WO2010012494A1

WO2010012494A1 - Heating/cooling device having opportunity for testing and method for testing a heating/cooling device

Info

Publication number: WO2010012494A1
Application number: PCT/EP2009/005583
Authority: WO
Inventors: Lutz Timman; Vinh Duong; Stefan Roth; Thomas Uschkureit; Jürgen Koeppel; Thomas Buck
Original assignee: Eppendorf Ag
Priority date: 2008-08-01
Filing date: 2009-07-31
Publication date: 2010-02-04
Also published as: EP2153901A1; EP2321051B1; CN102149474B; EP2321051A1; CN102149474A

Abstract

The invention relates to a heating/cooling device for carrying out a heating/cooling programme for at least one sample, in particular a PCR sample, comprising: at least one heating/cooling block which is constructed for receiving the at least one sample, at least one heating/cooling unit which is arranged for heating/cooling the at least one heating/cooling block, at least one temperature measuring unit which is assigned to this heating/cooling unit, at least one control circuit for controlling a temperature, to which control circuit are assigned at least one heating/cooling unit and at least one temperature measuring unit assigned to this at least one heating/cooling unit, at least one control unit which is constructed for controlling the heating/cooling of the at least one heating/cooling block, wherein the heating/cooling device comprises at least two temperature measuring units which are assigned to at least one control circuit, and a test unit for carrying out a test method is assigned to the heating/cooling device, wherein this test unit has a signal connection to at least one of these at least two temperature measuring units, and so by means of this signal connection, at least one test quantity of the heating/cooling device can be determined, which test value characterizes the operating state of the heating/cooling device. The invention additionally relates to a method for testing a heating/cooling device, wherein the method comprises the following steps: starting the method; operating at least this first heating/cooling unit for the period of at least one first time section from at least one first time; detecting at least one measurement temperature from this at least one first temperature measuring unit assigned to this first heating/cooling unit at least at a second time; determining at least one first test quantity of the heating/cooling device using this at least one measurement temperature; and comparing this first test quantity with a reference quantity.

Description

Tempering device with possibility of testing and method for testing a tempering device

The invention relates to a temperature control device for controlling the temperature of at least one testable sample and to a method for testing a tempering device.

Tempering devices are e.g. used as thermostats, thermal mixers or thermocyclers in testing, research or manufacturing laboratories to produce e.g. bring liquid sample to a desired temperature. Accurate setting of predetermined temperatures in samples is particularly important in chemical reactions whose successful performance critically depends on meeting at least one particular temperature or time-varying temperature profile. An example of such a chemical reaction is the polymerase chain reaction (PCR). By means of such a PCR reaction, DNA sections can be multiplied very efficiently, which is why this method, with further increasing importance, e.g. used in pharmacy, medicine, research or forensics.

The exact observance of certain temperature values, which are cyclically applied to a sample during a PCR tempering program, is critical for the successful performance of a PCR, in particular a quantitative PCR. In the PCR, the cycle sections denaturation, primer hybridization and elongation are controlled via different, precisely defined temperature levels. The quality of the PCR depends crucially on the performance of the components of the temperature control device used and thus on their operating condition. In particular, if, for example, medical or legal medical reasons make high demands on the reliability and reproducibility of a PCR, it is important to control the operating state of a temperature control device used. It is customary in Temperierungsvorrichtungen with electrically adjustable tempering, such as Peltier elements, to set a desired temperature by means of a control loop whose actuator comprises the Peltier element and its measuring element comprises a temperature sensor. In this control circuit, the actuator is operated with the aim to bring the temperature determined by the measuring element in accordance with a target temperature. However, disturbances of such a device can occur, which impair their performance, without hindering the function of the device during operation in a way that is immediately perceptible to the user. Such disturbances may be, for example, power deviations of the tempering device over its lifetime or the drift of sensors. In particular, for checking the operability of temperature sensors, it is known to use external thermometer and calibration sets that measure a temperature on the device. However, such a review requires a relatively high amount of hardware, personnel and time.

The object of the present invention is to provide an improved tempering device, which in particular operates reliably and in which, in particular, possible operating disturbances are easier to detect, and to provide an improved method for testing the function of a tempering device.

This object is achieved by the tempering device according to claim 1 and the method according to claim 6 of the present invention. Preferred developments of the invention are the subject of the dependent claims.

The tempering device according to the invention for carrying out a tempering program with at least one sample, in particular PCR sample, comprises: at least one tempering block, which is designed to receive the at least one sample, at least one temperature control, which is arranged for controlling the temperature of this at least one tempering, at least one temperature measuring device , which is assigned to this tempering device, at least one control loop for controlling a temperature, the at least one tempering device and at least one of these at least one tempering device At least one control device, which is designed to control the temperature of the at least one Temperierblocks, wherein the Temperierungsvorrichtung comprises at least two temperature measuring devices, which are associated with at least one control loop, and the Temperierungsvorrichtung is associated with a test device for performing a test method, wherein this test device comprises a signal connection to at least one of these at least two temperature measuring devices, so that by means of this signal connection at least one test variable of the temperature control device can be determined, which characterizes the operating state of the temperature control device.

Such a tempering device is preferably a thermal mixer for the simultaneous mixing and tempering of at least one sample or a thermostat, which are designed to carry out a tempering program with at least one sample. The tempering program has at least the step of tempering this at least one sample to at least one target temperature. This is preferably done by manually or automatically setting at least one setpoint temperature as the target temperature at this at least one control loop.

Furthermore, this tempering device preferably has the function of a thermal cycler or is designed as a thermal cycler. This is preferably suitable for carrying out a PCR reaction in at least one PCR sample. This tempering device is preferably a thermal cycler. The tempering program preferably comprises at least the tempering steps of a PCR cycle, during which the PCR sample is tempered in chronological order to at least two or three temperatures. By means of a single tempering program, a PCR reaction is preferably carried out in at least one PCR sample by repeatedly repeating the tempering steps of a PCR cycle, in particular 10 to 70 times. It may be desirable to find out the critical temperature levels of a PCR by applying a spatial temperature gradient, ie a spatially varying temperature profile with at least two different temperatures. For this purpose, a temperature gradient is generated in the Temperierblock along a route along which a plurality are arranged by PCR samples, which are thus exposed to different temperatures, which lead to different good PCR results. The temperature gradient can be generated, for example, by at least two tempering devices arranged below the tempering block, as described in WO 98/020975 A1. This has the advantage that the Temperierblock can also be brought to a uniform temperature by these at least two tempering produce the same temperature. Furthermore, a temperature gradient can be used to keep the samples provided in the recordings of a tempering block at different temperatures, which makes sense, for example, if the samples pass through different reaction phases in groups. Thus, a temperature gradient may have continuous temperature changes or be stepped. Alternatively, the generation of a temperature gradient can be provided by other arrangements in which at least two different temperatures are applied to the tempering block. The tempering device may have one or more tempering devices, possibly even one each for a small number of samples, eg one per sample or one each two samples.

Other possible temperature control devices are workstations and other devices with which one or more samples can be subjected to a tempering program at the same time.

The tempering block is preferably designed according to the tempering block described in WO 98/020975 A1. In the present case, a tempering block is a component whose design makes it possible to temper at least one sample arranged on or in the tempering block. The tempering block preferably has at least one integrally manufactured, preferably essentially cuboidal, component made of a material having good thermal conductivity, in particular metal, for example aluminum or silver. It is also possible and preferred that this tempering is divided into at least two, in particular 3, 4, 5, 6 or more integrally manufactured sections of a good thermal conductivity material, which are separated by a poor thermal conductivity medium or material. In this component or in each of these sections is located, preferably at the top, at least one receptacle for a sample or a sample. benbehältnis. This receptacle is preferably formed in a depression on the upper side of this section or this tempering block. This receptacle or depression is preferably designed for large-area contacting of a sample container in order to achieve efficient heat transfer from the temperature-control block to the sample container and the sample contained therein. If a tempering block is mentioned below, a tempering block section is always meant, unless otherwise described or meaningful.

Preferably, this tempering block is designed to receive a plurality of samples or Probenbehältnissen. Preferably, this tempering is designed for receiving at least one sample plate, in which a plurality of sample containers are formed side by side. Such a sample plate is preferably a microtiter plate or a PCR plate. The number of sample containers is particularly preferably in each case 2, 4, 8, 12, 16, 24, 48, 96, 384 or 1536.

