US20010010917A1 - Method and device for preparing samples for detecting a nucleotide sequence - Google Patents
Method and device for preparing samples for detecting a nucleotide sequence Download PDFInfo
- Publication number
- US20010010917A1 US20010010917A1 US09/825,826 US82582601A US2001010917A1 US 20010010917 A1 US20010010917 A1 US 20010010917A1 US 82582601 A US82582601 A US 82582601A US 2001010917 A1 US2001010917 A1 US 2001010917A1
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- United States
- Prior art keywords
- cavity
- primer
- nucleotide sequence
- analysis solution
- lid
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- 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
- C12Q1/6813—Hybridisation assays
- C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Analytical Chemistry (AREA)
- Biotechnology (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
Description
- The invention relates to a method for preparing samples for detecting a nucleotide sequence by means of polymerase chain reaction (PCR). It furthermore relates to a device in accordance with the preamble of
claim 14. - U.S. Pat. No. 5,455,175 discloses a so-called thermocycler with which a plurality of liquid biological samples can be exposed repeatedly to a pre-set temperature profile in order to carry out the PCR. To shorten the time required for the temperature treatment, a small volume of each of the biological samples is taken up in a thin-walled glass capillary. To this end, each of the individual samples must be filled into the capillary and then sealed in. This is time-consuming.
- DE 33 36 738 A1 discloses a titer plate in accordance with the preamble of
claim 14. The lid of the known titer plate can only be removed from the support with the expenditure of considerable force. A sample taken up in the known device is difficult to heat externally; the device is unsuitable for carrying out the PCR. - Object of the present invention is to overcome the disadvantages of the prior art. In particular, it is intended to provide a method and a device with which the time required for preparing the samples for PCR is reduced. A further aim of the invention is a simplified and improved, in particular real-time, detection and an increase in sensitivity.
- This object is achieved by the features of
claims claims 2 to 13 and 15 to 43. - In accordance with the invention, there is provided a method for preparing samples for detecting a nucleotide sequence by means of polymerase chain reaction, where
- a) an analysis solution is filled into at least one cavity provided on a support,
- b) a lid configured complementary to the shape of the cavity is placed onto the support in such a way that at least some of the analysis solution is displaced into a gap formed between the cavity and the lid and
- c) the gap is sealed by means of at least one seal provided near an opening of the cavity.
- The proposed process considerably shortens the time for sample preparation. The procedure of sealing the sample solution into a capillary is dispensed with.
- The analysis solution can have added to it a first and/or a second primer. It is regarded as particularly advantageous to have a third primer, preferably with its 5′-terminal end, bound to the internal face of the lid which extends into the cavity. In this manner, it is possible to bind, to the third primer, a nucleotide sequence which may be present in a sample. This can be achieved in a particularly simple fashion by immersing the internal face of the lid into the sample. After the amplification cycles have been concluded, it is furthermore possible to accumulate the amplified nucleic acid on the internal face by binding it to the third primer. The accumulation is expediently carried out by applying an electrical field. The nucleotide sequence is shifted toward the third primer under the influence of an electrical field.
- To detect the presence of the nucleotide sequence of interest, it is expedient to examine the analysis solution and/or one of the primers for their fluorescence properties. Upon binding of the nucleotide sequence to be detected to one of the primers, a change in the fluorogenic properties of the substances present in the analysis solution may take place. Upon binding of the nucleotide sequence to be detected to one of the primers, a spatial relationship between two fluorophoric groups is preferably alterable in such a way that a fluorescence reaction can be generated, altered or quenched.
- In a further embodiment, the analysis solution is heated and cooled cyclically. A typical temperature cycle consists of a first heating of the analysis solution to 90 to 92° C., a cooling to 50 to 55° C. and a second heating to 72 to 75° C. During the first heating, denaturation takes place, during the cooling, renaturation, and during the second heating the synthesis of the nucleotide sequence. The abovementioned cycle is repeated approximately 30 times.
