Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
  • B01L3/502753—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 bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
• • 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
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L7/00—Heating or cooling apparatus; Heat insulating devices
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L7/00—Heating or cooling apparatus; Heat insulating devices
  • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
  • C12N15/09—Recombinant DNA-technology
  • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/34—Purifying; Cleaning
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/02—Adapting objects or devices to another
  • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
  • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0631—Purification arrangements, e.g. solid phase extraction [SPE]
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0689—Sealing
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/16—Reagents, handling or storing thereof
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/04—Closures and closing means
  • B01L2300/046—Function or devices integrated in the closure
  • B01L2300/048—Function or devices integrated in the closure enabling gas exchange, e.g. vents
• • 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
• • 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
  • B01L2300/0681—Filter
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0809—Geometry, shape and general structure rectangular shaped
  • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
  • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
• • 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
  • B01L2400/04—Moving fluids with specific forces or mechanical means
  • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
  • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2400/00—Moving or stopping fluids
  • B01L2400/06—Valves, specific forms thereof
  • B01L2400/0622—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
  • B01L2400/0638—Valves, specific forms thereof with moving parts membrane valves, flap 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
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6844—Nucleic acid amplification reactions
  • C12Q1/6851—Quantitative amplification
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6844—Nucleic acid amplification reactions
  • C12Q1/686—Polymerase chain reaction [PCR]

Definitions

• the invention relates to a microfluidic device and to a method for using the same for the separation, purification and concentration of components of fluidic media.
• the invention relates to a microfluidic device and a method for the preparation of blood samples and a method for purifying nucleic acids and method for combining said methods with a detection method of the biological ingredients.
• Separating, purifying, fractionating and concentrating components from liquid or gaseous media, and splitting individual constituents followed by separating, refining, fractionating and concentrating components is conventionally associated with numerous manipulations.
• the main technologies are centrifugation and column- or particle-based techniques.
• the sample to be separated is applied to liquid density gradients and different fractions are obtained corresponding to the size.
• Long-term handling steps and centrifugation, often also ultracentrifugation, are disturbing here.
• a connection of sample components to porous surfaces which serve as sheu len.
• centrifugation the sample is driven through this column, manual washing steps with repeated centrifugation steps make this process consuming.
• Pressure-driven columns with specific or semi-specific binding of target molecules or fractionation according to size of the target components and their subsequent elution via pressure-driven liquid inflow are further techniques.
• the object of the invention is therefore a microfluidic device that is easy to adjust forth and is adaptable to both the sample volumes to be processed as well as the pre and subsequent processes. In addition, it is an object to provide a method for their use.
• the present invention describes a microfluidic device with a fluidic channel system with at least one fluidic interface.
• the microfluidic device is designed as a closed unit and has at least one inserted functional element, which is preferably designed as a porous functional element. Through the porousgnacsele ment a sample and / or medium can be performed. Subsequently, the functional element can be used to direct further liquids or gases. That the functional element can sequentially perform various tasks in the processing of fluids in a microfluidic system.
• the microfluidic device has at least one structured component which forms the main or basic component of the microfluidic device.
• the structured component is usually formed as a flat and / or often cuboid body, which is preferably produced by injection molding before.
• this structured component structures are introduced.
• this includes a microfluidic channel system.
• the channels or part thereof are preferably introduced on the top and / or bottom of the structured component.
• the structured component may further comprise liquid reservoirs, channel tapers, valves, switch manifolds, venting membranes, chambers, cavities, and / or reaction cavities either incorporated in the structured component or inserted into cavities provided therefor.
• the microfluidic device also has at least one component applied to the structured component.
• the component can also be designed and designated as a cover plate. This component is placed on the top and / or bottom of the structured component.
• the component may be formed a partially transparent or partially light-tight plate.
• the component may also be formed as a foil, which on the top and / or bottom, for. glued, bonded, pressed or welded, in order to close the microfluidic structures fluid-tight and, if necessary, gas-tight.
• a film is preferably made of synthetic material and has a very small thickness compared to the width and catches, which allows high flexibility. A preferred thickness is less than / equal to 1mm here.
• a plate against has a lower flexibility, since the thickness is greater compared to the width and catches. therefore plates are preferably used with a thickness of greater than or equal than 1mm.
• the microfluidic device according to the invention contains at least one porous functional element.
• the at least one functional element can be realized for example by a filter, a membrane, a frit, or a functional paper or similar elements.
