Device, system and method for the calibration of a thermocycler

Abstract

The present invention relates to a device (10), system (200) and process for the remote calibration of a thermocycler (50).

Description

[0001] DEVICE, SYSTEM AND METHOD FOR THE CALIBRATION OF A THERMOCYCLER

[0002] DESCRIPTION

[0003] Technical field of the invention

[0004] The present invention relates to the field of the apparatuses for biological analysis.

[0005] In particular, the invention relates to a device, system and process for the calibration of a thermocycler through wireless communication structures and protocols.

[0006] Background

[0007] In recent years there has been a notable increase in performing molecular diagnostic tests based upon the amplification of the nucleic acid sequences, wherein minimum amounts of DNA, or RNA, are taken and are replicated several times, so as to be able to highlight, for example, small traces of a microorganism in a sample, without having to perform a culture. These tests, in particular those using suitably devised markers and fluorescent enzymes, offer a rapid and quantitative analysis of the nucleic acid sequences, which is essential in many diagnostic applications.

[0008] The quantity PCR, also known with English terms Real-Time PCR (Polymerase Chain Reaction), is one of the most common methods for amplifying and quantifying DNA. However, there are other methods for amplifying and quantifying DNA which exploit temperature cycles and isotherm reactions.

[0009] Generally, these tests are performed by specific laboratory machines, called thermocycling machines, or thermocyclers, which perform temperature cycles on the DNA, or RNA, sample through a series of thermal phases. For example, such thermal phases can provide the DNA denaturation at high temperatures, the matching of the primer starters, or initial primers, at lower temperatures and the DNA extension by DNA polymerase enzyme at intermediate temperatures. These cycles are repeated even for 20-40 times and allow to produce a great quantity of amplified DNA.

[0010] The success of these diagnostic tests is based not only upon an accurate design of reagents and analysis protocols, but especially upon the precise control of the thermocycler performances, in particular the thermal control and the accuracy in reading the samples. The fact of achieving and keeping optimum performances of the thermocycler is fundamental in order to obtain reliable and accurate results, however it has significant challenges and / or drawbacks.

[0011] In fact, currently the maintenance of such machines requires to perform practical procedures applied directly on site by trained and specialized operators, who have to be equipped with calibration devices and / or diagnostic apparatuses. It results clear that in order to guarantee a continuous operativity of the machines the presence of a specialized operator is requested and this may result to be an obstacle.

[0012] An additional drawback relates to the fact that the calibration devices made available do not give the possibility of modifying some performance parameters required for the correct operation of the thermocycler itself.

[0013] Additionally, the risk of experiencing deviations in the operation of the thermocycler outside the producers’ specifications is high, or anisotropies between the sample test sites inside the thermocycler, which is not possible to correct on site with the known calibration devices and, consequently, it results necessary to send the thermocycler to a specialized laboratory to perform expensive setting procedures by expert technicians.

[0014] In case a general re-calibration of the thermocycler becomes necessary, the latter is typically sent to specialized laboratories, causing shutdowns which can last days or even weeks. Such approach not only is time consuming, but further involves the risk of interrupting crucial diagnostic activities.

[0015] Summary of the invention

[0016] The technical problem placed and solved by the present invention is then to provide a device for the calibration of a thermocycler which allows to obviate to the drawbacks mentioned above with reference to the known art.

[0017] Such problem is solved by a device for the calibration according to claim 1 . The invention further relates to a system and a calibration process of a thermocycler according to claims 6 and 11 , respectively.

[0018] Preferred features of the present invention are set forth of the depending claims.

[0019] According to an aspect of the present invention, a device for the remote calibration of a thermocycler is provided, wherein the calibration device comprises:

[0020] - a main body shaped to be housed inside a reaction chamber of the thermocycler,

[0021] - sensor means carried by said main body and configured to detect at least an operating parameter of the thermocycler inside said reaction chamber,

[0022] - a local control unit configured to process the detected operating parameter,

[0023] - a, preferably wireless, communication module configured for a bidirectional communication of the local control unit with a remote-control unit and the thermocycler itself.

