EP1521635A1 - Device for handling liquids contained in a plurality of channels - Google Patents

Device for handling liquids contained in a plurality of channels

Info

Publication number
EP1521635A1
EP1521635A1 EP03760576A EP03760576A EP1521635A1 EP 1521635 A1 EP1521635 A1 EP 1521635A1 EP 03760576 A EP03760576 A EP 03760576A EP 03760576 A EP03760576 A EP 03760576A EP 1521635 A1 EP1521635 A1 EP 1521635A1
Authority
EP
European Patent Office
Prior art keywords
channel
chamber
channels
pump element
channel carrier
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03760576A
Other languages
German (de)
French (fr)
Inventor
David GÜTIG
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.)
Epigenomics AG
Original Assignee
Epigenomics AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Epigenomics AG filed Critical Epigenomics AG
Publication of EP1521635A1 publication Critical patent/EP1521635A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1095—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices for supplying the samples to flow-through analysers
    • G01N35/1097—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices for supplying the samples to flow-through analysers characterised by the valves
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0622—Valves, specific forms thereof distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/0644—Valves, specific forms thereof with moving parts rotary valves
    • 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

Definitions

  • the invention relates to a device for handling liquids in different channels, consisting of a channel support and a pump element.
  • the dosing pump in the device from DE 10013528 is carried by a pump mounting plate, which complicates the construction of the dosing device.
  • a sensible guidance of the sealing surfaces can only be achieved by additional components.
  • Manual and motorized valves are also known and are offered in a variety of technological variants. Manual and motorized rotary valves are offered by companies such as Rheodyne, Omnifit and Argus GmbH, Ettlingen (www.argus-valves. Com). Further known valve technologies are, for example, pinch valves, ball valves and diaphragm valves.
  • valves and pumps are also often offered, such as by Cavro, for example, but these are far too expensive for single use.
  • the combination of a rotary valve with a piston pump at an outlet also has the further disadvantage that the path between the valve and the pump is a dead volume.
  • Integrated fluidic systems have also been proposed for complex processes (RC Anderson, et al.; A miniature integrated device for automated multistep genetic assays; Nucleic Acids Res. (2000), 12, e60; PK Yuen, et al.; Microchip module for blood sample preparation and nucleic acid amplification reactions; Genome Research (2001), 11, 405-412). It is state of the art to integrate the actuators for valves and pumps. However, this requires complex and costly production. Furthermore, integrated diaphragm pumps only have small working volumes. Another known way is to integrate membrane valves, for example, and to outsource the actuators to a reusable operating platform. However, an additional actuator is required for each valve function. The systems described therefore have a number of disadvantages.
  • Disposable components should be those components that can come into contact with the liquids.
  • the simple and robust properties of rotary valves are to be realized, the disadvantage of the dead volume between the rotary valve and the pump being minimized.
  • the drive functions should be carried out with a minimal number of compactly arranged actuators which, for easy interchangeability of the disposable components, should only act on the disposable components from one side.
  • the object is achieved by a device for handling liquids in at least two channels with the features characterized in the main claim.
  • Advantageous refinements of the device according to the invention are characterized in the dependent subclaims.
  • the present invention thus relates to a device for handling liquids in at least two channels, consisting of a component, hereinafter called channel support, in which the channels start in a star shape - from a cone and a second component, hereinafter called a pump element, which has at least one Contains variable volume chamber and through a conical end with at least one integrated lateral opening to at least one of the volumes, the cone of the components being fitted into one another, so that by rotating the components relative to one another about the cone axes, at least one opening of the pump element tes can be brought into contact with at least one of the channels of the channel carrier, and a connection between see at least one volume and at least one channel, and other openings and channels are closed by conical surfaces.
  • a component hereinafter called channel support
  • a pump element which has at least one Contains variable volume chamber and through a conical end with at least one integrated lateral opening to at least one of the volumes, the cone of the components being fitted into one another, so that by rotating the components relative to one another about
  • a piston is arranged therein, which is movable in the direction of the cone axes and the volume of at least one chamber of the pump element can be varied by a piston.
  • a spring is arranged therein which moves the piston.
  • a linear reactor is arranged therein that moves the piston.
  • the channels in the channel carrier being formed by joining together at least two surfaces, at least one of the surfaces being structured with the open channels, and the channels being capped by joining the surfaces.
  • At least part of the channel support and its structure can be obtained by milling, injection molding, hot stamping, laser cutting, stamping and / or etching.
  • the channel support consists of plastic, glass, metal or cellulose material.
  • At least one channel of the channel carrier leads to a chamber structured in the channel carrier. It is also preferred according to the invention that at least one channel of the channel carrier leads to a chamber structured in the channel carrier which is accessible through at least one further opening.
  • At least one channel of the channel carrier leads to a chamber structured in the channel carrier in which reagents are placed. It is particularly preferred that the reagents are in solid form.
  • the present invention also relates to the use of a device according to the invention, an automated bisulfite reaction being carried out.
  • This device consists of a channel support and a pump element (FIG. 1), which are preferably arranged on an operating platform.
  • the channels of the channel support are arranged in a star shape starting from a cone.
  • the channels in the channel support preferably come about by joining together at least two surfaces, at least one of the surfaces being structured with the open channels, and the channels being capped by joining the surfaces.
  • At least a part of the channel support is manufactured on a milling machine or is preferably an injection molded part. Alternatively, it is also preferred that at least a part of the channel carrier is hot stamped or preferably structured with a laser. Alternatively, it is also preferred that at least a part of the channel carrier is punched or structured by etching. At least part of the channel support is made of plastic (e.g.
  • PMMA polymethyl methacrylate
  • PVC polyvinyl chloride
  • PDMS polydimethylsiloxane
  • polysulfone polystyrene, polymethylpentene, polypropylene, polyethylene, polyvinylidine fluoride or ABS (acrylonitrile butadiene styrene) Copolymer
  • glass metal or cellulose material.
  • the cone of the pump element being fitted into the cone of the channel support, so that by rotating the components relative to one another about the cone axes, at least one opening of the pump element with at least one of the channels of the channel support are brought into contact and a connection is established between at least one volume and at least one channel, and all other openings and channels are closed by conical surfaces.
  • the chamber of the pump element is designed as a cylinder and the volume is varied with a movable piston. It is particularly preferred that the piston is driven back to its starting position with a spring when it has been brought out of it.
  • the operating platform preferably has the function of fixing the channel carrier and pressing the pump element against the channel carrier in such a way that the cones of these components are fitted into one another.
  • the pump element is particularly preferably rotated about the cone axes by a motor arranged in the operating platform.
  • the movement of the piston is preferred performed by a linear reactor arranged in the operating platform.
  • a connection is established between the channel and the chamber and the chamber volume is increased.
  • the chamber volume is preferably varied by a piston which is moved in the direction of the cone axes.
  • the piston is preferably moved out of the starting position with a linear reactor and particularly preferably driven back with a spring.
  • a chamber of the pump element is connected to a channel of the channel support, which is connected to the structural element and sucks in the liquid. It is preferred that structural elements contain at least one further opening through which pressure equalization takes place.
  • the channel and chamber are connected and the chamber volume is reduced.
  • structural elements of the channel carrier To fill a structural element of the channel carrier with liquid from the chamber of the pump element, this is connected to a channel of the channel carrier which is connected to the structural element and the liquid is expelled from the chamber of the pump element. It is preferred that structural elements contain at least one further opening through which pressure equalization takes place.
  • the liquid is sucked in and out encountered.
  • the liquid for movement is preferably first expelled and then sucked in.
  • a first channel of the channel carrier is brought into connection with a chamber of the pump element and the liquid to be dosed is sucked into the chamber. Air that is possibly present in the chamber is preferably expelled after the suction.
  • the chamber is particularly preferably connected to a ventilation channel of the channel carrier provided for this purpose. Then the chamber is connected to other channels of the channel carrier and the liquid is expelled in a controlled manner.
  • a volume is metered into the flow element which exceeds the volume of the flow element.
  • At least one further opening of the flow element is preferably connected to a chamber, which is referred to below as the collecting chamber.
  • the collecting chamber particularly preferably has at least one further opening which is connected to the conical surface of the channel support by a further channel and through which the liquid passing through the flow element is sucked in. It is very particularly preferred if the openings for liquid transport are located at the bottom of the collecting chamber and there is at least one further opening for pressure compensation above the maximum expected filling level of the collecting chamber. Furthermore, it is preferred to place the liquid in the collecting chamber and then to suck it in through the flow element.
