Thermal unit for temperature management of a dPCR thermal cycler

Abstract

This invention relates to a thermal unit for temperature management of a dPCR thermal cycler, and also to a thermal unit for a device for simultaneously thermally cycling multiple biological samples, also known as temperature cycling, such a device itself, and a method for simultaneously thermally cycling multiple biological samples using such a device and thermal unit. The thermal unit has at least one heat block (3) and a cooling structure (2), the heat block (3) comprising at least one thermoelectric transducer (31) and a heat transfer plate (33) attached to the thermoelectric transducer (31) for dissipating heat energy from the thermoelectric transducer (31), and the cooling structure (2) comprising a radiator (21), at least one fan (221), and exhaust pipes (24a, 24b).

Description

Technical Field

[0001] Generally, the present invention relates to the technical field of sample analysis, such as biological sample analysis, and further to the technical field of high-throughput analysis of biological samples.

[0002] In particular, the present invention relates to a thermal unit of an apparatus for simultaneously thermally cycling multiple biological samples, also known as temperature cycling, the apparatus itself, and a method for simultaneously thermally cycling multiple biological samples using such an apparatus and thermal unit.

[0003] In other words, the present invention generally relates to a thermal cycling structure for performing chemical and / or biological reactions such as polymerase chain reaction (PCR), wherein such a thermal cycling structure may be an internal component of laboratory equipment such as a thermal cycler or a circulating variable-temperature heater, and wherein such a thermal cycling structure typically includes at least a sample confinement unit, a heat pump with a heat sink, and a control unit for controlling the heating and cooling of the heat pump during thermal cycling. The present invention particularly relates to a thermal unit of such a thermal cycling structure for simultaneously generating multiple nucleic acid amplification reactions during thermal cycling of biological samples by means of such a thermal cycling device, wherein the thermal cycling structure may contain more than one such thermal unit. Furthermore, the present invention relates to a method for simultaneously thermally cycling multiple biological samples using such a device or thermal unit, wherein the thermal cycling scheme is executed under feedback control of a computer or the like. Background Technology

[0004] Biological samples are typically collected from patients by healthcare workers in hospitals or private clinics for laboratory analysis, such as determining the concentration levels of different components in the collected sample. Accordingly, the terms "sample" and "biological sample" refer to material that may potentially contain a target analyte. Biological samples can originate from any biological source, such as physiological fluids (including blood, saliva, lens fluid, cerebrospinal fluid, sweat, urine, feces, semen, breast milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid), tissues, cultured cells, etc., and the sample may be suspected of containing a certain antigen or nucleic acid.

[0005] For a variety of biological, biochemical, diagnostic, or therapeutic applications, the ability to accurately determine the amount or concentration of a substance or compound (such as an antigen or nucleic acid as mentioned above) in a biological sample contained in a reaction mixture is crucial. To achieve this accurately, various methods have been developed over the years, such as the well-known polymerase chain reaction (PCR), in forms such as digital PCR (dPCR), real-time PCR (qPCR), or reverse transcription polymerase chain reaction (RT-PCR). PCR enables the in vitro synthesis of nucleic acids in biological samples. It specifically replicates DNA fragments; that is, PCR is a cost-effective way to copy or amplify small fragments of DNA or RNA in a sample. In particular, in clinical diagnostics, PCR is used to quantify nucleic acid chains in the form of DNA or RNA fragments by amplification in order to detect diseases or mutations. To run this PCR, a so-called thermal cycler is typically required to heat and cool the sample and reaction mixture within the reaction vessel in multiple cycles. Here, dPCR is a very recent variant of the PCR method, designed to achieve greater precision and sensitivity. It involves applying the PCR method to single DNA molecules isolated into individual microfluidic reaction containers. This allows for counting the actual number of target DNA molecules after PCR, yielding a “numerical” result for each reaction container. This constitutes the main difference compared to other more conventional PCR methods. However, it requires a large number of reaction containers, typically 20,000 or more, which can be arranged within a single microfluidic consumable.

[0006] As mentioned above, the development of dPCR for amplifying DNA or RNA fragments has yielded significant benefits in gene analysis and the diagnosis of various hereditary diseases, as well as in the detection of viral load. In a typical PCR process, a specific target nucleic acid is amplified through a series of cyclic steps. The cyclic steps involve denaturing the nucleic acid in the reaction mixture at relatively high temperatures (e.g., above 90°C, typically around 94°C to 95°C) to separate the double-stranded DNA, then (b) cooling the reaction mixture to a temperature at which short oligonucleotide primers bind to single-stranded target nucleic acids (e.g., at an annealing temperature of around 52°C to 56°C) to allow the primers to bind to the separated DNA strands to provide a template (annealing), and then (c) using a polymerase to extend / lengthen the primers, for example at an extension temperature of around 72°C, to generate new DNA strands, thus replicating the original nucleic acid sequence. Repeated cycles of denaturation, annealing, and extension, typically around 25 to 30 cycles, lead to an exponential increase in the amount of target nucleic acids present in the sample, with the time spent heating and cooling the sample having a significant impact on the overall process time. Accordingly, the shorter the time spent at suboptimal temperatures, the better or more accurate the resulting chemical outcomes. Specifically, after reaching each temperature plateau, any reaction mixture needs to be held at that plateau for a specific minimum time, where this minimum holding time is the minimum time required to complete one thermal cycle. Any transition time between PCR temperature plateaus is an addition to this minimum cycle time. Therefore, since the number of thermal cycles can be large, this additional time unnecessarily prolongs the total time required to complete PCR. Thus, reducing heating and cooling times is crucial for efficient and cost-effective processes and for increasing the throughput of thermal cycling equipment used for PCR. Accordingly, there is a need to make diagnostic assays faster, cheaper, and easier to perform, while achieving both accuracy and efficiency.

[0007] Common thermal cycling devices used for PCR amplification of DNA fragments, such as those disclosed in WO 2007 / 146443 A2, essentially consist of a sealing device for receiving the sample and a heat pump attached to the sealing device, where the combination of the sealing device and the heat pump can also be referred to as a heating block or hot block. Heat pumps are often provided in the form of thermoelectric devices or thermoelectric coolers (TECs), for example, in the form of Peltier elements, and are typically used for actively heating and cooling the sealing device and thus for actively controlling the temperature supplied to the sample. TECs are solid-state heat pumps, typically made of semiconductor material sandwiched between ceramic plates, where the heat pumped is proportional to the amount of current flowing through the TEC, resulting in increased temperature control. By reversing the current, the TEC can function as a heater or cooler, which is very useful for thermal cycling at different temperatures. In other words, the TEC converts electrical energy into heat or cold energy. Here, in addition to the sealer used to receive the sample via the hot block, the TEC can be further combined with a heat sink or cooling block attached to one side, wherein the sample sealer is arranged on the other side of the Peltier element.

[0008] A combination of one or more TECs with a cooling block can also be referred to as a "Peltier sandwich structure" or "thermal unit." To ensure accurate and reliable thermal performance of such thermal units, heat transfer between their components is critical, and this heat transfer must be as high as possible and within tight tolerances. Therefore, a thermally conductive foil or phase change material can be provided between the TEC, the cooling block, and the sample sealer. This foil is thin and brittle, making it difficult to apply, and some types of foil require heating after assembly to melt, thus sealing any tiny gaps and irregularities between the thermal unit components to ensure adequate heat transfer. However, due to the complexity of such thermal unit assemblies and the thermal performance requirements, replacing only the Peltier element within the thermal unit in the event of failure or defect is only feasible under high operating loads, resulting in high costs and is therefore not a common practice.