[0024] Said local control unit is configured to communicate to the thermocycler a calibration signal provided by the remote-control unit and suitable to determine a calibrated operating parameter depending upon the detected operating parameter.

[0025] Advantageously, by means of the calibration device it is then possible to calibrate remotely the thermocycler, without the need for a manual intervention. In other terms, the invention allows to process a calibration signal through a remote-control unit depending upon the operating parameters detected by the calibration device. The calibration signal is preferably communicated to the thermocycler by the remote-control unit through said calibration device.

[0026] The invention allows to calibrate effectively a thermocycler by acting on operating and performance parameters in a simple and rapid way, without the need for the in-situ presence of a specialized operator or sending the thermocycler to technical assistance.

[0027] Preferably, said operating parameter comprises a temperature piece of data of and / or an emission and / or lighting piece of data. More preferably several operating parameters are detected.

[0028] Said main body can include a plurality of reference elements, for example seats which reproduce the positioning on a typical cartridge of the biological samples to be analysed with the thermocycler. Such seats can be shaped like the typical seats of a cartridge for thermocyclers suitable to receive a biological sample. The above-mentioned sensor means comprise at least a temperature sensor arranged inside the main body, for example between said plurality of seats.

[0029] In this way, there is the advantage of measuring the temperature for the calibration of the operating parameter exactly at the biological samples to be analysed.

[0030] According to an embodiment of the invention, a detectable and calibratable operating parameter comprises a relative position of the plurality of the reference elements with respect to a predetermined detection position. For example, in case the operating parameter relates to the fluorescence of the biological sample by the thermocycler, the latter, as it is known, is measured during the amplification process of the nucleic agents and the correct position of the samples is fundamental for a correct process execution.

[0031] According to a preferred embodiment, the calibration signal is communicated to the thermocycler through the wireless communication module. Said wireless communication module can comprise one or more antennas for the transmission of wireless signals by using Bluetooth and / or Wi-Fi communication standards.

[0032] The present invention also relates to a calibration system comprising:

[0033] ■ a calibration device as described above,

[0034] ■ a thermocycler operatively associated to said calibration device,

[0035] ■ a remote-control unit configured for a bidirectional communication with the calibration device and the thermocycler.

[0036] The remote-control unit is configured to provide to the calibration device and / or to the thermocycler the calibration signal generated depending upon the operating parameter detected by said sensor means carried by the calibration device.

[0037] The main advantage of the calibration system of the invention consists in the remote calibration of the thermocycler by the above-mentioned device, by exploiting an independent detection of data processed by a remote-control unit without the need for having an in situ trained operator.

[0038] Advantageously, moreover, the complexity of the instruments used for the calibration of the thermocycler is reduced, by making the workflow wholly remote and automatable.

[0039] According to an additional aspect the present invention relates to a calibration process which provides the steps of: a) inserting the calibration device in the reaction chamber of the thermocycler, b) performing with said thermocycler a predetermined analysis protocol, c) detecting at least an operating parameter of the thermocycler inside said reaction chamber through sensor means of the calibration device and corresponding sensor means of the thermocycler, d) transmitting the data associated to the at least a detected operating parameter to a remote-control unit in bidirectional communication with the thermocycler and the calibration device, e) comparing the piece of data detected by the sensor means of the calibration device with the piece of data detected by the sensor means of the thermocycler, f) generating with the remote-control unit a calibration signal of the thermocycler if the comparison returns a value outside a predefined range of values, g) transmitting the calibration signal to the thermocycler and / or to the calibration device in order to obtain a calibrated operating parameter of the thermocycler.

[0040] In this way there is the advantage of calibrating the thermocycler remotely in a rapid and simple way, since it is possible to monitor the calibration process. Moreover, the period of time required for the setting and calibration process decreases, by reducing drastically the machine shutdowns, and removing the need for trained personnel.

[0041] As mentioned above, the calibration signal comprises at least a corrective parameter of the temperature. Advantageously, the calibrated temperature parameter is obtained by means of a polynomial interpolation algorithm which allows to obtain temperature correction coefficients.

