EP4378585A1 - Dispositif et procédé pour effectuer une trempe précise et précise de substances chimiques pour la synthèse, l'homogénéisation et le diagnostic - Google Patents

Dispositif et procédé pour effectuer une trempe précise et précise de substances chimiques pour la synthèse, l'homogénéisation et le diagnostic Download PDF

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Publication number
EP4378585A1
EP4378585A1 EP22210225.3A EP22210225A EP4378585A1 EP 4378585 A1 EP4378585 A1 EP 4378585A1 EP 22210225 A EP22210225 A EP 22210225A EP 4378585 A1 EP4378585 A1 EP 4378585A1
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EP
European Patent Office
Prior art keywords
thermal
sample carrier
tempering
sample
way valve
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
EP22210225.3A
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German (de)
English (en)
Inventor
Jan KÖNIG
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Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
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Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
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Priority to EP22210225.3A priority Critical patent/EP4378585A1/fr
Publication of EP4378585A1 publication Critical patent/EP4378585A1/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
    • B01L7/54—Heating or cooling apparatus; Heat insulating devices using spatial temperature gradients
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25B—REFRIGERATION MACHINES, PLANTS OR SYSTEMS; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS
    • F25B21/00—Machines, plants or systems, using electric or magnetic effects
    • F25B21/02—Machines, plants or systems, using electric or magnetic effects using Peltier effect; using Nernst-Ettinghausen effect
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/028—Modular arrangements
    • 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
    • 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
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1827—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using resistive heater
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25B—REFRIGERATION MACHINES, PLANTS OR SYSTEMS; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS
    • F25B2321/00—Details of machines, plants or systems, using electric or magnetic effects
    • F25B2321/02—Details of machines, plants or systems, using electric or magnetic effects using Peltier effects; using Nernst-Ettinghausen effects
    • F25B2321/023—Mounting details thereof

Definitions

  • the invention relates to a device and a method for carrying out a rapid and precise temperature control or a temperature-controlled reaction sequence of chemical or biological substances, in particular mixtures of substances, according to the preamble of claim 1 or claim 13.
  • the invention relates both to process engineering apparatus for synthesis, such as chemical reactors, in particular laboratory reactors or bioreactors, in which substances (main products and by-products) are synthesized by means of chemical or biological reactions from starting materials and mixtures of substances (also referred to as educts or precursors) under the influence of heat, as well as process engineering apparatus for mixing chemical substances and mixtures of substances, such as mixing devices, in particular laboratory mixing devices, and process engineering apparatus for diagnostics, such as thermocyclers for the polymerase chain reaction (PCR).
  • process engineering apparatus for synthesis such as chemical reactors, in particular laboratory reactors or bioreactors, in which substances (main products and by-products) are synthesized by means of chemical or biological reactions from starting materials and mixtures of substances (also referred to as educts
  • the main external stimuli used to trigger chemical reactions are redox, heat, pH, light, etc.
  • Chemical or biological reactions that require increased activation energy can be started or accelerated by a controlled supply of heat (increase in temperature) or slowed down or stopped by a targeted reduction in temperature.
  • chemical or biological substances can be degraded/decomposed by adding a corresponding amount of thermal energy, such as in pyrolysis or calcination. Precisely because of the temperature sensitivity organic and biological substances, rapid and precise temperature changes are necessary for the synthesis and reproduction of substances.
  • the temperature-specific reaction sequence can also be used to adjust specific material properties, as described above.
  • organic materials such as polymers can have different properties that result from the temperature-dependent polyreaction (polymerization, polycondensation and polyaddition) with regard to the molecular structure (linear or cross-linked) and from the temperature-dependent phase states.
  • temperature-dependent polyreaction polymerization, polycondensation and polyaddition
  • molecular structure linear or cross-linked
  • temperature-dependent phase states By heating quickly, for example, undesirable by-products or side effects can be avoided.
  • desired properties can be "frozen” or undesirable back reactions can be avoided.
  • the invention relates in particular to a device and a method for carrying out syntheses - known as parallel synthesis - as used, among other things, in combinatorial chemistry to produce various molecules with special properties.
