EP2482982B1 - Flat body in the manner of a chip card for biochemical analysis - Google Patents
Flat body in the manner of a chip card for biochemical analysis Download PDFInfo
- Publication number
- EP2482982B1 EP2482982B1 EP10760321.9A EP10760321A EP2482982B1 EP 2482982 B1 EP2482982 B1 EP 2482982B1 EP 10760321 A EP10760321 A EP 10760321A EP 2482982 B1 EP2482982 B1 EP 2482982B1
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- EP
- European Patent Office
- Prior art keywords
- flat body
- sensor chip
- microfluidic device
- cup
- flat
- 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.)
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Classifications
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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
- B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
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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
- 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
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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
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0663—Whole sensors
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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
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0672—Integrated piercing tool
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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
- 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
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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
- 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
- B01L2300/0883—Serpentine channels
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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
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0887—Laminated structure
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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
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
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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
- B01L3/02—Burettes; Pipettes
- B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
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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
- B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
- B01L3/5082—Test tubes per se
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
Definitions
- the present invention relates to a flat body in the manner of a chip card for the biochemical analysis of substances according to the preamble of claim 1.
- the flat body has at least two microfluidic devices and at least one sensor chip.
- the at least one sensor chip is integrated in the flat body and is in direct contact with at least one first microfluidic device.
- a flat body for biochemical analysis of substances such as DNA and proteins known.
- This flat body has the shape of a chip card, which is designed analogously to a credit card.
- the flat body includes a semiconductor chip having a sensor array and integrated circuits, the semiconductor chip being potted in a flat plastic material and being electrically connected to electrical contacts for reading the chip through an external readout unit.
- On a front side of the flat body are formed as recesses in the plastic microfluidic device such as reaction chambers and channels. The front side is covered with a film and the microfluidic devices are so fluid-tight with respect to the environment, that is tightly sealed against liquids and / or gases.
- the film of the chip card is pierced via a pointed needle analogous to a syringe tip, and the liquid is injected into a microfluidic device of the chip card.
- the liquid comes into contact with sensors of the sensor array on the chip and constituents of the liquid can be detected directly or indirectly. Detection may be optical or electrochemical. Substances which are necessary for chemical reactions to detect the constituents of the liquid can already be located on or in the chip card or can likewise be injected into this via a pointed needle.
- the absorption capacity of microfluidic devices on a chip card for receiving liquid is usually very low and is often limited to only a few milliliters, or to microliters or in extreme cases only to nanoliters.
- Another problem with supplying liquid to or into the chip card via pointed needles may be the introduction of contaminants.
- the slightest chemical or biochemical impurities can lead to errors in the quantitative and / or qualitative detection.
- any additional device e.g. a needle with which the liquid to be examined is brought into contact increases the probability of contamination.
- An increased effort, which is cost and time consuming, must be provided to ensure the detection quality, e.g. by thorough cleaning of all devices.
- the device comprises a reaction chamber and a flat body.
- the sample is amplified within the reaction chamber using reagents. Subsequently, the amplified sample is transferred to the flat body, wherein the flat body has an optical detection device for detecting the nucleic acids.
- the WO 2009/115608 A2 relates to a cartridge system for sample preparation and sample analysis, wherein the cartridge system comprises a flat body and a sample container.
- the sample container can be inserted linearly into the flat body so that a fluid transfer of the sample from the sample container to the flat body takes place.
- Detection devices for analyzing the sample are provided in the flat body.
- the object of the present invention is therefore to provide a flat body in the form of a chip card for biochemical analysis, in which it is possible in a simple and cost-effective manner, fluids such.
- Liquids to introduce directly from a vessel in microfluidic devices of the flat body.
- it is an object to introduce fluids into the microfluidic devices of the flat body, wherein the fluids are brought into contact with or flow through as few autarkic individual parts as possible.
- the flat body according to the invention in the manner of a chip card for the biochemical analysis of substances comprises at least two microfluidic devices and at least one sensor chip.
- the at least one sensor chip is integrated in the flat body and is in direct contact with at least one first microfluidic device.
- the flat body integrally comprises a second microfluidic device in the manner of a pipette. Integral means that the second microfluidic device and the remaining flat body are made of at least one material together and form a coherent body, without the second microfluidic device is attached to the flat body, clamped or otherwise repeatedly attached separable and fastened.
- the advantage of a flat body with integrated pipette lies in the possibility of large quantities of liquid between a vessel, as e.g. represents an e-cup, and the flat body easy and fast exchange. Since the flat body and the pipette integrated therein can be made of one material together, both have the same chemical and biochemical purity levels. An entrainment of impurities by additional parts in the flat body is thus prevented.
- the possible production in one step reduces costs and effort and leads to a higher stability than plugging solutions of e.g. Syringe cannula needles made of metal.
- the flat body may comprise a first clamping device, which is designed to attach an e-cup directly mechanically to the flat body.
- E-cups are used as reaction vessels and are available eg from Eppendorf® and then known by the short form "Eppi". By default, the vessels have different sizes and can accommodate different volumes of solution, eg from 0.2 ml to 2 ml. They are characterized by good chemical resistance and are dimensionally stable up to more than 100 ° C.
- the clamping device would have a diameter substantially equal to the inner diameter of an e-cup to be fastened at its opening. A mechanical attachment of the e-cup directly to the flat body by the terminals represents a particularly simple and stable way to attach the e-cup to the flat body.
- the flat body may comprise a second clamping device, which is designed to fasten a lid of an e-cup directly mechanically to the flat body. This increases the stability of the attachment of an E-cup to the flat body and leads to an improvement of the handling, since the lid does not disturb movably relative to the flat body during filling or the removal of liquid from the E-Cup.
- the second microfluidic device may be elongated and comprise at one end a tip with a fluidic opening. It can be designed so that when mounting an E-cup on the first and / or second clamping device, the tip of the second microfluidic device is arranged with the fluidic opening in the region of a lower end of the E-cup. As a result, an almost complete removal of liquid from the e-cup is made possible with the aid of the second microfluidic device.
- the flat body may consist of a plastic material, in particular an injection-molded plastic. Injection molding plastic is easy to work with and enables cost-effective production of the flat body.
- the microfluidic devices may be formed on a front side of the flat body and covered with a foil, in particular a self-adhesive foil of plastic material. This allows a simple and cost-effective production of the flat body with microfluidic devices.
- the at least two microfluidic devices may include channels and / or chambers, which are formed as depressions in a flat plane of the front side of the flat body. Furthermore, the at least two microfluidic devices may comprise valves formed in the flat body. The at least two microfluidic devices may also comprise a recess, which is formed as a recess in a flat plane of the rear side of the flat body and in which the sensor chip embedded is, in particular with electrical contacts of the sensor chip in a plane with the flat plane of the back of the flat body and with a sensor array of the sensor chip in direct contact with at least one chamber on the front side of the flat body.
- the at least two microfluidic devices are thereby suitable for facilitating good handling of liquids and for transporting liquids from an e-cup to sensors on the chip.
- chemical reactions of liquids or substances in the liquids can take place eg in chambers with solid phase reagents.
- the flat body may have a thickness in the range of one millimeter, a length in the range of 85 millimeters and a width in the range of 54 millimeters.
- At least one microfluidic device may be configured to include dry reagents, especially in channels and / or reaction spaces having a cross-section in the range of one or more square millimeters.
- the second microfluidic device may have a length in the range of 45 millimeters.
- the second microfluidic device may be in fluidic contact with sensors of the sensor chip via the first microfluidic device.
- a cross section through the second microfluidic device, perpendicular to the front side of the flat body, may have a substantially rectangular outer periphery with an open recess towards the front side of the flat body.
- the sensor chip may comprise an array of electrochemical sensors. As a result, with the flat body electrochemical measurements are possible, which are easier, cheaper and better to perform in the smallest space than optical measurements.
- the sensor chip may further comprise an integrated circuit for processing electrical signals from the sensors.
- the sensor chip can also comprise electrical contacts for the electrical readout of the sensor chip, in particular for the electrical readout of the sensor chip with the aid of an external data processing unit.
- the flat body can have at least one opening on its front and / or rear side, which is in fluidic contact with the at least one first microfluidic device, and / or which is designed to connect an external pump.