[0042] It will be also appreciated that the calibration process provides a step of verifying the correct matching of the calibration device with the thermocycler. Preferably, when the calibration device is inserted into the reaction chamber of the thermocycler, the correct positioning of the main body of the calibration device in said chamber is verified. In the affirmative case, the calibration device transmits a signal containing such piece of information to the the remote-control unit, in order to guarantee a correct detection of the operating parameters and a correct calibration.

[0043] According to a preferred embodiment, the above-mentioned analysis protocol is a thermal protocol, functional for the calibration of the thermocycler, and it is implemented as a sequence of phases which preferably comprises a phase of initial heating (or pre-heating) and a plurality of phases of progressive heating inside the reaction chamber.

[0044] In detail, each phase of progressive heating comprises a dynamic peak followed by a period at constant temperature and, in particular for the calibration of the temperature sensors of the thermocycler, the comparison is performed based upon temperature data detected during the period at constant temperature.

[0045] Advantageously, the calibration process comprises an additional verification step subsequent to the transmission of the calibration signal to store the calibrated operating parameter of the thermocycler in the remote-control unit.

[0046] This has the advantage of allowing to monitor the operating performances of the thermocycler during each operating cycle and with reference to parameters always updated on the remote-control unit.

[0047] Other advantages, features and use modes of the present invention will result evident from the following detailed description of some embodiments, shown by way of example and not for limitative purposes.

[0048] Brief description of figures

[0049] The figures of the enclosed drawings will be referred to, wherein:

[0050] ■ Figure 1 is an exploded view of a calibration device of a thermocycler according to a preferred embodiment of the present invention;

[0051] ■ Figure 2 shows a perspective view of a component of the device of Figure 1 ;

[0052] ■ Figure 3 shows a section view of Figure 2;

[0053] ■ Figure 4 shows a schematic representation of a calibration system according to an embodiment of the present invention and comprising the device of Figure 1 ;

[0054] ■ Figure 5a shows the calibration device of Figure 1 under extracted condition and under a condition inserted in a thermocycler.

[0055] ■ Figures 5b and 5c show a schematic representation of two embodiments of the communication between the devices and units composing the calibration system of the present invention;

[0056] Figure 6 is a block diagram of a calibration process of the thermocycler according to a preferred embodiment of the present invention;

[0057] ■ Figures 7, 8 and 9, show, each one, details of a same graph representing a preferred example of calibration protocol implemented by the present invention to perform the calibration of the operating temperature of the thermocycler;

[0058] ■ Figure 10 shows results of experimental tests obtained by implementing the present invention.

[0059] The thicknesses and the curvatures represented in the above-mentioned figures are to be meant as purely exemplifying, they are generally magnified and not necessarily shown in proportion.

[0060] Detailed description of preferred embodiments

[0061] Various embodiments and variants of the invention will be described hereinafter and this with reference to the above-illustrated figures.

[0062] Analogous components are designated in the several figures with the same numeral reference.

[0063] In the following detailed description, additional embodiments and variants with respect to embodiments and variants already treated in the same description will be illustrated limitedly to the differences with what already shown. Moreover, the different embodiments and variants described hereinafter are likely to be used in combination, if compatible.

[0064] By firstly referring to Figure 1 , according to a preferred embodiment of the invention a calibration device is designated as a whole with 10.

[0065] The calibration device 10 is configured for the remote calibration of a thermocycler 50 apt to amplify sequences of nucleic acids, such as DNA and RNA, contained in biological samples. The thermocycler 50 uses one or more cycles, or protocols, for amplifying the sequences of nucleic acids.

[0066] The present invention also relates to a calibration system 200 (Figure 4) which comprises the calibration device 10, the thermocycler 50 and a remote-control unit 100, which will be described in detail hereinafter.

[0067] The device 10 is configured to be housed in a reaction chamber of the thermocycler 50. Said reaction chamber, illustrated in detail subsequently and designated with the reference 51 in Figure 5, then results to be shaped suitably to receive and house the device 10.

[0068] As illustrated in Figure 1 , the calibration device 10 preferably comprises a containment shell 11 provided with an upper element 13 and a lower element 15 which can be coupled therebetween to define one single body.