- Heating can be effected by means of light, preferably infra-red radiation, resistance heating or by passing of gas or a fluid around the cavity. Rapid cooling is effected expediently by passing a gas, for example air, or a fluid around the cavity, or by means of a Peltier element.
- Furthermore provided in accordance with the invention is a device for detecting a nucleotide sequence which may be present in a sample by means of polymerase chain reaction, where the cavity has a surrounding lateral wall which widends conically toward the opening and the gap has a width of not more than 1 mm.
- The proposed device allows time-saving sample preparation. By using it, the time required for carrying out a PCR can be reduced considerably. The lid can be lifted without great expenditure of force after the PCR has been carried out.
- It is advantageous to provide a facility for cyclically heating and cooling the analysis solution. Moreover, a facility for examining the fluorescence properties of the analysis solution and/or one of the primers may be provided.
- The support can be made of a translucent material, preferably of glass or plastic. The cavity is expediently designed to have planar sections; preferably, it has a flat bottom. On the support and/or on the internal face of the lid, a further seal may be provided at sections located between the cavities or on projections arranged on the internal face of the lid. Like the seal, the further seal can be made of, for example, rubber, silicone, teflon or other suitable materials.
- It is considered to be especially advantageous for the support to have 96 cavities and for the lid 96 projections which are complementary to the shape of the cavities. Thus, for example the support can have approximately the dimension of a conventional 96-well microtiter plate. Naturally, the support may also have a fraction or a multiple of the abovementioned number of cavities.
- In accordance with a further embodiment, the lid can be made of an electricroconductive material, preferably a plastic. The support can exhibit an electrode, preferably an electrode made of platinum, so that an electrical field can be applied between the lid and the support, by which nucleotide sequence present in the analysis solution can be shifted to the internal face and accumulated by field-inversion cycles.
- The plastic can comprise a polycarbonate, a trimenthylthiophene, triaminobenzene and/or a polycarbene, and at least sections of the internal face of the lid can be provided with a substance which binds biomolecules. Binding of the nucleotide sequence to the plastic can be mediated here by streptavidin or avidin.
- The analysis solution advantageously has a first and/or second primer added to it. It is considered as especially advantageous for a third primer to be bound to the internal face of the lid facing the cavity, preferably with a 5′-terminal end. This allows the amplified nucleotide sequence to be removed from the analysis solution.
- In accordance with a further embodiment, a means for exciting fluorescence between the bottom and the internal face of the lid is provided. It is possible that the radiation originating from the excitation means can be focused toward the internal face of the lid. This is advantageous in particular when the nucleotide sequence is bound to the internal face via the third primer. The means for exciting fluorescence is expediently generated by a laser diode. Thus, it takes the form in this instance of laser light. Excitation of the support bottom can also be achieved by a so-called gally-mode laser (Science 1998, 280, p 1501, 1544 ff.) in a pre-set manner, either simultaneously or successively.
- There may furthermore be provided a facility for detecting the fluorescence, a facility for evaluating the fluorescence observed, and a facility for shifting the support relative to the means for exciting the fluorescence and/or to the detection facility. Moreover, there may be provided a facet-eye-like means for separately exciting and/or detecting the fluorescence between each bottom and the internal face of the corresponding lid. This saves yet more analysis time.
- Expediently, at least sections of the lid and/or the support are black so that heat radiated at them is absorbed in an efficient manner. In particular, they are composed of a highly thermoconducting material.
- There may furthermore be provided a facility for cyclically heating and cooling the analysis solution, it being advantageous to provide, for heating, a means for generating light, preferably infra-red radiation, a resistance heating or a means for passing a gas or a fluid around the cavity. It is furthermore expedient to provide a means for cooling, the cooling preferably being achieved by passing a gas or a fluid around the cavity, or by means of a Peltier element.
