Thermal unit and device for thermal cycling of a biological sample, and method for thermal cycling of a biological sample using such a device

Abstract

To provide a thermal unit that significantly improves thermal cycling of a large number of reaction vessels for dPCR.SOLUTION: The present invention provides a thermal unit for simultaneous thermal cycling of a plurality of samples, with at least one thermal block and a cooling structure 2, the thermal block comprising at least one thermoelectric energy converter and a thermal transfer plate attached to the thermoelectric energy converter for dissipation of thermal energy away from the thermoelectric energy converter, and the cooling structure comprising a thermal sink 21, at least one air fan 221 and an exhaust air duct 24b, wherein the thermal sink is connected to the thermal transfer plate on a first side 211 and is exposed to the air fan on a second side 212, with the air fan providing a stream of intake air towards the second side of the thermal sink, and the exhaust air duct guides a stream of exhaust air away from the second side of the thermal sink, with the stream of intake air and the stream of exhaust air being structurally separated from each other.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Generally, the present invention relates to the technical field of sample analysis, such as the analysis of biological samples, and more particularly 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 thermocycling a plurality of biological samples simultaneously, also called thermal cycling, such an apparatus itself, and a method for thermocycling a plurality of biological samples simultaneously using such an apparatus and thermal unit.

[0003] In other words, the present invention generally relates to a thermal cycling structure for carrying out chemical and / or biological reactions, for example, polymerase chain reaction (PCR), and such a thermal cycling structure can be provided inside experimental instruments such as thermocyclers or thermal cyclers. Such a thermal cycling structure typically includes at least a sample mount, 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 a plurality of nucleic acid amplification reactions while thermocycling a biological sample by such a thermal cycling apparatus, and the thermal cycling structure can include two or more of such thermal units. Further, the present invention relates to a method for thermocycling a plurality of biological samples simultaneously using such an apparatus and thermal unit, and the thermocycling protocol is executed under feedback control by a computer or the like.

Background Art

[0004] Biological samples are usually collected from patients for laboratory analysis by medical personnel in hospitals or private practitioners, for example, to determine the concentration levels of various components in the collected samples. Thus, the terms "sample" and "biological sample" refer to materials that can potentially contain the target analyte, and biological samples can be derived from any biological origin such as physiological fluids including blood, saliva, aqueous humor, cerebrospinal fluid, sweat, urine, feces, semen, milk, ascites, mucous membranes, synovial fluid, ascites, amniotic fluid, tissues, cultured cells, etc., and the sample can be suspected of containing a specific antigen or nucleic acid.

[0005] For many biological, biochemical, diagnostic or therapeutic applications, it is essential to accurately determine the amount or concentration of a specific substance or compound in a biological sample contained in a reaction mixture such as the aforementioned specific antigen or nucleic acid. To enable accurate achievement of this goal, methods such as the well-known polymerase chain reaction (PCR) in the form of, for example, digital PCR (dPCR), real-time PCR (qPCR), or reverse transcription polymerase chain reaction (RT-PCR) have been developed over the years, which enables in vitro synthesis of nucleic acids in biological samples and can specifically replicate DNA segments, that is, it is a cost-effective method of copying or amplifying small segments of DNA or RNA in a sample. In clinical diagnosis, PCR is particularly used to quantify nucleic acid strands in the form of sections of DNA or RNA by amplification in order to enable detection of diseases and mutations. To perform such PCR, usually a so-called thermocycler is required to heat and cool the sample and reaction mixture in the reaction vessel over many cycles. Here, dPCR is a rather new variant of the PCR method to achieve higher accuracy and higher sensitivity, and the PCR method is applied to a single DNA molecule separated in an independent microfluidic reaction vessel, and the actual number of target DNA molecules after PCR can be counted, resulting in a "digital" result for each reaction vessel. This constitutes the main difference compared to other more common PCR methods. However, usually more than 20,000 large numbers of reaction vessels are required and can be placed within one microfluidic consumable.

[0006] As described above, the development of dPCR for amplifying DNA or RNA segments has brought great benefits to gene analysis, the diagnosis of many genetic diseases, or the detection of viral loads. In the process of typical PCR implementation, a specific target nucleic acid is amplified by a series of repetitions of the following steps cycle, and the nucleic acids present in the reaction mixture are (a) denatured at a relatively high temperature, e.g., above 90 °C, usually about 94 - 95 °C, to separate double-stranded DNA that is denatured, e.g., by denaturation, and then (b) at an annealing temperature of about 52 - 56 °C, e.g., for primer binding with the separated DNA strands to provide a template (annealing), the reaction mixture is cooled to the temperature at which short oligonucleotide primers bind to single-stranded target nucleic acids, and then (c) at an extension temperature of about 72 °C, e.g., for generating new DNA strands, the primers are extended / elongated using a polymerase enzyme, and as a result, the original nucleic acid sequence is replicated. The repeated cycles of denaturation, annealing, and extension, usually about 25 - 30 repeated cycles, exponentially increase the amount of target nucleic acid present in the sample, and the heating and cooling times of the sample have a great impact on the overall processing time. Therefore, the less time wasted at non-optimal temperatures, the better or more accurate chemical results can be obtained. In particular, a specific minimum time for holding the reaction mixture at each temperature plateau is required after reaching the same temperature plateau, and such a minimum holding time is the minimum time required to complete one thermal cycle. The time during the transition between PCR temperature plateaus is added to this minimum cycle time. Therefore, since the number of thermal cycles can be large, such additional time unnecessarily lengthens the total time required to complete the PCR implementation. Therefore, shortening the heating and cooling times is essential for an efficient and cost-effective process and for improving the throughput of thermal cycling devices for PCR. Therefore, it is necessary to enable diagnostic tests to be performed faster, cheaper, and more easily while achieving accuracy and efficiency.

[0007] For example, a generally known thermal cycling device for amplifying DNA segments by PCR, as disclosed in International Publication No. WO 2007 / 146443, basically consists of a mount for receiving a sample and a heat pump attached to the mount, and the combination of the mount and the heat pump is sometimes called a heat block. The heat pump is often provided in the form of a thermoelectric device or a thermoelectric cooler (TEC), for example, in the form of a Peltier element, and is usually used for active heating and cooling of the mount, and thus is used to actively control the temperature applied to the sample. A TEC is typically a solid-state heat pump made of semiconductor materials sandwiched between ceramic plates, and the amount of heat pumped is proportional to the amount of current flowing through the TEC. With improved temperature control, by reversing the current, the TEC functions as a heater or a cooler and is very useful for thermal cycling at various temperatures. In other words, the TEC converts electrical energy into heating or cooling. Here, in addition to the mount for receiving the sample by the heat block, the TEC can be further combined with a heat sink or a cooling block attached to one side, and the sample mount is arranged on the other side of the Peltier element.

