EP2821138B2 - Flow cell with integrated dry substance - Google Patents

Flow cell with integrated dry substance Download PDF

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Publication number
EP2821138B2
EP2821138B2 EP13175335.2A EP13175335A EP2821138B2 EP 2821138 B2 EP2821138 B2 EP 2821138B2 EP 13175335 A EP13175335 A EP 13175335A EP 2821138 B2 EP2821138 B2 EP 2821138B2
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EP
European Patent Office
Prior art keywords
flow cell
cavity
support element
passage
cell according
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EP13175335.2A
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German (de)
French (fr)
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EP2821138B8 (en
EP2821138B1 (en
EP2821138A1 (en
Inventor
Lutz Weber
Tina Röser
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Thinxxs Microtechnology GmbH
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Thinxxs Microtechnology GmbH
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Priority to EP13175335.2A priority Critical patent/EP2821138B2/en
Priority to DK13175335.2T priority patent/DK2821138T4/en
Priority to ES13175335T priority patent/ES2704424T5/en
Application filed by Thinxxs Microtechnology GmbH filed Critical Thinxxs Microtechnology GmbH
Priority to PCT/EP2014/064290 priority patent/WO2015001070A1/en
Priority to US14/902,787 priority patent/US10232367B2/en
Priority to CN201480046983.0A priority patent/CN105517710B/en
Publication of EP2821138A1 publication Critical patent/EP2821138A1/en
Publication of EP2821138B1 publication Critical patent/EP2821138B1/en
Priority to US16/265,127 priority patent/US10946376B2/en
Publication of EP2821138B8 publication Critical patent/EP2821138B8/en
Publication of EP2821138B2 publication Critical patent/EP2821138B2/en
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    • 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
    • B01L3/502707—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 manufacture of the container or its components
    • 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
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • 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
    • B01L2200/04—Exchange or ejection of cartridges, containers or reservoirs
    • 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
    • B01L2200/0689—Sealing
    • 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
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • 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
    • B01L2200/12—Specific details about manufacturing devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/044—Connecting closures to device or container pierceable, e.g. films, membranes
    • 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
    • B01L2300/0877—Flow chambers
    • 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
    • B01L2300/12—Specific details about materials
    • B01L2300/123—Flexible; Elastomeric
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B01L2300/163—Biocompatibility

