EP3524353A1 - Dispositif de thermocyclage d'échantillons biologiques, instrument de surveillance le comprenant et procédé de thermocyclage d'échantillons biologiques à l'aide d'un tel dispositif - Google Patents

Dispositif de thermocyclage d'échantillons biologiques, instrument de surveillance le comprenant et procédé de thermocyclage d'échantillons biologiques à l'aide d'un tel dispositif Download PDF

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Publication number
EP3524353A1
EP3524353A1 EP18156326.3A EP18156326A EP3524353A1 EP 3524353 A1 EP3524353 A1 EP 3524353A1 EP 18156326 A EP18156326 A EP 18156326A EP 3524353 A1 EP3524353 A1 EP 3524353A1
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EP
European Patent Office
Prior art keywords
heat exchanger
heat
mount
fluid
primary
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18156326.3A
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German (de)
English (en)
Inventor
Paul Federer
Sven Ebert
Pius Hermann
Stefan VOLLENWEIDER
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.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics 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 F Hoffmann La Roche AG, Roche Diagnostics GmbH filed Critical F Hoffmann La Roche AG
Priority to EP18156326.3A priority Critical patent/EP3524353A1/fr
Publication of EP3524353A1 publication Critical patent/EP3524353A1/fr
Withdrawn legal-status Critical Current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
    • B01L2200/14—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
    • B01L2300/18—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
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B01L2300/1844—Means for temperature control using fluid heat transfer medium using fans
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B01L2300/185—Means for temperature control using fluid heat transfer medium using a liquid as fluid

Definitions

  • the present invention relates to the technical field of sample analysis, such as the analysis of biological samples, and further to the technical field of high throughput analysis of biological samples.
  • the present invention is directed to a device for thermocycling biological samples, to an instrument for simultaneously monitoring multiple nucleic acid amplification reactions during thermocycling biological samples by means of such device, and also to a method for thermocycling biological samples using such device for thermocycling biological samples.
  • thermocycling structure or device also referred to as thermocycler or thermal cycler
  • thermocycler or thermal cycler for performing chemical and/or biological reactions, such as, for example, Polymerase Chain Reactions (PCR)
  • thermocycling device can be provided as internal part of a laboratory instrument, and wherein such thermocycling device usually includes at least a sample mount, a heat pump with a heat sink, as well as a control unit for controlling the heating and cooling of the heat pump during thermocycling.
  • PCR Polymerase Chain Reactions
  • the present invention also relates to an instrument for simultaneously monitoring multiple nucleic acid amplification reactions during thermocycling biological samples by means of such thermocycling device, wherein the monitoring instrument further comprises an excitation light source for applying excitation energy to the nucleic acid amplification reactions and a sensor for simultaneously detecting light emitted from the multiple nucleic acid amplifications, and moreover to a respective thermocycling method using such a thermocycling device.
  • sample and “biological sample” refer to material(s) that may potentially contain an analyte of interest, wherein the biological sample can be derived from any biological source, such as a physiological fluid, including blood, saliva, ocular lens fluid, cerebrospinal fluid, sweat, urine, stool, semen, milk, ascites fluid, mucous, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cultured cells, or the like, and wherein the sample can be suspected to contain a certain antigen or nucleic acid.
  • a physiological fluid including blood, saliva, ocular lens fluid, cerebrospinal fluid, sweat, urine, stool, semen, milk, ascites fluid, mucous, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cultured cells, or the like, and wherein the sample can be suspected to contain a certain antigen or nucleic acid.
  • PCR Polymerase Chain Reaction
  • dPCR digital PCR
  • multiplex PCR multiplex PCR
  • thermocycling can be utilized to provide heating and cooling of reactants in a sample provided inside a reaction vessel for amplifying such DNA or RNA segments
  • laboratory instruments including thermocyclers are commonly used in order to achieve an automatic procedure of diagnostic assays based on PCR, in which, during a PCR conduct, the liquid PCR-samples have to be heated and cooled to differing temperature levels repeatedly and have to be maintained for a certain amount of time at different temperature plateaus.
  • thermal uniformity throughout a thermal block of a thermal cycler should be maintained, so that different sample wells can be heated and cooled uniformly to obtain uniform sample yields between samples wells.
  • a specific target nucleic acid is amplified by a series of reiterations of a cycle of steps in which nucleic acids present in the reaction mixture are (a) denatured at relatively high temperatures, for example at a denaturation temperature of more than 90° C, usually about 94°-95°C, for separation of the double-stranded DNA, then (b) the reaction mixture is cooled down to a temperature at which short oligonucleotide primers bind to the single stranded target nucleic acid, for example at an annealing temperature of about 52°-56° C for primer binding at the separated DNA strands in order to provide templates (annealing), and, thereafter, (c) the primers are extended/elongated using a polymerase enzyme, for example at an extension temperature at about 72°C for creation of new DNA strands, so that the original nucleic acid sequence has been replicated.
  • a polymerase enzyme for example at an extension temperature at about 72°C for creation of new DNA strands,
  • thermocycling device for PCR
  • thermocycling devices for amplifying DNA segments by means of PCR basically consist of a mount for receiving the samples, often also referred to as a sample tempering mount, and a heat pump attached to the mount, wherein the combination of mount and heat pump can also be referred to as heat block or thermal block.
  • the heat pump often provided in the form of a thermoelectric device or thermoelectric cooler (TEC), for example in the form of a Peltier element, is usually used for active heating and cooling of the mount and, thus, for actively controlling the temperature provided to the samples.
  • TEC thermoelectric device
  • Peltier element for example in the form of a Peltier element
  • TECs are solid-state heat pumps usually made from semiconductor materials sandwiched between ceramic plates, wherein an amount of heat pumped is proportional to the amount of current flowing through the TEC, resulting in increased temperature control, wherein, by reversing the current, TECs can function as heaters or coolers, which is highly useful for thermocycling at different temperatures.
  • TECs in general require some kind of heat dissipation means, such as a heat sink thermally coupled to the TEC, to dissipate the heat away from the TEC and, for example, into the ambient environment, which heat sinks are often additionally provided with a fan used as air cooling means in order to facilitate heat dissipation of the heat sink to the ambient air.
  • a heat sink thermally coupled to the TEC
  • WO 2006/105919 A1 discloses a device for the simultaneous thermocycling of multiple samples, which device basically comprises a mount for receiving the samples, a heat pump attached to the mount, and a heat sink, wherein a so-called thermal base in the form of a vapor chamber component using Vapor Chamber Technology (“VC-Tech”) is provided in between the heat pump and the heat sink in thermal contact therewith.
