WO2022233783A1

WO2022233783A1 - A temperature controller and a method for controlling a temperature of a sample, and an analysis instrument

Info

Publication number: WO2022233783A1
Application number: PCT/EP2022/061706
Authority: WO
Inventors: Wouter VLEUGELS; Bart Vandevelde; Erik EMMEN
Original assignee: Imec Vzw
Priority date: 2021-05-03
Filing date: 2022-05-02
Publication date: 2022-11-10

Abstract

A temperature controller (100) for controlling a sample temperature comprises: a heater block (112) and a cooler block (122; 222), the heater block (112) being between the cooler block (122; 222) and the sample (102); wherein the temperature controller (100) controls switching of sample 5temperature between a first, high and a second, low sample temperature; wherein the temperature controller (100) provides heat by the heater block (112) and transports fluid of a first, high fluid temperature through at least one cooler block conduit (124; 224a, 224b) for bringing the sample to the first sample temperature; and wherein the temperature controller (100) provides10cooling by the cooler block (122; 222) by transporting fluid of a second, low fluid temperature through the at least one cooler block conduit (124; 224a, 224b) for bringing the sample to the second sample temperature, wherein the second fluid temperature is lower than the second sample temperature.15Figure for publication:

Description

A TEMPERATURE CONTROLLER AND A METHOD FOR CONTROLLING A TEMPERATURE OF A SAMPLE. AND AN ANALYSIS INSTRUMENT

Technical field

The present inventive concept relates to a temperature controller for controlling a temperature of a sample and a method for controlling a temperature of a sample. The present inventive concept also relates to an analysis instrument comprising the temperature controller. In particular, the present inventive concept relates to fast switching of temperatures of the sample.

Background

Thermal cycling between two different temperatures of a sample may be used for preparing the sample for analysis. For instance, thermal cycling is used in polymerase chain reaction (PCR) for amplification of DNA in a sample. PCR may be used with reverse transcriptase for generating a DNA sequence matching with viral RNA, such that the amplification of DNA may allow identifying whether a person carries an infectious disease. Such reverse transcriptase polymerase chain reaction (RT-PCR) may for instance be used for detecting presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Screening for infectious diseases, such as SARS-CoV-2, in a fast and inexpensive manner may allow screening to be performed frequently and enable quick identification of persons carrying disease. Such identification of diseased persons would allow measures to be taken for preventing or reducing spreading of the disease. Further, if tests may be analyzed in a very short time, testing could be performed e.g. at entry points into a building or any place where people may gather, so as to enable identifying people carrying the disease before allowing people to enter through the entry point.

Fast thermal cycling of samples may be utilized for enabling performing screening for infectious diseases in a short time. Flence, it would be desired to provide a fast control of switching of temperatures of a sample. Summary

An objective of the present inventive concept is to enable control of temperature of a sample to allow fast switching between a first, high temperature and a second, low temperature of the sample. This and other objectives of the present inventive concept are at least partly met by the invention as defined in the independent claims. Preferred embodiments are set out in the dependent claims.

According to a first aspect, there is provided a temperature controller for controlling temperature of a sample; said temperature controller comprising: a heater comprising a heater block and a cooler comprising a cooler block, wherein the heater block is configured to be arranged between the cooler block and the sample; wherein the temperature controller is configured for controlling temperature of the sample to be switched between a first, high sample temperature and a second, low sample temperature; wherein the cooler comprises a first temperature fluid conduit loop and a second temperature fluid conduit loop for circulating a fluid in each of the fluid conduit loops and wherein the cooler is configured to control fluid in the first temperature fluid conduit loop to maintain a first, high fluid temperature and to control fluid in the second temperature fluid conduit loop to maintain a second, low fluid temperature, wherein the cooler is further configured to control transport of each of the fluid of the first temperature fluid conduit loop and the fluid of the second temperature fluid conduit loop through at least one cooler block conduit extending through the cooler block; wherein the temperature controller is configured to provide heat by the heater block and to transport fluid of the first, high fluid temperature through the at least one cooler block conduit for bringing the temperature of the sample to the first, high sample temperature; and wherein the temperature controller is configured to provide cooling by the cooler block by transporting fluid of the second, low fluid temperature through the at least one cooler block conduit for bringing the temperature of the sample to the second, low sample temperature, wherein the second, low fluid temperature is lower than the second, low sample temperature.

Thanks to the temperature controller of the first aspect, thermal energy may efficiently be provided to and from a sample so as to efficiently heat and cool the sample. In particular, transfer of energy may be directed such that energy is mainly transferred towards the sample during heating and from the sample during cooling. The temperature controller uses a heater block for providing a mass which is heated and which may hence dissipate heat, when the sample is to be brought to a first, high temperature. The temperature controller further uses a cooler block for extracting energy from the sample for cooling the sample, when the sample is to be brought to a second, high temperature. The heater block and the cooler block may be in contact and arranged as close to the sample as possible, with the heater block being arranged between the cooler block and the sample. This implies that no mechanical movement of the heater block, the cooler block or the sample is needed during switching of temperatures. This may be beneficial in thermal cycling, wherein the temperature is to be switched a large number of times, such as 40 cycles per sample, which would cause wear on mechanical parts if a movement is to be made during each cycle.

However, the heater block being arranged close to or in contact with the cooler block implies that a large proportion of heat dissipated by the heater block may act to increase the temperature of the cooler block rather than to increase the temperature of the sample. Thanks to the temperature controller of the first aspect fast thermal cycling is facilitated even though the heater block is arranged between the sample and the cooler block. The cooler of the temperature controller comprises a first temperature fluid conduit loop and a second temperature conduit loop. This allows a fast manner of providing fluids of different temperatures to be transported through the cooler block for controlling the temperature of the cooler block. Thus, when the temperature of the sample is to be raised to the first, high sample temperature, fluid of the first, high fluid temperature from the first temperature fluid conduit loop may be transported through the cooler block such that the temperature of the cooler block is raised by the fluid of the first, high fluid temperature. This implies that the cooler block may aid in heating the sample and may further avoid that heat dissipated by the heater block to a large degree is directed towards the cooler block instead of towards the sample. Hence, a very fast heating of the sample to the first, high temperature may be provided.

Further, the use of a combination of a cooler block and a heater block also enables the fluid of the second, low temperature to be maintained at a temperature substantially below the second, low sample temperature. Thus, when the sample is to be brought to the second, low sample temperature, the fluid of the second, low fluid temperature may be transported through the cooler block. Having a second, low fluid temperature at a substantially lower temperature than the second, low sample temperature allows the sample to be quickly cooled down towards the second, low sample temperature. When the temperature of the sample approaches the second, low sample temperature, heating by the heater may be initialized to ensure that the sample quickly is brought to an equilibrium at the second, low sample temperature.

According to an embodiment, the second, low fluid temperature is at least 10° C lower than the second, low sample temperature, such as at least 30°C lower. The lower the temperature of the fluid having the second, low fluid temperature, the faster the temperature controller will be able to cool the sample to the second, low sample temperature.

The first, high sample temperature and the second, low sample temperature may both be above room temperature or a temperature of an ambience. The second, low fluid temperature may be selected to also be above room temperature or the temperature of the ambience, so as to avoid condensation on the cooler or another surface. Hence, it should be realized that the term “cooler” does not necessarily imply an element that provides a cooling action in relation to ambient temperature, since the cooler block may even be warmer than an ambience. However, the “cooler” provides cooling in relation to the temperature of the sample at its first, high sample temperature.

For keeping the sample at a steady-state of the second, low sample temperature, the cooler and the heater may be used in combination to provide an equilibrium at which the sample is held at the second, low sample temperature. Alternatively, the heater may be used in isolation for holding the sample at the second, low sample temperature.

Hence, the temperature controller of the first aspect allows a fast switching time both for switching the sample from the second, low sample temperature to the first, high sample temperature and for switching the sample from the first, high sample temperature to the second, low sample temperature. Thus, the temperature controller may be suitably used for providing fast switching of temperatures in a thermal cycling process.

The cooler block could have one cooler block conduit, such that the fluid to be transported through the cooler block conduit may be selected. Alternatively, the cooler block could have two cooler block conduits, wherein each cooler block conduit could be dedicated to the first and second temperature fluid conduit loop, respectively. Then, in order to control action by the cooler block, the flow rates through the respective cooler block conduits could be controlled between at least two levels of flow rates. The fluid flow through a cooler block conduit may even be turned off, so as to avoid transport of a fluid to counter-act a desired cooling or heating action of the sample.

