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EP4552743A1 - Thermocycleur compact de précision avec accumulateur de chaleur et procédé de thermorégulation rapide d'échantillons - Google Patents

Thermocycleur compact de précision avec accumulateur de chaleur et procédé de thermorégulation rapide d'échantillons Download PDF

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Publication number
EP4552743A1
EP4552743A1 EP24211668.9A EP24211668A EP4552743A1 EP 4552743 A1 EP4552743 A1 EP 4552743A1 EP 24211668 A EP24211668 A EP 24211668A EP 4552743 A1 EP4552743 A1 EP 4552743A1
Authority
EP
European Patent Office
Prior art keywords
heat
heat reservoir
cavity
thermocycler
strips
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.)
Pending
Application number
EP24211668.9A
Other languages
German (de)
English (en)
Inventor
Frieder Weidhase
Werner Lehmann
Gerd Fischer
Stephan Opperskalski
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.)
Attomol Molekulare Diagnostika GmbH
Original Assignee
Attomol Molekulare Diagnostika 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 Attomol Molekulare Diagnostika GmbH filed Critical Attomol Molekulare Diagnostika GmbH
Publication of EP4552743A1 publication Critical patent/EP4552743A1/fr
Pending legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other
    • 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
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/147—Employing temperature sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • 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
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • 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
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1822—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using Peltier 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
    • B01L2300/18—Means for temperature control
    • B01L2300/1855—Means for temperature control using phase changes in a medium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/06—Test-tube stands; Test-tube holders

Definitions

  • the invention relates to a compact, fast, thermal cycler with a heat reservoir and a method for rapid temperature control of samples for accelerated, miniaturized cooling and heating, preferably in medical diagnostics and bioanalytics, particularly in fluorescence microscopy, to thermally initiate, control, or terminate enzymatic reactions and molecular interactions.
  • PCR polymerase chain reaction
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • thermocyclers Traditionally, a number of different configurations for thermocyclers are known. Ideas for solutions for accelerated, miniaturized cooling and heating have been published time and again, but the desire for even greater speed, precision in temperature profiles, and exact temperature control have not been fully met. To increase the speed of PCR analysis and the associated manufacturing effort, numerous solutions have been developed in the past, some of which have even been protected by patents. For example, there are ULTRA FAST PCR devices that use thin tubes or channels in conjunction with temperature-controlled surfaces for heat transfer. These can be found online, for example, at https://www.nextgenpcr.com/.
  • Rapid temperature changes can also be achieved with suitable circulating cold and warm liquids, as in the solution according to the EP 000002535427 A2 suggested.
  • Peltier elements for heating and cooling has become established as the so-called gold standard, as it improves the temperature profiles and the accuracy of the The use of Peltier elements, which have long been known for their excellent controllability, has been in use since 1987.
  • Patent US 4,639,883 Another known solution is the use of discrete Peltier elements, which are connected to the other separate components of the ThermoCycler using thermal pastes or thermal adhesives.
  • EP 1 090 141 B1 a heating block and separate Peltier elements, as well as a heat sink.
  • Various physical effects for heating and cooling have been proposed for conventional thermocyclers, some of which are also used on a large scale. Despite the desire for ever shorter amplification times, newer, relatively fast solutions, in particular, lack sensitivity and precise quantification.
  • the detection reagent consists of a sample pad, a conjugate pad, an NC membrane, and an absorption pad.
  • the product is simple and convenient to use, has a short detection time, high sensitivity, and is well suited for large-scale screening of primary medical institutions and key outbreak areas of epidemic situations.
  • isothermal amplification is less sensitive than the classic quantifiable QPCR diagnostic tests.
  • Another disadvantage of such tests is that the false-negative rate is relatively high and no quantitative Ct values are provided.
  • TSHC target-specific hybrid capture
  • the invention is based on the object of creating a compact precision thermocycler with a heat reservoir and a method for rapid temperature control of samples, i.e. for rapid, miniaturized cooling and heating, wherein the thermocycler has a long service life, the method enables higher speed of PCR or mRNA analysis, guarantees more precise, precisely definable, quickly controllable temperature profiles, improves the accuracy of temperature control, the thermocycler requires a small volume, is easy to handle, can be operated in an energy-efficient manner and can be used in particular in fluorescence microscopy.