  • VC-Tech Vapor Chamber Technology
  • Such thermal base provides an improved spreading of heat across its entire cross section area in order to provide a high thermal conductivity between the heat pump and the heat sink.
  • the heat dissipation capabilities of the device are limited by the heat transfer properties of the heat sink.
  • fans can be provided in order to improve the heat transfer abilities of the heat sink.
  • heat sink designs which are usually cooled by air with a fan are not only noisy, large and heavy but also mandatorily determine a direction of the cooling air flow in close proximity to the mount and, thus, in close proximity to the sample, which is not desired and, thus, require counter measures to direct the air flow further away from the sample.
  • the mounts of thermocycler are usually made of a solid material which requires a smart overall thermal design in order to achieve a superior thermal homogeneity of the mount due to the fact that already small temperature differences on the cooling side of the mount result in thermal inhomogeneity on the sample receiving side of the mount.
  • thermocyclers use mostly forced air, extruded heat sinks and sometimes also heat spreaders between the heat sink and the bottom side of the heat pump, for example in the form of thermal interface plates, thermal interface grease, or the above mentioned vapor chamber technology, wherein such heat sinks can only provide limited heat transfer from the heat sink's fin surfaces into the cooling air, wherein a maximizing of heat transfer rates generally results in large scale heat sinks and, thus, in an increased size and weight of the thermocycler.
  • a heat exchange setup is rather stiff and inflexible, since such large-sized heat sink needs to be arranged directly underneath the heat pump and in almost direct connection with its bottom side.
  • mount heating/cooling is based on thermal conductance
  • a homogeneous and/or at least symmetric placement of thermal heating and cooling elements such as the generally used TECs
  • the prior art suggestions as presented above can not fulfill the needs of users nowadays and, thus, do not provide satisfying solutions. Therefore, the general need exists these days in the present technical field to provide a device for simultaneous thermocycling biological samples with a further improved heating/cooling performance in order to make diagnostic assays a lot faster and, thus, cheaper to perform while maintaining or even improving precision as well as efficiency.
  • thermocycling biological samples can be a thermocycler or thermocycler unit for the simultaneous thermocycling of multiple samples to perform multiple nucleic acid amplification reactions, wherein such device can be an internal or integral part of a laboratory instrument, such as an analytical instrument or the like, and more particularly wherein such device can be provided inside a housing of such instrument.
  • the inventive device comprises a mount for receiving the biological samples, a heat pump for heating and cooling the mount, the heat pump being thermally coupled to the mount, a heat sink, and a control unit for controlling the thermocycling of the biological samples.
  • the combination of mount, heat pump and heat sink can also be referred to as thermal block unit of the inventive device.
  • the heat sink of the device comprises a primary heat exchanger with an inner space perfused by a heat exchanging fluid, and a secondary heat exchanger, wherein the primary heat exchanger is thermally coupled to the heat pump, and wherein the secondary heat exchanger is thermally coupled to the heat pump through the primary heat exchanger.
  • the heat exchanging fluid can be a heat exchanging liquid, such as a water-based cooling liquid medium, for example a mixture of water and ethanol, wherein the inner space of the primary heat exchanger provides a cavity where the liquid cooling medium can flow through for heat transfer to the secondary heat exchanger.
  • a heat exchanging liquid such as a water-based cooling liquid medium, for example a mixture of water and ethanol
  • the heat sink of the present invention which is used for heat dissipation of the heat pump, is not implemented in the form of a commonly known heat sink with fins, but is implemented in the form of a combination of primary heat exchanger provided at the heat pump, i.e.
  • the mount tempering can be operated at optimum conditions, e.g.
  • the secondary heat exchanger can be arranged well away from the PCR application site and in various orientations, the secondary heat exchanger can be arranged in a flexible manner in numerous locations within, at or outside of a thermal cycler, as desired.
  • the mount for receiving the biological samples can be implemented as a mount comprising at least one flat surface or, alternatively, a surface geometry with a plurality of wells, i.e. with a structured upper side comprising recesses in order to provide a certain well geometry for receiving reaction vessels, i.e. for receiving either one or a plurality of single reaction vessels or a plurality of reaction vessels combined into a multi-well plate or the like.
  • the surface of the mount can have a curved shape, and is preferably suitable for use with thermal interface material.
  • the same can be received in the well geometry of the mount, wherein the mount as well as the respective multi-well plate can provide, for example, 6, 12, 24, 48, 96, 384 or 1536 sample wells, or even more.
  • the mount can be a mount with a flat upper side, i.e.
  • the mount can substantially be a plate for receiving, on its surface, a cartridge, a slide or any other kind of consumable comprising the biological samples, or a microfluidic device comprising one or more flow channels connected to an array of sample wells for receiving the biological samples.
  • the mount can comprise either a flat lower side, or alternatively a structured lower side, wherein the lower side of the mount can be integrated with a heat exchanger or with an additional heating/cooling element.
  • the mount of the present invention can use Vapor Chamber Technology ("VC-Tech”), for example in the form of a compact liquid heat exchanger provided within the mount, such as a vapor chamber, i.e.
  • a heat pipe for heat spreading and isothermalizing in order to be able to absorb or provide required thermal energy
  • a vapor chamber is generally able to transport heat from a heat source to a heat sink with a very small temperature gradient.
  • the use of VC-Tech in the mount of the present invention can achieve superior thermal homogeneity, even in case of undesired uneven thermal heating and/or cooling.
  • fins within the vapor chamber a more effective heat transfer from liquid to the solid can be achieved, and the high thermal capacity of water based cooling medium fins allows for a smaller heat transfer surface and, therefore, miniaturized vapor chamber design.
  • the mount is able to distribute any applied temperature much more evenly and rapidly to or from the reaction vessels, i.e. the samples undergoing PCR.
  • a superior vessel-to-vessel uniformity can be provided, which can ensure consistent results over all reaction vessels, wherein a fast transient response of all vessels on the same temperature level right after reaching the target plateau temperature allows a reduction of the plateau time and speeding up the whole PCR process.
  • a heat pump is generally to be understood as a component that moves heat from one location, i.e. the heat source, to another location, usually in the form of a sink or heat sink.
  • a heat pump may be thought of as a "heater” if the objective is to warm the mount, or as a “cooler” if the objective is to cool the mount.
  • thermoelectric heating or cooling by means of the Peltier effect is used to create a heat flux.
  • thermoelectric cooler preferably in the form of a Peltier element
  • TEC preferably in the form of a Peltier element
  • TEC is used as a solid-state active heat pump with consumption of electrical energy, depending on the direction of the current, which heat pump transfers heat from its one side to the other, for example in order to provide heat to the mount during heating phases, such as during PCR denaturation, or to retract heat from the mount during cooling phases, such as during PCR annealing, and provide the heat to a sink or heat sink.