Thus, when the temperature of the sample is to be brought to the first, high sample temperature, fluid of the first, high fluid temperature is transported through one cooler block conduit, but fluid of the second, low fluid temperature may also simultaneously be transported through another cooler block conduit. However, the flow rates of the fluid of the second, low fluid temperature and the fluid of the first, high fluid temperature may be controlled to ensure that the heater block need not unduly warm up the cooler block such that the sample would be slowly raised to the first, high sample temperature. Similarly, when the temperature of the sample is to be brought to the second, low sample temperature, fluid of the second, low fluid temperature is transported through one cooler block conduit, but fluid of the first, high fluid temperature may also simultaneously be transported through another cooler block conduit.

The heater block may be configured to be in contact with the sample during controlling of temperature of the sample. Possibly, the contact may be via one or more intermediate layers between the heater block and the sample. This may facilitate transfer of heat from the heater block towards the sample. The heater block may further be configured to be in contact with the cooler block. This may also facilitate transfer of heat from the sample towards the cooler block. Thus, the transfer of heat may occur through thermal conduction.

It should be realized that the cooler block may be detached from the heater block, when the sample is to be heated to the first, high sample temperature. This may further avoid that heat is transferred from the heater block towards the cooler block instead of towards the sample. However, detaching of the cooler block from the heater block may involve a mechanical movement, which may be undesired in order to avoid mechanical wear.

It should further be realized that the temperature controller may be used for controlling the temperature of the sample between more than two temperature levels, such as three temperature levels or even further temperature levels. The heater and the cooler using the two temperatures provided by the first and second temperature fluid conduit loops may be used in combination for providing more than two temperature levels. For instance, by providing different amounts of heating, differentiation between two or more low temperature levels or two or more high temperature levels may be provided.

Additionally, or alternatively, the cooler may comprise more than two fluid conduit loops for providing fluids of more than two different temperatures. Thus, three or more levels of temperatures of the fluid in the fluid conduit loops may be used for controlling a temperature of the sample between three or more temperature levels.

Further, in some applications, temperature of the sample may need to follow a particular curve when being increased from a low temperature to a high temperature in order to follow a melting curve of a substance in the sample. Thus, the temperature controller may be configured to control change of temperature of the sample to follow a melting curve between the second, low sample temperature and the first, high sample temperature. The melting curve may define a linear increase of temperature or a step-wise increase.

According to an embodiment, the temperature controller further comprises a controlling unit for providing control signals for controlling temperature controlling functions of the temperature controller.

The controlling unit may ensure that the temperature controller provides desired functionality for controlling the temperature of the sample. The controlling unit may thus control timing and selection of temperature controlling functions so as to achieve a desired control of the temperature of the sample.

According to an embodiment, the temperature controlling functions comprise at least one of heating of the heater block, selecting the fluid to be transported through the at least one cooler block conduit, and controlling a flow rate of the fluid transported through the at least one cooler block conduit.

The controlling of heating of the heater block may determine whether the heating of the heater block is to be activated or not. Further, the controlling of heating of the heater block may also determine an amount of heating by setting a level of the heating by the heater block.

The selecting of the fluid to be transported through the at least one cooler block conduit may determine which of the fluid of the first temperature fluid conduit loop or the fluid of the second temperature fluid conduit loop is to be transported in a cooler block conduit shared by the loops. Alternatively, a level of mixing of the fluids of the first and second temperature fluid conduit loop in the cooler block conduit shared by the loops may be controlled. This may determine whether the cooler block will aid in heating of the sample or whether the cooler block will act to cool down the sample.

The controlling of the flow rate of the fluid transported through the at least one cooler block conduit may determine an amount of heating/cooling provided by the cooler block. The controlled flow rate may apply to the fluid being transported through the cooler block conduit shared by the loops. Alternatively, each of the first and second temperature fluid conduit loop may be associated with its own cooler block conduit and the flow rate through the respective cooler block conduit may be controlled in order to control an amount of heating/cooling provided by the cooler block.

The controlling unit may be configured to control timing of changing of the temperature controlling functions, which may define a timing of switching the temperature of the sample from a first, high sample temperature to a second, low sample temperature or vice versa. Further, the controlling unit may be configured to control the temperature controlling functions during switching to provide a desired change of the temperature of the sample between steady states of the temperature (e.g. to follow a desired curve or to avoid overshoot/undershoot). Also, the controlling unit may be configured to control the temperature controlling functions to maintain a steady state of the temperature of the sample, when a steady state is desired. This may involve fine-tuning of the temperature controlling functions if a drift of the temperature of the sample occurs, so as to maintain the steady state.

According to an embodiment, the temperature controller further comprises a temperature sensor for providing an indication of a temperature of the sample as input to the controlling unit.

Thus, the controlling unit may use measurements by the temperature sensor for controlling the temperature controlling functions. Since the temperature sensor may provide input indicating the temperature of the sample, the controlling unit may determine temperature controlling functions to be used for achieving a desired temperature of the sample.

It should be realized that the controlling unit may use input from further sensors for controlling the temperature controlling functions. For instance, sensors may be used for measuring functions of the heater and/or cooler, such as measuring a heat provided by the heater block or a flow rate provided through a cooler block conduit. Thus, the sensors may provide input whether the heater and/or cooler functions as expected, which may further be used in controlling the temperature controlling functions.

The temperature sensor may be configured to measure the temperature of the sample by being configured so as to allow arrangement of the temperature sensor in the sample. Alternatively, the temperature sensor may measure the temperature of the sample by a non-contact sensing of the temperature, e.g. based on infrared radiation from the sample.

The temperature sensor may alternatively be configured to provide an indirect measurement of the temperature of the sample. For instance, the temperature sensor may be arranged at a surface which is configured to be in contact with a device carrying the sample. Thus, the temperature sensor may be configured to measure a temperature at an outer surface of such a device carrying the sample. However, there may be one or more layers between the outer surface of the device and the actual sample such that the measured temperature may not be equal to the temperature of the sample. The relation between the measured temperature and the temperature of the sample may be described by an estimation function, such that the actual temperature of the sample need not be measured. The estimation function may be determined e.g. by calibration. In particular, the temperature controller may be configured to be used with samples that are always provided in the same type of device for carrying the sample such that a calibration applies to any sample being used with the temperature controller.

According to an embodiment, the controlling unit is configured to provide control signals for proportional-integral-derivative, PID, regulation of the temperature of the sample.

This implies that the controlling unit provides an accurate control of the temperature of the sample. PID regulation may avoid or reduce overshoot / undershoot of a target temperature during switching of the temperatures of the sample. Hence, PID regulation may ensure that a steady state at a desired temperature is quickly achieved.

The PID regulation may control the temperature controlling functions, such as to control timing and amount of heating by the heater block, selecting the fluid to be transported through the at least one cooler block conduit, and controlling the flow rate of the fluid transported through the at least one cooler block conduit. For instance, it should be realized that the heater and/or cooler may be activated only during a part of a time for switching of the temperatures of the sample. It should however be realized that other types of regulation may be used, such as PI regulation or PD regulation.

Further, the PID regulation may use multiple setpoints for allowing an improved control of the switching of the temperatures of the sample. Also or alternatively, the PID regulation may utilize lead-lag compensation to take lag of an effect of a control action into account, or the PID regulation may comprise cascading multiple PID controllers for improving control by the PID regulation.

According to another embodiment, the controlling unit is configured to use open-loop control for switching the temperatures of the sample in a first cycle, wherein an error of an end result of the open-loop control is determined and used in control for switching the temperatures of the sample in a second cycle.

Thus, the controlling unit need not adapt control of the temperature of the sample based on any feedback information during switching of the temperatures of the sample. This implies that a simple regulation is provided.

However, the result of the obtained temperature based on the open- loop control may be compared to a desired temperature. An error in the obtained temperature may thus be used for correcting the regulation in a next cycle that is to switch the temperatures of the sample. In this way, a closed- loop control is obtained based on the error identified for the switching of the temperatures in the first cycle.

Hence, a regulation that does not require fast processing and calculations for adapting the control during switching of the temperatures of the sample is provided. Still, the regulation may be accurate based on using the error from a first cycle to adapt regulation in a second cycle.

This is useful in an application where the temperature of the sample is to be switched in a plurality of cycles.

According to an embodiment, the heater block is electrically operated for controlling heat dissipated by the heater block.

This provides a suitable control of the heating by the heater block. An amount of heating may be controlled by controlling a signal for electrically operating the heater block.