• the one or more functional elements may contain reagents, ie the one or more filters, membranes, frits, functional papers may contain reagents or reagents may be applied thereto. All these examples of functional elements are at least partially passable for fluids. They can be membranes and / or filters for size exclusion, such as laser-structured membranes (track etch) with well-defined pore size, silicon sieve, filter paper with a coarse mesh.
• Functional elements that use the size exclusion and / or connection to the surface of the functional element are various elements such as porous three-dimensional structures such as frits, silicon membranes, silica membranes, three-dimensionally aggregated particles, filter mats made of various materials, silica mats, PET filters, thin-layer chromatography material or plasma All of these functional elements may additionally be provided with reagents to implement a specific binding of target molecules to these functional elements and to realize a targeted detachment of the target molecules from functional elements.
• the microfluidic device has at least one fluidic interface.
• two fluidic interfaces are arranged on the microfluidic device.
• the at least one fluidic interface can be arranged vertically, horizontally and / or at any angle to the microfluidic device and the media addition and / or the admission with positive or negative pressure, as well as simply for venting serve.
• microfluidic device can be closed by using at least one integrated valve, at least one external switch or at least one valve or at least one cap.
• microfluidic device used in particular for the separation, purification, fractionation and concentration of components of a supplied medium or a sample.
• microfluidic device comprise a plurality of functional elements and may optionally also have one or more fluid reservoirs.
• the microfluidic device is operated by a corresponding method, whereby in addition to separation, purification, fractionation and concentration of components, intervening reaction steps can be carried out in order to obtain, separate and concentrate desired target components.
• a particularly advantageous embodiment of the microfluidic device is designed as a functional unit or as a microfluidic system.
• microfluidic device can be done both manually and by means of simp cher devices or devices which are coupled to the microfluidic device or closed to, for example, to supply pressure or process media.
• a method for the purification of nucleic acids in which a sample is supplied via the fluidic interface (4.1) and in a Christskam number (6) is mixed with reagents. The cells in the sample then lyse. The sample is then passed over a functional element, while the output (4.2) is closed and unwanted molecules either directly with the sample in a waste reservoir (7) or by flushing the functional element (5) with reagents from the liquid reservoirs (8) while the target molecules, nucleic acids, remain on the functional element (5) and are first detached from one of the liquid reservoirs (8) by a special reagent, the fluid outlet (4.3) at the waste reservoir (7) being closed in advance and the outlet (4.2) open and the nucleic acids obtained can be removed from the fluidic system via the now open outlet (4.2).
• the nucleic acids are DNA or RNA.
• a sample is supplied via the fluidic interface (4.1) and filtered via a functional element (5), so that the cells remain behind and undesired components enter the waste reservoir (7), whose fluidic interface (4.3) is opened, which is made possible by closing the fluidic interfaces (4.2 and 4.3) behind the second functional element (5) in the direction of flow, and then by contacting the cells with reagents in the cavity (6) above the first functional element.
• a sample is preferably supplied via the fluidic interface (4.1) and filtered via a functional element (5), so that the cells remain behind and unwanted components enter the waste reservoir (7) whose fluidic interface (4.3) is opened, which is made possible by closing the fluidic interfaces (4.2 and 4.3) behind the second functional element (5) in the direction of flow, and then by contacting the cells with reagents in the cavity (6) above the first functional element.
• the purified nucleic acid can be subjected to subsequent amplification and detection.
• the purified nucleic acid may be an RNA and then first subjected to a Rever sen transcription and then an amplification and detection.
• the purified nucleic acid may be a DNA and amplified and detected by qPCR and / or amplified and detected by isothermal amplification.
• the purified nucleic acid may be DNA that is pre-amplified in a first chamber (20) by nonspecific PCR and subsequently detected in a specific qPCR.
• the purified nucleic acid may be RNA that is subjected to a Rever sen transcription in a first chamber (20) and in a second chamber (20) amplified and detected by qPCR.
• the purified nucleic acid may be RNA which is subjected to both reverse transcription and qPCR (one-step RT-PCR) in a chamber (20).
• qPCR chambers (20) may be arranged to run the qPCR in parallel PCR chambers.
• the qPCR can be a duplex PCR with internal control amplification and / or the qPCR can be a multiplex PCR with internal control amplification.