  • the liquids to be mixed are sucked into the chamber sequentially or in parallel. Prefers the mixture is then expelled and sucked in at least once, so as to intensify the mixing.
  • the chamber is particularly preferably connected to a mixing channel of the channel support provided for this purpose.
  • the mixing channel is very particularly preferably provided with structural elements which promote mixing.
  • the mixing chamber To mix liquids in a chamber of the channel support, hereinafter referred to as the mixing chamber, the liquids are dosed sequentially or in parallel into the mixing chamber. The mixture is then preferably sucked in and expelled at least once in order to intensify the mixing.
  • the mixing chamber is particularly preferably provided with structural elements which promote mixing.
  • the liquid is metered into a structural element of the channel support, hereinafter referred to as absorber, which contains at least one surface which binds at least one component to be separated.
  • the liquid is preferably sucked in again after the separation.
  • the absorber is particularly preferably designed as a flow element.
  • a liquid is metered into the absorber which detaches the bound component again (hereinafter referred to as eluent).
  • pillar a liquid, it is metered into a flow element of the channel support, which is filled with a pillar material.
  • a liquid it is metered into a flow element of the channel support, which at least contains a filter.
  • the flow element is preferably filled with a filter material.
  • the tempering chamber To temper a liquid, it is dosed into a chamber of the channel support, which is called the tempering chamber in the following. This is kept at the desired temperature by contact with a heating or cooling element.
  • the heating or cooling element is preferably a component of the channel support.
  • the heating or cooling element is particularly preferably part of an operating platform and in mechanical contact with at least one wall of the temperature control chamber.
  • 160 ng DNA are placed in a first chamber of the channel support in 3 ⁇ l H 2 0 bidest.
  • This first chamber is open at the top and connected to the pump element via a channel.
  • 17 ⁇ l of a bisulfite reaction solution are placed in a second chamber.
  • This second chamber is open at the top and connected to the pump element via a channel.
  • 20 ⁇ l desulfonation solution are placed in a third chamber.
  • This third chamber is open at the top and connected to the pump element via a channel.
  • Approximately 1 ml H 2 0 bidist. are presented in a fourth chamber.
  • This fourth chamber is open at the top and connected to the pump element via a channel.
  • Another chamber, which is open at the top and is connected to the pump element by a channel remains empty and is used to hold waste.
  • heating chamber there is also a flat chamber (hereinafter referred to as the heating chamber) with a capacity of 40 ⁇ l in the channel support, which is heated by a heating element in the operating platform and via a further small opening for pressure relief. the same.
  • Another structural element with a volume of 200 ⁇ l (in the following purification chamber) is filled with pre-swollen column material (0.2 g Sephadex G50 with 190 ⁇ l H 2 0 bidest.).
  • This structural element is connected via a further channel on the other side to a further chamber which is open at the top. Furthermore, this open chamber is connected to the plug valve by a further channel.
  • the bisulfite reaction solution is completely sucked up with the pump element and released into the chamber with the DNA solution.
  • the mixture is then completely absorbed and completely released into the heating chamber.
  • the mixture in the heating chamber is brought to 95 ° C. for 3 minutes, then to 50 ° C. for 10 minutes, then to 95 ° C. for 30 seconds, then to 50 ° C. for 30 minutes, then to 95 ° again for 30 seconds C and finally for 3 h at 50 ° C.
  • 180 ⁇ l of H 2 O are taken up from the fourth chamber and released into the purification chamber at a flow rate of 10 ⁇ l / s.
  • Liquid which is then in the collecting chamber, is taken up via the direct channel with the pump element and released into the waste chamber. The mixture is then taken up again and released into the purification chamber, the flow rate being approximately 10 ⁇ l / s.
  • 180 ⁇ l H 2 0 are taken up from the third chamber and released into the purification chamber at a flow rate of approximately 10 ⁇ l / s.
  • the liquid that has collected in the collecting chamber behind the purification chamber is absorbed via the direct channel connection to the pump element and released into the waste chamber. Then a further 20 ⁇ l of H 2 O are taken up from the third chamber and released again into the purification chamber at a flow rate of approximately 10 ⁇ l / s.
  • the liquid that is now in the collecting chamber contains the purified DNA fraction.
  • This liquid is pumped ment taken through the direct channel and released into the third chamber with the desulfonation solution. Then 40 .mu.l of H 2 O is taken up from the fourth chamber with the pump element and released three times into the heating chamber and taken up again. The H 2 0 is then released into the waste chamber.
  • the mixture of DNA solution and desulfonation solution is then taken up from the third chamber and released into the heating chamber and kept at 95 ° C. for 10 min. Finally, the mixture with the pump element is taken up again and released into the third chamber, where it is available for further use.
  • the optical analysis of a liquid is another application example of the new device.
  • the liquid is metered into a chamber of the channel carrier.
  • the liquid for example, is optically detected: fluorescent components or FRET (Fluoresence Resonance Energy Transfer) pairs.
  • the liquid for example, is detected electronically: electrochemical potentials or attached components.
  • Another application example is the hybridization of DNA in a liquid.
  • the liquid with the DNA is metered into a chamber of the channel support, hereinafter called the hybridization chamber, in which at least one hybridization partner for the DNA is immobilized on at least one surface.
  • the hybridization partners are preferably immobilized on at least one component of the channel carrier before the channel carrier is completely assembled.
  • the hybridization chamber is particularly preferably at the same time a temperature control chamber.
  • the DNA is very particularly preferred before hybridization and possibly denatured at least once during hybridization. It is further preferred to move the liquid with the DNA at least once during the hybridization.
  • the hybridization partners are DNA, RNA, PNA, LNA or derivatives and modifications thereof.
  • the hybridization chamber is at the same time designed as an optical cell in which optical changes due to the accumulation of components by the hybridization are detected.
  • a spatial resolution is preferably achieved in the optical detection and the hybridization is detected in different regions.
  • At least one hybridization partner is immobilized on at least one electrode, hereinafter referred to as the detection electrode, in the hybridization chamber and at least one electroactive component is brought into the hybridization chamber.
  • electroactive component is brought into the hybridization chamber.
  • these are intercalating components, modified DNA, modified DNA derivatives and components that undergo redox reactions with DNA or DNA derivatives.
  • the degree of hybridization at the detection electrodes is determined by measuring the potential or applying suitable electrical voltage patterns and recording the voltage-current curves.
  • At least one further electrode is used in the hybridization chamber.
  • intercalating dye instead of an intercalating dye, other methods for real-time detection of the polymerase chain reaction can also be used, such as, for example, the TaqMan Assay, the Molecular Beacon Assay and the Scorpion Assay.
  • Figure 1 1: Channel A; 2: channel B; 3: sample liquid; 4: side opening; 5: pump element; 6: volume in the pump element; 7: cone; 8: channel carrier; 9: pistons
  • Figure 2 View of the operating platform 1: temperature control block; 2: holder for the pump element; 3: motor for rotating the pump element; 4: linear reactor; 5: pump element; 6: channel carrier
  • Figure 3 Section through platform, channel support and pump element

Abstract

The invention relates to a device for handling liquids contained in at least two channels. Said device consists of one component, referred to subsequently as a channel support, in which the channels extend in a stellate manner from a cone and a second component, subsequently referred to as a pump element, which contains at least one chamber with a variable volume and has a cone-shaped end with at least one integrated lateral opening that is directed towards at least one of the volumes. The cones of the components are fitted into one another in such a way as to permit contact between at least one opening of the pump element and at least one of the channels in the channel support, by rotating the components in relation to one another about the cone axes, the formation of a connection between at least one volume and at least one channel and the closure of other openings and channels by cone surfaces.

Description

Vorrichtung zur Handhabung von Flüssigkeiten in einer Device for handling liquids in one
Mehrzahl von KanälenMajority of channels
Gebiet der ErfindungField of the Invention
Die Erfindung betrifft eine Vorrichtung zur Handhabung von Flüssigkeiten in verschiedenen Kanälen, bestehend aus einem Kanalträger und einem Pumpenelement.The invention relates to a device for handling liquids in different channels, consisting of a channel support and a pump element.
