EP1987362A2 - Dispositif et procédé de traitement ou d'épuration d'échantillons, notamment d'acides nucléiques - Google Patents

Dispositif et procédé de traitement ou d'épuration d'échantillons, notamment d'acides nucléiques

Info

Publication number
EP1987362A2
EP1987362A2 EP07711460A EP07711460A EP1987362A2 EP 1987362 A2 EP1987362 A2 EP 1987362A2 EP 07711460 A EP07711460 A EP 07711460A EP 07711460 A EP07711460 A EP 07711460A EP 1987362 A2 EP1987362 A2 EP 1987362A2
Authority
EP
European Patent Office
Prior art keywords
sample material
chamber
mixing chamber
receiving
transferred
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07711460A
Other languages
German (de)
English (en)
Inventor
Ralf-Peter Peters
Holger Bartos
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Microparts GmbH
Original Assignee
Boehringer Ingelheim Microparts GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Microparts GmbH filed Critical Boehringer Ingelheim Microparts GmbH
Publication of EP1987362A2 publication Critical patent/EP1987362A2/fr
Withdrawn legal-status Critical Current

Links

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
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/304—Micromixers the mixing being performed in a mixing chamber where the products are brought into contact
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/71725—Feed mechanisms characterised by the means for feeding the components to the mixer using centrifugal forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0621—Control of the sequence of chambers filled or emptied
    • 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
    • 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
    • B01L2300/0803—Disc shape
    • B01L2300/0806—Standardised forms, e.g. compact disc [CD] format
    • 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
    • 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
    • B01L2300/087—Multiple sequential chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0874—Three dimensional network
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0677—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
    • B01L2400/0683—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers mechanically breaking a wall or membrane within a channel or chamber
    • 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
    • B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break
    • 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
    • B01L2400/0694—Valves, specific forms thereof vents used to stop and induce flow, backpressure valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • 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
    • B01L3/502738—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 integrated valves
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0439—Rotary sample carriers, i.e. carousels
    • G01N2035/0446—Combinations of the above
    • G01N2035/0449—Combinations of the above using centrifugal transport of liquid

Definitions

  • the present invention relates to a device and a method for the treatment, in particular separation, or purification of sample material, in particular of nucleic acids.
  • the present invention relates in particular to microfluidic methods, systems or devices whose structures have a size of about 1 to 5000 ⁇ m and / or whose cavities each have a volume of about 1 to 5000 ⁇ l.
  • the following statements relate in particular to devices and methods in which capillary, pressure and / or centrifugal forces act and are crucial for the function.
  • the present invention relates in particular to the purification of sample material, more preferably of nucleic acids, such as DNA or RNA, which is initially present as a mixture, for example as a blood, cell culture, food or soil sample.
  • sample material more preferably of nucleic acids, such as DNA or RNA
  • the following description is primarily directed to the purification of nucleic acids from the initial sample material.
  • the invention is not limited thereto.
  • Other compounds, such as proteins, fats or metabolites, or cells or cell components, such as organelles, may also be analyzed, for example.
  • the specified devices and methods can also be used for the other treatment of sample material or for other purposes, in particular in the field of microfluidic systems, devices and methods.
  • a known sequence for DNA purification provides for the subsequent sequence.
  • 20 ⁇ l of a protease (enzyme solution) are pipetted as first treatment liquid into a centrifuge vessel and 200 ⁇ l per sample material and 200 ⁇ l of a lysis buffer are added as a second treatment liquid.
  • a mixing device mixes the liquids in the closed centrifuge tube. Then, the centrifuge tube is transferred kubator in a home, where it is stored for ten minutes at an elevated temperature, for example, 56 0 C. The centrifuge tube is transferred to a centrifuge and centrifuged. Subsequently, the centrifuge vessel is removed, opened and ethanol added as a further treatment liquid. Followinged by a further mixing and centrifuging.
  • the previous centrifugation was used to remove drops on the inside of the container, in particular from the lid or the like.
  • the mixture (lysate) is then transferred to a so-called centrifuge column with a separating agent for DNA and centrifuged.
  • the mixture is passed through the separation means into a collection container, wherein DNA is bound in the separation means and the collection container receives the filtrate.
  • the collecting container is exchanged, the centrifuge column is opened, a washing solution, in particular a washing buffer, is added and centrifuged again. This step is repeated with a second wash solution and a second wash buffer, respectively.
  • the centrifuge column is opened and a solvent such as a certain buffer or distilled water is added and incubated at room temperature for about one minute, that is stored.