  • the methodology of parallel synthesis is used in pharmaceutical-chemical research, particularly drug research, for the simultaneous synthesis and purification of a large number of active ingredients from structurally similar compounds.
  • Precise temperature control also plays a crucial role in parallel syntheses for reaction optimization, for example in peptides, and is addressed by this invention.
  • the invention relates to a device and a method for carrying out a chemical, biological and/or biochemical reaction by tempering according to the preamble of claim 1 or claim 13.
  • a device for carrying out a chemical and/or biochemical reaction by tempering is usually designed with sample carrier holders for receiving sample vessels.
  • RNA can also be amplified in reverse transcription PCR (RT-PCR).
  • thermocyclers which have so-called thermoblocks with several sample carrier holders for holding the sample vessels for the heat treatment of the samples.
  • the thermoblocks are made of aluminum or silver and are heated or cooled by Peltier modules, for example.
  • the disadvantage of this arrangement is that the thermal mass of the thermoblocks is large and the thermal paths over which the heat must be conducted between the Peltier modules and the sample vessels are energy-inefficient.
  • Such a thermocycler is described, for example, in the publication Xianbo Qiu et.
  • the EN 10 2010 003 365 It is known to arrange a Peltier module and a temperature sensor on each sample vessel so that the individual sample vessels can be individually tempered.
  • the disadvantage of this arrangement is that the sample carrier holders are very small, energy-inefficient and complex to control.
  • the invention is therefore based on the object of proposing a method and a device for carrying out chemical and/or biochemical reactions and mixing processes by temperature control, in particular the polymerase chain reaction, which enable very rapid temperature changes and precise temperature control and operate in an energy-efficient manner.
  • the device according to the invention for carrying out a chemical, biological and/or biochemical reaction by temperature control comprises at least two sample carrier receptacles for holding chemical and/or biochemical samples and/or sample vessels with chemical and/or biochemical samples and at least one thermal three-way valve as a temperature control element.
  • the sample carrier receptacles are arranged next to one another.
  • the thermal three-way valve has at least two Peltier modules and is in thermal Contact with the at least two sample carrier receptacles, so that the two sample carrier receptacles are arranged at different thermal interfaces of the thermal three-way valve.
  • adjacent means in relation to the sample carrier receptacles that they are directly or indirectly adjacent to one another, i.e. that other elements can be located in between, but the two adjacent sample carrier receptacles are spatially close to one another and no other sample carrier receptacle is arranged between them.
  • adjacent is also used as a synonym.
  • thermal three-way valve refers to a component that conducts heat between three thermal interfaces. Heat can be both supplied to and removed from each interface.
  • the thermal three-way valve has at least two Peltier modules and a thermal conductor that thermally connects the two Peltier modules.
  • the thermal conductor can be located between the two Peltier modules. Alternatively, the thermal conductor is arranged in thermal contact with the two Peltier modules, but can be arranged in any spatial location.
  • the Peltier modules can act as electrically operated heat pumps or, if higher electrical currents are selected, as Joule heaters.
  • the thermal conductor can dissipate heat to the environment or absorb it from the environment or serve to conduct heat between the two Peltier modules.
  • the thermal interfaces are one interface to the neighboring sample carrier holders that are in thermal contact and a third thermal interface to the environment via the thermal conductor.
  • the invention is based on the applicant's finding that the arrangement of a thermal three-way valve between adjacent samples enables targeted temperature control of the samples, while at the same time preventing the energy supplied to the system from building up due to the electrical operation of the Peltier modules (Joule heating) and causing thermal runaway of the system.
  • the device according to the invention thus differs in essential aspects from previously known devices: Due to the thermal three-way valve provided according to the invention between two sample carrier receptacles, the two samples are in thermal contact with a thermal interface of the thermal three-way valve. This allows the heating and cooling of the samples in the sample carrier receptacles to be controlled in a targeted manner, for example by using the heat in a sample vessel with the sample as a heat reservoir and by means of the Peltier modules of the thermal three-way valve, the required thermal energy only has to be pumped over a short distance from the sample as a heat reservoir into the adjacent sample vessel to be heated.