[0008] A combination of one or more TECs and a cooling block may also be referred to as a "Peltier sandwich" or a "thermal unit". To ensure the accurate and reliable thermal performance of such a thermal unit, heat transfer between its components is important and needs to be as high as possible and within strict tolerances. Therefore, a conductive foil or a phase change material can be provided between the TEC, the cooling block, and the sample mount. Since such foils are thin and fragile, they are difficult to apply, and for some types of foils, after assembly, they need to be heated to melt and close the micro-gaps or non-uniformities between the components of the thermal unit to ensure sufficient heat transfer. However, such a thermal unit assembly is complex, and considering the thermal performance that needs to be guaranteed, the replacement of only the Peltier element within the thermal unit in case of a failure or defect can only be carried out with a high workload and is therefore costly and not a common method.

[0009] Furthermore, commonly known thermal cycling devices are often designed for standard qPCR or RT-PCR applications, meaning they can only accommodate microtiter plates or single cuvettes. Therefore, the maximum number of reaction cavities in one PCR microtiter plate only increases up to 384 wells. However, this number of wells is not sufficient when compared to the over 20,000 cavities required for at least dPCR. Also, the shape of the cavities in a 384-well plate or single cuvette is usually in a shape such as cylindrical or conical. Therefore, to ensure that the temperature achieved in the thermal cycler is correctly transferred to each part of the sample / reaction mixture within the well or cuvette, it is necessary to adapt the design of the operating surface of the thermal cycler that receives the well or cuvette to each respective cylindrical or conical shape. Therefore, a customized thermal cycler can only accommodate one type of plate or cuvette, i.e., only the customized ones. Furthermore, depending on which type of plate or cuvette needs to be thermally cycled, there are thermal cyclers where the user can exchange the heat block. However, such exchange procedures are quite inconvenient, increase the handling cost of the equipment, and create an undesirable risk of damaging the thermal cycler or the heat block during the exchange procedure. Also, to ensure that the measured temperature matches the actual temperature of the operating surface that receives the well or cuvette, recalibration of the newly assembled thermal cycler after the heat block exchange is required, which is also quite inconvenient and increases the handling cost of the equipment.

[0010] Finally, to achieve an efficient and cost-effective process and improve the thermal cycle throughput, the transition time between different temperature levels during PCR is accelerated to shorten the heating and cooling times. Various types of heat sinks have been used within the thermal unit of a generally known thermal cycling apparatus, such as a heat sink with a specific fin arrangement, a heat sink based on heat pipe and vapor chamber technology. For example, European Patent No. 3524353 teaches an apparatus for thermal cycling of biological samples, which provides a heat pump for heating and cooling the samples. However, since this apparatus is not suitable for thermal cycling a large number of samples at short cycle intervals, the throughput of the samples is low. Therefore, there is still a desire to further increase the thermal cycle throughput by optimizing the heating and cooling times during thermal cycling. Therefore, due to these and other problems and drawbacks, the above-known concepts cannot meet the needs of today's users and thus do not provide a satisfactory solution. Therefore, there is a general need in the art to provide an improved thermal cycling apparatus having a thermal unit in which the heating and cooling times during thermal cycling are optimized, can be monitored after assembly, and can be easily replaced by a field service engineer in case of failure or defect. Summary of the Invention

[0011] The present invention addresses the above problems of the known prior art and significantly improves the thermal cycling of a large number of reaction vessels for dPCR. According to a first aspect of the present invention, a thermal unit for simultaneously thermal cycling a plurality of samples is provided, comprising at least one heat block and a cooling structure. The heat block comprises at least one thermoelectric energy converter and a heat transfer plate attached to the thermoelectric energy converter for dissipating thermal energy from the thermoelectric energy converter. The cooling structure comprises a heat sink, at least one air fan, and an exhaust duct. The heat sink is connected to the heat transfer plate on a first side and is exposed to the air fan on a second side, and the air fan provides an intake air flow towards the second side of the heat sink. The exhaust duct guides the exhaust air flow away from the second side of the heat sink, and the intake air flow and the exhaust air flow are structurally separated from each other. Thus, the thermal unit according to the present invention comprises two main assemblies, namely at least one heat block for heating or cooling a plurality of samples and a cooling structure for removing thermal energy from the thermal unit.

[0012] The heat block includes at least one thermoelectric energy converter which is a device for transferring electrical energy into thermal energy. Here, the thermoelectric energy converter can be heated or cooled. For example, the thermoelectric energy converter can be a thermoelectric cooler, a Peltier element also known as a TEC. Such a Peltier element converts electrical energy into heating or cooling. The thermoelectric energy converter is an element for actively heating or cooling a plurality of samples, and the thermoelectric energy converter is an element including two opposing sides. During the operation of the thermoelectric energy converter, one of these opposing sides is heated and the opposite side is cooled. Which of these opposing sides actually gets hot depends on the operating mode of the thermoelectric energy converter. By changing the operating mode, especially by changing the direction of the current, the side to be heated can be switched. One side of the thermoelectric energy converter is thermally connected to a plurality of samples. When heating the sample during the thermal cycle, the side of the thermoelectric energy converter thermally connected to the sample is heated. In this operating mode, the opposing side of the thermoelectric energy converter is cooled. When cooling the sample during the thermal cycle, the side thermally connected to the sample is cooled. In this operating mode, the opposing side of the thermoelectric energy converter is heated. The thermal energy generated on the side opposite to the side thermally connected to the sample needs to be directed away from the thermoelectric energy converter. In this regard, the cooling structure of the heat unit according to the present invention is provided to remove the thermal energy generated during the cooling of the sample. The heat block includes a heat transfer plate connected to the thermoelectric energy converter for transferring / removing this thermal energy from the heat unit.

[0013] The cooling structure comprises several elements. One of these elements is a heat sink that is thermally connected to the heat transfer plate of the heat block. The heat sink is an element that receives the thermal energy generated by the thermoelectric energy converter and transmitted by the heat transfer plate, and is made of a material with high thermal conductivity. The thermal energy transmitted by the heat transfer plate is dissipated to the heat sink. The heat sink itself is heated by this dissipated thermal energy, and the thermal energy in the heat sink must be further removed from the heat unit. The heat sink is made of a thermally conductive material, for example, cast and machined aluminum, and is used to transfer the dissipated heat from the thermoelectric energy converter to the ambient environment outside the heat unit. Further, the heat sink can be used as a base plate and incorporates a mechanical interface to ensure the correct placement and fixation of the components of the heat unit. Here, at least one air fan is provided to assist in removing the thermal energy from the heat sink. This air fan provides an intake air flow towards the second side of the heat sink. This second side of the heat sink faces the side of the heat sink that is thermally connected to the heat transfer plate of the heat block. The intake air flow is heated by the thermal energy of the heat sink, thus diverting this thermal energy away from the heat sink. After absorbing the thermal energy from the heat sink, an exhaust duct is provided to direct the intake air flow. After absorbing the thermal energy by the intake air flow, the same is true when it is called the exhaust air flow, because it no longer exhibits the characteristics of the intake air such as the ambient temperature, but exhibits different characteristics such as a temperature rise. Therefore, the temperature of the exhaust air flow is higher than the temperature of the intake air flow because it is absorbing the thermal energy from the heat sink.