Stand der TechnikState of the art
Ein Vielzahl von chemischen und molekularbiologischen Prozessen mit Flüssigkeiten wird mit Hilfe von Pipetten manuell durchgeführt (T. Maniatis et al . , Molecular Clo- ning: A Laboratory Manual, 1989) . Zur Einsparung personeller Ressourcen und zur Vermeidung menschlicher Fehler werden standardisierte Prozesse zur Handhabung von Flüs- sigkeiten in der Regel automatisiert. Ein bekannter Weg ist die Nachbildung der manuellen Schritte mit einem Roboter, der mit einer Pipettiereinheit ausgestattet ist. Diese Roboter lohnen sich aber erst bei einem hohen Probendurchsatz und sind sehr schwierig zu bedienen (L.G. Mendoza et al.; High-throughput microarray-based enzyme- linked immunosorbent assay; Biotechniques (1999), 4, 778- 788) .A variety of chemical and molecular biological processes with liquids are carried out manually using pipettes (T. Maniatis et al., Molecular Cloning: A Laboratory Manual, 1989). In order to save human resources and avoid human errors, standardized processes for handling liquids are generally automated. A well-known way is to simulate the manual steps with a robot that is equipped with a pipetting unit. However, these robots are only worthwhile with a high sample throughput and are very difficult to use (L.G. Mendoza et al .; High-throughput microarray-based enzyme-linked immunosorbent assay; Biotechniques (1999), 4, 778-788).
Für die Automatisierung von komplexen molekularbiologi- sehen Prozessen ist der Transfer von Flüssigkeiten erforderlich. Typische Prozesse dieser Art laufen in Reaktionsgefäßen ab, die mit den benötigten Reagenzien befüllt werden.The transfer of liquids is required for the automation of complex molecular biological processes. Typical processes of this type take place in reaction vessels that are filled with the required reagents.
Ein kritischer Punkt bei dem Transfer von Flüssigkeiten in komplexen molekularbiologischen Prozessen ist häufig das Auftreten von Fremdkontamination. Es ist Stand der Technik, dem Problem der Fremdkontamination mit Einwegkomponenten zu begegnen. Bei diagnostischen Anwendungen, bei denen die Kontamination von Proben untereinander aus- geschlossen werden uss, geht man sogar so weit, dass ein abgeschlossenes System für jede Probe verlangt wird.A critical point in the transfer of liquids in complex molecular biological processes is common the occurrence of external contamination. It is state of the art to counter the problem of external contamination with disposable components. In diagnostic applications in which the contamination of samples from one another has to be ruled out, one goes so far that a closed system is required for each sample.
Die Benutzung der Einwegkomponenten ermöglicht in idealer Weise die Entsorgung potentiell kontaminierter Komponen- ten. Die bekannten Vorrichtungen geschlossener Schlauchsysteme mit Schlauchpumpen und Schlauchquetschventilen führen jedoch zu komplizierten und kostspieligen Apparaturen. Die Schläuche sind bei steigender Komplexität auch umständlich zu wechseln.The use of disposable components ideally enables the disposal of potentially contaminated components. However, the known devices of closed hose systems with hose pumps and hose pinch valves lead to complicated and costly apparatus. With increasing complexity, the hoses are also difficult to change.
Vorrichtungen mit Pumpen zum gerichteten Transport von Flüssigkeiten sind bekannt, und eine große Vielzahl von Kolben- und Membranpumpen sind in vielen Varianten kommerziell erhältlich. Beispiele aus der Patentliteratur sind U.S. 4.741.732 und U.S. 5.034.994 von Crankshaw et al .Devices with pumps for the directed transport of liquids are known, and a large variety of piston and diaphragm pumps are commercially available in many variants. Examples from the patent literature are U.S. 4,741,732 and U.S. 5,034,994 to Crankshaw et al.
Aus DE 10013528 ist eine Vorrichtung zur Handhabung von Flüssigkeiten bekannt, die einen Kanalträger und ein Pu - penelement in Form einer Dosierpumpe aufweist. Nachteilig ist dabei, dass jeder Pumpe nur ein Dosierkanal zugeordnet ist. Damit ist es nicht möglich, in mehrere Kanäle zu dosieren.From DE 10013528 a device for handling liquids is known which has a channel support and a pump element in the form of a metering pump. The disadvantage here is that only one metering channel is assigned to each pump. It is therefore not possible to dose into several channels.
Die Dosierpumpe in der Vorrichtung aus DE 10013528 wird von einer Pumpenaufnahmeplatte getragen, was den Aufbau der Dosiervorrichtung verkompliziert Eine vernünftige Führung der Dichtflächen ist nur durch zusätzliche Komponenten realisierbar. Manuelle und motorisierte Ventile sind ebenfalls bekannt und werden in einer Vielzahl von technologischen Varianten angeboten. Manuelle und motorisierte Drehventile werden z.B. von Firmen wie Rheodyne, Omnifit und der Argus GmbH, Ettlingen (www. argus-valves . com) angeboten. Weitere bekannte Ventiltechnologien sind zum Beispiel Schlauchquetschventile, Kugelventile und Membranventile.The dosing pump in the device from DE 10013528 is carried by a pump mounting plate, which complicates the construction of the dosing device. A sensible guidance of the sealing surfaces can only be achieved by additional components. Manual and motorized valves are also known and are offered in a variety of technological variants. Manual and motorized rotary valves are offered by companies such as Rheodyne, Omnifit and Argus GmbH, Ettlingen (www.argus-valves. Com). Further known valve technologies are, for example, pinch valves, ball valves and diaphragm valves.
Vielfach werden auch, wie zum Beispiel von der Firma Cav- ro, Kombinationen von Ventilen und Pumpen angeboten, die jedoch für den Einmalgebrauch viel zu teuer sind. Die Kombination eines Drehventils mit einer Kolbenpumpe an einem Ausgang hat auch den weiteren Nachteil, dass der Weg zwischen Ventil und Pumpe ein Totvolumen ist.Combinations of valves and pumps are also often offered, such as by Cavro, for example, but these are far too expensive for single use. The combination of a rotary valve with a piston pump at an outlet also has the further disadvantage that the path between the valve and the pump is a dead volume.
Für komplexe Abläufe sind auch integrierte fluidische Systeme vorgeschlagen worden (R.C. Anderson, et al . ; A miniature integrated device for automated multistep gene- tic assays; Nucleic Acids Res. (2000), 12, e60; P.K. Yuen, et al . ; Microchip module for blood sample prepara- tion and nucleic acid amplification reactions; Genome Research (2001), 11, 405-412). Dabei ist es Stand der Technik, die Aktoren für Ventile und Pumpen zu integrieren. Dies verlangt jedoch eine aufwendige und kostspielige Fertigung. Des weiteren haben integrierte Membranpumpen nur kleine Arbeitsvolumina. Ein anderer bekannter Weg ist es zum Beispiel Membranventile zu integrieren, und die Aktoren in eine wiederverwendbare Operationsplattform auszulagern. Dabei ist jedoch pro Ventilfunktion ein ex- ferner Aktor nötig. Die beschriebenen Systeme sind also mit einer Vielzahl von Nachteilen behaftet.Integrated fluidic systems have also been proposed for complex processes (RC Anderson, et al.; A miniature integrated device for automated multistep genetic assays; Nucleic Acids Res. (2000), 12, e60; PK Yuen, et al.; Microchip module for blood sample preparation and nucleic acid amplification reactions; Genome Research (2001), 11, 405-412). It is state of the art to integrate the actuators for valves and pumps. However, this requires complex and costly production. Furthermore, integrated diaphragm pumps only have small working volumes. Another known way is to integrate membrane valves, for example, and to outsource the actuators to a reusable operating platform. However, an additional actuator is required for each valve function. The systems described therefore have a number of disadvantages.
Aufgabenstellungtask
Es ist Aufgabe der Erfindung, eine preiswerte, einfache Vorrichtung zur automatischen Handhabung von Flüssigkei- ten in einem geschlossenen System bereitzustellen, das aus einer wiederverwendbaren Operationsplattform und Einwegkomponenten besteht. Einwegkomponenten sollen dabei diejenigen Komponenten sein, die mit den Flüssigkeiten in Kontakt kommen können. Weiterhin sollen die einfachen und robusten Eigenschaften von Drehventilen realisiert werden, wobei der Nachteil des Totvolumens zwischen Drehventil und Pumpe minimiert werden soll. Die Antriebsfunktionen sollen zur Kostenreduzierung mit einer minimalen An- zahl kompakt angeordneter Aktoren durchgeführt werden, die zur leichten Austauschbarkeit der Einwegkomponenten nur von einer Seite an die Einwegkomponenten angreifen sollen.It is an object of the invention to provide an inexpensive, simple device for the automatic handling of liquid to be provided in a closed system consisting of a reusable operating platform and disposable components. Disposable components should be those components that can come into contact with the liquids. Furthermore, the simple and robust properties of rotary valves are to be realized, the disadvantage of the dead volume between the rotary valve and the pump being minimized. In order to reduce costs, the drive functions should be carried out with a minimal number of compactly arranged actuators which, for easy interchangeability of the disposable components, should only act on the disposable components from one side.