  • a first metallic heat reservoir 1 which is generally designed as a plate-shaped support base, is installed and arranged in the novel, compact precision thermocycler for accelerated, miniaturized cooling and heating in medical diagnostics, so that it can be set to an optimized temperature (e.g., 40°C) by means of a temperature control and separate heating elements, such as Peltier elements 7.
  • a temperature control and separate heating elements such as Peltier elements 7.
  • One, two, or more cavity strips 10 are arranged in the first heat reservoir 1.
  • Several continuously open sample receiving openings 14 or planar support surfaces are, in turn, distributed in the cavity strips 10.
  • At least one, two, or more cooling blocks 2 can optionally be arranged on this heat reservoir 1.
  • the heat reservoir 1 and the cooling block(s) 2 are thermally coupled.
  • At least one microcomputer 4 is integrated in the supply and control block 3.
  • One, two, or more thermally coupled heat pipes 6 are arranged inside each cavity strip 10 or arrangeable heat dissipation strips.
  • the heat reservoir 1 is directly connected to one flat side of the Peltier elements 7.
  • the other flat side of the Peltier elements 7 is thermally connected directly to the cavity strips 10.
  • One, two, or more temperature sensors 11 are arranged in or on the heat reservoir 1 and on the cavity strips 10.
  • the first heat reservoir 1 or further arranged heat reservoirs can be thermally insulated in the direction of a movable xyz object stage 12.
  • the cavity strips 10 of other temperature zones will be separated from each other by an insulator 9, which can be strip-shaped. All components are arranged on a guided stage adapter 8 that can be moved along two or three axes.
  • a second heat reservoir 5 or additional heat reservoirs can preferably be arranged in order to adapt the thermocycles to a required sample-specific temperature control as quickly as possible.
  • the solution according to the invention can be mounted on two- or three-axis movable xyz stage 12 or stage adapter 8 of commercially available fluorescence microscopes or an automatic pipetting device coupled with a fluorescence microscope with viewing direction 13.
  • first heat reservoir 1 and/or the cavity strip 10 consists of fast heat-conducting materials such as silver, copper or aluminum and the second heat reservoir 5 consists of non-metals with phase transition (PCM material), which has a high heat storage capacity and is designed with an enlarged surface.
  • PCM material non-metals with phase transition
  • the continuously open sample receiving openings 14 in the cavity strip(s) 10 are conical, whereby Transparent, thermostable reaction vessels with a planar bottom can be inserted into these, or transparent, planar, thermostable slides or biochips can be placed on the planar support surface. This enables the analysis of a wide variety of samples using different types of sample containers.
  • a heatable weighting plate can be arranged above the cavity strip(s) 10 in order to counteract the formation of condensate.
  • the Peltier element(s) 7 consist of ceramic or metal plates, which are connected by soldering, gluing, or pressing to the cavity strip(s) 10 and, on the other hand, to the heat reservoir 1, ensuring rapid and low-loss heat flow.
  • additional insulation 9 is arranged between the different temperature zones.
  • heat conductors, heat pipes 6, heat foils, thermal pastes, heat spreaders and/or vapor chambers are embedded inside the cavity strip 10, the heat reservoir 1, or arrangeable heat dissipation strips.
  • Peltier elements 7 can be arranged on both sides of the cavity strips 10 if required in order to improve the heat input or heat dissipation.
  • one or more cavity strips 10 can form a temperature zone, which are distributed in strips and separated from each other by thermal insulators 9.
  • thermal insulators 9 Several heat pipes 6, heat spreaders, and/or vapor chambers can be embedded inside a cavity strip 10 to accelerate the heat transfer to the heat reservoir 1 and the propagation speed of the heat flows during heating and cooling.