[0014] An exhaust duct is provided to remove the flow of exhaust from the thermal unit. The exhaust duct guides the flow of exhaust away from the second side of the heat sink. The exhaust duct guides the flow of exhaust from the thermal unit in a controlled manner. According to the present invention, the intake flow and the exhaust flow are structurally separated from each other to provide a controlled induction of thermal energy from the thermal unit. The structural separation between the intake flow and the exhaust flow is mainly effected by the exhaust duct. Optionally, additional elements can be provided to separate the exhaust flow from the intake flow. The advantage of such a structural separation of the two air flows according to the present invention is that the dissipation of thermal energy from the heat sink is provided with very high efficiency respectively. Such a structural separation between the intake flow and the exhaust flow can ensure that the intake flow impinges on the heat sink at an optimal low ambient temperature. The flow of cold air can absorb a greater amount of thermal energy than the flow of hot air, such as the flow of air that has already been heated by crossing the exhaust. In the case of cold intake air, the gradient between the intake air temperature and the heat sink temperature becomes large. By separating the two air flows, it can be ensured that these two flows do not mix, i.e., the intake flow is not heated by mixing with the exhaust flow. Since the thermal cycle of the dPCR sample needs to be performed at short intervals of heating and cooling, a large amount of thermal energy is accumulated in the heat sink in a short time and needs to be efficiently removed from the thermal unit. Therefore, the structural separation of the intake flow from the exhaust flow as presented by the present invention is particularly useful for the thermal unit that needs to exhibit high heating and cooling performance.

[0015] According to certain embodiments of the present invention, the exhaust flow is directed substantially orthogonal to the intake flow, and at least a portion of the exhaust flow can be directed by an exhaust duct around at least one air fan. In this embodiment, the air fan is arranged to direct an intake flow that is essentially orthogonal to the heat sink and the heat transfer plate. Thus, the intake flow is directed towards the heat sink at an angle of approximately 90 degrees with respect to the longitudinal axis of the heat sink, and after impinging on the heat sink, is deflected by the same 90 degrees. After this deflection, the intake flow flows essentially parallel to the longitudinal axis of the heat sink, i.e., parallel to the longitudinal direction of the heat sink and the heat transfer plate. During this parallel intake flow, the passing air flow becomes hot by receiving thermal energy from the heat sink. By taking in thermal energy from the heat sink, the deflected intake flow is heated and thereby becomes an exhaust flow that carries heat away from the heat sink. Due to the deflection of the flow direction, the exhaust flow flows substantially orthogonal to the intake flow as initially provided by the air fan. Based on the described differences between the intake and exhaust flows, these flow directions intersect each other. To prevent such intersection and thus the mixing of air between these two flows, at least one flow is bypassed and its direction intersects the direction of the other flow. In the described embodiment, the exhaust flow is directed around at least one air fan and thus, for example, by an exhaust duct, the intake flow is directed. Here, the exhaust duct structurally separates both air flows from each other. The exhaust duct typically guides the exhaust flow by a duct wall adjacent to the exhaust flow.

[0016] According to another specific embodiment of the present invention, the heat sink includes a cooling fin structure on at least its second side, and the cooling fins can protrude from the second side of the heat sink substantially parallel to the intake air flow provided by an air fan. Also, the cooling fins can be provided in the form of a swaged fin structure. In this embodiment, the heat sink comprises a cooling fin structure for increasing the surface area available for dissipating and transferring thermal energy to the air flow provided by at least one air fan. The cooling fin structure is typically disposed on the second side of the heat sink, i.e., the side of the heat sink opposite the first side connected to the heat transfer plate, and is directed towards the intake air flow provided by the air fan. It is also possible to provide an additional cooling fin structure on another part of the heat sink, for example, a part of the heat sink that does not constitute the first or second side of the heat sink. More specifically, the cooling fins protrude from the second side of the heat sink. These cooling fins have a typical plate-like fin shape with two large opposing main surfaces, small side surfaces, and small end surfaces. The side surface facing the end surface is connected to the heat sink. The main surfaces of the cooling fins provide a large surface area for effectively transferring thermal energy to the cooling air flow. The cooling fins direct the intake / exhaust air flow between the main surfaces, i.e., the cooling fins direct the intake air flow provided by the air fan along the heat sink. According to a specific embodiment, the cooling fins can be provided in the form of a plate fin structure or as a pin fin structure. An effective method of manufacturing a heat sink with a cooling fin structure is to crimp both elements together as one part. The swaged cooling fin structure has a lifting bevel. The swaged heat sink with a cooling fin structure can be efficiently fabricated from a metal with high thermal conductivity such as copper, copper alloy, aluminum, aluminum alloy, etc. Alternatively, the heat sink with a cooling fin structure can also be manufactured by casting or the like.

[0017] According to a more specific embodiment of the present invention, at least in the region of the air fan, the cooling fin structure of the heat sink is arranged in a star shape to guide the intake air provided by the air fan toward the side surface of the heat sink. In this specific embodiment, the cooling fin structure of one air fan is star-shaped when viewed from the plan view of the second side surface of the heat sink. The flow of the intake air provided by the air fan reaches the second side surface of the heat sink that is orthogonal to this second side surface, that is, directly collides with the second side surface. In this way, the cooling fin structure provided in a star shape spreads the colliding intake air flow in a number of lateral directions. Due to such spreading, the cold intake air is dispersed over the cooling fin structure and thus over the entire heat sink. Therefore, the heat transfer from the heat sink to the colliding flow of the intake air is very effective. More specifically, the cooling fin structure can be particularly star-shaped at the location where the flow of the intake air collides with the second side surface of the heat sink. In the region near the side surface of the heat sink, the cooling fin structure can be arranged in the form of parallel plate fins in order to effectively guide the intake / exhaust air flow toward the side surface of the heat sink.

[0018] According to another specific embodiment of the present invention, the first side surface of the heat sink faces the second side surface of the heat sink, that is, faces the side opposite to the air fan. More specifically, the first side surface of the heat sink that is thermally connected to the heat transfer plate of the heat block faces the second side surface of the heat sink that faces the flow of the intake air provided by the air fan. Since the first side surface and the second side surface face each other but are arranged parallel to each other, the heat transfer from the heat block to the flow of the cooling air is very effective. It is also possible to arrange the second side surface at a specific angle, for example, a right angle, with respect to the first side surface. Such an orthogonal arrangement of the first side surface and the second side surface of the heat sink can have specific advantages when there is not enough available space in the heat unit to arrange the two sides facing each other.

[0019] According to certain embodiments of the present invention, at least one air fan is disposed within a through hole of a guide plate of a cooling structure, and an exhaust duct can be formed by a second side surface of the heat sink and the guide plate. Thus, the heat unit can include a guide plate that is part of the cooling structure. Such a guide plate can be provided to more effectively direct the intake flow and / or the exhaust flow. More specifically, the guide plate can at least partially cover the second side surface of the heat sink and the cooling fin structure. The guide plate further provides a through hole in or adjacent to which at least one air fan is disposed. The intake flow is drawn by the air fan and directed through the through hole in the guide plate towards the second side surface of the heat sink as described above. The guide plate can also provide means for assembling at least one air fan. The second side surface of the heat sink may comprise a cooling fin structure, and the guide plate can form at least part of the exhaust duct together. In this part of the exhaust duct, the exhaust flow is directed between the heat sink and the guide plate.