  • the samples are heated and/or cooled in an energy-efficient and time-optimized manner by arranging two sample carrier holders in thermal contact with a thermal interface of the thermal three-way valve.
  • the thermal three-way valve comprises two Peltier modules and a thermal conductor in between.
  • the two Peltier modules are mounted on two sides of the thermal conductor as a mechanical support.
  • the thermal conductor can dissipate heat to the environment or absorb it from the environment or serve to conduct heat between the two Peltier modules.
  • the thermal interfaces are an interface to the neighboring sample carrier holders that are in thermal contact (first and second thermal interface) and a third thermal interface to the environment via the thermal conductor.
  • This design has the advantage that the short paths allow for very efficient heat conduction.
  • the thermal three-way valve comprises two Peltier modules and a thermal conductor.
  • the two Peltier modules are mounted on the same side of the thermal conductor as a mechanical support.
  • the thermal conductor can, depending on the operating mode of the Peltier modules, dissipate heat to the environment or absorb it from the environment or serve to conduct heat between the two Peltier modules.
  • the thermal interfaces are each an interface to the neighboring sample carrier holders that are in thermal contact (first and second thermal interface) and a third thermal interface to the environment via the thermal conductor.
  • This elongated design has the advantage that a very simple and narrow design is possible.
  • the at least two sample carrier receptacles are in thermal contact with the thermal three-way valve located therebetween at the respective thermally opposite ends of the thermal three-way valve in the corresponding operating mode, enabling efficient cooling and heating of the samples.
  • the thermal three-way valve acts as an electrically switchable thermal diode between the first and second sample carrier holders with a hot side that can be switched on and off and a cold side that can be switched on and off.
  • a sample carrier holder can be efficiently heated on the hot side of the correspondingly switched Peltier modules operated as a heat pump and a sample carrier holder can be efficiently cooled on the cold side of the correspondingly switched Peltier modules operated as a heat pump, since the required thermal energy is only pumped over a short distance from the sample to be cooled to the adjacent sample to be heated by means of the Peltier modules of the thermal three-way valve.
  • the sample to be cooled initially acts as a heat reservoir for the sample to be heated.
  • both effective areas namely the cold side for cooling and the hot side for heating, are used simultaneously.
  • the sample carrier holder and preferably a sample vessel located therein with a sample (chemical or biological substance) on the hot side of the two Peltier modules operated as a heat pump is or are thus heated, while the sample carrier holder and a sample vessel located therein with a second sample are cooled on the cold side.
  • the three-way valve consists of at least two Peltier modules that are coupled to the sample carrier holder.
  • the two Peltier modules in the heat path of the three-way valve can also be operated in opposite directions, so that heat can be absorbed or released via the thermal conductor in between.
  • Defined temperatures can be preset for heating and cooling.
  • the process steps can be repeated cyclically.
  • the method according to the invention has the advantage that the dissipation of excess heat prevents the energy supplied to the system from building up due to the electrical operation of the Peltier modules (Joule heating) and leading to thermal runaway of the system.
  • the tempering element acts at least in one of the method steps A to D as a so-called thermal diode between the first and the second sample carrier receptacle, which is in thermal contact with the first and the second sample carrier receptacle such that the two adjacent (neighboring) sample carrier receptacles are arranged at the thermally opposite ends of the thermal diode and heat is exchanged between the neighboring sample vessels.
  • This embodiment has the advantage of energy-efficient cooling or heating of the two sample vessels and the samples of chemical substances or mixtures of substances contained therein, since the heat in a sample vessel with sample is used as a heat reservoir and the required thermal energy only has to be pumped over a short distance from the sample to be cooled as a heat reservoir into the sample vessel to be heated by means of the Peltier modules.
  • the tempering element acts as a thermal diode between the first and the second sample carrier holder in all process steps A to F.
  • the two sample carrier holders are arranged at the thermally opposite ends of the thermal diode.
  • Process steps B and C as well as process steps D and E take place simultaneously by cooling one of the two at least two sample carrier holders. is heated, while the other sample carrier holder is heated at the opposite end of the thermal diode.