  • Compact precision ThermoCyclers can operate in a device configuration with an automated inverted or upright light or fluorescence microscope, whereby the device configuration consists of a compact precision ThermoCycler with arranged microscope adapter, a light or fluorescence microscopic optics, a camera, a two or three-axis movable, motorized xyz object stage 12 and a connected and connected control and evaluation software in order to automatically temper samples in coordination with the fully automatic measuring and evaluation process.
  • Compact precision thermocyclers can operate in a device configuration with an automated inverted or upright light or fluorescence microscope, with an upstream station for loading samples into the cavities (sample receiving openings 14), a transport device (tray, conveyor belt) for the targeted movement and positioning of one, or two or more compact precision thermocyclers, and a second station for analysis equipped with at least one microscope and an evaluation device, such as a camera.
  • the cavity strips 10 are force-fitted with reaction chambers containing at least the reaction solution and/or a sample. Temperature control is achieved via thermally connected heat conductors multidirectionally between the sample, cavity strip 10, Peltier element 7, heat reservoir 1, and, if required, a second heat reservoir 5 in an energy-saving and controllable manner, so that recuperation occurs during successive heating and cooling cycles.
  • This makes it possible for heat to be released passively or actively to an ambient medium, such as the ambient air, at an accelerated rate as needed. In principle, however, analysis can also be performed under a different protective medium.
  • reaction solutions, reaction gels, reaction solids or reaction gases are rapidly tempered qualitatively and quantitatively thermocyclically, isothermally or by a temperature gradient in order to investigate chemical and/or enzymatic reactions, crystallizations, molecular interactions or conformational changes, the growth of cells, tissues or
  • ThermoCycler makes it possible to To thermally start, appropriately control, or precisely terminate reaction solutions in order to conduct polymerase chain reactions, ligase chain reactions, isothermal nucleic acid amplifications, and melting curve analyses of nucleic acids and proteins.
  • the integrated microcomputer 4 contains control software with comprehensive algorithms that regulates the process in such a way that heat can be transferred from the heat reservoir 1 via the heat conduction system and from the Peltier element 7 into the sample with very little loss and quickly, and then dissipated back into the heat reservoir 1 or the respective arranged heat reservoirs, in order to realize rapid thermal cycles in the sample with the greatest possible energy efficiency.
  • the heat reservoirs 1 and 5 are set to a temperature between the upper temperature level (denaturation at 94-96° C) and the room temperature (at 25° C) and the small temperature differences to be bridged are controlled by means of Peltier elements 7.
  • the advantage of the solution according to the invention lies in the fact that the heat loss occurring during operation of the Peltier elements 7 is not dissipated through intensive cooling during each cycle, as was previously the case, but is temporarily stored directly in the ThermoCycler. This is because it is complex and expensive to repeatedly dissipate large amounts of heat (cooling) and subsequently reinsert it (heating). These heat flows to and from the heat reservoir 1, in conjunction with direct temporary storage, significantly reduce the energy required for operation, resulting in a recuperation effect. In addition to energy savings, the entire arrangement can also be significantly reduced in size and made very compact. Furthermore, the disclosed invention reduces the thermal material load on all components, particularly the Peltier elements 7.
  • the service life is also increased when the compact precision ThermoCycler is integrated into a microscopic measuring instrument enclosed by a housing, which is known to react sensitively to temperature fluctuations.
  • the negative impacts on the working environment caused by waste heat and fan noise are well-known disturbances.
  • Heat reservoir 1 can be easily adjusted to an optimized temperature.
  • the optimal temperature e.g., 40°C
  • the effect of recuperation is particularly effective with optimal temperature control, i.e., up to the extent limited by the efficiency of the Peltier elements 7 during cooling.
  • a further significant advantage is that the power loss peaks that occur during cooling can be quickly dissipated into a metallic (for example made of silver, copper or aluminum) heat reservoir 1.
  • a further increase in heat storage capacity can be achieved by using a second heat reservoir 5 consisting of PCM material (phase change material).
  • PCM material phase change material
  • the metallic heat reservoir 1 quickly absorbs, in particular, the short-term power peaks, while the second PCM heat reservoir 5 temporarily stores relatively larger amounts of heat. This results in an overall better power-to-mass ratio, since the PCM material can absorb and release significantly more heat energy than metallic versions in the relevant temperature range.