The tempering device is preferably associated with a control circuit and is preferably an electrically controllable device. In the context of this invention, the assignment of a component, for example the tempering device or the tempering device to a control loop, preferably determines the functional assignment according to which the component assumes a function of the control loop and contributes, for example, as part of the control loop for controlling the temperature of at least one section of the tempering block, and For example, the tempering device serves as an actuator of the control loop. This tempering device preferably comprises a Peltier element. However, it is also possible to provide another type of tempering device, for example comprising an electrical resistance element. The tempering device is preferably arranged on the underside thereof for tempering this at least one tempering block. The tempering device preferably contacts the tempering block over a large area, since this tempering device has a dimension which allows the tempering of a multiplicity of samples by means of a single tempering device. For this purpose, this tempering device is preferably arranged below a plurality of receptacles for samples or Probenbehältnissen, which are arranged above this temperature control in Temperierblock. Each tempering device is assigned at least one temperature measuring device. As a result, this temperature measuring device is suitable for measuring the temperature set on the tempering block by means of this tempering device. However, the measured temperature can also be influenced to a lesser extent by tempering devices to which the temperature measuring device is not assigned. The assignment of the temperature measuring device to a tempering device, which is functionally associated with a control loop, preferably requires that this temperature measuring device takes over a function of the control loop and contributes, for example as part of the control loop for controlling the temperature of at least a portion of the tempering, and in particular that temperature measuring device as a measuring element of Control circuit serves.

In order to detect a temperature of the tempering block, this temperature measuring device is preferably arranged on this tempering block. The temperature measuring device is preferably arranged at a distance from this tempering device. This distance is preferably such that it corresponds to a distance between the tempering device and a receptacle of the tempering block. This has the advantage that by means of this temperature measuring device, the temperature can be detected, which is applied to this recording and which is thus applied to the sample container. The distance can also be chosen differently. Furthermore, it is preferred that at least one temperature measuring device is arranged in an edge region of a tempering block. Preferably, at least two temperature control devices are arranged at a maximum possible distance from each other on the temperature control, wherein the maximum distance, for example by the length or width of the tempering (-abschnitts) and / or the dimensions and / or other predetermined parameters, eg the arrangement position of the temperature measuring device on the Top or edge side of the tempering can be determined. The edge region of the tempering block can have a different temperature from the ambient temperature or by convective heat transport of ambient air than a more central region of the tempering block. Therefore, the measurement in the edge region of the tempering is particularly advantageous to allow temperature control there as well. Furthermore, the measurement in the edge area be advantageous to produce and control a temperature gradient in the tempering, which extends from one end, ie edge region of the tempering to the other end. Moreover, the measurement in the edge region can also be advantageous because the heat flow in the tempering block is not hindered by this temperature measuring device. A temperature measuring device is preferably attached to the tempering, eg glued, or at least partially embedded in a recess or opening of the tempering. The temperature measuring device is preferably an electronic component, and may comprise, for example, a semiconductor temperature sensor, a thermocouple or a pyrometer.

Preferably, at least one temperature measuring device is arranged at a small distance or in direct contact with at least one tempering device. This small distance is preferably less than 0.5 times, 0.25 times or 0.1 times a thickness of the tempering block. Such a temperature measuring device is preferably functionally assigned to a control loop or preferably not functionally assigned to a control loop. The advantage of a small distance is that a shorter heat transfer path between the temperature measuring device and tempering is created, whereby a change in the temperature of a tempering device can be measured faster than at a greater distance between the temperature measuring device and tempering. This is particularly advantageous in order to test the functionality of this tempering device, in particular with the test method according to the invention. A shorter overall duration of the measurement process can lead to more frequent testing, which helps to better monitor the reliability of the tempering device.

The tempering device further preferably has at least one temperature measuring device designed as a safety sensor. Such a safety sensor is preferably signal-connected to the control device and configured to detect a predetermined, extreme temperature in the tempering device, the detection of which preferably leads to a securing operation of the tempering device, eg the output of a warning signal or the switching off of the tempering device. A security sensor is preferably for securing the Temperature of the tempering arranged in the vicinity of a control circuit associated with a temperature measuring device. The fuse sensor is not assigned to a control loop. In this way, a defective control circuit is less likely to cause the failure of the safety sensor. Said environment of a temperature measuring device is preferably at a distance located around this area, wherein the distance is preferably less than the maximum distance between two at least one control loop associated temperature measuring devices of Temperierungsvorrichtung, preferably less than the minimum distance between two at least one control loop associated temperature measuring devices of Temperierungsvorrichtung , preferably smaller than a width of a tempering device, preferably smaller than the height of a tempering block, which may be, for example, three cm, and preferably less than one cm. A safety sensor may in particular also be arranged in direct or indirect contact with another temperature measuring device, in particular without being separated from a section of the temperature control block or from ambient air.

A control loop is preferably associated with a control device which is designed to control the temperature control of the at least one tempering block. However, it is also possible and preferred that a tempering device and at least one temperature measuring device associated with a tempering device are provided, which are at least temporarily not associated with a control circuit, for example by being programmatically exempted from their control functions (actuator, measuring element) or switched off. This activation of this tempering device and of this temperature measuring device provides a further increased flexibility in the design of a test method. Furthermore, the independence of a component, in particular a temperature measuring device, from the control loop to increase the reliability of testing this control loop by means of this component lead. In the regulation of a temperature in a tempering block by means of this control circuit, this control device is signal-connected to this at least one control circuit and to at least one temperature measuring device assigned to this at least one control circuit. As signal-connected, at least two devices are considered within the scope of the invention, between which signals can be exchanged. These signals are preferably bound to a medium, such as an electrical conductor or semiconductor. It is possible and preferable for these signals exchanged between two signal-connected devices to be exchanged via a switching device, for example by a first device sending a signal to the switching device where the signal is buffered and optionally also modified before the second device responds to the buffered signal accesses to receive this. For example, said temperature measuring device of a control loop can provide a measuring signal which is buffered by a memory device of the control loop so that the test device can access this memory device in order to receive this measuring signal. In this example, the test device is signal connected to the temperature measuring device. However, it is also possible that these signals are transmitted without binding to a conductive material, ie through the free space, in particular electromagnetic waves (eg radio waves or infrared light) as well as through an at least gas-filled space such as sound waves. The term "signal-connected" covers both unidirectional and bidirectional signal transmission paths.

Each control circuit is preferably assigned at least two temperature measuring devices and at least one tempering device assigned to these temperature measuring devices. In conventional tempering devices, in particular thermocyclers, these often have more than one tempering device per control loop and temperature sensor. As a rule, an error of a tempering device can not be detected, since power deviations do not have to lead to a faulty temperature at the temperature measuring device, which is provided for measuring the temperature of the section in the tempering, which is tempered by this tempering. Nevertheless, the performance deviations lead to inhomogeneous temperature distribution at this sample block, since different performances are introduced at different locations via the individual tempering devices. In addition, faulty sensor values, eg due to changes in the contact or due to drift, are not detected. To improve this situation, every tem- Periereinrichtung associated with at least one temperature measuring device and in particular associated with a second temperature measuring device. In this way, a number of test methods can be carried out in a flexible manner, in particular by means of the test device. By comparing test variables, in particular temperature measurements and temperature change rates, with reference variables or in particular other determined test variables, the operating state of a component assembly, individual components of the temperature control device or the temperature control device can be determined in total. The test device is preferably signal-connected with at least one, in particular each, control loop and preferably with at least one, in particular each, temperature-measuring device associated with this control loop.

Particularly preferably, the tempering device comprises at least one control loop to which at least two tempering devices and at least two temperature measuring devices are assigned, wherein each tempering device is assigned at least one temperature measuring device. In particular, the tempering device preferably comprises a number of control circuits, to each of which two tempering devices and two temperature measuring devices are assigned. This number is preferably 2, 3, 4, 5, 6, 7, 8, or larger.

Preferably, each temperature control is assigned exactly one temperature measuring device and preferably this temperature measuring device is assigned to exactly this tempering. It is further preferred that a tempering device at least two temperature measuring devices, in particular exactly two, are assigned. In this way, the test of the temperature control can be further improved and in particular reliable and accurate, and thus the tempering be improved. Furthermore, each tempering device is preferably associated with precisely two temperature measuring devices, and these two temperature measuring devices are assigned precisely to these tempering devices.

The tempering device preferably comprises at least two tempering devices, which are arranged for controlling the temperature of this at least one tempering block, and at least two temperature measuring devices, wherein each tempering device tion is associated with at least one temperature measuring device, and at least one first control loop and a second control loop. In particular, the use of at least two control circuits may allow at least two different temperatures to be applied to this at least one tempering block. These are preferably at least two tempering devices for generating a temperature gradient extending in the at least one tempering block, that is to say a temperature profile having at least two different temperature values. It is understood that by means of two different tempering a single temperature can be applied to at least one tempering. Preferably, this test device comprises a signal connection to each tempering device and each temperature measuring device of this first and second control loop, wherein the test device can determine a first test variable, which is associated with this first control loop, and a second test variable can be determined, which is assigned to this second control loop. Preferably, this test device comprises a means for comparing these two test variables or for comparing one of these test variables with a reference variable. The reference size may be a stored size or a measured size, in particular a test size.