[0009] Furthermore, common thermal cycling devices are often designed for standard qPCR or RT-PCR applications, meaning they can only accommodate microtiter plates or single cuvettes. Therefore, a single PCR microtiter plate can only hold a maximum of 384 wells. However, this number is insufficient compared to the at least 20,000 or more wells required for dPCR. Moreover, the geometry of the 384-well plate or single cuvette is typically cylindrical or conical. Therefore, to ensure that the temperature generated in the thermal cycler is accurately transferred to every part of the sample / reaction mixture inside the well or cuvette, the design of the operating surface of the thermal cycler receiving the well or cuvette must be adapted to the corresponding cylindrical or conical shape. Accordingly, the adapted thermal cycler can only accommodate one type of plate or cuvette, i.e., the one already adapted to it. Additionally, some thermal cyclers allow users to replace the heat block depending on the type of plate or cuvette requiring thermal cycling. However, this replacement procedure is highly inconvenient, increases instrument management costs, and carries the risk of unintended damage to the thermal cycler or heat block during the replacement process. Furthermore, the newly assembled thermal cycler needs to be recalibrated after replacing the heat block to ensure that the measured temperature truly matches the actual temperature of the receiving orifice or cuvette's operating surface, which is again inconvenient and increases instrument management costs.

[0010] Finally, to accelerate the transition time between different temperature levels during PCR, thereby reducing heating and cooling times and thus achieving an efficient and cost-effective process and increasing thermal cycling throughput, various types of radiators are used within the thermal units of common thermal cycling devices, such as radiators with specific fin arrangements or radiators based on heat pipe and vapor chamber technologies. For example, EP 3 524 353 A1 teaches a device for thermally cycling biological samples that provides a heat pump for heating and cooling the samples. However, this device is not suitable for thermal cycling of large numbers of samples at short cycle intervals and therefore only provides a low sample throughput. Accordingly, it is still desirable to further increase thermal cycling throughput by optimizing the heating and cooling times during thermal cycling. Therefore, due to these and other problems and drawbacks, the known concepts presented above cannot meet the needs of today's users and therefore cannot provide a satisfactory solution. Therefore, there is a need in the art for providing an improved thermal cycling device with optimized heating and cooling times during thermal cycling, and including a thermal unit that can be monitored after assembly and easily replaced by a field service engineer in the event of a failure or defect. Summary of the Invention

[0011] This invention addresses the aforementioned problems of the prior art and significantly improves the thermal cycling of large-scale reaction vessels used in dPCR. According to a first aspect of the invention, a thermal unit for simultaneously thermally cycling multiple samples is provided, having at least one heat block and a cooling structure. The heat block includes at least one thermoelectric transducer and a heat transfer plate attached to the thermoelectric transducer for dissipating heat energy from the transducer. The cooling structure includes a radiator, at least one fan, and an exhaust pipe. The radiator is connected to the heat transfer plate on a first side and exposed to the fan on a second side, wherein the fan provides an intake airflow toward the second side of the radiator. The exhaust pipe guides an exhaust flow away from the second side of the radiator, wherein the intake and exhaust flows are structurally separated from each other. Thus, the thermal unit according to the invention comprises two main components: at least one heat block for heating or cooling multiple samples and a cooling structure for removing heat energy from the thermal unit.

[0012] A hot block contains at least one thermoelectric transducer, which is a device that converts electrical energy into heat energy. Here, the thermoelectric transducer can either heat or cool. For example, the thermoelectric transducer can be a Peltier element, also known as a thermoelectric cooler (TEC). This Peltier element converts electrical energy into heat or cold energy. A thermoelectric transducer is an element that actively heats or cools multiple samples, wherein the thermoelectric transducer is an element comprising two opposite sides. During operation of the thermoelectric transducer, one of these opposite sides is heated, while the opposite side is cooled. Which of these opposite sides is actually heated depends on the operating mode of the thermoelectric transducer. The heated side can be switched by changing its operating mode, particularly by changing the direction of the current. One side of the thermoelectric transducer is thermally connected to multiple samples. If the samples are heated during thermal cycling, the side of the thermoelectric transducer thermally connected to the samples is heated. In this operating mode, the opposite side of the thermoelectric transducer is cooled. If the samples are cooled during thermal cycling, the side of the thermoelectric transducer thermally connected to the samples is cooled. In this operating mode, the opposite side of the thermoelectric transducer is heated. The heat generated on the opposite side from the side thermally connected to the sample must be directed away from the thermoelectric transducer. In this regard, a cooling structure for the thermal unit according to the invention is provided to remove the heat generated during sample cooling. The heat block includes a heat transfer plate connected to the thermoelectric transducer to transfer / remove this heat from the thermal unit.

[0013] The cooling structure comprises several components. One of these components is a radiator, which is thermally connected to the heat transfer plate of the heat block. The radiator is a component that receives heat energy generated by the thermoelectric transducer and transferred through the heat transfer plate, and is made of a material with good thermal conductivity. The heat energy transferred by the heat transfer plate is dissipated into the radiator. The radiator itself is heated by this dissipated heat energy, whereby the heat energy in the radiator must be further removed from the heat unit. The radiator is made of a thermally conductive material (e.g., cast and machined aluminum) and is used to transfer the dissipated heat energy leaving the thermoelectric transducer to the surrounding environment outside the heat unit. In addition, the radiator can serve as a base plate and incorporates mechanical interfaces to ensure the proper positioning and fixation of the heat unit components. Now, to assist in removing heat energy from the radiator, at least one fan is provided. This fan provides an intake airflow toward a second side of the radiator. This second side of the radiator is opposite to the side of the radiator thermally connected to the heat transfer plate of the heat block. The intake airflow is heated by the heat energy of the radiator and thus guides this heat energy away from the radiator. An exhaust pipe is provided to guide the intake airflow after it has absorbed heat from the radiator. After absorbing heat through the intake airflow, the same airflow is called the exhaust airflow because it no longer exhibits the characteristics of the intake airflow, such as ambient temperature, but instead exhibits different characteristics, such as an elevated temperature. Therefore, the temperature of the exhaust airflow is higher than that of the intake airflow because it has absorbed heat from the radiator.

[0014] An exhaust pipe is provided to remove the exhaust flow from the heat unit. The exhaust pipe guides the exhaust flow away from the second side of the radiator. The exhaust pipe guides the exhaust flow to the outside of the heat unit in a controlled manner. According to the invention, the intake and exhaust flows are structurally separated from each other to provide controlled guidance for the removal of heat energy from the heat unit. The structural separation between the intake and exhaust flows is primarily achieved by the exhaust pipe. Optionally, other elements may be provided to separate the exhaust flow from the intake flow. The advantage of this structural separation of the two airflows according to the invention is that heat energy is dissipated from the heat blocks of the radiator with very high efficiency. This structural separation between the intake and exhaust flows ensures that the intake airflow impacts the radiator at an optimal low ambient temperature. A cold airflow can absorb a greater amount of heat energy than a hot airflow (such as an airflow that has been heated by the cross-exhaust). With regard to the cold intake airflow, the gradient between the intake airflow temperature and the radiator temperature is greater. By separating the two airflows, it is ensured that the two airflows do not mix, i.e., the intake airflow is not heated by mixing with the exhaust flow. Because the thermal cycling of dPCR samples must be completed within short intervals of heating and cooling, a large amount of heat energy accumulates in the radiator in a short time and must be effectively removed from the thermal unit. Therefore, the structural separation of the inlet and outlet airflows presented in this invention is particularly useful for thermal units that require high heating and cooling performance.