[0069] The calibration device 10 comprises a local control unit 12 thereto sensor means 16 are connected, configured to detect at least an operating parameter of the thermocycler 50 inside the reaction chamber. The local control unit 12 is preferably arranged inside the containment shell 11 .

[0070] The local control unit 12 is configured to process the operating parameter detected by the sensor means 16. Moreover, the local control unit 12 is advantageously configured to communicate a calibration signal to the thermocycler 50 so as to obtain a calibrated operating parameter of the thermocycler 50.

[0071] In particular, said operating parameter comprises a temperature piece of data and / or a lighting piece of data. Preferably, several operating parameters are detected which comprise several temperature data and / or lighting data, and / or additional operating parameters of the thermocycler 50.

[0072] The calibrated operating parameter allows to correct the operation of the thermocycler 50 with reference, for example, to the thermal and optical performances.

[0073] The calibration device 10 provides a main body 17 and can carry a plurality of reference elements which, in the illustrated example, comprise seats 20 shaped to simulate the structures of some types of cartridges suitable to the operation with the thermocycler 50. Said seats, in particular, reproduce the biological sample housings. According to embodiments, the seats 20 can be through- seats. In particular, the main body 17 of the calibration device 10 is shaped to be housed inside the reaction chamber 51 of the thermocycler 50, in a position suitable to detect the operating parameter. The main body 17 is coupled to the containment shell 11 of the local control unit 12.

[0074] The sensor means 16 comprises at least a temperature sensor arranged inside the main body 17, preferably placed between the plurality of reference elements 20. Such temperature sensor is apt to measure the temperature inside the reaction chamber 51. Such temperature is preferably detected with respect to a time interval determined by each cycle, or protocol, in particular a thermal one, of analyses performed with the thermocycler.

[0075] The main body 17 (Figures 1 , 2 and 3) preferably comprises a supporting plate 19 for the positioning of the biological samples, in particular, containing nucleic acids.

[0076] The main body 17 is advantageously implemented as a substantially rectangular element or however having a shape like a disposable cartridge usually used for the analysis of the biological samples in thermocyclers.

[0077] As illustrated in Figures 2 and 3, the seats 20 are obtained on an upper face 21 of the supporting plate 19, which, at a lateral wall 23 faced towards the containment shell 11 , is provided with one or more housing holes 22 apt to house a corresponding sensor 16.

[0078] Preferably, the supporting plate 19 is metallic and is apt to provide thermal conductivity for the temperature detection by the sensor means 16.

[0079] The local control unit 12 comprises a measurement chip connected to the sensor means 16, processing means and a, preferably wireless, communication module - the latter designated as a whole with reference 32.

[0080] The processing means is configured to process one or more operating parameters acquired by the sensor means 16 and referred to said time interval. The communication module 32 of the calibration device 10 is configured for a bidirectional communication of the local control unit 12 with a remote-control unit 100 and with a control unit of the thermocycler 50. In the illustrated example, the module is of wireless type and can include one or more antennas 31 for the transmission of said wireless signals. Such module can use, for example, Bluetooth and / or Wi-Fi communication standards.

[0081] In a preferred embodiment of the invention, the remote-control unit 100 is configured to generate and provide a calibration signal of the thermocycler 50 depending upon one or more detected operating parameters. The calibration signal can be communicated to the thermocycler 50 and / or transmitted to the local control unit 12 of the calibration device 10 through said communication module 32.

[0082] Preferably, the communication module is of wireless type and it is apt to transmit to the remote-control unit 100 (or to the thermocycler 50) a signal containing even data identifying the calibration device 10, one piece or more data related to the detection time interval and / or data processed by the processing means.

[0083] For example, the identifying data can include series number, hardware version, software version etc. and the processed data preferably comprise calibration parameters thereamong at least a polynomial coefficient for correcting the temperature.

[0084] According to the preferred embodiments, the local control unit 12 comprises an electronic card 29 thereon at least a connector 30 and the processing means / communication module 32 are welded.