This control device preferably comprises electrical circuits which are designed to control the temperature control of the at least one tempering block. Furthermore, this control device preferably comprises means for digital data processing. The control device preferably comprises a computing unit, which may be a CPU, a microprocessor or a microcontroller. Preferably, this control device comprises circuits which are designed for processing program code, in particular for executing programs for temperature control or programs for carrying out a test method, in particular according to the invention. Furthermore, the control device preferably comprises at least one memory unit for storing data or signals, which is preferably also removable from the control device. This memory unit preferably comprises data memory for the temporary storage of data, for example RAM and / or data memory for the permanent storage of data, eg hard disk or flash memory. Furthermore, this control device preferably comprises at least one interface for establishing a signal connection between this control device and another device, eg a test device in an external embodiment, an external data memory, a control device, an external PC, a control panel or another device. Furthermore, this control device preferably comprises circuits, eg power electronics, for controlling power supply components, which can serve, for example, the power supply of this control device, this at least one tempering device or this at least one temperature measuring device. In order to regulate a temperature in this tempering block by means of this control circuit, this control device is signal-connected to this at least one control loop and to at least one temperature measuring device assigned to this at least one control loop.

The test device is preferably arranged in the temperature control device and is preferably structurally integrated into the control device. However, it is also possible and preferred that the test device is an at least substantially separate component. The tester preferably includes electrical circuitry suitable for processing signals necessary to perform the test procedure. Preferably, the electrical circuits of the test device are at least substantially separate from the circuits of the controller, insofar as no signal lines need to be shared. In this case, the circuits of the test device are preferably arranged spatially offset from the circuits of the control device. This has the advantage that their arrangement is more flexible and can be designed, for example, to minimize harmful thermal or corrosive influences, for example by encapsulation. In this way, the reliability of the test device and thus of the tempering device can be improved. The test device preferably comprises at least one signal connection to a tempering device by outputting signals which influence the operating state of the tempering device. The test device preferably further comprises at least one signal connection to a control loop in that it can exchange signals with at least one component of the control loop, for example its actuator, which regulates the power supply to the tempering device, or its measuring element (sensor). Furthermore, the test device is preferably provided with a power control device. signal connected, which controls the output of a tempering power and measures.

Furthermore, it is possible and preferred that this test device, which is assigned to this tempering device for carrying out a test method, is arranged outside this tempering device, wherein this test device comprises a signal connection with this at least one temperature measuring device. In the case of such a test device, this signal connection preferably takes place in an external embodiment via an interface which is provided on this tempering device, in particular on this control device. In this way, it is possible that a central control of the test procedure takes place, e.g. from a control center or a laboratory information management system (LIMS), which in particular can control a plurality of tempering devices.

The carrying out of a test method by means of an external test device preferably takes place without manual intervention by a user on this tempering device and is preferably carried out automatically. An external test device may in particular comprise a control device which has a microcontroller, an input device, for. Keyboard, input panel, and output device, e.g. Display, can include. Preferably, an external test device is a PC or a workstation. In particular, an external test device may be part of an external control center or controller, e.g. PC or workstation that performs other tasks to control other devices, e.g. in an automatic measuring system or by means of a LIMS.

Preferably, this tempering device and in particular this control device for remote control of at least one function of this tempering device or a component of this tempering device is formed. This tempering device, in particular this control device, is preferably designed for remote access to at least one component of this tempering device. Preferably, this tempering device, in particular this control device, is designed for the remote access of an external test device, which is this Tempering device is assigned for performing a test method. Since this external test device also comprises a signal connection to a control circuit and a temperature measuring device, the test method can be carried out remotely in this design. For example, it can be provided that the test procedure is carried out remotely by a service specialist or is carried out automatically in order to detect the operating status of this temperature control device and / or operating data, in particular this at least one test variable of the temperature control device, for function monitoring or for remote diagnosis of the operating state thereof Temperierungsvorrichtung to win. In particular, it can be provided that this external test device is part of a diagnostic and maintenance device, which connects a service specialist for carrying out a test method with this tempering device. However, it is also possible and preferred for this external test device to be in signal connection with this temperature control device over greater distances. This tempering device, in particular this control device, is preferably designed for signal connection via a network or internet connection or similar transmission lines. In this case, an external test device can be in signal communication with this temperature control device via this transmission line and start and execute a test procedure. Since a signal connection can also take place wirelessly and thus over greater distances and through walls and obstacles, for example by electromagnetic signal transmission in the GHz range, a test of a test variable of this tempering device can be made even more flexible.

The tempering device preferably further comprises a starting device which is suitable for manually and / or automatically starting a test method carried out by this test device. The starting device is preferably structurally integrated in the test device or the control device, but may also be designed separately. The starting device preferably comprises circuits which are suitable for processing a start signal and / or in particular for processing a start program code. The starting device is preferably designed for manual starting, in particular for the immediate or delayed start of a test method of the test device of this tempering device. The starting device can at least one input device, such as an actuator such as a button or sensor array on a control panel of Temperierungsvorrichtung have, which is signal-connected to this test device and is formed at least to effect a start signal by the user. Furthermore, the starting device is preferably designed for automatically starting a test method of the test device of this tempering device. Automatic starting also includes semi-automatic starting. To carry out a semi-automatic starting, the starting device is preferably designed such that the actuation of an input device by the user leads to the automatic, in particular program-controlled, starting of the test method, eg by means of a start program. In particular, the starting device is equipped with at least one start program, which the user can select by means of this input device in order to determine the start of at least one test procedure.

The starting device, in particular a starting program, is preferably designed such that the starting of a test procedure preferably takes place automatically at each, in particular before or after each measurement carried out by means of this tempering device on this at least one sample, in particular for each performance of a tempering program. The starting device, in particular a start program, is furthermore preferably designed so that the starting of the test method is carried out automatically at regular intervals after every nth (n> = 1) startup of the tempering device or every nth application of the tempering device in a tempering program. Furthermore, the starting device, in particular a starting program, is preferably designed so that the starting of the testing method is automatically provided after a certain total operating time of the tempering device. Furthermore, the starting device, in particular a start program, is preferably designed so that the starting of the test procedure automatically takes place after a predetermined inactivity time of the temperature control device, in which the temperature control device in particular automatically switches itself out of a stand-by mode in order to carry out this test procedure. The starting device, in particular a start program, is furthermore preferably designed such that starting the test method and the type of test method to be carried out are of a specific type Temperature control program is assigned. This assignment can be permanently stored in the tempering device or the test device or assigned by the user, in particular by means of the input device. In particular, it can be provided that the user automatically receives a test result when carrying out a tempering program or that a certificate is issued which provides information about the operating state of the tempering device, in particular before, during or after the tempering program. By means of these various starting methods, the reliability of the tempering device can be improved and, at the same time, a test procedure can be carried out flexibly and comfortably for the user. Preferably, the tempering device, in particular the starting device, is designed to carry out a plurality of, in particular all, the described starting possibilities.

The test device is designed to carry out a test method. A test method comprises a series of processes in this test device, which is signal-connected to the tempering device, wherein the at least one test variable of the tempering device, which characterizes the operating state of the tempering device, can be determined by these processes. These processes include in particular the generation of this start signal, as well as the control of at least one temperature measuring device and the processing of the measured data. The execution of a test procedure preferably takes place by means of the execution of at least one test program code. Furthermore, the implementation preferably takes place before or after the execution of a tempering program of this tempering device. However, it is also possible and preferred for the test method to take place partially or completely during the performance of the tempering program of the tempering device. Preferably, the test device for performing a test method is at least partially formed during the execution of a tempering program. In this way, on the one hand, time can be saved and, on the other hand, a test can be obtained which individually monitors the course of a tempering program, eg by determining a test variable at each set temperature value or each time a temperature value is reached, which characterizes the operating state of the tempering device during this step. This allows, for example, for each tempering Program to issue a detailed certificate, which improves the reliability of performing a PCR.

Furthermore, this tempering device preferably comprises at least one power control device, which is designed to control and / or measure the power delivered to at least one tempering device, in particular the electrical power. Furthermore, this test device preferably comprises a signal connection with this at least one power measuring device, so that the power delivered to such a temperature control device can be detected and available as data for use in a test method, in particular within a test method according to the invention. Such a power measuring device for measuring an electric power P = U * l can e.g. include a digital power meter. In a digital power meter instantaneous values of current and voltage are digitized by means of the largest possible sampling rate and charged in a computing unit to determine the electrical power P = LTI.

The tempering device, in particular the control device, preferably comprises at least one timer, which is preferably in signal connection with the test device. Preferably, the test device comprises at least one timer.

The tempering device and / or the test device are each preferably designed to carry out the test method according to the invention.

Further features and advantages of the tempering device according to the invention will become apparent from the following description of the test method according to the invention and its design options.