According to an embodiment, the heater block is configured to be controlled for fine adjustment of sample temperature at each of the first, high sample temperature and the second, low sample temperature. Hence, when the temperature of the sample is close to a desired level at the first, high sample temperature or the second, low sample temperature, the heater block may be controlled in order to set and maintain the temperature of the sample to the desired level. The heating by the heater block may be quickly changed which may facilitate using the heater block for fine adjustments of the temperature of the sample.

It should further be realized that the heater block may be configured to select different levels of sample temperature at a low sample temperature level or at a high sample temperature level so as to allow switching between different temperature levels by using only the heater block.

According to an embodiment, the heater block is formed by aluminum nitride.

Aluminum nitride may be a suitable material for enabling high efficiency of heating, since aluminum nitride provides a high thermal conductivity. Thus, using an aluminum nitride heater block, accurate and fast temperature control may be provided.

According to an embodiment, the cooler comprises a single cooler block conduit and wherein the cooler is configured to selectively control which of the fluids of the first and second temperature fluid conduit loops to be transported through the single cooler block conduit or wherein the cooler is configured to control mixing of the fluids of the first temperature and second temperature fluid conduit loops into the single cooler block conduit.

This implies that the heating or cooling action by the cooler is controlled through a single cooler block conduit. By selecting which fluid to be transported through the single cooler block conduit, the heating or cooling action of the cooler is directly selected. Hence, an effect of the cooler block is determined only by a single cooler block conduit which allows for a simple control of the action of the cooler.

According to an embodiment, each of the first temperature and second temperature fluid conduit loops comprises a valve for selectively switching fluids to be provided to the single cooler block conduit.

Thus, a valve may control the path of the fluid of each of the first temperature and second temperature fluid conduit loops. The valve can be used to select whether fluid is to be transported through the cooler block or is to be transported in a loop outside the cooler block. Further valve(s) may be used for controlling whether the fluid having passed the cooler block through the cooler block conduit is to be returned to the first temperature or the second temperature fluid conduit loop.

Fluid may be constantly transported through the respective fluid conduit loop and selected whether to be transported through the single cooler block conduit or not. Since the fluid is constantly transported through the respective fluid conduit loop, the fluid may be quickly provided into the single cooler block conduit by simply switching the valve. There is no need to initiate transport of fluid through the fluid conduit loop, as this transport is constantly occurring.

Using valves is a suitable manner of switching fluids to be provided to the single cooler block conduit. The valves may be fast-acting such that a switching of the fluids being passed through the cooler block conduit may be very quickly provided. For instance, the valve may provide a response within an order of tens of milliseconds from receiving a control signal.

The valves of the first temperature and second temperature fluid conduit loops may be simultaneously switched for opening the valve of one of the fluid conduit loops to the single cooler block conduit and closing the valve of the other of the fluid conduit loops to the single cooler block conduit.

If the fluids are to be mixed in the single cooler block conduit, the mixing of the fluids may be controlled via flow rates provided into the single cooler block conduit. The valves may be utilized for controlling the flow rates, possibly in combination with a pump for pumping fluid through the respective fluid conduit loop.

According to an embodiment, the cooler comprises two cooler block conduits, each being dedicated to a respective one of the first temperature and second temperature fluid conduit loops and wherein the cooler is configured to control a flow rate of the fluid through each of the cooler block conduits.

By having different cooler block conduits through the cooler block, there may not be a need to use valves for switching the paths to be taken by fluid through the respective fluid conduit loop. Flence, few components may be needed in the cooler, such that a simple set-up of the cooler may be provided. The flow rate of the respective fluid may be used for controlling the heating or cooling action of the cooler block.

Flow of a fluid that is not going to contribute to the switching of temperatures of the sample may be turned off. The corresponding cooler block conduit may even be emptied to avoid fluid in the cooler block conduit counter-acting a desired heating or cooling of the sample.

According to an embodiment, each of the first temperature and second temperature fluid conduit loops comprises a pump for pumping the fluid through the fluid conduit loop.

The pumps may be used for controlling the flow rate of the respective fluid flows in the first temperature and second temperature fluid conduit loops.

According to an embodiment, each of the first temperature and second temperature fluid conduit loops comprises a buffer container for holding a buffer volume of the fluid at the first, high fluid temperature and second, low fluid temperature, respectively, wherein each of the first temperature and second temperature fluid conduit loops further comprises a temperature controlling loop comprising a pump and a temperature controlling unit for controlling the temperature of the first, high fluid temperature and second, low fluid temperature, respectively.

The buffer volume of the fluid ensures that a relatively large volume of fluid is used for the respective first temperature and second temperature fluid conduit loops. This implies that any change of temperature of fluid while being transported through the fluid conduit loop including through the cooler block conduit will have a small relative effect on the temperature of the entire buffer volume.

Further, the temperature controlling loop ensures that the fluid in each of the buffer containers is maintained at a constant, desired temperature. The temperature controlling loop may be controlled based on a measured temperature, e.g. using a temperature sensor in the buffer container.

The pump of the temperature controlling loop may pump fluid at a controlled flow rate through the temperature controlling loop such that the flow rate may be dependent on a level of adjustment of the temperature of the buffer volume needed. The temperature controlling unit may be configured to apply heat or to cool the fluid being transported through the temperature controlling loop. Thus, depending on whether the temperature of the buffer volume is too low or too high, the temperature controlling unit may heat or cool the fluid, respectively. The temperature controlling unit may comprise two separate elements for heating and cooling the fluid, such that the elements may be set up for efficient heating and cooling, respectively.

According to an embodiment, the fluid of each of the first temperature and second temperature fluid conduit loops is any coolant liquid. The coolant liquid may be based on water. However, in order to avoid corrosion and/or microbiological growth, substance(s) may be added to water forming the coolant liquid.

The coolant liquid may preferably have a high specific heat capacity. For such reason, water may be used in the coolant liquid. However, it should be realized that other coolant liquids may be used.

According to an embodiment, the temperature controller is configured to provide thermal cycling of the temperature of the sample between the first, high sample temperature and the second, low sample temperature for amplification of DNA targets using polymerase chain reaction (PCR).

Thermal cycling may be used in polymerase chain reaction for amplification of DNA targets. Amplification of DNA targets allows producing a large amount of DNA targets in the sample so as to facilitate detection of presence of the DNA target in the sample. This may be useful e.g. in determination of presence of a viral RNA in a sample, such as for detecting presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The thermal cycling may involve a large number of cycles of a high sample temperature and a low sample temperature. Hence, if the time required for a single switching of the sample temperatures may be reduced, an overall time for performing thermal cycling may be substantially reduced. Hence, thanks to the fast switching of temperatures enabled by the temperature controller, very efficient thermal cycling for PCR may be provided.

According to an embodiment, the temperature controller is configured to control temperature of the sample to be switched between a first, high sample temperature higher than 90°C and a second, low sample temperature lower than 65°C.

This may be suitable temperatures for providing thermal cycling for PCR. According to an embodiment, the first, high sample temperature may be 95°C and the second, low sample temperature may be 60°C.

PCR may also involve initial steps before amplification of DNA targets through thermal cycling is performed, wherein additional temperature(s) of the samples may be used. The temperature controller may be configured to also set the sample to additional temperatures using control by the first temperature and second temperature fluid conduit loops in combination with the heater. According to an embodiment, the temperature controller is configured to switch the temperatures of a sample of a volume of less than 30 pi from the second, low sample temperature to the first, high sample temperature, and vice versa, in less than three seconds.

This implies that switching of temperatures of the sample is performed very quickly. This is particularly advantageous if thermal cycling involving many cycles of switching the temperatures is to be performed.

Using the temperature controller, a test based on PCR may be performed to provide an analysis result within 5 minutes from providing the sample to an analysis instrument.

With a test that may be quickly performed, such as within 5 minutes from being provided to the analysis instrument, a high throughput of test results may be provided by the analysis instrument. This implies that the analysis instrument may be suitable for being placed at a point that is passed by many people for screening people for infectious diseases, such as SARS-CoV-2 at such a point. For instance, the analysis instrument may be suitable for being placed at an entrance to an airport, a shop, or a company facility, for screening people before admitting people through the entrance. The high throughput of the analysis instrument may allow such screening to be performed without long queues being formed.

According to a second aspect, there is provided an analysis instrument for analysis of a sample, said analysis instrument comprising: a receptacle for receiving a collecting device holding a sample to be analyzed; a temperature controller according to the first aspect; wherein the temperature controller is arranged in relation to the receptacle of the analysis instrument for allowing the heater block to be in contact with the collecting device when the collecting device is arranged in the receptacle.