  • the process steps can be repeated in any order and as often as desired
  • thermal energy can be dissipated via the third thermal interface of the thermal three-way valve, for example in the form of a mechanical holder (thermal conductor) of the tempering element.
  • the method according to the invention also has the described advantages of the device according to the invention.
  • the method according to the invention is preferably carried out by means of the device according to the invention and/or a preferred embodiment.
  • the device according to the invention is preferably designed to carry out the method according to the invention and/or a preferred embodiment.
  • thermal three-way valve and “temperature control element” are used synonymously unless otherwise stated.
  • a thermal three-way valve is a temperature control element for controlling the temperature of sample vessels or the samples contained therein.
  • the device comprises a plurality of tempering elements.
  • Tempering elements are at least partially electrically connected in series and can be controlled together.
  • the tempering elements are preferably arranged adjacent to one another and can be controlled together.
  • tempering elements arranged in a line are also referred to as a tempering series.
  • the tempering elements of a tempering series can be electrically controlled individually or are electrically connected in series and controlled together.
  • a temperature control row is arranged in thermal contact with a plurality of sample carrier receptacles.
  • each linear, parallel temperature control row is provided, each of which is arranged in contact with a large number of sample carrier receptacles.
  • Each sample carrier receptacle is arranged in thermal contact with at least one adjacent temperature control element of a temperature control row. This arrangement results in the advantage of short thermal paths.
  • the device preferably has at least one edge element which comprises at least one Peltier module and is in thermal contact with at least one sample carrier holder. This results in the advantage that each sample carrier holder is in thermal contact with two Peltier modules and can therefore be tempered more easily and homogeneously.
  • the sample carrier receptacles are also arranged linearly and parallel to the temperature control rows, so that each sample carrier receptacle is arranged between two temperature control elements of two adjacent temperature control rows or between a temperature control row and an edge element.
  • control of the tempering elements is carried out in such a way that the sample carrier receptacles are each arranged in contact with two hot sides of the tempering elements or two cold sides of the tempering elements.
  • This special arrangement of the temperature control elements between the sample carrier holders means that a linear row of sample carrier holders is heated, while the row next to it can be cooled. This has the advantage that the heat only has to be transported over a minimal distance and both sides of the Peltier modules can be used to their full effect. By coupling the temperature control elements and the sample carrier holders in this way, the energy requirement is significantly reduced.
  • the thermal conductor of the thermal three-way valve is designed as a mechanical holder for the sample carrier holders and temperature control elements.
  • the Peltier modules can be connected to the thermal conductor either in a material-locking manner or via a thermal interface material.
  • the thermal conductor is preferably made of at least one material with a good thermal conductivity > 3 W/m*K, preferably > 10 W/m*K, particularly preferably > 50 W/m*K. Suitable materials are, for example, copper and copper alloys, aluminum and aluminum alloys, brass, graphite, silicon and ceramics, e.g. based on Al 2 O 3 .
  • thermal conductors preferably consist of various electrically conductive and non-conductive layers, for example as an electrical circuit board / circuit board. This has the advantage that the temperature control element can be easily formed from two Peltier modules as a single unit and the structure is simplified.
  • the thermal conductor can preferably also be designed so that it functions as a heat exchanger fin and has a fluid flowing around it if necessary.
  • the thermal conductor can be designed as a component of the Peltier modules, e.g. as a ceramic plate coated with copper on both sides, which thermally connects the two Peltier modules and electrically insulates them from each other.
  • several Peltier modules are applied to the thermal conductor.
  • the thermal conductor can be designed as a heat pipe.
  • the heat pipe is preferably designed such that it is integrated into the holder, particularly preferably between the two Peltier modules of the thermal three-way valve.
  • the sample carrier holders are preferably designed for the highest possible dynamics of temperature changes. A small volume is advantageous here, for example due to a low wall thickness.
  • the sample carrier holder is preferably made of a material with a low thermal mass (product of density and heat capacity of the material).
  • the device comprises at least one heating element.
  • the heating element is provided in direct or indirect thermal connection with the sample vessels.