[0085] The calibration device 10 can include even a supporting element 33 thereon the local control unit 12 is rested and it is configured to guarantee the grounding for possible electrostatic discharges generated by the same. In particular, the supporting element 33 is arranged below the electronic card 29 and it is in contact therewith.

[0086] With reference now to Figure 4 and 5, the thermocycler 50 comprises a control unit 52 configured to control one or more operating parameters of the thermocycler 50. Figure 5a shows the calibration device 10 in extracted position and in position inserted into the thermocycler 50.

[0087] The thermocycler 50 preferably comprises sensor means which is associated to the control unit 52 and configured to detect at least one operating parameter inside the reaction chamber 51. Preferably the sensor means is configured to detect several operating parameters inside the reaction chamber 51. The sensor means can comprise temperature sensors and optical sensors for detecting, for example, the emission and the fluorescence.

[0088] Inside the chamber 51 one or more light modules can be present apt to emit a beam of uniform light (or excitation light) according to specific wavelengths to illuminate the biological samples at interest areas in which the fluorescence is detected during the process for amplifying the nucleic acids.

[0089] Inside the reaction chamber 51 a thermoelectric module is preferably present to perform one or more thermal cycles.

[0090] The above-mentioned operating parameters comprise, for example, power data of the light beam emitted by each light module, temperature data and / or data of measuring the fluorescence of the biological samples in relation to the position of the same.

[0091] Advantageously, it is possible to verify the correct positioning of the calibration device 10 inside the thermocycler 50. In particular, it is possible to verify the correct positioning of the main body 17 inside the reaction chamber 51 through the above-mentioned sensor means.

[0092] Such verification can be performed, for example, by reading the temperature curves on the thermocycler 50 and / or on the calibration device 10 and / or through the CMOS sensor of the thermocycler 50 configured to read the fluorescence of the biological samples.

[0093] The control unit 52 of the thermocycler comprises a communication module 61 configured for a bidirectional communication with the remote-control unit 100 and with the calibration device 10. Similarly to what described for the calibration device 10, the communication module can integrate functionalities of wireless type and comprise one or more (not illustrated) antenna for transmitting signals, in which Bluetooth and / or Wi-Fi communication standards are used.

[0094] It is to be noted that the remote-control unit 100 (Figure 5b) is in bidirectional communication, preferably in wireless mode and through Wi-Fi protocol, both with the communication module 32 of the calibration device 10 and with the communication module 61 of the thermocycler 50. As said, the remote-control unit 100 is configured to generate and provide a calibration signal of at least an operating parameter of the thermocycler 50 based upon the data detected by the sensor means 16 of the calibration device 10.

[0095] The communication module 32 of the calibration device 10 advantageously allows a direct transmission to the remote-control unit 100 of data detected and associated to parameters of the thermocycler 50 and the reception of the calibration signal for a possible calibration of said detected parameters.

[0096] In a preferred embodiment of the invention, the communication module 61 of the thermocycler 50 allows a direct transmission to the remote-control unit 100 of data related to one or more operating parameters of the thermocycler 50.

[0097] According to an alternative embodiment (Figure 5c), the bidirectional communication, preferably in wireless mode and through the Bluetooth standard, can provide a direct communication between the calibration device 10, in particular the local control unit 12, and the thermocycler 50, in particular the relative control unit 52. Through this communication protocol a direct communication of the calibration device 10 with the remote-control unit 100 can be excluded.

[0098] In each case, the thermocycler 50 and the calibration device 10 can advantageously comprise means 101 for storing the calibration signal.

[0099] Preferably the remote-control unit 100 further comprises its own storing means, such as for example a data bank of the detected operating parameters. In this way the system allows to monitor the performances of the thermocycler 50 and a recording of the operating data over time.

[0100] The remote-control unit 100 is preferably configured to receive said data and to analyse them with the purpose of determining one or more corrective parameters for setting the thermocycler 50.

[0101] This has the advantage of allowing a remote calibration of the thermocycler 50 by means of the calibration device 10 without the need for having a trained operator on site. Moreover, such calibration is quick and can be remotely controlled, as the operating parameters of the thermocycler 50 can be remotely controlled.