[0020] Alternatively or additionally, the exhaust duct can be formed by a guide plate and a duct cover plate. Here, it is possible to provide a duct cover plate connected to the guide plate. Thereby, at least a part of the exhaust duct can be formed by the side surfaces of the guide plate facing the side surfaces of the guide plate facing the heat sink, and the duct cover plate covers at least a part of the guide plate. The guide plate and the duct cover plate together provide a kind of channel through which the exhaust flow is guided. Due to the shape of the guide plate, the intake flow and the exhaust flow do not mix with each other. Since the duct cover plate covers at least a part of the guide plate, the duct cover plate also has through holes for the respective intake flows for at least one air fan. The exhaust duct can be provided in combination with the guide plate by the second side surface of the heat sink, or the exhaust duct can be provided in combination with the duct cover plate by the guide plate. Furthermore, the exhaust duct may be provided by combining both of these possibilities.

[0021] Furthermore alternatively or additionally, the heat sink and the guide plate can be connected by a snap - fit connection. The snap - fit connection is suitable for the rapid and reliable assembly of both components. In this regard, in the form of alternative or additional embodiments, the guide plate can be made of an elastic material such as, for example, a plastic or metal sheet. The guide plate can also be provided with tongue - shaped elements that allow elastic deformation as a means of snap - fit connection to the heat sink. Of course, the guide plate and the heat sink can also be connected to each other in different ways, for example, by an adhesive connection such as an adhesive, or by additional connection elements such as bolts and screws.

[0022] According to another specific embodiment of the present invention, the heat unit further includes an intake duct for directing ambient air towards the air fan, and the intake duct is structurally separated from the exhaust duct, for example, by a separation wall. In this embodiment, the intake duct is provided as an additional component of the heat unit to guide ambient air to the air fan and the heat sink. The intake duct can be designed as a kind of channel between the environment of the heat unit and the air fan. The intake duct is structurally separated from the exhaust duct to ensure that the intake air flow can be realized, for example, by one or more separation walls.

[0023] According to certain embodiments of the present invention, at least one heat block further comprises at least one upper plate having a substantially flat upper surface for thermal contact with a dPCR consumable, and at least one thermoelectric energy exchanger is attached to the lower surface of the upper plate facing its upper surface. Preferably, a clamping mechanism may be provided for clamping together the upper plate, the thermoelectric energy converter, and the heat transfer plate to provide thermal contact between the upper plate and the thermoelectric energy converter and / or between the thermoelectric energy converter and the heat transfer plate. In this embodiment, at least one heat block includes an upper plate provided for contacting and heating or cooling a consumable dPCR that is consumable with the sample. Such an upper plate can have a substantially flat upper surface. In this regard, such a flat upper surface can be optimal for excellent heat transfer between the upper plate and the dPCR consumable, which typically exhibits a flat lower surface. The upper plate can be made of a material with high thermal conductivity, such as copper. The lower surface of the upper plate can be thermally connected to the thermoelectric energy converter. During operation of the thermal unit, thermal energy needs to be transferred from the thermoelectric energy converter to both the upper plate and the heat transfer plate. Therefore, a clamping mechanism can be provided to press these three elements together. By using the clamping mechanism, reliable large-area contact is ensured, and thus efficient heat transfer between these elements is ensured. For example, the clamping mechanism can be made of metal elements fixed to each other by screw joints or the like. Optionally, the clamping mechanism can be spring-loaded. Such a spring-loaded embodiment of the clamping mechanism can efficiently compensate for the thermal expansion of the three elements during operation. Furthermore, with a spring-loaded clamping mechanism, it is possible to ensure that the clamping force is evenly distributed without adjustment during assembly. Since the clamping force during operation is constant for a spring-loaded clamping mechanism, it can also reduce mechanical stress on the thermoelectric energy converter. Therefore, based on such a clamping mechanism, the thermoelectric energy converter is sandwiched between the upper plate and the heat transfer plate.

[0024] According to a more specific embodiment of the present invention, the heat block further comprises at least one heat transfer medium, for example, in the form of a heat transfer foil or any other type of heat transfer medium, between the upper plate and the thermoelectric energy converter and / or between the thermoelectric energy converter and the heat transfer plate. In this embodiment, heat transfer within the heat block is further improved by using one or more heat transfer media between the elements. Such a heat transfer medium is a heat transfer foil. The heat transfer medium has excellent thermal conductivity and can fill small gaps between thermally connected elements. Thus, the heat transfer medium reduces the thermal resistance between these elements. As an alternative to or in addition to the heat transfer foil, a heat transfer paste can also be used to reduce the thermal resistance within the heat block.

[0025] According to a specific embodiment of the present invention, the heat block further comprises at least one temperature sensor within or on the upper plate for temperature control, and at least two temperature sensors can be provided for temperature control and for process control based on redundancy. In this embodiment, at least one temperature sensor is provided, and the sensor is connected to the upper plate. Here, such a temperature sensor can be arranged within the upper plate. The temperature sensor measures the temperature of the upper plate. To improve the reliability of the heat block, two temperature sensors can be provided if desired, and one of these temperature sensors determines the temperature as a redundant sensor for process control, thereby enhancing the certainty of the measurement.

[0026] According to a more specific embodiment of the present invention, the heat block further comprises an electronic substrate for supporting a thermoelectric energy converter and a temperature sensor, such as in the form of a printed circuit board assembly. The electronic substrate can be configured to calibrate temperature deviation compensation and store respective calibration data in an internal memory. Further, the electronic substrate can include an analog-to-digital converter for converting an analog temperature signal of any temperature sensor into a digital signal. In this embodiment, an electronic substrate is provided for controlling the thermoelectric energy converter. The electronic substrate is connected to at least one temperature sensor and receives its signal as an input for controlling the operation of the thermoelectric energy converter. Since the signal of the temperature sensor is usually an analog signal, the electronic substrate 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 substrate can be a printed circuit board, PCB, or a printed circuit board assembly, PCBA. In order to compensate for the tolerances of the analog temperature sensor, the measuring unit, the thermoelectric energy converter, and the assembly process, calibration is performed once after assembly so that the temperature value used for controlling the thermoelectric energy converter matches the actual temperature of the upper plate within strict tolerances. The electronic substrate attached to the heat block has a memory for storing such individual calibration data. The heat block and its individual calibration data are designed as spare parts and can be easily attached or removed from the thermal unit on-site during assembly or when replacement is required.