• FIG. 1a shows a first embodiment of the microfluidic device according to the invention in a plan view
• FIG. 1b shows the first embodiment according to FIG. 1a in a sectional view along a not-drawn finie from the entrance to the exit;
• FIG. 2a shows a second embodiment of the microfluidic device according to the invention in a plan view
• FIG. 2b shows the second embodiment according to FIG. 2a in a sectional illustration along a not-shown finie from the entrance to the exit;
• FIG. 3a shows a third embodiment of the microfluidic device according to the invention in a plan view
• FIG. 3b shows the third embodiment according to FIG. 3a in a sectional view along the fin 3b
• FIG. 3c shows the third embodiment according to FIG. 3a in a sectional view along the fin 3cd
• FIG. 3d shows the third embodiment with caps according to FIG. 3a in a sectional representation along the fin 3 cd
• FIG. 3b shows the third embodiment according to FIG. 3a in a sectional view along the fin 3b
• FIG. 3c shows the third embodiment according to FIG. 3a in a sectional view along the fin 3cd
• FIG. 3d shows the third embodiment with caps according to FIG. 3a in a sectional representation along the fin 3 cd
• FIG. 4a shows a fourth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 4b shows the fourth embodiment according to FIG. 4a in a sectional view along the fin 4b
• FIG. 4c shows the fourth embodiment according to FIG. 4a in a sectional view along the fin 4cd
• FIG. 4d shows the fourth embodiment with caps according to FIG. 4a in a sectional view along the fin 4cd
• FIG. 5a shows a fifth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 5b shows the fifth embodiment according to FIG. 5a in a sectional view along the line 5b
• FIG. 5c shows the fifth embodiment according to FIG. 5a in a sectional view along the line 5cd
• FIG. 5d shows the fifth embodiment with caps according to FIG. 5a in a sectional view along the line 4cd
• FIG. 5b shows the fifth embodiment according to FIG. 5a in a sectional view along the line 5b
• FIG. 5c shows the fifth embodiment according to FIG. 5a in a sectional view along the line 5cd
• FIG. 5d shows the fifth embodiment with caps according to FIG. 5a in a sectional view along the line 4cd
• FIG. 5e shows the fifth embodiment with caps according to FIG. 5a in a sectional view along the line 5e;
• FIG. 6a a sixth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 6b the sixth embodiment of Figure 6a in a sectional view along the not a drawn line from the entrance to the exit.
• FIG. 6c shows the sixth embodiment with caps according to FIG. 6a in a sectional view along the non-drawn line from the input to the output;
• FIG. 7a a seventh embodiment of the microfluidic device according to the invention in a plan view
• FIG. 7b the seventh embodiment of Figure 7a in a sectional view along the not a drawn Finie by the liquid reservoirs.
• FIG. 7c shows the seventh embodiment with caps according to FIG. 7a in a sectional representation along the not-shown finie from the input to the output;
• FIG. 8b the eighth embodiment of Figure 8a in a sectional view taken along the not-recorded Finie by the liquid reservoirs.
• FIG. 8c shows the eighth embodiment with caps according to FIG. 8a in a sectional illustration along the not-shown finie from the input to the output;
• FIG. 9a a ninth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 9b the ninth embodiment of Figure 9a in a sectional view along the not a drawn Finie by the liquid reservoirs.
• FIG. 9c shows the ninth embodiment with caps according to FIG. 9a in a sectional view along the not-shown finie from the entrance to the exit;
• FIG. 10a shows a tenth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 10 b shows the tenth embodiment according to FIG. 10 a in a sectional view along the not-shown fin through the liquid reservoirs;
• FIG. 10c shows the tenth embodiment with caps according to FIG. 10a in a sectional view along the not-shown finie from the entrance to the exit;
• FIG. 1 a shows an eleventh embodiment of the microfluidic device according to the invention in a plan view
• FIG. 1b shows the eleventh embodiment according to FIG. 1a in a sectional view along the not-drawn line through the liquid reservoirs
• FIG. 1 c shows the eleventh embodiment with caps according to FIG. 1 a in a sectional view along the non-drawn line from the entrance to the exit;
• FIG. 12 a shows a twelfth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 13 a shows a thirteenth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 13b shows a thirteenth embodiment of the microfluidic device according to the invention in cross-section 1;
• FIG. 13c shows a fourteenth embodiment of the microfluidic device according to the invention in cross-section 2;
• FIG. 14 a shows a fourteenth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 14b shows a fourteenth embodiment of the microfluidic device according to the invention in cross-section 1;
• FIG. 14 c shows a fourteenth embodiment of the microfluidic device according to the invention in cross-section 2;
• 15a shows a fifteenth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 15b shows a fifteenth embodiment of the microfluidic device according to the invention in cross-section 1;
• 15c shows a fourteenth embodiment of the microfluidic device according to the invention in cross-section 2;
• FIG. 16 a shows a sixteenth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 16b shows a sixteenth embodiment of the microfluidic device according to the invention in cross-section 1;
• FIG. 17 a shows a seventeenth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 17 b shows a seventeenth embodiment of the microfluidic device according to the invention in cross-section 1;
• FIG. 18 a shows an eighteenth embodiment of the microfluidic device according to the invention in a plan view
• FIG. 19 shows a nineteenth embodiment of the microfluidic device according to the invention in a plan view
• FIGS. 1 and 2 The basic version of the microfluidic device is shown in FIGS. 1 and 2.