- small amounts of substances used for the detection in particular in liquid form, can be supplied to the flat body via this opening or openings.
- a negative pressure in the microfluidic devices can also be achieved via the at least one opening, e.g. be generated by means of a pump and serve to suck liquid from an e-cup in the flat body or its microfluidic devices into it.
- the second microfluidic device can take up liquid from the E-cup in a first step and deliver liquid into the E-cup in a second step, wherein in particular the first and the second step are repeated at intervals.
- This allows a kind of rinsing of the microfluidic devices with liquid from the e-cup.
- reactions which require a large amount of solution with large volume, not perform in the microfluidic devices, but in a docked E-Cup.
- a combination of reactions in the E-cup and the microfluidic devices in different order is also possible.
- a liquid to be examined for example, blood, urine, fresh or waste water
- the flat body according to the invention and the method for its use are particularly well suited but are not limited to being used at low concentrations of substance to be detected and large volumes of solution of the liquid required for detection. If the concentration of the substance to be detected is so low that a volume of liquid necessary for the detection exceeds the capacity of the microfluidic devices formed in or on the flat body, reactions can be carried out in a docked E cup and the ready-reacted liquids can be carried out via the second microfluidic Device are supplied to the sensors of the sensor chip in the flat body.
- the sensors of the sensor chip can detect, for example, DNA, RNA, peptides or antibodies.
- Substances which are involved in the detection and in the preparation can be stored, for example, in chambers or channels of the flat body, in particular as dry reagents.
- the chemical reaction can be liquid an e-cup are sucked into the microfluidic devices and mixed with the stored substances, eg for dissolving dry reagents, and then released again to the e-cup. In the e-cup can then react a larger volume of fluid than in the microfluidic devices.
- a portion of the liquid in the e-cup may be drawn over the first into the second microfluidic device, eg by applied vacuum to openings of the first microfluidic device, and at the sensors detection of reaction products or directly from in the liquid contained substances.
- Fig. 1 is merely for explanatory purposes a plan view of a front side 7 of the flat body without cover and a section through a E cup 5 shown.
- the flat body 1 is in the form of a chip card or in the form of a credit card. Values for the size ratios of such a chip card are, for example, height H x width B x thickness D equal to 5.5 cm x 8.5 cm x 0.1 cm.
- On the front side 7 microfluidic devices 4, 7 are formed as depressions in the flat body 1.
- the flat body 1 consists for example of a plastic material, in particular an injection-molded plastic.
- Microfluidic devices 4 are, for example, channels 9 and chambers 10, which may have a width in the range of 1 mm to 5 mm and a depth of about 100 ⁇ m.
- chambers may have a length of 1mm to 10mm and channels may have a length in the range of 1cm to 100cm.
- reagents can be stored, for example, in dried form.
- a sensor chip 2 is fixed, for example by gluing.
- the sensor chip 2 with a sensor array on one side and electrical contacts for reading the sensor chip 2 on the other side of the sensor chip 2 is arranged in the recess such that the side of the sensor chip 2 with the sensor -Array forms the bottom of a microfluidic chamber 10 ', which serves as a reaction and / or detection chamber.
- the side of the sensor chip 2 with the electrical contacts forms with the rear side 8 of the flat body 1 a plane.
- Sensors of the sensor array can detect optically or electrochemically substances or reaction products in a liquid which is located in the microfluidic chamber 10 '. Electrical signals from the sensors can be delivered via the electrical contacts of the sensor chip 2 to external measuring and data processing devices or processed by integrated circuits on the sensor chip 2 and displayed directly or transmitted via the electrical contacts.
- the microfluidic devices 3, 9, 10, 10 ' are supplied.
- a control of the supply can be effected via valves 11, which are formed in the flat body 1. It is also fluids such as air via the inlet and outlet openings 12 are supplied to the flat body or removed, with a positive or negative pressure in the microfluidic devices 3, 9, 10, 10 'is generated.
- the flat body 1 comprises a second microfluidic device 4 which has the shape and function of a flattened pipette.
- the second microfluidic device 4 is in one piece with the flat body made of e.g. Made of plastic.
- the length L may be in the range of 2.5 cm, depending on the size of an e-cup 5 to be used. The length should be close to the depth of the e-cups 5, i. the distance from the opening 15 to the bottom 14 of the e-cup 5 amount. As a result, an almost complete removal of liquid from an e-cup 5 with the aid of the second microfluidic device 4 is made possible.
- the thickness of the second microfluidic device 4 is equal to the thickness of the flat body, e.g. 1 mm.
- a channel 9 ' is formed as a depression which corresponds approximately to the size of channels 9 of the first microfluidic device 3 in the remaining flat body 1. So its width is in the range of 1mm and its depth in the range of 100 ⁇ m.
- the channel 9 ' is fluidically connected via channels 9 and / or chambers 10 with sensors of the sensor chip 2.
- the width of the second microfluidic device 4 is e.g. 2mm.
- an e-cup 5 are attached to the flat body 1 by clamping.
- a section through an e-cup 5 is shown.
- reaction vessels in the form of "Eppis" can be used which absorb, for example, a volume of liquid in the range of 1ml to 100ml.
- liquid can be contained in the e-cup 5 to be examined liquid such as blood, urine, process water or drinking water.
- This liquid can be prepared in the e-cup 5 for examination.
- cells can be digested, DNA multiplied, markers coupled and / or a fish out or concentrated by means of certain molecules in the e-cup 5 done.
- the liquid to be examined can be introduced untreated via the second microfluidic device 4 into the flat body 1.
- liquid may be contained in the e-cup 5 instead of the liquid to be examined in a study substances involved.
- the second microfluidic device 4 is fluidically connected to the first microfluidic device 3 and is introduced into an e-cup 5 such that liquid from the e-cup 5 via the second microfluidic device 4 via capillary forces or a negative pressure in the first microfluidic device 3 into the first microfluidic device 3 and the sensor array of the sensor chip 2 passes. Via an overpressure in the first microfluidic device 3, fluid from the first microfluidic device 3 can be introduced into the e-cup 5 via the second microfluidic device 4.
- Chemical reactions that require a lot of solution volume and therefore can not be performed in a microfluidic device 3 take place in the e-cup "outsourced”. Subsequently, the reaction product in the flat body 1 can be further processed or detected directly via the sensors.
- the clamping device 6a is formed as a broadening of the second microfluidic device 4. This makes possible a simple and cost-effective production of the clamping device 6a in one step together with the flat body 1 including the second microfluidic device 4 as an integral body made of injection-molded plastic.
- the Microfluidic devices 3, 4 are sealed by means of a foil.
- a self-adhesive and / or glued foil completely cover the front side 7 of the flat body 1, including the first and second microfluidic devices 3, 4.
- a thermally welded film can be applied partially or completely on the flat body 1.
- the openings 12 can be pierced if necessary by needles.
- An opening at the tip 13 of the second microfluidic device 4 may also be made by tearing, cutting or piercing as needed, or alternatively, when a foil is applied to the flat body 1, the opening at the tip 13 may be formed.
- the clamping device 6a has substantially a width corresponding to the inner diameter of the opening 15 of the E-cup or is slightly, for example about 1mm, larger.
- the simplest form of the clamping device is rectangular, in particular with rounded corners.
- Friction leads to a mechanical clamping of the e-cup 5 to the flat body 1, especially to the clamping device 6a of the Flat body 1.
- a simple pushing on the E-cup 5 on the clamping device 6a is also given if the clamping device 6a has the outline of a section through a barrel, with convex bulges on the two opposite edges.
- Fig. 1 only a rectangular shape of the clamping device 6a shown.
- the thickness of the clamping device is equal to or substantially equal to the thickness of the remaining flat body. 1
- FIG. 2 an embodiment of the flat body 1 with a clamping device 6a and a clamping device 6b is shown.
- the clamping device 6a is analogous to the previously described clamping device 6a.
- a clamping device 6b for clamping a lid of an e-cup 5 is formed in the flat body 1.
- the clamping device 6b is made of two recesses in an edge 17 of the flat body 1 adjacent to the second microfluidic device 4 constructed.
- the recesses with their dimensions have the inverse shape and dimensions of the lower lid part, which in the closed E-cup 5 in the direction of e-cup 5 has.