[0015] According to a specific embodiment of the invention, the exhaust flow is guided substantially perpendicular to the intake airflow, wherein at least a portion of the exhaust flow can be guided around at least one fan by means of an exhaust pipe. In this embodiment, the fan is positioned such that it guides the intake airflow substantially perpendicular to the radiator and heat transfer plate. Accordingly, the intake airflow is directed toward the radiator and at approximately 90 degrees to the longitudinal axis of the radiator, and deviates by the same 90 degrees after impacting the radiator. After this deviation, the intake airflow flows substantially parallel to the longitudinal axis of the radiator, i.e., parallel to the longitudinal direction of the radiator and heat transfer plate. During this parallel flow of the intake airflow, the passing airflow is heated by receiving heat energy from the radiator. By acquiring heat energy from the radiator, the deviated intake airflow is heated, thus becoming an exhaust flow that carries heat away from the radiator. Due to the deviation in flow direction, the exhaust flow flows substantially perpendicular to the intake airflow initially provided by the fan. Based on the described differences between the intake and exhaust airflows, the directions of these airflows will intersect each other. To prevent such intersecting and thus to prevent gas mixing between the two airflows, when the direction of one airflow intersects the direction of another airflow, at least one airflow is diverted. In the described embodiments, for example, an exhaust flow is guided around at least one fan and thus around the intake flow by means of an exhaust pipe. Here, the exhaust pipe structurally separates the two airflows from each other. Typically, the exhaust pipe guides the exhaust flow by means of a pipe wall that intersects with the exhaust flow.

[0016] According to another specific embodiment of the invention, the radiator includes a cooling fin structure on at least its second side, wherein the cooling fins protrude from the second side of the radiator and are substantially parallel to the intake airflow provided by the fan. Furthermore, the cooling fins may be provided in the form of a forged fin structure. In this embodiment, the radiator includes the cooling fin structure to increase the surface area available for dissipating and transferring heat energy to the airflow provided by at least one fan. The cooling fin structure is typically located on the second side of the radiator, i.e., on the side of the radiator opposite to the first side connected to the heat transfer plate, and thus oriented to the intake airflow provided by the fan. Additional cooling fin structures may also be provided on another portion of the radiator, for example, on a portion of the radiator that does not constitute either the first or second side of the radiator. More specifically, the cooling fins protrude from the second side of the radiator. These cooling fins have a typical plate-like fin form, having two large, opposite main surfaces, small side surfaces, and a small end face. The side opposite to the end face is connected to the radiator. The main surfaces of the cooling fins provide a large surface area for effectively transferring heat energy to the cooling intake airflow. Cooling fins guide the intake / exhaust airflow between their main surfaces; that is, the cooling fins guide the intake airflow provided by the fan along the radiator. According to a specific embodiment, the cooling fins may be provided in the form of a plate fin structure, or alternatively in the form of a pin fin structure. An efficient way to manufacture a radiator with a cooling fin structure is to forge two elements into a single device. The forged cooling fin structure includes raised ramps. Forged radiators with cooling fin structures can be effectively made from metals with good thermal conductivity, such as copper, copper alloys, aluminum, or aluminum alloys. Alternatively, radiators with cooling fin structures can also be manufactured by casting, etc.

[0017] According to another specific embodiment of the invention, the cooling fin structure of the radiator, at least in the fan region, is arranged in a star shape to guide the intake airflow provided by the fan toward the lateral sides of the radiator. In this particular embodiment, when viewed in plan view from the second side of the radiator, the cooling fin structure for one fan has a star shape. The intake airflow provided by the fan arrives at the second side of the radiator perpendicularly, i.e., it directly impacts the second side. Therefore, the cooling fin structure provided in a star shape spreads the impacting intake airflow in multiple lateral directions. Through this spreading, the cold intake airflow is distributed across the entire cooling fin structure and thus onto the radiator. Therefore, the heat transfer from the radiator to the impacting intake airflow is very efficient. More specifically, the cooling fin structure may be particularly star-shaped at the location where the intake airflow impacts the second side of the radiator. In the region near the lateral sides of the radiator, the cooling fin structure may be arranged in the form of parallel plate fins to effectively guide the intake / exhaust airflow toward the lateral sides of the radiator.

[0018] According to another specific embodiment of the invention, the first side of the radiator is opposite to the second side of the radiator, i.e., facing away from the fan. More specifically, the first side of the radiator, which is thermally connected to the heat transfer plate of the heat block, is opposite to the second side of the radiator facing the airflow provided by the fan. By arranging the first and second sides as opposite but parallel to each other, heat transfer from the heat block to the cooling airflow is very efficient. The second side can also be arranged at an angle relative to the first side, such as a right angle. This vertical arrangement of the first and second sides of the radiator may have certain advantages if there is not enough available space within the heat unit to arrange two opposite sides.

[0019] According to a specific embodiment of the invention, at least one fan is disposed within a through-hole in a guide plate of a cooling structure, wherein an exhaust pipe may be formed by a second side of a radiator and the guide plate. Accordingly, the thermal unit may include a guide plate as part of the cooling structure. This guide plate may be provided to more effectively guide the intake airflow and / or exhaust airflow. More specifically, the guide plate may at least partially cover the second side of the radiator and the cooling fin structure. The guide plate further provides a through-hole for positioning at least one fan in or beside the through-hole. The fan draws in intake airflow and guides it through the through-hole in the guide plate in a direction toward the second side of the radiator, as described above. The guide plate may also provide components for assembling at least one fan. The second side of the radiator, which may be provided with a cooling fin structure, and the guide plate may together form at least a portion of the exhaust pipe. In this portion of the exhaust pipe, the exhaust flow is guided to flow between the radiator and the guide plate.

[0020] Alternatively or additionally, the exhaust pipe may be formed by a guide plate and a pipe cover plate. Here, a pipe cover plate connected to the guide plate may be provided. Therefore, at least a portion of the exhaust pipe may be formed by this side of the guide plate (opposite to the side of the guide plate facing the radiator) and a pipe cover plate that at least partially covers the guide plate. The combination of the guide plate and the pipe cover plate provides a channel through which the exhaust flow is guided. The shape of the guide plate ensures that the intake and exhaust flows do not mix. Since the pipe cover plate covers at least a portion of the guide plate, the pipe cover plate also includes through-holes for the intake airflow of at least one fan. The exhaust pipe may be provided by a combination of a second side of the radiator and the guide plate, or the exhaust pipe may be provided by a combination of the guide plate and the pipe cover plate. Furthermore, the exhaust pipe may be provided by a combination of both possibilities.

[0021] Further alternatively or additionally, the radiator and guide plate can be connected by a snap-fit ​​connection. Snap-fit ​​connections allow for quick and reliable assembly of the two components. In this regard, and in alternative or additional embodiments, the guide plate can be made of a resilient material such as plastic or metal sheet. The guide plate can also be provided as having a tongue-shaped element that allows for elastic deformation, serving as a component for snap-fit ​​connection with the radiator. Of course, the guide plate and radiator can also be connected to each other in different ways, such as using adhesives, such as glue, or by means of additional connecting elements such as bolts or screws.