• the microfluidic device has two fluidic interfaces 4.1. and 4.2.
• a structured component 1 is designed as a planar or cuboidal component and has its own NEN sides or end faces two fluidic interfaces on 4.1. and 4.2. on.
• a fluidic channel system 2 is integrated or incorporated into the structured component 1 tur.
• Another component 3 closes an upper side of the structured component 1, so that the fluidic channel system 2 and the fluidic structures are liquid-tight and, when gases are used as the medium, also sealed in a gastight manner.
• a functional element 5, preferably a porous functional element 5, is arranged, which is located on or in the structured component 1.
• the porous functional element 5 can be flowed through both vertically, see FIG. 1b, and horizontally, see FIG. 2b. A bidirectional flow in both directions is possible.
• the functional element 5 can either be directly connected to the structured component 1 via the manufacturing process of the structured component 1, e.g. in the injection molding process by inserting the functional element, be integrated or subsequently introduced into the micro fluidic device.
• the functional element 5 has been inserted into a cavity 6 and is suspended from above, i.
• the channel 2 extends first in extension of the fluidic interface 4.1, to then continue to run on the underside of the structured component 1. Again, the channel 2 is closed by a further component 3. On the underside of the structured component 1, a cavity is formed, in which the functional element 5 is inserted or is, so that it can be flowed through horizontally and the opposite fluidic interface 4.2 flows to be issued there.
• the method for using the microfluidic device is such that a sample is introduced via the fluidic interface 4.1, with some predetermined constituents of the sample remaining in the functional element 5. This is achieved via the predetermined particle size of the functional element 5. Subsequently, the functional element 5 can be rinsed out, wherein different reagents or fragrances are rinsed through the functional element 5. Thereupon, the target component can be flushed out of the functional element 5, which can be done by special reagents, pressure, temperature or a combination of these methods.
• a reprinting with a displacement medium particularly advantageous here are e.g. Oils or higher viscous media than the previous fluids, wherein the same fluids are used, after the detachment of the target component from the functional element 5, to achieve a quantitative flushing of the target component.
• the target component in the eluate obtained can not only be purified but also enriched in comparison with the original medium. Flow through with different media thus also allows fractionation, i. the elution under defenceli cher components of the original medium from the functional element. 5
• FIGS. 3a-3d Another embodiment of the microfluidic device is shown in FIGS. 3a-3d.
• the micro fluidic device has been supplemented with reagent reservoirs 8.
• the structural Component 1 includes a fluidic channel system 2, and the further component 3 on the underside, that the fluidic structures liquid-tight and gas-tight vesch drownt when using gases as a medium and a functional element 5, preferably a porous functional element, which is on or in the structured component 1, as well as three fluidic interfaces 4.1, 4.2, 4.3, the functional element 5 being supplied both by the sample (medium) supplied via the fluidic interface 4.1 located at the top and by the reagents stored in the reagent reservoirs 8 can be flowed through in any order and by selectively closing the Ver fluidic interfaces 4.1, 4.2 and 4.3 with caps 11 (see Fig.
• the reagent reservoirs 8 may be formed as blisters, wherein pre-defined liquids are kept in encapsulated containers. That is, the three reagent reservoirs 8 may contain different types of liquids and / or different amounts thereof in order to be able to add them specifically for the treatment of the sample.
• the press on pressing the blister (A press) to open the encapsulated container, so that the liquid can be safely supplied to the channel system 2 and the functional element 5.
• the liquid can be kept in a waste chamber 7 of the micro-fluidic device or guided through the fluidic interface 4.3 at the top to the outside, wherein by closing the fluidic interfaces 4.1 and 4.3, each with a cap 11, the liquid speed via the fluidic interface 4.2 , which is then opened, can be removed.
• a target liquid can be removed, whereas when applying the sample through the fluidi cal interface 4.1 this is then closed by a cap.