  • a heat sink in the sense of the present invention is to be understood as a passive heat exchanging structure that transfers heat or cold generated by an electronic or a mechanical component, such as the above described heat pump, to a fluid medium, often air or a liquid coolant, where it is dissipated away from the heat pump, thereby allowing regulation of the heat pump's temperature at optimal levels.
  • Heat sinks are often used with components where the heat dissipation ability of the component itself is insufficient to moderate its temperature, or at least insufficient to moderate its temperature within the desired time frame, as is often the case with heat pumps in PCR applications.
  • a heat sink in the classical sense is designed to maximize its surface area in contact with the cooling medium surrounding it, such as air.
  • the heat sink in accordance with the present invention comprises a plurality of heat exchangers, i.e. at least a proximate or primary heat exchanger and a remote or secondary heat exchanger, with both heat exchangers being able to transfer heat or cold to a fluid medium, such as a heat exchanging fluid, for example in the form of a liquid coolant, to dissipate the heat or cold away from the source, i.e. the heat pump.
  • a fluid medium such as a heat exchanging fluid, for example in the form of a liquid coolant
  • the heat exchanging fluid perfuses an inside or inner space of the primary heat exchanger, wherein the "inner space” defines a space internal to the primary heat exchanger in or through which the heat exchanging fluid can flow/stream.
  • the primary heat exchanger is based on a fluid heating and/or cooling system, such as a liquid cooling system, wherein the fluid heating and/or cooling system enables a low noise design of the heat sink, which is light in weight and comprises a compact design, but still allows for efficient heating/cooling.
  • the thermal capacitance of the used fluid and/or the design of the primary heat exchanger achieve an optimized heat transfer to and from the heat pump and, thus, to and from the mount.
  • the mount of the device for thermocycling biological samples is connected to the heat pump and/or the heat pump is connected to the primary heat exchanger, for example by means of a releasable force-fit connection, such as clamping.
  • the mount, the heat pump and the primary heat exchanger are clamped together in order to form a tight connection therebetween, thereby constituting a thermal block unit as already mentioned above.
  • a clamping mechanism can be provided as part of the inventive device, which can be implemented in the form of a threaded connection, wherein, for example, threaded bolts or screws are guided through through-holes provided inside the primary heat exchanger and through-holes or gaps within the heat pump and are screwed into respective counterparts, such as threaded holes provided in the mount, wherein the screwing connection between bolts/screws and mount can be further fixed by means of adhesive or the like.
  • the bolts/screws can be further provided with disc springs or the like, fixed by means of screw heads or additional screw nuts, in order to provide a distinctive clamping pressure on the thus connected components of the inventive device by means of a distinct torque to be applied onto the screw nuts.
  • the secondary heat exchanger is thermally connected to the primary heat exchanger by means of a heat exchanging fluid circulation system for circulating the heat exchanging fluid between the primary heat exchanger and the secondary heat exchanger.
  • a heat exchanging fluid circulation system for circulating the heat exchanging fluid between the primary heat exchanger and the secondary heat exchanger.
  • the secondary heat exchanger can alternatively or additionally be thermally connected to the primary heat exchanger by means of a heat-transfer component such as a heat pipe or the like, which can further improve the function of the heat sink in regard to a fast control of the temperature of the heat pump.
  • a heat-transfer component such as a heat pipe or the like
  • the inner space or cavity of the primary heat exchanger can provide a location where the heat is collected and transferred to the heat pipe, to be transported to the secondary heat exchanger.
  • the circulation system can comprise a tubing connection between the primary heat exchanger and the secondary heat exchanger for circulatory transfer of the heat exchanging fluid between the primary heat exchanger and the secondary heat exchanger.
  • the tubing connection is established by means of one or several tubes, supporting the arrangement of the secondary heat exchanger spaced apart from the primary heat exchanger, wherein the tubing connection can be implemented in the form of a circular tubing connection in order to be able to discharge the heat exchanging fluid out of the inner space of the primary heat exchanger and towards the secondary heat exchanger, pass the heat exchanging fluid along the secondary heat exchanger, or also into an inner space provided inside the secondary heat exchanger, and recirculate the same to and into the primary heat exchanger.
  • the heat exchanging fluid for example a liquid cooling medium
  • the heat exchanging fluid can transport heat away from the primary heat exchanger and transfers it into the secondary heat exchanger for dissipation of the heat to ambient conditions at the location of the secondary heat exchanger which can be arranged outside the thermocycler, or for dissipation of the heat to adjacent laboratory infrastructure, for example a ventilation system, a cooling system or the like.
  • the fluid volume already provided inside the tubing system may already be regarded as an initial fluid reservoir.
  • at least one (additional) fluid reservoir accommodating heat exchanging fluid of a predetermined temperature can be provided as part of the circulation system, i.e. can be fluid-connected with the circulation system, or better with the tubing connection, which can be used, on demand, in case heat exchanging fluid of a certain temperature as stored inside the fluid reservoir can be used to heat or cool the heat exchanging fluid streaming inside the circulation system.
  • the circulation system can comprise a plurality of fluid reservoirs accommodating fluid of different predetermined temperatures. Accordingly, any such reservoir can be built as an extra volume in the liquid path provided by the circulation system.
  • the used tubes can be made of an inner layer of ethylene propylene diene monomer (EPDM) rubber and an outer layer of nitrile butadiene (NBR) rubber, preferably enforced with a synthetic mesh, or can be generally made of EPDM, NBR, fluorinated ethylenepropylene polymer (FEP), Polytetrafluoroethylene (PTFE), Polyvinyl chloride (PVC), polyethersulfone (PES), fluoroelastomer (FKM), silicone, or can also generally made of metal tubes or the like, or can additionally be jacketed by means of a heat isolating material.
  • EPDM ethylene propylene diene monomer
  • NBR nitrile butadiene
  • FEP fluorinated ethylenepropylene polymer
  • PTFE Polytetrafluoroethylene
  • PVC Polyvinyl chloride
  • PES polyethersulfone
  • FKM fluoroelastomer
  • silicone or can also generally made of metal tubes
  • the tubing connection can be established by flexible tubing, i.e. one or several flexible tubes or flexible pipes, in order for the secondary heat exchanger to be variably positioned in relation to the primary heat exchanger, for example far away from the primary heat exchanger and, thus, far away from the heat pump.