[0022] According to another specific embodiment of the invention, the thermal unit further includes an intake duct for directing ambient air toward the fan, wherein the intake duct is structurally separated from the exhaust duct, such as by means of a partition wall. In this embodiment, the intake duct is provided as an additional component of the thermal unit to guide ambient air to the fan and the heat sink. The intake duct may be designed as a passage between the ambient environment of the thermal unit and the fan. The intake duct is structurally separated from the exhaust duct to ensure that airflow can be achieved, for example, through one or more partition walls.

[0023] According to a specific embodiment of the invention, at least one hot block further includes at least one top plate having a substantially planar top side for thermal contact with dPCR consumables, wherein at least one thermoelectric transducer is attached to a bottom side of the top plate opposite its top side, wherein a clamping mechanism is provided for clamping the top plate, the thermoelectric transducer, and the heat transfer plate together to provide thermal contact between the top plate and the thermoelectric transducer and / or between the thermoelectric transducer and the heat transfer plate. In this embodiment, at least one hot block includes a top plate configured to contact and heat or cool the dPCR consumable containing a sample. This top plate may have a substantially planar top surface. In this respect, this planar top surface may be optimal for excellent heat transfer to and from the dPCR consumable, which typically exhibits a planar bottom surface. The top plate may be made of a material with high thermal conductivity, such as copper. The bottom side of the top plate may be thermally connected to the thermoelectric transducer. During operation of the hot unit, thermal energy must be transferred from the thermoelectric transducer to both the top plate and the heat transfer plate. Accordingly, a clamping mechanism can be provided to push the three components together. The use of the clamping mechanism ensures reliable, large-area contact between these components and thus effective heat transfer. For example, the clamping mechanism can be made of metallic components fixed together by screws or the like. Optionally, the clamping mechanism can be spring-loaded. Such spring-loaded embodiments of the clamping mechanism effectively compensate for the thermal expansion of the three components during operation. Furthermore, the spring-loaded clamping mechanism can ensure a uniform distribution of clamping force during assembly without any adjustment. The spring-loaded clamping mechanism also reduces mechanical stress on the thermoelectric transducer because its clamping force is constant during operation. Accordingly and based on this clamping mechanism, the thermoelectric transducer is clamped between the top plate and the heat transfer plate.

[0024] According to another specific embodiment of the invention, the hot block further comprises at least one heat transfer medium, such as in the form of heat transfer foil, or any other type of heat transfer medium, located between the top plate and the thermoelectric transducer and / or between the thermoelectric transducer and the heat transfer plate. In this embodiment, heat transfer within the hot block is further improved by using one or more heat transfer media between the elements. This heat transfer medium is a heat transfer foil. The heat transfer medium has good thermal conductivity and can fill small gaps between the elements to be thermally connected. Therefore, the heat transfer medium reduces the thermal resistance between these elements. As an alternative to the heat transfer foil, or also as an additional component, heat transfer paste may be used to reduce the thermal resistance within the hot block.

[0025] According to a specific embodiment of the invention, the hot block further includes at least one temperature sensor for temperature control located within or on the top plate, wherein at least two temperature sensors may be provided for both temperature control and redundancy-based process control. In this embodiment, at least one temperature sensor is provided, which is connected to the top plate. Here, this temperature sensor may be placed within the top plate. The temperature sensor measures the temperature of the top plate. To improve the reliability of the hot block, two temperature sensors may optionally be provided, wherein one of these temperature sensors measures the temperature as a redundant sensor for process control, thereby increasing the determinism of the measurement.

[0026] According to another specific embodiment of the invention, the hot block further includes an electronic circuit board, such as a printed circuit board assembly, for supporting the thermoelectric transducer and temperature sensor. The electronic circuit board is configured to calibrate temperature deviation compensation and to store corresponding calibration data in a built-in memory. Furthermore, the electronic circuit board may include an analog-to-digital converter for converting the analog temperature signal from any temperature sensor into a digital signal. In this embodiment, the electronic circuit board is provided to control the thermoelectric transducer. The electronic circuit board is connected to at least one temperature sensor and receives the signal from the temperature sensor as input for controlling the operation of the thermoelectric transducer. Since the temperature sensor signal is typically an analog signal, the electronic circuit board can provide an analog-to-digital converter to generate a digital signal based on the analog output of the temperature sensor. For example, the electronic circuit board may be a printed circuit board (PCB) or a printed circuit board assembly (PCBA). To compensate for tolerances in the analog temperature sensor, measuring section, thermoelectric transducer, and assembly process, a calibration is required after assembly to ensure that the temperature value used to control the thermoelectric transducer matches the actual temperature of the top plate within tight tolerances. The electronic circuit board attached to the hot block has a memory to store such independent calibration data. The heat block and its independent calibration data are designed as spare parts and can be easily attached to and removed from the heat unit during assembly or in the field if replacement is required.

[0027] According to a specific embodiment of the invention, the hot block constitutes a replaceable self-contained entity within the thermal unit. In this embodiment, which may include the features of the above embodiments, the hot block is a readily replaceable self-contained entity. Due to the stringent temperature tolerance requirements of the thermal cycler for samples during dPCR, the hot block must be calibrated before the thermal unit is operated. This calibration process is typically complex and very difficult to perform in the art. With a hot block designed as a self-contained entity, a calibration process is unnecessary after replacing the hot block. The calibration of such a self-contained entity may have already been performed in a laboratory or factory after its assembly, where the calibration process for the hot block is more reliable and easier to perform.

[0028] According to another specific embodiment of the invention, the heat sink is configured to receive a plurality of heat blocks, such as six heat blocks. In this embodiment, the heat sink is designed to be connected to a plurality of heat blocks. Therefore, a heat unit may contain more than one heat block. These heat blocks can be assembled onto the heat sink adjacent to each other such that their top plates form a large common top plate. Moreover, several heat blocks can be placed adjacent to each other, with gaps between their top plates. In this embodiment, a cooling structure is provided to remove heat from the plurality of heat blocks.

[0029] According to a second aspect of the invention, an apparatus is provided for simultaneously thermally cycling multiple samples in a dPCR consumable, the apparatus comprising a housing and at least one thermal unit according to any one of the above embodiments, locked within the housing, wherein the exhaust pipe of each thermal unit is partially formed by a second side of a heat sink and a guide plate, and partially formed by the guide plate and a tube cover plate. The tube cover plate may be fixed relative to the housing. The apparatus according to the invention comprises at least one thermal unit according to one or more of the above embodiments. The apparatus according to the invention also comprises other components. The apparatus comprises a housing that surrounds at least a portion of the apparatus. The housing may consist of several elements. These elements are parts of the housing. One of these housing parts may be a tube cover plate, which is assembled to the guide plate of at least one thermal unit. A heat sink of a cooling structure may serve as an assembly base for the apparatus. The heat sink may provide a mechanical interface for connecting other parts of the apparatus, such as the housing, a heat block, and other components. The mechanical interface ensures the proper positioning and fixation of the apparatus components.