Definitions

  • the invention relates to a flow cell with a dry substance arranged in a cavity within the flow cell, the flow cell having the features of claim 1 .
  • Microfluidic flow cells as they are increasingly used as a "mini laboratory" for the analysis and/or synthesis of fluids, particularly in diagnostics, contain reaction substances in liquid and/or solid form that are to be introduced into the flow cells during the production of the flow cells.
  • a reagent liquid to be dried ie a carrier liquid with a dissolved or suspended reagent.
  • the entire component of the flow cell that is only partially wetted with the reagent liquid must be subjected to a drying process before further assembly, which is often combined with a heat treatment for the purpose of acceleration or is carried out as a freeze-drying process to protect the reagents and with regard to stability and resuspension properties.
  • the disadvantage is that the component, whose dimensions usually far exceed those of the area that is only to be dried, occupies a lot of space in a drying chamber. Furthermore, the drying treatment can affect this component of the flow cell itself, particularly sensitive components mounted thereon. Above all, the dry substance formed can then be subject to impairments due to air contact, in particular humidity, and welding heat or the influence of adhesives used during assembly in the course of final assembly of the flow cell, through which the corresponding channel areas of a microfluidic flow cell must be hermetically sealed in many cases.
  • a method for introducing a dry substance into a flow cell, as described above, is z. B. from the EP 2 198 964 B1 out.
  • One from the WO 2012/154306 A1 known flow cell has a cavity that is accessible after opening a hatch or flap and has a recess in a floor for receiving a cuboid support element. The hatch or flap must be closed when the flow cell is in operation.
  • a flow cell with the features of the preamble of claim 1 is in each case from WO 2011/051735 A2 and WO 2008/134462 A1 out.
  • the object of the invention is to create a new microfluidic flow cell of the type mentioned at the outset with an integrated dry substance that can be produced more easily than in the prior art without adversely affecting the dry substance or other components of the flow cell due to the production environment.
  • the dry substance can be formed by drying a reagent liquid separately from the rest of the flow cell on a carrier element, which is used solely to hold the dry substance and allows the dry substance to be introduced into the flow cell in a final assembly step. Impairment of flow cell components by the drying process and impairment of the dry reagent introduced by further assembly work on the flow cell are eliminated.
  • the carrier element can have significantly smaller dimensions than the flow cell, with the dimensions of the carrier element being based on the size of the area carrying the dry reagent. Coatings that promote adhesion of the dry substance to its carrier surface can advantageously remain limited to the carrier surface of the carrier element, so that impairments of welded or adhesive connections by such coatings can be ruled out.
  • the cavity can form a channel network for the transport, analysis and/or synthesis of a fluid.
  • carrier elements possibly with different dry substances, can be used in the flow cell.
  • the cavity is delimited by a recess in a plate-shaped substrate and a foil-like cover closing the recess.
  • the passage is formed in the substrate, which is thicker than the film-like cover.
  • the carrier element is preferably designed in such a way that it can be detachably and/or non-detachably connected to the flow cell while closing the cavity.
  • the shape of the passage is preferably adapted to the shape of the carrier element. Fluid-tightness can be achieved in particular by welding and/or gluing, possibly also just by mechanically pressing the carrier element into the passage.
  • the support element expediently fills the passage completely, at least in cross section, with the support element and the passage preferably having a circular shape in cross section, which is advantageous in terms of production technology.
  • the carrier element tapers towards the cavity, while the passage narrows.
  • a tight closure of the cavity in the form of a press fit can be achieved simply by mechanically pressing the carrier element into the passage.
  • the carrier element preferably has a section which protrudes outwards from the flow cell and which can serve as a grip part to simplify manual handling or automated assembly.
  • the protruding section can overlap the flow cell on the outside in the manner of a collar, with the collar being able to achieve an additional sealing of the cavity.
  • the carrier element can be screwed into the passage.
  • the support surface of the support member may be flush with or set back from an adjacent wall surface of the cavity. Alternatively, the support member protrudes into the cavity from the adjacent wall surface.
  • the carrier surface expediently has a structuring, coating and/or surface modification that promotes adhesion of the dry substance.
  • the carrier element and the carrier surface carrying the dry reagent are preferably made of plastic.
  • the carrier surface can be formed by a separate surface component made of glass, silicon, ceramic or metal that is connected to the rest of the carrier element and can be applied by means of welding or gluing. This is advantageous if surface properties other than those that can be realized by a plastic surface or coating are necessary for the application of the dry reagent.
  • Dry reagents include salts, buffers, e.g. for cell lysis, magnetic and non-magnetic beads, enzymes, antibodies, DNA fragments, proteins, PCR reagents or alternatively cells.
  • the flow cell shown as a detail comprises a plate-shaped substrate 1 with a recess 2 which is covered by a film 4 bonded and/or welded to the substrate, forming a cavity 3 .
  • the cavity 3 is part of an in 1 Otherwise not shown channel network of the flow cell, in particular it forms a channel area in which a dry reagent 5 containing antibodies, for example, adheres to a channel wall 6 .
  • the dry reagent 5 originates from a reagent liquid 7 introduced by dispensing before the recess 2 is covered by the film 4 into the recess 2 forming a channel or chamber region of the flow cell.
  • a heat treatment or /and subjected to freeze drying was subjected to a heat treatment or /and subjected to freeze drying.
  • Out 2 discloses a method for introducing a dry substance, in particular a dry reagent 5, into a flow cell, in which the dry reagent 5 is applied to a separate carrier part 8.
  • a cavity 3 in a flow cell which is, for example, an area of an in 3 Channel 9 shown can act, has a through-opening 10 into which the carrier element 8 with a conical section 11 having a carrier surface 13 for the dry reagent 5 can be inserted with fluid-tight closure of the cavity 3 .
  • the carrier surface 13 forms part of the wall surface of the cavity 3.
  • a fluid transported or processed in the cavity 3 can thus interact with the dry reagent; in particular, the dry reagent can be dissolved and resuspended by the fluid.
  • components of the fluid such as cells or analytes can interact with the dry reagent and/or bind to it, in that the fluid flows over the carrier surface, possibly several times changing the direction of transport.
  • the carrier element 8 fitted into the through-opening 10 can be glued or welded to the substrate.
  • a section 12 of the carrier element that protrudes beyond the through-opening 10 on the side of the substrate 1 facing away from the cavity 3 8 serves as the mounting of the carrier element 8 facilitating handle part.
  • the meandering channel 9 serves to redissolve the dry reagents 5 introduced by the carrier elements 8 by flushing them alternately.
  • the substrate 1 and the film 4 of the flow cell are preferably made of a plastic, in particular both of the same plastic, with PMMA, PC, PS, PEEK, PP, PE, COC and COP, for example, being suitable for this purpose.
  • the carrier element 8 is also preferably a plastic part, which in particular consists of the same plastic as the substrate. The production of the substrate and the carrier elements from plastic is expediently carried out by injection molding.
  • the carrier surface 13 of the carrier element 8 accommodating the dry reagent 5 can be flush with the adjacent wall surface 14 of the cavity 3 or set back to this wall surface.
  • the carrier element 8 can also protrude with the carrier surface 13 into the cavity 3 .
  • This can be advantageous in order to generate turbulence locally in a laminar flow that is normally present in microchannels by abruptly changing the channel cross section and/or in order to increase the flow rate of the fluid in the channel area into which the carrier element 8 is introduced by reducing the channel cross section achieve, for example, to accelerate and control a redissolution of the dry reagent.
  • assembly and/or component tolerances can be compensated for.
  • figure 5 shows further embodiments for carrier elements 8 according to Figure 5a cylindrical and according Figure 5b can be cylindrical with a collar 15 engaging behind the substrate 1 .
  • Figure 5c shows an embodiment of a cylindrical support element 8 having a collar 13 and having an external thread 16 which engages in an internal thread in the passage opening in question.
  • the carrier element 8 can advantageously be detached from the flow cell, provided that there is no adhesive bonding or welding to the substrate 1 in addition to the screw connection.
  • the solubility can be advantageous if the dry reagent is to be separated from the flow cell again after interaction with the fluid and subjected to further analysis.
  • a carrier element 8 which can be detached from the flow cell and has an extended handle part 17 is shown Figure 5e .
  • the carrier element 8 can be pressed into the relevant through-opening in the substrate 1 while sealing the cavity 3 fluid-tight.
  • the guidance of the carrier element 8 can be improved.
  • Figure 5d shows a carrier element 8 with a conical section and a collar 15 protruding from a through-opening, which is sealed against the substrate 1 by an annular seal 18 .
  • the rotationally symmetrical carrier elements can have a marking that makes it possible to insert the carrier elements into the passage in a desired rotational position.
  • Figure 6a has a carrier element with a depression 19 for receiving a dry reagent 5 .
  • a carrier surface 13 is formed with a multiplicity of receiving depressions in the form of grooves 20 arranged crosswise with typical cross-sectional dimensions of 0.01 ⁇ 0.01 mm 2 to 1 ⁇ 1 mm 2 for a dry reagent.
  • the surface of the carrier surface 13 can be enlarged in a simple manner, so that either a larger quantity of dry reagent 5 can be accommodated with the same dimensions of the carrier element 8 and/or the dry substance can dry more homogeneously than a large drop on a smooth carrier surface and/or or the microstructure of the support surface 13 formed by the receiving depressions 20 can generate turbulence when the fluid flows over it, which positively influence the release behavior.
  • the grooves could be in the form of concentric circles.
  • Figure 6c shows a receiving surface with a porous element 21 applied to the support surface by clamping, gluing or welding, in which a dry substance can settle.
  • the porous element 21 advantageously forms an enlarged surface for receiving the dry reagent 5.
  • Figure 6d has a carrier element with a treated carrier surface, wherein the treatment can be, for example, a wet-chemical treatment, a plasma treatment or a corona treatment.
  • the treatment can be carried out, for example, by means of plasma polymerisation or lead to a coating 22 by means of a PVD process, for example a glass or metal coating.
  • the carrier component shown is formed in two parts with a separate surface component 26 .
  • the surface component 26 forming the support surface does not consist, for example, of a plastic, as is preferred for the rest of the support component, but of glass, silicon, metal or ceramic. If the functionalization, ie the application of the dry reagent to the carrier surface, requires such materials, as is the case with protein (e.g. antibodies) or nucleic acid-based analysis technologies, the use of these materials, which are often significantly more expensive than plastic, is limited. advantageously only on a surface area, with dimensions of 0.5 ⁇ 0.5 mm to 5 ⁇ 5 mm and thicknesses between 0.1 and 1 mm being considered.
  • the surface component 26 can be attached to the rest of the support component by means of clamps or by gluing or welding.
  • a large number of carrier elements 8 can be processed simultaneously by the carrier elements 8 being arranged in step 7a on a carrier tablet 24 having rows of holes 23.
  • a layer 22 that improves the adhesion of a substance is produced simultaneously on all carrier surfaces 13 of the carrier elements 8 .
  • the coating can also cover other surface areas of the carrier element 8 that are not intended for application of the dry reagent 5 .
  • a drying treatment takes place, so that the dry substance 5 adhering thereto is deposited on the layers 22.
  • step 7e the finished carrier elements 8 provided with a dry substance 5 can be removed for processing.
  • the carrier element 8 has a carrier surface for a dry substance 5 which is formed by a membrane 27 .
  • This membrane can be connected in one piece to the rest of the carrier element 8 or formed by a separate component connected to the rest of the carrier element, which preferably consists of the same plastic as the rest of the carrier element.
  • the membrane 27 is transparent, which closes off a through opening 28 formed in the carrier element 8 at one end, there is the possibility of optical detection of the interaction of the fluid with the dry substance 5 in accordance with Figure 8b to control. Furthermore, according to Figure 8c the possibility of forming the membrane 27 convex or concave by pneumatic or mechanical pressurization.
  • the interaction between the dry substance and the fluid can be stimulated in particular by alternating bulging and inward arching of the membrane 27 and both improved resuspension of dry substances and improved accumulation of components of the fluid on dry substances, eg in the case of antibodies, can be achieved.