  • the device comprises a heating element and a temperature sensor, particularly preferably the heating element is designed as a temperature sensor.
  • the heating element device can be heated to an initial temperature in parts or completely. This has the advantage that, if the initial temperature is well below the target temperatures required for the polymerase chain reaction, faster heating can be achieved using the temperature control elements, as the heating element can also supply additional thermal energy directly to the sample vessel and heat it to the target temperature.
  • the heating element is designed to completely enclose the sample vessel, and the sample carrier holder is particularly preferably designed as a heating element. This ensures direct thermal contact.
  • the heat supplied to or removed from a sample is determined in each temperature cycle by measuring the temperature change over time with the temperature sensor and measuring the heating power of the heating element and/or the temperature control element.
  • This in-situ heat quantity measurement determines the heat absorption of the individual sample vessels from the thermal energy supplied or removed and the time course of the heating or cooling during each cycle. If the thermal energy supplied changes, or the time constants of the heating or cooling change, it can be concluded that the sample composition has changed and thus the time course of the chemical reaction and thus the reaction state. It can be helpful for this to be done if an additional temperature sensor in the form of a thermocouple is integrated into the sample vessels. This has the advantage that both the heating and cooling processes of the individual sample vessels can be controlled very precisely. In-situ monitoring of the sample is therefore possible.
  • an in-situ analysis preferably an optical analysis of the sample, is carried out simultaneously with the method steps.
  • This has the advantage that the reaction in the reaction vessel can be monitored and in the polymerase chain reaction the DNA content in the sample can be determined in-situ and the usual subsequent, time-consuming agarose gel electrophoresis can be eliminated.
  • the samples are heated at a heating rate of more than 10 Kelvin/second, preferably more than 15 Kelvin/second.
  • the samples are preferably cooled at a cooling rate of more than -5 Kelvin/second, preferably more than -10 Kelvin/second.
  • the object of the invention is also achieved by a manufacturing method according to claim 16 for producing a device for carrying out a polymerase chain reaction according to one of the embodiments of the invention described above.
  • the invention is particularly suitable for chemical, biochemical and biological reactors and laboratory reactors for chemical synthesis or for carrying out biotechnological processes, especially in batch or fed-batch operation but also for parallel synthesis in combinatorial chemistry or drug research.
  • Fed-batch processes are synthesis or production processes in which the reactor is started with a small initial volume. As soon as the essential reactant substance is used up or growth-limiting concentrations of waste materials are reached, either fresh reactant substance or a specially formulated solution is added periodically or continuously until the maximum working volume is reached. With fed-batch operation, the synthesis rate or yield can be increased and the product concentrations can be increased.
  • Figure 1 shows a first embodiment of a device 1 according to the invention for carrying out a polymerase chain reaction.
  • the device comprises two sample carrier holders 6a, 6b for holding sample vessels (not shown).
  • the device is also designed with a thermal three-way valve as tempering elements 7 and two edge elements 5a, 5b.
  • the thermal three-way valve transfers heat between three thermal interfaces. Heat can be added to or removed from each interface.
  • the thermal three-way valve as a temperature control element 7 comprises two Peltier modules 4a, 4b and a thermal conductor 8 in between as a mechanical holder.
  • the thermal conductor can dissipate heat to the environment or absorb it from the environment or serve to conduct heat between the two Peltier modules 4a, 4b.
  • the thermal interfaces are each an interface to the neighboring sample carrier holders in thermal contact (first and second thermal interface) and a third thermal interface via the thermal conductor to the environment.
  • the sample carrier holders 6a, 6b, the two edge elements 5a, 5b and the temperature control element 7 are arranged in a holder.
  • the holder comprises the thermal conductor 8 and a base plate 9.
  • the two Peltier modules 4a, 4b in the tempering element 7b are applied to the thermal conductor 8 of the holder in such a way that the Peltier modules 4a, 4b and the thermal conductor 8 located between them can form a thermal three-way valve.
  • the edge elements 5a, 5b each comprise a Peltier module 15a, 15b in thermal contact with a sample carrier holder.
  • each sample carrier holder is in thermal contact with two Peltier modules 4a, 4b, 15a, 15b and can therefore be tempered more easily and homogeneously.