[0030] According to a third aspect of the invention, a method for simultaneously thermally cycling multiple samples is provided, the method comprising the steps of: providing an apparatus as described above, wherein each thermal unit comprises multiple hot blocks, and executing a thermal cycling scheme under computer feedback control. Here, the thermal cycling scheme may include nucleic acid amplification, wherein the multiple hot blocks may operate in a non-overlapping power consumption mode. The maximum power consumption of the apparatus according to the invention is limited by the power supplied by the environmental (e.g., in a laboratory) electrical equipment. The power consumption of the thermoelectric transducers depends on the state of the thermal cycling process, particularly on the current temperature, target temperature, and rate of temperature change. Power consumption is typically high during heating and cooling. Between temperature changes, when the temperature remains constant, power consumption is generally low. With all thermoelectric transducers operating simultaneously, this results in the power consumption of all transducers being superimposed. During heating and cooling, this superposition leads to undesirable high power consumption and will be significantly limited by the power supplied by the electrical equipment. Therefore, simultaneous operation of multiple thermoelectric transducers is only possible when using a small number of thermoelectric transducers. In this case, only a small number of samples can be processed simultaneously using thermal cycling. Therefore, the throughput of the apparatus will be very low. However, here, and according to the invention, the operating modes of the thermoelectric transducers and the hot blocks can prevent the overlap of power peaks during temperature variations. This can be achieved by specifically altering the time profile of operating a particular thermoelectric transducer, i.e., while one thermoelectric transducer with high power consumption is heating up, another thermoelectric transducer operates at a constant temperature with low power consumption. The result of this operation is that the total sum of power consumption of the thermoelectric transducers is lower than that of simultaneous operation with high power consumption. When the above-described apparatus is operated according to the method of the invention, the power provided by the electrical equipment is utilized in a very efficient manner. Using the method according to the invention, a larger number of hot blocks can be operated simultaneously using a given amount of available power compared to the simultaneous heating and cooling of the hot blocks. To control and operate the method of the invention, a thermal cycling scheme under computer feedback control is provided. A computer program is written using software tools that calculate the real-time compensation required for the characteristics of different hot blocks.

[0031] According to a specific embodiment of the method of the present invention, the method further includes the step of calculating real-time compensation for the peak power consumption of a heat block during temperature variation. Another possibility is to provide a hold time to the peak power consumption of any other heat block during the temperature variation time and / or hold time, wherein the operation of multiple heat blocks in a non-overlapping power consumption mode is based on this real-time compensation. In this embodiment, the method includes the step of calculating real-time compensation for the peak power consumption between different heat blocks corresponding to each thermoelectric transducer. This real-time compensation calculation is performed by a computer or an electronic circuit board provided by one or more thermal units of the device. Real-time compensation between power consumption peaks can be calculated when the temperature remains constant and the power consumption is low, which occurs during the temperature rise period, or alternatively, real-time compensation can be calculated between hold times. According to this embodiment of the method, real-time compensation always exists between the times of maximum power consumption of each heat block. Thus, the device operates in a non-overlapping power consumption mode, and the total power consumption of the device remains as low as possible.

[0032] According to a specific embodiment as an alternative, a dPCR consumable containing a sample can also be supplied by two hot blocks, wherein the thermal unit comprises a total of six hot blocks. Thus, the six hot blocks form three pairs, two hot blocks per pair, thereby accommodating a total of three consumables. The two hot blocks in a pair operate simultaneously without real-time compensation to apply the same temperature to the entire consumable at any given time. Real-time compensation is calculated between multiple pairs of hot blocks operating in a non-overlapping power consumption mode. Therefore, the method further includes the step of calculating real-time compensation for the peak power consumption of a pair of hot blocks during temperature variation. Another possibility is to provide a hold time to the peak power consumption of any other pair of hot blocks during the temperature variation time and / or hold time, wherein the real-time compensation for multiple pairs of hot blocks operating in a non-overlapping power consumption mode is based on this. In this embodiment, the method includes the step of calculating real-time compensation for the peak power consumption between different pairs of hot blocks corresponding to each pair of thermoelectric transducers. This real-time compensation calculation is performed by a computer or an electronic circuit board provided by one or more thermal units of the device. When the temperature remains constant and power consumption is low, real-time compensation between power consumption peaks can be calculated, occurring during the heating period, or alternatively, real-time compensation between holding times can be calculated. According to this embodiment of the method, real-time compensation always exists between the maximum power consumption times of each pair of hot blocks. This allows the device to operate in a non-overlapping power consumption mode, and keeps the total power consumption of the device as low as possible.

[0033] As used herein and in the appended claims, the singular forms “a,” “an,” “the,” and “the” include plural referents unless the context explicitly states otherwise. Similarly, the words “comprising,” “containing,” and “including” should be interpreted inclusively rather than exclusively; in other words, they mean “including, but not limited to.” Likewise, the word “or” is intended to include “and” unless the context explicitly states otherwise. The terms “multiple,” “various,” or “multiple” refer to two or more, i.e., 2 or >2, which are integer multiples, where the terms “single” or “unique” refer to one, i.e., =1. Furthermore, the term “at least one” should be understood to mean one or more, i.e., 1 or >1, which are also integer multiples. Accordingly, the use of singular or plural words also includes multiple or single quantities, respectively. Furthermore, when the words “in this document,” “above,” “previously,” and “below,” and words with similar meanings are used in this application, these words should refer to the application as a whole and not any particular part of the application.

[0034] Furthermore, certain terms are used for convenience and are not intended to limit the invention. The terms “right,” “left,” “up,” “down,” “below,” “under,” and “above” refer to the orientation of the figures. Terms include explicitly mentioned terms as well as their derivatives and terms with similar meanings. Moreover, spatial relative terms (such as “below,” “below,” “under,” “above,” “above,” “near,” “far,” etc.) may be used to describe the relationship between one element or feature and another element or feature as shown in the figures. These spatial relative terms are intended to cover different positions and orientations of the device in use or operation, in addition to the positions and orientations illustratively illustrated in the figures. For example, if the device in the figures is flipped, an element described as “below” or “under” other elements or features will be “above” or “above” other elements or features. Thus, the exemplary term “below” can cover both above and below positions and orientations. The device may be oriented in other ways (rotated 90 degrees or in other orientations), and the spatial relative descriptive terms used herein will be interpreted accordingly. Similarly, descriptions of movement along and around various axes include various spatial device positions and orientations.

[0035] To avoid repetition in the accompanying drawings and in the description of various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. The description of specific embodiments of this disclosure is not intended to be exhaustive or to limit this disclosure to the precise forms disclosed. Although specific embodiments and examples of this disclosure are described herein for illustrative purposes, various equivalent modifications may be within the scope of this disclosure, as will be recognized by those skilled in the art. Specific elements of any of the foregoing embodiments may be combined with or substituted for elements in other embodiments. Furthermore, although advantages associated with certain embodiments of this disclosure have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need to necessarily exhibit such advantages to fall within the scope of this disclosure as defined by the appended claims. The omission of an aspect in the specification or drawings does not mean that the aspect is missing from the embodiments incorporating that aspect. Rather, the aspect may have been omitted for clarity and to avoid lengthy description. In such cases, the following applies to the remainder of this specification: if the figures contain reference numerals not explained in the directly related parts of the specification for the purpose of clarity, then reference is made to the preceding or following descriptive sections. Furthermore, for clarity, if not all features of a part are provided with reference symbols in the accompanying drawings section, refer to other sections of the same drawings. Similar numbers in two or more drawings represent the same or similar elements.

[0036] The following examples are intended to illustrate various specific embodiments of the invention. Therefore, the specific modifications discussed below should not be considered as limiting the scope of the invention. It will be apparent to those skilled in the art that various equivalent examples, changes, and modifications can be made without departing from the scope of the invention, and therefore it should be understood that such equivalent embodiments should be included herein. Other aspects and advantages of the invention will become apparent from the following description of specific embodiments shown in the accompanying drawings.