  • the PCM material can be selected according to the optimal required heat reservoir temperature. To dissipate sufficient energy from the first heat reservoir 1 despite the slower heat storage in the second heat reservoir 5, the contact surface between the two reservoirs is increased by extending metal pins or fins of the first heat reservoir 1 deep into the PCM.
  • the metallic first heat reservoir 1 significantly determines the speed and effectiveness of the overall arrangement.
  • ThermoCycler includes the guide for the movable stage adapter 8, fastening elements, and the insulation between the Temperature zones 9 and several cavity strips 10.
  • thermal insulation can be arranged in the direction of the xyz object stage 12 so that, for example, a microscope is not heated.
  • the compact design and small dimensions allow for easy use in a variety of commercially available microscopes.
  • the combination is preferably carried out with automated microscopes, so that the temperature control and the measurement process can be carried out fully automatically, software-controlled, and coordinated.
  • the compact precision ThermoCycler itself with appropriate measurement technology based on optical or electrical sensors. This measurement technology can be fully integrated, but is preferably connected via the microscope adapter as an independent reader module.
  • thermocyclic temperature control of reaction chambers allows a range of investigations on microscopic structures with simultaneous temperature control of the reaction chamber and thus also of the microstructures, which were previously not possible or at least not optimally possible.
  • fluorescence-coupled, thermocyclic or isothermal reactions such as multiplex real-time PCR or LAMP on biochips and bead assays, e.g. for the detection of various microorganisms or molecular tumor markers.
  • multiplex detection methods can also be combined with melting curve analyses to measure the binding strength of analytes such as the avidity of antibodies or to analyze single nucleotide polymorphisms (SNPs) in genes.
  • SNPs single nucleotide polymorphisms
  • step gradients or linear gradients are used with simultaneous stepwise or continuous analysis of the reaction.
  • a thermal reaction control By means of the disclosed method of coupling eversen or, preferably, inverse multicolor fluorescence microscopy with a thermal reaction control, cells, tissues, or biomolecules can be examined individually or combined in multiplex systems down to single-molecule resolution, i.e., the optical resolution of nanostructures. It is also possible to use the microscope optics in such a way that the aforementioned reactions can optionally be measured summatively without optical resolution of the micro- and nanostructures in the reaction space.
  • the integration of a sufficient number of microscopically viewable cavity strips 10 in a ThermoCycler can now be implemented for the first time without exceeding the standard dimensions of the microtest plate specimen holder of a microscope.
  • the 96-well format commonly used in routine laboratories is achieved.
  • Each of these cavity strips 10 can be individually controlled as a temperature zone.
  • Fig. 1 shows the exploded view of a compact precision ThermoCycler with a heat reservoir 1.
  • the cooling block 2 serves to dissipate excess heat loss. It is advantageously constructed as a unit consisting of a square aluminum profile with an integrated fan. To ensure that the first heat reservoir 1 quickly reaches the optimal operating temperature, the first heat reservoir 1 is connected to a demand heater 15.
  • one or more heat reservoirs made of PCM material 5 can be connected downstream of the fast-acting metallic heat reservoir 1.
  • the combination of a first heat reservoir 1 and at least one second heat reservoir 5 results in a highly effective, complex heat reservoir that combines the properties of high volume and weight efficiency, high thermal energy storage capacity, and rapid heat power absorption.
  • the relatively slow charging and discharging rate of the PCM heat reservoir 5 can be significantly increased by increasing the contact surface between the two reservoirs. This effect is advantageously achieved by arranging metal pins or fins on the first heat reservoir 1, which are designed to extend deep into the PCM heat reservoir 5. At the same time, this eliminates an undesirable heat transfer surface compared to a more obvious separate design of the heat reservoirs.
  • the cavity strips 10 contain conical openings (cavities) for accommodating sample vessels, such as Nucleolink modules (Nunc).