  • flexible tubing i.e. one or several flexible tubes or flexible pipes
  • the secondary heat exchanger can be provided within a housing of the instrument accommodating the thermocycler, such as an analytical instrument, and can be placed therein independently of the primary heat exchanger, it becomes possible to position the secondary heat exchanger, for example, near a front part of the inner space of the housing.
  • Such positioning makes it possible to unobstructedly suck cool ambient air, for example by means of a fan or the like, via a ventilation opening, a ventilation grille or the like, which is provided on the front side of the housing. Furthermore, the described variable positionability of the secondary heat exchanger independently from the primary heat exchanger results in the fact that the risk of warm air generated by neighboring laboratory appliances being sucked into the housing can be avoided due to the possibility of arranging the secondary heat exchanger in a location away from the warm air source, and the cooling efficiency of the thermal mount unit can be significantly improved.
  • the presently described improved cooling concept based on the possibility of a forced airflow input from the front side of the housing can be implemented by means of a forced input of air entering through a ventilation opening provided at the top and/or bottom of a loading flap of the housing, and is further supported by a hot air outlet, e.g. another ventilation opening, provided at the back side of the thermocycler in a respective suitable position.
  • a hot air outlet e.g. another ventilation opening
  • any kind of cooling fan provided for the heat sink can now be integrated directly with the thermocycler unit, and does not necessarily have to be provided integrally with the housing or the loading flap anymore, resulting in a fan integration within the housing's inner space, and directly at the thermocycler unit, achieving a significantly reduced noise level for the benefit of a user as well as a design advantage since the ventilation openings, i.e. the air supply, can be hidden anywhere in the housing.
  • thermocycler unit within the housing of an analytical instrument allows a free arrangement of the second heat exchanger as well as its respective fan, if any, around the thermocycler unit inside the housing.
  • the fan can sit directly at or on the secondary heat exchanger, making it an integral part of the thermocycler unit and, thus, resulting in the fact that the entire thermocycler unit is a secluded and, thus, interchangeable unit within the analytical instrument.
  • the presently described solution achieves sufficient heating/cooling performance in order to omit the provision of any kind of extruded heat sink element arranged directly underneath the TECs, sufficient air flow areas exists inside the housing, so that the fan does not have to arranged directly at the ventilation openings but can be arranged in a distance away from any ventilation opening. This is advantageous since such further distance from the housing, preferably supported by a certain deflection of air flow within the housing, helps to further reduce the mentioned noise level.
  • At least one fluid pump such as a liquid pump, is connected to the primary heat exchanger and the secondary heat exchanger for pumping the heat exchanging fluid and controlling the flow speed of heat exchanging fluid in the heat sink, i.e. in the previously described circulation system between the primary heat exchanger and the secondary heat exchanger.
  • the fluid pump of the device can be used to achieve fluid flow, and can be controllable, e.g. the pump performance as well as the direction of flow can be controlled.
  • the fluid pump can be arranged between the primary heat exchanger and the secondary heat exchanger, and can be connected within the circulation system, such as a connecting part within the tubing connection as described above, in order to be providing the function of pumping heat exchanging fluid from the primary heat exchanger to the secondary heat exchanger, and/or vice versa.
  • a heating or cooling capacity within the primary heat exchanger can be well controlled, wherein the addition of different temperature level fluid reservoirs as described above can further improve the controllability of the heating or cooling capacity of the heat sink, since the contents of such fluid reservoirs are very fast available and can be transported by means of the fluid pump into the primary heat exchanger.
  • a thermal coupling between the mount and the heat pump and/or between the heat pump and the primary heat exchanger is established by means of a thermal interface material, wherein any such thermal interface material can comprise at least one of a carbon based material, such as graphite, for example pure pyrolytic graphite, or graphene, a silicone compound, a phase change material and thermal grease, or a combination thereof.
  • any thermal coupling connection between components of the presently described device can be provided with such thermal interface material, in order to ensure a sufficient thermal conductivity at the contact surfaces of such components.
  • any heating or cooling component is thermally connected to its adjacent component or components by means of using thermal interface material as mentioned before, in order to enhance the thermal coupling between any of those coupled components.
  • the primary heat exchanger can be a so called solid-to-liquid heat exchanger, i.e. a heat exchanger in which heat is transferred between a solid object, such as the outer hull of the primary heat exchanger comprising an inner space, and a liquid such as one example of the heat exchanging fluid provided inside the inner space of the primary heat exchanger, wherein the primary heat exchanger in the form of a solid-to-liquid heat exchanger can be a compact liquid heat exchanger providing a compact design.
  • the inner space of the primary heat exchanger can comprise one or more projections for surface enlargement, such as fins, provided on the inner surface of the inner space of the primary heat exchanger and surrounded by the heat exchanging fluid, wherein the fins can be pin fins or swage fins, or any other suitable kind of respective surface enlarging projection.
  • the secondary heat exchanger can comprise a similar structure as the primary heat exchanger. Additionally, the secondary heat exchanger may also be provided with external fins, such as known from usual heat sinks.
  • the primary heat exchanger can consist of one or more parts made from copper or other suitable thermally conducting materials, such as aluminum or silver, wherein the solid parts of the primary heat exchanger constitute the parts made from thermally conducting material.
  • the part of the primary heat exchanger which is not directly connected to any heat producing components and/or the mount can consist of a thermally conducting material, but does not have to consist of such a thermally conducting material, which can improve the design and weight of the primary heat exchanger.
  • the primary heat exchanger can be designed with different layers of material, and the layers can be made of different material, for example one material for an upper layer or layers, and another material for lower layers.
  • the primary heat exchanger's side without contact to the mount or the heat pump can be made out of a plastic or polymer material without any thermal relevance.
  • a thickness of an interface side of the primary heat exchanger can be used as a thermal reservoir.
  • the primary heat exchanger can also comprise at least one through hole provided for allowing an assembly of the device in the manner of a thermally sandwiched structure, meaning that all components of the inventive device can be assembled to form a thermally sandwiched structure by means of respective through holes and respective connectors, such as screws or the like, in order to force the components of the device to be sandwiched together.
  • the same can comprise a temperature sensor for controlling its heat exchange rate, wherein the detection values of the temperature sensor can be used by a control unit or the like to counteract any undesired measured heat exchange rate values.
  • the secondary heat exchanger can comprise an inner space containing heat exchanging fluid pumped through its inner space, similar to the primary heat exchanger, wherein a heat exchange rate of the secondary heat exchanger can be controlled by means of a pump speed sensor which controls the speed of the fluid pumped through the inner space of the secondary heat exchanger, and/or a volume flow sensor, also referred to as fluid flow sensor, which controls the flow volume flowing through the secondary heat exchanger.
