010-11-30 Elément micro-fluidique destiné à l'analyse d'un échantillon de liquide

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WO2013172003A1 (fr) * 2012-05-16 2013-11-21 パナソニック株式会社 Puce de détection d'organismes et dispositif de détection d'organismes équipé de celle-ci
WO2014100150A1 (fr) * 2012-12-20 2014-06-26 Flir Detection, Inc. Dispositif et procédés pour la détection d'analytes comprenant l'utilisation d'un code à barres colorimétrique
JP6349721B2 (ja) * 2013-12-24 2018-07-04 凸版印刷株式会社 試料分析チップ
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WO2015185763A1 (fr) 2014-06-06 2015-12-10 Roche Diagnostics Gmbh Cartouche rotative avec chambre de dosage pour analyse d'un échantillon biologique
EP2952257A1 (fr) 2014-06-06 2015-12-09 Roche Diagnostics GmbH Cartouche rotative pour le traitement et l'analyse d'un échantillon biologique
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WO2017091213A1 (fr) * 2015-11-24 2017-06-01 Hewlett-Packard Development Company, L.P. Dispositifs ayant un élément de distribution d'échantillon
EP3173149A1 (fr) 2015-11-26 2017-05-31 Roche Diagnostics GmbH Détermination d'une quantité d'un analyte dans un échantillon de sang
EP4023338B1 (fr) 2016-04-14 2024-10-02 Roche Diagnostics GmbH Cartouche et mesure optique d'un analyte avec ladite cartouche
CN107305210B (zh) * 2016-04-20 2019-09-17 光宝电子(广州)有限公司 生物检测卡匣及其检测流体的流动方法
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EP2329877A1 (fr) 2011-06-08
EP2506959A1 (fr) 2012-10-10
US20120301371A1 (en) 2012-11-29
US8911684B2 (en) 2014-12-16

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