Effects and features of this second aspect are largely analogous to those described above in connection with the first aspect. Embodiments mentioned in relation to the first aspect are largely compatible with the second aspect.

The analysis instrument may be configured to provide fast results of analysis based on processing of the sample through switching of temperatures of the sample being enabled in a very fast manner.

The analysis instrument may be configured to receive a collecting device defining a cavity, such as a particle collection chamber, within which a sample to be analyzed is held. Thus, the heater block may be in direct contact with the collecting device. However, it should be realized that the collecting device may be arranged in a sample collector, carrying the collecting device and which may facilitate sample collection being performed by the collecting device. For example, the sample collector may guide a flow of air exhaled by a human being towards the collecting device for performing sampling therein. The sample collector may be received in the receptacle, such that the heater block may be arranged in physical contact with the collecting device via other structures, such as outer and inner walls of the sample collector.

According to a third aspect, there is provided a method for controlling temperature of a sample, said method comprising: arranging a heater block in contact with a collecting device holding the sample, wherein the heater block is further arranged between the sample and a cooler block, which is in contact with the heater block; bringing the temperature of the sample to a first, high sample temperature by providing heat by the heater block and by transporting fluid of a first, high fluid temperature through at least one cooler block conduit extending through the cooler block; switching the temperature of the sample to a second, low sample temperature by cooling the sample by the cooler block by transporting fluid of the second, low fluid temperature through the at least one cooler block conduit for bringing the temperature of the sample to the second, low sample temperature, wherein the second, low fluid temperature is lower than the second, low sample temperature.

Effects and features of this third aspect are largely analogous to those described above in connection with the first and second aspects. Embodiments mentioned in relation to the first and second aspects are largely compatible with the third aspect.

The method enables very fast switching of temperatures of the sample form a first, high fluid temperature to a second, low fluid temperature and vice versa.

Brief description of the drawings

The above, as well as additional objects, features and advantages of the present inventive concept, will be better understood through the following illustrative and non-limiting detailed description, with reference to the appended drawings. In the drawings like reference numerals will be used for like elements unless stated otherwise.

Fig. 1 is a schematic view of a temperature controller according to an embodiment. Fig. 2 is a schematic view of the temperature controller illustrating an alternative arrangement of cooler block conduits through a cooler block of the temperature controller.

Fig. 3 is a schematic view of an analysis instrument according to an embodiment.

Fig. 4 is a flowchart of a method according to an embodiment.

Detailed description

Referring now to Fig. 1 , a temperature controller 100 will be described. The temperature controller 100 is configured to be used for controlling a temperature of a sample 102. The temperature controller 100 is configured to provide fast switching of temperatures of the sample 102. This implies that the temperature controller 100 is particularly useful in controlling temperature of a sample 102 that is to be subject to numerous switching of temperatures. The temperature controller 100 may thus allow an overall time for preparing the sample 102, e.g. for preparing the sample for analysis, to be substantially reduced by the time required for each individual switching of temperatures of the sample 102 being reduced.

The temperature controller 100 may thus be particularly useful when a polymerase chain reaction (PCR) is to take place in the sample 102. PCR allows a DNA target, a particular DNA region, to be exponentially amplified. PCR may involve denaturation of double-stranded DNA to form two single- stranded DNA templates at a high temperature and annealing of primers to each of the single-stranded DNA templates at a low temperature. This process may then be repeated for exponential amplification of the DNA target. Thus, thermal cycling may be used in PCR to switch at least between the high temperature and the low temperature of the sample 102.

PCR may be used e.g. in DNA cloning for sequencing, for analysis of genetic fingerprints for DNA profiling and in diagnosis of infectious diseases. Diagnosis of infectious diseases may be desired to be performed in large scale, e.g. for screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Then, the speed of performing PCR may be very important in allowing screening to be quickly performed. This enables capacity of screening to be increased and may also enable screening of infectious diseases at entry points into a building or any place where people may gather, so as to enable identifying people carrying the disease before allowing people to enter through the entry point. It should be mentioned that when screening for infectious diseases based on screening of presence of a viral RNA, the sample may first be subject to reverse transcription of RNA into DNA, before amplification of DNA targets using PCR, so called reverse transcription polymerase chain reaction (RT-PCR).

The sample 102 may be collected in any suitable manner. It is envisaged that the temperature controller 100 may be used with a sample 102 that is collected by capturing airborne particles, such as aerosols and/or droplets in the flow of air exhaled by a human being. Thanks to capturing airborne particles, analysis of the airborne particles in the exhaled breath may be performed.

The airborne particles may be captured in a collecting device, which may provide a particle collecting chamber in which the airborne particles are captured by impaction, such that particles are removed from the flow of air by the flow of air being forced to change direction. Thanks to the flow of air being forced to change direction, momentum of particles having a certain size will cause the particles not to follow the flow of air in its change of direction and instead the particles will be captured on a collection surface in the particle collecting chamber.

Then, a liquid reagent may be provided to the particle collecting chamber to react with the collected airborne particles therein forming the sample 102 which may undergo thermal cycling and further be analyzed based on amplification of DNA targets.

The collecting device may comprise walls defining the particle collecting chamber, such that the collecting device is substantially forms a container for holding the sample 102. The walls of the particle collecting chamber may also form outer walls of the collecting device. The collecting device may, at least during collection of particles, be arranged in a sample collector which provides an interface for allowing a flow of air from a human being to be provided through the collecting device. Thus, the sample collector may provide an inlet for receiving a flow of air from the human being and may guide the flow of air through the collecting device.

The collecting device may be removed from the sample collector after the particles have been collected in the particle collecting chamber. However, according to an embodiment, the collecting device may be arranged in relation to an outer wall of the sample collector such that there is direct contact between the collecting device and the outer wall of the sample collector or indirect contact via one or more material layers therebetween.

The particle collection chamber may also be sealed, which may contribute to a safe handling and a reduced risk of spreading potentially hazardous captured particles.

It should be realized that the temperature controller 100 may be configured to control temperature of the sample 102 comprising captured airborne particles, which is processed for exposing and amplifying DNA targets. Thus, the temperature controller 100 may be suitably used for controlling temperature of such a sample, but it should be realized that the temperature controller 100 may be used in other applications as well.

The temperature controller 100 is configured for controlling temperature of the sample 102 to be switched between a first, high sample temperature and a second, low sample temperature. The temperature controller 100 facilitates fast switching back and forth between the first, high sample temperature and the second, low sample temperature in numerous cycles.

The temperature controller 100 comprises a heater 110 comprising a heater block 112. The heater block 112 may expose a surface of the heater block 112 externally to the temperature controller 100 such that the exposed surface may be brought in contact with the sample 102. The heater block 112 may thus be arranged in direct contact with the collecting device for transferring heat to the sample 102 held within the container defined by the collecting device such as a particle collection chamber therein. However, the heater block 112 may be arranged in indirect contact with the collecting device and the sample 102 therein, e.g. through one or more layers of the sample collector. There may be several layers between the surface of the heater block 112 and the sample 102 after sealing of the collecting device in the sample collector.

The heater block 112 is configured to provide conductive heating to the sample 102. Thus, heat may be transferred to the sample 102 so as to increase the temperature of the sample 102.

The heater block 112 may be electrically operated in order to control an amount of heat dissipated by the heater block 112. Thus, an electrical signal may control a temperature level of the heater block 112 such that the heat transferred by the heater block 112 may be controlled. The heater block 112 may thus be adjusted to provide fine-tuning of heating action provided by the heater block 112. The heater block 112 may comprise a small thermal mass, such that that the temperature of the heater block 112 may be quickly changed.

Further, the heater block 112 may be configured to provide a high power density, such as 100 W/cm², in order to provide an efficient heating of the sample 102. The heater block 112 may for instance be formed by aluminum nitride providing high thermal conductivity.

The heater block 112 may provide fine adjustment of the temperature of the sample 102 at both the first, high sample temperature and the second, low sample temperature. It should further be realized that even though the heater 110 mainly provides transfer of heat towards the sample 102, conductive transfer of heat may also occur from the sample 102 towards the heater 110, when the sample 102 is brough from the first, high sample temperature to the second, low sample temperature. However, it should further be realized that the heater 110 may still, when the sample 102 is brought to the second, low sample temperature and maintained in the second, low sample temperature, be warmer than ambient temperature, such that the sample 102 may also or mainly transfer heat towards an ambience for cooling the sample 102.