  • the fluid pump pumping the heat exchanging fluid through the secondary heat exchanger can be controlled to pump more or less fluid therethrough, in order to change the heat exchange rate to the desired level controlled by the pump speed sensor and/or the volume flow sensor.
  • the secondary heat exchanger can also interact with a working fluid for cooling the secondary heat exchanger, wherein the heat exchange rate of the secondary heat exchanger is controlled by means of a working fluid pump, meaning that the secondary heat exchanger can be connected to a working fluid by means of an interior channel, a working fluid pipe or the like, wherein the secondary heat exchanger can be heated and/or cooled not only indirectly by the heat exchanging fluid received from the primary heat exchanger or the fluid reservoirs within the circulation system, but can also be actively heated or cooled by means of the working fluid, which can be a cooling fluid or the like.
  • the secondary heat exchanger can interact with a fan and/or a radiator, in particular in case the secondary heat exchanger is provided with external fins or the like in order to enlarge the overall surface area of the secondary heat exchanger, wherein the heat exchange rate of the secondary heat exchanger is controlled by means of a fan speed sensor and/or a radiator temperature sensor.
  • another kind of fluid cooling structure or mechanism can also be provided for the secondary heat exchanger, or also another element with a different temperature in thermal connection with the secondary heat exchanger, for dissipation of heat. Accordingly, in case the secondary heat exchanger dissipates heat to ambient air by e.g.
  • a radiator or a fan, or to laboratory infrastructure such as a cooled water circuit or a different cold/heat reservoir
  • its heat exchange rate is monitored and can be affected by means of a respective control based on the monitoring results, such as provided directly from the secondary heat exchanger temperature sensor, or indirectly from the pump speed sensor, the volume flow sensor, the fan speed sensor and/or the radiator temperature sensor.
  • all components of the inventive device can be equipped with sensors, such as temperature sensors, flow sensors, vibration sensors, pressure sensors, etc.
  • the ambient air temperature can be monitored, for example by means of an ambient sensor monitoring, for example humidity and/or ambient temperature, wherein a temperature difference between ambient temperature and the temperature of the heat exchanging fluid can be monitored, in order to control heat transfer in an accurate manner.
  • the mount can be made of solid material, such as silver or aluminum, solid ceramic, a carbon based material or any combination thereof, and can function as a heat conductor for achieving thermal homogeneity, as also already described further above.
  • the mount can consist of several parts and materials, the mount can be made of solid thermal conductive material, such as copper, and can comprise a vapor chamber (VCM; 3D heat pipe) for transporting and distributing heat between the heat pump and the biological samples in a uniform manner.
  • VCM vapor chamber
  • the heat pump can be placed at almost any location of the mount, not necessarily between mount and primary heat exchanger, due to the excellent thermal conductivity of a vapor chamber.
  • a vapor chamber mount is described in WO 2013/075839 A2 .
  • the same can be one of a thermoelectric device, a resistive heater, or a combination thereof, wherein the thermoelectric device can be a Peltier element.
  • the resistive heater can be one of a ceramic heater, a heating foil, a heating cartridge or a wire wound heater.
  • the heat pump can be arranged between the mount and the primary heat exchanger, for example in a sandwiched manner, as already indicated above in relation to another specific embodiment of the present invention.
  • the heat pump can be arranged at least in part inside a recess provided in the mount, in more detail in a recess provided in the side of the mount opposite of the side receiving the biological samples.
  • a perimeter heater or edge heater can also be provided at the mount in order to minimize any thermal non-uniformity across the samples or any kind of sample holder.
  • Such perimeter heater can be positioned at the side of or on top of the mount and around a sample holder, such as a multi-well plate, to counter any heat loss at its edges.
  • a heated cover can be provided, designed to keep the reaction vessels closed during thermal cycling and to heat the upper portion of such vessels to prevent condensation and the like.
  • the inventive device can further comprise at least one sensor for controlling the temperature at the biological samples received in the mount, wherein such sensor can be a temperature sensor, a fan speed sensor or a fluid flow sensor, and wherein such sensor can be provided at the mount, at the heat pump, at the primary heat exchanger, and/or at the secondary heat exchanger.
  • a respective sensor at any of the components of the inventive device, the temperature of the biological samples during PCR can be monitored closely, and the heating/cooling function of the device can be controlled based on the measured temperature values of the samples, in order to regulate the different temperature plateaus of the PCR accurately and efficiently.
  • such sensor(s) for example temperature sensors
  • sensors in the heat exchangers such as fan speed sensors, temperature sensors, and other sensors are used to control their respective heating/cooling rate, wherein the heating/cooling power can be significantly varied by changing fan speed and/or fluid pump speed.
  • a heat sink temperature measurement can be carried out by the mentioned control algorithm, for linearizing thermal output power from the heat pump.
  • a device for PCR application for one or more samples wherein the samples are placed on a mount with or without well geometry, wherein the device includes the mount, one or more heater elements at any position of the mount, a primary heat exchanger, a secondary heat exchanger for exchanging heat to ambient air or laboratory infrastructure, and a connecting element between the primary and the secondary heat exchangers, for example in the form of cooling liquid tubes or the like, or, alternatively or additionally, a heat pipe, wherein the thermal layers of the device, i.e. its components, can be thermally connected via thermal interface material, and wherein the thermal components can be equipped with sensors, such as temperature sensors, fan speed sensors, fluid flow sensors, volume flow sensors or the like, to control the temperature at the samples in or on the mount.
  • sensors such as temperature sensors, fan speed sensors, fluid flow sensors, volume flow sensors or the like
  • an instrument for simultaneously monitoring multiple nucleic acid amplification reactions during thermocycling biological samples comprising a device for thermocycling the biological samples as described previously, and wherein the instrument further comprises one or several excitation light sources for applying excitation energy to the nucleic acid amplification reactions occurring inside one or several reaction vessels received by the mount, and one or more sensors for simultaneously detecting light emitted from the multiple nucleic acid amplifications.
  • an instrument can be structured similar to the already known Roche LightCycler® instruments which provide high-performance, and high-throughput PCR platforms which can be used, for example, for gene detection, gene expression analysis, genetic variation analysis, and array data validation.
  • Such benchtop instrument solutions comprise, inter alia, a plate-based real-time PCR device as a robotically controllable, automated high-throughput solution for general laboratory use.
  • an automated processing system such as an analytical, pre-analytical or post-analytical processing system, which is commonly employed in state-of-the-art laboratories for automatically processing biological sample
  • an automated processing system can comprise the previously described device, or even the entire previously described instrument.
  • the term "laboratory instrument” or “instrument” of the laboratory encompasses any apparatus or apparatus component operable to execute one or more processing steps / workflow steps on one or more biological samples, and covers analytical instruments, pre-analytical instruments, and also post-analytical instruments.