  • the angle of the cones e.g., 17.2° is selected so that the sample vessels are held in the cavity strip 10 in a self-locking and force-fitting manner during cyclic temperature changes due to friction. This ensures good, stable heat transfer between the samples via the sample vessels and the cavity strips 10.
  • Peltier elements 7 are used, in accordance with the gold standard of classical PCR technology.
  • the characteristic curve of the temperature in the Fig. 2 demonstrates the outstanding precision of the temperature control achieved without any significant overshoots in the temperature curves.
  • additional heat pipes 6 are embedded inside the cavity strips 10. This effectively increases the speed of the temperature transitions by an order of magnitude.
  • the Peltier elements 7 positioned at both ends of the heat pipes 6 can, if necessary, significantly increase the heat transfer capacity of the heat pipes 6 by up to four times compared to the use of a heat pipe 6 with a single-sided temperature control. This is done by introducing a heat flow into the cavity strips 10 from both sides and additionally halving the path of the heat flow.
  • temperature sensors 11 are arranged, which are suitably attached to a temperature zone at least in each cavity strip 10 and to the heat reservoir 1.
  • the energy supply to the Peltier elements 7 is controlled by an attached energy supply and control block 3.
  • the corresponding algorithms are implemented in the form of digital control by means of a microcomputer 4 integrated into the energy supply and control block 3.
  • the ThermoCycler according to the invention can be mounted directly on an xyz stage 12 of a conventional fluorescence microscope (in Figure 1 only schematically indicated).
  • a feasible dead weight of the inventive ThermoCycler of only approximately 1.5 kg state-of-the-art xyz stages of standard microscopes with high acceleration rates and thus very short travel times can be used.
  • Fig. 1 shows the preferred viewing direction of a microscope 13, i.e. the viewing direction of the microscope 13 is from below onto the bottom of the sample vessels and thus through them onto the samples.
  • This viewing direction offers the advantage that imaging particles of the samples (e.g. beads during the evaluation of bead assays, see Rödiger et al. 2012, Rödiger et al. 2017, Hanschmann et al. 2021), which collect and settle at the bottom of the sample containers, thus generally keeping the distance of the particles to the microscope constant within narrow limits.
  • This fulfills an essential prerequisite for quantitative, high-quality PCR analysis by providing sharp, high-contrast images in real time, from which the data for the evaluation of, for example, PCR or melting curve analyses is ultimately extracted.
  • optical arrangement described here primarily refers to inverted microscopes. In principle, however, the solution according to the invention can also be used with upright microscopes, if this is advantageous, for example, for in situ studies on living cells. Imaging can also be omitted entirely or optionally during analysis.
  • the biochips can be placed on the upper support surface of the cavity bars 10. Depending on the scale, up to 96 Observation points can be used. Further possible configurations of this approach include the placement of suitable slides and the arrangement of biochips and slides on the underside of the cavity strips 10 using a simple, suitable pressure or suction option.
  • Fig. 2 shows in the temperature range from 28° C to 32° C (lower solid line) the only very slight fluctuations in the temperature of the heat reservoir 1 with a compact precision ThermoCycler according to the invention as a result of the absorption or release of heat energy during heating or cooling.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