Description

Die betreffenden Abschnitte der Beschreibung ändern sich wie folgt:The relevant sections of the description will change as follows:

Die Erfindung betrifft eine Flusszelle, mit einer innerhalb der Flusszelle in einem Hohlraum angeordneten Trockensubstanz, wobei die Flusszelle die Merkmale des Anspruchs 1 aufweist.The invention relates to a flow cell with a dry substance arranged in a cavity within the flow cell, the flow cell having the features of claim 1 .

Mikrofluidische Flusszellen, wie sie zunehmend als "Minilabor" zurAnalyse oder/und Synthese von Fluiden insbesondere in der Diagnostik zum Einsatz kommen, enthalten Reaktionssubstanzen in flüssiger oder/und fester Form, die während der Herstellung der Flusszellen in die Flusszellen einzubringen sind.
Zur Einbringung einer Trockenreagenz wird in einem Montageschritt, in welchem der für die Aufnahme der Trockenreagenz innerhalb der Flusszelle vorgesehene Bereich, z.B. eines Kanals oder einer Kammer, noch zugänglich ist, an die betreffende Stelle eine zu trocknende Reagenzflüssigkeit gebracht, d.h. eine Trägerflüssigkeit mit darin gelöster oder suspendierter Reagenz. Danach ist das gesamte, mit der Reagenzflüssigkeit nur stellenweise benetzte Bauteil der Flusszelle vor deren weiterer Montage einem Trocknungsprozess zu unterziehen, der zwecks Beschleunigung oftmals mit einer Wärmebehandlung verbunden ist oder zur Schonung der Reagenzien sowie im Hinblick auf Stabilität und Resuspendierungseigenschaften als Gefriertrocknungsprozess erfolgt. Nachteilig belegt das Bauteil, dessen Abmessungen diejenigen des nur zu trocknenden Bereichs zumeist weit überschreiten, in einer Trocknungskammer viel Raum. Ferner kann die Trocknungsbehandlung dieses Bauteil der Flusszelle selbst beeinträchtigen, insbesondere daran montierte empfindliche Komponenten. Vor allem kann die gebildete Trockensubstanz dann im Zuge der Fertigmontage der Flusszelle Beeinträchtigungen durch Luftkontakt, insbesondere Luftfeuchtigkeit, und Schweißwärme oder dem Einfluss bei der Montage verwendeter Klebemittel unterliegen, durch die entsprechende Kanalbereiche einer mikrofluidischen Flusszelle in vielen Fällen hermetisch zu verschließen sind. Ein Verfahren zum Einbringen einer Trockensubstanz in eine Flusszelle, wie es vorangehend beschrieben ist, geht z. B. aus der EP 2 198 964 B1 hervor.Microfluidic flow cells, as they are increasingly used as a "mini laboratory" for the analysis and/or synthesis of fluids, particularly in diagnostics, contain reaction substances in liquid and/or solid form that are to be introduced into the flow cells during the production of the flow cells.
To introduce a dry reagent, a reagent liquid to be dried, ie a carrier liquid with a dissolved or suspended reagent. After that, the entire component of the flow cell that is only partially wetted with the reagent liquid must be subjected to a drying process before further assembly, which is often combined with a heat treatment for the purpose of acceleration or is carried out as a freeze-drying process to protect the reagents and with regard to stability and resuspension properties. The disadvantage is that the component, whose dimensions usually far exceed those of the area that is only to be dried, occupies a lot of space in a drying chamber. Furthermore, the drying treatment can affect this component of the flow cell itself, particularly sensitive components mounted thereon. Above all, the dry substance formed can then be subject to impairments due to air contact, in particular humidity, and welding heat or the influence of adhesives used during assembly in the course of final assembly of the flow cell, through which the corresponding channel areas of a microfluidic flow cell must be hermetically sealed in many cases. A method for introducing a dry substance into a flow cell, as described above, is z. B. from the EP 2 198 964 B1 out.

Aus der DE 10 2008 021 364 A1 geht eine Flusszelle hervor, bei der Ausnehmungen in einem Substrat durch eine Folienabdeckung verschlossen sind. Die Folienabdeckung trägt auf der Innenseite Trockenreagenzien, die den durch die abgedeckten Ausnehmungen gebildeten Hohlräumen zugewandt sind.From the DE 10 2008 021 364 A1 discloses a flow cell in which recesses in a substrate are closed by a film cover. The film cover carries dry reagents on the inside, which face the cavities formed by the covered recesses.

Eine aus der WO 2012/154306 A1 bekannte Flusszelle weist einen Hohlraum auf, der nach Öffnung einer Luke oder Klappe zugänglich ist und in einem Boden eine Vertiefung für die Aufnahme eines quaderförmigen Trägerelements aufweist. Im Betrieb der Flusszelle ist die Luke bzw. Klappe zu verschließen. Eine Flusszelle mit den Merkmalen des Oberbegriffs des Anspruchs 1 geht jeweils aus der WO 2011/051735 A2 und WO 2008/134462 A1 hervor.One from the WO 2012/154306 A1 known flow cell has a cavity that is accessible after opening a hatch or flap and has a recess in a floor for receiving a cuboid support element. The hatch or flap must be closed when the flow cell is in operation. A flow cell with the features of the preamble of claim 1 is in each case from WO 2011/051735 A2 and WO 2008/134462 A1 out.

Der Erfindung liegt die Aufgabe zugrunde, eine neue mikrofluidische Flusszelle der eingangs genannten Art mit einer integrierten Trockensubstanz zu schaffen, die sich leichter als nach dem Stand der Technik ohne Beeinträchtigungen der Trockensubstanz oder anderer Bestandteile der Flusszelle durch die Fertigungsumgebung herstellen lässt.The object of the invention is to create a new microfluidic flow cell of the type mentioned at the outset with an integrated dry substance that can be produced more easily than in the prior art without adversely affecting the dry substance or other components of the flow cell due to the production environment.

Diese Aufgabe wird mit den Merkmalen des Anspruchs 1 gelöst.This object is achieved with the features of claim 1.

Vorteilhaft kann die Bildung der Trockensubstanz durch Trocknung einer Reagenzflüssigkeit getrennt von der gesamten übrigen Flusszelle an einem Trägerelement erfolgen, das allein der Aufnahme der Trockensubstanz dient und die Einbringung der Trockensubstanz in die Flusszelle in einem abschließenden Montageschritt erlaubt. Beeinträchtigungen von Bauteilen der Flusszelle durch den Trocknungsprozess sowie Beeinträchtigungen der eingebrachten Trockenreagenz durch weitere Montagearbeiten an der Flusszelle entfallen. Das Trägerelement kann wesentlich kleinere Abmessungen als die Flusszelle aufweisen, wobei sich die Abmessungen des Trägerelements an der Größe des die Trockenreagenz tragenden Bereichs orientieren. Die Anhaftung der Trockensubstanz an ihrer Trägerfläche fördernde Beschichtungen können vorteilhaft auf die Trägerfläche des Trägerelements beschränkt bleiben, sodass Beeinträchtigungen von Schweiß- oder Klebeverbindungen durch solche Beschichtungen auszuschließen sind.Advantageously, the dry substance can be formed by drying a reagent liquid separately from the rest of the flow cell on a carrier element, which is used solely to hold the dry substance and allows the dry substance to be introduced into the flow cell in a final assembly step. Impairment of flow cell components by the drying process and impairment of the dry reagent introduced by further assembly work on the flow cell are eliminated. The carrier element can have significantly smaller dimensions than the flow cell, with the dimensions of the carrier element being based on the size of the area carrying the dry reagent. Coatings that promote adhesion of the dry substance to its carrier surface can advantageously remain limited to the carrier surface of the carrier element, so that impairments of welded or adhesive connections by such coatings can be ruled out.