Thus, in particular when the second, low sample temperature is above ambient temperature, the heater block 112 may need to provide heat towards the sample 102 for maintaining the sample 102 at the second, low sample temperature and avoiding that the temperature of the sample 102 is further cooled to the ambient temperature.

The temperature controller 100 further comprises a cooler 120. The cooler 120 comprises a cooler block 122. The cooler block 122 is configured to be in contact with the heater block 112 for conductive transfer of heat. The heater block 112 is further configured to be arranged between the cooler block 122 and the sample 102. This implies that temperature controlling action by the cooler block 122 occurs via the heater block 112. Thus, when the sample 102 is to be cooled, the cooler block 122 may cool the heater block 112, which further acts to cool the sample 102.

Arrangement of the heater block 112 between the cooler block 122 and the sample 102 allows a simple interface of the temperature controller 100 towards the sample 102 as a single surface of the temperature controller 100 is exposed for being brought in direct or indirect contact with walls defining the particle collection chamber holding the sample 102. When using the heater block 112 to increase the temperature of the sample to the first, high sample temperature, it is desired that the transfer of heat is mainly directed towards the sample 102. Hence, the cooler 120 is configured to aid in heating of the sample 102 by providing a heating of the cooler block 122 such that the heat from the heater block 112 is at least only to a small degree directed towards the cooler block 122.

The cooler block 122 could be detached from the heater block 112 during heating of the sample 102 to the first, high sample temperature, but this would require moving the cooler block 122 back and forth into and out of contact with the heater block 112 causing mechanical wear in the temperature controller 100.

The cooler 120 comprises a first temperature fluid conduit loop 130 and a second temperature fluid conduit loop 150 for circulating a fluid in each of the fluid conduit loops 130, 150. The cooler 120 is configured to control fluid in the first temperature fluid conduit loop 130 to maintain a first, high fluid temperature and to control fluid in the second temperature fluid conduit loop 150 to maintain a second, low fluid temperature.

The cooler 120 may thus use the fluid of the first temperature fluid conduit loop 130 for aiding the heating of the sample 102 to the first, high fluid temperature, by the fluid of the first temperature fluid conduit loop 130 being used to heat the cooler block 122.

The cooler 120 may use the fluid of the second temperature fluid conduit loop 150 for bringing the temperature of the sample 102 to the second, low sample temperature by the fluid of the second temperature fluid conduit loop 150 being used for cooling the cooling block 122.

The cooler 120 is configured to control transport of each of the fluid of the first temperature fluid conduit loop 130 and the fluid of the second temperature fluid conduit loop 150 through at least one cooler block conduit 124 extending through the cooler block 122.

As shown in Fig. 1, a single cooler block conduit 124 may be used, such that the cooler 120 is configured to control which of the fluids of the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150 is to be transported through the cooler block conduit 124 or control a mix of the fluids being transported through the cooler block conduit 124.

The temperature controller 100 is configured to provide heat by the heater block 112 and to transport fluid of the first, high fluid temperature through the cooler block conduit 124 for bringing the temperature of the sample 102 to the first, high sample temperature. This implies that a fast heating of the sample 102 may be provided since heat will not be lost or will be insignificantly lost from the heater block 112 towards the cooler block 122.

The temperature controller 100 is configured to provide cooling by the cooler block 122 by transporting fluid of the second, low fluid temperature through the cooler block conduit 124 for bringing the temperature of the sample 102 to the second, low sample temperature. The second, low fluid temperature is lower than the second, low sample temperature and may be substantially lower than the second, low sample temperature. Thus, the cooler 120 may be used for quickly bringing the temperature of the sample 102 down. At a steady-state for the sample 102 at the second, low sample temperature, additional heating by the heater 110 may be needed in order to maintain the sample 102 at the second, low sample temperature. The possibility of using the heater 110, possibly in combination with cooling by the cooler 120 through the fluid of the second, low fluid temperature, enables a the fluid of the second, low fluid temperature to be maintained at a temperature below the second, low sample temperature. This facilitates fast cooling of the sample 102 towards a second, low sample temperature and maintaining the sample 102 at a steady-state at the second, low sample temperature.

In the embodiment shown in Fig. 1 , the first temperature fluid conduit loop 130 comprises a buffer container 136, which is configured to hold a buffer volume of the fluid at the first, high fluid temperature. The first temperature fluid conduit loop 130 further comprises a pump 134 for pumping the fluid from the buffer container 136 through the first temperature fluid conduit loop 130. The pump 134 may be controlled for controlling the transport of fluid through the first temperature fluid conduit loop 130. The pump 134 may control the flow rate of the fluid through the first temperature fluid conduit loop 130.

The first temperature fluid conduit loop 130 further comprises a valve 132 for selectively controlling whether fluid of the first temperature fluid conduit loop 130 is to be transported through the single cooler block conduit 124 or back to the buffer container 136. Thus, the valve 132 may be a three- way valve for controlling fluid from the pump 134 to be directed either towards the single cooler block conduit 124 or directly back to the buffer container 136. The first temperature fluid conduit loop 130 further comprises a first temperature controlling loop 140. The first temperature controlling loop 140 comprises a separate pump 142 for pumping fluid from the buffer container 136 through the first temperature controlling loop 140. The first temperature controlling loop 140 is configured to maintain the fluid of the buffer volume in the buffer container 136 at the desired first, high fluid temperature.

A temperature sensor (not shown) may measure the temperature of the fluid in the buffer container 136 or the temperature of fluid in the first temperature controlling loop 140. The temperature sensor may provide input for determining whether the fluid in the first temperature controlling loop 140 needs to be heated or cooled. The first temperature controlling loop 140 may further comprise a temperature controlling unit 144 for providing heat transfer to or from the fluid in the first temperature controlling loop 140. The temperature controlling unit 144 may comprise two separate elements, which may be selectively activated for either cooling or heating the fluid in the first temperature controlling loop 140.

Similar to the first temperature conduit loop 130, the second temperature fluid conduit loop 150 comprises a buffer container 156, which is configured to hold a buffer volume of the fluid at the second, low fluid temperature. The second temperature fluid conduit loop 150 further comprises a pump 154 for pumping the fluid from the buffer container 156 through the second temperature fluid conduit loop 150. The pump 154 may be controlled for controlling the transport of fluid through the second temperature fluid conduit loop 150. The pump 154 may control the flow rate of the fluid through the second temperature fluid conduit loop 150.

The second temperature fluid conduit loop 150 further comprises a valve 152 for selectively controlling whether fluid of the second temperature fluid conduit loop 150 is to be transported through the single cooler block conduit 124 or back to the buffer container 156. Thus, the valve 152 may be a three-way valve for controlling fluid from the pump 154 to be directed either towards the single cooler block conduit 124 or directly back to the buffer container 156.

The second temperature fluid conduit loop 150 further comprises a second temperature controlling loop 160. The second temperature controlling loop 160 comprises a separate pump 162 for pumping fluid from the buffer container 156 through the second temperature controlling loop 160. The second temperature controlling loop 160 is configured to maintain the fluid of the buffer volume in the buffer container 156 at the desired second, low fluid temperature.

A temperature sensor (not shown) may measure the temperature of the fluid in the buffer container 156 or the temperature of fluid in the second temperature controlling loop 160. The temperature sensor may provide input for determining whether the fluid in the second temperature controlling loop 160 needs to be heated or cooled. The second temperature controlling loop 160 may further comprise a temperature controlling unit 164 for providing heat transfer to or from the fluid in the second temperature controlling loop 160. The temperature controlling unit 164 may comprise two separate elements, which may be selectively activated for either cooling or heating the fluid in the second temperature controlling loop 160.

As mentioned, the valves 132, 152 may be used for selecting whether the respective fluids of the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150 is to be transported through the single cooler block conduit 124. Thus, the valves 132, 152 may be controlled such that one of the fluids of the first temperature fluid conduit loop 130 and second temperature fluid conduit loop 150 is provided through the single cooler block conduit 124 at a time. This allows selectively switching fluids to be provided to the single cooler block conduit 124 using the valves 132 and 152. However, the valves 132, 152 may both be set to provide fluid flow into the single cooler block conduit 124 such that the fluids are mixed and a relative mixture of the fluids (and corresponding temperature of the fluid being passed through the single cooler block conduit 124) may be based on a relative flow rate provided by the pumps 134, 154.