[0027] According to certain embodiments of the present invention, the heat block constitutes a replaceable self - contained entity within the thermal unit. In this embodiment, which can include the features of the above - mentioned embodiment, the heat block is a self - contained entity that can be easily replaced. Since the thermocycler for samples during dPCR requires strict temperature tolerances, it is necessary to calibrate the heat block before the operation of the thermal unit. Such a calibration process is usually complex and quite difficult to perform on - site. Since the heat block is designed as a self - contained entity, no calibration process is required after replacing the heat block. The calibration of such a self - contained entity can already be performed after assembly in a laboratory or factory, and the reliability of the heat block calibration process is high and easy to execute.

[0028] According to another certain embodiment of the present invention, the heat sink is configured to receive a plurality of heat blocks, for example, six heat blocks. In this embodiment, the heat sink is designed to be connected to a plurality of heat blocks. Thus, the thermal unit can include a plurality of heat blocks. These heat blocks can be assembled adjacent to the heat sink, so that their upper plates form one large common upper plate. Also, the plurality of heat blocks can be arranged side - by - side with a gap between their upper plates. In this embodiment, one cooling structure is provided to remove thermal energy from the plurality of heat blocks.

[0029] According to a second aspect of the present invention, there is provided an apparatus for simultaneous thermal cycling of a plurality of samples in a dPCR consumable, comprising a housing and at least one thermal unit fixed within the housing and described in any one of the above embodiments, wherein the exhaust duct of each thermal unit is formed partially by a second side surface of the heat sink and the guide plate, and partially by the guide plate and the duct cover plate. The duct cover plate can be fixed to the housing. The apparatus according to the present invention includes at least one thermal unit according to one or more of the above embodiments. The apparatus according to the present invention also includes further components. The apparatus includes a housing surrounding at least a part of the apparatus. The housing can be composed of several elements. These elements are part of the housing. One of these parts of the housing can be a duct cover plate assembled to the guide plate of at least one thermal unit. The heat sink of the cooling structure functions as an assembly base of the apparatus. The heat sink can provide a mechanical interface for connecting other parts of the apparatus, such as the housing, the heat block, and other components. The correct arrangement and fixation of the components of the apparatus are ensured by the mechanical interface.

[0030] According to a third aspect of the present invention, a method for simultaneous thermal cycling of a plurality of samples is provided, which comprises providing an apparatus as described above, wherein each thermal unit includes a plurality of heat blocks, and executing a thermal cycling protocol under computerized feedback control. Here, the thermal cycling protocol can include nucleic acid amplification, and the plurality of heat blocks can operate in a non-overlapping power consumption mode. The maximum power consumption of the apparatus according to the present invention is limited, for example, by the power provided by the electrical facilities in the laboratory environment. The power consumption of the thermoelectric energy converter depends on the state of the thermal cycle process, particularly on the current temperature, target temperature, and ramp rate. During ramp-up and ramp-down, the power consumption is usually high. When the temperature is kept constant between ramps, the power consumption is usually low. If all thermoelectric energy converters are executed simultaneously, this leads to an addition of the power consumption of all converters. Such an addition during ramp-up and ramp-down leads to an undesired high power consumption and is severely limited by the power provided by the electrical facilities. Therefore, the simultaneous operation of a plurality of thermoelectric energy converters can only be achieved for a small number of thermoelectric energy converters. In this case, only a very small number of samples can be processed simultaneously in a thermal cycle. Therefore, the throughput of the apparatus is significantly reduced. However, according to the present invention, the thermoelectric energy converter and the heat block can operate in such a way that the overlap of power peaks during ramping is prevented. This can be achieved by specifically shifting the timing profile for operating a particular thermoelectric energy converter, i.e., during the ramp-up of one thermoelectric energy converter with high power consumption, another thermoelectric energy converter is operated at a constant temperature with low power consumption. As a result of such an operation, the addition of the power consumption of the thermoelectric energy converter is less than in the case of simultaneous operation with high power consumption. When the above apparatus operates according to the method of the present invention, the power provided by the electrical facilities is utilized in a very effective way. In the method according to the present invention, more heat blocks can be operated simultaneously with a certain amount of available power compared to simultaneously performing ramp-up and ramp-down of the heat blocks.To control and execute the method of the present invention, a thermal cycling protocol under computer feedback control is provided. The computer is programmed with software tools that calculate the necessary timely offsets for the profiles of the various heat blocks.

[0031] According to a particular embodiment of the method according to the present invention, the method further comprises the step of calculating a timely offset of the peak power consumption of one heat block during ramping. Another possibility is to provide a holding time for the peak power consumption of any other heat block during the ramping time and / or the holding time, and the operation of multiple heat blocks in a non-overlapping power consumption pattern is based on such timely offsets. In this embodiment, the method includes the step of calculating a timely offset of the peak power consumption between different heat blocks or respective thermoelectric energy converters. This calculation of the timely offset is performed by an electrical substrate provided by one or more thermal units of the computer or device. The timely offset can be calculated between the peaks of the power consumption that occur during ramping, or alternatively, during the holding time when the temperature is kept constant and the power consumption is low. According to an embodiment of the method, there is always a timely offset during the time of the maximum power consumption of each heat block. In this way, the device operates in a non-overlapping power consumption pattern and the total power consumption of the device is kept as low as possible.

[0032] According to an alternative specific embodiment, one dPCR consumable containing a sample can also be supplied by two heat blocks, and the thermal unit includes a total of six heat blocks. Thus, the six heat blocks form three pairs of two heat blocks each, holding a total of three consumables. A pair of two heat blocks operates simultaneously without a timely offset in order to apply the same temperature to the entire consumable at any time. The timely offset is calculated between pairs of heat blocks operating in a non-overlapping power consumption pattern. Thus, this method further includes the step of calculating a timely offset of the peak power consumption of a pair of heat blocks during ramping. Another possibility is to provide a holding time for the peak power consumption of any other pair of heat blocks during the ramping time and / or the holding time, and the operation of multiple pairs of heat blocks in a non-overlapping power consumption pattern is based on such timely offsets. In this embodiment, this method includes the step of calculating a timely offset of the peak power consumption between different pairs of heat blocks or each pair of thermoelectric energy converters. This calculation of the timely offset is performed by an electrical substrate provided by one or more thermal units of a computer or device. The timely offset can be calculated between the peaks of the power consumption occurring during ramping, or it can be calculated during the holding time when the temperature is kept constant and the power consumption is low. According to an embodiment of this method, there is always a timely offset during the time of the maximum power consumption of each pair of heat blocks. In this way, the device operates in a non-overlapping power consumption pattern, and the total power consumption of the device is kept as low as possible.

[0033] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include the plural forms unless the context clearly dictates otherwise. Similarly, the words "comprising", "including", and "containing" are to be construed inclusively rather than exclusively, that is, in the sense of "including, but not limited to". Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The terms "plurality", "multiple", or "multitude" refer to two or more in integer multiples, that is, 2 or >2, and the terms "single" or "sole" refer to 1, that is, =1. Further, the term "at least one" should be understood as one or more, that is, 1 or >1, and this is also in integer multiples. Thus, words using the singular or plural forms also include the plural and singular forms, respectively. Further, the words "herein", "above", "previously", "below", and words of similar meaning, when used in this application, shall refer to the entire application rather than a particular part of the application.