- the clamping device 6b leads to an improved mechanical connection of an E-cup 5 with the flat body 1 and increased stability of an arrangement E-cup 5 and flat body 1.
- a simple handling of flat body 1 in conjunction with an E-cup 5 is allowed.
- An e-cup 5 can be used in conjunction with the flat body 1 as Sample vessel for supplying the investigated or involved in the reaction of liquids serve as an external reaction vessel or serve as a waste container for liquids to be disposed of.
- the total length of the E-Cup 5 is 30mm and the length in the interior of the E-Cup 5 29mm.
- the outer diameter of the E-Cup 5 is 7.6mm. Decisive for the dimensions of the clamping device 6a, however, the outer diameter of 10 mm and the inner diameter of 6.5 mm of the circular upper edge of the E-cup 5, which has the shape of a brim.
- the clamping device 6a thus also has a width in the range of 6.5 mm or slightly larger, for example, 6.6 mm in this embodiment. As a result, a mechanical attachment is achieved by clamping when pushing the e-cup 5.
- the distance between the transition of the clamping device 6a to the remaining flat body 1 in relation to the tip 13 of the clamping device 6a is 29mm or slightly less at a length of the interior of the e-cup. This ensures that when pushed the E-cup until it stops at the transition of the clamping device 6a to the rest of the flat body 1, the tip 13 in the region of the bottom 14 of E-cup 5 is arranged. Thus, all the liquid in an e-cup 5 can be handled by the second microfluidic device 4.
- the length of the distance of the transition of the clamping device 6a to the remaining flat body 1 in relation to the tip 13 of the clamping device 6a may be formed longer than 29mm. In the event that the entire liquid volume of the E-Cup 5 does not have to be used or handled, the length can also be shorter than 29 mm.
Description
Die vorliegende Erfindung betrifft einen Flachkörper nach Art einer Chip-Karte zur biochemischen Analyse von Substanzen gemäß dem Oberbegriff des Anspruchs 1. Der Flachkörper weist wenigstens zwei mikrofluidische Einrichtungen und wenigstens einen Sensor-Chip auf. Der wenigstens eine Sensor-Chip ist in dem Flachkörper integriert und steht in direktem Kontakt mit wenigstens einer ersten mikrofluidischen Einrichtung.The present invention relates to a flat body in the manner of a chip card for the biochemical analysis of substances according to the preamble of claim 1. The flat body has at least two microfluidic devices and at least one sensor chip. The at least one sensor chip is integrated in the flat body and is in direct contact with at least one first microfluidic device.
In der Biosensorik werden Lab-on-a Chip Systeme eingesetzt, um einfach und kostensparend biochemische Analysen durchführen zu können. So ist z.B. aus der
Bei einer biochemischen Analyse einer Flüssigkeit, wie sie z.B. durch Blut oder Urin gegeben ist, wird über eine spitze Nadel analog einer Spritzenspitze die Folie der Chip-Karte durchstochen, und die Flüssigkeit wird in eine mikrofluidische Einrichtung der Chip-Karte injiziert. Über Kanäle und Reaktionskammern gelangt die Flüssigkeit in Kontakt mit Sensoren des Sensor-Arrays auf dem Chip und Bestandteile der Flüssigkeit können direkt oder indirekt nachgewiesen werden. Ein Nachweis kann optisch oder elektrochemisch erfolgen. Substanzen, welche für chemische Reaktionen zum Nachweis der Bestandteile der Flüssigkeit notwendig sind, können sich schon auf bzw. in der Chip-Karte befinden oder können ebenfalls in diese über eine spitze Nadel injiziert werden.In a biochemical analysis of a liquid, as e.g. is given by blood or urine, the film of the chip card is pierced via a pointed needle analogous to a syringe tip, and the liquid is injected into a microfluidic device of the chip card. Via channels and reaction chambers, the liquid comes into contact with sensors of the sensor array on the chip and constituents of the liquid can be detected directly or indirectly. Detection may be optical or electrochemical. Substances which are necessary for chemical reactions to detect the constituents of the liquid can already be located on or in the chip card or can likewise be injected into this via a pointed needle.
Die Aufnahmekapazität von mikrofluidischen Einrichtungen auf einer Chip-Karte zur Aufnahme von Flüssigkeit ist in der Regel nur sehr gering und ist häufig auf nur wenige Milliliter, oder auf Mikroliter oder im Extremfall nur auf Nanoliter beschränkt.The absorption capacity of microfluidic devices on a chip card for receiving liquid is usually very low and is often limited to only a few milliliters, or to microliters or in extreme cases only to nanoliters.
Bei biochemischen Substanzen, welche in der zu untersuchenden Flüssigkeit nur in sehr geringer Konzentration vorkommen, kann dies dazu führen, dass die Gesamtmenge an Flüssigkeit, mit welcher die Chip-Karte befüllt werden kann, nicht ausreicht um die Nachweisgrenze der biochemischen Substanz zu erreichen bzw. zu überschreiten. Ein Nachweis der biochemischen Substanz ist dann nur bei chemischer Vervielfältigung der biochemischen Substanz, z.B. im Fall von DNA durch PCR, möglich. Im Falle des Nachweises ganzer Zellen kann eine zeit- und kostenintensive Vervielfältigung, z.B. in einem Brutschrank notwendig werden. Bei z.B. chemischen Spurenelementen in Urin oder Wasser kann eine chemische Vervielfältigung ausgeschlossen sein und somit ein Nachweis schwer oder gar nicht möglich werden.With biochemical substances, which occur in the liquid to be examined only in very low concentration, this can mean that the total amount of liquid with which the chip card can be filled is insufficient to reach the detection limit of the biochemical substance or To exceed. Detection of the biochemical substance is then only upon chemical amplification of the biochemical substance, e.g. in the case of DNA by PCR, possible. In the case of detection of whole cells, time-consuming and costly duplication, e.g. become necessary in an incubator. At e.g. Chemical trace elements in urine or water can be excluded from a chemical duplication and thus a detection difficult or impossible.
Ein weiteres Problem der Zuführung von Flüssigkeit zur bzw. in die Chip-Karte über spitze Nadeln kann in der Einschleppung von Verunreinigungen liegen. Gerade in Hinblick auf einen Nachweis von Spurenelementen, DNA oder Peptiden können geringste chemische oder biochemische Verunreinigungen zu Fehlern beim quantitativen und/oder qualitativen Nachweis führen. Mit jeder zusätzlichen Vorrichtung, wie sie z.B. eine Nadel darstellt, mit welcher die zu untersuchende Flüssigkeit in Kontakt gebracht wird, steigt die Wahrscheinlichkeit der Verunreinigung. Ein erhöhter Aufwand, welcher kosten- und zeitintensiv ist, muss zur Gewährleistung der Nachweisqualität erbracht werden, z.B. durch gründliche Reinigung aller Vorrichtungen.Another problem with supplying liquid to or into the chip card via pointed needles may be the introduction of contaminants. Especially with regard to the detection of trace elements, DNA or peptides, the slightest chemical or biochemical impurities can lead to errors in the quantitative and / or qualitative detection. With any additional device, e.g. a needle with which the liquid to be examined is brought into contact increases the probability of contamination. An increased effort, which is cost and time consuming, must be provided to ensure the detection quality, e.g. by thorough cleaning of all devices.
Aus der
Die
Aufgabe der vorliegenden Erfindung ist es deshalb, einen Flachkörper nach Art einer Chip-Karte zur biochemischen Analyse anzugeben, bei welchem es auf einfache und kostengünstige Weise möglich wird Fluide wie z.B. Flüssigkeiten, direkt aus einem Gefäß in mikrofluidische Einrichtungen des Flachkörpers einzubringen. Insbesondere ist es Aufgabe Fluide in die mikrofluidischen Einrichtungen des Flachkörpers einzubringen, wobei die Fluide mit so wenig wie möglich autarken Einzelteilen in Kontakt gebracht werden bzw. diese durchströmen. Weiterhin ist es Aufgabe einen Flachkörper anzugeben, welchem große Mengen an Fluid direkt aus bzw. in ein Gefäß, wie es z.B. ein E-Cup darstellt, zu und/oder abgeführt werden kann.The object of the present invention is therefore to provide a flat body in the form of a chip card for biochemical analysis, in which it is possible in a simple and cost-effective manner, fluids such. Liquids to introduce directly from a vessel in microfluidic devices of the flat body. In particular, it is an object to introduce fluids into the microfluidic devices of the flat body, wherein the fluids are brought into contact with or flow through as few autarkic individual parts as possible. It is also an object to provide a flat body, which contains large quantities of fluid directly from or into a vessel, as e.g. represents an e-cup, can be added to and / or removed.