• the functional element 5 may either be directly connected to the structured component 1 during the manufacturing process of the structured component, e.g. in the injection molding process by inserting the functional element 5, be integrated or introduced later.
• the method for using the microfluidic device is such that the sample is introduced via the fluidic interface 4.1, the fluidic interface 4.1 is closed after the sample has been introduced, and the fluidic interface 4.3 for removing the waste is closed by a cap 11 , Components of the sample remain in the functional element 5. Thereafter, the functional element 5 can be rinsed out, in which case various reagents or fragrances are rinsed through the functional element 5. In the next step, the target component is rinsed out of the functional element 5, which can be done by special reagents, pressure, tempera ture or a combination of these methods, wherein the unwanted fractions are stored either in the waste chamber 7 or from the microfluidic device via the fluidic interface 4.3 be rinsed out.
• Target components are then obtained via the fluidic interface 4.2, wherein a reprinting with a displacer after the detachment of the target component from the functional element 5 is particularly advantageous in order to obtain a quantitative flushing out of the target component, so that the target component in the resulting eluate not via this method only purified, but can also be enriched in comparison to the original medium.
• the flow through with different media also allows fractionation, ie the elution of different components of the original medium from the functional element.
• the microfluidic device may have valves in the fluidic channel system 2, which may be manufacturedstal tet as diaphragm valves, rotary valves or other valves, and serve the channel system 2 or parts thereof to selectively close, for example.
• the microfluidic device can have a preceding reaction space 6, as in FIG. Reference source could not be found.
• the structured component 1 a fluidic channel system 2, which is arranged on the underside of the structured component 1 tur.
• the underside of the structured component 1 and the fluidic channel system 2 introduced therein is liquid-tight with the further component 3 and also gas-tight when the gas is used as a medium.
• the microfluidic device according to FIGS. 4a-4d has a plurality of reagent reservoirs 8, of which at least one can provide a liquid supply in front of the cavity 6. Likewise, a liquid supply to the cavity 6 but before the functional element 5 is possible, which is not shown here. Three further reagent reservoirs 8 are arranged to allow fluid or reagent delivery to the functional element 5, i. the reagent reservoirs 8 deliver their media into the functional element 5. The addition can be delayed.
• the microfluidic device according to FIG. 4a-4d has further fluidic interfaces on which a fluidic interface 4.3 is connected behind a chamber 7 and a further fluidic interface 4.2 parallel to the chamber 7.
• the sample passes through the subsequently to be closed fluidic interface 4.1 (Fig. 4d) into the cavity 6 and is there mixed with a reagent from a reagent reservoir 8. Then, the resulting liquid is passed through the functional element 5, wherein the functional element 5 can be flowed through both the media from the cavity / reaction space 6 and by reagents from other reagent reservoirs 8 in any order.
• the liquid can be held in the waste chamber 7 in the microfluidic device or be discharged to the outside via the fluidic interface 4.3 connected to the chamber 7 at the top of the structured component 1.
• liquid can then be withdrawn via the opened fluidic interface 4.2, for example for removal of a target fluid. whereas, when the sample is applied through the fluidic interface 4.1, it is subsequently closed.
• the micro fluidic device may have an additional functional element 5, as shown in Fig. 5a-d.
• a plurality of reagent reservoirs 8 are present, which can supply liquids or media in front of the first functional element 5 or can supply the second functional element 5 with liquids.
• the first and second functional element 5 are connected in series.
• the microfluidic device has two chambers 7, one of which is coupled to the first functional element 5 and having a fluidic interface 4.4.
• a first fluidic interface 4.1 is arranged on the upper side of the structured component 1 and via the channel system 2 with the first functional element 5, which is flowed through vertically.
• the second functional element 5 is arranged, which is connected to the second chamber 7.
• the second Kam mer 7 is connected to the fluidic interface 4.3, wherein before the second chamber 7 a Ka nala livingeist is arranged to the fluidic interface 4.2.
• the structured component 1 is here covered with two other components 3, the liquidi cal channel system 2 liquid-tight and close when using gases as a medium gas-tight ver.
• the upper component 3 does not completely cover the upper side of the structured component 1, so that the plurality of fluidic interfaces 4.1, 4.2, 4.3 and 4.4 are not covered by the upper component 3.
• the lower component completely covers the structured component 1.