  • edge elements 5a, 5b with the Peltier modules 15a, 15b are also designed as thermal three-way valves in the elongated form, as shown in Figure 10 described.
  • Figure 2 shows the heat flow in the schematic embodiment according to Figure 1 .
  • the left sample carrier holder 6a is cooled and the right sample carrier holder 6b is heated.
  • the tempering element 7 acts as a thermal diode, the cold side of which is in contact with the sample carrier holder 6a and the hot side of which is in contact with the sample carrier holder 6b.
  • the tempering element 7 thus conducts heat away from the sample carrier holder 6a towards the sample carrier holder 6b. The heat flow thus occurs from the sample carrier holder 6a to the sample carrier holder 6b.
  • the edge element 5a is arranged in contact with the sample carrier holder 6a.
  • the edge element 5a is arranged with the cold side on the sample carrier holder 6b and thus conducts heat away from the sample carrier holder 6b.
  • the edge element 5b is arranged in contact with the sample carrier holder 6b.
  • the edge element 5b is arranged with the hot side on the sample carrier holder 6b and thus transports heat to the sample carrier holder 6b.
  • Figure 3 shows a schematic representation of another embodiment in plan view.
  • the device is designed with a plurality of tempering elements 7 in the form of seven tempering rows, identified by way of example as 7a, 7b, 7c.
  • the tempering elements of a tempering row are electrically connected in series and can be controlled together.
  • the tempering rows 7a, 7b, 7c can be controlled individually and independently of one another.
  • tempering rows are in this case linear and arranged parallel to one another.
  • Seven tempering rows identified by way of example as 7a, 7b, 7c, and two edge elements 5a, 5c are provided.
  • the sample carrier holders identified by way of example as 6a, 6b, 6c, are provided between the linear, parallel tempering rows 7a, 7b, 7c.
  • the sample carrier holders 6a, 6b, 6c are also linear, arranged in parallel and in this case form a 12 ⁇ 8 matrix.
  • the edge elements 5a, 5c each comprise a Peltier module and are in thermal contact with the outer sample carrier receptacles of the matrix. The edge elements 5a, 5c thus thermally seal the device off from the outside.
  • Each temperature control row 7a, 7b, 7c is thus in contact with several sample carrier holders 6a, 6b, 6c, in this case with 24 sample carrier holders 6a, 6b, 6c each.
  • Each sample carrier holder 6a, 6b, 6c is arranged in thermal contact with at least two adjacent temperature control rows 7a, 7b, 7c.
  • Each temperature control row 7a, 7b, 7c is thus in contact with two sample carrier holders 6a, 6b in rows.
  • Each temperature control row for example designated as 7.1, is thus in contact with 12 sample carrier holders in columns, for example designated as 6.1, 6.2, 6.3.
  • the temperature control elements of the temperature control rows 7a, 7b, 7c act as a thermal diode between two sample carrier holders 6a, 6b that are adjacent in rows.
  • the two sample carrier holders 6a, 6b are each arranged at the two oppositely acting ends of this thermal diode.
  • Figure 4 shows another embodiment analogous to Figure 1 with an additional heating element 10.
  • the heating element 10 is arranged in direct thermal connection with the sample carrier holder 6 by enveloping the sample carrier holder 6 on the outside.
  • the heating element can be used to preheat the device by heating the device partially or completely to a starting temperature. This has the advantage that at a starting temperature in the range just below the temperature required for the polymerase chain reaction, Target temperatures can be heated more quickly using the tempering elements, since only the difference up to the target temperature needs to be heated.
  • a rectangular sample carrier holder 6 is shown, which has flat outer surfaces.
  • the heating element 10 is designed to lie flat against these flat outer surfaces.
  • an embodiment is shown in which the sample carrier holder 6 is designed as a heating element 10.
  • the heating element 10 is provided on both sides between the tempering element 7 and the sample carrier holder 6.
  • the heating element 10 is provided in the areas in which the sample carrier holder 6 is not in contact with the tempering element 7.
  • Figure 6 shows a schematic representation of the method according to the invention in the partial figures a and b.