Die Aufgabe wird gelöst durch eine Vorrichtung zur Handhabung von Flüssigkeiten in mindestens zwei Kanälen mit den im Hauptanspruch gekennzeichneten Merkmalen. Vorteilhafte Ausgestaltungen der erfindungsgemäßen Vorrichtung sind in den abhängigen Unteransprüchen gekennzeichnet.The object is achieved by a device for handling liquids in at least two channels with the features characterized in the main claim. Advantageous refinements of the device according to the invention are characterized in the dependent subclaims.
Beschreibungdescription
Gegenstand der vorliegenden Erfindung ist also eine Vorrichtung zur Handhabung von Flüssigkeiten in mindestens zwei Kanälen, bestehend aus einer Komponente, im folgenden Kanalträger genannt, in der die Kanäle sternförmig- von einem Kegel ausgehen und einer zweiten Komponente, im folgenden Pumpenelement genannt, welche mindestens eine Kammer mit variablem Volumen beinhaltet und durch ein ke- gelförmiges Ende mit mindestens einer integrierten seitlichen Öffnung zu mindestens einem der Volumina, wobei die Kegel der Komponenten ineinander eingepasst sind, so dass durch Drehen der Komponenten relativ zueinander um die Kegelachsen mindestens eine Öffnung des Pumpenelemen- tes mit mindestens einem der Kanäle des Kanalträgers in Kontakt gebracht werden kann, und eine Verbindung zwi- sehen mindestens einem Volumen und mindestens einem Kanal zustande kommt, und andere Öffnungen und Kanäle durch Kegelflächen verschlossen werden.The present invention thus relates to a device for handling liquids in at least two channels, consisting of a component, hereinafter called channel support, in which the channels start in a star shape - from a cone and a second component, hereinafter called a pump element, which has at least one Contains variable volume chamber and through a conical end with at least one integrated lateral opening to at least one of the volumes, the cone of the components being fitted into one another, so that by rotating the components relative to one another about the cone axes, at least one opening of the pump element tes can be brought into contact with at least one of the channels of the channel carrier, and a connection between see at least one volume and at least one channel, and other openings and channels are closed by conical surfaces.
Bevorzugt ist, dass ein Kolben darin angeordnet ist, der in Richtung der Kegelachsen bewegbar ist und das Volumen mindestens einer Kammer des Pumpenelements durch einen Kolben variierbar ist.It is preferred that a piston is arranged therein, which is movable in the direction of the cone axes and the volume of at least one chamber of the pump element can be varied by a piston.
Weiterhin ist bevorzugt, dass darin eine Feder angeordnet ist, die den Kolben bewegt.It is further preferred that a spring is arranged therein which moves the piston.
Besonders bevorzugt ist ferner, dass darin ein Linearreaktor angeordnet ist, der den Kolben bewegt.It is also particularly preferred that a linear reactor is arranged therein that moves the piston.
Eine erfindungsgemäße Vorrichtung ist bevorzugt, wobei die Kanäle in dem Kanalträger durch Zusammenfügen von mindestens zwei Flächen gebildet sind, wobei mindestens eine der Flächen mit den offenen Kanälen strukturiert ist, und die Kanäle durch das Zusammenfügen der Flächen gedeckelt werden.A device according to the invention is preferred, the channels in the channel carrier being formed by joining together at least two surfaces, at least one of the surfaces being structured with the open channels, and the channels being capped by joining the surfaces.
Weiterhin ist bevorzugt, dass mindestens ein Teil des Kanalträgers und dessen Struktur erhältlich ist durch Frä- sen, Spritzgießen, Heißprägen, Laserschneiden, Stanzen und/oder Ätzen.It is further preferred that at least part of the channel support and its structure can be obtained by milling, injection molding, hot stamping, laser cutting, stamping and / or etching.
Besonders bevorzugt ist es, dass mindestens ein Teil des Kanalträgers aus Kunststoff, Glas, Metall oder Cellulose Material besteht.It is particularly preferred that at least part of the channel support consists of plastic, glass, metal or cellulose material.
Erfindungsgemäß bevorzugt ist ferner, dass mindestens ein Kanal des Kanalträgers zu einer in den Kanalträger strukturierten Kammer führt. Erfindungsgemäß bevorzugt ist auch, dass mindestens ein Kanal des Kanalträgers zu einer in den Kanalträger strukturierten Kammer führt, die durch mindestens eine weitere Öffnung zugänglich ist.It is further preferred according to the invention that at least one channel of the channel carrier leads to a chamber structured in the channel carrier. It is also preferred according to the invention that at least one channel of the channel carrier leads to a chamber structured in the channel carrier which is accessible through at least one further opening.
Besonders bevorzugt ist es erfindungsgemäß, dass mindestens ein Kanal des Kanalträgers zu einer in den Kanalträger strukturierten Kammer führt, in der Reagenzien vorgelegt sind. Dabei ist es besonders bevorzugt, dass die Re- agenzien in fester Form vorliegen.It is particularly preferred according to the invention that at least one channel of the channel carrier leads to a chamber structured in the channel carrier in which reagents are placed. It is particularly preferred that the reagents are in solid form.
Ein Gegenstand der vorliegenden Erfindung ist auch die Verwendung einer erfindungsgemäßen Vorrichtung, wobei man eine automatisierte Bisulfitreaktion durchführt.The present invention also relates to the use of a device according to the invention, an automated bisulfite reaction being carried out.
Beschrieben wird eine Vorrichtung zum Handhaben von Flüssigkeiten in einer Mehrzahl von Kanälen. Diese Vorrichtung besteht aus einem Kanalträger und einem Pumpenelement (Fig. 1) , die bevorzugt auf einer Operationsplatt- form angeordnet werden.An apparatus for handling liquids in a plurality of channels is described. This device consists of a channel support and a pump element (FIG. 1), which are preferably arranged on an operating platform.
Die Kanäle des Kanalträgers sind sternförmig von einem Kegel ausgehend angeordnet. Vorzugsweise kommen die Kanäle in dem Kanalträger durch Zusammenfügen von mindestens zwei Flächen zustande, wobei mindestens eine der Flächen mit den offenen Kanälen strukturiert ist, und die Kanäle durch das Zusammenfügen der Flächen gedeckelt werden.The channels of the channel support are arranged in a star shape starting from a cone. The channels in the channel support preferably come about by joining together at least two surfaces, at least one of the surfaces being structured with the open channels, and the channels being capped by joining the surfaces.
Es ist bevorzugt, dass mindestens ein Teil des Kanalträ- gers auf einer Fräse gefertigt wird oder vorzugsweise ein Spritzgussteil ist. Alternativ ist es auch bevorzugt, dass mindestens ein Teil des Kanalträgers heiß geprägt oder vorzugsweise mit einem Laser strukturiert wird. Alternativ ist es ebenso bevorzugt, dass mindestens ein Teil des Kanalträgers gestanzt wird oder durch Ätzen strukturiert wird. Mindestens ein Teil des Kanalträgers wird aus Kunstoff (z.B. Polymethylmethacrylat (PMMA) , Po- lycarbonat, Polytetrafluorethylen (TEFLON™) , Polyvinylchlorid (PVC), Polydimethylsiloxan (PDMS) , Polysulfon, Polystyren, Polymethylpenten, Polypropylen, Polyethylen, Polyvinylidin Fluorid oder ABS (Acrylonitril-butadien- styren Copolymer) , Glas, Metall oder Cellulose Material gefertigt .It is preferred that at least a part of the channel support is manufactured on a milling machine or is preferably an injection molded part. Alternatively, it is also preferred that at least a part of the channel carrier is hot stamped or preferably structured with a laser. Alternatively, it is also preferred that at least a part of the channel carrier is punched or structured by etching. At least part of the channel support is made of plastic (e.g. polymethyl methacrylate (PMMA), polycarbonate, polytetrafluoroethylene (TEFLON ™), polyvinyl chloride (PVC), polydimethylsiloxane (PDMS), polysulfone, polystyrene, polymethylpentene, polypropylene, polyethylene, polyvinylidine fluoride or ABS (acrylonitrile butadiene styrene) Copolymer), glass, metal or cellulose material.