  • processing steps thereby refers to physically executed processing steps, such as conducting the particular steps of a PCR conduct.
  • analytical encompasses any process step carried out by one or more laboratory devices or operative units which are operable to execute an analytical test on one or more biological samples.
  • analytical processing is a technical procedure to characterize the parameters of a biological sample or of an analyte. Such characterization of parameter comprises, for example, the determination of the concentration of particular proteins, nucleic acids, metabolites, ions or molecules of various sizes in biological samples derived from humans or laboratory animals, or the like.
  • the gathered information can be used to evaluate e.g. the impact of the administration of drugs on the organism or on particular tissues. Further analyses may determine optical, electrochemical or other parameters of the samples or the analytes comprised in a sample.
  • thermocycling biological samples using a device for thermocycling the biological samples as described previously comprises, inter alia, the step of monitoring the temperature at the biological samples, for example by means of the sensors as described further above, and the step of controlling the output of the heat pump and/or the heat exchange rate of the primary heat exchanger and/or the output of any further heater, such as an edge heater, wherein the controlling step is carried out based on the detected and monitored temperature at the biological samples resulting from the monitoring step.
  • a thermal performance of the inventive device can be actively influenced by controlling the heat pump or any additional heaters, by controlling the performance of the heat sink, i.e. the primary heat exchanger and/or the secondary heat exchanger, and/or by monitoring and exploiting further environmental parameters or design parameters as mentioned above.
  • the above described step of controlling the heat exchange rate of the primary heat exchanger can be executed by the control unit of the described device, wherein the controlling step can comprise a control of the heat exchange rate of the second heat exchanger and/or a stop or reverse of a flow of heat exchanging fluid through the inner space of the primary heat exchanger.
  • the step of controlling the heat exchange rate of the primary heat exchanger can also include the control of fluid speed to cool the heat exchange fluid in the heat sink above ambient temperature and approximate to the predetermined lowest temperature of the thermocycles controlled by the control unit.
  • thermocycler specific method feature for the controlling step is, for example, the stop of a flow of heating or cooling liquid in the heat sink at certain PCR protocol steps, which can minimize thermal losses during the PCT temperature plateau phases.
  • active control of the temperature of the heat exchanging fluid such as cooling liquid flowing through the heat sink, can be used to control the overall thermal performance of the device.
  • reversing the fluid flow can be used to fill the primary heat exchanger and/or the secondary heat exchanger with a heat exchanging fluid with either a higher or lower temperature compared to the fluid currently in place inside the primary heat exchanger and/or the secondary heat exchanger.
  • the inside of the already described fluid reservoirs can be refilled or replenished with fluid of a certain (high or low) temperature.
  • the flow path as defined by the circulation system i.e. the tubing system, optionally together with the fluid reservoirs and pumps, if any, can be modified in a certain way, for example by inclusion of additional tubing, reservoirs and pumps, in order to achieve a certain control effect, for example by prolonging the flow path, increasing the flow speed, and/or enlarging the amount of fluid provided inside the flow path of the heat exchanging fluid.
  • control unit of the described device, which can also control any kind of actuation or monitoring of the above described device and its components
  • control unit encompasses any physical or virtual processing device, such as a CPU or the like, which can also control the entire instrument or even an entire workstation comprising one or more laboratory instruments in a way that workflow(s) and workflow step(s) are conducted.
  • the control unit may, for example, carry different kinds of application software and instruct the automated processing system or a specific instrument or device thereof to conduct pre-analytical, post analytical and analytical workflow(s)/ workflow step(s).
  • the control unit may receive information from a data management unit regarding which steps need to be performed with a certain sample.
  • control unit might be integral with a data management unit, may be comprised by a server computer and/or be part of one instrument or even distributed across multiple instruments of the automated processing system.
  • the control unit may, for instance, be embodied as a programmable logic controller running a computer-readable program provided with instructions to perform operations.
  • a user interface can additionally be provided, wherein the term "user interface" as used herein encompasses any suitable piece of application software and/or hardware for interactions between an operator and a machine, including but not limited to a graphical user interface for receiving as input a command from an operator and also to provide feedback and convey information thereto.
  • a system / device may expose several user interfaces to serve different kinds of users / operators.
  • Fig.1 shows a functional concept of a device 1 for thermocycling biological samples according to an embodiment of the present invention, wherein the device 1 is intended for PCR applications, for example as one main component of an analysis instrument.
  • the device 1 comprises a sample tempering mount 2 and a heat pump 3, which are illustrated in fig. 1 as one functional unit for the sake of simplicity, wherein the mount 2 can also be implemented as a mount including a heat pipe in the form of a vapor chamber or the like.
  • the mount 2 can comprise a structured upper side with recesses in order to provide a certain well geometry for receiving reaction vessels, or with a flat upper side for receiving a cartridge, a slide or any other kind of consumable bearing the biological samples to be thermocycled, or a microfluidic device comprising one or more flow channels connected to an array of sample wells for receiving the biological samples.
  • the device 1 comprises a heat sink 4 consisting, in a functional sense, of a primary heat exchanger 5 and a secondary heat exchanger 6, wherein the mount 2, the heat pump 3 and the primary heat exchanger 5 constitute a functional unit which can be sandwiched together, for example by means of a clamping mechanism for clamping these components together in order to achieve a tight thermally-connected unit.
  • the mount 2, the heat pump 3 and the primary heat exchanger 5 can comprise a thermal interface material 5 thereinbetween, wherein, in use of the device 1, thermal interface material 31 is only depicted in fig. 1 between the lower side of the mount-heat pump-combination 2, 3, i.e. the lower side of the heat pump 3, and the upper side of the primary heat exchanger 5, in order to improve the thermal conductivity between these components.
  • the primary heat exchanger 5 is connected to the secondary heat exchanger by a heat exchanging fluid circulation system 8, wherein, in fig. 1 , only a single line stands for the circulation system 8 circulating heat exchanging fluid between the two heat exchangers 5, 6, i.e. within the heat sink 4.
  • the secondary heat exchanger 6 can be arranged away from the primary heat exchanger 5 without disrupting the functional unit of the heat sink 4, since a thermal connection between the primary heat exchanger 5 and the secondary heat exchanger 6 is established by a connecting element, such as fluid-bearing tubes or a heat pipe, constituting a circulation system 8 for heat exchanging fluid.
  • a connecting element such as fluid-bearing tubes or a heat pipe
  • the device 1 comprises a particular monitoring system based on a plurality of sensors 9, which are for control and prediction of the overall tempering of the device 1.