  • the method according to the invention for carrying out a polymerase chain reaction is carried out using a device with at least two sample carrier holders 6a, 6b for holding sample vessels and at least one tempering element 7. Two edge elements 5a, 5b are also provided.
  • the device is as described Figure 4 described.
  • the device is preheated or tempered to a starting temperature, in this case in the range of 35 - 50° Celsius.
  • the starting temperature enables faster heating to the various target temperatures in the process.
  • the temperature must be low enough that cooling by dissipating heat is still possible.
  • the tempering element 7 acts as a thermal diode and the first and second sample carrier holders 6a, 6b are arranged at the thermally opposite ends of the thermal diode.
  • Partial figure 6a shows the state in which the left sample carrier holder 6a is heated and the right sample carrier holder 6b is cooled.
  • the heat flow, shown by the arrows, of the tempering element 7 acting as a thermal diode occurs from the right sample carrier holder 6b to the left sample carrier holder 6a.
  • Partial figure 6b shows the state in which the left sample carrier holder 6a is cooled and the right sample carrier holder 6b is heated.
  • the heat flow, shown by the arrows, of the tempering element 7 acting as a thermal diode occurs from the left sample carrier holder 6a to the left sample carrier holder 6b.
  • Figure 7 shows a schematic representation of another embodiment of the invention.
  • the device comprises two sample carrier holders 6a, 6b for holding sample vessels (not shown).
  • the device is also designed with a tempering element 7 and two edge elements 5a, 5b.
  • the Sample carrier holders 6a, 6b, the two edge elements 5a, 5b and the tempering element 7 are arranged in a holder.
  • the holder comprises a thermal conductor 8 and a base plate 9.
  • the two Peltier modules 4a, 4b are attached to the thermal conductor 8 of the holder in a material-locking manner or by means of a thermal interface, so that the Peltier modules 4a, 4b and the thermal conductor 8 in between form a thermal three-way valve.
  • the Peltier modules 4a, 4b each comprise three elements made of two thermoelectric materials, for example ( Bi,Sb) 2 (Te,Se) 3 , which are alternately n- and p-conductive.
  • the three elements made of the two thermoelectric materials are electrically connected to one another in a meandering shape in series via electrical conductors and are arranged parallel to the heat flow.
  • the thermal conductor 8 is in this case made of an electrically non-conductive ceramic, e.g. Al 2 O 3 or AIN with a thermal conductivity of > 20 W/m*K or > 150 W/m*K in the temperature range of 273K - 373 K.
  • an electrically non-conductive ceramic e.g. Al 2 O 3 or AIN with a thermal conductivity of > 20 W/m*K or > 150 W/m*K in the temperature range of 273K - 373 K.
  • the temperature control element 7 can be easily formed from two Peltier modules without a substrate directly on the thermal conductor 8 of the holder and does not have any further elements, such as additional electrical insulation, with the corresponding thermal mass and the additional thermal interfaces, which would disturb the heat transport.
  • the edge elements 5a, 5b each comprise a Peltier module 15a, 15b, wherein the Peltier modules are also mounted without additional electrical insulation 8.1, 8.2 of the holder.
  • FIG 8 shows a schematic representation of another embodiment analogous to Figure 1 with an additional temperature sensor 10, which in this case also acts as a heating element.
  • the temperature sensor 10 is arranged in direct thermal connection with the sample carrier holder 6 by enveloping the sample carrier holder 6 on the outside.
  • Figure 9 shows a schematic representation of another embodiment of the invention in plan view.
  • the device is designed with a plurality of tempering elements, identified by way of example as 7a, 7b, 7c.
  • the tempering elements 7a, 7b, 7c can be controlled individually electrically.
  • the tempering elements 7a, 7b, 7c are arranged in rows/lines, running parallel, and form a 12 ⁇ 7 matrix.
  • the sample carrier holders identified by way of example as 6a, 6b, 6c, are provided between the matrix-shaped tempering elements 7a, 7b, 7c.
  • the sample carrier holders 6a, 6b, 6c are also arranged in a linear, parallel manner and in this case form a 12 ⁇ 8 matrix.