Das Pumpenelement ist gekennzeichnet durch mindestens ei- ne Kammer mit variablem Volumen und durch ein kegeligesThe pump element is characterized by at least one chamber with variable volume and by a conical one
Ende mit mindestens einer integrierten seitlichen Öffnung zu mindestens einem der Volumina, wobei der Kegel des Pumpenelements" in den Kegel des Kanalträgers eingepasst wird, so dass durch Drehen der Komponenten relativ zuein- ander um die Kegelachsen mindestens eine Öffnung des Pumpenelementes mit mindestens einem der Kanäle des Kanalträgers in Kontakt gebracht werden und eine Verbindung zwischen mindestens einem Volumen und mindestens einem Kanal zustande kommt, und alle anderen Öffnungen und Ka- näle durch Kegelflächen verschlossen werden.End with at least one integrated lateral opening to at least one of the volumes, the cone of the pump element " being fitted into the cone of the channel support, so that by rotating the components relative to one another about the cone axes, at least one opening of the pump element with at least one of the channels of the channel support are brought into contact and a connection is established between at least one volume and at least one channel, and all other openings and channels are closed by conical surfaces.
Bevorzugt ist es, dass die Kammer des Pumpenelements als Zylinder ausgestaltet ist und mit einem beweglichen Kolben das Volumen variiert wird. Besonders bevorzugt ist es, dass der Kolben mit einer Feder in seine Ausgangslage zurückgetrieben wird, wenn er aus dieser herausgebracht wurde .It is preferred that the chamber of the pump element is designed as a cylinder and the volume is varied with a movable piston. It is particularly preferred that the piston is driven back to its starting position with a spring when it has been brought out of it.
Bevorzugt hat die Operationsplattform die Funktion, den Kanalträger zu fixieren und das Pumpenelement so gegen den Kanalträger zu pressen, dass die Kegel dieser Komponenten ineinander eingepasst werden. Das Drehen des Pumpenelements um die Kegelachsen wird besonders bevorzugt durch einen in der Operationsplattform angeordneten Motor durchgeführt. Die Bewegung des Kolbens wird bevorzugt durch einen in der Operationsplattform angeordneten Linearreaktor durchgeführt.The operating platform preferably has the function of fixing the channel carrier and pressing the pump element against the channel carrier in such a way that the cones of these components are fitted into one another. The pump element is particularly preferably rotated about the cone axes by a motor arranged in the operating platform. The movement of the piston is preferred performed by a linear reactor arranged in the operating platform.
Zum Ansaugen einer Flüssigkeit aus einem Kanal des Kanal- trägers in eine Kammer des Pumpenelements wird eine Verbindung zwischen dem Kanal und der Kammer hergestellt und das Kammervolumen vergrößert. Die Variation des Kammervolumens erfolgt vorzugsweise durch einen Kolben, der in Richtung der Kegelachsen bewegt wird. Bevorzugt wird der Kolben mit einem Linearreaktor aus der Ausgangslage herausbewegt und besonders bevorzugt mit einer Feder zurückgetrieben.In order to draw in a liquid from a channel of the channel carrier into a chamber of the pump element, a connection is established between the channel and the chamber and the chamber volume is increased. The chamber volume is preferably varied by a piston which is moved in the direction of the cone axes. The piston is preferably moved out of the starting position with a linear reactor and particularly preferably driven back with a spring.
Zur Entnahme einer Flüssigkeit aus einem Strukturelement des Kanalträgers wird eine Kammer des Pumpenelements mit einem Kanal des Kanalträgers verbunden, der mit dem Strukturelement verbunden ist und die Flüssigkeit ansaugt. Es ist bevorzugt, dass Strukturelemente mindestens eine weitere Öffnung enthalten, durch die ein Druckaus- gleich stattfindet.To remove a liquid from a structural element of the channel support, a chamber of the pump element is connected to a channel of the channel support, which is connected to the structural element and sucks in the liquid. It is preferred that structural elements contain at least one further opening through which pressure equalization takes place.
Zum Ausstoßen einer Flüssigkeit aus einer Kammer des Pumpenelements in einen Kanal des Kanalträgers werden Kanal und Kammer verbunden und das Kammervolumen verkleinert.To eject a liquid from a chamber of the pump element into a channel of the channel support, the channel and chamber are connected and the chamber volume is reduced.
Zum Befüllen eines Strukturelements des Kanalträgers mit Flüssigkeit aus der Kammer des Pumpenelements wird dieses mit einem Kanal des Kanalträgers verbunden, der mit dem Strukturelement verbunden ist und die Flüssigkeit aus der Kammer des Pumpenelements ausgestoßen. Es ist bevorzugt, dass Strukturelemente mindestens eine weitere Öffnung enthalten, durch die ein Druckausgleich stattfindet.To fill a structural element of the channel carrier with liquid from the chamber of the pump element, this is connected to a channel of the channel carrier which is connected to the structural element and the liquid is expelled from the chamber of the pump element. It is preferred that structural elements contain at least one further opening through which pressure equalization takes place.
Zum Bewegen einer Flüssigkeit in einem Strukturelement des Kanalträgers wird die Flüssigkeit angesaugt und aus- gestoßen. Bevorzugt wird die Flüssigkeit zum Bewegen erst ausgestoßen und dann angesaugt.To move a liquid in a structural element of the channel carrier, the liquid is sucked in and out encountered. The liquid for movement is preferably first expelled and then sucked in.
Zum Dosieren wird ein erster Kanal des Kanalträgers in Verbindung mit einer Kammer des Pumpenelements gebracht und die zu dosierende Flüssigkeit in die Kammer angesaugt. Bevorzugt wird nach dem Ansaugen eventuell in der Kammer vorhandene Luft ausgestoßen. Besonders bevorzugt wird dafür die Kammer mit einem dafür vorgesehenen Ent- lüftungskanal des Kanalträgers verbunden. Dann wird die Kammer mit weiteren Kanälen des Kanalträgers verbunden und die Flüssigkeit kontrolliert ausgestoßen.For dosing, a first channel of the channel carrier is brought into connection with a chamber of the pump element and the liquid to be dosed is sucked into the chamber. Air that is possibly present in the chamber is preferably expelled after the suction. For this purpose, the chamber is particularly preferably connected to a ventilation channel of the channel carrier provided for this purpose. Then the chamber is connected to other channels of the channel carrier and the liquid is expelled in a controlled manner.
Zum Pumpen einer Flüssigkeit durch ein Strukturelement des Kanalträgers mit mindestens zwei Öffnungen, im folgenden Durchflusselement genannt, wird ein Volumen in das Durchflusselement dosiert, welches das Volumen des Durchflusselements überschreitet. Bevorzugt ist mindestens eine weitere Öffnung des Durchflusselements mit einer Kam- mer verbunden, die im folgenden Auffangkammer genannt wird. Besonders bevorzugt hat die Auffangkammer mindestens eine weitere Öffnung, die durch einen weiteren Kanal mit der Kegelfläche des Kanalträgers verbunden ist und durch welche die das Durchflusselement passierende Flüs- sigkeit angesaugt wird. Ganz besonders bevorzugt ist es, wenn die Öffnungen zum Flüssigkeitstransport sich am Boden der Auffangkammer befinden, und mindestens eine weitere Öffnung zum Druckausgleich oberhalb des maximal zu erwartenden Füllstands der Auffangkammer vorhanden ist. Weiterhin ist es bevorzugt, die Flüssigkeit in der Auffangkammer vorzulegen und dann durch das Durchflusselement anzusaugen.For pumping a liquid through a structural element of the channel support with at least two openings, hereinafter called a flow element, a volume is metered into the flow element which exceeds the volume of the flow element. At least one further opening of the flow element is preferably connected to a chamber, which is referred to below as the collecting chamber. The collecting chamber particularly preferably has at least one further opening which is connected to the conical surface of the channel support by a further channel and through which the liquid passing through the flow element is sucked in. It is very particularly preferred if the openings for liquid transport are located at the bottom of the collecting chamber and there is at least one further opening for pressure compensation above the maximum expected filling level of the collecting chamber. Furthermore, it is preferred to place the liquid in the collecting chamber and then to suck it in through the flow element.
Zum Mischen von Flüssigkeiten in einer Kammer des Pumpen- elements werden die zu mischenden Flüssigkeiten sequen- ziell oder parallel in die Kammer angesaugt. Bevorzugt wird das Gemisch dann mindestens einmal ausgestoßen und angesaugt, um so die Durchmischung zu verstärken. Besonders bevorzugt wird die Kammer dazu mit einem dafür vorgesehenem Mischkanal des Kanalträgers verbunden. Ganz be- sonders bevorzugt ist der Mischkanal mit Strukturelementen versehen, die das Mischen begünstigen.To mix liquids in a chamber of the pump element, the liquids to be mixed are sucked into the chamber sequentially or in parallel. Prefers the mixture is then expelled and sucked in at least once, so as to intensify the mixing. For this purpose, the chamber is particularly preferably connected to a mixing channel of the channel support provided for this purpose. The mixing channel is very particularly preferably provided with structural elements which promote mixing.
