EP2228132A1 - Dispositif isotherme PCR - Google Patents

Dispositif isotherme PCR Download PDF

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Publication number
EP2228132A1
EP2228132A1 EP09154744A EP09154744A EP2228132A1 EP 2228132 A1 EP2228132 A1 EP 2228132A1 EP 09154744 A EP09154744 A EP 09154744A EP 09154744 A EP09154744 A EP 09154744A EP 2228132 A1 EP2228132 A1 EP 2228132A1
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EP
European Patent Office
Prior art keywords
chamber
temperature
reaction liquid
liquid
reaction
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Withdrawn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
EP09154744A
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German (de)
English (en)
Inventor
Dr. Thomas Rothmann
Dr. Ralf Himmelreich
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.)
Qiagen GmbH
Original Assignee
Qiagen 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 Qiagen GmbH filed Critical Qiagen GmbH
Priority to EP09154744A priority Critical patent/EP2228132A1/fr
Publication of EP2228132A1 publication Critical patent/EP2228132A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • B01L7/525—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 with physical movement of samples between temperature zones
    • 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
    • B01F33/45—Magnetic mixers; Mixers with magnetically driven stirrers
    • B01F33/452—Magnetic mixers; Mixers with magnetically driven stirrers using independent floating stirring elements
    • 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
    • B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
    • B01L2300/0841—Drums
    • 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
    • B01L2300/18—Means for temperature control
    • 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
    • B01L2300/18—Means for temperature control
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B01L2300/185—Means for temperature control using fluid heat transfer medium using a liquid as fluid
    • 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
    • B01L2400/0457—Moving fluids with specific forces or mechanical means specific forces passive flow or gravitation
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28C—HEAT-EXCHANGE APPARATUS, NOT PROVIDED FOR IN ANOTHER SUBCLASS, IN WHICH THE HEAT-EXCHANGE MEDIA COME INTO DIRECT CONTACT WITHOUT CHEMICAL INTERACTION
    • F28C3/00—Other direct-contact heat-exchange apparatus
    • F28C3/04—Other direct-contact heat-exchange apparatus the heat-exchange media both being liquids
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28D—HEAT-EXCHANGE APPARATUS, NOT PROVIDED FOR IN ANOTHER SUBCLASS, IN WHICH THE HEAT-EXCHANGE MEDIA DO NOT COME INTO DIRECT CONTACT
    • F28D21/00—Heat-exchange apparatus not covered by any of the groups F28D1/00 - F28D20/00
    • F28D2021/0019—Other heat exchangers for particular applications; Heat exchange systems not otherwise provided for
    • F28D2021/0052—Other heat exchangers for particular applications; Heat exchange systems not otherwise provided for for mixers