Die angegebene Aufgabe wird bezüglich des Flachkörpers nach Art einer Chip-Karte zur biochemischen Analyse von Substanzen mit den Merkmalen des Anspruchs 1 gelöst.The stated object is achieved with respect to the flat body in the manner of a chip card for the biochemical analysis of substances having the features of claim 1.
Vorteilhafte Ausgestaltungen des erfindungsgemäßen Flachkörpers nach Art einer Chip-Karte zur biochemischen Analyse von Substanzen und des Verfahrens zur Verwendung des Flachkörpers gehen aus den jeweils zugeordneten abhängigen Unteransprüchen hervor. Dabei können die Merkmale des Hauptanspruchs mit Merkmalen der Unteransprüche und Merkmale der Unteransprüche untereinander kombiniert werden.Advantageous embodiments of the flat body according to the invention in the manner of a chip card for the biochemical analysis of substances and of the method for using the flat body will become apparent from the respectively associated dependent subclaims. In this case, the features of the main claim with features of the subclaims and features of the subclaims can be combined with each other.
Der erfindungsgemäße Flachkörper nach Art einer Chip-Karte zur biochemischen Analyse von Substanzen umfasst wenigstens zwei mikrofluidische Einrichtungen und wenigstens einen Sensor-Chip. Der wenigstens eine Sensor-Chip ist in dem Flachkörper integriert und steht in direktem Kontakt mit wenigstens einer ersten mikrofluidischen Einrichtung. Der Flachkörper umfasst integral eine zweite mikrofluidische Einrichtung
nach Art einer Pipette. Dabei bedeutet Integral, dass die zweite mikrofluidische Einrichtung und der restliche Flachkörper aus wenigstens einem Material gemeinsam hergestellt sind und einen zusammenhängenden Körper bilden, ohne das die zweite mikrofluidische Einrichtung an den Flachkörper gesteckt, geklemmt oder sonstig wiederholt trenn- und befestigbar angebracht ist.The flat body according to the invention in the manner of a chip card for the biochemical analysis of substances comprises at least two microfluidic devices and at least one sensor chip. The at least one sensor chip is integrated in the flat body and is in direct contact with at least one first microfluidic device. The flat body integrally comprises a second microfluidic device
in the manner of a pipette. Integral means that the second microfluidic device and the remaining flat body are made of at least one material together and form a coherent body, without the second microfluidic device is attached to the flat body, clamped or otherwise repeatedly attached separable and fastened.
Der Vorteil eines Flachkörpers mit integrierter Pipette liegt in der Möglichkeit große Flüssigkeitsmengen zwischen einem Gefäß, wie es z.B. ein E-Cup darstellt, und dem Flachkörper einfach und schnell auszutauschen. Da der Flachkörper und die darin integrierte Pipette aus einem Material zusammen hergestellt werden können, weisen beide gleiche chemische und biochemische Reinheitsgrade auf. Ein Einschleppen von Verunreinigungen durch zusätzliche Teile in den Flachkörper wird so verhindert. Die mögliche Herstellung in einem Schritt verringert Kosten und Aufwand und führt zu einer höheren Stabilität als bei Aufstecklösungen von z.B. Spritzen-Kanülen-Nadeln aus Metall.The advantage of a flat body with integrated pipette lies in the possibility of large quantities of liquid between a vessel, as e.g. represents an e-cup, and the flat body easy and fast exchange. Since the flat body and the pipette integrated therein can be made of one material together, both have the same chemical and biochemical purity levels. An entrainment of impurities by additional parts in the flat body is thus prevented. The possible production in one step reduces costs and effort and leads to a higher stability than plugging solutions of e.g. Syringe cannula needles made of metal.
Der Flachkörper kann eine erste Klemmeinrichtung umfassen, welche ausgebildet ist eine E-Cup direkt mechanisch an dem Flachkörper zu befestigen. E-Cups werden als Reaktionsgefäße benutzt und sind z.B. von Eppendorf® erhältlich und dann unter der Kurzform "Eppi" bekannt. Die Gefäße weisen standardmäßig verschiedene Größen auf und können entsprechend verschiedene Volumina Lösung, z.B. von 0,2 ml bis 2 ml aufnehmen. Sie zeichnen sich durch eine gute Chemikalienresistenz aus und sind bis über 100°C Formstabil. Die Klemmeinrichtung würde einen Durchmesser im Wesentlichen gleich dem Innendurchmesser einer zu befestigenden E-Cup an ihrer Öffnung aufweisen. Eine mechanische Befestigung der E-Cup direkt an dem Flachkörper durch das Klemmen stellt eine besonders einfache und stabile Möglichkeit dar, die E-Cup an dem Flachkörper zu befestigen.The flat body may comprise a first clamping device, which is designed to attach an e-cup directly mechanically to the flat body. E-cups are used as reaction vessels and are available eg from Eppendorf® and then known by the short form "Eppi". By default, the vessels have different sizes and can accommodate different volumes of solution, eg from 0.2 ml to 2 ml. They are characterized by good chemical resistance and are dimensionally stable up to more than 100 ° C. The clamping device would have a diameter substantially equal to the inner diameter of an e-cup to be fastened at its opening. A mechanical attachment of the e-cup directly to the flat body by the terminals represents a particularly simple and stable way to attach the e-cup to the flat body.
Der Flachkörper kann eine zweite Klemmeinrichtung umfassen, welche ausgebildet ist einen Deckel einer E-Cup direkt mechanisch an dem Flachkörper zu befestigen. Dies erhöht die Stabilität der Befestigung einer E-Cup an dem Flachkörper und führt zu einer Verbesserung des Handlings, da der Deckel nicht beweglich relativ zum Flachkörper beim Befüllen oder der Entnahme von Flüssigkeit aus der E-Cup stört.The flat body may comprise a second clamping device, which is designed to fasten a lid of an e-cup directly mechanically to the flat body. This increases the stability of the attachment of an E-cup to the flat body and leads to an improvement of the handling, since the lid does not disturb movably relative to the flat body during filling or the removal of liquid from the E-Cup.
Die zweite mikrofluidische Einrichtung kann länglich ausgebildet sein und an einem Ende eine Spitze mit einer fluidischen Öffnung umfassen. Sie kann so ausgebildet sein, dass bei Befestigung einer E-Cup an der ersten und/oder zweiten Klemmeinrichtung die Spitze der zweiten mikrofluidische Einrichtung mit der fluidischen Öffnung im Bereich eines unteren Endes der E-Cup angeordnet ist. Dadurch wird eine nahezu vollständige Entnahme von Flüssigkeit aus der E-Cup mit Hilfe der zweiten mikrofluidischen Einrichtung ermöglicht.The second microfluidic device may be elongated and comprise at one end a tip with a fluidic opening. It can be designed so that when mounting an E-cup on the first and / or second clamping device, the tip of the second microfluidic device is arranged with the fluidic opening in the region of a lower end of the E-cup. As a result, an almost complete removal of liquid from the e-cup is made possible with the aid of the second microfluidic device.
Der Flachkörper kann aus einem Plastik-Material bestehen, insbesondere einer Spritzgussplastik. Spritzgussplastik ist leicht zu verarbeiten und ermöglicht eine kostengünstige Herstellung des Flachkörpers. Die mikrofluidischen Einrichtungen können auf einer Vorderseite des Flachkörpers ausgebildet sein und mit einer Folie, insbesondere einer selbstklebenden Folie aus Plastik-Material, abgedeckt sein. Dies ermöglicht eine einfache und kostengünstige Herstellung des Flachkörpers mit mikrofluidischen Einrichtungen.The flat body may consist of a plastic material, in particular an injection-molded plastic. Injection molding plastic is easy to work with and enables cost-effective production of the flat body. The microfluidic devices may be formed on a front side of the flat body and covered with a foil, in particular a self-adhesive foil of plastic material. This allows a simple and cost-effective production of the flat body with microfluidic devices.