Zum Mischen von Flüssigkeiten in einer Kammer des Kanalträgers, im folgenden Mischkammer genannt, werden die Flüssigkeiten sequenziell oder parallel in die Mischkammer dosiert. Bevorzugt wird dass Gemisch dann mindestens einmal angesaugt und ausgestoßen, um die Durchmischung zu verstärken. Besonders bevorzugt ist die Mischkammer mit Strukturelementen versehen, die das Mischen begünstigen.To mix liquids in a chamber of the channel support, hereinafter referred to as the mixing chamber, the liquids are dosed sequentially or in parallel into the mixing chamber. The mixture is then preferably sucked in and expelled at least once in order to intensify the mixing. The mixing chamber is particularly preferably provided with structural elements which promote mixing.
Zum Abtrennen von mindestens einer Komponente aus einer Flüssigkeit wird die Flüssigkeit in ein Strukturelement des Kanalträgers dosiert, im folgenden Absorber genannt, das mindestens eine Oberfläche beinhaltet, welche mindes- tens eine abzutrennende Komponente bindet. Bevorzugt wird die Flüssigkeit nach dem Abtrennen wieder angesaugt. Besonders bevorzugt ist der Absorber als Durchflusselement ausgebildet .In order to separate at least one component from a liquid, the liquid is metered into a structural element of the channel support, hereinafter referred to as absorber, which contains at least one surface which binds at least one component to be separated. The liquid is preferably sucked in again after the separation. The absorber is particularly preferably designed as a flow element.
Zum Aufnehmen einer in dem Absorber abgetrennten Komponente wird eine Flüssigkeit in den Absorber dosiert, welche die gebundene Komponente wieder ablöst (im folgenden Eluent genannt) .To take up a component separated in the absorber, a liquid is metered into the absorber which detaches the bound component again (hereinafter referred to as eluent).
Zum Säulen einer Flüssigkeit wird diese in ein Durchflusselement des Kanalträgers dosiert, welches mit einem Säulenmaterial gefüllt ist.To pillar a liquid, it is metered into a flow element of the channel support, which is filled with a pillar material.
Zum Filtrieren einer Flüssigkeit wird diese in ein Durch- flusselement des Kanalträgers dosiert, welches mindestens einen Filter enthält. Bevorzugt ist das Durchflusselement mit einem Filtermaterial gefüllt.To filter a liquid, it is metered into a flow element of the channel support, which at least contains a filter. The flow element is preferably filled with a filter material.
Zum Temperieren einer Flüssigkeit wird diese in eine Ka - mer des Kanalträgers dosiert, welche im folgenden Temperierkammer genannt wird. Diese wird durch Kontakt mit einem Heiz- oder Kühlelement auf der gewünschten Temperatur gehalten. Bevorzugt ist das Heiz- oder Kühlelement ein Bestandteil des Kanalträgers. Besonders bevorzugt ist das Heiz- oder Kühlelement Bestandteil einer Operationsplattform und in mechanischem Kontakt zu mindestens einer Wandung der Temperierkammer.To temper a liquid, it is dosed into a chamber of the channel support, which is called the tempering chamber in the following. This is kept at the desired temperature by contact with a heating or cooling element. The heating or cooling element is preferably a component of the channel support. The heating or cooling element is particularly preferably part of an operating platform and in mechanical contact with at least one wall of the temperature control chamber.
Die folgende Durchführung einer automatisierten Bisul- fitreaktion ist ein Beispiel für eine Anwendung der neuen Vorrichtung:The following implementation of an automated bisulfite reaction is an example of an application of the new device:
160 ng DNA werden in einer ersten Kammer des Kanalträgers vorgelegt in 3μl H20 bidest. Diese erste Kammer ist nach oben offen und über einen Kanal mit dem Pumpenelement verbunden. 17μl einer Bisulfitreaktionslösung werden in einer zweiten Kammer vorgelegt. Diese zweite Kammer ist nach oben offen und über einen Kanal mit dem Pumpenelement verbunden. 20 μl Desulfonierungslösung werden in ei- ner dritten Kammer vorgelegt. Diese dritte Kammer ist nach oben offen und über einen Kanal mit dem Pumpenelement verbunden. Ca. 1 ml H20 bidest. werden in einer vierten Kammer vorgelegt. Diese vierte Kammer ist nach oben offen und über einen Kanal mit dem Pumpenelement verbunden. Eine weitere nach oben offene Kammer, die mit einem Kanal mit dem Pumpenelement verbunden ist, bleibt leer und dient zur Aufnahme von Abfall. Desweiteren ist in dem Kanalträger eine flache Kammer (im folgenden Heizkammer) mit 40 μl Fassungsvermögen vorhanden, die über ein Heizelement in der Operationsplattform temperiert wird und über eine weitere kleine Öffnung zum Druckaus- gleich verfügt. Ein weiteres Strukturelement mit 200μl Volumen (im folgenden Aufreinigungskammer) ist mit vorgequollenem Säulenmaterial (0,2 g Sephadex G50 mit 190μl H20 bidest.) gefüllt. Dieses Strukturelement ist über ei- nen weiteren Kanal auf der anderen Seite mit einer weiteren nach oben offenen Kammer verbunden. Des weiteren ist diese offene Kammer mit einem weiteren Kanal mit dem Kegelventil verbunden.160 ng DNA are placed in a first chamber of the channel support in 3μl H 2 0 bidest. This first chamber is open at the top and connected to the pump element via a channel. 17μl of a bisulfite reaction solution are placed in a second chamber. This second chamber is open at the top and connected to the pump element via a channel. 20 μl desulfonation solution are placed in a third chamber. This third chamber is open at the top and connected to the pump element via a channel. Approximately 1 ml H 2 0 bidist. are presented in a fourth chamber. This fourth chamber is open at the top and connected to the pump element via a channel. Another chamber, which is open at the top and is connected to the pump element by a channel, remains empty and is used to hold waste. There is also a flat chamber (hereinafter referred to as the heating chamber) with a capacity of 40 μl in the channel support, which is heated by a heating element in the operating platform and via a further small opening for pressure relief. the same. Another structural element with a volume of 200μl (in the following purification chamber) is filled with pre-swollen column material (0.2 g Sephadex G50 with 190μl H 2 0 bidest.). This structural element is connected via a further channel on the other side to a further chamber which is open at the top. Furthermore, this open chamber is connected to the plug valve by a further channel.