[0037] References to "embodiments" that are not within the scope of the appended claims throughout this specification are merely possible exemplary implementations and are therefore not part of this invention. Attached Figure Description

[0038] Figure 1 is a conceptual exploded view of the cooling structure of the thermal unit according to an embodiment of the present invention;

[0039] Figure 2 is a conceptual perspective view of the assembled cooling structure of the thermal unit shown in Figure 1 without the tube cover, shown from below.

[0040] Figure 3 is a conceptual cross-sectional perspective view of the assembled cooling structure of the thermal unit shown in Figure 1, viewed from below.

[0041] Figure 4 is Figure 1And a conceptual cross-sectional side view of the assembly cooling structure of the thermal unit shown in Figure 3;

[0042] Figure 5 is a conceptual perspective view of the heat block of a thermal unit according to an embodiment of the present invention; and

[0043] Figure 6 is a conceptual exploded diagram of an apparatus for simultaneously thermally cycling multiple samples in dPCR consumables according to an embodiment of the present invention.

[0044] List of reference numerals

[0045] 1 thermal unit

[0046] 2 Cooling Structure

[0047] 21 Radiator

[0048] The first side of the 211 radiator

[0049] The second side of the 212 radiator

[0050] 2121 Cooling fin structure

[0051] 2122 Snap-on Interface

[0052] 2123 Connection Interface

[0053] 22 guide board

[0054] 221 fan

[0055] 223 pushers

[0056] 224 gaps

[0057] 23 pipe cover plate

[0058] Through holes in the 231 pipe cover plate

[0059] The first part of the 24a exhaust pipe

[0060] The second part of the 24b exhaust pipe

[0061] 242 arrows

[0062] 25 intake pipe

[0063] 251 partition wall

[0064] Arrows A to F

[0065] 3 hot blocks

[0066] 31 Thermoelectric transducer

[0067] 32 top plate

[0068] 321 Top Surface

[0069] 33 heat transfer plate

[0070] 34 Electronic Circuit Board

[0071] 4. Outer shell

[0072] 5. Downward limit switch

[0073] 100 Device for simultaneous thermal cycling Detailed Implementation

[0074] Figure 1 shows a conceptual exploded view of the cooling structure 2 of the thermal unit 1 according to an embodiment of the present invention. The embodiment of the cooling structure 2 shown includes three main components: a heat sink 21, a guide plate 22, and a pipe cover plate 23.

[0075] The uppermost component in the exemplary illustration of Figure 1 is a heat sink 21. The heat sink 21 is made of a metal with high thermal conductivity, such as aluminum or an aluminum alloy. The heat sink 21 is manufactured by forging or the like. The heat sink 21 includes a first side 211 intended to connect to the heat block 3 of the heat unit 1. The heat sink 21 includes a second side 212 opposite to the first side and oriented towards the observer in Figure 1. The second side 212 of the heat sink 21 is intended to connect to a guide plate 22, which is shown as a component in the center of the exploded view of Figure 1. A cooling fin structure 2121 is arranged on the second side 212 of the heat sink 21. The cooling fin structure 2121 includes a plurality of cooling fins protruding from the second side 212. In the region surrounding the center of the second side 212, the cooling fins of the cooling fin structure 2121 are arranged in a star pattern. In the region of the cooling fin structure 2121 where the cooling fins are arranged in the aforementioned star-shaped pattern (also called the star region), the intake airflow provided by the two fans 221 impacts or strikes the second side 212 of the radiator 21. The intake airflow is then distributed and guided by the cooling fins to the lateral sides of the radiator 21. In the left and right regions of the star region, the cooling fins are arranged parallel to each other. In these regions adjacent to the star region, the cooling fins guide the intake / exhaust airflow to the lateral sides of the radiator 21.

[0076] The radiator 21 has the general function of absorbing and dissipating heat energy from one or more heat blocks 3 (not shown in FIG. 1). The radiator 21 transfers heat energy from the heat blocks 3 to itself via its first side 211. An intake airflow is provided by two fans 221 and impacts the second side 212 of the radiator 21. The second side 212 and the cooling fin structure 2121 then redirect the intake airflow so that it subsequently flows parallel to the second side 212. The intake airflow receives heat energy from the cooling fin structure 2121 and transports that heat energy outside the cooling structure 2. The radiator 21 is also intended to serve as a component base to allow for the attachment of other components. Therefore, the radiator 21 includes several mechanical interfaces to ensure the proper positioning and attachment of such other components. For example, the radiator 21 includes four snap-fit ​​interfaces 2122, which are mechanical interfaces for connecting the radiator 21 to the guide plate 22. The radiator 21 also includes several connection interfaces 2123, which are also mechanical interfaces intended for connection to other components of the thermal unit 1 of the device 100. The radiator 21 may also include other mechanical interfaces, which are not described or shown in further detail.

[0077] In the center of the exploded view of Figure 1, a guide plate 22 is arranged. The guide plate 22 is intended for assembly with the heat sink 21. In the assembled state, the guide plate 22 covers the largest portion of the second side 212 of the heat sink 21. The guide plate 22 of the currently described embodiment carries at least one fan, in the form of two fans 221. However, any number of fans can be used here. Each fan 221 is positioned in a separately provided through-hole. The fan 221 draws in ambient air and generates an intake airflow that flows through the through-hole of the guide plate 22 in a direction toward the second side 212 of the heat sink 21. Moreover, the guide plate 22 includes four push rods 223, which are mechanical interfaces for connection with the heat sink 21. The guide plate 22 and the heat sink 21 are connected to each other, for example, by means of a snap-fit ​​connection. This snap-fit ​​connection is provided by a combination of the four push rods 223 snapping into their respective snap-fit ​​interfaces 2122. The guide plate 22 also includes a first portion 24a and a second portion 24b of an exhaust pipe. The first portion 24a of the exhaust pipe is shown only in Figures 2 through 4. The second portion 24b of the exhaust pipe, as shown in Figure 1, is provided by a recess in a guide plate 22 oriented towards the observer. This recess is positioned between the outer edge of the guide plate 22 and the portion of the guide plate 22 carrying the two fans 221. In the exemplary illustration of Figure 1, the exhaust flow flows from the right side of the guide plate 22, around the two fans 221 and the two through-holes, toward the left side of the guide plate 22, as indicated by the two arrows 242. In the assembled state, the second portion 24b of the exhaust pipe is covered by a pipe cover plate 23, shown as the lowest component in the exploded view of Figure 1. The pipe cover plate 23 is a flat component containing two through-holes 231. In the assembled state, these through-holes 231 are positioned coaxially with the through-holes of the guide plate 22. The intake airflow is drawn through the through-holes 231 into the fans 221. In the embodiment shown in Figure 1, the guide plate 22 may be made of a plastic material, and the pipe cover 23 may be made of stainless steel sheet. The pipe cover 23 can be assembled to the heat sink 21 using connecting elements such as screws. The pipe cover 23 is connected to one or more mechanical interfaces of the heat sink 21. The mechanical connection between the pipe cover 23 and the heat sink 21 presses the pipe cover 23 against the guide plate 22. This mechanical connection provides a seal between the pipe cover 23 and the guide plate 22, and thus seals the second portion 24b of the exhaust pipe.