  • the solvent dissolves the DNA bound to the separating agent.
  • the solvent is transferred together with the DNA in the sampling container, so that in the sampling container, the purified sample material, ie the DNA together with the solvent without the other ingredients, such as cell debris, degradation products from the protein degradation or the like is present.
  • the object of the present invention is to provide a device and a method for the treatment or purification of sample material, in particular 01029
  • nucleic acids specify the flow and handling over the prior art are simplified and / or a simple, inexpensive, largely automated and / or rapid treatment or purification of sample material is made possible.
  • a first aspect of the present invention is to use a microfluidic device with a particular flat or disc-shaped platform for the treatment or purification of the sample material.
  • the apparatus comprises a sample chamber for receiving sample material, a storage chamber for receiving a solvent, a reaction chamber with a separation means in particular for the selective, reversible or temporary binding of certain sample material, such as nucleic acids, a collection chamber, in particular for excess liquids and / or a removal device for Inclusion of treated or purified sample material.
  • the chambers and the removal device are formed in or on the platform and connected to each other such that the sample material in a separation step by centrifugal forces from the first chamber via the reaction chamber into the collection chamber can be transferred, wherein components of the sample material, such as nucleic acids, from Separating agent are retained or bound in the reaction chamber, and that the solvent is transferred in a removal step by centrifugal forces in the reaction chamber to dissolve bound sample material and then transferred from the reaction chamber as treated or purified sample material in the removal device.
  • the further steps are carried out in the microfluidic device.
  • Another aspect that can also be realized independently is to incorporate the separating agent, in particular a binder, filter medium or the like, directly into the platform and, in particular, to flow perpendicular to the plate plane. This allows a simple compact design.
  • a second, independently realizable aspect of the present invention provides for a particularly effective mixing of fluids, such as sample material with treatment liquids, with a simple construction of the microfluidic device.
  • a mixing chamber is preferably connected only via a channel with an additional mixing chamber.
  • the fluids to be mixed are - at least partially transferred by centrifugal forces through the channel in the additional mixing chamber - preferably alternately or repeatedly in succession and transferred from this by gas pressure and / or elastic restoring forces back into the mixing chamber.
  • corresponding variation of the rotational speed (rotational speed or angular velocity) of the preferably flat or disk-shaped device or platform enables very efficient mixing. In particular, no separate mixing device is required.
  • a third, likewise independently realizable aspect of the present invention provides for a direct mounting of a container for receiving treated sample material on the disc-shaped rotatable platform.
  • this container is a so-called Eppendorf cup or another standard container widely used in analytics. After filling, the container is released from the platform. The immediate placement or retention of the container on the platform eliminates the need for an additional step of removing the treated sample and transferring it to the container.
  • the immediate arrangement of the container on the platform can also serve for other purposes, for example for the supply or provision of sample material or other liquids.
  • the removal from the container and transfer into a chamber or the microfluidic channel system of the device then takes place preferably by centrifugal, pressure, gravitational and / or capillary forces.
  • Fig. 1 is a not to scale view of a portion of a proposed device according to a first embodiment
  • Fig. 2 is a fragmentary sectional view of Figure 1 taken along line II - II.
  • FIG. 3 is a fragmentary sectional view of Figure 1 taken along line III - III;
  • FIG. 4 shows a view, not to scale, of part of a proposed device according to a second embodiment
  • FIG. 5 is a partial enlargement of FIG. 4 along line V -
  • Fig. 6 is a corresponding to Fig. 2, fragmentary section of Figure 1, wherein a differently designed separating means is provided.
  • Fig. 7 is a perspective, not to scale view of a proposed device according to a third embodiment.
  • FIG. 1 shows, in a not to scale, very schematic view, part of a proposed device 1 according to a first embodiment. This is in particular a microfluidic system in the aforementioned sense.
  • the device 1 has a platform 2, which is formed in particular flat or plate-shaped.
  • the device 1 or platform 2 preferably has the form of a round disc, for example a compact disc (CD) or the like.
  • the device 1 or platform 2 can also be constructed from a plurality of, preferably segment-like modules M or - as in the illustration example - be designed as a single, preferably segment-like module M.
  • the module M or the modules M - possibly also different modules M - is or can then be mounted or held on a support 3, for example.
  • other configurations and configurations are possible.
  • the device 1 or platform 2 is rotatable about an axis of rotation 4 indicated in FIG. 1-which here runs perpendicular to the plane of the drawing-to produce centrifugal forces.