In einem ersten Schritt wird die Bisulfitreaktionslösung vollständig mit dem Pumpenelement aufgesaugt und in die Kammer mit der DNA Lösung abgegeben. Das Gemisch wird dann vollständig aufgesaugt und vollständig in die Heizkammer abgegeben. Die Gemisch in der Heizkammer wird für 3 Minuten auf 95°C gebracht, dann für 10 min auf 50°C, dann für 30 sec auf 95 °C, dann für 30 min auf 50 °C, dann wieder für 30 sec auf 95 °C und abschließend für 3 h auf 50°C. Während des Inkubationsvorgangs werden 180 μl H20 aus der vierten Kammer aufgenommen und mit einer Flussra- te von lOμl/s in die Aufreinigungskammer abgegeben. DieIn a first step, the bisulfite reaction solution is completely sucked up with the pump element and released into the chamber with the DNA solution. The mixture is then completely absorbed and completely released into the heating chamber. The mixture in the heating chamber is brought to 95 ° C. for 3 minutes, then to 50 ° C. for 10 minutes, then to 95 ° C. for 30 seconds, then to 50 ° C. for 30 minutes, then to 95 ° again for 30 seconds C and finally for 3 h at 50 ° C. During the incubation process, 180 μl of H 2 O are taken up from the fourth chamber and released into the purification chamber at a flow rate of 10 μl / s. The
Flüssigkeit, die sich dann in der Auffangkammer befindet, wird über den direkten Kanal mit dem Pumpenelement aufgenommen und in die Abfallkammer abgegeben. Dann wird das Gemisch wieder aufgenommen und in die Aufreinigungskammer abgegeben, wobei die Flussrate etwa 10 μl/s beträgt. Aus der dritten Kammer werden 180μl H20 aufgenommen und mit einer Flussrate von etwa 10 μl/s in die Aufreinigungskammer abgegeben. Die Flüssigkeit, die sich in der Auffangkammer hinter der Aufreinigungskammer gesammelt hat, wird über die direkte Kanalverbindung mit dem Pumpenelement aufgenommen und in die Abfallkammer abgegeben. Dann werden weitere 20 μl H20 aus der dritten Kammer aufgenommen und wieder mit der Flussrate von etwa 10 μl/s in die Aufreinigungskammer abgegeben. Die Flüssigkeit, die sich nun in der Auffangkammer befindet, enthält die aufgereinigte DNA Fraktion. Diese Flüssigkeit wird mit dem Pumpenele- ment durch den direkten Kanal aufgenommen und in die dritte Kammer mit der Desulfonierungslösung abgegeben. Dann wird 40 μl H20 aus der vierten Kammer mit dem Pumpenelement aufgenommen und drei Mal in die Heizkammer ab- gegeben und wieder aufgenommen. Anschließend wird das H20 in die Abfallkammer abgegeben.Liquid, which is then in the collecting chamber, is taken up via the direct channel with the pump element and released into the waste chamber. The mixture is then taken up again and released into the purification chamber, the flow rate being approximately 10 μl / s. 180μl H 2 0 are taken up from the third chamber and released into the purification chamber at a flow rate of approximately 10 μl / s. The liquid that has collected in the collecting chamber behind the purification chamber is absorbed via the direct channel connection to the pump element and released into the waste chamber. Then a further 20 μl of H 2 O are taken up from the third chamber and released again into the purification chamber at a flow rate of approximately 10 μl / s. The liquid that is now in the collecting chamber contains the purified DNA fraction. This liquid is pumped ment taken through the direct channel and released into the third chamber with the desulfonation solution. Then 40 .mu.l of H 2 O is taken up from the fourth chamber with the pump element and released three times into the heating chamber and taken up again. The H 2 0 is then released into the waste chamber.
Dann wird das Gemisch aus DNA Lösung und Desulfonierungslösung aus der dritten Kammer aufgenommen und in die Heizkammer abgegeben und für 10 min bei 95 °C gehalten. Abschließend wird das Gemisch mit dem Pumpenelement wieder aufgenommen und in die dritte Kammer abgegeben, wo es zur weiteren Verwendung zur Verfügung steht .The mixture of DNA solution and desulfonation solution is then taken up from the third chamber and released into the heating chamber and kept at 95 ° C. for 10 min. Finally, the mixture with the pump element is taken up again and released into the third chamber, where it is available for further use.
Die optische Analyse einer Flüssigkeit ist ein weiteres Anwendungsbeispiel der neuen Vorrichtung. Dazu wird die Flüssigkeit in eine Kammer des Kanalträgers dosiert. Optisch detektiert werden beispielsweise in der Flüssigkeit: fluoreszierende Komponenten oder FRET (Fluoresence Resonance Energy Transfer) Paare. Elektronisch detektiert werden beispielsweise in der Flüssigkeit: elektrochemische Potentiale oder angelagerte Komponenten.The optical analysis of a liquid is another application example of the new device. To do this, the liquid is metered into a chamber of the channel carrier. The liquid, for example, is optically detected: fluorescent components or FRET (Fluoresence Resonance Energy Transfer) pairs. The liquid, for example, is detected electronically: electrochemical potentials or attached components.
Eine weiteres Anwendungsbeispiel ist die Hybridisierung von DNA in einer Flüssigkeit. Dazu wird die Flüssigkeit mit der DNA in eine Kammer des Kanalträgers dosiert, im folgenden Hybridisierungskammer genannt, in der mindestens ein Hybridisierungspartner für die DNA an mindestens einer Oberfläche immobilisiert ist.Another application example is the hybridization of DNA in a liquid. For this purpose, the liquid with the DNA is metered into a chamber of the channel support, hereinafter called the hybridization chamber, in which at least one hybridization partner for the DNA is immobilized on at least one surface.
Bevorzugt werden die Hybridisierungspartner auf mindestens einer Komponente des Kanalträgers immobilisiert, bevor der Kanalträger vollständig zusammengesetzt wird. Besonders bevorzugt handelt es sich bei der Hybridisie- rungskammer gleichzeitig um eine Temperierkammer. Ganz besonders bevorzugt wird die DNA vor dem Hybridisieren und eventuell mindestens einmal während der Hybridisierung denaturiert. Weiterhin ist es bevorzugt, die Flüssigkeit mit der DNA während der Hybridisierung mindestens einmal zu bewegen. Bei den Hybridisierungspartnern han- delt es sich um DNA, RNA, PNA, LNA oder Derivate und Modifikationen davon.The hybridization partners are preferably immobilized on at least one component of the channel carrier before the channel carrier is completely assembled. The hybridization chamber is particularly preferably at the same time a temperature control chamber. The DNA is very particularly preferred before hybridization and possibly denatured at least once during hybridization. It is further preferred to move the liquid with the DNA at least once during the hybridization. The hybridization partners are DNA, RNA, PNA, LNA or derivatives and modifications thereof.
Zur optischen Detektion von Hybridisierungsereignissen an immobilisierten Hybridisierungspartnern wird die Hybridi- sierungskammer gleichzeitig als optische Zelle gestaltet, in der optische Veränderungen aufgrund der Anlagerungen von Komponenten durch die Hybridisierung detektiert werden. Bevorzugt wird bei der optischen Detektion eine räumliche Auflösung erreicht und die Hybridisierung in verschiedenen Regionen erfasst.For the optical detection of hybridization events on immobilized hybridization partners, the hybridization chamber is at the same time designed as an optical cell in which optical changes due to the accumulation of components by the hybridization are detected. A spatial resolution is preferably achieved in the optical detection and the hybridization is detected in different regions.
Zur elektronischen Detektion von Hybridisierungsereignissen wird mindestens ein Hybridisierungspartner auf mindestens einer Elektrode, im folgenden Detektionselektrode genannt, in der Hybridisierungskammer immobilisiert und mindestens eine elektroaktive Komponente in die Hybridisierungskammer gebracht. Dabei handelt es sich um inter- kalierende Komponenten, modifizierte DNA, modifizierte DNA Derivate und Komponenten, die Redoxreaktionen mit DNA oder DNA Derivaten eingehen. Je nach Art der elektroakti- ven Komponente wird durch Potenzialmessung oder Anlegen geeigneter elektrischer Spannungsmuster und Erfassung der Spannung-Strom-Kurven der Hybridisierungsgrad an den De- tektionselektroden ermittelt. Dabei wird mindestens eine weitere Elektrode in der Hybridisierungskammer benutzt.For the electronic detection of hybridization events, at least one hybridization partner is immobilized on at least one electrode, hereinafter referred to as the detection electrode, in the hybridization chamber and at least one electroactive component is brought into the hybridization chamber. These are intercalating components, modified DNA, modified DNA derivatives and components that undergo redox reactions with DNA or DNA derivatives. Depending on the type of electroactive component, the degree of hybridization at the detection electrodes is determined by measuring the potential or applying suitable electrical voltage patterns and recording the voltage-current curves. At least one further electrode is used in the hybridization chamber.
Ein zusätzliches Beispiel ist die Durchführung einer PCR- Reaktion in der erfindungsgemäßen Vorrichtung:An additional example is the implementation of a PCR reaction in the device according to the invention:
Zur Durchführung der PCR werden lOng DNA Templat in 2μl bidest. Wasser mit 2,5μl lOx PCR Puffer (Qiagen) , 0,2μl Taq Polymerase (Qiagen) , 0,2 dNTPs (25mM pro Base), 2μl Primermix (jeweils 6,25pmol) und 18,lμl bidest. Wasser gemischt und in die Temperierkammer transferiert. Dann wird die Mischung nach dem folgenden Temperaturprogramm temperiert: 11 Minuten bei 9β°C, dann 40mal für 1 Minute bei 55 °C, gefolgt von 1 Minute bei 72 °C und 1 Minute bei 96°C. Abschließend wird nach einer Minute bei 55°C die Mischung für weitere 20 Minuten bei 72 °C gehalten. Bei Zusatz von interkalierenden Fluoreszensfarbstoffen wie Sybrgreen kann der Fortgang der PCR mit bekannten optischen Anregungs- und Detektionseinheiten direkt beobachtet und ausgewertet werden.To carry out the PCR, lOng DNA template in 2μl bidest. Water with 2.5μl lOx PCR buffer (Qiagen), 0.2μl Taq polymerase (Qiagen), 0.2 dNTPs (25mM per base), 2μl primer mix (6.25pmol each) and 18, lμl bidist. Mixed water and transferred to the temperature control chamber. Then the mixture is tempered according to the following temperature program: 11 minutes at 9 ° C, then 40 times for 1 minute at 55 ° C, followed by 1 minute at 72 ° C and 1 minute at 96 ° C. Finally, after one minute at 55 ° C, the mixture is kept at 72 ° C for a further 20 minutes. With the addition of intercalating fluorescent dyes such as Sybrgreen, the progress of the PCR can be directly observed and evaluated using known optical excitation and detection units.