Die wenigstens zwei mikrofluidischen Einrichtungen können Kanäle und/oder Kammern, welche als Vertiefungen in einer flachen Ebene der Vorderseite des Flachkörpers ausgebildet sind, umfassen. Weiterhin können die wenigstens zwei mikrofluidischen Einrichtungen Ventile umfassen, ausgebildet in dem Flachkörper. Die wenigstens zwei mikrofluidischen Einrichtungen können auch eine Ausnehmung umfassen, welche als Vertiefung in einer flachen Ebene der Rückseite des Flachkörpers ausgebildet ist und in welcher der Sensor-Chip eingebettet ist, insbesondere mit elektrischen Kontakten des Sensor-Chips in einer Ebene mit der flachen Ebene der Rückseite des Flachkörpers sowie mit einem Sensor-Array des Sensor-Chips in direktem Kontakt zu wenigstens einer Kammer auf der Vorderseite des Flachkörpers. Die wenigstens zwei mikrofluidischen Einrichtungen sind dadurch geeignet ein gutes Handling von Flüssigkeiten zu ermöglichen und Flüssigkeiten aus einer E-Cup zu Sensoren auf dem Chip zu transportieren. Auf dem Weg aus der E-Cup zu den Sensoren können chemische Reaktionen von Flüssigkeiten bzw. Substanzen in den Flüssigkeiten z.B. in Kammern mit Festphasenreagenzien erfolgen.The at least two microfluidic devices may include channels and / or chambers, which are formed as depressions in a flat plane of the front side of the flat body. Furthermore, the at least two microfluidic devices may comprise valves formed in the flat body. The at least two microfluidic devices may also comprise a recess, which is formed as a recess in a flat plane of the rear side of the flat body and in which the sensor chip embedded is, in particular with electrical contacts of the sensor chip in a plane with the flat plane of the back of the flat body and with a sensor array of the sensor chip in direct contact with at least one chamber on the front side of the flat body. The at least two microfluidic devices are thereby suitable for facilitating good handling of liquids and for transporting liquids from an e-cup to sensors on the chip. On the way from the E-Cup to the sensors, chemical reactions of liquids or substances in the liquids can take place eg in chambers with solid phase reagents.
Der Flachkörper kann eine Dicke im Bereich von einem Millimeter, eine Länge im Bereich von 85 Millimeter und eine Breite im Bereich von 54 Millimeter aufweisen. Wenigstens eine mikrofluidische Einrichtung kann ausgebildet sein Trockenreagenzien zu beinhalten, insbesondere in Kanälen und/oder Reaktionsräumen mit einem Querschnitt im Bereich von einem oder mehreren Quadrat-Millimetern. Die zweite mikrofluidische Einrichtung kann eine Länge im Bereich von 45 Millimetern aufweisen.The flat body may have a thickness in the range of one millimeter, a length in the range of 85 millimeters and a width in the range of 54 millimeters. At least one microfluidic device may be configured to include dry reagents, especially in channels and / or reaction spaces having a cross-section in the range of one or more square millimeters. The second microfluidic device may have a length in the range of 45 millimeters.
Die zweite mikrofluidische Einrichtung kann über die erste mikrofluidische Einrichtung in fluidischen Kontakt mit Sensoren des Sensor-Chips stehen.The second microfluidic device may be in fluidic contact with sensors of the sensor chip via the first microfluidic device.
Ein Querschnitt durch die zweite mikrofluidische Einrichtung, senkrecht zur Vorderseite des Flachkörpers, kann einen im Wesentlichen rechteckigen Außenumfang mit einer offenen Ausnehmung zur Vorderseite des Flachkörpers hin aufweisen. Dadurch wird eine erhöhte Stabilität bei einfacher Herstellung erreicht, da die zweite mikrofluidische Einrichtung die Flache Form des Flachkörpers aufweist.A cross section through the second microfluidic device, perpendicular to the front side of the flat body, may have a substantially rectangular outer periphery with an open recess towards the front side of the flat body. As a result, an increased stability is achieved with a simple production, since the second microfluidic device has the flat shape of the flat body.
Der Sensor-Chip kann ein Array aus elektrochemischen Sensoren umfassen. Dadurch werden mit dem Flachkörper elektrochemische Messungen möglich, welche einfacher, kostengünstiger und besser auf kleinsten Raum durchzuführen sind als optische Messungen. Der Sensor-Chip kann weiterhin eine integrierte Schaltung zum verarbeiten elektrischer Signale der Sensoren umfassen. Der Sensor-Chip kann auch elektrische Kontakte zum elektrischen Auslesen des Sensor-Chips umfassen, insbesondere zum elektrischen Auslesen des Sensor-Chips mit Hilfe einer externen Datenverarbeitungseinheit.The sensor chip may comprise an array of electrochemical sensors. As a result, with the flat body electrochemical measurements are possible, which are easier, cheaper and better to perform in the smallest space than optical measurements. The sensor chip may further comprise an integrated circuit for processing electrical signals from the sensors. The sensor chip can also comprise electrical contacts for the electrical readout of the sensor chip, in particular for the electrical readout of the sensor chip with the aid of an external data processing unit.
Der Flachkörper kann wenigstens eine Öffnung auf seiner Vorder- und/oder Rückseite aufweisen, welche in fluidischem Kontakt mit der wenigstens einen ersten mikrofluidischen Einrichtung steht, und/oder welche ausgebildet ist eine äußere Pumpe anzuschließen. Über diese Öffnung bzw. Öffnungen können zusätzlich kleine Mengen an zum Nachweis verwendeten Substanzen, insbesondere in flüssiger Form dem Flachkörper zugeführt werden. So sind z.B. Labeling-Stoffe in frischer Form vor einer eigentlichen elektrochemischen Messung der Flüssigkeit aus einer E-Cup in den mikrofluidischen Einrichtungen des Flachkörpers zuführbar und können mit Substanzen der Flüssigkeit reagieren. Auch ein Unterdruck in den mikrofluidischen Einrichtungen kann über die wenigstens eine Öffnung z.B. mit Hilfe einer Pumpe erzeugt werden und dazu dienen, Flüssigkeit aus einer E-Cup anzusaugen in den Flachkörper bzw. dessen mikrofluidischen Einrichtungen hinein.The flat body can have at least one opening on its front and / or rear side, which is in fluidic contact with the at least one first microfluidic device, and / or which is designed to connect an external pump. In addition, small amounts of substances used for the detection, in particular in liquid form, can be supplied to the flat body via this opening or openings. Thus, e.g. Labeling substances in fresh form before an actual electrochemical measurement of the liquid from an e-cup in the microfluidic devices of the flat body fed and can react with substances of the liquid. A negative pressure in the microfluidic devices can also be achieved via the at least one opening, e.g. be generated by means of a pump and serve to suck liquid from an e-cup in the flat body or its microfluidic devices into it.
Ein erfindungsgemäßes Verfahren zur Verwendung des zuvor beschriebenen Flachkörpers umfasst die Schritte:
- eine E-Cup wird mit einer zu untersuchenden Flüssigkeit befüllt, und
- die zweite mikrofluidische Einrichtung wird derart in die E-Cup eingeführt, dass sie in direktem Kontakt zu der zu untersuchenden Flüssigkeit steht, und
- die Flüssigkeit wird durch die zweite mikrofluidische Einrichtung in die erste mikrofluidische Einrichtung transportiert, insbesondere direkt und insbesondere durch einen Unterdruck und/oder Kapillarkräfte, und
- die zu untersuchende Flüssigkeit wird über den Sensor-Chip gleitet, und
- wenigstens ein Sensor des Sensor-Chips interagiert mit wenigstens einer chemischen und/oder biochemischen Substanz der zu untersuchenden Flüssigkeit und/oder mit einem Reaktionsprodukt einer Substanz der zu untersuchenden Flüssigkeit.
- an e-cup is filled with a liquid to be examined, and
- the second microfluidic device is introduced into the E-Cup in such a way that it is in direct contact with the fluid to be examined, and
- the liquid is transported by the second microfluidic device into the first microfluidic device, in particular directly and in particular by a negative pressure and / or capillary forces, and
- the fluid to be tested slides over the sensor chip, and
- at least one sensor of the sensor chip interacts with at least one chemical and / or biochemical substance of the liquid to be examined and / or with a reaction product of a substance of the liquid to be examined.