Es versteht sich, dass der Hohlraum ein Kanalnetzwerk zum Transport, zur Analyse oder/und Synthese eines Fluids bilden kann. In die Flusszelle können mehrere Trägerelemente, ggf. mit unterschiedlichen Trockensubstanzen, einsetzbar sein.It goes without saying that the cavity can form a channel network for the transport, analysis and/or synthesis of a fluid. Several carrier elements, possibly with different dry substances, can be used in the flow cell.

In einer Ausführungsform der Erfindung ist der Hohlraum durch eine Ausnehmung in einem plattenförmigen Substrat und eine die Ausnehmung verschließende, folienartig ausgebildete Abdeckung begrenzt. Der Durchgang ist in dem im Vergleich zur folienartigen Abdeckung dickeren Substrat gebildet.In one embodiment of the invention, the cavity is delimited by a recess in a plate-shaped substrate and a foil-like cover closing the recess. The passage is formed in the substrate, which is thicker than the film-like cover.

Es versteht sich, dass der Durchgang zweckmäßig zu einer Außenfläche der Flusszelle geführt ist, sodass die Einbringung der Trockensubstanz in die Flusszelle bei deren Herstellung in einem letzten Montageschritt erfolgen kann.It goes without saying that the passage is expediently led to an outer surface of the flow cell, so that the dry substance can be introduced into the flow cell during its production in a final assembly step.

Das Trägerelement ist vorzugsweise so gestaltet, dass es sich unter Verschluss des Hohlraums mit der Flusszelle lösbar und/oder unlösbar verbinden lässt. Vorzugsweise ist der Durchgang in seiner Form an die Form des Trägerelements angepasst. Fluiddichtheit kann insbesondere durch Einschweißen oder/und Einkleben erreicht werden, ggf. auch nur durch mechanisches Eindrücken des Trägerelements in den Durchgang.The carrier element is preferably designed in such a way that it can be detachably and/or non-detachably connected to the flow cell while closing the cavity. The shape of the passage is preferably adapted to the shape of the carrier element. Fluid-tightness can be achieved in particular by welding and/or gluing, possibly also just by mechanically pressing the carrier element into the passage.

Entsprechend füllt zweckmäßig das Trägerelement den Durchgang zumindest im Querschnitt vollständig aus, wobei das Trägerelement und der Durchgang im Querschnitt vorzugsweise eine fertigungstechnisch vorteilhafte Kreisform aufweisen.Accordingly, the support element expediently fills the passage completely, at least in cross section, with the support element and the passage preferably having a circular shape in cross section, which is advantageous in terms of production technology.

In weiterer Ausgestaltung der Erfindung verjüngt sich das Trägerelement zu dem Hohlraum hin, während sich der Durchgang verengt. Insbesondere kann so allein durch mechanisches Eindrücken des Trägerelements in den Durchgang ein dichter Verschluss des Hohlraums in Form einer Presspassung erreicht werden.In a further embodiment of the invention, the carrier element tapers towards the cavity, while the passage narrows. In particular, a tight closure of the cavity in the form of a press fit can be achieved simply by mechanically pressing the carrier element into the passage.

Vorzugsweise weist das Trägerelement einen von der Flusszelle nach außen vorstehenden Abschnitt auf, der als Griffteil zur Vereinfachung einer manuellen Handhabung oder automatisierten Montage dienen kann.The carrier element preferably has a section which protrudes outwards from the flow cell and which can serve as a grip part to simplify manual handling or automated assembly.

Der vorstehende Abschnitt kann die Flusszelle in der Art eines Kragens außenseitig übergreifen, wobei durch den Kragen eine zusätzliche Abdichtung des Hohlraums erreicht werden kann.The protruding section can overlap the flow cell on the outside in the manner of a collar, with the collar being able to achieve an additional sealing of the cavity.

In einer weiteren Ausführungsform ist das Trägerelement in den Durchgang einschraubbar.In a further embodiment, the carrier element can be screwed into the passage.

Die Trägerfläche des Trägerelements kann bündig oder zurückversetzt zu einer angrenzenden Wandoberfläche des Hohlraums angeordnet sein. Alternativ steht das Trägerelement von der angrenzenden Wandoberfläche in den Hohlraum hinein vor.The support surface of the support member may be flush with or set back from an adjacent wall surface of the cavity. Alternatively, the support member protrudes into the cavity from the adjacent wall surface.

Zweckmäßig weist die Trägerfläche eine die Anhaftung der Trockensubstanz fördernde Strukturierung, Beschichtung oder/und Oberflächenmodifizierung auf.The carrier surface expediently has a structuring, coating and/or surface modification that promotes adhesion of the dry substance.

Das Trägerelement und die die Trockenreagenz tragende Trägerfläche besteht bevorzugt aus Kunststoff. Alternativ kann die Trägerfläche durch ein separates, mit dem übrigen Trägerelement verbundenes Oberflächenbauteil aus Glas, Silizium, Keramik oder Metall gebildet sein und mittels Schweißen oder Kleben aufgebracht werden. Dies ist vorteilhaft, wenn andere als durch eine Kunststoffoberfläche oder Beschichtung realisierbare Oberflächeneigenschaften für das Aufbringen der Trockenreagenz notwendig sind.The carrier element and the carrier surface carrying the dry reagent are preferably made of plastic. Alternatively, the carrier surface can be formed by a separate surface component made of glass, silicon, ceramic or metal that is connected to the rest of the carrier element and can be applied by means of welding or gluing. This is advantageous if surface properties other than those that can be realized by a plastic surface or coating are necessary for the application of the dry reagent.

Als Trockenreagenzien kommen unter anderem Salze, Puffer z.B. für die Zelllyse, magnetische und nicht magnetische Beads, Enzyme, Antikörper, DNA-Fragmente, Proteine, PCR-Reagenzien oder alternativ auch Zellen in Betracht.Dry reagents include salts, buffers, e.g. for cell lysis, magnetic and non-magnetic beads, enzymes, antibodies, DNA fragments, proteins, PCR reagents or alternatively cells.