Anstatt eines interkalierenden Farbstoffes sind auch andere Methoden zur Echtzeiterfassung der Polymerase- Kettenreaktion anwendbar, wie zum Beispiel der TaqMan As- say, der Molecular Beacon Assay und der Scorpion Assay.Instead of an intercalating dye, other methods for real-time detection of the polymerase chain reaction can also be used, such as, for example, the TaqMan Assay, the Molecular Beacon Assay and the Scorpion Assay.
Legende zu den Figuren:Legend for the figures:
Figur 1: 1: Kanal A; 2: Kanal B; 3: Probenflüssigkeit; 4: seitliche Öffnung; 5: Pumpenelement; 6: Volumen im Pumpenelement; 7: Konus; 8: Kanalträger; 9: KolbenFigure 1: 1: Channel A; 2: channel B; 3: sample liquid; 4: side opening; 5: pump element; 6: volume in the pump element; 7: cone; 8: channel carrier; 9: pistons
Figur 2: Ansicht der Operationsplattform 1: Temperierblock; 2: Aufnahme für das Pumpenelement; 3: Motor zum Drehen des Pumpenelements; 4: Linearreaktor; 5: Pumpenelement; 6: KanalträgerFigure 2: View of the operating platform 1: temperature control block; 2: holder for the pump element; 3: motor for rotating the pump element; 4: linear reactor; 5: pump element; 6: channel carrier
Figur 3: Schnitt durch Plattform, Kanalträger und Pumpen- elementFigure 3: Section through platform, channel support and pump element
1: Temperierblock; 2: Aufnahme für das Pumpenelement; 3: Motor zum Drehen des Pumpenelements; 4: Linearreaktor; 5: Stößel vom Linearreaktor; 6: Feder zum Andrücken des Pumpenelements an den Kanalträger; 7: Pumpenelement; 8: Ka- nalträger; 9: Feder zum Zurücktreiben des Pumpenkolbens; 10: Kolben Figur 4 : Aufsicht auf den Kanalträger1: temperature control block; 2: holder for the pump element; 3: motor for rotating the pump element; 4: linear reactor; 5: ram from the linear reactor; 6: spring for pressing the pump element onto the channel support; 7: pump element; 8: channel support; 9: spring for driving back the pump piston; 10: pistons Figure 4: Top view of the channel support
1: Temperierkammer; 2: Konus; 3: Säule; 4: Säulenmaterial; 5: Fritte; 6: Auffangkammer; 7: Abfall; 8: Desulfo- nierungslösung; 9: Bisulfitlösung; 10: DNA in Lösung; 11: H20 1: temperature chamber; 2: cone; 3: pillar; 4: column material; 5: frit; 6: collecting chamber; 7: waste; 8: desulfonation solution; 9: bisulfite solution; 10: DNA in solution; 11: H 2 0

Claims

Patentansprüche claims
1. Vorrichtung zur Handhabung von Flüssigkeiten in mindestens zwei Kanälen, bestehend aus einer1. Device for handling liquids in at least two channels, consisting of one
Komponente, im folgenden Kanalträger genannt, in der die Kanäle sternförmig von einem Kegel ausgehen und einer zweiten Komponente, im folgenden Pumpenelement genannt, welche mindestens eine Kammer mit variablem Volumen beinhaltet und durch ein kegelförmiges Ende mit mindestens einer integrierten seitlichen Öffnung zu mindestens einem der Volumina, wobei die Kegel der Komponenten ineinander eingepasst sind, so dass durch Drehen der Komponenten relativ zueinander um die Ke- gelachsen mindestens eine Öffnung des Pumpenelementes mit mindestens einem der Kanäle des Kanalträgers in Kontakt gebracht werden kann, und eine Verbindung zwischen mindestens einem Volumen und mindestens einem Kanal zustande kommt, und andere Öffnungen und Kanäle durch Kegelflächen verschlossen werden.Component, hereinafter referred to as channel support, in which the channels start in a star shape from a cone and a second component, hereinafter referred to as a pump element, which contains at least one chamber with variable volume and through a conical end with at least one integrated lateral opening to at least one of the volumes , the cones of the components being fitted into one another so that by rotating the components relative to one another about the cone axes, at least one opening of the pump element can be brought into contact with at least one of the channels of the channel carrier, and a connection between at least one volume and at least one a channel is created, and other openings and channels are closed by conical surfaces.
2. Vorrichtung nach Anspruch 1, dadurch gekennzeichnet, dass ein Kolben darin angeordnet ist, der in Richtung, der Kegelachsen bewegbar ist und das Volumen mindes- tens einer Kammer des Pumpenelements durch einen Kolben variierbar ist.2. Device according to claim 1, characterized in that a piston is arranged therein which is movable in the direction of the cone axes and the volume of at least one chamber of the pump element can be varied by a piston.
3. Vorrichtung nach Anspruch 2, dadurch gekennzeichnet, dass darin eine Feder angeordnet ist, die den Kolben bewegt.3. Device according to claim 2, characterized in that a spring is arranged therein which moves the piston.
4. Vorrichtung nach Anspruch 2, dadurch gekennzeichnet, dass darin ein Linearreaktor angeordnet ist, der den Kolben bewegt. 4. The device according to claim 2, characterized in that a linear reactor is arranged therein, which moves the piston.
5. Vorrichtung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass die Kanäle in dem Kanalträger durch ' Zusammenfügen von mindestens zwei Flächen gebildet sind, wobei mindestens eine der Flächen mit den offenen Kanälen strukturiert ist, und die Kanäle durch das Zusammenfügen der Flächen gedeckelt sind.5. Device according to one of the preceding claims, characterized in that the channels in the channel support are formed by 'joining at least two surfaces, at least one of the surfaces being structured with the open channels, and the channels being capped by joining the surfaces ,
6. Vorrichtung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass mindestens ein Teil des6. Device according to one of the preceding claims, characterized in that at least part of the
Kanalträgers und dessen Struktur erhältlich ist durch Fräsen, Spritzgießen, Heißprägen, Laserschneiden, Stanzen und/oder Ätzen.Channel carrier and its structure is available by milling, injection molding, hot stamping, laser cutting, stamping and / or etching.
7. Vorrichtung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass mindestens ein Teil des Kanalträgers aus Kunststoff, Glas, Metall oder Cellu- lose Material besteht.7. Device according to one of the preceding claims, characterized in that at least part of the channel support consists of plastic, glass, metal or cellulose material.
8. Vorrichtung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass mindestens ein Kanal des Kanalträgers zu einer in den Kanalträger strukturierten Kammer führt.8. Device according to one of the preceding claims, characterized in that at least one channel of the channel carrier leads to a structured in the channel carrier chamber.
9. Vorrichtung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass mindestens ein Kanal des Kanalträgers zu einer in den Kanalträger strukturierten Kammer führt, die durch mindestens eine weitere Öffnung zugänglich ist.9. Device according to one of the preceding claims, characterized in that at least one channel of the channel carrier leads to a structured in the channel carrier chamber, which is accessible through at least one further opening.
10. Vorrichtung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass mindestens ein Kanal des Kanalträgers zu einer in den Kanalträger strukturierten Kammer führt, in der Reagenzien vorgelegt sind. 10. Device according to one of the preceding claims, characterized in that at least one channel of the channel carrier leads to a structured in the channel carrier chamber in which reagents are presented.
11. Vorrichtung nach Anspruch 11, dadurch gekennzeichnet, dass die Reagenzien in fester Form vorliegen.11. The device according to claim 11, characterized in that the reagents are in solid form.
12. Verwendung der Vorrichtung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass man eine automatisierte Bisulfitreaktion durchführt. 12. Use of the device according to one of the preceding claims, characterized in that one carries out an automated bisulfite reaction.
EP03760576A 2002-06-24 2003-06-23 Device for handling liquids contained in a plurality of channels Withdrawn EP1521635A1 (en)

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