The object underlying the invention is further solved by the method according to the invention for testing at least one first test variable of a tempering device. The method can be carried out in particular by tempering devices designed as thermomixers, thermostats or thermocyclers. The method according to the invention for testing at least one first test variable of a tempering device which serves to control the temperature of at least one sample, in particular a PCR sample, wherein this tempering device has at least one tempering block, which is designed to receive the at least one sample, at least one first tempering device is arranged for controlling the temperature of this at least one tempering, at least a first temperature measuring device and at least one second temperature measuring device associated with at least one control loop, each tempering is associated with at least one temperature measuring device, at least one control device which is designed to control the temperature of the at least one tempering , and at least one first control loop, to which these at least one first tempering device and these at least one, this at least one first tempering device assign te, are associated with the first temperature measuring device, comprises the following steps: starting the process; Operating at least this first tempering device for the duration of at least a first time period from at least a first time; Detecting at least one measurement temperature with said at least one first temperature measuring device associated with said first temperature control device at least for a second time; Determining at least a first test variable of the temperature control device using this at least one measurement temperature; Comparison of this first test size with a reference size.

An advantage of this test method according to the invention is that the operating state of a tempering device and its components, in particular the operating state of a composite of components can be monitored, this composite comprising at least one first tempering device and further this at least one, this at least one first tempering associated, includes first temperature measuring device. The determined first test variable can be assigned to at least this first tempering device and at least to this first temperature measuring device. In particular, this first test variable is assigned to this component group and characterizes its operating state. By comparing this first Test variable with a reference size, which may be stored for example in a memory device of the temperature control, which is provided via an interface, or which is calculated by the controller, the operating state can be monitored. In particular, if more than one tempering device is provided, or if measurement data from at least two different temperature measuring devices are available, the operating state of this tempering device can be monitored by comparing two or more test variables, wherein z. For example, a first test variable of a first tempering device and a second test variable of a second tempering device can be assigned or a first test variable of a first temperature measuring device and a second test variable of a second temperature measuring device can be assigned.

Preferably, in addition to the first test size, i. either at least partially simultaneously or at least partially in time, a second test size determined. This can be assigned to a second temperature measuring device and / or a second control loop, which can be constructed analogously to this first control loop. This has the advantage that the operating state of this temperature control device can be characterized, in particular, even without the use of a reference variable present as stored data, in which these first and second test variables are compared and an error is indicated if there is a deviation within a predetermined tolerance. As a result, the reliability of the test method and its functionality can be further increased.

In a first embodiment of the method according to the invention, this additionally relates to the testing of a second test variable of this tempering device, wherein at least one second tempering device and at least one second temperature measuring device, which is assigned to this second tempering device, are assigned to this first control loop, and wherein the method comprising the steps of: operating said second tempering device for the duration of at least a first time period from at least a first time; Detecting at least one measurement temperature from this at least one second, second temperature measuring associated with this second temperature measuring device at least one second time; Determining at least a second test variable of the temperature control device using this at least one measurement temperature; Comparison of this second test size with a reference size. The method is therefore advantageous in the case of temperature control devices which, for example, have at least two tempering devices to increase the temperature control power, to each of which at least one temperature measuring device is assigned. By the method individually detects the measuring temperatures of these temperature measuring devices, two test variables can be determined, which give information about the operating state individually or in comparison with each other or with a reference variable.

Preferably, two test variables are determined for this one first control loop, the comparison of which gives information about the operating state of the tempering devices and temperature measuring devices used in this control loop. Furthermore, in this design of the test method and the tempering device can be detected with high probability, if there is a malfunction in a composite of a tempering and its associated temperature measuring device. However, it can not be detected without further measures, if a fault, which is detected for such a composite, a defective tempering or a defective temperature measuring device is the cause. However, this problem can be solved with further constructional measures, i. with the Temperierungsvorrichtung in a further embodiment and the tempering in its second embodiment, are solved. The tempering devices and the temperature measuring devices of the control loop must be able to be selectively excluded from being involved in the control loop, and e.g. be designed switchable by means of the test device. In particular, in such a case, in a tempering apparatus in which each control circuit has at least one temperature measuring device assigned to this tempering device, by means of this embodiment of the inventive method it can be determined which individual component of these temperature measuring devices and tempering devices is defective.

For this purpose, a control circuit preferably has the same number of tempering devices and temperature measuring devices, in particular at least two tempering devices. directions and at least two temperature measuring devices, in particular a number of three or four, and more preferably two. During normal tempering operation of the tempering device, the two tempering devices T1 and T2, which are assigned to at least a portion of the at least one tempering block in the tempering device, and the two temperature measuring devices S1 and S2, which are each assigned to their temperature control for controlling the temperature of a portion, for regulation the temperature of this section used. In this case, T1 and S1 or T2 and S2 may each be arranged closer to each other according to their mutual association than T1 and S2 or T2 and S1. To control the temperature, that is, the temperature of this section, the temperature control T1 and T2 and the temperature measuring devices S1 and S2 are used.

First, a temperature difference is determined, which is measured by operating the temperature device T1 within a constant time interval by the temperature measuring device S1 as the first test variable. Furthermore, a temperature difference is determined, which is determined within this time period by operating the tempering device T2 of this temperature measuring device S2 as a second measured variable. By comparing in each case the first test variable and the second test variable with a reference variable, it can first be determined in which composite of components T1, S1, or T2, S2 there is a malfunction. Thereafter, a third test variable, and preferably a fourth test variable, is determined one after the other. The third test variable is the temperature difference which is determined at S1 due to a temperature change by means of T2 within a predetermined period of time and the fourth test variable is the temperature difference that results at the temperature measuring device S2 within this time period due to a temperature control by means of T1. Thus, a temperature control of the tempering block (section) is initially carried out exclusively via the composite T2, S1 and optionally exclusively via T1, S2. A comparison of this third test variable with another reference variable provides information as to whether there is a malfunction in the pair of components T1, S2 or T2, S1. By comparison with the first and second test variables, it can be concluded which component T1, T2, S1 or S2 has a defect. If, for example, the composite S1, T1 has a malfunction, which is determined by means of the first test variable, and the composite S2, T2 no Malfunction on, which is determined by means of the second test variable, so there is a defect in the temperature measuring device S1 when the composite S1, T2 results in a malfunction, which can be determined by means of this third test variable. This diagnosis can be confirmed if the optionally to be determined fourth test variable, which corresponds to the composite T1, S2, no malfunction results.

In a third embodiment of the method according to the invention, this likewise additionally relates to the testing of a second test variable of this tempering device, wherein this tempering device comprises at least one second control loop different from this first control loop, at least one second tempering device and at least this second control circuit, associated with at least one second tempering, associated temperature measuring device, and wherein the method comprises the steps of: operating this second tempering device for the duration of at least a first time period from at least a first time; Detecting at least one measurement temperature from said at least one second second temperature measuring device associated with said second temperature control device at least for a second time; Determining at least a second test variable of the temperature control device using this at least one measurement temperature; Comparison of this second test size with a reference size. The method is thus advantageous in Temperierungsvorrichtungen having two or more, preferably independent, control circuits. Such tempering devices are e.g. used to generate a temperature gradient in the temperature block. By the method individually capturing the measuring temperatures of the temperature measuring devices of these control loops, two test variables can be determined, which individually or in comparison with each other or with a reference variable provide information about the operating state.

In particular, when the tempering device of a tempering device is associated with a plurality of temperature measuring devices, a fourth embodiment of the method according to the invention is preferably used. This method is designed to determine a difference between measurement temperatures as a test variable of a tempering apparatus, and in addition to the steps of the method according to the invention. the following steps: detecting at least one measurement temperature from at least one second temperature measuring device at least for a second time; Use this measurement temperature to determine this test size by forming at least a difference in the measurement temperatures of these first and second temperature measurement devices, and using this difference as this test size. The second time at which the measuring temperature is detected with the first temperature measuring device, that is, the second time of the first temperature measuring device, and the second time of the second temperature measuring device are preferably the same time. The measurements can also be made at different times. The said difference is a measure of the deviation of the operating state of the tested temperature measuring devices. This embodiment of the method can also be used in particular in combination with the above-described configurations of the method, which relate to the determination of this second test variable, ie both this first and this second test variable can be a temperature difference with two, in particular different or even same, temperature measuring devices has been determined.