  • FIG. 1- which here runs perpendicular to the plane of the drawing-to produce centrifugal forces.
  • FIG. 1- which here runs perpendicular to the plane of the drawing-to produce centrifugal forces.
  • the proposed device 1 is used for a treatment, for example separation or reaction, or a purification of sample material 5.
  • the sample material 5 is blood, blood components, a cell culture, a tissue sample, a food sample, a soil sample or other, in particular chemical or biological samples.
  • the proposed device 1 and the proposed method for the purification of nucleic acids, such as DNA or RNA, from the initially present (raw) sample material 5 are particularly preferably used.
  • the device 1 and the described methods may also be used for other treatments, examinations or the like of the sample material 5.
  • the previous and following statements apply accordingly or in addition.
  • the sample material 5 is preferably in a flowable or fluidizable form, in particular as a fluid, for example as a liquid with cell components, proteins or the like.
  • the sample material 5 will also be referred to as a liquid in a simplified manner, even if it contains solid or undissolved constituents, large molecules, in particular proteins, or the like. More preferably, the sample material 5 is a biological sample or constituents thereof.
  • the device 1 or platform 2 has a sample chamber 6 for receiving sample material 5, a storage chamber 7 for receiving a solvent 8, a reaction chamber 9 with a separating means 10, in particular for the selective, reversible or temporary binding of sample material 5, in particular nucleic acids, such as DNA or RNA, a collection chamber 11 for excess sample material 5, excess liquids or the like and / or a removal device 12 for receiving treated or purified sample material 5, in particular nucleic acids, such as DNA or RNA, or the like, on.
  • a sample chamber 6 for receiving sample material 5
  • a storage chamber 7 for receiving a solvent 8
  • a collection chamber 11 for excess sample material 5, excess liquids or the like
  • a removal device 12 for receiving treated or purified sample material 5, in particular nucleic acids, such as DNA or RNA, or the like, on.
  • FIG. 2 shows a preferred construction of the device 1.
  • the platform 2 is preferably made of a plate material, in particular of plastic.
  • the chambers 6, 7, 9 and 11 are preferably formed by corresponding depressions from a flat side or both flat sides.
  • the channels 13 to 16 are preferably formed by corresponding grooves, grooves or other recesses, in particular along the flat sides det. In the illustrated example, the channels 13 to 16 or sections thereof run on opposite sides as needed, for example, to achieve a particularly compact arrangement of the cavities and / or desired flow characteristics, directions or the like.
  • the plate material may for example be produced by injection molding and provided with the cavities (chambers, channels, openings, recesses or the like). However, the plate material may also be manufactured and / or processed in any other suitable manner.
  • the cavities are suitably by a cover 17 or - as in the illustration - on both sides by covers 17, preferably Foil or the like, covered and thereby liquid-tight and in particular at least largely closed gas-tight. Any chemicals, coatings, release agent 10 or the like are applied, incorporated or used before covering, if necessary.
  • the chambers 6, 7, 9 and 11 and the removal device 12 are arranged and / or in particular via corresponding channels 13 to 16 connected to each other in such a way that the sequence explained below or a similar sequence is made possible.
  • the sample material 5 is preferably pretreated before it is introduced into the sample chamber 6.
  • the pretreatment of the sample material 5 takes place in particular in such a way that cells originally contained in the sample material are lysed and existing proteins are degraded, in particular by protease.
  • a heating to above 50 0 C for a predetermined time is preferably carried out in the pretreatment.
  • a separation of cell debris or other constituents can take place.
  • the pretreated sample material 5 is filled into the sample chamber 6, in particular pipetted.
  • the sample chamber 6 is accordingly designed to be open. Alternatively, pipetting can also take place in an open pre-chamber, not shown, from which the sample material 5 is in particular automatically transferred by capillary forces into the then closed or covered sample chamber 6.
  • the storage chamber 7 is preferably designed to be open accordingly. However, if required, an unillustrated, open pre-chamber may also be used here, into which the solvent 8 is filled or pipetted, preferably to be transferred by capillary forces into the then closed storage chamber 7.
  • the device 1 or platform 2 or the support 3 is rotated in order to remove the sample material 5 by centrifugal forces from the first chamber 6 via the reaction chamber 9 in a separation step to overflow the collection chamber 11, wherein sample material 5 - more precisely components of the sample material 5, in particular DNA and / or RNA - retained by the separation means 10 in the reaction chamber 9 and preferably bound or become.