- To improve the thermoconductivity while simultaneously having good transparency properties, the support can have a bottom made of glass. The seal is expediently formed by a recess surrounding the lateral wall, which is preferably made of plastic, and a surrounding reinforcement which is provided at the projection so that it complements the recess and which can lock positively into the recess. The seal is expediently self-sealing when the pressure in the cavity rises, for example owing to an increase in temperature, by pressing the reinforcement against the recess. The lid can be put on or taken off in a particularly simple fashion by gently bending it, owing to a high flexibility of the sections between the projections.
- Finally, there is claimed a kit for carrying out the method according to the invention, with
- a) a support with at least one cavity and
- b) a lid configured complementary to the cavity which can be placed onto the support in such a way that at least some of the analysis solution taken up by the cavity can be displaced into a gap formed between the cavity and the lid and
- c) an analysis solution comprising at least one first primer.
- The analysis solution can comprise a second primer. A third primer can be bound to an internal face of the lid facing the cavity, preferably with its 5′-terminal end.
- Use examples of the invention are illustrated in greater detail hereinbelow with reference to the drawing.
- FIG. 1 shows a schematic cross-sectional view through a first device,
- FIG. 2 the device of FIG. 1 upon excitation and detection,
- FIG. 3 a schematic cross-sectional view of a second device upon excitation and detection,
- FIG. 3a a schematic cross-sectional view of the device of FIG. 3,
- FIG. 4 a schematic partial cross-sectional view of a third device,
- FIG. 5 a schematic cross-sectional view of a seal and
- FIG. 6 the cross-sectional view of FIG. 5 in the unlocked state.
- In FIG. 1, a
support 1 hasseveral cavities 2. Alid 3 is provided on its internal face I with a plurality ofprojections 4. Theprojections 4 have a shape which is complementary to thecavity 2. Between a bottom B of thecavity 2 and theopposite projection 4 which runs in parallel a gap G is formed. Thecavity 2 is furthermore delimited by a surrounding lateral wall LW which opens out conically from the bottom B to the opening of thecavity 2. The gap G formed between theprojection 4 and thecavity 2 has a width of not more than 1 mm. Aseal 5 is provided in the vicinity of the opening of thecavity 2. 6 denotes an electrode integrally molded into thelid 3. Thesupport 1 can have a counterelectrode (not shown here). - FIG. 2 shows the device of FIG. 1 upon excitation and detection.7 schematically designates an optical facility for exciting the analysis solution taken up by the gap G. It takes the form of a facet-eye-like means by means of which a plurality or all of the
cavities 2 can simultaneously receive, for example, laser light. Theoptical facility 7 is focused at the internal face I, of thelid 3, which is arranged opposite of the bottom B. 8 designates a fluorometer. Thefluorometer 8, too, can be provided with a faceteye-like means so that the fluorescence emanating from a plurality or all of thecavities 2 can be detected. An infra-red radiation source 9 and afan 10 are located opposite thesupport 1. - FIGS. 3 and 3a show a schematic cross-section through a second device. Here, the infra-
red radiation source 9 is arranged opposite thelid 3. Thelid 3 is made of a black, highly thermoconductive material, for example a glass or metal. For better absorption, the external face A of thelid 3, which is opposite the internal face I, is coated with a black paint. Thefirst seal 5 is designed as a self-sealing locking connection. Asecond seal 12 in the vicinity of the edge of the opening of thecavity 2 is composed of rubber or elastomer. It is provided between the internal face I of thelid 3 and an upper face U of thesupport 1. When thelid 3 is shut, an analysis solution taken up by thecavity 2 is displaced into a gap segment GS located between the lateral wall LW and a facing curved surface CS of theprojection 4. - In FIG. 4, too, the