It should further be realized that the valves 132, 152 may be set to separate fluid flow into two paths, such that part of the fluid flows directly to the buffer container 136, 156 and part of the fluid flows to the single cooler block conduit 124. This may be used when mixing fluids in the single cooler block conduit 124, but it may also be used in controlling flow rate of fluid of a single fluid conduit loop 130, 150 being passed through the single cooler block conduit 124.

The single cooler block conduit 124 may be branched after having passed the cooler block 120 into two different paths corresponding to the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150, respectively. Each path may be associated with a stop valve 138, 158. The stop valve 138 selectively passes fluid from the cooler block conduit 124 to the buffer container 136 of the first temperature fluid conduit loop 130. The stop valve 158 selectively passes fluid from the cooler block conduit 124 to the buffer container 156 of the second temperature fluid conduit loop 150. Thus, when the valve 132 is opened for transporting fluid of the first temperature fluid conduit loop 130 to the cooler block conduit 124, the stop valve 138 is also opened for passing fluid from the cooler block conduit 124 to the buffer container 136, while the stop valve 158 is closed for preventing fluid to pass to the buffer container 156. Similarly, when the valve 152 is opened for transporting fluid of the second temperature fluid conduit loop 150 to the cooler block conduit 124, the stop valve 158 is also opened for passing fluid from the cooler block conduit 124 to the buffer container 156, while the stop valve 138 is closed for preventing fluid to pass to the buffer container 136.

The fluid of each of the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150 may be any coolant liquid. The coolant liquid may be based on water. However, in order to avoid corrosion and/or microbiological growth, substance(s) may be added to water forming the coolant liquid.

Further, it should be realized that the same fluid or different fluids may be used in the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150. In particular, the fluid to be used may be selected based on the temperature that the fluid is intended to hold in the respective fluid conduit loop 130, 150.

The temperature controller 100 may further comprise a controlling unit 170. The controlling unit 170 may be configured to control temperature controlling functions of the temperature controller 100 so as to control the heating and/or cooling to be provided by the temperature controller 100.

The temperature controller 100 may comprise a temperature sensor 172. The temperature sensor 172 may provide input to the controlling unit 170 for providing feedback to the controlling unit 170 of an effect of temperature controlling functions of the temperature controller 100 such that the controlling unit 170 may provide control of the temperature controlling functions in dependence of the feedback from the temperature sensor 172.

It should be realized that the temperature controller 100 may comprise additional or alternative sensors for providing input to the controlling unit 170. For instance, the temperature controller 100 may comprise sensors for measuring flow rate through the cooler block conduit 124 such as to allow determining whether a desired flow rate is provided or not.

The temperature sensor 172 may be configured to measure the temperature of the sample 102 by the temperature sensor 172 being configured for insertion into the sample 102. Alternatively, the temperature sensor 172 may measure the temperature of the sample 102 by a non- contact sensing of the temperature, e.g. based on infrared radiation from the sample 102.

The temperature sensor 172 may alternatively provide an indication of the temperature of the sample 102 by measuring a temperature in another location, which temperature may be related to the temperature of the sample 102 through an estimation function. The estimation function may be obtained through calibration.

In particular, if the sample 102 is provided in a collecting device arranged in a sample collector, wherein a sealing is provided to reduce risk of spreading potentially hazardous captured particles, it may be impossible and undesired to introduce the temperature sensor 172 into the particle collection chamber in which the sample 102 is provided. In such case, the temperature sensor 172 may be arranged to make contact with an outer surface of the sample collector. Thus, the temperature sensor 172 may measure a temperature at an outer surface of the sample collector. The relation between the measured temperature and the temperature of the sample 102 may be described by the estimation function, such that the actual temperature of the sample 102 may be determined using the measured temperature and converting the measured temperature to an estimate of the temperature of the sample 102 via the estimation function.

The controlling unit 170 may provide control of the temperature controlling functions of the temperature controller 100 using input from sensors, such as the temperature sensor 172. The controlling unit 170 may be configured to provide control signals to each of the components of the temperature controller 100.

The controlling unit 170 may provide a control signal for activating heating by the heater block 112, such as to define a timing of when the heating is activated. The control signal to the heater 110 may also define an amount of heating to be provided by the heater block 112. The controlling unit 170 may further provide control signals for activating and controlling cooling by the cooler 120. For simplicity, Fig. 1 only indicates a general control line between the controlling unit 170 and the cooler 120, but it should be realized that control signals may be provided to individual components of the cooler 120.

The controlling unit 170 may be configured to provide control signals to the valves 132, 152, 138, 158 for controlling a path followed by the fluid of the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150. The controlling unit 170 may further set a position, at least of the valves 132, 138 for controlling how large portions of the fluid flow at an inlet into the valve 132, 138 are directed to each outlet of the valve 132, 138. The controlling of the valves 132, 152, 138, 158 may select whether the fluid of the first temperature fluid conduit loop 130 or the fluid of the second temperature fluid conduit loop 150 is transported through the single cooler block conduit 124. The controlling of the valves 132, 152, 138, 158 may alternatively act to control mixing of the fluids of the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150 in the single cooler block conduit 124.

The controlling unit 170 may be configured to provide control signals to the pumps 134, 154 for controlling a flow rate of the fluid of the first temperature fluid conduit loop 130 and the fluid of the second temperature fluid conduit loop 150, respectively. The flow rate may be set by the pumps 134, 154, possibly in combination with the valves 132, 152.

The controlling unit 170 may further be configured to provide control signals to the first temperature controlling loop 140 and the second temperature controlling loop 160 for maintaining a constant temperature of the fluids of the first temperature fluid conduit loop 130 and the second temperature fluid conduit loop 150, respectively. The control signals to the first temperature controlling loop 140 and the second temperature controlling loop 160 may control the flow rate through the controlling loops 140, 160 by controlling the pumps 142 and 162, respectively. The control signals to the first temperature controlling loop 140 and the second temperature controlling loop 160 may further control the heating or cooling to be applied to the fluid in the first temperature controlling loop 140 and the second temperature controlling loop 160 by controlling the temperature controlling units 144 and 164, respectively. The controlling unit 170 may be configured to provide control signals for controlling switching of the temperature of the sample 102 from a first, high sample temperature to a second, low sample temperature and vice versa. The controlling unit 170 may further be configured to provide control signals for maintaining a steady state of the temperature of the sample 102 at the first, high sample temperature and at the second, low sample temperature.

The temperature controller 100 may be configured to bring the sample from the second, low sample temperature to the first, high sample temperature by providing heating by the heater block 112 and by transporting fluid of the first, high fluid temperature through the single cooler block conduit 124. The amount of heating by the heater block 112 and the flow rate through the single cooler block conduit 124 may be changed during the heating of the sample 102 so as to provide a fast switching of temperatures of the sample 102 and a fast settling of the temperature to a steady state at the first, high sample temperature.

The temperature controller 100 may be configured to maintain the sample 102 in a steady state at the first, high sample temperature by providing a heating by the heater block 112. The transporting of the fluid of the first, high fluid temperature through the single cooler block conduit 124 may also be maintained during the steady state. Any adjustment of the temperature controller 100 for adapting to a drift in the temperature of the sample 102 during steady state may suitably be provided by controlling the heating by the heater block 112, since the heating by the heater block 112 may provide a fast response in temperature of the sample.

The temperature controller 100 may be configured to bring the sample from the first, high sample temperature to the second, low sample temperature by providing cooling by the cooler block 122 by transporting fluid of the second, low fluid temperature through the single cooler block conduit 124. Also, at least at a stage when the temperature of the sample is approaching the second, low sample temperature, the temperature controller 100 may provide heating by the heater block 112 (to prevent that the temperature of the sample is brought below the desired second, low sample temperature). The heating by the heater block 112 and the flow rate through the single cooler block conduit 124 may be changed during the cooling of the sample 102 so as to provide a fast switching of temperatures of the sample 102 and a fast settling of the temperature to a steady state at the second, low sample temperature.

The temperature controller 100 may be configured to maintain the sample 102 in a steady state at the second, low sample temperature by providing a heating by the heater block 112. This may be relevant if the second, low sample temperature is higher than an ambient temperature. The transporting of the fluid of the second, low fluid temperature through the single cooler block conduit 124 may also be maintained during the steady state. Any adjustment of the temperature controller 100 for adapting to a drift in the temperature of the sample 102 during steady state may suitably be provided by controlling the heating by the heater block 112, since the heating by the heater block 112 may provide a fast response in temperature of the sample.