  • Edge elements 5a, 5c are provided on two outer edges.
  • the edge elements 5a, 5c each comprise a Peltier module and are in thermal contact with the outer sample carrier receptacles of the matrix. The edge elements 5a, 5c thus thermally seal the device off from the outside.
  • Each temperature control element 7a, 7b, 7c is in thermal contact with two sample carrier holders 6a, 6b, 6c.
  • the temperature control element 7a, 7b, 7c represents a thermal diode.
  • the two sample carrier holders 6a, 6b are each arranged at the two ends of the temperature control elements of this thermal three-way valve.
  • FIG 10 shows a schematic representation of a further embodiment of the invention with an elongated thermal three-way valve as a temperature control element 7.
  • the thermal three-way valve comprises two Peltier modules 15a.1, 15a.2, 15b.1, 15b.2 and a thermal conductor.
  • the two Peltier modules 15a.1, 15a.2, 15b.1, 15b.2 are attached to the same side of the thermal conductor as a mechanical holder.
  • the device comprises two sample carrier holders 6a, 6b, a tempering element 7 in the form of two edge elements 5a, 5b.
  • the two Edge elements are connected to each other via the thermal conductor 8 and form a thermal three-way valve.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Clinical Laboratory Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Mechanical Engineering (AREA)
  • Thermal Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
EP22210225.3A 2022-11-29 2022-11-29 Dispositif et procédé pour effectuer une trempe précise et précise de substances chimiques pour la synthèse, l'homogénéisation et le diagnostic Pending EP4378585A1 (fr)

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EP22210225.3A EP4378585A1 (fr) 2022-11-29 2022-11-29 Dispositif et procédé pour effectuer une trempe précise et précise de substances chimiques pour la synthèse, l'homogénéisation et le diagnostic

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EP22210225.3A EP4378585A1 (fr) 2022-11-29 2022-11-29 Dispositif et procédé pour effectuer une trempe précise et précise de substances chimiques pour la synthèse, l'homogénéisation et le diagnostic

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0275829A2 (fr) * 1987-01-19 1988-07-27 Agrogen-Stiftung Dispositif de congélation à basse température d'éprouvettes à matériaux biologiques disposées dans des récipients
US20070289314A1 (en) * 2006-06-14 2007-12-20 Fluke Corporation Temperature calibration device having reconfigurable heating/cooling modules to provide wide temperature range
DE102007057651A1 (de) * 2007-11-28 2009-06-18 Nickl, Julius, Dr. Thermisches Schwingen zum zyklischen Temperieren von biologischen medizinischen und chemischen Proben
DE102010003365A1 (de) 2010-03-26 2011-09-29 Micropelt Gmbh Vorrichtung zur Durchführung der PCR und PCR-Verfahren
GB2604915A (en) * 2021-03-19 2022-09-21 Bg Res Ltd An apparatus and associated methods for thermal cycling

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0275829A2 (fr) * 1987-01-19 1988-07-27 Agrogen-Stiftung Dispositif de congélation à basse température d'éprouvettes à matériaux biologiques disposées dans des récipients
US20070289314A1 (en) * 2006-06-14 2007-12-20 Fluke Corporation Temperature calibration device having reconfigurable heating/cooling modules to provide wide temperature range
DE102007057651A1 (de) * 2007-11-28 2009-06-18 Nickl, Julius, Dr. Thermisches Schwingen zum zyklischen Temperieren von biologischen medizinischen und chemischen Proben
DE102010003365A1 (de) 2010-03-26 2011-09-29 Micropelt Gmbh Vorrichtung zur Durchführung der PCR und PCR-Verfahren
GB2604915A (en) * 2021-03-19 2022-09-21 Bg Res Ltd An apparatus and associated methods for thermal cycling

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIANBO QIU: "Temperature Control for PCR Thermocyclers Based on Peltier-Effect Thermoelectric Proceedings of the 2005 IEEE", ENGINEERING IN MEDICINE AND BIOLOGY 27TH ANNUAL CONFERENCE, 1 September 2005 (2005-09-01)

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