Definitions

  • the invention relates to a method and a device for carrying out a polymerase chain reaction, which is abbreviated PCR.
  • a PCR is used to amplify the genetic material DNA using the enzyme DNA polymerase. More specifically, only a short, well-defined part of a DNA strand can be amplified by PCR. In PCR, the products of previous cycles serve as starting materials for the next cycle. It is an exponential duplication achieved. For example, a PCR process includes 12-50 cycles.
  • One cycle of a PCR begins with a denaturation.
  • the reaction liquid containing the double-stranded DNA therein is heated to typically 94-96 ° C to separate the strands of DNA.
  • the reaction liquid with the separated DNA strands is cooled to a few degrees below the melting point of the primer used, so that a primer hybridization takes place. This temperature is typically 55-65 ° C.
  • the temperature is maintained at 55-65 ° C for about 30 seconds to allow specific attachment of the primers to the DNA.
  • the reaction liquid is reheated to a temperature of typically 68-72 ° C for about 30 seconds per 500 base pairs. The exact temperature depends on the working optimum of the DNA polymerase used. This last step of a cycle is called elongation or amplification.
  • the DNA polymerase fills in the missing strands with free nucleotides.
  • an apparatus for rapidly heating and cooling a reaction vessel to various temperatures for carrying out a polymerase chain reaction comprises two surfaces for contact with the reaction vessel enclosed therebetween. An area serves as a heater. A cavity of the device is used for cooling, by cooling air in the cavity is introduced.
  • the device comprises sensors with which the respective desired temperature is measured and controlled. Disadvantageously, the entire device must always be cooled and then reheated to effect the temperature changes. Therefore, a relatively large amount of energy has to be expended and the respectively desired temperatures of the reaction liquid are reached relatively slowly.
  • the publication EP 0 402 995 B1 discloses a device for charging a reaction vessel with at least two temperature changes.
  • the apparatus includes heating elements for heating at least one sidewall of a selected chamber portion of the reaction vessel and moving means which move the reaction vessel and the heating elements along a predetermined path relative to each other.
  • the apparatus further includes cooling elements that deliver cooling fluid over the heating elements to directly cool them at repeating intervals, and that are movable in unison with the heating elements.
  • 89 A1 is a Thermocyler for carrying out a PCR is known, which includes a reaction vessel with a particularly large, the heat transfer surface serving, so as to be able to cool mainly fast.
  • the desired temperature change is brought about solely by heating or cooling with the aid of heating or cooling elements provided for this purpose.
  • Is heated in the prior art for example, with Peltier elements, infrared radiation or a hot fluid by heat exchange. Cooling is done, for example, with a cold fluid via heat exchange or with the help of Peltier elements.
  • reaction liquid for carrying out a PCR through a microfluidic system with chambers of different temperatures.
  • first chamber which is heated to such an extent that the reaction liquid reaches the temperature required for denaturation, which is also hereafter
  • the reaction liquid is then pumped into a next chamber, which is cooled in such a way that the reaction liquid in this chamber is brought to the annealing temperature, ie the temperature required for the primer hybridization.
  • reaction liquid is heated from the annealing to the temperature required for the amplification or elongation, hereinafter also called elongation temperature,
  • elongation temperature the temperature required for the amplification or elongation
  • only small volumes of liquid can be used. It must be pumped very precisely to ensure that the reaction liquid is in the desired range.
  • three chambers and connecting lines are needed to perform the PCR can.
  • a required temperature of a reaction liquid is adjusted by mixing with a second liquid whose temperature is suitably different from the temperature of the reaction liquid.
  • the second liquid may also be a reaction liquid. Since a desired temperature of a reaction liquid is obtained by mixing two previously differently tempered liquids, it is not necessary to additionally heat or cool a reaction chamber, which would be energy-consuming and lead to large time delays. For the implementation of the method, only a suitable temperature-controlled chamber and means for mixing are needed.
  • the structure can be correspondingly simple and inexpensive.
  • reaction liquid which has been previously brought to Denaturierungstemperatur and whose temperature is therefore above the temperature required for the amplification or elongation
  • reaction liquid previously has been brought to Annealingstemperatur and therefore the temperature is below the temperature required for the amplification. It is thus achieved that the part of the reaction liquid which is to be brought from the annealing temperature to the elongation temperature is heated very rapidly in the desired manner by the mixing. Since reaction liquid is used for heating, which must be cooled anyway, the desired result in an energetically favorable manner reached. Larger amounts of liquid can be tempered in the desired manner quickly and easily in the desired manner,
  • a device for carrying out the method is therefore particularly suitable for mobile use, which is powered by an internal power supply such as battery, fuel cell and / or by solar cells with energy.
  • the ratio between the two liquid volumes of the reaction liquids or liquids to be mixed is selected such that the temperature can not be exceeded or exceeded by mixing the warmer (reaction) liquid with the cooler (reaction) liquid. It therefore does not have to be tempered additionally in order to achieve the desired elongation temperature.
  • the PCR is carried out in a chamber which comprises a first and one spatially different second region.
  • the first area of this chamber is heated so that a reaction liquid in this area can be heated to Denaturéesstemperatur.
  • the second region is cooled in such a way that a reaction liquid located in this second region can be cooled to the annealing temperature.
  • the first area is spatially separated from the second area.
  • the part of the reaction liquid which is in the first region is heated to denaturation temperature and held until the present double strands of DNA have been separated to the desired extent in this part of the reaction liquid.
  • the reaction liquid located there is at the annealing temperature cooled and held until the desired extent the primer hybridization is carried out, then the two parts of the reaction liquid are mixed by means of a stirring element, so as to reach the elongation temperature.
  • the chamber in which the PCR is carried out according to the claim is flat.
  • a chamber is made flat if the width and / or depth of the chamber exceeds the height of the chamber by a multiple.