  • the separating means 10 serves a selective, temporary or reversible binding of sample material 5 or at least one particular component of the sample material 5.
  • the separating means 10 if necessary, only a retention or separation or filtration of the sample material 5 or components of the sample material. 5 serve.
  • the separating element 10 may also be formed as a filter element, membrane or the like.
  • the device 1 or platform 2 is rotated at a first rotational speed (rotational speed or angular velocity) in order to first transfer the sample material 5 from the first chamber 6 via the channel 13 into the reaction chamber 9.
  • the rotational speed is chosen such that in particular a channel or capillary stop KS - for example, at the transition from the first chamber 6 to the channel 13 - can only be overcome upon reaching or exceeding the first rotational speed.
  • a stop KS can be realized for example by a sudden cross-sectional widening, but also by a suitable valve device, at a certain pressure or a certain force bursting membrane or the like.
  • the sectional, schematic section of FIG. 2 along line II-II of FIG. 1 illustrates a possible structure of the device 1 or platform 2 without sample material 5 in the region of the reaction chamber 9.
  • the sample material 5 flows through the channel 13 in the illustrated example from above into the reaction chamber 9 and is passed through the separating means 10 arranged therein.
  • the separating means 10 preferably has a in FIG. 1 and 2 indicated, porous body and / or glass fibers, in particular in the form of a glass fiber membrane, or the like for the selective, temporary or reversible binding of a component to be purified of the sample material 5, in particular of nucleic acids on.
  • the separating means 10 comprises or consists of a surface coating, membrane, protrusions and / or the like for the desired temporary binding of at least one desired constituent of the sample material 5.
  • the separating means 10 is preferably formed by a glass fiber membrane inserted into the reaction chamber 9, which can selectively and temporarily or reversibly bind certain constituents of the sample material 5, in particular nucleic acids.
  • a coating in particular an SiO 2 coating, so-called beads, magnetic particles or the like can be used.
  • the separating means 10 may, for example, also have small particles 38, in particular beads, so-called beads, rods or the like, preferably having a size of about 200 nm to 200 ⁇ m, to which the constituent of the sample material 5 to be purified binds.
  • the separating means 10 then preferably additionally comprises a type of filter 39, membrane or other suitable structure or means to retain the corpuscles 38 and in particular to prevent transport of the corpuscles 38 into the collecting chamber 11.
  • the sample material 5 is passed over the channel 14 into the collection chamber 11 after flowing through or through the separating means 10.
  • the discharge preferably takes place on the opposite side of the feed line, in particular in order to enable or to achieve a good flow through the separating means 10 (preferably transversely or perpendicular to the plate plane E).
  • the channels 13 and 14 are thus arranged or formed on opposite flat sides of the platform 2 or connected to the reaction chamber 9.
  • the channel 14 which connects the reaction chamber 9 to the collection chamber 11 is preferably initially guided starting from the reaction chamber 9 towards the axis of rotation 4, specifically in an arc up to a point P closest to the axis of rotation 4, so that the program can be forwarded.
  • a removal step follows. It is particularly preferable to refill, refill or fill in the solvent 8 after the separation step, even if this is possible in principle.
  • the rotational speed of the device 1 is further increased, so that the solvent 8 in particular an optional Kapillarpour. Overcome channel stop KS and can flow through the channel 15 into the reaction chamber 9.
  • the solvent 8 in particular a so-called ionization buffer, distilled water or the like, dissolves there the components of the sample material 5, in particular bound components, in particular bound by the separation means 10, in particular nucleic acids, such as DNA or RNA.
  • the solvent 8 in the illustrated embodiment from below (FIG. 2) - that is, in the direction opposite to the direction in which the sample material 5 flows through the separating means 10 - is guided through the separating means 10.
  • the solvent 8 can then continue to flow via the channel 16 into the removal device 12 together with the sample material 5, ie the purified DNA or RNA, dissolved by the separation means 10. This is done in particular 01,029
  • the separating means 10 comprises the already mentioned bodies 38, in particular so-called beads or the like, which bind constituents of the sample material 5 to be purified or separated
  • the solvent 8 can also only serve to bind these bodies 38 together with the bound constituents, that is, in particular the purified DNA or RNA, to be transported via the channel 16 into the removal device 12 or to be issued or made available in any other way.
  • the term "solvent" is thus to be understood in a very broad sense, since in particular a dissolution of the purified or bound components of the body 38 or beads by the solvent 8 or in the device 1 or platform 2 does not have to occur or, although this can be done in principle.