support 1 is configured complementary to thelid 3. Again, it is made of a highly thermoconductive material. The bottom B is made of a transparent material, for example a glass window 11. - FIG. 5 shows a schematic partial cross-sectional view through the
first seal 5. Here, a surroundingreinforcement 13 provided at the curved surface CS of theprojection 4 engages, in the closed state, positively and nonpositively into a surroundingrecess 14 provided at the lateral wall LW. FIG. 6 shows thefirst seal 5 in the as yet nonpositively locked state. - The device has the following function:
- To prepare the samples, analysis solution is pipetted into the
cavity 2 of thesupport 1. Pipetting can be carried out for example with the aid of an automatic pipette. The analysis solution preferably takes the shape of a so-called master mix in which all the agents required for carrying out the PCR are present. In particular, a first and a second primer are present in the analysis solution. A third primer is bound to the internal face I of thelid 3 in the region of theprojections 4. The nucleotide sequence to be detected is bound to the third primer. Binding can take place for example by previously dipping thelid 3 into a sample solution in which the nucleotide sequence to be detected is present. - To prepare the samples, the
lid 3 now only needs to be placed onto thesupport 1 in such a way that theprojections 4 are immersed into thecomplementary cavities 2. During this process, the third primer with the nucleotide sequence bound to it comes into contact with the analysis solution. Thelid 3 is closed with thesupport 1 so that a seal is formed, for example by thereinforcements 13 provided at theprojections 4 locking into thecomplementary recesses 14 of thecavities 2. In this state, some of the analysis solution is displaced into the gap G. - Then, in particular the gap G formed between the internal face I and the bottom B is subjected to the temperature treatment required for carrying out the PCR. Thereupon, or else between each temperature cycle, the region located between internal face I and bottom B of each
cavity 2 is excited by means of theoptical facility 7 and then tested for fluorescence using thefluorometer 8. A change in fluorescence indicates the presence or absence of the nucleotide sequence of interest. - The temperature cycles are caused by repeatedly activating or deactivating the
IR radiation source 9 or thefan 10. -
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- I Internal face
- B Bottom
- W Lateral wall
- G Gap
- EF External face
- U Upper face
- S Curved surface
- GS Gap segment
Claims (13)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/825,826 US6440724B2 (en) | 1998-06-12 | 2001-04-04 | Method and device for preparing samples for detecting a nucleotide sequence |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19826153 | 1998-06-12 | ||
DE19826153.5 | 1998-06-12 | ||
DE19826153A DE19826153C2 (en) | 1998-06-12 | 1998-06-12 | Method and device for the detection of a nucleotide sequence possibly contained in a sample |
US09/719,376 US6383802B1 (en) | 1998-06-12 | 1999-05-29 | Method and device for preparing samples for detecting a nucleotide sequence |
US09/825,826 US6440724B2 (en) | 1998-06-12 | 2001-04-04 | Method and device for preparing samples for detecting a nucleotide sequence |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DE1999/001589 Division WO1999064157A1 (en) | 1998-06-12 | 1999-05-29 | Method and device for preparing samples for detecting a nucleotide sequence |
US09/719,376 Division US6383802B1 (en) | 1998-06-12 | 1999-05-29 | Method and device for preparing samples for detecting a nucleotide sequence |