Preferably, an absolute value, eg a time, a temperature or a time difference or a temperature difference is used as the test variable. For this purpose, a setpoint temperature is preferably set by means of the control loop, and the then measured temperature value used for the test procedure. In a fifth embodiment, the method according to the invention therefore preferably additionally comprises the steps of: applying a setpoint temperature from at least this first time to this control loop, to which these at least one tempering device and this at least one temperature measuring device associated with this at least one tempering device are assigned; Use the measurement temperature measured at this second time as this test size. Preferably, the at least one measurement temperature is detected, which is measured by this at least one, this first temperature control associated first temperature measuring device at this first time. It is also possible for the power consumption of this first tempering device between this first and second time to be detected by means of a power control device as a test variable, in particular in parallel with the latter step, and compared with reference data for the power consumption of this first temperature control device becomes. Preferably, this second time is selected so that the temperature-controlled tempering block or tempering block section has assumed the setpoint temperature within a tolerance. Preferably, the method comprises the step of selecting this first time period to include a waiting time, eg 0 to 900 seconds, 10 to 50 seconds, or preferably 20 to 40 seconds, following the time at which the temperature to be tempered Temperierblock or Temperierblockabschnitt within a tolerance has reached the target temperature to achieve a stable temperature measurement. For this purpose, the measuring temperature is preferably repeated at times after this first time, for example periodically, by means of this first temperature measuring device. This setpoint temperature plus a tolerance is preferably used as this reference variable. However, it is also possible for this reference variable to be different, in particular smaller, than this setpoint temperature, so that a comparison of the measurement temperature with the reference variable can take place, in particular, before reaching the setpoint temperature on the temperature control block, so that a shortened test procedure is made possible, which is especially true can lead to a shortened overall duration of the test procedure.

As an alternative to an absolute value, for example a time, temperature or difference, a time value change, eg temperature change rate or rate, can be used as the test variable. In this way, relevant for the operation of a tempering device performance parameters can be determined and the performance of the device can be determined. The mentioned temporal value change can be represented by the quotient of value difference divided by time difference. This quotient can be eg temperature difference divided by time span. To determine this quotient, it is possible to specify a time span and to measure the temperature difference that occurs when the predetermined period of time has elapsed. The variable size in this case is the temperature difference. Alternatively, the temperature can be repeatedly measured, and the time and thus the time period can be determined at which sets a predetermined temperature or temperature difference. The variable size in this case is the time or the time span. In both cases, either the quotient or the variable size can be used as test variable. If one chooses the variable size as a test variable, then the respectively predetermined (constant) value, eg a fixed temperature difference, will also be the basis of the reference quantity, which used for comparison with the test size. The use of the variable size as a test variable offers the particular advantage that the calculation step of the quotient formation and thus the calculation time is saved.

For this purpose, in a sixth embodiment, the method according to the invention preferably comprises the steps of: detecting at least one measurement temperature from this at least one temperature measuring device associated with this tempering device at a third time; Forming the difference between two measurement temperatures, one of which was measured at this second time and the other at that third time; Forming a second time period corresponding to the difference of said third time and said second time; and using this difference of two measurement temperatures or this second time period as this first test quantity. In all embodiments of the method, this third time is preferably behind this second time.

As an alternative to the sixth embodiment, in a seventh embodiment, the method according to the invention preferably comprises the steps of: detecting at least one measurement temperature from this at least one temperature measuring device associated with this tempering device at a third time; Forming the quotient of the difference between two measurement temperatures, one of which was measured at this second time and the other at this third time, and a second time period corresponding to the difference of this third time and second time, and using this quotient of difference and second time period as this first test size.

As described above, a period of time can be set and the temperature difference that occurs at the lapse of the predetermined time period can be measured. To this end, the method in an eighth embodiment preferably further comprises the steps of: using a predetermined second time period; Using the sum of this second time and this predetermined second time period as this third time. In this case, the second time period is kept constant and the temperature difference at this first temperature measuring device is determined at the beginning and end of this second time period. When determining a quotient, this third time is preferably selected so that the tempering block does not yet reach the setpoint temperature. enough. Then, the temperature difference or quotient is detected during a period in which the temperature of the tempering block changes continuously. However, the third time can also be selected such that the tempering block has already reached the setpoint temperature within a tolerance.

As described above, it is also possible and preferably provided that a time difference or a quotient is used as this first test quantity, the difference of the measurement temperatures being kept constant by determining at what third time this temperature difference is measured. For this purpose, the method in a ninth embodiment preferably comprises the steps: repeated detection of at least one variable measuring temperature from this temperature measuring device associated with at least one temperature measuring device at times after this second time; Comparison of this variable measuring temperature with a reference temperature; Detecting a time when this variable measurement temperature within a tolerance has reached this comparison temperature and using this time as this third time. The reference temperature is preferably this target temperature or another predetermined, e.g. stored in the tempering, temperature.

Depending on whether a variable or this quotient according to the sixth or seventh embodiment of the method is determined by this temperature difference or this second period is kept constant, other functional errors of Temperierungsvorrichtung can be determined. This increases the flexibility of the test procedure.

The tempering, in particular in the sixth or seventh embodiment of the method, can be done either by applying a set temperature to the control loop or by applying a constant power to the tempering. In the case of a constant temperature difference, the method in a tenth embodiment therefore preferably includes the step of applying a setpoint temperature from at least this first time and for at least the duration of this first time period to this first control loop, to which this at least one first tempering device and this at least one, this at least one first tempering associated, first temperature measuring device, are assigned. In this case, this reference temperature is preferably this target temperature. Furthermore, with the temperature difference kept constant, it is preferably provided that the method in an eleventh embodiment comprises the step of operating this at least one first temperature control device for the duration of at least this first time period from at least one first time with constant power.

In order to further increase the reliability of the test method and its functionality, it is preferably provided that at least one second test variable is determined, which is compared either with this first test variable or with a reference variable.

In the event that at least two different test variables are determined by the test method, it is preferred that the method comprises at least one of the two steps: using this second test variable as reference variable for comparison with this first test parameter; Use this first test size as reference for comparison with this second test size.

For all embodiments or modifications of the method, it is preferred that this reference size is a reference temperature, which is e.g. is stored in a memory device of Temperierungsvorrichtung, or which is the Temperierungsvorrichtung provided via a data interface.

The method is preferably started manually by the user, preferably via an input panel on the tempering device. Preferably, the method is started either manually by the user or automatically. Furthermore, the method is preferably started automatically for each measurement carried out by means of this tempering device on this at least one sample, in particular for one, in particular each, carrying out a tempering program with at least one sample, in particular before, after or during the execution of a tempering program. Preferably, starting the method automatically takes place automatically at regular intervals after every nth (n> = 1) in Operating the Temperierungsvorrichtung or every nth application of Temperierungsvorrichtung. Furthermore, it is preferred that the starting of the method is provided automatically after a certain total operating time of the tempering device. Furthermore, it is preferred that the starting of the method takes place automatically after a predetermined inactivity time of the tempering device, in which the tempering device, in particular, switches itself on automatically from a stand-by mode in order to carry out this test method. In this way, the reliability of the tempering device can be improved and at the same time a test procedure for the user can be carried out in a comfortable manner. The tempering device is preferably designed to carry out a plurality of, in particular all, the described starting possibilities.

The inventive method is preferably designed to have a short total duration of its implementation, which is preferably less than 40 minutes, preferably less than 30 minutes, preferably less than 25 minutes, more preferably less than 20 minutes, even more preferably less than 15 minutes more preferably less than 10 minutes, more preferably less than 9.5 minutes, and even more preferably less than 6 minutes. Most preferably, the total duration of the process of the invention is less than 5 minutes. Furthermore, the tempering device according to the invention, in particular also its test device, is preferably designed to carry out a test method with such a short overall duration. A short total duration offers the advantage that more time is available for carrying out the primary function of a tempering device, namely the performance of at least one tempering program. Thus, the operation flow is less delayed when using a tempering device, which performs the test method according to the invention, and the use of this tempering device becomes more efficient and comfortable. Furthermore, a short process time allows the test procedure to be carried out more often, in particular automatically. This improves the reliability of the tempering device. In the event that the test procedure is carried out completely during the execution of a tempering program, the duration of the method can even be designated as zero. The tempering device according to the invention and / or the method according to the invention preferably also has a documentation function, by means of which data can be recorded permanently, ie permanently with regard to current interruption. The tempering device preferably has a documentation device, which may comprise a memory device or parts of a memory device also used for storing other data. This documentation device is preferably arranged in this tempering device, but may also be designed as an external device, for example as part of an external PC, which is connected to the tempering device via a data interface. The documentation device is preferably used for storing a test log book which provides data entries which include, for example, date, time, serial number, user and / or test result (eg, passed / failed). Accordingly, the method preferably comprises the step: entering at least one data entry into a documentation device of the tempering device. By documenting test results, the maintenance and thus the reliability of the device can be improved.