Dabei kann die zweite mikrofluidische Einrichtung in einem ersten Schritt Flüssigkeit aus der E-Cup aufnehmen und in einem zweiten Schritt Flüssigkeit in die E-Cup abgeben, wobei insbesondere der erste und der zweite Schritt intervallartig wiederholt werden. Dadurch ist eine Art spülen der mikrofluidischen Einrichtungen mit Flüssigkeit aus der E-Cup möglich. Weiterhin ist es möglich Reaktionen, welche eine große Lösungsmenge mit großem Volumen benötigen, nicht in den mikrofluidischen Einrichtungen durchzuführen, sondern in einer angedockten E-Cup. Eine Kombination von Reaktionen in der E-Cup und den mikrofluidischen Einrichtungen in unterschiedlicher Reihenfolge ist so ebenfalls möglich.In this case, the second microfluidic device can take up liquid from the E-cup in a first step and deliver liquid into the E-cup in a second step, wherein in particular the first and the second step are repeated at intervals. This allows a kind of rinsing of the microfluidic devices with liquid from the e-cup. Furthermore, it is possible reactions, which require a large amount of solution with large volume, not perform in the microfluidic devices, but in a docked E-Cup. A combination of reactions in the E-cup and the microfluidic devices in different order is also possible.
Als zu untersuchende Flüssigkeit kann z.B. Blut, Urin, Frisch- oder Abwasser verwendet werden. Der erfindungsgemäße Flachkörper und das Verfahren zu dessen Verwendung eignen sich besonders gut, sind darauf aber nicht beschränkt, bei geringen Konzentrationen an nachzuweisender Substanz und großen Lösungsvolumina der zum Nachweis benötigten Flüssigkeit eingesetzt zu werden. Wenn die Konzentration der nachzuweisenden Substanz so gering ist, dass ein Volumen der zum Nachweis nötigen Flüssigkeit die Kapazität der im bzw. am Flachkörper ausgebildeten mikrofluidischen Einrichtungen übersteigt, können Reaktionen in einem angedockten E-Cup durchgeführt werden und die fertig reagierten Flüssigkeiten über die zweite mikrofluidische Einrichtung den Sensoren des Sensor-Chips im Flachkörper zugeführt werden. Die Sensoren des Sensor-Chips können z.B. DNA, RNA, Peptide oder Antikörper nachweisen. Am Nachweis und an der Vorbereitung, z.B. durch Lyse von Zellen, beteiligte Substanzen können z.B. in Kammern oder Kanälen des Flachkörpers, insbesondere als Trockenreagenzien gelagert werden. Zur chemischen Reaktion kann Flüssigkeit aus einer E-Cup in die mikrofluidischen Einrichtungen gesogen werden und mit den gelagerten Substanzen gemischt werden, z.B. zum Lösen von Trockenreagenzien, und anschließend an die E-Cup wieder abgegeben werden. In der E-Cup kann dann ein größeres Flüssigkeitsvolumen als in den mikrofluidischen Einrichtungen reagieren. Anschließend kann ein Teil der Flüssig-keit in der E-Cup über die erste in die zweite mikrofluidische Einrichtung gezogen werden, z.B. durch einen angelegten Unterdruck an Öffnungen der ersten mikrofluidischen Einrichtung, und an den Sensoren ein Nachweis von Reaktionsprodukten oder direkt von in der Flüssigkeit enthaltenen Substanzen erfolgen.As a liquid to be examined, for example, blood, urine, fresh or waste water can be used. The flat body according to the invention and the method for its use are particularly well suited but are not limited to being used at low concentrations of substance to be detected and large volumes of solution of the liquid required for detection. If the concentration of the substance to be detected is so low that a volume of liquid necessary for the detection exceeds the capacity of the microfluidic devices formed in or on the flat body, reactions can be carried out in a docked E cup and the ready-reacted liquids can be carried out via the second microfluidic Device are supplied to the sensors of the sensor chip in the flat body. The sensors of the sensor chip can detect, for example, DNA, RNA, peptides or antibodies. Substances which are involved in the detection and in the preparation, for example by lysis of cells, can be stored, for example, in chambers or channels of the flat body, in particular as dry reagents. The chemical reaction can be liquid an e-cup are sucked into the microfluidic devices and mixed with the stored substances, eg for dissolving dry reagents, and then released again to the e-cup. In the e-cup can then react a larger volume of fluid than in the microfluidic devices. Subsequently, a portion of the liquid in the e-cup may be drawn over the first into the second microfluidic device, eg by applied vacuum to openings of the first microfluidic device, and at the sensors detection of reaction products or directly from in the liquid contained substances.
Die mit dem Verfahren zur Verwendung eines Flachkörpers verbundenen Vorteile sind analog den Vorteilen, welche zuvor im Bezug auf den Flachkörper beschrieben wurden.The advantages associated with the method of using a flat body are analogous to the advantages previously described with respect to the flat body.
Bevorzugte Ausführungsformen der Erfindung mit vorteilhaften Weiterbildungen gemäß den Merkmalen der abhängigen Ansprüche werden nachfolgend anhand der Figuren näher erläutert, ohne jedoch darauf beschränkt zu sein.Preferred embodiments of the invention with advantageous developments according to the features of the dependent claims are explained in more detail with reference to the figures, but without being limited thereto.
Es wird in den Figuren dargestellt:
- Fig. 1
- eine schematische Darstellung einer Aufsicht auf eine Vorderseite des Flachkörpers mit ersten und einer zweiten mikrofluidischen Einrichtung nach Art einer Pipette und mit einer Klemmeinrichtung für eine E-Cup, und
- Fig. 2
- eine schematische Darstellung einer Aufsicht analog der in
Fig. 1 gezeigten mit einer Klemmeinrichtung nach einem zweiten Ausführungsbeispiel, mit Klemmung einer E-Cup und Klemmung eines Deckels der ECup.
- Fig. 1
- a schematic representation of a plan view of a front side of the flat body with first and a second microfluidic device in the manner of a pipette and with a clamping device for an e-cup, and
- Fig. 2
- a schematic representation of a plan view analogous to in
Fig. 1 shown with a clamping device according to a second embodiment, with clamping an e-cup and clamping a lid of the ECup.
In der
In einer Ausnehmung auf der Rückseite 8 des Flachkörpers 1, welche eine Größe von Höhe H' x Breite B' x Tiefe T' im Bereich von 1,4cm x 1,3cm x 800µm aufweisen kann, ist ein Sensor-Chip 2 befestigt, z.B. durch Kleben. Der Sensor-Chip 2 mit einem Sensor-Array auf einer Seite und elektrischen Kontakten zum auslesen des Sensor-Chips 2 auf der anderen Seite des Sensor-Chips 2 ist derart in der Ausnehmung angeordnet, dass die Seite des Sensor-Chips 2 mit dem Sensor-Array den Boden einer mikrofluidischen Kammer 10' bildet, welche als Reaktions- und/oder Nachweis-Kammer dient. Die Seite des Sensor-Chips 2 mit den elektrischen Kontakten bildet mit der Rückseite 8 des Flachkörpers 1 eine Ebene. Sensoren des Sensor-Arrays können optisch oder elektrochemisch Substanzen oder Reaktionsprodukte in einer Flüssigkeit, welche sich in der mikrofluidischen Kammer 10' befindet, nachweisen. Elektrische Signale der Sensoren können über die elektrischen Kontakte des Sensor-Chips 2 an externe Mess- und Datenverarbeitungs-Einrichtungen abgegeben werden oder durch integrierte Schaltungen auf dem Sensor-Chip 2 verarbeitet werden und direkt angezeigt oder über die elektrischen Kontakte übertragen werden.In a recess on the back 8 of the flat body 1, which may have a size of height H 'x width B' x depth T 'in the range of 1.4cm x 1.3cm x 800μm, a sensor chip 2 is fixed, for example by gluing. The sensor chip 2 with a sensor array on one side and electrical contacts for reading the sensor chip 2 on the other side of the sensor chip 2 is arranged in the recess such that the side of the sensor chip 2 with the sensor -Array forms the bottom of a microfluidic chamber 10 ', which serves as a reaction and / or detection chamber. The side of the sensor chip 2 with the electrical contacts forms with the rear side 8 of the flat body 1 a plane. Sensors of the sensor array can detect optically or electrochemically substances or reaction products in a liquid which is located in the microfluidic chamber 10 '. Electrical signals from the sensors can be delivered via the electrical contacts of the sensor chip 2 to external measuring and data processing devices or processed by integrated circuits on the sensor chip 2 and displayed directly or transmitted via the electrical contacts.