The controlling unit 170 may be configured to provide control signals for proportional-integral-derivative, PID, regulation of the temperature of the sample 102. PID regulation may ensure that a steady state at a desired temperature is quickly achieved. The PID regulation may determine control signals in response to feedback sensor input for quickly bringing the temperature of the sample 102 to a setpoint defining a desired temperature level.

Further, the PID regulation may use multiple setpoints for allowing an improved control of the switching of the temperatures of the sample 102. Also or alternatively, the PID regulation may utilize lead-lag compensation to take lag of an effect of a control action into account, or the PID regulation may comprise cascading multiple PID controllers for improving control by the PID regulation.

According to another embodiment, the controlling unit 170 is configured to use open-loop control for switching the temperatures of the sample 102 in a first cycle, wherein an error of an end result of the open-loop control is determined and used in control for switching the temperatures of the sample 102 in a second cycle.

Thus, the controlling unit 170 need not adapt control of the temperature of the sample 102 based on any feedback information during switching of the temperatures of the sample 102.

However, the result of the obtained temperature based on the open- loop control may be compared to a desired temperature. An error in the obtained temperature may thus be used for correcting the regulation in a next cycle that is to switch the temperatures of the sample 102. In this way, a closed-loop control is obtained based on the error identified for the switching of the temperatures in the first cycle.

The controlling unit 170 may be implemented as a general-purpose processing unit, such as a central processing unit (CPU), which may execute the instructions of one or more computer programs in order to implement the functionality of the controlling unit 170. The controlling unit 170 may alternatively be implemented as firmware arranged in an embedded system, or as a specifically designed processing unit, such as an Application-Specific Integrated Circuit (ASIC) or a Field-Programmable Gate Array (FPGA), which may be configured to implement the functionality of the controlling unit 170.

The controlling unit 170 may be configured to control thermal cycling of the temperature of the sample 102 between the first, high sample temperature and the second, low sample temperature. This may be used for facilitating amplification of DNA targets using PCR in the sample 102.

The controlling unit 170 may be configured to control temperature of the sample 102 to be switched between a first, high sample temperature higher than 90°C and a second, low sample temperature lower than 65°C. For instance, the first, high sample temperature may be 95°C and the second, low sample temperature may be 60°C, which may be suitable for PCR.

The fluid of the first temperature fluid conduit loop 130 may be held at a first, high fluid temperature corresponding to the desired first, high sample temperature. Thus, the fluid of the first temperature fluid conduit loop 130 may be maintained at a temperature of 95°C.

The fluid of the second temperature fluid conduit loop 150 may be held at a second, low fluid temperature substantially below the desired second, low sample temperature. Thus, the fluid of the second temperature fluid conduit loop 150 may be maintained at a temperature of 30°C.

The temperature controller 100 may be used with a sample of a volume less than 30 pi for enabling very fast switching of temperatures of the sample 102. The temperature controller 100 may be configured to switch the temperatures of the sample of the volume of less than 30 mI from the second, low sample temperature to the first, high sample temperature, and vice versa, in less than three seconds. The cooling of the sample from the first, high sample temperature to the second, low sample temperature may be slower than the heating from the second, low sample temperature to the first, high sample temperature. According to an embodiment, the temperature controller 100 may provide heating of the sample from the second, low sample temperature to the first, high sample temperature in 1.5 seconds and cooling of the sample from the first, high sample temperature to the second, low sample temperature in 2.5 seconds.

Referring now to Fig. 2, the temperature controller 100 may alternatively comprise a separate cooler block conduit 224a, 224b through the cooler block 222. A first cooler block conduit 224a is dedicated to and part of the first temperature fluid conduit loop 230. A second cooler block conduit 224b is dedicated to and part of the second temperature fluid conduit loop 250. The cooler 220 may thus not necessarily comprise any valves for controlling flow through the first temperature fluid conduit loop 230 and the second temperature fluid conduit loop 250, respectively, since the fluid may follow the same path throughout temperature control. However, the cooler 220 may anyway comprise valves to not allow fluid to be transported through the cooler block 222 to counter-act a desired heating or cooling of the sample 102.

A cooling action by the cooler 220 may be controlled by selecting whether fluid of the first temperature fluid conduit loop 230 and fluid of the second temperature fluid conduit loop 250, respectively, is to be transported through the cooler block 222. The cooling action by the cooler 220 may also or alternatively be controlled by selecting a flow rate through the first cooler block conduit 224a and the second cooler block conduit 224b, respectively.

In an embodiment, the fluid of the second temperature fluid conduit loop 250 may be directed to not be transported through the second cooler block conduit 224b, when the sample 102 is to be brought to the first, high sample temperature. Thus, fluid is only transported through the first cooler block conduit 224a, when the sample 102 is to be brought to the first, high sample temperature. Similarly, the fluid of the first temperature fluid conduit loop 230 may be directed to not be transported through the first cooler block conduit 224a, when the sample 102 is to be brought to the second, low sample temperature. Thus, fluid is only transported through the second cooler block conduit 224b, when the sample 102 is to be brought to the second, low sample temperature.

Referring now to Fig. 3, an analysis instrument 300 for analysis of a sample 102 will be described. The analysis instrument 300 comprises a receptacle 302 for receiving a collecting device holding the sample 102 to be analyzed. The receptacle 302 may for instance be configured to receive a sample collector that carries the collecting device in which the sample 102 has been collected.

The receptacle 302 may be shaped and designed to be used with a particular sample collector, such that the receptacle 302 may arrange the sample collector in the analysis instrument 300 for facilitating interaction of the analysis instrument 300 with the sample 102.

The analysis instrument 300 comprises the temperature controller 100, which is configured to provide control of the temperature of the sample 102 while the sample 102 is held in the receptacle. The receptacle 302 and/or the temperature controller 100 may be arranged to be movable within the analysis instrument 300 for providing a relative movement between the receptacle 302 and the temperature controller 100 such that the heater block 112 may be brought into contact with an outer surface of the sample collector, when the sample collector is placed in the receptacle 302. Alternatively, the temperature controller 100 may be arranged such that the heater block 112 is brought into contact with the outer surface of the sample collector, when the sample collector is placed in the receptacle 302.

The temperature controller 100 may provide preparation of the sample 102 while the sample 102 is arranged in the analysis instrument 300. For instance, the temperature controller 100 may provide thermal cycling of the sample 102, which may be used for amplification of DNA targets using PCR in the sample 102.

The analysis instrument 300 may further comprise a measurement unit 304 for performing measurements on the sample 102. The measurements may be performed while the sample 102 is held in the receptacle 302. The measurement unit 304 may for instance comprise a light source and a photo sensitive detector for performing light-based measurements on the sample 102. Information acquired by the measurement unit 304, such as by the photo-sensitive detector, may then be processed in order to provide an analysis result of the sample 102.

The light-based measurement may comprise detecting light emitted through luminescence. For instance, the light-based measurement may comprise detecting light being emitted based on stimulation by light, such that the light-based measurement may comprise detecting light emitted through fluorescence. Also, or alternatively, the light-based measurement may comprise detecting scattered light, such as detecting elastically scattered light through e.g. Rayleigh or Mie scattering, or detecting inelastically scattered light through e.g. Raman scattering.

The measurement unit 304 may be arranged in relation to the receptacle such that the measurement unit 304 is provided access to the sample 102 for performing measurements when the sample 102 is held by the receptacle 302. For instance, the measurement unit 304 may be arranged such that, when a sample collector is arranged in the receptacle 302, the measurement unit 304 is arranged in relation to an optical window of a sample collector so as to have optical access to the sample 102 through the optical window. It should be realized that the receptacle 302 and/or the measurement unit 304 may be arranged to be movable within the analysis instrument 300 for providing a relative movement between the receptacle 302 and the measurement unit 304 such that the measurement unit 304 is positioned in relation to the sample 102 for enabling measurements to be performed.

The analysis instrument 300 may have a separate sample preparation configuration wherein the temperature controller 100 is arranged in relation to the sample 102 for providing preparation of the sample 102 through switching of temperatures of the sample 102 and sample analysis configuration wherein the measurement unit 304 is arranged in relation to the sample 102 for providing analysis of the sample 102, such that at least one of the receptacle 302, the temperature controller 100 and the measurement unit 304 may be moved between the sample preparation configuration and the sample analysis configuration. However, according to an embodiment, sample preparation and analysis may be provided such that switching of temperatures of the sample 102 and measurements of the sample 102 may be performed in a common position of the sample 102 as held by the receptacle 302. This also implies that measurements may be performed at different temperatures of the sample 102 or between actions of subjecting the sample 102 to heating or cooling.