[0034] Furthermore, certain terms are used for convenience and are not intended to limit the present invention. The terms "right", "left", "upward", "downward", "below", and "above" refer to the directions in the figures. The terms include those explicitly mentioned terms, as well as their derivatives and terms with similar meanings. Also, spatially relative terms (such as "down", "below", "lower", "up", "above", "proximal", "distal", etc.) are used to describe the relationship of one element or function to another element or function as shown in the figures. These spatially relative terms are intended to encompass various positions and orientations of the device during use or operation in addition to the positions and orientations shown in the figures. For example, if the device in the figure is turned over, an element described as "down" or "below" another element or function will be "up" or "above" the other element or function. Thus, the exemplary term "down" can encompass both the position and direction of up and down. The device may be oriented in other ways (rotated 90 degrees or in other directions), and the spatially relative descriptors used herein can be interpreted accordingly. Similarly, descriptions of movement along and around various axes include the various positions and orientations of the particular device.

[0035] To avoid repeating the figures and descriptions of various aspects and exemplary embodiments, it should be understood that many features are common to many aspects and embodiments. The description of particular embodiments of the present disclosure is not intended to be exhaustive or to limit the present disclosure to the exact forms disclosed. Particular embodiments and examples of the present disclosure are described herein for illustrative purposes, but as will be recognized by those skilled in the art, various equivalent modifications are possible within the scope of the present disclosure. The particular elements of the foregoing embodiments can be combined with, or used in place of, elements of other embodiments. Further, the advantages associated with particular embodiments of the present disclosure have been described in the context of those embodiments, but other embodiments can exhibit such advantages as well, and not all embodiments need to exhibit such advantages to be within the scope of the present disclosure defined by the appended claims. The omission of an aspect from the description or figures does not mean that the aspect is missing from the embodiments incorporating that aspect. Instead, aspects may be omitted for clarity and to avoid redundant description. In this context, the following applies to the remainder of this description. Where reference symbols not described in the directly relevant part of the description are included in the drawings for clarity, refer to the previous or subsequent description part. Further, for clarity, where not all features of a component are labeled with reference symbols in a section of the drawings, refer to other sections of the same drawing. Similar numerals in two or more figures represent the same or similar elements.

[0036] The following examples are intended to illustrate various particular embodiments of the present invention. Accordingly, the particular modifications discussed below should not be construed as limitations on the scope of the present invention. It will be apparent to those skilled in the art that various equivalents, changes, and modifications can be made without departing from the scope of the present invention, and thus it should be understood that such equivalent embodiments are included herein. Further aspects and advantages of the present invention will become apparent from the following description of the particular embodiments shown in the figures.

[0037] References to "embodiments" throughout the description that are not included in the appended claims are merely illustrative of possible exemplary implementations and are, therefore, not part of the present invention.

Brief Description of the Drawings

[0038]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Description of the Reference Numerals

[0039] 1 Thermal unit 2 Cooling structure 21 Heat sink 211 First side of the heat sink 212 Second side of the heat sink 2121 Cooling fin structure 2122 Snap interface 2123 Connection interface 22 Guide plate 221 Air fan 223 Tappet 224 Gap 23 Duct cover plate 231 Through hole of the duct cover plate The first part of the exhaust duct 24a The second part of the exhaust duct 24b Arrow 242 Intake duct 25 Partition wall 251 Arrows A - F Heat block 3 Thermoelectric energy converter 31 Upper plate 32 Upper surface 321 Heat transfer plate 33 Electronic substrate 34 Housing 4 Downholder 5 Apparatus for simultaneous thermal cycle 100

Best Mode for Carrying Out the Invention

[0040] FIG. 1 is a conceptual exploded view of a cooling structure 2 of a heat unit 1 according to an embodiment of the present invention. The illustrated embodiment of the cooling structure 2 includes three main components, namely, a heat sink 21, a guide plate 22, and a duct cover plate 23.

[0041] The component at the uppermost part of the figure in Fig. 1 is the 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 swaging or the like. The heat sink 21 has a first side surface 211 for the purpose of connecting to the heat block 3 of the heat unit 1. The heat sink 21 has a second side surface 212 that faces the first side surface and is directed towards the observer in Fig. 1. The second side surface 212 of the heat sink 21 is intended to be connected to the guide plate 22 shown as a component in the center of the exploded view of Fig. 1. The cooling fin structure 2121 is arranged on the second side surface 212 of the heat sink 21. The cooling fin structure 2121 includes a plurality of cooling fins protruding from the second side surface 212. In the region near the center of the second side surface 212, the cooling fins of the cooling fin structure 2121 are arranged in a star shape. In the region of the cooling fin structure 2121 where the cooling fins are arranged in the aforementioned star shape (also referred to as the star-shaped region), the intake air flow provided by the two air fans 221 collides or hits the second side surface 212 of the heat sink 21. Next, the intake air flow is dispersed and guided to the side surface of the heat sink 21 by the cooling fins. In the left and right regions from the star-shaped region, the cooling fins are arranged parallel to each other. In these regions adjacent to the star-shaped region, the cooling fins guide the intake / exhaust air flow straight to the side surface of the heat sink 21.

[0042] The heat sink 21 has a general function of absorbing and dissipating thermal energy from one or more heat blocks 3 not shown in FIG. 1. The thermal energy from the heat block 3 is transmitted to the heat sink 21 by its first side surface 211. The intake air flow is provided by two air fans 221 and impinges on the second side surface 212 of the heat sink 21. Next, the second side surface 212 and the cooling fin structure 2121 redirect the intake air flow to flow parallel to the second side surface 212. The intake air flow receives thermal energy from the cooling fin structure 2121 and transports it away from the cooling structure 2. The heat sink 21 is also implemented as an assembly base so that additional components can be fixed thereon. Thus, the heat sink 21 comprises several mechanical interfaces to ensure the correct placement and fixation of such other components. For example, the heat sink 21 comprises four snap-in interfaces 2122 which are mechanical interfaces for connecting the heat sink 21 to the guide plate 22. The heat sink 21 further comprises several connection interfaces 2123 which are also mechanical interfaces intended to be connected to other components of the thermal unit 1 of the device 100. The heat sink 21 can also include additional mechanical interfaces, which are not further described or illustrated in more detail.