[0102] In this sense, the calibration device 10 is functional to an independent detection of the operating parameters of the thermocycler 50. Such detection is communicated to a remote unit, or the remote-control unit 100, like for example a provider of cloud services, to generate and provide the calibration signal.

[0103] The calibration signal preferably comprises operating instructions to modify in real time the operation of the thermocycler 50 but also calibration protocols which can be performed directly by the calibration device 10 and by the thermocycler 50 itself for the calibration of the latter.

[0104] The system 200 of the invention then is based upon an architecture so as to guarantee a calibration even in temporary absence of communication with the remote-control unit 100 since the calibration device 10 and / or the thermocycler 50 can continue to send or apply (for example recursively or periodically) the signal containing the protocol of instructions for the calibration which has been generated and transmitted by the remote-control unit 100 and stored in the respective storage means.

[0105] Advantageously, the remote-control unit 100 is configured to further provide a setting signal of the calibration device 10.

[0106] For example, the temperature sensor means of the calibration device 10 are set, analogously to what happens with the temperature sensor means of the thermocycler 50, preferably with respect to a reference temperature probe. The reference probe can be an external probe, for example a Pt100 platinum thermoresistance. The setting can be performed after the assembly in the thermocycler 50 and controlled periodically.

[0107] The corrective parameters related to the measurement of the temperature of the calibration device 10 are preferably determined through a polynomial fitting. The coefficients of the polynomial for the calculation of said corrective parameters can be stored for example in the calibration device 10 and in the remote-control unit 100.

[0108] The process (Figure 6) for the calibration of the thermocycler 50 through the calibration device 10 firstly provides to insert (step a) the latter in the reaction chamber 51. In this phase, preferably, the correct insertion and positioning of the main body 17 inside the reaction chamber 51 is verified (step a’). This allows to guarantee that the main body 17 lies with the reference elements 20 at the interest regions in which the fluorescence analysis is performed.

[0109] Subsequently, with the thermocycler 50 a predetermined analysis protocol is started (step b).

[0110] Figure 7 illustrates an analysis protocol example, in particular a predetermined thermal protocol. It comprises in sequence a phase of initial heating r1 and a plurality of phases of progressive heating r2. Each phase of progressive heating r2, illustrated in detail in Figures 8 and 9, comprises a dynamic phase, with a temperature peak d followed by a static phase with period p at constant temperature. For example, in the phase of pre-heating r1 there can be a ramp with temperatures from about 35°C to about 95°C, and in the phases of progressive heating r2, with periods p at constant temperature, there are temperatures of about 40°C, 60°C, 80°C to 95°C.

[0111] While performing the protocol one provides (step c) to detect at least an operating parameter of the thermocycler inside the reaction chamber 51 through the sensor means 16 of the calibration device 10 and corresponding sensor means 53 of the thermocycler 50.

[0112] Then, the data associated to one or more detected operative parameters are transmitted (step d) to the remote-control unit 100. Said remote-control unit 100, the thermocycler 50 and the calibration device 10 are in mutual bidirectional communication.

[0113] As far as the thermocycler 50 is concerned, the data related to the detected parameters are preferably collected and stored in one single file to be transmitted to the remote-control unit 100.

[0114] The data detected by the sensor means 16 of the calibration device 10 are compared (step e) with the data detected by the sensor means 53 of the thermocycler 50, preferably through the remote-control unit 100.

[0115] In detail, for the calibration of the temperature sensors of the sensor means 53 of the thermocycler 50 the temperature data detected in the static phase, that is in the period p at constant temperature of the phase of progressive heating r2, are compared. In order to evaluate the thermal performances of the thermocycler 50 the temperature data detected in the dynamic phase, that is at the dynamic peaks of the phases of progressive heating r2, are compared. The compared temperature data relate to the prominence of the dynamic peak d and to the derivative of the ramp connecting the peak to the period p at constant temperature.

[0116] The remote-control unit 100 generates (step f) a calibration signal of the thermocycler 50 if the above-mentioned comparison returns a value outside a predefined range of values.