• the sample passes through the subsequently to be closed fluidic interface 4.1 in the cavity / reaction chamber 6, in which the first functional element 5 is arranged. Particles are retained by the first functional element 5 and passed through the fluidic channel system 2 by closing the fluidic interface 4.1 to the second functional element 5 and from there via the chamber 7 to the fluidic interface 4.3 or directly from the microfluidic Vorrich device via the fluidic interface 4.4 led out.
• the microfluidic device has two functional elements 5, which are connected in series.
• the first functional element 5 is arranged in a cavity 6 and is flowed through from above, ie vertically.
• the first functional element 5 is coupled to a reagent reservoir 8.
• the second functional element 5 is arranged on the underside and coupled via the channel system 2 with the output of the first functional element 5, wherein a further reagent reservoir 8 is interposed for additional liquid addition.
• the first functional element 5 receives the sample via the fluidic interface 4.1, which then either runs independently through the first functional element 5 or through reagents from the reagent reservoir 8 further into the second functional element 5 is driven.
• the second functional element 5 the eluate is then removed via the fluidic interface 4.2 from the microfluidic device.
• reagents from the reagent reservoir 8, which in front of the first functional element 5 into the fluidic channel system 2 or from the reagent reservoir 8, which meets only before the second functional element 5 in the fluidic channel system 2, are moved.
• the first functional element 5 is a unit for generating plasma or serum from blood and the second functional element 5 serves to remove hemolyzed red blood cells.
• this embodiment according to FIGS. 6a-6c makes it possible to give larger volumes of the sample via the first functional element 5 and remove interfering components by the second functional element 5, so that both the problem of generating larger plasma / Serum quantities on a microfluidic chip can be remedied by a further step and, in addition, blood samples which already show aging effects or which have generally already lysed red blood cells can be used.
• the microfluidic device has two functional elements 5 connected in series behind one another, wherein the first functional element 5 is acted upon by the sample via the fluidic interface 4.1.
• the sample then either runs independently through the first functional element 5 running or is driven by reagents from the first associated reagent reservoir 8 further into the second functional element 5.
• the eluate can then be discharged from the device via the fluidic interface 4.2, whereby reagents from the reagent reservoir 8, before the first functional element 5 into the fluidic channel system 2 or from the reagent reservoir, only before the second Functional element 5 meets in the fluidic channel system 2, can be moved.
• the first functional element 5 is a unit for generating plasma or serum from blood, wherein the second functional element 5 is used for the extraction of nucleic acids from the recovered plasma / serum.
• the reagent reservoir 8 connected to the first functional element 5 is connected for diluting and expelling the recovered plasma / serum.
• the reagent reservoirs 8 connected upstream of the second functional element 5 are used to expel unwanted components and are used to detach the target component.
• a heat supply can be effected, whereby the detachment can be intensified.
• the fluid management within the microfluidic device is made possible by the opening and closing of the corresponding fluidic interfaces 4.1, 4.2 and 4.3, so that the target fraction can be obtained cleanly via one of the fluidic interface 4.2 or 4.3 or directly into adjoining areas of the fluidic channel system 2 can be transported.
• FIGS. 8a-8c The microfluidic device according to FIGS. 8a-8c will now be described. Here are mistakes! Reference source could not be found, three wireless 5, wherein the first functional element 5 is acted upon via the fluidic interface 4.1 with the sample.
• the sample then either runs independently through the first functional element 5 or is driven further by reagents from the first reagent reservoir 8 to the second functional element 5, wherein the process step is repeated on the second functional element 5 and the eluate is passed on to the third functional element 5 , wherein a part remains on the third functional element 5 and unwanted components can be washed out through the reagents of the reagents reservoire 8 and either remain in the waste chamber 7 or be discharged to the fluidic interface 4.2 or 4.3.
• the desired component can be obtained by closing the part of the fluidic channel system 2, which is directly connected to the waste reservoir 7, via the fluidic interface 4.2 or be passed to a further processing function in the fluidic channel system 2.
• FIGS. 9a-9c which is similar to FIG. 8a-8c constructed, with an additional detection space 6 is present.
• the detec tion space is covered by an at least partially transparent region of the component 3 or the structured component 1 is at least partially transparent in the region of the detection space 6 in order to make a visual inspection of the state of the eluate can.
• the sample then either runs independently by the functional element 5 or is driven by reagents from the first reagent reservoir 8 to the second functional element 5, wherein the process step on the second functional element 5 is repeated and then the eluate is passed through the third functional element 5, wherein a Part of the eluate remains on the third functional element 5 and unwanted components on the reagents of the reagents reservoire 8 are washed out and either remain in the waste chamber 7 or be removed.