[0043] In the center of the exploded view of FIG. 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 most of the second side surface 212 of the heat sink 21. The guide plate 22 of the embodiment of this specification holds at least one air fan in the form of two air fans 221. However, any number of air fans can be used here. Each of the air fans 221 is arranged in the provided through holes. The air fans 221 suck in the ambient air and create an intake air flow that flows through the through holes of the guide plate 22 in a direction towards the second side surface 212 of the heat sink 21. The guide plate 22 also includes four tappets 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 a snap-fit connection. Such a snap-fit connection is provided by a combination of four tappets 223 that snap into respective snap interfaces 2122. The guide plate 22 also includes a first part 24a and a second part 24b of the exhaust duct. The first part 24a of the exhaust duct is only shown in FIGS. 2 to 4. As shown in FIG. 1, the second part 24b of the exhaust duct is provided by a recess in the guide plate 22 facing the observer. This recess is arranged between the outer edge of the guide plate 22 and the part of the guide plate 22 that holds the two air fans 221. In the view of FIG. 1, as represented by two arrows 242, the exhaust air flow flows from the right side of the guide plate 22 around the two air fans 221 and the two through holes in the direction of the left side of the guide plate 22. In the assembled state, the second part 24b of the exhaust duct is covered by a duct cover plate 23 which is shown as the lowest component in the exploded view of FIG. 1. The duct cover plate 23 is a flat component including two through holes 231. In the assembled state, these through holes 231 are arranged coaxially with the through holes of the guide plate 22. The intake air flow is sucked by the air fans 221 through the through holes 231.In the embodiment shown in FIG. 1, the guide plate 22 can be made of a plastic material, and the duct cover plate 23 can be made of a stainless steel metal sheet. The duct cover plate 23 can be assembled to the heat sink 21 using connection elements, for example screws. The duct cover plate 23 is connected to one or more mechanical interfaces of the heat sink 21. The mechanical connection between the duct cover plate 23 and the heat sink 21 presses the duct cover plate 23 against the guide plate 22. This mechanical connection provides a seal between the duct cover plate 23 and the guide plate 22, and thus also seals the second portion of the exhaust duct 24b.

[0044] As shown in Fig. 1, Fig. 2 shows a conceptual perspective view of the assembled cooling structure 2 of the heat unit 1. In Fig. 2, the heat sink 21 and the guide plate 22 are connected to each other by a snap - fit connection between the tappet 223 and the snap - in interface 2122. The duct cover plate 23 is omitted in Fig. 2 to improve the visibility of the second part 24b of the exhaust duct. Fig. 2 shows that most of the area of the second side 212 of the heat sink 21 is covered by the guide plate 22. The guide plate 22 and the heat sink 21 together form the first part 24a of the exhaust duct. Inside the first part 24a of the exhaust duct, the exhaust flow is guided by the cooling fin structure 2121 from the central part of the second side 212 of the heat sink 21 to the side of the heat sink 21. The exhaust flow exits the first part 24a of the exhaust duct on the side of the heat sink 21 directed towards the left side of Fig. 2. Another part of the exhaust flow exits the first part 24a of the exhaust duct on the right side of the heat sink 21 through the gap 224 in the guide plate 22. The path of a part of the exhaust flow through the gap 224 is symbolized by two arrows 242. After flowing through the gap 224, the exhaust enters the second part 24b of the exhaust duct. The exhaust flows around the two air fans 221 along the duct provided by the guide plate 22 in combination with the duct cover plate 23. As shown in Fig. 2, the exhaust flow exits the second part 24b of the exhaust duct on the left side of the guide plate. The second part 24b of the exhaust duct is adjacent to the outlet of the first part 24a of the exhaust duct. Thereby, the confluence of the exhaust leaving the first part 24a and the second part 24b of the exhaust duct then leaves the cooling structure 2 on the left side of Fig. 2. Thus, all of the exhaust flow can be easily removed from the heat unit 1 by additional components not shown in Fig. 2.

[0045] As shown in FIG. 1, FIG. 3 shows a conceptual cross-sectional perspective view of the assembled cooling structure 2 of the heat unit 1. In FIG. 3, the duct cover plate 23 is assembled to the cooling structure 2. In the cross-sectional view of FIG. 3, the first portion of the exhaust duct 24a is clearly visible between the heat sink 21 and the guide plate 22. The second portion 24b of the exhaust duct is only partially visible because most of it is covered by the duct cover plate 23. The cross-sectional view of FIG. 3 shows two intake ducts 25 provided by the combination of the through holes 231 of the duct cover plate 23 and the guide plate 22. The intake duct 25 directs ambient air towards the air fan 221. The intake duct 25 is separated from the exhaust ducts 24a, 24b by a separation wall 251. Thereby, the intake flow is structurally separated from the exhaust flow within the cooling structure 2.

[0046] As shown in FIG. 1, FIG. 4 shows a conceptual cross-sectional side view of the assembled cooling structure 2 of the heat unit 1. In the cross-sectional view of FIG. 4, the intake / exhaust flow through the cooling structure 2 is indicated by arrows A to F. The intake air flow coming from the surroundings of the cooling structure 2 enters the cooling structure 2 via the intake duct 25 as symbolized by arrow A. Next, the intake air flow is sucked by the two air fans 221 and directed towards the second side 212 of the heat sink 21. After the intake duct 25 and the air fans 221, the intake air flow impinges on the cooling fin structure 2121. Next, the cooling fin structure 2121 deflects the intake air flow, i.e., directs the intake air flow from the direction perpendicular to the second side 112 of the heat sink 21 represented by arrow A to the direction parallel to the second side 212 represented by arrow B. A part of the intake air is deflected to the left side of the heat sink 21 through the cooling fin structure 2121 and through the first part 24a of the exhaust duct. On the way through the heat sink 21, the intake air takes heat energy from the heat sink 21, i.e., is heated and thus becomes exhaust air. This part of the exhaust air leaves the first part 24a of the left exhaust duct as represented by arrow C. Another part of the intake air is directed to the right side of the heat sink 21 by another part of the first part 24a of the exhaust duct. This part of the intake air is also heated to exhaust air on the way through the first part 24a of the exhaust duct, and this part of the exhaust air flows through the gap 224 to the second part 24b of the exhaust duct as represented by arrow D. From the right side of the second part 24b of the exhaust duct formed by the guide plate 22 and the duct cover plate 23, the exhaust air is directed to the left side of the second part 24b of the exhaust duct as represented by arrow E. Finally, the exhaust air exits the second part 24b of the exhaust duct and the left cooling structure 2 as represented by arrow F.

[0047] FIG. 5 shows a conceptual perspective view of the heat block 3 of the thermal unit 1 according to an embodiment of the present invention. An upper plate 32 is provided on the upper part of the heat block 3. The upper plate 32 has a flat upper surface 321. This flat upper surface 321 is an area where consumables including samples for thermal cycling are placed. Since these consumables usually include a flat lower surface, excellent heat transfer between the flat upper surface 321 and the lower surface of the consumables can be ensured. The heat block 3 shown in FIG. 5 includes two thermoelectric energy converters 31 attached to the lower surface of the upper plate 32. The two thermoelectric energy converters 31 are not visible in FIG. 5 because they are covered by the upper plate 32. For example, the thermoelectric energy converter 31 can be a thermoelectric cooler, a Peltier element also known as a TEC. Such a TEC converts electrical energy into heating or cooling. The upper plate 32 can be cooled or heated by the thermoelectric energy converter 31. On the side opposite to the connection with the upper plate 32, the thermoelectric energy converter 31 is connected to a heat transfer plate 33. The heat transfer plate 33 transfers thermal energy from the thermoelectric energy converter 31 to the cooling structure 2, which is not shown in FIG. 5. The heat transfer plate 33 further includes several connections, for example, to connect the electronic substrate 34 to the heat block 3. Such an electronic substrate 34 for supporting the thermoelectric energy converter can be a printed circuit board assembly, a PCBA, which can be connected to one or more temperature sensors inside or on the upper plate 32 and is configured to calibrate temperature deviation compensation and can store respective calibration data in the built-in memory. Such an electronic substrate 34 is assembled on the side surface of the heat transfer plate 33 facing the left side of FIG. 5. The heat transfer plate 33 in FIG. 5 is made of an aluminum alloy and thus has a high thermal conductivity. The upper plate 32, the thermoelectric energy converter 31, and the heat transfer plate 33 can be fixed to each other by a clamping mechanism, which is also not shown in FIG. 5. Such a clamping mechanism can ensure a certain connection force between the three components.