  • the said bodies 38 can also be releasably secured to a corresponding structure of the separating means 10 or filters 39 or the like, and be detachable from the solvent 8.
  • the channel 16 is preferably as well as the channel 14 on the axis of rotation 4 facing side connected to the reaction chamber 9 and preferably extends first to the rotation axis 4 out, in particular in an arc, up to a rotation axis 4 closest point P.
  • the channel 16 or at least its connection preferably runs on the upper side in FIG. 1, ie the flat side of the platform 2 opposite the channels 14 and 15, at least with its section connected to the reaction chamber 9. Because of this connection of the channel 15 opposite the port of the channel 16, the flow through the separating means 10 opposite to the flow of the sample material 5 from the sample chamber 6 through the separating means 10 is reached in the collecting chamber 11.
  • the channel 16 preferably has an arcuate course as well as the channel 14, wherein the point P of the channel 16 closest to the axis of rotation 4, however, preferably has a greater distance from the axis of rotation 4 than in the case of the channel 14.
  • the sample material 5 initially transferred from the first chamber 6 into the reaction chamber 9 may, if appropriate, flow temporarily into the channel 16, but becomes particularly due to the position of the collection chamber 11, which is more remote radially from the axis of rotation 4 compared to the removal device 12 higher centrifugal forces via the channel 14 back from the channel 16 into the collection chamber 11 promoted or sucked.
  • the channel 16 in its hydrophilic or hydrophobic properties - for example by appropriate choice of material, coating or the like - be adapted to the solvent 8 with the sample material 5 dissolved by the separating means 10 that only the solvent 8 with this sample material 5 through the channel 16 flows into the removal device 12.
  • a valve device not shown, for example, a bursting membrane, a channel or capillary stop or the like can be used to ensure that only the solvent 8 with the sample material 5 dissolved by the separating means 10 through the channel 16 in the removal device 12th flows.
  • a vent 16 associated with the channel 16 or the removal device 12 is in this case released or opened, for example, by a control fluid (not shown), piercing, incising or perforating the cover 17 or otherwise only when the solvent 8 has been purified Sample material 5 should flow into the removal device 12.
  • This release or opening can be achieved, for example, by achieving or exceeding a certain rotational speed, or by opening or releasing the vent 18, for example the cover 17, which receives and ventilates the device 1 or an associated pipetting device.
  • the removal device 12 preferably has a storage chamber 19 in the illustrated example.
  • the storage chamber 19 is preferably such EP2007 / 001029
  • the purified sample material 5 can be taken directly from the storage chamber 19.
  • the extraction device 12 in the illustrated example a container 20, which serves to receive treated or purified sample material 5 - ie the release agent 10 by the solvent 8 dissolved components, such as nucleic acids, together with the solvent 8 -.
  • the container 20 is designed in particular as a so-called Eppendorf cup or other standard standard vessel and preferably releasably or separably supported on the platform 2, in particular by clamping and / or latching attached thereto, or for example glued or screwed.
  • the attachment is particularly such that the container 20 is kept sufficiently strong even when the centrifugal forces occurring - so even with strong rotation.
  • the platform 2 has for this purpose an opening adapted to the container 20 with suitable undercuts or the like, in order to secure the container 20, preferably in a form-fitting manner, against falling out or unintentional release from the platform 2, as in the schematic, fragmentary section of FIG Fig. 3 along line III-III of Fig. 1 indicated.
  • the covers 17 are omitted for reasons of simplicity.
  • the at least substantially cylindrical container 20 preferably extends transversely and in particular perpendicularly to the disc or plate plane E of the device 1 or platform 2.
  • the container 20 may also be substantially in or parallel to said plane E and / or extend radially with respect to the axis of rotation 4.
  • the container 20 can also be secured by a screw connection, not shown.
  • a screw or nut on the side facing away from the container 20 of the platform 2 are attached and bolted to the container 20 to its form-liquid securing to the platform 2.
  • the container 20 may also be screwed directly into the platform 2 or the carrier 3 or connected in a form-fitting manner in any other way.
  • the container 20 and the platform 2 or the carrier 3 corresponding, interlocking threaded sections, undercuts or the like. On.
  • the container 20 is preferably rigid or at least rigid. However, the container 20 may, if necessary, also be a soft container, such as a bag or the like. If necessary, an arrangement in a corresponding recess, for example under the cover 17, in the platform 2 is possible.