  • large heat transfer surfaces are available to heat the first area and to cool the second area.
  • an agitating element is positioned in one embodiment of the invention so that the stirring element contributes to the spatial separation. For example, if the first area is in a left half of the compartment and the second area is in a right half of the chamber, then the agitating element is placed and aligned so that it separates the left half of the compartment from the right, When the reaction liquid is to be cooled or heated, the stirring element then extends along the boundary between the first and second chamber regions and thus spatially separates the two parts of the reaction liquid.
  • the stirring element may for example be part of a magnetic stirrer or connected to a shaft extending into the chamber. If it is a magnetic stirrer, then the desired alignment is achieved, for example, by means of a suitably oriented magnetic field.
  • the two regions of the chamber can be separated from one another by a separating means, so as to be able to heat part of the reaction liquid in the first chamber, without this part of the liquid being able to mix with the second part of the reaction liquid, during which is cooled.
  • a release agent may comprise pressing means, which compress the boundary area between the first and second area and thus seal the two areas against each other.
  • the shell of the chamber is made of deformable material.
  • the mixing is effected by compressing parts of the chamber and then releasing them again.
  • the walls of the chamber to be cooled or heated are preferably made of a material which is able to conduct heat well in comparison to a band-shaped wall region which lies between the area to be heated and the area to be cooled.
  • This embodiment of a chamber further contributes to the fact that the method can be performed energetically favorable.
  • the energy is supplied in particular by means of a battery, a solar cell and / or a fuel cell, that is generally by an internal power supply, so that the process can be carried out mobile independently of an external power supply. Especially with one internal energy supply, it is important to use as little energy as possible.
  • the reaction liquid contained in the chamber comprises heat-stable polymerase, nucleobases, primers, salt and pH buffer as well as template nucleic acid RNA or DNA.
  • the oils or metals form a second phase in the PCR reaction, which on the one hand can be easily separated from the reaction liquid and on the other hand do not endanger the PCR.
  • an oil first floats on the reaction liquid and is heated to a suitable temperature together with a suitable portion of the reaction chamber.
  • the reaction liquid is cooled in a lower chamber area and brought to annealing temperature.
  • the oil is mixed with the reaction liquid.
  • the chamber is rotated 180 ° such that the heated area of the chamber is at the bottom and the cooled area at the top. If the mixing is stopped, the oil passes by gravity into the cooled chamber area of the reaction chamber.
  • the reaction liquid then passes into the region of the chamber which is heated.
  • the reaction liquid is brought to the denaturation and the oil to a suitable low temperature, so as to cool the reaction liquid in due time by mixing again quickly and in an energetically favorable manner.
  • reaction liquid floats on the liquid metal when not mixed. In principle, therefore, the same method can be carried out, as has been described above using the example of the oil.
  • a total of three different liquids are used, such as a liquid metal, a reaction liquid and an oil. It is convenient to heat the oil in an upper portion of the chamber and then to cool the liquid metal in a lower portion. In principle, however, it is not excluded that the upper area is cooled and the lower one is heated. The reaction liquid therebetween is mixed with the heated liquid when the temperature of the reaction liquid is to be appropriately increased. The reaction liquid therebetween is mixed with the cooled liquid when the temperature of the reaction liquid is appropriately lowered.
  • a liquid metal such as a liquid metal, a reaction liquid and an oil. It is convenient to heat the oil in an upper portion of the chamber and then to cool the liquid metal in a lower portion. In principle, however, it is not excluded that the upper area is cooled and the lower one is heated. The reaction liquid therebetween is mixed with the heated liquid when the temperature of the reaction liquid is to be appropriately increased. The reaction liquid therebetween is mixed with the cooled liquid when the temperature of the reaction liquid is appropriately lowered.
  • FIG. 1 shows a plan view of a flat-shaped chamber 1, in which a PCR is performed.
  • the chamber 1 has a circular base whose diameter is several times greater than the height of the chamber.
  • a left half 1a of the chamber is provided with heating means, not shown, in order to heat this left chamber portion 1a can.
  • a Mederhwood shown on the right 1b is provided with coolants, which are able to cool the right half of the chamber 1 b,
  • a stirring rod 2 of a magnetic stirrer In the basic position this separates the left half of the chamber 1 a from the right half of the chamber 1 b.
  • Suitable heating and cooling means are the known, for example initially mentioned means for these and for other embodiments of the invention.
  • FIG. 2a shows a side section of a further embodiment of a chamber according to the invention
  • an associated supervision is shown in FIG. 2b.
  • the commercial half shown on the left can be heated with a first Peltier element 3.
  • the commercial half shown on the right can be cooled with a second Peltier element 4.
  • the height of the chamber with a square base is 1 mm. Width and length or depth of the chamber are 10 mm.
  • the chamber volume is about 100 ⁇ l.
  • a stirring rod 2 of a magnetic stirrer In the chamber 1 is again a stirring rod 2 of a magnetic stirrer.
  • the qPCR was each set up with a standard dilution series of genomic DNA from E. coli. For every 25 ⁇ l final PCR volume 20 ng / 2 ng / 0.2 ng / 0.02 ng of genomic Escherichia coli DNA, ie different amounts were used for calibration measurements. To this end, in a PCR tube 1, 2.5 ⁇ l QIAGEN QuantiTect Probe PCR Master Mix, 0.1 ⁇ l EFwd (5 pmol / ⁇ l); 0.1 ⁇ l ERev (5 pmol / ⁇ l); 0.05 ⁇ L EPro (5 pmol / ⁇ L), 10.25 ⁇ L bidistilled water and 2 ⁇ L E.coli standard dilution solution started.
  • the evaluation of the qPCR shows that even under the unusual 4-step cycling conditions a PCR is successful.
  • the standards in the Amplification Plot ( Fig. 3 ) or in the evaluation graphic ( Fig. 4 ) do not differ significantly from each other.
  • the structure of the chamber together with associated facilities is simple and therefore inexpensive. The simple structure allows a small design of the overall device with which the process is performed.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Clinical Laboratory Science (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
EP09154744A 2009-03-10 2009-03-10 Dispositif isotherme PCR Withdrawn EP2228132A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09154744A EP2228132A1 (fr) 2009-03-10 2009-03-10 Dispositif isotherme PCR