[0048] FIG. 6 shows a conceptual exploded view of an apparatus 100 for simultaneous thermal cycling of a plurality of samples in a dPCR consumable according to an embodiment of the present invention. The lowest component in the figure of FIG. 6 is the thermal unit 1, which, as already partially described, has a cooling structure 2 as described above, corresponding to the embodiments shown in FIGS. 1 to 4. The cooling structure 2 is shown from above so that the first side surface 211 of the heat sink 21 facing the heat block 3 is visible. In the embodiment shown in FIG. 6, the thermal unit 1 includes six heat blocks 3 shown on top of the cooling structure 2. The heat blocks 3 should be assembled to the cooling structure 2 with their heat transfer plates 33 connected to the first side surface 211 of the heat sink 21. Two heat blocks 3 are arranged adjacent to each other such that the six heat blocks 3 each form three groups of two heat blocks 3. A downholder 5 is shown above the group of heat blocks 3, i.e., above the thermal unit 1. The downholder 5 is assembled on top of the thermal unit 1 and is provided to press a consumable containing a sample for thermal cycling against the upper plate 32 of the heat block 3. By pressing the consumable against the upper plate 32, heat transfer between the heat block 3 and the sample is further improved. The downholder 5 can also be provided with a function of opening and closing a door or window of the housing 4 to insert and remove the consumable from the heat block 3. The housing 4 is shown on the upper surface of the figure of FIG. 6 and is assembled on top of the other components. The housing 4 covers the other components, particularly the heat block 3 loaded with samples during thermal cycling. The housing 4 can be made of a stainless steel sheet material or a plastic material. The housing 4 is permanently fixed to the heat sink 21 of the thermal unit 1.

[0049] While the present invention has been described in connection with its specific embodiments, it should be understood that this description is for the purpose of illustration only. Accordingly, the present invention is intended to be limited only by the scope of the claims appended hereto.

Claims

**Claim 1** A thermal unit (1) for simultaneous thermal cycling of a plurality of samples, comprising at least one heat block (3) and a cooling structure (2), wherein the heat block (3) comprises at least one thermoelectric energy converter (31) and a heat transfer plate (33) attached to the thermoelectric energy converter (31) for dissipating thermal energy from the thermoelectric energy converter (31), and the cooling structure (2) comprises a heat sink (21), at least one air fan (221), and exhaust ducts (24a, 24b), the heat sink (21) is connected to the heat transfer plate (33) on a first side surface (211) and is exposed to the air fan (221) on a second side surface (212), and the air fan (221) provides an intake air flow towards the second side surface (212) of the heat sink (21), the exhaust ducts (24a, 24b) direct an exhaust air flow away from the second side surface (212) of the heat sink (21), and the intake air flow and the exhaust air flow are structurally separated from each other, at least a part of the exhaust air flow is guided by the exhaust ducts (24a, 24b) around the at least one air fan (221), a thermal unit (1). **Claim 2** The thermal unit (1) according to claim 1, wherein the exhaust air flow is guided substantially orthogonally to the intake air flow. **Claim 3** The thermal unit (1) according to claim 1 or 2, wherein the heat sink (21) comprises a cooling fin structure (2121) at least on its second side surface (212). **Claim 4** The thermal unit (1) according to claim 3, wherein in at least the region of the air fan (221), the cooling fin structure (2121) of the heat sink (21) is arranged radially and guides the intake air provided by the fan (221) towards the side surface of the heat sink (21). **Claim 5** The thermal unit (1) according to any one of claims 1 to 4, wherein the first side surface (211) of the heat sink (21) faces the second side surface (212) of the heat sink (21). **Claim 6** The thermal unit (1) according to any one of claims 1 to 5, wherein the at least one air fan (221) is arranged in a through hole of a guide plate (22) of the cooling structure (2). **Claim 7** The thermal unit (1) according to any one of claims 1 to 6, further comprising an intake duct (25) for directing ambient air towards the air fan (221), the intake duct (25) being structurally separated from the exhaust ducts (24a, 24b).

8. The thermal unit (1) according to any one of claims 1 to 7, wherein the at least one heat block (3) further comprises at least one upper plate (32) having a substantially flat upper surface (321) for thermal contact with a dPCR consumable, and the at least one thermoelectric energy converter (321) is attached to the lower surface of the upper plate (32) facing the upper surface (321).

9. The thermal unit (1) according to claim 8, wherein the heat block (3) further comprises at least one heat transfer medium between the upper plate (32) and the thermoelectric energy converter (31) and / or between the thermoelectric energy converter (31) and the heat transfer plate (33).

10. The thermal unit (1) according to claim 8 or 9, wherein the heat block (3) further comprises at least one temperature sensor in or on the upper plate (32) for temperature control.

11. The thermal unit (1) according to claim 10, wherein the heat block (3) further comprises an electronic substrate (34) for supporting the thermoelectric energy converter (31) and the temperature sensor.

12. The thermal unit (1) according to any one of claims 1 to 11, wherein the heat block (3) forms an exchangeable self - contained entity within the thermal unit (1) and / or the heat sink (21) is configured to receive a plurality of heat blocks (3).

13. An apparatus (100) for simultaneous thermal cycling of a plurality of samples in a dPCR consumable, comprising a housing (4) and at least one thermal unit (1) according to any one of claims 1 to 12 fixed within the housing (4), wherein the exhaust ducts (24a, 24b) of each thermal unit (1) are formed partially by the second side surface (212) of the heat sink (21) and the guide plate (22), and partially by the guide plate (22) and the duct cover plate (23).

14. A method for simultaneous thermal cycling of a plurality of samples, providing the apparatus (100) according to claim 13, wherein each thermal unit (1) comprises a plurality of heat blocks (3), executing a thermal cycling protocol under computerized feedback control, and including wherein the plurality of heat blocks (3) operate in a non-overlapping power consumption mode. **Claim 15** The method further includes calculating a timely offset of the peak power consumption of one heat block (3) or a pair of two heat blocks (3) during the ramp time and / or hold time to the peak power consumption of any other heat block (3) or pair of two heat blocks (3) during the ramp time and / or hold time, and the operation of the plurality of heat blocks (3) or the plurality of pairs of two heat blocks (3) in the non-overlapping power consumption mode is based on the timely offset, the method according to claim 14.

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