Referring now to Fig. 4, a method for controlling temperature of a sample is briefly described.

The method comprises arranging 402 a heater block 112 in contact with a collecting device holding the sample 102. The heater block 112 is arranged between the sample 102 and a cooler block 122, which is in contact with the heater block 112. The heater block 112 may be arranged in direct contact with the collecting device for transferring heat to the sample 102 held within a container defined by the collecting device such as a particle collection chamber therein. However, the heater block 112 may be arranged in indirect contact with the collecting device and the sample 102 therein, e.g. through one or more layers of a sample collector holding the collecting device.

The method further comprises bringing 404 the temperature of the sample 102 to a first, high sample temperature by providing heat by the heater block 112 and by transporting fluid of a first, high fluid temperature through at least one cooler block conduit 124 extending through the cooler block 122. The transporting of the fluid of the first, high fluid temperature though the cooler block conduit 124 may thus ensure that the cooler block 122 may aid in heating of the sample 102 and may avoid heat being transferred from the heater block 112 to the cooler block 122 instead of towards the sample 102.

The method further comprises switching 406 the temperature of the sample 102 to a second, low sample temperature by cooling the sample by the cooler block by transporting fluid of the second, low fluid temperature through the at least one cooler block conduit 124 for bringing the temperature of the sample to the second, low sample temperature. The second, low fluid temperature is lower than the second, low sample temperature. The second, low fluid temperature may be substantially lower than the second, low sample temperature such that the sample may be quickly brought to the second, low sample temperature.

The method may further comprise stabilizing the temperature of the sample at the second, low sample temperature by also providing heating by the heater block 112.

In the above the inventive concept has mainly been described with reference to a limited number of examples. However, as is readily appreciated by a person skilled in the art, other examples than the ones disclosed above are equally possible within the scope of the inventive concept, as defined by the appended claims.

Claims

1. A temperature controller (100) for controlling temperature of a sample; said temperature controller (100) comprising: a heater (110) comprising a heater block (112) and a cooler (120; 220) comprising a cooler block (122; 222), wherein the heater block (112) is configured to be arranged between the cooler block (122; 222) and the sample (102); wherein the temperature controller (100) is configured for controlling temperature of the sample (102) to be switched between a first, high sample temperature and a second, low sample temperature; wherein the cooler (120; 220) comprises a first temperature fluid conduit loop (130; 230) and a second temperature fluid conduit loop (150; 250) for circulating a fluid in each of the fluid conduit loops (130, 150; 230, 250) and wherein the cooler (120; 220) is configured to control fluid in the first temperature fluid conduit loop (130; 230) to maintain a first, high fluid temperature and to control fluid in the second temperature fluid conduit loop (150; 250) to maintain a second, low fluid temperature, wherein the cooler (120; 220) is further configured to control transport of each of the fluid of the first temperature fluid conduit loop (130; 230) and the fluid of the second temperature fluid conduit loop (150; 250) through at least one cooler block conduit (124; 224a, 224b) extending through the cooler block (122; 222); wherein the temperature controller (100) is configured to provide heat by the heater block (112) and to transport fluid of the first, high fluid temperature through the at least one cooler block conduit (124; 224a, 224b) for bringing the temperature of the sample to the first, high sample temperature; and wherein the temperature controller (100) is configured to provide cooling by the cooler block (122; 222) by transporting fluid of the second, low fluid temperature through the at least one cooler block conduit (124; 224a, 224b) for bringing the temperature of the sample to the second, low sample temperature, wherein the second, low fluid temperature is lower than the second, low sample temperature.

2. The temperature controller according to claim 1 , further comprising a controlling unit (170) for providing control signals for controlling temperature controlling functions of the temperature controller (100).

3. The temperature controller according to claim 2, wherein the temperature controlling functions comprise at least one of heating of the heater block (112), selecting the fluid to be transported through the at least one cooler block conduit (124; 224a, 224b), and controlling a flow rate of the fluid transported through the at least one cooler block conduit (124; 224a, 224b).

4. The temperature controller according to claim 2 or 3, further comprising a temperature sensor (172) for providing an indication of a temperature of the sample as input to the controlling unit (170).

5. The temperature controller according to any one of claims 2-4, wherein the controlling unit (170) is configured to provide control signals for proportional-integral-derivative, PID, regulation of the temperature of the sample.

6. The temperature controller according to any one of the preceding claims, wherein the heater block (112) is electrically operated for controlling heat dissipated by the heater block (112).

7. The temperature controller according to any one of the preceding claims, wherein the heater block (112) is configured to be controlled for fine adjustment of sample temperature at each of the first, high sample temperature and the second, low sample temperature.

8. The temperature controller according to any one of the preceding claims, wherein the heater block (112) is formed by aluminum nitride.

9. The temperature controller according to any one of the preceding claims, wherein the cooler (120) comprises a single cooler block conduit (124) and wherein the cooler (120) is configured to selectively control which of the fluids of the first and second temperature fluid conduit loops (130, 150) to be transported through the single cooler block conduit (124) or wherein the cooler (120) is configured to control mixing of the fluids of the first temperature and second temperature fluid conduit loops (130, 150) into the single cooler block conduit (124).

10. The temperature controller according to claim 9, wherein each of the first temperature and second temperature fluid conduit loops (130, 150) comprises a valve (132, 152) for selectively switching fluids to be provided to the single cooler block conduit (124).

11.The temperature controller according to any one of claims 1-8, wherein the cooler (220) comprises two cooler block conduits (224a, 224b), each being dedicated to a respective one of the first temperature and second temperature fluid conduit loops (230, 250) and wherein the cooler (220) is configured to control a flow rate of the fluid through each of the cooler block conduits (224a, 224b).

12. The temperature controller according to any one of the preceding claims, wherein each of the first temperature and second temperature fluid conduit loops (130, 150; 230, 250) comprises a pump (134, 154) for pumping the fluid through the fluid conduit loop (130, 150; 230, 250).

13. The temperature controller according to any one of the preceding claims, wherein each of the first temperature and second temperature fluid conduit loops (130, 150; 230, 250) comprises a buffer container (136, 156) for holding a buffer volume of the fluid at the first, high fluid temperature and second, low fluid temperature, respectively, wherein each of the first temperature and second temperature fluid conduit loops (130, 150; 230, 250) further comprises a temperature controlling loop (140, 160) comprising a pump (142, 162) and a temperature controlling unit (144, 164) for controlling the temperature of the first, high fluid temperature and second, low fluid temperature, respectively.

14. The temperature controller according to any one of the preceding claims, wherein the temperature controller (100) is configured to provide thermal cycling of the temperature of the sample between the first, high sample temperature and the second, low sample temperature for amplification of DNA targets using polymerase chain reaction.

15. The temperature controller according to claim 14, wherein the temperature controller (100) is configured to control temperature of the sample to be switched between a first, high sample temperature higher than 90°C and a second, low sample temperature lower than 65°C.

16. The temperature controller according to claim 15, wherein the temperature controller (100) is configured to switch the temperatures of a sample of a volume of less than 30 pi from the second, low sample temperature to the first, high sample temperature, and vice versa, in less than three seconds.

17. An analysis instrument (300) for analysis of a sample (102), said analysis instrument (300) comprising: a receptacle (302) for receiving a collecting device holding a sample (102) to be analyzed; a temperature controller (100) according to any one of the preceding claims; wherein the temperature controller (100) is arranged in relation to the receptacle (302) of the analysis instrument (300) for allowing the heater block (112) to be in contact with the collecting device when the collecting device is arranged in the receptacle (302).

18. A method for controlling temperature of a sample (102), said method comprising: arranging (402) a heater block (112) in contact with a collecting device holding the sample (102), wherein the heater block (112) is further arranged between the sample (102) and a cooler block (122; 222), which is in contact with the heater block (112); bringing (404) the temperature of the sample (102) to a first, high sample temperature by providing heat by the heater block (112) and by transporting fluid of a first, high fluid temperature through at least one cooler block conduit (124; 224a, 224b) extending through the cooler block (122;

222); switching (406) the temperature of the sample (102) to a second, low sample temperature by cooling the sample (102) by the cooler block (122; 222) by transporting fluid of the second, low fluid temperature through the at least one cooler block conduit (124; 224a, 224b) for bringing the temperature of the sample (102) to the second, low sample temperature, wherein the second, low fluid temperature is lower than the second, low sample temperature.