  • a temperature sensor 91 or alternatively a heat flux sensor or the like, is provided at the unit of mount 2 and heat pump 3 for measuring the temperature of mount 2 and heat pump 3
  • another temperature sensor 91 is provided on the thermal interface material 31 for measuring its temperature
  • a further temperature sensor is provided at the primary heat exchanger 5 for measuring its temperature
  • a further temperature sensor 91 is provided at the secondary heat exchanger 6 for measuring its temperature
  • a fluid flow sensor or volume flow sensor 92 is provided at the heat exchanging fluid circulation system 8 for measuring the fluid flow, i.e.
  • the sensor 92 might also be able to measure the temperature of the heat exchanging fluid, or the pump speed of a pump (not shown) provided in the fluid circulation system 8, in order to improve the monitoring capability of the device 1.
  • All sensors 9 are connected to a control element or control unit 7, for example in the form of a CPU 7, which is able to receive the measuring signals from the sensors 9 and process the same, in order to monitor the temperatures at different locations of the device 1, and to control and actively influence the temperature of the samples at the mount 2 in regard to the PCR thermocycling requirements.
  • fig. 2 depicts the concept of the device 1 of fig. 1 in a structural manner. Accordingly, it can be gathered from fig. 2 that the device 1 comprises the mount 2 with a flat surface 21, wherein several heating/cooling elements, depicted in form of heat pumps or TECs 3, such as Peltier elements, are provided in between the mount 2 and the primary heat exchanger 5 in the form of a solid-to-liquid heat exchanger. Reference sign 3 in fig. 2 can also illustrate the position of a heating element, as an alternative to a Peltier element. Furthermore, additional heating/cooling elements are depicted in fig.
  • a connection surface between the heat pumps 3 arranged in between the mount 2 and the primary heat exchanger 5 are provided with thermal interface material 31, in order to enhance any temperature conductivity between the mount 2, the heat pumps 3 and the heat sink 4, constituting a thermal block unit, wherein the components of the thermal block unit, i.e.
  • the mount 2, the primary heat exchanger 5 and the heat pumps 3 arranged therebetween can be clamped together in order to establish a tight thermally conducting assembly.
  • a respective clamping mechanism is described further below in regard to figs. 3 and 4 .
  • the remaining part of the heat sink 4, i.e. the secondary heat exchanger 6, can be arranged in a spaced-away manner distant from the primary heat exchanger 5, wherein the secondary heat exchanger 6 used to support a temperature compensation function of the primary heat exchanger 5 in regard to the mount 2 can be arranged far away from the thermal block unit in order to be thermally independent therefrom.
  • the primary heat exchanger 5 comprises an inner space 51 filled with heat exchanging fluid 41, such as a cooling liquid or the like, and the primary heat exchanger 5, or better the inner space 51 of the primary heat exchanger 5, is in fluid connection with the secondary heat exchanger 6 by means of a connecting element, such as a flexible tubing system or the like, constituting the heat exchanging fluid circulation system 8.
  • a fluid pump 82 is provided as part of the heat exchanging fluid circulation system 8, and is, thus, arranged in between the primary heat exchanger 5 and the secondary heat exchanger 6.
  • the temperature of the mount 2 needs to be decreased rapidly by means of the heat pumps 3, and the removed heat must be removed from the heat pumps 3.
  • the primary heat exchanger 5 acquires the heat to be removed, transfers the same to the heat exchanging fluid 41.
  • the heated-up heat exchanging fluid 41 is then transported away, i.e. out of the primary heat exchanger 5 into the tubing of the heat exchanging fluid circulation system 8 by means of the fluid pump 82.
  • the temperatures are monitored by the control unit 7, processed, and, in line with a respective algorithm, the control unit 7 drives the fluid pump 82 in order to increase or decrease the heat exchanging fluid flow speed in the heat exchanging fluid circulation system 8.
  • the control unit 7 drives the fluid pump 82 in order to increase or decrease the heat exchanging fluid flow speed in the heat exchanging fluid circulation system 8.
  • heat can be removed from the primary heat exchanger 5 faster or slower, as desired, in order to control the heat removal from the heat pumps 3 arranged in between the mount 2 and the primary heat exchanger 5.
  • the heat is removed from the primary heat exchanger 5 and transferred into the heat exchanging fluid 41 which, then, is transferred by means of the fluid pump 82 and the heat exchanging fluid circulation system 8 to the secondary heat exchanger 6, which can transfer the removed heat to ambient air or laboratory infrastructure.
  • fig. 3 depicts the concept of another embodiment of the device 1' in a structural manner. Accordingly, it can be gathered from fig. 3 that the device 1' comprises a mount 2' with a structure in its upper surface, wherein the mount's upper surface comprises indentations 2 which can be used as wells for receiving the biological samples to be thermocycled, or for receiving a multi-well plate comprising a plurality of wells comprising the biological samples therein, wherein several heat pumps 3, such as Peltier elements, are provided in between the mount 2' and the primary heat exchanger 5' in the form of a solid-to-liquid heat exchanger.
  • the mount' with a structure in its upper surface
  • the mount's upper surface comprises indentations 2 which can be used as wells for receiving the biological samples to be thermocycled, or for receiving a multi-well plate comprising a plurality of wells comprising the biological samples therein, wherein several heat pumps 3, such as Peltier elements, are provided in between the mount 2' and the primary heat exchanger 5
  • the primary heat exchanger 5' comprises an inner space 51' including fins 511', such as pin fins or swage fins, within the inner space 51', for example protruding from one large inner surface side of the inner space 51', the fins 511' providing a more effective heat transfer from the solid parts of the primary heat exchanger 5' to the heat exchanging fluid 41 perfusing the inner space 51' of the primary heat exchanger 5, i.e. flowing or being streamed through the inner space 51' of the primary heat exchanger 5'.
  • a high thermal capacity of the fins 511' allows for a smaller heat transfer surface and, therefore, for a miniaturized design of the primary heat exchanger 5'.
  • a comprehensive heating/cooling of the mount 2' can be achieved by the structure of device 1', wherein any thermal connection between the heat pumps 3 and the mount 2' as well as between the heat pumps 3 and the primary heat exchanger 5' is amplified by the use of thermal interface material 31, in order to enhance any temperature conductivity between the mount 2', the heat pumps 3 and the primary heat exchanger 5'.
  • thermal interface material 31 in order to enhance any temperature conductivity between the mount 2', the heat pumps 3 and the primary heat exchanger 5'.