EP24211668.9A 2023-11-10 2024-11-08 Thermocycleur compact de précision avec accumulateur de chaleur et procédé de thermorégulation rapide d'échantillons Pending EP4552743A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE102023131381.9A DE102023131381A1 (de) 2023-11-10 2023-11-10 Kompakter Präzisions-ThermoCycler mit Wärmespeicher und Verfahren zur schnellen Temperierung von Proben

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EP4552743A1 true EP4552743A1 (fr) 2025-05-14

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Citations (10)

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Publication number Priority date Publication date Assignee Title
US4639883A (en) 1984-11-28 1987-01-27 Rca Corporation Thermoelectric cooling system and method
EP1090141B1 (fr) 1999-04-08 2006-03-22 Analytik Jena AG Thermocycleur rapide a enceinte chauffante
EP1710017A1 (fr) * 2005-04-04 2006-10-11 Roche Diagnostics GmbH Thermocycle d'un bloc contenant plusieurs échantillons
WO2008070198A2 (fr) * 2006-05-17 2008-06-12 California Institute Of Technology Système de cyclage thermique
US20080274511A1 (en) * 2002-12-23 2008-11-06 Lim Hi Tan Device for carrying out chemical or biological reactions
EP2167964A1 (fr) 2007-06-13 2010-03-31 Attomol GmbH Molekulare Diagnostika Procédé pour exécution et exploitation d'essais "mix&measure" pour l'évaluation des cinétiques de réaction ainsi que des concentrations et affinités des analytes en format multiplex
US7829691B2 (en) 2000-06-15 2010-11-09 Qiagen Gaithersburg, Inc. Detection of nucleic acids by type specific hybrid capture method
US20140038192A1 (en) * 2012-07-31 2014-02-06 Gen-Probe Incorporated System, method, and apparatus for automated incubation
CN111521805B (zh) 2020-05-12 2021-09-14 北京倍肯恒业科技发展股份有限公司 一种2019新型冠状病毒抗原检测试剂及其制备方法
DE102022109312A1 (de) * 2021-05-05 2022-11-10 Frieder Weidhase Vorrichtung zum beschleunigten, miniaturisierten Kühlen und Heizen in der Medizintechnik

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4639883A (en) 1984-11-28 1987-01-27 Rca Corporation Thermoelectric cooling system and method
EP1090141B1 (fr) 1999-04-08 2006-03-22 Analytik Jena AG Thermocycleur rapide a enceinte chauffante
US7829691B2 (en) 2000-06-15 2010-11-09 Qiagen Gaithersburg, Inc. Detection of nucleic acids by type specific hybrid capture method
US20080274511A1 (en) * 2002-12-23 2008-11-06 Lim Hi Tan Device for carrying out chemical or biological reactions
EP1710017A1 (fr) * 2005-04-04 2006-10-11 Roche Diagnostics GmbH Thermocycle d'un bloc contenant plusieurs échantillons
WO2008070198A2 (fr) * 2006-05-17 2008-06-12 California Institute Of Technology Système de cyclage thermique
EP2535427A2 (fr) 2006-05-17 2012-12-19 California Institute of Technology Système de cycle thermique
EP2167964A1 (fr) 2007-06-13 2010-03-31 Attomol GmbH Molekulare Diagnostika Procédé pour exécution et exploitation d'essais "mix&measure" pour l'évaluation des cinétiques de réaction ainsi que des concentrations et affinités des analytes en format multiplex
US20140038192A1 (en) * 2012-07-31 2014-02-06 Gen-Probe Incorporated System, method, and apparatus for automated incubation
CN111521805B (zh) 2020-05-12 2021-09-14 北京倍肯恒业科技发展股份有限公司 一种2019新型冠状病毒抗原检测试剂及其制备方法
DE102022109312A1 (de) * 2021-05-05 2022-11-10 Frieder Weidhase Vorrichtung zum beschleunigten, miniaturisierten Kühlen und Heizen in der Medizintechnik

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HANSCHMANN, HRÖDIGER, SKRAMER, THANSCHMANN, KSTEIDLE, MFINGERLE, VSCHMIDT, CLEHMANN, WSCHIERACK, P: "LoopTag FRET Probe System for Multiplex qPCR Detection of Borrelia Species", LIFE 2021, vol. 11, 2021, pages 1163, Retrieved from the Internet <URL:https://doi.org/10.3390/life11111163>
RÖDIGER, SLEHMANN, WSCHRÖDER, CSCHIERACK, P: "Bead-Technologien. Mikropartikelsysteme für die Nukleinsäurediagnostik", BIOSPEKTRUM, 2013, pages 153 - 156
RÖDIGER, SSCHIERACK, PBÖHM, ANITSCHKE, JBERGER, EFRÖMMEL, USCHMIDT, CRUHLAND, MSCHIMKE, IROGGENBUCK, D: "A Highly Versatile Microscope Imaging Technology Platform for the Multiplex RealTime Detection of Biomolecules and Autoimmune Antibodies", ADV BIOCHEM ENGIN/BIOTECHNOL, 2012

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