  • the container 20 can be detached from the device 1 or the platform 2, if necessary, this can be done by separating, cutting, breaking, unscrewing or in any other suitable manner ,
  • the particular releasable mounting or mounting of the container 20 on a particular plate-shaped or disc-shaped platform 2 of a microfluidic device 1, which is rotatable in particular about a rotation axis 4 perpendicular to the plate or disc plane E, and regardless of the above or below described treatment or purification of sample material 5 can be used, not only for the reception of sample material 5 and / or other liquids, but optionally also for the addition or supply of sample material 5 and / or other liquids.
  • the container 20 can then be connected to a filling or Aufhahmehunt, for example, the sample chamber 6 or the storage chamber 7, in particular by appropriate, preferably latching or clamping attachment to or in the respective chamber to supply the respective liquid or the like.
  • the container 20 is preferably arranged not on the underside as in the illustration but on the upper side of the platform 2 in the position of use to effect or assist in emptying the container 20 by gravity.
  • the sample chamber 6 preferably has a greater distance from the axis of rotation 4 than the storage chamber 7, that is arranged radially outward.
  • the reaction chamber 9, which in turn is arranged radially further outside, is arranged radially closer to the axis of rotation 4 than the removal device 12 and the collection chamber 11.
  • the collection chamber 11 has a radially greater distance from the axis of rotation 4 than the removal device 12.
  • the collection chamber 11 is preferably provided with a vent 21 to allow filling with the excess or by the reaction chamber 9 has flowed sample material 5 and optionally other liquids, which will be discussed later in more detail.
  • the liquids, including the sample material 5, are preferably transported or guided substantially parallel to the plate or slice plane E of the platform 2 in the illustrated example, in particular on one of the two flat sides of the platform 2.
  • the reaction chamber 9 or the separating means 10 is preferably traversed substantially transversely or obliquely to the plane of the plate E and / or substantially parallel to the axis of rotation 4. This allows, in particular, optimal utilization of the thickness of the platform 2 in order to allow a corresponding extent of the separating means 10 in this direction.
  • This arrangement of the separating means 10, for example a filter, in the platform 2 and the entire flow across the plate plane E can also be used independently of the proposed device 1 in other microfluidic systems, devices and methods.
  • the liquids including the sample material 5 are guided from one to the other flat side.
  • an opening 22 is provided to connect the running on the bottom in the illustration example channel 14 to the preferably arranged at the top of collecting chamber 11.
  • at least one washing step takes place between the separation step and the removal step, in the case of the illustration two washing steps.
  • the device 1 or platform 2 has at least one first receiving chamber 23 for a first washing liquid 24 and, in the depiction example, a second receiving chamber 25 for a second washing liquid 26. If necessary, these can be filled with the same or different washing liquid-in particular corresponding to the first chamber 6 and the storage chamber 7 directly or indirectly-preferably by pipetting or otherwise adding the washing liquid (s) 24, 26.
  • washing liquid 24, 26 is in each case a so-called washing buffer.
  • the rotational speed is increased, initially only to the extent that only the first washing liquid 24 from the first, so radially more distant receiving chamber 23 overcome a capillary or channel stop KS or the like and via a channel 27 - preferably on the upper side as the sample material 5 - can flow into the reaction chamber 9.
  • the washing liquid 24 flows through the separating agent 10, as a result of which it is rinsed. Further, the washing liquid 24 via the channel 14 - according to the sample material 5 - forwarded or transferred into the collection chamber 11.
  • the second washing liquid 26 can overcome an associated capillary or KS stop from the second receiving chamber 25 (closer to the rotary axis 4) and flow via a channel 28 into the reaction chamber 9 in order to move the separating means 10 in FIG to flush accordingly.
  • the channel 28 is connected to the first Aufhahmehunt 23, so that the second washing liquid 26 first flows through the first Aufhahmehunt 23 and then through the adjoining channel 27 to the reaction chamber 9.
  • the channel 28 may, if necessary, also be routed directly to the reaction chamber 9.
  • the number of washing steps can be varied according to need and application. After the two abovementioned washing steps have been carried out, drying of the separating means 9 preferably takes place, in particular by further centrifuging and / or gentle heating, for example by appropriate irradiation, in the device 1 rotating device 1 or the like. Only then does the removal step, which is initiated or carried out by (further) increasing the rotational speed, as described above.
  • the chambers 6, 7, 9, 11, 19, 23, 25 may have any desired shape as required and optionally also be formed by correspondingly widened channels or the like. In particular, the chambers can, if necessary, also continuously merge into subsequent channels or vice versa.