[0078] Figure 2 shows a conceptual perspective view of the assembled cooling structure 2 of the heat unit 1 shown in Figure 1. In Figure 2, the radiator 21 and the guide plate 22 are connected to each other by a snap-fit ​​connection between the push rod 223 and the snap-fit ​​interface 2122. To improve the visibility of the second part 24b of the exhaust pipe, the pipe cover plate 23 is omitted in Figure 2. Figure 2 shows that most of the area of ​​the second side 212 of the radiator 21 is covered by the guide plate 22. The guide plate 22 and the radiator 21 together form the first part 24a of the exhaust pipe. Within the first part 24a of the exhaust pipe, the exhaust flow is guided by the cooling fin structure 2121 from the central portion of the second side 212 of the radiator 21 to the side of the radiator 21. The exhaust flow exits the first part 24a of the exhaust pipe on the lateral side of the radiator 21, which is oriented towards the left side in Figure 2. Another portion of the exhaust flow exits the first section 24a of the exhaust pipe on the right side of the radiator 21 and flows through a slot 224 within the guide plate 22. The path of that portion of the exhaust flow flowing through the slot 224 is indicated by two arrows 242. After flowing through the slot 224, the exhaust enters the second section 24b of the exhaust pipe. The exhaust flow follows the conduit provided by the combination of the guide plate 22 and the pipe cover plate 23 and flows around the two fans 221. The exhaust flow exits the second section 24b of the exhaust pipe on the left side of the guide plate, as shown in Figure 2. The second section 24b of the exhaust pipe is adjacent to the outlet of the first section 24a of the exhaust pipe. Therefore, in Figure 2, the combined exhaust flow exiting the first section 24a and the second section 24b of the exhaust pipe then exits the cooling structure 2 on the left side. Thus, the total exhaust flow can be easily removed from the heat unit 1 by other components, not shown in Figure 2.

[0079] Figure 3 shows a conceptual cross-sectional perspective view of the assembled cooling structure 2 of the thermal unit 1 shown in Figure 1. In Figure 3, the pipe cover plate 23 is assembled onto the cooling structure 2. In the cross-sectional view of Figure 3, the first portion 24a of the exhaust pipe is clearly visible between the radiator 21 and the guide plate 22. The second portion 24b of the exhaust pipe is only partially visible because it is mostly covered by the pipe cover plate 23. The cross-sectional view in Figure 3 shows two intake pipes 25 provided by the combination of the through-hole 231 in the pipe cover plate 23 and the guide plate 22. The intake pipes 25 direct ambient air toward the fan 221. The intake pipes 25 are separated from the exhaust pipes 24a and 24b by a partition wall 251. Therefore, within the cooling structure 2, the intake airflow is structurally separated from the exhaust airflow.

[0080] Figure 4 shows a conceptual cross-sectional side view of the assembled cooling structure 2 of the thermal unit 1 shown in Figure 1. In the cross-sectional view of Figure 4, the intake / exhaust airflow through the cooling structure 2 is indicated by arrows A to F. The intake airflow from the periphery of the cooling structure 2 enters the cooling structure 2 via the intake pipe 25, as indicated by arrow A. The intake airflow is then drawn in by two fans 221 and directed to the second side 212 of the radiator 21. After passing through the intake pipe 25 and the fans 221, the intake airflow impacts the cooling fin structure 2121. The cooling fin structure 2121 then deflects the intake airflow, that is, directs the intake airflow from the direction perpendicular to the second side 112 of the radiator 21 as indicated by arrow A to the direction parallel to the second side 112 as indicated by arrow B. A portion of the intake airflow is deflected by the cooling fin structure 2121 to the left side of the radiator 21 and flows through the first portion 24a of the exhaust pipe. Along its path through radiator 21, the intake air carries away heat from radiator 21, i.e., it is heated and thus becomes exhaust. This portion of the exhaust exits the first section 24a of the exhaust pipe on the left-hand side, as indicated by arrow C. Another portion of the intake air is directed by the other portion of the first section 24a of the exhaust pipe to the right-hand side of radiator 21. This portion of the intake air is also heated and becomes exhaust along its path through the first section 24a of the exhaust pipe. This portion of the exhaust flows through slit 224 and enters the second section 24b of the exhaust pipe, as indicated by arrow D. The exhaust is directed from the right-hand side of the second section 24b of the exhaust pipe formed by guide plate 22 and pipe cover plate 23 to the left-hand side of the second section 24b of the exhaust pipe, as indicated by arrow E. Finally, the exhaust exits the second section 24b of the exhaust pipe and the cooling structure 2 on the left-hand side, as indicated by arrow F.

[0081] Figure 5 shows a conceptual perspective view of a heat block 3 of a heat unit 1 according to an embodiment of the present invention. A top plate 32 is provided on top of the heat block 3. The top plate 32 includes a planar top surface 321. This planar top surface 321 is the area where consumables containing samples undergoing thermal cycling will be placed. Since these consumables typically include a planar lower surface, excellent heat transfer between the planar top surface 321 and the lower surface of the consumables is ensured. The heat block 3 shown in Figure 5 includes two thermoelectric transducers 31 attached to the lower surface of the top plate 32. The two thermoelectric transducers 31 are not visible in Figure 5 because they are covered by the top plate 32. For example, the thermoelectric transducers 31 can be Peltier elements, also known as thermoelectric coolers (TECs). This TEC converts electrical energy into heat or cold energy. The top plate 32 can be cooled or heated by the thermoelectric transducers 31. On the side opposite to the top plate 32, the thermoelectric transducers 31 are connected to a heat transfer plate 33. The heat transfer plate 33 transfers heat from the thermoelectric transducer 31 to the cooling structure 2 (not shown in FIG. 5). The heat transfer plate 33 further includes several connections, for example, to connect an electronic circuit board 34 to the heat block 3. Such an electronic circuit board 34, used to support the thermoelectric transducer, can be a printed circuit board assembly (PCBA) that can be connected to one or more temperature sensors located in or at the top plate 32, and can be configured for calibrating temperature deviation compensation and for storing the corresponding calibration data in a built-in memory. Such an electronic circuit board 34 is assembled on the side of the heat transfer plate 33 oriented towards the left side in FIG. 5. The heat transfer plate 33 in FIG. 5 is made of aluminum alloy and therefore has high thermal conductivity. The top plate 32, the thermoelectric transducer 31, and the heat transfer plate 33 can be secured to each other by means of a clamping mechanism (not shown in FIG. 5). This clamping mechanism ensures a constant connection force between the three components.

[0082] Figure 6 shows a conceptual exploded view of an apparatus 100 for simultaneously thermally cycling multiple samples in a dPCR consumable according to an embodiment of the present invention. The bottommost component illustrated in Figure 6 is the thermal unit 1, which has been partially described above. The thermal unit 1 includes the cooling structure 2 as described above, and this cooling structure 2 corresponds to the components in Figures 1 to 2. Figure 4The embodiment shown in FIG. 6. The cooling structure 2 is shown in a top view, making the first side 211 of the heat sink 21 oriented toward the heat blocks 3 visible. In the embodiment shown in FIG. 6, the thermal unit 1 comprises six heat blocks 3, which are shown above the cooling structure 2. The heat blocks 3 are assembled onto the cooling structure 2, and their heat transfer plates 33 are connected to the first side 211 of the heat sink 21. Two heat blocks 3 are arranged adjacent to each other, such that the six heat blocks 3 form three groups, each group having two heat blocks 3. Above the groups of heat blocks 3, i.e., above the thermal unit 1, a downward limiter 5 is shown. The downward limiter 5 is assembled onto the thermal unit 1 and is configured to press the consumable containing the sample undergoing thermal cycling against the top plate 32 of the heat blocks 3. By pressing the consumable against the top plate 32, the heat transfer between the heat blocks 3 and the sample is further improved. The downward limiter 5 may also include a door or window for opening and closing the housing 4 to load or unload consumables onto or from the hot block 3. On the top side of the exemplary illustration shown in Figure 6, and which will be assembled onto other components, is the housing 4. The housing 4 covers other components, particularly the hot block 3 on which the sample is loaded, during thermal cycling. The housing 4 may be made of stainless steel sheet metal or plastic material. The housing 4 is permanently fixed to the heat sink 21 of the thermal unit 1.