• the desired component can be obtained by closing the part of the fluidic channel system 2, which is directly connected to the waste reservoir 7, and either removed via the fluidic interface 4.2 or passed to another function in the fluidic channel system 2.
• the eluate then passes through the fluidic interface, output 4.2, from the device, wherein reagents from the reagent reservoir 8, which is connected to the first functional element 5 to the fluidic channel system 2 or from the reagents zienreservoir, the only before the second functional element 5 meets the fluidic channel system 2, can be moved.
• the first functional element 5 is a unit for generating plasma or serum from blood.
• the second functional element 5 is used for the extraction of nucleic acids from the plasma / serum obtained.
• the reagent reservoir 8 connected to the first functional element 5 is provided for diluting and expelling the recovered plasma / serum.
• the functional element 5 upstream reagent reservoirs 8 are used to drive unwanted ter components and to detach the target component.
• the detachment of the target component can also be enhanced by temperature supply, wherein the fluid guide is made possible by the opening and closing of the corresponding fluidic interfaces, so that the Zielfftress can be obtained cleanly via a fluidic interface 4.2 or 4.3 or directly in closing areas of the fluidic channel system 2 can be transported.
• FIG. 10A-10c is similar to the embodiment according to FIGS. 9a-9c.
• a second detection space 6 available.
• indicator solutions from one of the reagent reservoirs 8 optically recognizable reactions, for example color changes, can be produced, which can then be observed in one of the two detection spaces 6.
• FIG. 11 a lc is similar to the embodiment according to FIG. 10 a - 10 c.
• an array of reagents is arranged in the second detection space, which act a reaction of the eluate be, which can then be perceived optically.
• the embodiment according to FIG. 12 exemplarily displays measuring windows 13, which are e.g. can be read optically and preferably have several depths to extend the dynamic range of the measurement.
• concentration determinations of eluted samples e.g. the determination of the concentration of eluted nucleic acids or protein.
• one measuring window 13 is arranged behind the second and third functional element 5.
• FIGS. 13a-13c shows a fluidic system with a directly coupled syringe pump 14, 15, which is formed integrally with the structured component 1 or can be manufactured separately.
• the syringe pump includes a body 14 and a plunger 15.
• the syringe pump can be operated via the plunger 15 and both for the storage of fluids, for the reception of waste during use of the fluidic system as well as for the control and control of the fluids during use of the fluidic system can be used.
• the syringe pump is connected to the channel system 2.
• FIGS. 14a-14c additionally contains, in addition to the components of embodiment FIG. 13, a rotary valve 16 which can switch the individual regions of the fluidic network or channel strands starting from the syringe pump 14, so that sections are separated or together fluidly can be controlled.
• FIG. 4b shows a sectional view along the line 14b
• FIG. 14c shows a view along the line 14c.
• the embodiment according to FIGS. 15a-15c includes a fluidic system similar to the embodiment of FIG. 14, which, instead of a reaction chamber or detection chamber 12, as shown in FIG. 14a, with a downstream reagent array, contains a plurality of parallel reaction chambers 20, eg for PCR (Polymerase Chain Reaction), Real Time PCR, Quantitative Real Time PCR (qPCR) or a combined reverse transcription with PCR (PCR, Real Time PCR, qPCR).
• the filling of the chambers 20 takes place in parallel or successively and is achieved in each case by a vent at the end of this fluidic network area by a gas-permeable membrane 23, wherein alternatively a closed air reservoir through the compressibility of air, Boyle-Mariotte effect, can be used. Both in the channel system 2 and in the reaction chambers 6 reagents may be presented.
• the embodiment of FIGS. 16a, 16b includes an additional chamber 20 which may contain reagents, preferably reagents for PCR or reverse transcription.
• reagents may be present in one or more of the chambers 6 and PCR chambers 20, in particular dry reagents for reverse transcription or PCR (RT-PCR, qPCR, PCR).
• the embodiment according to FIGS. 17 a, 17 b additionally includes the option of closing the PCR chamber 20, each with a membrane valve 21, which is particularly advantageous in order to keep the fluids in the PCR chamber 20 even at high temperatures.
• the embodiment according to FIG. 18a includes by way of example a series of diaphragm valves 21, which serve for fluid control in the fluidic system and are arranged at different locations in the channel system 2 in order to close part of the channel system 2 and thus to control the fluid flow inside the microfluidic device enable.
• FIG. 19 shows a number of functional elements that sequentially process the sample from the fluid inlet.