The result of a test procedure is preferably output to the user. This can be done visually, eg via a control panel of the tempering device, and / or acoustically, eg via a loudspeaker of the tempering device. Furthermore, it is preferred that the tempering device according to the invention and / or the method according to the invention comprises a detection function with which a certificate can be produced by means of a test procedure that has been carried out. For this purpose, the temperature control device is preferably designed to output a detection data record in a certificate by outputting or imaging detection data, for example visually via an optional control panel of the tempering device or via a data interface to an external device, eg a PC, a mobile data memory or a printer. Accordingly, the method preferably comprises the step: creating a certificate from proof data. This verification data may include user-selectable or default text as well as a header with date, time, username, device serial number, or device type. In addition, these detection data comprise at least one test result of a previously performed test procedure, eg an overall result and one or more partial results. It is possible for the method to be performed at least partially simultaneously and repeatedly several times and in succession, and in particular by means of different components, and furthermore that several different of the described embodiments of the method may be combined. In a combined method, the inventive method is performed several times, in at least one of the described embodiments. In a combined method, at least one method in an embodiment for determining an absolute value as a test variable with at least one method in a configuration for determining a change in value (said sixth or seventh embodiment of the method) is preferably used as a test variable to determine one or more test variables , As a result, a particularly reliable overall result of the tests of the operating state of the tempering device can be obtained.

Further features and advantages of the test method according to the invention will become apparent from the above description of the tempering device according to the invention and its embodiments.

The method according to the invention is preferably provided for carrying out with a tempering device according to the invention. However, it is also possible and preferred that this method according to the invention is carried out with another tempering device.

Further features and advantages of the invention will become apparent from the following description of the figures and the figures. Like reference numerals in the figures indicate substantially similar components or method steps to avoid repetition.

Figures 1 to 7 are schematic representations of different embodiments of the temperature control device according to the invention. Figures 7 to 12 show schematically the flow of the inventive method in different embodiments.

FIG. 13 schematically shows the sequence of a method which combines the method according to the invention in two configurations to form a combined method.

The tempering device 1 is a thermal cycler, which is designed for automatically carrying out a polymerase chain reaction (PCR) in a plurality of PCR samples. The thermal cycler 1 has a housing 2 and a heated lid 3. It comprises a substantially cuboid tempering 4, which is a one-piece made of metal component. The tempering block 4 has at its top a plurality of receptacles 5, which are adapted to receive a plurality of sample containers, e.g. from a PCR plate are formed. The sample containers and the receptacles 5 are designed so that between the outer wall of the sample containers and the inner wall of the receptacles 5 as large a contact surface is achieved, which is the same for each sample container to ensure optimal and reproducible heat transfer between Temperierblock 4 and sample container. The tempering 4 is heated by the temperature control device 6, which is a Peltier element. At the tempering 4 further two temperature measuring devices 7, T are mounted, by means of which the temperature of the tempering can be measured.

The control of the temperature control device 1 by means of the control device 8. This takes in particular the control of the temperature of the tempering 4.

The Peltier element 6 is in large-area contact with the underside of the tempering block 4, so that the plurality of receptacles 5 are located above the Peltier element 6.

As a functional component of the temperature control, the control device 8 comprises a control circuit 9, to which these tempering device 6 and these two elements Raturmessinrichtungen 7 are assigned. The control circuit 9 comprises the circuits of the controller 10, which receives via the connections 11, 13 two temperature actual values measured by the temperature measuring devices 7, T as a controlled variable of the control circuit 9. The controlled variable is formed, for example, by averaging from the two actual temperature values. By comparison, in particular difference formation, of the actual temperature value with the set temperature setpoint (target temperature), the controller 10 sets a control value which ultimately determines the power with which the temperature control device 6 is operated via the connection 12.

The tempering device comprises a test device 14, with which a test method can be carried out, in which at least one test variable can be determined, which characterizes the operational readiness of the tempering device. The test device 14 is arranged within the tempering device 1 and is structurally integrated into the control device 8. Via the signal line 15, the controller 10 and the signal line 11, the test device 14 is signal-connected to the temperature sensor 7 and signal-connected analogously to the second temperature sensor T. Thus, the test device comprises a signal connection to the control circuit 9, in particular to the controller 10, and is in particular designed to control the output to the temperature control device 6 by influencing the control value of the control loop. An advantage of using two temperature measuring devices 7 and 7 ^' , which are associated with a tempering device 6, is that an additional data source is provided, which can provide information about the operating state of the device that not only the total failure of a component detected but also performance deviations of the components can be detected. The sensor T not only measures the temperature controlled by means of the tempering device 6, but also supplies a comparison value for the data measured by means of the sensor 7. By means of the described signal connections of the test device 14 with the components of the tempering device, a test method with the tempering device can be carried out without the need for expensive additional hardware. In this way, the reliability of the test device and the tempering device is improved. The test device is assigned a section of a memory device (data memory, not shown) in which a program code for carrying out a test method, in particular the test method according to the invention, is stored. Furthermore, the test device 14 is assigned a further section of a memory device which stores the results of at least one test method. The test device 14 further comprises a starting device 18 for automatically starting a test method, wherein this starting device is in signal connection with this test device, so that an automatic starting of this test method is made possible. The starting device comprises a circuit logic, which in the exemplary embodiment is designed to carry out the test method after each execution of a tempering program, which may for example consist of performing a PCR. The starting device is structurally integrated into the control device 8.

In FIG. 2, the embodiment of the tempering device according to the invention, the thermal cycler 21, comprises a test device 24, which is designed as an external test device. The test device 24 is signal-connected via a signal line 17, a signal interface 16 to the control device 28, and signal-connected via the signal line 15, the controller 10 and the signal line 11 with the temperature measuring device 7 and signal-connected in a similar manner with the sensor T and the temperature control device 6. In this exemplary embodiment too, the existing structure of the tempering device, in particular the sensors, is used for carrying out a test method, so that expensive additional hardware is not required. The test device 24 can be integrated in an external control device, eg a PC, from which a central control of the test methods of different temperature control devices can take place. Preferably, the test device 24 is integrated into a laboratory information management system (LIMS). The external embodiment has the particular advantage that test methods, in particular the method according to the invention, can be adapted or changed more easily and that the test results are available more directly for external data evaluation and monitoring. FIG. 3 shows a tempering device (thermocycler) 31, which comprises a control circuit 32 to which a first Peltier element 38 and a second Peltier element 39 are assigned. Furthermore, the temperature measuring devices 7 and T (temperature sensors) are assigned to the control circuit 32, wherein the temperature sensor 7 is assigned to the tempering device 39 and the temperature sensor T is assigned to the temperature control device 38. The temperature of the Temperierblocks 4, which is measured by the temperature sensor 7 is thereby influenced substantially by the temperature control 39, which is located closer to this sensor 7, as the tempering device 38. Accordingly, the temperature measured by the sensor T is closer to the closer Temperature control 38 influenced. By this assignment of temperature sensor 7 to Peltier element 39 and from sensor T to Peltier element 38, numerous test methods can be carried out, which improve the reliability of tempering device 31. On the other hand, it is possible to generate a temperature gradient along the recordings 5 by means of these two tempering devices 38, 39. The test device 14 'is signal-connected via the signal connection 15, the controller 33 and the signal line 34 with the temperature sensor 7 and signal-connected via the signal line 15, the controller 33 and the signal line 35 with the tempering device 39. Accordingly, the test device 14 'is signal-connected to the sensor T and the tempering device 38. The test device 14 'can be designed to temporarily switch off the tempering device 38 or the tempering device 39, so that regulation is only possible with a tempering device. This opens up possibilities for further test procedures which improve the reliability of the tempering device by providing detailed information about the operating state.

FIG. 4 shows a tempering device 41, which comprises two control circuits 42 and 42 ', wherein each control circuit is assigned two tempering devices and two temperature measuring devices, and each temperature control device is assigned a temperature measuring device. In this case, the tempering 4 is divided into two sections 4a and 4b, which are interrupted by a material of poorer thermal conductivity, eg air. This disturbing influences between the control circuits 42 and 42 ', in particular disturbing control vibrations are reduced. The control circuit 42 comprises the Peltier- elements 48 and 49 as actuators, a temperature on the portion 4a of the Apply tempering blocks, which are measured by the temperature sensor 51, which is associated with the temperature device 48, and the temperature measuring device 50, which is associated with the tempering 49. These actual temperature values are transmitted to the controller 43 of the control circuit 42, whereby the control loop is closed. Analogously, the control circuit 42 'is constructed. The test device 54 includes signal connections to the control circuits 42 and 42 'as well as signal connections to the temperature sensors 50, 51, 50', 51 '. By means of this arrangement of components in the tempering device 41, it is possible to provide further methods, in particular methods according to the invention, for testing the operating state in the tempering device, whereby the reliability of the tempering device 41 is improved.