Über Zu- und Ablauföffnungen 12 und mikrofluidische Kanäle 9 können Flüssigkeiten, welche zur Probenvorbereitung, zum Aufschluss von z.B. Zellen und/oder für Nachweisrektionen verwendet werden, den mikrofluidischen Einrichtungen 3, 9, 10, 10' zugeführt werden. Eine Steuerung der Zufuhr kann über Ventile 11 erfolgen, welche im Flachkörper 1 ausgebildet sind. Es können auch Fluide wie Luft über die Zu- und Ablauföffnungen 12 dem Flachkörper zugeführt oder entnommen werden, wobei ein Über- bzw. Unterdruck in den mikrofluidischen Einrichtungen 3, 9, 10, 10' erzeugt wird.Via inlet and
Erfindungsgemäß umfasst der Flachkörper 1 eine zweite mikrofluidische Einrichtung 4, welche die Form und Funktion einer abgeflachten Pipette aufweist. Die zweite mikrofluidische Einrichtung 4 ist in einem Stück mit dem Flachkörper zusammen aus z.B. Plastik hergestellt. Die Länge L kann im Bereich von 2,5 cm liegen, abhängig von der Größe einer zu verwendenden E-Cup 5. Die Länge sollte nahezu der Tiefe der E-Cup 5, d.h. dem Abstand von der Öffnung 15 bis zum Boden 14 der E-Cup 5 betragen. Dadurch wird eine fast vollständige Entnahme von Flüssigkeit aus einer E-Cup 5 mit Hilfe der zweiten mikrofluidischen Einrichtung 4 ermöglicht. Die Dicke der zweiten mikrofluidischen Einrichtung 4 ist gleich der Dicke des Flachkörpers, z.B. 1mm. Mittig in der zweiten mikrofluidischen Einrichtung 4 auf der Vorderseite 7 des Flachkörpers 1 ist ein Kanal 9' als Vertiefung ausgebildet, welcher in etwa der Größe von Kanälen 9 der ersten mikrofluidischen Einrichtung 3 im restlichen Flachkörper 1 entspricht. So liegt seine Breite im Bereich von 1mm und seine Tiefe im Bereich von 100µm. Der Kanal 9' ist über Kanäle 9 und/oder Kammern 10 mit Sensoren des Sensor-Chips 2 fluidisch verbunden. Die Breite der zweiten mikrofluidischen Einrichtung 4 beträgt z.B. 2mm.According to the invention, the flat body 1 comprises a second
Über eine Klemmeinrichtung 6a des Flachkörpers 1 kann eine E-Cup 5 an dem Flachkörper 1 durch Klemmen befestigt werden. In
Die zweite mikrofluidische Einrichtung 4 ist fluidisch mit der ersten mikrofluidischen Einrichtung 3 verbunden und wird in eine E-Cup 5 derart eingeführt, dass über Kapillarkräfte oder einen Unterdruck in der ersten mikrofluidischen Einrichtung 3 Flüssigkeit aus der E-Cup 5 über die zweite mikrofluidische Einrichtung 4 in die erste mikrofluidische Einrichtung 3 und zum Sensor-Array des Sensor-Chips 2 gelangt. Über einen Überdruck in der ersten mikrofluidischen Einrichtung 3 kann Flüssigkeit aus der ersten mikrofluidischen Einrichtung 3 über die zweite mikrofluidische Einrichtung 4 in die E-Cup 5 eingebracht werden. So können z.B. chemische Reaktionen, welche viel Lösungsvolumen benötigen und aus diesem Grund nicht in einer mikrofluidischen Einrichtung 3 durchgeführt werden können, in der E-Cup "ausgelagert" stattfinden. Anschließend kann das Reaktionsprodukt im Flachkörper 1 weiterverarbeitet oder direkt über die Sensoren nachgewiesen werden.The second
Zur einfachen Handhabung einer E-Cup 5 in Verbindung mit dem Flachkörper 1 ist die Klemmvorrichtung 6a als eine Verbreiterung der zweiten mikrofluidischen Einrichtung 4 ausgebildet. Dies macht eine einfache und kostengünstige Herstellung der Klemmeinrichtung 6a in einem Schritt zusammen mit dem Flachkörper 1 inklusive der zweiten mikrofluidischen Einrichtung 4 als ein integraler Körper aus Spritzgussplastik möglich. Die mikrofluidischen Einrichtungen 3, 4 werden mit Hilfe einer Folie abgedichtet. So kann z.B. eine selbstklebende und/oder geklebte Folie die Vorderseite 7 des Flachkörpers 1 inklusive der ersten und zweiten mikrofluidischen Einrichtungen 3, 4 vollständig bedecken. Alternativ kann partiell oder vollständig auf dem Flachkörper 1 eine thermisch angeschweißte Folie aufgebracht werden. Die Öffnungen 12 können bei Bedarf durch Nadeln durchstochen werden. Eine Öffnung an der Spitze 13 der zweiten mikrofluidischen Einrichtung 4 kann ebenfalls bei Bedarf durch Aufreißen, Aufschneiden oder Anstechen hergestellt werden, oder alternativ kann bei Aufbringen einer Folie auf den Flachkörper 1 die Öffnung an der Spitze 13 ausgebildet werden.For easy handling of an
Die Klemmvorrichtung 6a weist im Wesentlichen eine Breite entsprechend dem Innendurchmesser der Öffnung 15 der E-Cup auf oder ist geringfügig, um z.B. etwa 1mm, größer. Die Einfachste Form der Klemmeinrichtung ist rechteckig, insbesondere mit abgerundeten Ecken. Bei Aufschieben der E-Cup 5 auf die Klemmeinrichtung 6a drücken zwei gegenüberliegende Kanten gegen die Innenwand der E-Cup im Bereich der Öffnung 15. Reibung führt zu einem mechanischen Klemmen der E-Cup 5 an den Flachkörper 1, speziell an die Klemmeinrichtung 6a des Flachkörpers 1. Ein einfaches Aufschieben der E-Cup 5 auf die Klemmvorrichtung 6a ist auch gegeben, wenn die Klemmeinrichtung 6a den Umriss eines Schnittes durch ein Fass aufweist, mit konvexen Auswölbungen an den zwei gegenüberliegenden Kanten. Der Einfachheit halber ist in
In
Die Klemmeinrichtung 6b führt zu einer verbesserten mechanischen Verbindung einer E-Cup 5 mit dem Flachkörper 1 und einer erhöhten Stabilität einer Anordnung E-Cup 5 und Flachkörper 1. Ein einfaches Handling von Flachkörper 1 in Verbindung mit einer E-Cup 5 wird erlaubt. Über die zweite mikrofluidische Einrichtung 4 wird ein Flüssigkeitsaustausch zwischen Flachkörper 1 und E-Cup 5 ermöglicht, insbesondere bei Anschluss externer Pumpen über die Zu- und Ablauf-Öffnungen 12 des Flachkörpers 1. Eine E-Cup 5 kann in Verbindung mit dem Flachkörper 1 als Probengefäß zur Zufuhr der zu untersuchenden oder an der Reaktion beteiligter Flüssigkeiten dienen, als externes Reaktionsgefäß dienen oder als Abfallbehälter für zu entsorgende Flüssigkeiten dienen.The
Bei Verwendung einer E-Cup 5 mit einem möglichen Flüssigkeitsvolumen von 500µl ist die Gesamtlänge der E-Cup 5 30mm und die Länge im Innenraum der E-Cup 5 29mm. Der äußere Durchmesser der E-Cup 5 beträgt 7,6mm. Entscheidend für die Dimensionen der Klemmeinrichtung 6a sind jedoch der Außendurchmesser von 10mm und der Innendurchmesser von 6,5mm des kreisrunden oberen Randes der E-Cup 5, welcher die Form einer Krempe aufweist. Die Klemmeinrichtung 6a weist somit in diesem Ausführungsbeispiel ebenfalls eine Breite im Bereich von 6,5mm auf oder geringfügig größer, z.B. 6,6mm. Dadurch wird bei aufschieben der E-Cup 5 eine mechanisches Befestigung durch Klemmen erreicht. Der Abstand des Übergangs der Klemmeinrichtung 6a zum restlichen Flachkörper 1 im Verhältnis zur Spitze 13 der Klemmeinrichtung 6a beträgt bei einer Länge des Innenraums der E-Cup 5 29mm oder geringfügig weniger. Dadurch ist sichergestellt, dass bei Aufschieben der E-Cup bis zum Anschlag an den Übergang der Klemmeinrichtung 6a zum restlichen Flachkörper 1 die Spitze 13 im Bereich des Bodens 14 der E-Cup 5 angeordnet ist. So kann die gesamte Flüssigkeit in einer E-Cup 5 durch die zweite mikrofluidische Einrichtung 4 gehändelt werden. Bei einem nicht vollständigen Aufstecken der E-Cup 5 auf die Klemmeinrichtung 6a kann die Länge des Abstands des Übergangs der Klemmeinrichtung 6a zum restlichen Flachkörper 1 im Verhältnis zur Spitze 13 der Klemmeinrichtung 6a auch länger ausgebildet sein als 29mm. Im Falle, dass nicht das gesamte Flüssigkeitsvolumen der E-Cup 5 verwendet bzw. gehändelt werden muss, kann die Länge auch kürzer als 29mm sein.When using an E-Cup 5 with a possible liquid volume of 500μl the total length of the
Claims (10)
- Flat body (1) formed as a chip card for biochemical analysis of substances, with at least two microfluidic devices (3, 4) and with at least one sensor chip (2), wherein the at least one sensor chip (2) is integrated in the flat body (1) and in direct contact with at least one first microfluidic device (3), and wherein the flat body (1) includes integrally a second microfluidic device (4), which has an elongate design and at one end has a tip (13) with a fluidic opening,
characterized in
that the flat body (1) comprises a first clamping device (6b) which is configured to attach a cover (16) of a reaction vessel (5) onto the flat body (1) in a direct mechanical manner. - Flat body (1) according to claim 1, characterized in that the flat body (1) comprises a second clamping device (6a) which is configured to attach a reaction vessel (5) onto the flat body (1) in a direct mechanical manner.