  • the mount 2', the primary heat exchanger 5' and the heat pumps 3 arranged therebetween can be mechanically connected together, for example by means of a mechanical interface mount in the form of screws 52', or alternatively threaded bolts, or the like, in combination with a respective counterpart in the mount, such as a threaded hole, as well as a spring or a nut-spring combination, connecting and pulling/pushing the primary heat exchanger 5' and the mount 2' together, thereby sandwiching the heat pumps 3 thereinbetween, i.e. clamping these components together, in order to establish a tight thermally conducting assembly.
  • the screws 52' can pass through one or several through holes 53' provided in the primary heat exchanger 5' and fit into respective threaded holes provided in the mount 2'.
  • a heat sink 4' consists of the primary heat exchanger 5' and a secondary heat exchanger 6', wherein the secondary heat exchanger 6', can be arranged in a spaced-away manner distant from the primary heat exchanger 5', and wherein the secondary heat exchanger 6' supporting a temperature compensation function of the primary heat exchanger 5' in regard to the mount 2' can be arranged far away from the thermal block unit in order to be thermally independent therefrom.
  • the primary heat exchanger 5' is in fluid connection with the secondary heat exchanger 6' by means of a heat exchanging fluid circulation system 8 comprising a fluid pump 82' arranged within the fluid connection between the primary heat exchanger 5' and the secondary heat exchanger 6', which achieves the same function as described in regard to the previously described embodiment.
  • the secondary heat exchanger 6' not only allows a streaming of the heat exchanging fluid 41 there through in order to achieve a fluid-to-solid temperature transfer, but also further comprises fins 61' on its outer surface, such as pin fins or swage fins, for example protruding from an outer surface of the secondary heat exchanger 6' to the outside, which fins 61' providing a more effective heat transfer from the solid parts of the primary heat exchanger 6' to the ambient air.
  • fins 61' on its outer surface, such as pin fins or swage fins, for example protruding from an outer surface of the secondary heat exchanger 6' to the outside, which fins 61' providing a more effective heat transfer from the solid parts of the primary heat exchanger 6' to the ambient air.
  • a fan 62' is provided in connection with the secondary heat exchanger 6' as depicted in fig. 3 . Accordingly, in case the temperature of the heated-up heat exchanging fluid 41 inside the secondary heat exchanger 6' is too high, the fan can be activated and its speed, i.e. the fan speed, can not only be monitored by the control unit 7 but can also be increased or decreased, as desired, in order to improve a cooling performance of the secondary heat exchanger 6'.
  • a modified or complemented embodiment of the device 1' for thermocycling the biological samples as described in regard to fig. 3 is shown, which is almost identical but with the difference that the modified device 1' comprises additional fluid reservoirs 81 within the heat exchanging fluid circulation system 8.
  • one fluid reservoir 81 is provided in fluidic connection in between the inner space 51' of the primary heat exchanger 5' and the fluid pump 82, and another fluid reservoir 81 is provided between the inner space 51' of the primary heat exchanger 5' and the secondary heat exchanger 6' on the other side of the circulation circle.
  • Each fluid reservoir 81 can accommodate heat exchanging fluid 41 of a predetermined temperature, which fluid can be provided as part of the circulation system 8, i.e.
  • the additional fluid in the fluid reservoirs 81 can be used, on demand, in case heat exchanging fluid 41 of a certain temperature as stored inside the respective fluid reservoir 81 can be used to heat or cool the heat exchanging fluid 41 streaming inside the circulation system 8.
  • one of the depicted fluid reservoirs 81 can store cold heat exchanging fluid 41, and the other can store heated heat exchanging fluid 41, and the control unit 7 can activate the one or the other fluid reservoir 81 in case the heat exchanging fluid 41 inside the tubing of the system 8 must be cooled down or heated up, by adding the respective cold or hot heat exchanging fluid 41 from one of the reservoirs 81.
  • the circulation system 8 can comprise multiple hot and/or cold fluid reservoirs 81 accommodating heat exchanging fluid 41 of different predetermined temperatures, thereby enabling a certain control of the temperature of the heat exchanging fluid 41 provided to the secondary heat exchanger 6' or returning to the primary heat exchanger 5'.
  • the depicted flowchart shows the main steps of a method using the inventive device 1, 1' of the present invention.
  • the method for thermocycling biological samples using the device 1, 1' is based on the measuring values as received from the sensors 9.
  • the method monitors in step 100 the temperature or other values as received from the sensors 9, and it is determined, in the same step 100, for example based on the values from the flow sensor 92 or the temperature sensors 91 that the temperature at the mount 2, 2', i.e. the temperature at the samples to be cycled, is too high or is in need of cooling down.
  • the control unit 7 proceeds to step 200, i.e.
  • control unit 7 can increase the fluid pump's performance, or can stop the pumping at all or reverse the pumping direction, and, optionally, can introduce cold heat exchanging fluid 41 from the fluid reservoirs 81.
  • control unit 7 can increase/decrease the output of the heaters 3', as desired, and/or can activate or increase the function of the fan 61' in case the temperature of the primary heat exchanger 5, 5' needs to be decreased as fast as possible.
  • control unit 7 can stop or reverse the flow of heat exchanging fluid 41 through the inner space 51, 51' of the primary heat exchanger 5, 5'.
  • control unit 7 can open one or several of the fluid reservoirs 81 in order to add heated or cooled heat exchanging fluid 41.

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EP18156326.3A 2018-02-12 2018-02-12 Dispositif de thermocyclage d'échantillons biologiques, instrument de surveillance le comprenant et procédé de thermocyclage d'échantillons biologiques à l'aide d'un tel dispositif Withdrawn EP3524353A1 (fr)

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EP3858487A1 (fr) 2020-01-30 2021-08-04 Roche Diagnostics GmbH Unité thermique et dispositif de cyclage thermique d'échantillons biologiques et procédé de cyclage thermique d'échantillons biologiques utilisant un tel dispositif
WO2021195296A1 (fr) * 2020-03-26 2021-09-30 Ontera Inc. Dispositifs et procédés de thermocyclage photonique
WO2022129400A1 (fr) 2020-12-17 2022-06-23 Totalenergies Onetech Système pour contrôler la température d'une puce microfluidique et appareil microfluidique pour surveiller une substance dans une puce microfluidique comprenant un tel système
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Publication number Priority date Publication date Assignee Title
EP3858487A1 (fr) 2020-01-30 2021-08-04 Roche Diagnostics GmbH Unité thermique et dispositif de cyclage thermique d'échantillons biologiques et procédé de cyclage thermique d'échantillons biologiques utilisant un tel dispositif
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CN115301307A (zh) * 2021-05-04 2022-11-08 纬创资通股份有限公司 热环循装置、检测装置及温度控制方法

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