FIG. 5 shows the tempering device 61, which comprises two control circuits 62 and 62 ', wherein each control loop is assigned a tempering device and a temperature measuring device. Furthermore, each temperature control is assigned exactly one temperature measuring device. The control circuit 62 is associated with the Peltier element 66, which tempered the section 4a of the tempering 4 to produce a temperature in the tempering, which is measured by the temperature sensor 67, which is the tempering device 66 of the control circuit 62, and measured as the actual temperature to the Regulator 63 of the control circuit 62 is transmitted, whereby the control loop is closed. Analogously, the control loop 62 'is constructed. Instead of a tempering block separated into sections, it is also possible to use a one-piece tempering block 4. The test device 74 is signal-connected by means of the signal line 75, the controller 63 and the signal line 64 to the temperature sensor 67. Analogously, the test device 74 is signal-connected to the temperature sensor 67 '. Furthermore, the test device 74 in each case includes a signal connection to the control circuits 62 and 62 'and the tempering devices 66 and 66'. In this way, various test methods can be carried out by means of the components connected to the test device 74, as described, of the thermal cycler 61, as a result of which its operating state can be reliably monitored. FIG. 6 shows the thermal cycler 81, whose tempering block 4 consists of four sections 4a, 4b, 4c and 4d, wherein each tempering block section is tempered by a tempering device and assigned to its own control loop. The control circuit 82 is associated with the Peltier element 86, which generates a temperature in the section 4a of the tempering 4, which is measured by the temperature sensor 87 and transmitted as an actual temperature to the controller 83 of the control circuit 82, whereby the control loop is closed. Analogously, the control circuits 82 ', 82 "and 82"' are constructed. The test device 94 is signal-connected via the signal line 95, the controller 83 and the signal line 84 to the temperature measuring device 87 and signal-connected via the signal line 95, with the controller 83 and the signal line 85 with the tempering device 86. Analogously, the test device is signal-connected to the corresponding components of the control circuits 82 ', 82 "and 82'". By means of these signal connections, numerous test methods, in particular test methods according to the invention, can be carried out with the tempering device 81, which monitor their operating state and thus improve their reliability.

FIG. 7 schematically shows the sequence of the method 100 for testing at least one first test variable of a tempering device. This tempering device suitable for carrying out the method, which is in particular the test device according to the invention and can correspond to one of the designs according to FIGS. 1 to 6, is designed for tempering at least one sample, in particular a PCR sample. For this purpose, the tempering device comprises at least one tempering block, which is designed to accommodate the at least one sample, at least one first tempering device, which are arranged for controlling the temperature of this at least one tempering, at least a first temperature measuring device and at least one second temperature measuring device, each tempering associated with at least one temperature measuring device is, at least one control device which is designed to control the temperature of the at least one Temperierblocks, preferably a timer, and at least one first control circuit to which these at least one first temperature control and these at least one, associated with at least one first temperature control, associated first temperature measuring device , The method 100 includes the steps of: 101 starting the method; 102 operating at least this first tempering device for the duration of at least a first time period from at least a first time; 103 detecting at least one measurement temperature from said at least one first temperature measuring device associated with said first temperature control device at least for a second time; 104 determining at least a first test variable of the tempering device using this at least one measurement temperature; 105 Comparison of this first test size with a reference size. In the method 100, a predetermined variable stored in the tempering device is used as the reference variable in accordance with step 106.

The method 110 shown in FIG. 8 shows an embodiment of the method 100 which, in addition to the steps 101 to 105, comprises the steps of: 111 applying a setpoint temperature from at least this first time to this control loop, to which these at least one tempering device and these at least one associated with at least one tempering, associated with temperature measuring device; 114 Use the measurement temperature measured at this second time as this test size. Step 111 causes the control circuit to temper the tempering, ie to heat or cool, to reach a target temperature of the tempering. The second time point of the measurement of the temperature, which is then used as a test variable (step 114), can be selected, for example, such that the change in the temperature of the tempering block is monitored by means of this temperature measuring device, for example. For this purpose, it is measured until there are no more changes within a predetermined limit value, whereby the temperature is evaluated as adjusted at least after the further waiting of a waiting time and the temperature measurement of step 103 takes place. As an alternative to observing the temperature value, a latency (waiting time) can also be set, in particular taking into account the magnitude of the temperature jump and the starting temperature and setpoint temperature and, in particular, taking into account the history of the temperatures on the tempering block, within which a stable temperature setting is normally expected. This latency may be, for example, 30 seconds. If, in step 105, a deviation of the test variable determined in step 104, in this case a temperature, from the predefined and expected the reference size (step 106), the test result is negative and is output to the user accordingly.

Accordingly, the method 110 includes the step 107, which provides that the test result is output from the tester. This is preferably done visually, e.g. via a display on the tempering device or via an external output device, e.g. may be the display of an external PC, which may be signal connected to the test device via a data interface. The test method 110 can be carried out in particular by a test device of the temperature control device according to the invention. Furthermore, the test results are electronically stored and documented, e.g. with a documentation device of the tempering device according to the invention or on an external PC. The assignment of at least one Temperiermesseinrichtung to this tempering to a composite makes it possible that the operating state of this network can be monitored. The comparison of step 105 of the measured test size, e.g. the temperature which is applied to the sensor at a certain time, with a predetermined comparison variable, which would be expected under normal operating condition of the tempering device, provides information on whether there is a malfunction in this composite or not. Thus, the failure of this composite component can be detected. In particular, if the starting of the method is automatic, e.g. After every tenth execution of a tempering program, the reliability of the tempering device can be improved.

FIG. 9 shows the method 120, which, in addition to testing a first test variable according to the steps 101 to 105, relates to the testing of a second test variable of this temperature control device. The method is suitable, for example, for a tempering apparatus whose first control loop is assigned at least one second tempering device and at least one second temperature measuring device assigned to this at least one second tempering device. Furthermore, the method is suitable for a tempering device, which comprises at least one, different from this first control loop, second control loop, said second control loop at least one second tempering device and at least one, this at least at least one second tempering associated, second temperature measuring device are assigned. Examples of such tempering devices are the themocycers shown in FIGS. 3 to 6.

The method 120 includes the steps of: 101 starting the method; 102 operating at least this first tempering device for the duration of at least a first time period from at least a first time; 103 detecting at least one measurement temperature from said at least one first temperature measuring device associated with said first temperature control device at least for a second time; 104 determining at least a first test variable of the tempering device using this at least one measurement temperature; 105 comparing this first test variable with a reference size which is this second test size (step 106b). Furthermore, the method 120 provides that the steps are carried out simultaneously or simultaneously with the steps 102 to 105: 102 'operating this second tempering device for the duration of at least a first time period from at least a first time; 103 'detecting at least one measuring temperature from said at least one second second temperature measuring device associated with said second temperature control device at least for a second time; 104 'determining at least one second test variable of the temperature control device using this at least one measurement temperature; 105 'Compare this second test size with a reference size which is this first test size (step 106b). Alternatively or additionally, each test variable may be compared to a stored reference size. An advantage of the determination of a second test variable and thus an advantage of the method 120 is that the temperature control and temperature measuring devices can monitor each other so that a better monitoring of the operating state of the tempering device is made possible, thereby becoming more reliable.

FIG. 10 shows the method 130 which, in addition to the method steps 101 to 105, comprises the steps of: 131 detecting at least one measurement temperature from this at least one temperature measuring device associated with this tempering device at a third time; 134 forming the difference between two measurement temperatures, one of which was measured at this second time and the other at that third time, Forming a second time period corresponding to the difference of this third time and second time and using this second time period as this first test size. The reference variable "time interval" is determined as a change in value with respect to a predetermined (constant) temperature difference, and the reference variable with which this test variable is compared was determined and determined with reference to this constant temperature difference This method has the dimension of a temporal change in value, in particular of a rate and in particular of a rate of change of temperature By means of such a (temporal) change in value, not only can the failure of a combination of tempering device and the at least one associated temperature measuring device, The performance of this composite may also be tested according to method 140. A temperature difference, time difference, or the quotient of the two values is determined by either specifying a time difference and applying the ei determining temperature difference is determined or alternatively, by determining within which time a predetermined temperature difference is formed.

The second of the named alternatives is carried out in the method 140 shown in FIG. 11, which comprises in addition to the method steps 101 to 105 and 131 and 134 the steps: 141 Repeated detection of at least one variable measurement temperature from this at least one first temperature measuring device associated with said first temperature control device at times after this second time, compare this variable measuring temperature with a reference temperature; 143 Detecting a time when this variable measurement temperature within a tolerance has reached this comparison temperature and using this time as this third time. The time difference determined in step 104 as a test variable may either be compared to a stored size (step 106) or compared to another test size (step 106b).