[0117] It is specified that, advantageously, the thermocycler 50 and the calibration device 10 can be configured to compare the data associated to the operating parameters of the thermocycler 50 detected by the respective sensor means.

[0118] If the comparison returns a value outside the predefined range of values, the thermocycler 50 or the calibration device 10 can, respectively, apply and communicate (to the thermocycler 50) the calibration signal transmitted by the remote-control unit 100 and containing the protocols to perform the calibration.

[0119] Moreover, according to embodiment variants, the calibration signal can be generated even if the results of the above-mentioned comparison is within the predefined range of values, but the thermocycler has exceeded a threshold, for example, related to the number of performed analyses or with respect to the moment of the last calibration procedure.

[0120] For the correction of the temperature data of the reaction chamber 51 detected by the sensor means 16, 53 preferably a polynomial fitting is used and the corrective coefficients of the polynomial are stored in the thermocycler 50 and in the storage means 101 of the remote-control unit 100. As said, the corrective coefficients are advantageously calculated based upon the comparison of the data detected during the static phase of the protocol. In case, for additional detection of temperature data, a thermal probe can be positioned in the reaction chamber 51 , apt to detect temperature data and to compare them with the temperature data of the sensor means 16, 53. As mentioned above, the calibration signal can include additional calibration parameters. An additional detectable and calibratable parameter is associated to the “characteristic time” (tau) which describes the speed of conducting heat and the thermal inertia of the thermocycler 50, that is the temperature operating conditions in the reaction chamber 51 at the biological samples. Such temperature conditions are constantly determined, in use, based upon a processing of the series of previously acquired temperature data. Such parameter tau can be calculated theoretically but it can even be adjusted based upon the performances of the thermocycler 50 in the above-described calibration process. Said characteristic time (tau) is preferably determined based upon the temperature data detected in the dynamic phase and in the static phase.

[0121] The invention advantageously allows even the calibration of optical, or lighting, parameters of the thermocycler 50. In this case the calibrated corrective parameter is preferably obtained by measuring the intensity value of the light source of the thermocycler 50 and by comparing such value with a corresponding light intensity value of a reference thermocycler.

[0122] Once generated the calibration signal comprising one or more of the above- mentioned calibration parameters, said signal is transmitted to the thermocycler 50 in order to obtain the calibration of the detected operating parameter(s).

[0123] According to a preferred embodiment, an additional step is provided for verifying the correctness of the performed calibration procedure, subsequent to the transmission of the calibration signal. In particular, the preceding steps b) to e) can be repeated and the calibrated and verified operating parameter of the thermocycler 50 is stored in the remote-control unit 100.

[0124] Experimental results

[0125] Hereinafter results of experimental tests obtained by the above-described calibration process are shown.

[0126] In general terms, the invention has allowed to reduce the difference between the operating temperature of the thermocycler 50 and the temperature measured by the calibration device 10 from about 0.2°C to about 0.05°C.

[0127] With reference to Figure 10, the graph a) and the graph b) show the comparison between the trend over time of the temperature values detected for an operating adjustment of the thermocycler fixed at 60°C, respectively before and after the calibration process.

[0128] For each graph, the upper trend is associated to the detections of the calibration device 10 and the lower trend is associated to the detections performed by the (temperature) sensor means of the thermocycler 50.

[0129] It is noted, in particular, that in graph b) the trends are substantially overlapped at least at the period at constant temperature (static phase) by confirming the correctness of the calibration process.

[0130] The same considerations are applied to the trends shown in graphs c) and d) of the same Figure 10, wherein the comparison is shown between the trend over time of the temperature values detected for an operating adjustment of the thermocycler fixed at 95°C, respectively before and after the calibration process.

[0131] The present invention has been sofar described with reference to preferred embodiments. It is to be meant that other embodiments belonging to the same inventive core may exist, as defined by the protective scope of the herebelow reported claims.