Die Erfindung wird nachfolgend anhand von Ausführungsbeispielen und der beiliegenden, sich auf diese Ausführungsbeispiele beziehenden Zeichnungen weiter erläutert. Es zeigen:

Fig. 1
eine die Herstellung von Flusszellen mit integrierter Trockensubstanz nach dem Stand der Technik erläuternde Darstellung,
Fig. 2
eine die Herstellung einer Flusszelle erläuternde Darstellung,
Fig. 3
eine Detaildarstellung der in Fig. 2 gezeigten Flusszelle,
Fig. 4
Ausführungsbeispiele für die Anordnung einer Trägerfläche eines Träger-elements innerhalb eines Hohlraums einer Flusszelle,
Fig. 5
weitere Ausführungsbeispiele für Trägerelemente,
Fig. 6
Ausführungsbeispiele für Trägeroberflächen von Trägerelementen,
Fig. 7
eine die Aufbringung einer Trockensubstanz auf Trägerelemente erläuternde Darstellung, und
Fig. 8
ein Ausführungsbeispiel für ein erfindungsgemäßes Trägerelement.
The invention is explained in more detail below on the basis of exemplary embodiments and the accompanying drawings relating to these exemplary embodiments. Show it:
1
a representation explaining the production of flow cells with integrated dry substance according to the prior art,
2
a representation explaining the production of a flow cell,
3
a detailed representation of the 2 shown flow cell,
4
Exemplary embodiments for the arrangement of a carrier surface of a carrier element within a cavity of a flow cell,
figure 5
further exemplary embodiments for carrier elements,
6
Examples of carrier surfaces of carrier elements,
7
a representation explaining the application of a dry substance to carrier elements, and
8
an embodiment of a carrier element according to the invention.

Eine in Fig. 1 ausschnittsweise gezeigte Flusszelle umfasst ein plattenförmiges Substrat 1 mit einer Ausnehmung 2, die unter Bildung eines Hohlraums 3 durch eine mit dem Substrat verklebte oder/und verschweißte Folie 4 abgedeckt ist. Der Hohlraum 3 ist Teil eines in Fig. 1 im Übrigen nicht dargestellten Kanalnetzwerks der Flusszelle, insbesondere bildet er einen Kanalbereich, in dem eine z.B. Antikörper aufweisende Trockenreagenz 5 an einer Kanalwand 6 anhaftet.one inside 1 The flow cell shown as a detail comprises a plate-shaped substrate 1 with a recess 2 which is covered by a film 4 bonded and/or welded to the substrate, forming a cavity 3 . The cavity 3 is part of an in 1 Otherwise not shown channel network of the flow cell, in particular it forms a channel area in which a dry reagent 5 containing antibodies, for example, adheres to a channel wall 6 .

Die Trockenreagenz 5 entstammt einer vor der Abdeckung der Ausnehmung 2 durch die Folie 4 in die einen Kanal- oder Kammerbereich der Flusszelle bildende Ausnehmung 2 durch Dispensierung eingebrachten Reagenzflüssigkeit 7. Zur Bildung der Trockenreagenz 5 aus der Reagenzflüssigkeit 7 wurde das gesamte Substrat 1 einer Wärmebehandlung oder/und Gefriertrocknung unterzogen.The dry reagent 5 originates from a reagent liquid 7 introduced by dispensing before the recess 2 is covered by the film 4 into the recess 2 forming a channel or chamber region of the flow cell. To form the dry reagent 5 from the reagent liquid 7, the entire substrate 1 was subjected to a heat treatment or /and subjected to freeze drying.

Aus Fig. 2 geht ein Verfahren zur Einbringung einer Trockensubstanz, insbesondere einer Trockenreagenz 5, in eine Flusszelle hervor, bei welchem die Trockenreagenz 5 auf ein separates Trägerteil 8 aufgebracht wird. Ein Hohlraum 3 in einer Flusszelle, bei dem es sich z.B. um einen Bereich eines in Fig. 3 gezeigten Kanals 9 handeln kann, weist eine Durchgangsöffnung 10 auf, in welche das Trägerelement 8 mit einem konischen, eine Trägerfläche 13 für die Trockenreagenz 5 aufweisenden Abschnitt 11 unter fluiddichtem Verschluss des Hohlraums 3 einsetzbar ist. Die Trägerfläche 13 bildet nach der Montage einen Teil der Wandfläche des Hohlraums 3. Ein im Hohlraum 3 transportiertes oder verarbeitetes Fluid kann so in Wechselwirkung mit der Trockenreagenz treten, insbesondere kann die Trockenreagenz von dem Fluid aufgelöst und resuspendiert werden. Andererseits können Bestandteile des Fluids wie Zellen oder Analyten mit der Trockenreagenz interagieren und/oder daran binden, indem das Fluid, ggf. mehrmals unter Wechsel der Transportrichtung, die Trägerfläche überströmt.Out 2 discloses a method for introducing a dry substance, in particular a dry reagent 5, into a flow cell, in which the dry reagent 5 is applied to a separate carrier part 8. A cavity 3 in a flow cell, which is, for example, an area of an in 3 Channel 9 shown can act, has a through-opening 10 into which the carrier element 8 with a conical section 11 having a carrier surface 13 for the dry reagent 5 can be inserted with fluid-tight closure of the cavity 3 . After assembly, the carrier surface 13 forms part of the wall surface of the cavity 3. A fluid transported or processed in the cavity 3 can thus interact with the dry reagent; in particular, the dry reagent can be dissolved and resuspended by the fluid. On the other hand, components of the fluid such as cells or analytes can interact with the dry reagent and/or bind to it, in that the fluid flows over the carrier surface, possibly several times changing the direction of transport.

Das in die Durchgangsöffnung 10 eingepasste Trägerelement 8 kann mit dem Substrat verklebt oder verschweißt sein. Ein über die Durchgangsöffnung 10 hinaus auf der dem Hohlraum 3 abgewandten Seite des Substrats 1 vorstehender Abschnitt 12 des Trägerelements 8 dient als die Montage des Trägerelements 8 erleichternder Griffteil.The carrier element 8 fitted into the through-opening 10 can be glued or welded to the substrate. A section 12 of the carrier element that protrudes beyond the through-opening 10 on the side of the substrate 1 facing away from the cavity 3 8 serves as the mounting of the carrier element 8 facilitating handle part.

Im Unterschied zu dem den Stand der Technik betreffenden Beispiel von Fig. 1 braucht zur Bildung der Trockenreagenz 5 aus einer Reagenzflüssigkeit 7 nicht wie bei dem Beispiel von Fig. 1 das gesamte Substrat 1 einer Trocknung ausgesetzt zu werden, sondern lediglich das Trägerelement 8, was Platz in einer Trockenkammer spart. Die Hauptbauteile der Flusszelle, das Substrat 1 und die Folie 4 unterliegen keiner Beanspruchung durch den Trocknungsvorgang und die abschließend in die Flusszelle eingebrachte Trockensubstanz 5 keiner Beeinträchtigung durch eine nachträglich erfolgende Fertigstellung der Flusszelle unter Verschweißung von Substrat 1 und Folie 4.In contrast to the prior art example of FIG 1 does not need to form the dry reagent 5 from a reagent liquid 7 as in the example of FIG 1 the entire substrate 1 to be subjected to drying, but only the carrier element 8, which saves space in a drying chamber. The main components of the flow cell, the substrate 1 and the foil 4 are not subject to any stress from the drying process and the dry substance 5 finally introduced into the flow cell is not impaired by subsequent completion of the flow cell by welding substrate 1 and foil 4.