Publications (2)
Publication Number | Publication Date |
---|---|
US20010010917A1 true US20010010917A1 (en) | 2001-08-02 |
US6440724B2 US6440724B2 (en) | 2002-08-27 |
Family
ID=7870660
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/719,376 Expired - Fee Related US6383802B1 (en) | 1998-06-12 | 1999-05-29 | Method and device for preparing samples for detecting a nucleotide sequence |
US09/825,826 Expired - Fee Related US6440724B2 (en) | 1998-06-12 | 2001-04-04 | Method and device for preparing samples for detecting a nucleotide sequence |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/719,376 Expired - Fee Related US6383802B1 (en) | 1998-06-12 | 1999-05-29 | Method and device for preparing samples for detecting a nucleotide sequence |
Country Status (7)
Country | Link |
---|---|
US (2) | US6383802B1 (en) |
EP (1) | EP1096998B1 (en) |
JP (1) | JP2002517219A (en) |
AT (1) | ATE234682T1 (en) |
CA (1) | CA2334891A1 (en) |
DE (2) | DE19826153C2 (en) |
WO (1) | WO1999064157A1 (en) |
Cited By (3)
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US20070054273A1 (en) * | 2003-08-01 | 2007-03-08 | Capitalbio Corporation | Microarray devices having controllable reaction volume |
US7358081B2 (en) | 2002-03-07 | 2008-04-15 | Siemens Aktiengesellschaft | Devices for the electrochemical detection of a nucleotide sequence, analysis cassettes, systems of analysis cassettes, supplemental modules, and methods for producing analysis cassettes |
US20080124723A1 (en) * | 2006-06-30 | 2008-05-29 | Canon U.S. Life Sciences, Inc. | Combined thermal devices for thermal cycling |
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US7795012B2 (en) | 1999-05-06 | 2010-09-14 | Micronas Gmbh | Device for performing analysis on cell cultures |
DE19920811B4 (en) * | 1999-05-06 | 2004-08-19 | Micronas Gmbh | Device for carrying out tests on cell cultures |
DE19952160A1 (en) * | 1999-10-29 | 2001-05-03 | Markus Sauer | Method, device and dye-labeled peptide for the detection of a molecule, and method for producing a dye-labeled peptide and its use |
DE10035451C2 (en) * | 2000-07-19 | 2002-12-05 | November Ag Molekulare Medizin | Method and device for identifying a polymer sequence |
EP1416041A4 (en) * | 2001-07-06 | 2004-08-04 | Prec System Science Co Ltd | Reaction container and reaction device |
WO2003066907A1 (en) * | 2002-02-05 | 2003-08-14 | Genome Therapeutics Corporation | Seal for microtiter plate and methods of use thereof |
DE10208188B4 (en) | 2002-02-20 | 2006-05-24 | Amaxa Gmbh | Container with at least one electrode |
US20050287661A1 (en) * | 2002-10-08 | 2005-12-29 | James Landers | Methods and systems for multiplexing ir-mediated heating on a microchip |
US8007744B2 (en) | 2003-01-17 | 2011-08-30 | Greiner Bio-One Gmbh | Sample container for analyses |
DE10321042B4 (en) * | 2003-01-17 | 2006-09-21 | Greiner Bio-One Gmbh | Biochip supporting |
US9005549B2 (en) | 2003-01-17 | 2015-04-14 | Greiner Bio-One Gmbh | High throughput polymer-based microarray slide |
DE102004046724B3 (en) * | 2004-09-27 | 2006-02-02 | Zell-Kontakt Gmbh | Reaction container, comprises outlet surrounding reaction surface and provides supporting cover unit in order to form reaction chamber by arranging plane central area of cover unit in preset distance to surface |
US7816081B2 (en) | 2005-04-28 | 2010-10-19 | Hitachi Chemical Co., Ltd. | Method of minimizing reagent consumption in microplate-based reactions |
DE102005038252A1 (en) * | 2005-08-12 | 2007-02-15 | Mann, Wolfgang, Dr. | Plastic substrate for carrying out chemical and biological reactions in liquid droplets, comprises even flat surface, and reaction points formed as disk-shaped and/or circular hydrophilic surface intended on the uniform flat surface |
DE102010062064A1 (en) * | 2010-11-26 | 2012-05-31 | Hamilton Bonaduz Ag | Sample container for storage and processing of samples taken with a sampling tool |