Claims

CLAIMS1. A remote calibration device (10) of a thermocycler (50), which calibration device (10) comprises:- a main body (17) shaped to be housed inside a reaction chamber (51 ) of the thermocycler (50),- sensor means (16) carried by said main body (17) and configured to detect at least an operating parameter of the thermocycler (50) inside said reaction chamber (51 ),- a local control unit (12) configured to process the detected operating parameter,- a communication module (32) configured for a bidirectional communication of the local control unit (12) with a remote-control unit (100) and the thermocycler (50), wherein said local control unit (12) is configured to communicate to the thermocycler (50) a calibration signal, said calibration signal being provided by said remote-control unit (100) and suitable to determine a calibrated operating parameter of the thermocycler (50) depending upon the detected operating parameter.

2. The calibration device (10) according to claim 1 , wherein said communication module is a wireless communication module (32).

3. The calibration device (10) according to claim 1 or 2, wherein said at least an operating parameter comprises a temperature piece of data and / or a lighting piece of data.

4. The calibration device (10) according to any one of the preceding claims, wherein said sensor means (16) comprises a temperature sensor arranged inside the main body (17).

5. The calibration device (10) according to any one of the preceding claims, wherein said main body (17) carries a plurality of reference elements (20) andsaid operating parameter comprises a relative position of said plurality of reference elements (20) with respect to a predetermined position for detecting said at least an operating parameter.

6. A system (200) for the remote calibration of a thermocycler comprising:■ a calibration device (10) according to any one of the preceding claims,■ a thermocycler (50) operatively associated to said calibration device (10),■ a remote-control unit (100) configured for a bidirectional communication with said calibration device (10) and said thermocycler (50), wherein said remote-control unit (100) is configured to provide to the calibration device (10) and / or to the thermocycler (50) a calibration signal of at least an operating parameter of the thermocycler (50), said calibration signal being generated depending upon the operating parameter detected by said sensor means (16) carried by the calibration device (10).

7. The system (200) according to the preceding claim, wherein said calibration device (10) and said thermocycler (50) comprise means (101 ) for storing said calibration signal.

8. The system (200) according to claim 6 or 7, wherein said calibration device (10) and said thermocycler (50) comprise corresponding sensor means (53, 16) configured to detect the same operating parameter inside the reaction chamber (51 ).

9. The system (200) according to any one of claims 6 to 8, wherein said remotecontrol unit (100) is configured to provide a setting signal of the calibration device (10).

10. The system (200) according to any one of claims 6 to 9, wherein said bidirectional communication is of wireless type.

11. A process for the remote calibration of a thermocycler (50) through a calibration device (10) according to any one of claims 1 to 5, which process comprises the steps of: a) inserting the calibration device (10) in the reaction chamber (51 ) of the thermocycler (50), b) performing with said thermocycler (50) a predetermined analysisprotocol, c) detecting at least an operating parameter of the thermocycler (50) inside said reaction chamber (51 ) through sensor means (16) of the calibration device (10) and corresponding sensor means (53) of the thermocycler (50), d) transmitting the data associated to said at least a detected operating parameter to a remote-control unit (100) in bidirectional communication with said thermocycler (50) and said calibration device (10), e) comparing the piece of data detected by the sensor means (16) of the calibration device (10) with the piece of data detected by the sensor means (53) of the thermocycler (50) through said remote-control unit (100), f) generating with said remote-control unit (100) a calibration signal of the thermocycler (50) if the comparison returns a value outside a predefined range of values, g) transmitting said calibration signal to the thermocycler (50) and / or to the calibration device (10) in order to obtain a calibrated operating parameter of the thermocycler (50).

12. The calibration process according to the preceding claim, wherein said predetermined protocol comprises in sequence a phase of initial heating (r1) and a plurality of phases of progressive heating (r2), wherein each phase of progressive heating (r2) comprises a period (p) at constant temperature and said comparison step e) is performed based upon data detected during said period (p) at constant temperature.

13. The calibration process according to claim 11 or 12, comprising a verification protocol subsequent to step g) for transmitting said calibration signal, wherein steps b) to e) are repeated and said calibrated operating parameter of the thermocycler (50) is stored in said remote-control unit (100).

14. The calibration process according to any one of claims 11 to 13, wherein the communication between the remote-control unit (100), the calibration device (10) and the thermocycler (50) is of wireless type.

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