FIG. 12 shows the method 150, in which two time differences are determined as test variables. It can be carried out, for example, by a temperature control device, in which a temperature control device is associated with two temperature measuring devices. Examples of such a tempering device are the thermal cyclers shown in FIGS. 1 and 2. Together with the first temperature measuring device assigned to it, the tempering device forms a first component composite and, together with the second temperature measuring device assigned to it, forms a second component composite, with a separate test variable for identifying the efficiency of the composite being determined for each composite. The method 150 starts automatically (step 101) after a tempering program has been carried out, and tempering the tempering block with the tempering device from a first time (102). The control loop of the tempering, to which the tempering is assigned, for example, a setpoint is specified. In each case two temperature values are determined at two points in time by means of the two temperature measuring devices assigned to this tempering device. The two time points of the temperature measurements, namely first this second time and then this third time, are determined before the setpoint temperature is reached. The predetermined constant temperature difference, when reached this third time is recorded is, for example 3O ⁰ C. The assigned to the first composite component, calculated as the first test variable time difference between the third and second time is, for example 30 seconds associated with the second component composite second test size is, for example, 35 s. Assuming that the (reference) value for the time difference normally expected under the selected conditions would be 30 s with a tolerance of 0.5 s. Then either both temperature sensors are defective or the tempering device is defective. It is less likely that two components will fail at the same time than one component is defective. Therefore, in this case, it is more likely that the tempering device has a defect, for example, a faulty connection to the tempering block. In this way, the design of the temperature control device with two sensors per control loop and tempering device and the inventive method additional security in the analysis of the operating state of the temperature control can be obtained.

FIG. 13 shows a method 160 in which two differently configured inventive methods are combined to form a test method, whereby a particularly reliable test of the operating state of a temperature control device is achieved. The method 160 is carried out, for example, by a tempering device in which a tempering device is assigned two temperature measuring devices, cf. Fig. 1 and 2. A first test variable and a second test variable are determined in a temporally overlapping sequence. The method is started by a manual user input, which takes place, for example, via a control panel of the tempering device, in step 101. A setpoint is applied to the control circuit of the tempering device (162) and the tempering device is caused to heat up. The first test variable is a difference between two temperature values which are determined simultaneously by the temperature sensors assigned to the tempering device, specifically at this second time (103, 163) and whose difference is used as the first test variable (164, 104). In order to ensure that the temperature in the temperature control block is adjusted at the positions of both temperature sensors, this second time is preferably chosen so that a waiting time of eg 30 seconds is included after reaching the setpoint temperature, within which the temperature stabilizes.

The second test variable in method 160 is the time required to reach a given temperature difference. It thus corresponds to a rate of change of temperature without, however, explicitly calculating the quotient of temperature and time difference. The time period is determined by measuring not only at the times of this second time (103) of the method 160, but additionally using two further times and two further temperature values. These times are a third time (131), and another second time (103 '), this third time during the tempering, ie after this first time and after this further second time is provided. This further second time (103 ') is preferably selected such that the temperature setpoint has not yet been reached, so that the temperature between the times a e.g. Has rising, in particular substantially ramp-shaped course. The measured temperature difference may be provided by this first or second temperature sensor, or a combination of the sensors may be used, e.g. by averaging.

Both the first test size and the second test size are compared with stored reference values (105, 106, 105 ", 106") and a partial result of the test method is output (107, 107 ") time-saving additional test data can be determined, the information give about the operating state of the tempering device. Preferably, such a combined test method has further embodiments of the method according to the invention, in that, for example, after determination of the first test variable determined during a heating step, further test variables are determined which are determined during cooling steps. It can, for example, in this combined process successively the temperature values of 35 ⁰ C (baseline), 95 ⁰ C, 35 ⁰ C, 95 ° C, 75 ° C, 55 ° C, 35 ° C and 4 ° C are approached, and in any When these setpoints are reached, a test variable is determined. Thus, a test method is provided which gives information about the operability of the temperature control in different, operating temperature regions and both the heating power and the cooling power information. Such a combined test method gives a particularly complete information about the operating state of the tempering device.

Claims

claims

1. Tempering device (1; 21; 31; 41; 61; 81) for carrying out a tempering program for at least one sample, in particular a PCR sample, comprising:

at least one tempering block (4), which is designed to receive the at least one sample,

at least one tempering device (6, 38, 39, 48, 49, 86), which is arranged to control the temperature of this at least one tempering block (4),

at least one temperature measuring device, which is assigned to this tempering device,

at least one control circuit (9; 32; 42; 62; 82) for controlling a temperature to which at least one tempering device and at least one temperature measuring device associated with at least one tempering device are assigned,

at least one control device (8; 58; 68; 88), which is designed to control the temperature control of the at least one tempering block,

characterized in that

the tempering device comprises at least two temperature measuring devices (7; 50, 51; 67; 87) which are assigned to at least one control loop, and the tempering device is assigned a test device (14; 24; 14 ';54;74; 94) for carrying out a test method,

wherein said test device comprises a signal connection (15; 17; 75; 95) to at least one of said at least two temperature measuring devices (7; 50, 51; 67; 87),

so that by means of this signal connection (15; 17; 75; 95) at least one test variable of the tempering device can be determined, which characterizes the operating state of the tempering device.

2. Temperierungsvorrichtung according to claim 1, characterized in that it comprises at least one control loop, the at least two tempering and at least two temperature measuring devices are assigned, each tempering is associated with at least one temperature measuring device.

3. tempering device according to at least one of the preceding claims, characterized in that it comprises a starting device (18) for starting a test method, said starting device is in signal communication with this test device.

4. Temperierungsvorrichtung according to claim 5, characterized in that this starting device is designed for manually starting a test method.

5. Temperierungsvorrichtung according to at least one of the preceding claims, characterized in that it has the function of a thermal cycler, which is suitable for carrying out a PCR reaction in at least one PCR sample.

6. A method for testing at least one first test variable of a temperature control device, which serves to control the temperature of at least one sample, in particular a PCR sample, said temperature control device having at least one temperature element. at least one first tempering device, which are arranged for controlling the temperature of this at least one tempering block, at least one first temperature measuring device and at least one second temperature measuring device, wherein each tempering device is assigned at least one temperature measuring device, at least one control device, which is designed to control the temperature of the at least one Temperierblocks, and at least one first control circuit to which these at least one first temperature control and these at least one, at least one first tempering associated, associated first temperature measuring device comprises, and wherein the method comprises the following steps includes:

Starting the process (101);

Operating at least this first tempering device for the duration of at least a first time period from at least a first time (102); Detecting at least one measurement temperature from said at least one first temperature measuring device associated with said first temperature control device at least for a second time (103);

Determining at least a first test variable of the tempering device using this at least one measurement temperature (104); Comparison of this first test size with a reference size (105).

7. The method according to claim 6, characterized in that it additionally relates to the testing of a second test variable of this Temperierungsvorrichtung, said first control circuit at least one second temperature control and at least this second temperature measuring device, which is associated with said second temperature control, associated, and wherein the method comprises the following steps:

Operating this second tempering device for the duration of at least a first time period from at least a first time (102 '); Detecting at least one measurement temperature from said at least one second second temperature measuring device associated with said second temperature control device at least for a second time (103 '); Determining at least a second test variable of the temperature control device using this at least one measurement temperature (104 ¹ ); Comparison of this second test size with a reference size (105 ').

8. The method according to any one of claims 6 or 7, wherein the method comprises the steps:

Detecting at least one measurement temperature from said at least one second temperature measurement device at least for a second time (163); Using this measurement temperature to determine this test size by forming at least a difference in the measurement temperatures of these first and second temperature measurement devices, and using this difference as this test quantity (164).

9. The method according to any one of claims 6 to 8, characterized in that the method comprises the steps:

Applying a setpoint temperature from at least this first time to this control loop, to which these at least one tempering device and this at least one temperature measuring device associated with said at least one tempering device are assigned (111);

Use the measurement temperature measured at this second time as this test size (114).

10. The method according to any one of claims 6 to 8, characterized in that the method comprises the steps: Detecting at least one measurement temperature from said at least one first temperature measuring device associated with said first temperature control device at a third time (131);

Forming the difference of two measurement temperatures, one of which was measured at said second time and the other at that third time, forming a second time period corresponding to the difference of said third time and second time and using said second time period as said first test quantity. (134).

11. The method according to claim 10, characterized in that the method comprises the steps:

Repeated detection of at least one variable measurement temperature from said at least one of said first temperature control associated first temperature measuring device at times after this second time, comparing this variable measurement temperature with a reference temperature (141);

Detecting a time when this variable measurement temperature within a tolerance has reached this comparison temperature and using this time as this third time (143).

12. The method according to any one of claims 8, 10 or 11, characterized in that the method comprises the step:

Applying a setpoint temperature from at least this first time and for at least the duration of this first period of time to this control loop to which these at least one tempering device and these at least one, this at least one tempering associated, temperature measuring device are assigned (162).

13. The method according to any one of claims 6 to 12, characterized in that the method comprises the step:

4fl Using a stored in the tempering device size as a reference size (106).

14. The method according to any one of claims 6 to 12, characterized in that the method comprises the step:

Use a different test size than reference size (106b).

15. A combined method in which at least one method according to claim 9 is combined with at least one method according to claim 10 in order to determine one or more test variables.

16. The method according to any one of claims 6 to 15, characterized in that the method is carried out at least temporarily during the implementation of this tempering program.

17. The method according to any one of claims 6 to 16, characterized in that it is performed by a tempering device according to at least one of claims 1 to 5.