Wie Fig. 3 erkennen lässt, können in dem Kanal 9 mehrere Öffnungen für die Aufnahme von Trägerelementen 8 mit ggf. unterschiedlichen darauf angeordneten Trockenreagenzien 5 vorhanden sein. In dem Beispiel von Fig. 3 dient der mäanderförmige Kanal 9 der Rücklösung der durch die Trägerelemente 8 eingebrachten Trockenreagenzien 5 durch wechselseitiges Überspülen.As 3 can be seen, several openings for receiving carrier elements 8 with possibly different dry reagents 5 arranged thereon can be present in the channel 9 . In the example of 3 the meandering channel 9 serves to redissolve the dry reagents 5 introduced by the carrier elements 8 by flushing them alternately.

Das Substrat 1 und die Folie 4 der Flusszelle bestehen vorzugsweise aus einem Kunststoff, insbesondere beide aus dem gleichen Kunststoff, wobei hierfür z.B. PMMA, PC, PS, PEEK, PP, PE, COC und COP in Betracht kommen. Auch bei dem Trägerelement 8 handelt es sich vorzugsweise um ein Kunststoffteil, das insbesondere aus dem gleichen Kunststoff wie das Substrat besteht. Die Herstellung des Substrats und der Trägerelemente aus Kunststoff erfolgt zweckmäßig durch Spritzgießen.The substrate 1 and the film 4 of the flow cell are preferably made of a plastic, in particular both of the same plastic, with PMMA, PC, PS, PEEK, PP, PE, COC and COP, for example, being suitable for this purpose. The carrier element 8 is also preferably a plastic part, which in particular consists of the same plastic as the substrate. The production of the substrate and the carrier elements from plastic is expediently carried out by injection molding.

Wie sich Fig. 4 entnehmen lässt, kann die die Trockenreagenz 5 aufnehmende Trägerfläche 13 des Trägerelements 8 zu der angrenzenden Wandfläche 14 des Hohlraums 3 bündig oder zu dieser Wandfläche zurückversetzt sein. Gemäß Fig. 4b kann das Trägerelement 8 mit der Trägerfläche 13 auch in den Hohlraum 3 hinein vorstehen. Dies kann vorteilhaft sein, um in einer in Mikrokanälen normalerweise vorliegenden laminaren Strömung lokal durch abrupte Änderung des Kanalquerschnitts Turbulenzen zu erzeugen und/oder um in dem Kanalbereich, in den das Trägerelement 8 eingebracht ist, durch Verkleinerung des Kanalquerschnitts eine Vergrößerung der Fließgeschwindigkeit des Fluids zu erreichen, z.B. zur Beschleunigung und Steuerung einer Rücklösung der Trockenreagenz. Ferner ergibt sich der Vorteil, dass bei einer automatisierten Montage des Trägerelements 8 Montage- und/oder Bauteiltoleranzen ausgleichbar sind.How himself 4 can be seen, the carrier surface 13 of the carrier element 8 accommodating the dry reagent 5 can be flush with the adjacent wall surface 14 of the cavity 3 or set back to this wall surface. According to Figure 4b the carrier element 8 can also protrude with the carrier surface 13 into the cavity 3 . This can be advantageous in order to generate turbulence locally in a laminar flow that is normally present in microchannels by abruptly changing the channel cross section and/or in order to increase the flow rate of the fluid in the channel area into which the carrier element 8 is introduced by reducing the channel cross section achieve, for example, to accelerate and control a redissolution of the dry reagent. Furthermore, there is the advantage that in the case of an automated assembly of the carrier element 8, assembly and/or component tolerances can be compensated for.

Fig. 5 zeigt weitere Ausführungsformen für Trägerelemente 8, die gemäß Fig. 5a zylindrisch und gemäß Fig. 5b zylindrisch mit einem das Substrat 1 hintergreifenden Kragen 15 ausgebildet sein können. figure 5 shows further embodiments for carrier elements 8 according to Figure 5a cylindrical and according Figure 5b can be cylindrical with a collar 15 engaging behind the substrate 1 .

Fig. 5c zeigt eine Ausführungsform eines zylindrischen, einen Kragen 13 aufweisenden Trägerelements 8 mit einem Außengewinde 16, das in ein Innengewinde in der betreffenden Durchgangsöffnung eingreift. Vorteilhaft lässt sich bei letzterer Ausführungsform das Trägerelement 8 von der Flusszelle lösen, sofern nicht zusätzlich zur Schraubverbindung auch noch eine Verklebung oder Verschweißung mit dem Substrat 1 erfolgt. Die Lösbarkeit kann vorteilhaft sein, wenn die Trockenreagenz nach Wechselwirkung mit dem Fluid wieder von der Flusszelle getrennt und einer weiteren Analyse unterzogen werden soll. Figure 5c shows an embodiment of a cylindrical support element 8 having a collar 13 and having an external thread 16 which engages in an internal thread in the passage opening in question. In the case of the latter embodiment, the carrier element 8 can advantageously be detached from the flow cell, provided that there is no adhesive bonding or welding to the substrate 1 in addition to the screw connection. The solubility can be advantageous if the dry reagent is to be separated from the flow cell again after interaction with the fluid and subjected to further analysis.

Ein von der Flusszelle lösbares Trägerelement 8 mit einem verlängerten Griffteil 17 zeigt Fig. 5e. Das Trägerelement 8 lässt sich unter fluiddichtem Verschluss des Hohlraums 3 in die betreffende Durchgangsöffnung in dem Substrat 1 eindrücken.A carrier element 8 which can be detached from the flow cell and has an extended handle part 17 is shown Figure 5e . The carrier element 8 can be pressed into the relevant through-opening in the substrate 1 while sealing the cavity 3 fluid-tight.

Durch einen erhabenen Rand 25 gemäß Fig. 5f am Substrat 1, dessen Dicke typischerweise zwischen 0,5 und 3 mm beträgt, lässt sich die Führung des Trägerelements 8 verbessern.By a raised edge 25 according to Fig. 5f on the substrate 1, the thickness of which is typically between 0.5 and 3 mm, the guidance of the carrier element 8 can be improved.

Fig. 5d zeigt ein Trägerelement 8 mit einem konischen Abschnitt und einem aus einer Durchgangsöffnung vorstehenden Kragen 15, der gegen das Substrat 1 durch eine Ringdichtung 18 abgedichtet ist. Figure 5d shows a carrier element 8 with a conical section and a collar 15 protruding from a through-opening, which is sealed against the substrate 1 by an annular seal 18 .

Die rotationssymmetrischen Trägerelemente können eine Markierung aufweisen, die es ermöglicht, die Trägerelemente in einer gewünschten Drehposition in den Durchgang einzuführen.The rotationally symmetrical carrier elements can have a marking that makes it possible to insert the carrier elements into the passage in a desired rotational position.