- Flat body (1) according to claim 2, characterized in that the second microfluidic device (4) is configured such that when a reaction vessel (5) is attached to the second clamping device (4), the tip (13) of the second microfluidic device (4) is arranged with the fluidic opening in a region of a lower end of the reaction vessel (5).
- Flat body (1) according to any of the preceding claims, characterized in that the flat body (1) is formed of a plastic material, in particular an injection-molded plastic, and the microfluidic devices (3) are formed on a front side (7) of the flat body (1) and are covered by a film, in particular a self-adhesive plastic film.
- Flat body (1) according to any of the preceding claims, characterized in that the at least two microfluidic devices (3, 4) comprise channels (9, 9') and/or chambers (10, 10') formed as depressions in a flat plane on the front side (7) of the flat body (1), and/or comprise valves (11) formed in the flat body (1), and/or comprise a recess forming a depression in a flat plane on the rear side (8) of the flat body (1) embedding the sensor chip (2), in particular with electric contacts of the sensor chip (2) being coplanar with the flat plane on the rear side (8) of the flat body (1), and/or with a sensor array of the sensor chip (2) being in direct contact with at least one chamber (10') on the front side (7) of the flat body (1).
- Flat body (1) according to any one of the preceding claims, characterized in that the flat body (1) has a thickness in the range of one millimeter, a length in the range of 85 millimeters, and a width in the range of 54 millimeters, and/or at least one of the microfluidic devices (3) is designed to contain dry reagents, in particular in channels (9) and/or in reaction chambers (10, 10'), having a cross section in the range of one or several square millimeter, and/or the second microfluidic device has a length in the range of 45 millimeters.
- Flat body (1) according to any one of the preceding claims, characterized in that the second microfluidic device (4) is in fluidic contact with sensors of the sensor chip (2) via the first microfluidic device (3).
- Flat body (1) according to any of the preceding claims, characterized in that a cross section of the second microfluidic device (4) perpendicular to the front side (7) of the flat body (1) has a substantially rectangular outer perimeter with an open recess toward the front side (7) of the flat body (1).
- Flat body (1) according to any of the preceding claims, characterized in that the sensor chip (2) comprises an array of electrochemical sensors, and/or in that the sensor chip (2) comprises an integrated circuit for processing electric signals from the sensors, and/or in that the sensor chip (2) comprises electric contacts for electric readout of the sensor chip (2), in particular for electric readout of the sensor chip (2) by means of an external data processing unit.
- Flat body (1) according to any of the preceding claims, characterized in that the flat body (1) has at least one opening (12) on its front side and/or rear side (7, 8), which is in fluidic contact with the at least one first microfluidic device (3), and/or which is configured to connect an exterior pump.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE102009043226A DE102009043226B4 (en) | 2009-09-28 | 2009-09-28 | Flat body in the manner of a chip card for biochemical analysis and method for its use |
PCT/EP2010/064258 WO2011036289A1 (en) | 2009-09-28 | 2010-09-27 | Flat body in the manner of a chip card for biochemical analysis and method for the use thereof |
Publications (2)
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EP2482982A1 EP2482982A1 (en) | 2012-08-08 |
EP2482982B1 true EP2482982B1 (en) | 2017-08-16 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP10760321.9A Active EP2482982B1 (en) | 2009-09-28 | 2010-09-27 | Flat body in the manner of a chip card for biochemical analysis |
Country Status (7)
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US (1) | US9415390B2 (en) |
EP (1) | EP2482982B1 (en) |
JP (1) | JP5430766B2 (en) |
CN (1) | CN102548659B (en) |
BR (1) | BR112012006831B1 (en) |
DE (1) | DE102009043226B4 (en) |
WO (1) | WO2011036289A1 (en) |
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DE102009043226B4 (en) | 2009-09-28 | 2012-09-27 | Siemens Aktiengesellschaft | Flat body in the manner of a chip card for biochemical analysis and method for its use |
EP2514528A1 (en) * | 2011-04-19 | 2012-10-24 | Cellix Limited | Device and method for assessing the status of cells in a biological fluid |
EP2785460B1 (en) * | 2011-11-29 | 2021-01-27 | Caliper Life Sciences, Inc. | Systems and methods for sampling of amplification products |
US9689029B2 (en) | 2011-12-02 | 2017-06-27 | Caliper Life Sciences, Inc. | Systems and methods for sampling of amplification products |
US10241120B2 (en) * | 2011-12-06 | 2019-03-26 | Universite Libre De Bruxelles | Method and device for assaying an antigen present on erythrocytes or an antibody binding to an antigen present on erythrocytes |
CN104178413B (en) * | 2014-07-04 | 2016-05-25 | 宁波美晶医疗技术有限公司 | A kind of plastic packaging box packaging structure of rare cell separator |
US10086368B2 (en) | 2015-09-07 | 2018-10-02 | EXIAS Medical GmbH | Movable measurement cell |
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DE19846466A1 (en) * | 1998-10-08 | 2000-04-27 | Ghs Gesundheits Service Ag | Analysis method for the simultaneous determination of parameters from different media |
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DE102005049976A1 (en) | 2004-10-15 | 2006-04-20 | Siemens Ag | Cartridge card for automated DNA or protein analysis has a geometric array of micro-channels with dry reagents |
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2009
- 2009-09-28 DE DE102009043226A patent/DE102009043226B4/en active Active
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- 2010-09-27 WO PCT/EP2010/064258 patent/WO2011036289A1/en active Application Filing
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JP5430766B2 (en) | 2014-03-05 |
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EP2482982A1 (en) | 2012-08-08 |
US20120184043A1 (en) | 2012-07-19 |
DE102009043226B4 (en) | 2012-09-27 |
DE102009043226A1 (en) | 2011-03-31 |
WO2011036289A1 (en) | 2011-03-31 |
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BR112012006831A2 (en) | 2016-06-07 |
CN102548659A (en) | 2012-07-04 |
US9415390B2 (en) | 2016-08-16 |
BR112012006831A8 (en) | 2017-12-05 |
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