• the sample is introduced into the fluid inlet 4.1 and then reaches a reaction space 6 which may contain mixing elements and reagents and into which reagents reservoir 8 may be added to react with the sample.
• this mixture passes tointerventionslement 5 to receive by means of flow with different fluids from the reagent reservoirs 8, the purified target molecules whose volume can then be measured on the measuring loops 22 on the second rotary valve 16 and then with each one defined Volume can reach the next reaction chamber 6, wherein it may be submitted to dry or liquid reagents Kings NEN. Subsequently, this mixture enters the parallel reaction cavities 6, e.g. for a PCR (qPCR, RT-PCR, PCR) 20 can be used.
• the fluid control takes place via the fuel pump 14, the rotary valves 16 and the selective emptying of the reagent reservoirs 8.
• the embodiment according to FIG. 19 can be used in such a way that the output channels and / or the input channels from the reaction / PCR combs 20 are separated by a gel method. be sealed by welding, heat sealing or pressure and so the liquids remain in the chambers 20 during the temperature cycles of a PCR.
• a nucleic acid-containing sample is sucked into the reaction chamber 6 via the fluidic interface 4. 1 by means of the integrated syringe pump 14.
• the sample is mixed with lysis buffer from the reagent reservoirs 8 and actively lysed.
• the sample lysate is sucked through the element by the integrated syringe pump 14 via the rotary valve 16.
• the sample is cleaned in the functional element 5 by Waschpuf fer from the reagent reservoirs 8 so that clean nucleic acid remains in the functional element 5.
• Excess sample and washing buffer are sucked off by means of the syringe pump 14 and remain in this as waste.
• the mixture of eluate and PCR reagent is pressed via the rotary valve 16 into the PCR / qPCR / RT-PCR chambers 6/20 and these are flooded homogeneously.
• the PCR chambers 6/20 can subsequently be closed thermally at the chamber inlet and outlet, and then the temperature cycle is carried out with amplification and optical detection.
• an isothermal amplification of the nucleic acid takes place.
• the purified nucleic acid is RNA that undergoes reverse transcription prior to amplification.
• microfluidic device or fluidic functional unit according to the invention can be used as an independent component, but at the same time also be part of an expanded fluidic network. This is the case in particular with microfluidic chips, which cover further functions and cover the microfluidic device according to the invention and the method according to the invention for the operation of which only partial areas.
• Fluidic interfaces are elements that can be used to introduce or apply media, to bleed, to close or open to pressurize or create negative pressure, and also to interface with an instrument or for use by a manual operator.
• These fluidic interfaces may be of any shape, such as holes, recesses, mini luer, luer, luer-lok, olive or other geometries, and in a venting variant with gas-permeable but liquid-tight components, e.g. gas-permeable membranes, be closed.
• valves on the functional element in the form of diaphragm valves, rotary valves or passive valves e.g. via channel tapers, or surface modifications of the base material.
• the valves are mostly operated by a corresponding operating device, alternatively, a manual operation for some embodiments is possible.
• the elements can be connected to it directly in the production process of the structured element, for example as insert parts by injection molding (insert molding) or subsequently inserted.
• the parts of the fluidic network described as cavity 6, 7 can be designed as a chamber, channel, etc. and do not necessarily have to be in the geometric dimensions before or after this chamber, e.g. the channel cross sections differ.
• the reagent reservoirs 8 shown in the various embodiments can also be embodied as fluidic interfaces and fed via external reagent reservoirs, eg from an operating device.
• the fluid transport on the functional element can be effected via external pressure or vacuum admission, pressurization of reagent reservoirs, integrated pump valves, surface forces, capillary forces, etc.
• the present invention describes a microfluidic device with a fluidic system with at least one fluidic interface and at least one introduced porous functional element through which a sample is passed and th thereafter further liquids or gases can be directed.
• the entire device has at least one structured component and at least one component applied to the structured component, as well as the preferably porous functional element.
• the functional unit according to the invention serves for the separation, purification, fractionation and concentration of components.
• Special embodiments of the functional unit include a plurality of functional elements and also have liquid reservoirs on the micro fluidic device.
• the microfluidic device is to be operated with a corresponding method.
• the operation of the system can be done both manually and by means of simple devices or devices.
• PCR chamber 20 this can be synonymous with a chamber for the various forms of PCR, such as Real Time PCR, quantitative PCR, combined reverse transcription, reverse transcription or isothermal methods of amplification of nucleic acids such as NASBA, RCT etc . his.
• Fluidic interface e.g. Exit for waste, vent

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