  • the sample chamber 6 is designed as a mixing chamber for mixing the sample material 5, in particular with at least one first treatment liquid 33.
  • the device 1 or platform 2, in the second embodiment associated with the Probenippo Mixing chamber 6 and preferably in addition to the other chambers of the first embodiment further receiving chambers 29 to 32.
  • the receiving chamber 29 is used to receive sample material 5, which in the second embodiment, if necessary, not pretreated, in particular not lysed and / or was not subjected to a previous protein degradation.
  • the Aufhahmehunt 30 serves to receive a first treatment liquid 33, in particular a protease (enzyme solution), as already mentioned above.
  • the optional Aufhahmehunt 31 serves the optional inclusion of a second treatment liquid 34, for example a lysing agent, as explained above.
  • treatment liquids such as RNase A or the like may be used, which are mixed with the sample material 5.
  • the Aufhahmehunt 32 serves in the illustrated example of receiving a further treatment liquid 35, in particular of ethanol or other solvent or transport.
  • the filling of the Aufhahmehuntn 29 to 32 in turn, as needed directly, for example by pipetting done.
  • the receiving chambers 29 to 32 are formed open.
  • filling chambers can also be assigned to the receiving chambers 29 to 32, from which the respective liquid or the sample material 5 are transferred in particular by capillary forces into the then closed chambers 29 to 32.
  • the receiving chambers 29 to 31 are preferably spaced radially further from the axis of rotation 4 than the receiving chamber 32.
  • the mixing takes place in accordance with a particularly preferred aspect of the present invention which can also be implemented independently of the described embodiments in that the fluids to be mixed - here the sample material 5, the first treatment liquid 33 and optionally the second treatment liquid 34 - over a relatively small cross-section or narrow channel 37 and / or other, turbulent flow generating means are at least partially transferred into an additional mixing chamber 36.
  • the additional mixing chamber 36 is connected in particular only via the channel 37 with the mixing chamber 6 such that the fluids to be mixed can be converted by acting upon rotation of the device 1 centrifugal forces through the channel 37 in the additional mixing chamber 36.
  • FIG. 5 schematically shows, in a partial enlargement, this state in which air already contained in the additional mixing chamber 36, which is preferably designed as a blind hole, is already compressed.
  • the fluids to be mixed are preferably transferred alternately or several times partly from the mixing chamber 6 into the additional mixing chamber 36 and returned again.
  • This universal way of mixing fluids is particularly possible because the channel 37 at the additional mixing chamber 36 in Fig. 5 at the lowest - so from the rotation axis 4 farthest - point and the mixing chamber 6 in a always of the fluids to be mixed filled, ie also lower or far away from the axis of rotation 4 region of the mixing chamber 6 is connected.
  • the additional mixing chamber 36 may also have an elastically deformable wall-for example, by the cover 17 -and / or an elastically compressible element, not shown, in order to be able to generate counteracting or restoring forces which are the fluids to be mixed from the additional mixing chamber 36 can displace back into the mixing chamber 6.
  • centrifugal forces instead of centrifugal forces, other pressure forces or the like on the fluids to be mixed in the mixing chamber. 6 can act to at least partially pass over the fluids in the additional mixing chamber 36 can. By appropriate variation of these pressure forces, an alternating (partial) filling and emptying of the additional mixing chamber 36 with the fluids to be mixed - as described above - can be achieved.
  • the sample material 5 is heated together with the treatment liquids 33 and 34 for a predetermined time to a predetermined temperature, for example, at 56 ° C for ten minutes.
  • This heating can be done, for example, by a heater, not shown, in particular electrically operating, for example integrated in the platform 2 or cover 17, by external irradiation or in any other suitable manner.
  • the heating is performed by the device, not shown, for rotating the device 1 or an associated device.
  • the device 1 is stopped for incubation or during incubation or further mixed.
  • the incubation serves in particular a protein degradation, since, for example, protease works very effectively at said elevated temperature.
  • protease works very effectively at said elevated temperature.
  • RNase A in addition to or as an alternative to the lysis agent and / or the protease, it is also possible, for example, to use RNase A in order to degrade RNA in the sample material 5.
  • the separation step is performed.
  • the rotational speed is further increased, so that the further treatment liquid 35, in particular ethanol, can overcome an associated channel or capillary stop KS or the like due to the correspondingly increased centrifugal forces and can flow out of the receiving chamber 32 into the mixing chamber 6.
  • the sample material 5 together with the treatment liquids 33 to 35 through the channel 13 into the reaction chamber 9, through the separating means 10 and further into the collection chamber 1 1 flow.