Aus Fig. 6 gehen Ausführungsbeispiele von Trägerelementen 8 mit unterschiedlich gestalteten Trägerflächen 13 hervor, wobei Fig. 6a ein Trägerelement mit einer Vertiefung 19 für die Aufnahme einer Trockenreagenz 5 aufweist. Bei dem Ausführungsbeispiel von Fig. 6b ist eine Trägerfläche 13 mit einer Vielzahl von Aufnahmevertiefungen in Form von kreuzartig angeordneten Rillen 20 mit typischen Querschnittsabmessungen von 0,01 x 0,01 mm2 bis 1 x 1 mm2 für eine Trockenreagenz gebildet. Vorteilhaft lässt sich dadurch die Oberfläche der Trägerfläche 13 auf einfache Art und Weise vergrößern, sodass entweder eine größere Menge an Trockenreagenz 5 bei gleichen Abmessungen des Trägerelements 8 aufgenommen werden oder/und die Trockensubstanz homogener als ein großer Tropfen auf einer glatten Trägerfläche eintrocknen kann und/oder die durch die Aufnahmevertiefungen 20 gebildete Mikrostruktur der Trägerfläche 13 beim Überströmen durch das Fluid Turbulenzen erzeugen kann, welche das Rücklöseverhalten positiv beeinflussen. Die Rillen könnten alternativ auch die Form konzentrischer Kreise aufweisen. Fig. 6c zeigt eine Aufnahmefläche mit einem auf die Trägerfläche durch Klemmen, Kleben oder Schweißen aufgebrachten porösen Element 21, in dem sich eine Trockensubstanz absetzen kann. Vorteilhaft bildet das poröse Element 21 eine vergrößerte Oberfläche für die Aufnahme der Trockenreagenz 5.Out 6 go out embodiments of support elements 8 with differently designed support surfaces 13, wherein Figure 6a has a carrier element with a depression 19 for receiving a dry reagent 5 . In the embodiment of Figure 6b a carrier surface 13 is formed with a multiplicity of receiving depressions in the form of grooves 20 arranged crosswise with typical cross-sectional dimensions of 0.01×0.01 mm 2 to 1×1 mm 2 for a dry reagent. Advantageously, the surface of the carrier surface 13 can be enlarged in a simple manner, so that either a larger quantity of dry reagent 5 can be accommodated with the same dimensions of the carrier element 8 and/or the dry substance can dry more homogeneously than a large drop on a smooth carrier surface and/or or the microstructure of the support surface 13 formed by the receiving depressions 20 can generate turbulence when the fluid flows over it, which positively influence the release behavior. Alternatively, the grooves could be in the form of concentric circles. Figure 6c shows a receiving surface with a porous element 21 applied to the support surface by clamping, gluing or welding, in which a dry substance can settle. The porous element 21 advantageously forms an enlarged surface for receiving the dry reagent 5.

Fig. 6d weist ein Trägerelement mit einer behandelten Trägerfläche auf, wobei es sich bei der Behandlung z.B. um eine nasschemische Behandlung, eine Plasmabehandlung oder Koronabehandlung handeln kann. Alternativ kann die Behandlung z.B. mittels Plasmapolymerisation oder mittels PVD-Prozess zu einer Beschichtung 22 führen, z.B. einer Glas- oder Metallbeschichtung. Figure 6d has a carrier element with a treated carrier surface, wherein the treatment can be, for example, a wet-chemical treatment, a plasma treatment or a corona treatment. Alternatively, the treatment can be carried out, for example, by means of plasma polymerisation or lead to a coating 22 by means of a PVD process, for example a glass or metal coating.

Ein in Fig. 6e gezeigtes Trägerbauteil ist zweiteilig mit einem gesonderten Oberflächenbauteil 26 ausgebildet. Das die Trägeroberfläche bildende Oberflächenbauteil 26 besteht z.B. nicht wie vorzugsweise das übrige Trägerbauteil aus einem Kunststoff, sondern aus Glas, Silizium, Metall oder Keramik. Wenn die Funktionalisierung, d.h. die Aufbringung der Trockenreagenz auf die Trägerfläche, solche Materialien erfordert, wie das z.B. bei Protein- (z.B. Antikörper) oder Nukleinsäurebasierten Analysetechnologien der Fall ist, so beschränkt sich die Verwendung dieser Materialien, die oft deutlich teurer als Kunststoff sind, vorteilhaft nur auf einen Oberflächenbereich, wobei Abmessungen von 0,5 x 0,5 mm bis 5 x 5 mm und Dicken zwischen 0,1 und 1 mm in Betracht kommen. Das Oberflächenbauteil 26 kann auf dem übrigen Trägerbauteil mittels Klemmen oder durch Kleben oder Schweißen befestigt werden.a in Figure 6e The carrier component shown is formed in two parts with a separate surface component 26 . The surface component 26 forming the support surface does not consist, for example, of a plastic, as is preferred for the rest of the support component, but of glass, silicon, metal or ceramic. If the functionalization, ie the application of the dry reagent to the carrier surface, requires such materials, as is the case with protein (e.g. antibodies) or nucleic acid-based analysis technologies, the use of these materials, which are often significantly more expensive than plastic, is limited. advantageously only on a surface area, with dimensions of 0.5×0.5 mm to 5×5 mm and thicknesses between 0.1 and 1 mm being considered. The surface component 26 can be attached to the rest of the support component by means of clamps or by gluing or welding.

Zum Aufbringen der Trockensubstanz 5 lässt sich eine Vielzahl von Trägerelementen 8 gleichzeitig bearbeiten, indem die Trägerelemente 8 im Schritt 7a auf einem Reihen von Löchern 23 aufweisenden Trägertablet 24 angeordnet werden. Im nächstfolgenden Verfahrensschritt 7b wird gleichzeitig auf allen Trägerflächen 13 der Trägerelemente 8 eine die Haftung einer Substanz verbessernde Schicht 22 erzeugt. Die Beschichtung kann dabei auch andere, nicht zum Aufbringen der Trockenreagenz 5 vorgesehene Oberflächenbereiche des Trägerelements 8 bedecken. In den Verfahrensschritten 7c und 7d erfolgt nach Auftragen einer Reagenzflüssigkeit 7 auf die Schichten 22 eine Trocknungsbehandlung, sodass sich auf den Schichten 22 die daran anhaftende Trockensubstanz 5 absetzt. Schließlich können im Schritt 7e die fertiggestellten, mit einer Trockensubstanz 5 versehenen Trägerelemente 8 zur Verarbeitung entnommen werden.To apply the dry substance 5, a large number of carrier elements 8 can be processed simultaneously by the carrier elements 8 being arranged in step 7a on a carrier tablet 24 having rows of holes 23. In the next method step 7b, a layer 22 that improves the adhesion of a substance is produced simultaneously on all carrier surfaces 13 of the carrier elements 8 . The coating can also cover other surface areas of the carrier element 8 that are not intended for application of the dry reagent 5 . In method steps 7c and 7d, after a reagent liquid 7 has been applied to the layers 22, a drying treatment takes place, so that the dry substance 5 adhering thereto is deposited on the layers 22. Finally, in step 7e, the finished carrier elements 8 provided with a dry substance 5 can be removed for processing.

Es wird nun auf Fig. 8 Bezug genommen, wo ein weiteres Ausführungsbeispiel für ein Trägerelement 8 gezeigt ist.It will now open 8 Reference is made to where a further exemplary embodiment of a carrier element 8 is shown.