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP09154744A EP2228132A1 (fr) 2009-03-10 2009-03-10 Dispositif isotherme PCR

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EP2228132A1 true EP2228132A1 (fr) 2010-09-15

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0402995B1 (fr) 1989-06-12 1994-12-14 Johnson & Johnson Clinical Diagnostics, Inc. Dispositif de régulation de la température et récipient de réaction
EP0606961B1 (fr) 1989-06-12 1997-03-05 Johnson & Johnson Clinical Diagnostics, Inc. Dispositif de régulation de température pour récipient de réaction
US6171850B1 (en) 1999-03-08 2001-01-09 Caliper Technologies Corp. Integrated devices and systems for performing temperature controlled reactions and analyses
US20020127152A1 (en) * 2001-03-09 2002-09-12 The Regents Of The University Of California Convectively driven PCR thermal-cycling
WO2003007677A2 (fr) 2001-07-16 2003-01-30 Idaho Technology, Inc. Systeme de cyclage thermique et son procede d'utilisation
US20030036189A1 (en) 1998-11-25 2003-02-20 The Regents Of The University Of California PCR thermocycler
US20040132051A1 (en) * 2002-07-26 2004-07-08 Andersen Mark R. Mg-mediated hot start biochemical reactions
EP1464399A2 (fr) * 2003-04-02 2004-10-06 Hitachi, Ltd. Dispositif et procédé d'amplification d'acide nucléique
DE102004050139A1 (de) * 2004-10-14 2006-04-20 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Mikrofluidprozessor und Verfahren zur Durchführung einer Polymerasekettenreaktion
EP1860060A1 (fr) * 2006-05-22 2007-11-28 Micronas Holding GmbH Procédé et appareil pour mélanger des micro-gouttelettes
US20080153152A1 (en) * 2006-11-22 2008-06-26 Akira Wakabayashi Microfluidic chip
US20080176292A1 (en) * 2007-01-23 2008-07-24 Texas A&M University System Portable buoyancy driven pcr thermocycler

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0402995B1 (fr) 1989-06-12 1994-12-14 Johnson & Johnson Clinical Diagnostics, Inc. Dispositif de régulation de la température et récipient de réaction
EP0606961B1 (fr) 1989-06-12 1997-03-05 Johnson & Johnson Clinical Diagnostics, Inc. Dispositif de régulation de température pour récipient de réaction
US20030036189A1 (en) 1998-11-25 2003-02-20 The Regents Of The University Of California PCR thermocycler
US6171850B1 (en) 1999-03-08 2001-01-09 Caliper Technologies Corp. Integrated devices and systems for performing temperature controlled reactions and analyses
US20020127152A1 (en) * 2001-03-09 2002-09-12 The Regents Of The University Of California Convectively driven PCR thermal-cycling
WO2003007677A2 (fr) 2001-07-16 2003-01-30 Idaho Technology, Inc. Systeme de cyclage thermique et son procede d'utilisation
US20040132051A1 (en) * 2002-07-26 2004-07-08 Andersen Mark R. Mg-mediated hot start biochemical reactions
EP1464399A2 (fr) * 2003-04-02 2004-10-06 Hitachi, Ltd. Dispositif et procédé d'amplification d'acide nucléique
DE102004050139A1 (de) * 2004-10-14 2006-04-20 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Mikrofluidprozessor und Verfahren zur Durchführung einer Polymerasekettenreaktion
EP1860060A1 (fr) * 2006-05-22 2007-11-28 Micronas Holding GmbH Procédé et appareil pour mélanger des micro-gouttelettes
US20080153152A1 (en) * 2006-11-22 2008-06-26 Akira Wakabayashi Microfluidic chip
US20080176292A1 (en) * 2007-01-23 2008-07-24 Texas A&M University System Portable buoyancy driven pcr thermocycler

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KOPP MU; MELLO AJ; MANZ A.: "Chemical amplification: continousflow PCR on a chip", SIENCE, vol. 280, no. 5366, 15 May 1998 (1998-05-15), pages 046 - 8

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