  • a complete or at least sufficient or extensive emptying of the mixing chamber 6 can be achieved in this case in particular by appropriate microstructuring and / or due to the surface tension of the fluid mixture.
  • a complete emptying of the mixing chamber 6 is not always possible, useful or desirable.
  • cell debris or other constituents can remain in the mixing chamber 6 and, for example, only liquid or dissolved constituents or particles can be separated or discharged up to a certain size.
  • the second receiving chamber 25 with the second washing liquid 26 is not connected via the first receiving chamber 23, but with its channel 28 directly to the channel 27.
  • the device 1 is designed and used so that the sample material 5 and the other liquids 8, 24, 26 and 33 to 35 are all initially filled and then the individual steps are carried out as described above, so refilling or filling or filling during the procedure is not required.
  • control of the various steps or the process sequence takes place in particular by the rotational speed or its variation. Additionally or alternatively, individual steps can also be achieved by the selective venting already mentioned in connection with the removal device 12 and / or other effects, such as the opening of a valve, use of a control fluid or by external influences, for example by irradiation, heat, a magnetic field or electric current done.
  • 500 ⁇ l of a first washing buffer and, for the second washing liquid 26, 500 ⁇ l of a second washing buffer are then used as the first washing liquid 24 and passed through the separating means 10.
  • the cavities of the device 1 or platform 2 are adapted to the aforementioned volumes.
  • the volumes mentioned may, if necessary, also be smaller by up to an order of magnitude or smaller by one or two orders of magnitude. This then applies correspondingly to the cavities of the device 1 or platform 2.
  • the proposed device 1 or platform 2 or the support 3 may, if necessary, also be used in a so-called swing-out rotor (swing-out rotor) or another centrifuge and, for example, have an elongated, rectangular or other suitable shape for this purpose.
  • swing-out rotor swing-out rotor
  • another centrifuge for example, have an elongated, rectangular or other suitable shape for this purpose.
  • the proposed device 1 or platform 2 or the carrier 3 can also be used in other centrifuges or the like and / or have another shape.
  • 7 shows, in a schematic, perspective view as a related example, a third embodiment of the device 1 according to the invention.
  • another device 40 in particular in a block-like form, is provided which houses the cavities of the device 1 or platform 2 has.
  • the preferably block-like or thick construction also permits other spatial arrangements.
  • the device 1 or device 40 can be used or held in a swing-out rotor (swing-out rotor) or another centrifuge (not shown) in particular in such a way that the receiving chambers 6, 7, 23, which are preferably elongated or cylindrical in the manner of representation 25 are initially substantially perpendicular and can then swing or pivot during rotation in the direction of an axial plane with respect to the rotation axis (not shown in FIG. 7) or into the horizontal, for example around the co-rotating pivot axis 42 indicated in FIG.
  • a swing-out rotor swing-out rotor
  • another centrifuge not shown
  • the sample material is preferably pretreated before it is introduced into the sample chamber 6.
  • the openings of the chambers or cavities 12, 6, 23, 25, 7 and / or 21 can be closed if necessary, for example by plugs, a removable, detachable or otherwise disclosed cover 41, an adhesive strip o. The like.
  • the container 20 is not shown, but may also be integrated.
  • the individual channels and chambers can be round, semicircular or angular as needed.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Detergent Compositions (AREA)

Abstract

L'invention concerne un dispositif et un procédé d'épuration d'échantillons, notamment d'acides nucléiques. L'épuration est réalisée par un processus microfluidique centrifuge, une construction simple et compacte et un déroulement de processus simple étant rendus possibles. Si nécessaire, le mélange de l'échantillon avec une tampon de dissolution et une protéase peut être réalisé très simplement dans le dispositif. L'échantillon épuré est notamment transféré directement dans un contenant. Des contenants séparés d'élimination de liquides excédentaires ne sont pas nécessaires.
EP07711460A 2006-02-10 2007-02-07 Dispositif et procédé de traitement ou d'épuration d'échantillons, notamment d'acides nucléiques Withdrawn EP1987362A2 (fr)

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PCT/EP2007/001029 WO2007090620A2 (fr) 2006-02-10 2007-02-07 Dispositif et procédé de traitement ou d'épuration d'échantillons, notamment d'acides nucléiques

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CN114272964B (zh) * 2013-06-25 2024-04-23 华盛顿大学商业中心 样品体积的自数字化
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US8741136B2 (en) 2014-06-03

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