[0083] Although the invention has been described with reference to specific embodiments thereof, it should be understood that this specification is for illustrative purposes only. Accordingly, the invention is limited only by the scope of the appended claims.

Claims

1. A thermal unit (1) for simultaneous thermal cycling of multiple samples, having at least one heat block (3) and a cooling structure (2), the heat block (3) comprising at least one thermoelectric transducer (31) and a heat transfer plate (33) attached to the thermoelectric transducer (31) for dissipating heat energy from the thermoelectric transducer (31), and the cooling structure (2) comprising a radiator (21), at least one fan (221) and exhaust pipes (24a, 24b), wherein The radiator (21) is connected to the heat transfer plate (33) on a first side (211) and exposed to the fan (221) on a second side (212), wherein the fan (221) provides airflow toward the second side (212) of the radiator (21), and The exhaust pipes (24a, 24b) guide the exhaust flow away from the second side (212) of the radiator (21), wherein the intake flow and the exhaust flow are structurally separated from each other. The exhaust flow is guided substantially perpendicular to the intake airflow, wherein at least a portion of the exhaust flow is guided around the at least one fan (221) by means of the exhaust pipes (24a, 24b).

2. The heat unit (1) according to claim 1, wherein the heat sink (21) includes a cooling fin structure (2121) on at least its second side (212).

3. The heat unit (1) according to claim 2, wherein the cooling fins are substantially parallel to the airflow provided by the fan (221) and protrude from the second side (212) of the radiator (21).

4. The heat unit (1) according to claim 2, wherein the cooling fins are provided in the form of a forged fin structure.

5. The heat unit (1) according to any one of claims 2-4, wherein the cooling fin structure (2121) of the heat sink (21) at least in the region of the fan (221) is arranged in a star shape to guide the intake airflow provided by the fan (221) toward the side of the heat sink (21).

6. The heat unit (1) according to any one of claims 1-4, wherein the first side (211) of the heat sink (21) is opposite to the second side (212) of the heat sink (21).

7. The heat unit (1) according to any one of claims 1-4, wherein the at least one fan (221) is disposed in the through hole of the guide plate (22) of the cooling structure (2).

8. The thermal unit (1) according to claim 7, wherein The exhaust pipe (24a) is formed by the second side (212) of the radiator (21) and the guide plate (22) and / or the exhaust pipe (24b) is formed by the guide plate (22) and the pipe cover plate (23) and / or The heat sink (21) and the guide plate (22) are connected by a snap-fit ​​connection.

9. The thermal unit (1) according to any one of claims 1-4, further comprising an intake pipe (25) for directing ambient air toward the fan (221), wherein the intake pipe (25) is structurally separated from the exhaust pipes (24a, 24b).

10. The thermal unit (1) according to claim 9, wherein the intake pipe (25) is structurally separated from the exhaust pipe (24a, 24b) by means of a partition wall (251).

11. The thermal unit (1) according to any one of claims 1-4, wherein the at least one thermal block (3) further comprises at least one top plate (32) having a substantially planar top surface (321) for thermal contact with dPCR consumables, wherein the at least one thermoelectric transducer (31) is attached to a bottom side surface of the top plate (32) opposite to its top surface (321).

12. The thermal unit (1) according to claim 11, wherein a clamping mechanism is provided for clamping the top plate (32), the thermoelectric transducer (31) and the heat transfer plate (33) together to provide thermal contact between the top plate (32) and the thermoelectric transducer (31) and / or between the thermoelectric transducer (31) and the heat transfer plate (33).

13. The heat unit (1) according to claim 11, wherein the heat block (3) further comprises at least one heat transfer medium between the top plate (32) and the thermoelectric transducer (31) and / or between the thermoelectric transducer (31) and the heat transfer plate (33).

14. The thermal unit (1) according to claim 13, wherein the at least one heat transfer medium is in the form of a heat transfer foil.

15. The thermal unit (1) according to any one of claims 1-4, wherein the thermal block (3) further comprises at least one temperature sensor for temperature control located in the top plate (32).

16. The heating unit (1) according to any one of claims 1-4, wherein the heating block (3) further comprises at least one temperature sensor for temperature control located at the top plate (32).

17. The thermal unit (1) according to claim 15, wherein at least two temperature sensors are provided for temperature control and for redundancy-based process control.

18. The thermal unit (1) according to claim 15, wherein the thermal block (3) further comprises an electronic circuit board (34) for supporting the thermoelectric transducer (31) and the temperature sensor.

19. The thermal unit (1) according to claim 18, wherein the electronic circuit board (34) is in the form of a printed circuit board assembly.

20. The thermal unit (1) according to claim 18, wherein the electronic circuit board (34) is configured to calibrate temperature deviation compensation and to store the corresponding calibration data in a built-in memory.

21. The thermal unit (1) according to claim 18, wherein the electronic circuit board (34) includes an analog-to-digital converter for converting an analog temperature signal from an arbitrary temperature sensor into a digital signal.

22. The thermal unit (1) according to any one of claims 1-4, wherein the thermal block (3) constitutes a replaceable self-contained entity within the thermal unit (1), and / or wherein the heat sink (21) is configured to receive a plurality of thermal blocks (3).

23. The thermal unit (1) according to claim 22, wherein the heat sink (21) is configured to receive six heat blocks (3).

24. An apparatus (100) for simultaneously thermally cycling multiple samples in dPCR consumables, the apparatus comprising: The outer shell (4), and At least one thermal unit (1) according to any one of claims 1-23 is fixed inside the housing (4), wherein the exhaust pipe (24a, 24b) of each thermal unit (1) is formed in part by the second side (212) of the radiator (21) and the guide plate (22) and in part by the guide plate (22) and the pipe cover plate (23).

25. A method for simultaneously thermally cycling multiple samples, the method comprising the following steps: The apparatus (100) according to claim 24 is provided, wherein each thermal unit (1) comprises a plurality of thermal blocks (3), and The thermal cycling scheme is executed under computer feedback control. The plurality of hot blocks (3) operate in a non-overlapping power consumption mode.

26. The method of claim 25, wherein the thermal cycling protocol includes nucleic acid amplification.

27. The method according to claim 25 or 26, wherein the method further comprises the following steps: Calculate the real-time compensation of the peak power consumption of a single heat block (3) or a pair of heat blocks (3) during the temperature change time and / or hold time relative to the peak power consumption of any other heat block (3) or a pair of heat blocks (3) during the temperature change time and / or hold time, and wherein the operation of the plurality of heat blocks (3) or the plurality of pairs of heat blocks (3) in a non-overlapping power consumption mode is based on the real-time compensation.

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