EP3405285A4 (en) * | 2016-01-20 | 2019-06-19 | Triv Tech, LLC | Point-of-care nucleic acid amplification and detection |
CN109821586B (en) * | 2019-02-21 | 2021-05-04 | 贵州大学 | Quick cooling tank for metal workpiece post-quick cooling experiment |
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US5200313A (en) * | 1983-08-05 | 1993-04-06 | Miles Inc. | Nucleic acid hybridization assay employing detectable anti-hybrid antibodies |
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US5455175A (en) * | 1990-06-04 | 1995-10-03 | University Of Utah Research Foundation | Rapid thermal cycling device |
FR2672301A1 (en) | 1991-02-01 | 1992-08-07 | Larzul Daniel | Process and device for amplifying the number of a defined sequence of nucleic acid in a biological sample |
JPH07505297A (en) * | 1992-04-06 | 1995-06-15 | アボツト・ラボラトリーズ | Method and apparatus for detecting nucleic acids or analytes using total internal reflection |
DE4301693A1 (en) * | 1993-01-22 | 1994-07-28 | Cytech Biomedical Inc | Amplification methods and methods for the detection of solid phase polynucleotide sequences |
US5484734A (en) * | 1993-03-09 | 1996-01-16 | Torc Seimitsu Industries, Ltd. | Reaction vessel for preventing evaporation and a method thereof |
US5556773A (en) | 1993-08-06 | 1996-09-17 | Yourno; Joseph | Method and apparatus for nested polymerase chain reaction (PCR) with single closed reaction tubes |
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-
1998
- 1998-06-12 DE DE19826153A patent/DE19826153C2/en not_active Expired - Fee Related
-
1999
- 1999-05-29 CA CA002334891A patent/CA2334891A1/en not_active Abandoned
- 1999-05-29 AT AT99936358T patent/ATE234682T1/en not_active IP Right Cessation
- 1999-05-29 DE DE59904644T patent/DE59904644D1/en not_active Expired - Lifetime
- 1999-05-29 WO PCT/DE1999/001589 patent/WO1999064157A1/en active IP Right Grant
- 1999-05-29 JP JP2000553211A patent/JP2002517219A/en not_active Withdrawn
- 1999-05-29 US US09/719,376 patent/US6383802B1/en not_active Expired - Fee Related
- 1999-05-29 EP EP99936358A patent/EP1096998B1/en not_active Expired - Lifetime
-
2001
- 2001-04-04 US US09/825,826 patent/US6440724B2/en not_active Expired - Fee Related
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7358081B2 (en) | 2002-03-07 | 2008-04-15 | Siemens Aktiengesellschaft | Devices for the electrochemical detection of a nucleotide sequence, analysis cassettes, systems of analysis cassettes, supplemental modules, and methods for producing analysis cassettes |
US20070054273A1 (en) * | 2003-08-01 | 2007-03-08 | Capitalbio Corporation | Microarray devices having controllable reaction volume |
US8293519B2 (en) | 2003-08-01 | 2012-10-23 | Capitalbio Corporation | Microarray devices having controllable reaction volume |
US20080124723A1 (en) * | 2006-06-30 | 2008-05-29 | Canon U.S. Life Sciences, Inc. | Combined thermal devices for thermal cycling |
US7851185B2 (en) | 2006-06-30 | 2010-12-14 | Canon U.S. Life Sciences, Inc. | Combined thermal devices for thermal cycling |
US8507257B2 (en) | 2006-06-30 | 2013-08-13 | Canon U.S. Life Sciences, Inc. | Combined thermal devices for thermal cycling |
US9272282B2 (en) | 2006-06-30 | 2016-03-01 | Canon U.S. Life Sciences, Inc. | Combined thermal devices for thermal cycling |
US10226772B2 (en) | 2006-06-30 | 2019-03-12 | Canon U.S. Life Sciences, Inc. | Combined thermal devices for thermal cycling |
Also Published As
Publication number | Publication date |
---|---|
ATE234682T1 (en) | 2003-04-15 |
CA2334891A1 (en) | 1999-12-16 |
US6383802B1 (en) | 2002-05-07 |
WO1999064157A1 (en) | 1999-12-16 |
DE19826153A1 (en) | 1999-12-16 |
JP2002517219A (en) | 2002-06-18 |
DE19826153C2 (en) | 2002-11-07 |
EP1096998B1 (en) | 2003-03-19 |
EP1096998A1 (en) | 2001-05-09 |
US6440724B2 (en) | 2002-08-27 |
DE59904644D1 (en) | 2003-04-24 |
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