Das Trägerelement 8 weist eine Trägerfläche für eine Trockensubstanz 5 auf, die durch eine Membran 27 gebildet ist. Diese Membran kann einstückig mit dem übrigen Trägerelement 8 verbunden oder durch ein separates, mit dem übrigen Trägerelement verbundenes Bauteil gebildet sein, das vorzugsweise aus dem gleichen Kunststoff wie das übrige Trägerelement besteht.The carrier element 8 has a carrier surface for a dry substance 5 which is formed by a membrane 27 . This membrane can be connected in one piece to the rest of the carrier element 8 or formed by a separate component connected to the rest of the carrier element, which preferably consists of the same plastic as the rest of the carrier element.

Bei Transparenz der Membran 27, die eine in dem Trägerelement 8 gebildete Durchgangsöffnung 28 an einem Ende abschließt, besteht die Möglichkeit, durch optische Detektion die Wechselwirkung des Fluids mit der Trockensubstanz 5 gemäß Fig. 8b zu kontrollieren.
Ferner besteht gemäß Fig. 8c die Möglichkeit, durch pneumatische oder mechanische Druckbeaufschlagung die Membran 27 konvex oder konkav zu formen. Insbesondere durch alternierende Aus- und Einwölbung der Membran 27 lässt sich die Wechselwirkung zwischen der Trockensubstanz und dem Fluid stimulieren und sowohl eine verbesserte Resuspendierung von Trockensubstanzen als auch verbesserte Anlagerung von Bestandteilen des Fluids auf Trockensubstanzen, z.B. im Fall von Antikörpern, erreichen.If the membrane 27 is transparent, which closes off a through opening 28 formed in the carrier element 8 at one end, there is the possibility of optical detection of the interaction of the fluid with the dry substance 5 in accordance with Figure 8b to control.
Furthermore, according to Figure 8c the possibility of forming the membrane 27 convex or concave by pneumatic or mechanical pressurization. The interaction between the dry substance and the fluid can be stimulated in particular by alternating bulging and inward arching of the membrane 27 and both improved resuspension of dry substances and improved accumulation of components of the fluid on dry substances, eg in the case of antibodies, can be achieved.

Claims (11)

  1. Microfluidic flow cell having a dry substance (5) which is arranged within the flow cell in a cavity (3) and which serves for interacting with a fluid situated in the cavity (3), wherein the cavity (3) is delimited by a recess (2) in a substrate (1) and by a cover (4) which closes off the recess (2), and wherein the flow cell comprises a separate support element (8) having a support surface (13) for the dry substance (5), which surface is provided for arrangement adjacent to the cavity (3), wherein an outwardly open passage (10), which is led to an outer surface of the flow cell, opens into the cavity (3), and the separate support element (8) can be inserted into the passage (10) from the outside such that the cavity (3) is closed off and such that the support surface (13) is arranged adjacent to the cavity (3),
    characterized
    in that the support surface (13) for the dry substance (5) is formed by a membrane (27) which closes off a passage opening (28) in the support element (8) towards the cavity (3).
  2. Flow cell according to Claim 1,
    characterized
    in that the cavity (3) forms a channel network (9) for the transport, analysis and/or synthesis of a fluid, and in that, if appropriate, multiple such support elements (8) can be inserted into multiple passages (10).
  3. Flow cell according to Claim 1 or 2,
    characterized
    in that the recess (2) is formed in a plate-shaped substrate (1) and is closed off by a film-type cover (4), and in that the passage (10) is formed in the plate-shaped substrate.
  4. Flow cell according to Claim 3,
    characterized
    in that the passage (10) is led to a plate surface of the plate-shaped substrate (1).
  5. Flow cell according to one of Claims 1 to 4,
    characterized
    in that the support element (8) can be connected to the flow cell in a detachable manner, and/or in a non-detachable manner, such that the cavity (3) is closed off in a fluid-tight manner.
  6. Flow cell according to one of Claims 1 to 5,
    characterized
    in that the support element (8), at least in cross section, completely fills the passage (10), wherein preferably, the support element (8) and the passage (10) are circular in cross section and the support element (8) tapers towards the cavity (3) and the passage (10) narrows towards the cavity.
  7. Flow cell according to one of Claims 1 to 6,
    characterized
    in that the support element (8) has a portion (12; 15; 17) which projects outwardly from the flow cell, wherein, if appropriate, the portion engages behind the flow cell on the outside in the manner of a collar (15).
  8. Flow cell according to one of Claims 1 to 7,
    characterized
    in that the support surface (13) of the support element (8) is arranged so as to be flush with, or so as to be set back from, an adjacent wall surface (14) of the cavity (3), or in that the support element (8) projects into the cavity (3) from the adjacent wall surface (14) of the cavity (3).
  9. Flow cell according to one of Claims 1 to 8,
    characterized
    in that the dry substance adheres to the support surface (13), and the support surface (13) preferably has a structuring (19-21), coating (22) and/or surface modification which promotes the adhesion.
  10. Flow cell according to one of Claims 1 to 9,
    characterized
    in that the support surface (13) for the dry substance (5) is formed by a separate component (21; 26) which is connected to the rest of the support element (8) and which differs in material from the rest of the support element (8).
  11. Flow cell according to one of Claims 1 to 10,
    characterized
    in that the membrane (27) is transparent.
EP13175335.2A 2013-07-05 2013-07-05 Flow cell with integrated dry substance Active EP2821138B2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP13175335.2A EP2821138B2 (en) 2013-07-05 2013-07-05 Flow cell with integrated dry substance
DK13175335.2T DK2821138T4 (en) 2013-07-05 2013-07-05 FLOATING CELL WITH INTEGRATED DRY MATERIAL
ES13175335T ES2704424T5 (en) 2013-07-05 2013-07-05 Flow cell with integrated dry substance
PCT/EP2014/064290 WO2015001070A1 (en) 2013-07-05 2014-07-04 Flow cell with an integrated dry substance
US14/902,787 US10232367B2 (en) 2013-07-05 2014-07-04 Flow cell with an integrated dry substance
CN201480046983.0A CN105517710B (en) 2013-07-05 2014-07-04 Flow battery with the dry matter integrated
US16/265,127 US10946376B2 (en) 2013-07-05 2019-02-01 Carrier element for introducing a dry substance into a flow cell

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP13175335.2A EP2821138B2 (en) 2013-07-05 2013-07-05 Flow cell with integrated dry substance

Publications (4)

Publication Number Publication Date
EP2821138A1 EP2821138A1 (en) 2015-01-07
EP2821138B1 EP2821138B1 (en) 2018-10-24
EP2821138B8 EP2821138B8 (en) 2019-03-06
EP2821138B2 true EP2821138B2 (en) 2022-02-09

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US (1) US10232367B2 (en)
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CN (1) CN105517710B (en)
DK (1) DK2821138T4 (en)
ES (1) ES2704424T5 (en)
WO (1) WO2015001070A1 (en)

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Also Published As

Publication number Publication date
US20160167047A1 (en) 2016-06-16
EP2821138B8 (en) 2019-03-06
WO2015001070A1 (en) 2015-01-08
CN105517710A (en) 2016-04-20
DK2821138T4 (en) 2022-05-16
US10232367B2 (en) 2019-03-19
EP2821138B1 (en) 2018-10-24
ES2704424T3 (en) 2019-03-18
ES2704424T5 (en) 2022-05-20
DK2821138T3 (en) 2019-02-11
CN105517710B (en) 2017-04-05
EP2821138A1 (en) 2015-01-07

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