EP2108451A1 - Device for causing reactions in samples - Google Patents

Abstract

The device has base equipment (10), which has an acceptance area (20) for changeable reaction unit (22). The changeable reaction unit has an interation unit for interation with sample in reaction vessel. The base equipment has coupling device for coupling with another coupling device for coupling with the interation unit.

Description

The invention relates to a device for carrying out reactions in samples according to the preamble of claim 1 or 14.

Such a device, which is often also referred to as a thermal cycler, has a base unit which has at least one receiving area for at least one exchangeable reaction unit, and at least one exchangeable reaction unit which has at least one reaction vessel for a sample and is designed to be placed in the receiving area of the base unit is on. With such a thermal cycler, for example, temperature cycles can be run, which are required for carrying out a polymerase chain reaction (PCR). For example, the PCR reaction is well described in the US patents US 4,683,202 . US 4,683,195 . US 4,889,818 and EP 258,017 ,

In a conventional thermal cycler ( US 6,703,236 ), the base body has a heating and cooling device in the receiving area, in which then the reaction vessels containing the samples to be amplified, are used. Depending on the embodiment, a cover may additionally be provided on the base unit, which is formed either only as a heated lid ( US 5,475,610 ), or additionally includes an optical measuring device to cause and evaluate a fluorescence excitation of the samples and thus perform a real-time PCR ( US 5,928,907 ).

At the interfaces between the base unit and the reaction vessels used, it inevitably leads to losses in the transmission of heat, radiation and the like. For example, in the conventional thermocyclers, the base body is configured as a metal block containing bores as a receiving area into which the reaction vessels are then inserted. In order to subject the samples contained in the reaction vessels of a PCR reaction, the entire metal block must be cyclic be heated and cooled. For heating elements and cooling elements are positioned below the metal block in the conventional devices. This type of temperature control is very energy-consuming and there are local temperature deviations from the desired / set temperature. The latter has the consequence that due to these inhomogeneities, not every sample is exposed to exactly the same temperatures, and thus the results can deviate from one another due to temperature.

When real-time PCR is performed with conventional real-time thermocyclers, there is a long optical beam path between the sample and the detection device. Due to the long optical beam path, signal losses occur both in the irradiation of the exciting signal and in the detection of the emitted signal. Furthermore, the long optical beam path increases the probability that particles (dirt and moisture) will penetrate the beam path and adversely affect the signal strength.

Miniaturized thermal cyclers are known from the prior art, which seek to circumvent some of these disadvantages of conventional devices. In this context, for example, the US 2006/0288708 A1 and the WO 98/50147 A1 to mention. Both are miniaturized flow thermal cyclers that implement the essential components of the device for performing reactions in chip size samples. These miniaturized reaction systems have in common that they each contain a sample channel for passing a sample and at least one heating zone and one cooling zone in thermal contact with the sample channel, which components are usually arranged on a heat-insulating substrate. Both devices of the cited documents use to build the heating and cooling zones each Peltier components. In the case of US 2006/0288708 A1 In addition, a fluid channel is provided in thermal contact with the Peltier components to dissipate the excess heat or cold, which is formed during cooling or heating of the sample channel by the Peltier components, by means of a fluid flow; In addition, the integration of a temperature sensor and an optical detection system in the chip is possible. Naturally, such miniaturized flow thermal cyclers are only suitable for treating very small sample volumes in the flow-through method. They are also not designed to amplify samples from the back to miniaturized reaction systems. Since both heating and cooling devices are attached to these flow thermocyclers, there is a risk of burns when handling them.

There is therefore a need for an improved apparatus for performing reactions in samples having a higher operating efficiency than the conventional apparatuses, and a need still exist for an improved apparatus which allows for more accurate tempering; Furthermore, there is a need for an improved device that allows the reliable assignment of the measured values to the individual samples; Furthermore, there is a need for an improved device which has all these properties and in addition has no risk of burns.

It is thus an object of the present invention to provide an improved apparatus for performing reactions in samples which avoids the above-mentioned disadvantages of known apparatus. In particular, a device is to be created that allows a more accurate, energy-efficient and better controlled performance of the reactions in the respective samples.

This object is achieved by a device for carrying out reactions in samples having the features of claim 1. Advantageous embodiments and further developments are specified in the dependent claims.

The device has a base unit which has at least one receiving area for at least one exchangeable reaction unit, and at least one exchangeable reaction unit which has at least one reaction vessel for a sample and is designed to be placed in the receiving area of the base unit. The exchangeable reaction unit has at least one unit for interacting with the sample in the at least one reaction vessel and a first coupling device connected to the interaction unit; and the base unit includes second coupling means for coupling to the first coupling means of the removable reaction unit for coupling to the interaction unit.

In contrast to the conventional reaction systems, a system consisting of a base unit comprising a tempering body, which is preferably used to dissipate excess heat, that is to say as a heat sink, and a detachable or exchangeable reaction unit, is created. As a result of the integration of the interaction unit into the exchangeable reaction unit, this interaction unit interacts more directly with the reaction vessel or the sample therein, so that, for example, losses due to interfaces and long transmission paths between the base unit and the exchangeable reaction unit are avoided. In this way it is possible to carry out the reactions in the samples in the reaction vessel more efficiently, more accurately and with less expenditure of energy.

Due to the integration of the interaction unit (s) in the exchangeable reaction unit, it is advantageously also possible to use on a base unit different exchangeable reaction units with different shapes, sizes and numbers of reaction vessels. In addition, samples can be stored or stored in the exchangeable reaction units. Furthermore, if necessary, the replaceable reaction units can also be used successively on a plurality of base units in order to carry out a number of reactions on one sample in succession.

In the following, some of the terms used are defined and explained.

In the context of the present invention, the term "reactions in the samples" encompasses all possible influencing of the sample volumes in the reaction vessels. In particular, these reactions include tempering (increasing, decreasing or maintaining the temperature) as well as various chemical, biological and physical reactions. Furthermore, this term is also understood to mean the performance of detection reactions by means of fluorescence and / or electrical conductivity. The term also includes combinations of influencing measures, such as tempering and detection.

The term "interaction with the sample" includes all conceivable interactions between an element and the sample, in particular those for triggering reactions in the sample, detection and monitoring of chemical, biological and / or physical properties of the sample, tempering (ie increasing, decreasing or maintaining the temperature) of the sample, and the like. Since the device according to the invention can also be used, for example, to carry out a PCR, the interactions should in particular also include all those in connection with a PCR or real-time PCR.

The terms "unit of interaction" or "unit of interaction" describe an element that is capable of interacting with the sample. Interactions can take place in both directions: for example, a detection device sends a first exciting signal into the sample and the sample reacts with an emission of a second signal that is received by the detection device. Alternatively, it is one-way interactions: for example, a heating element can introduce heat into the sample and thus interact with the sample, but the sample itself does not interact with the heating element. If the heating element also had a temperature sensor, an interaction could again take place in both directions. These last examples are merely illustrative of the principle of unilateral and bilateral interactions, and are not meant to be limiting. By way of example, the term "unit for interaction" includes elements such as tempering devices, detection devices, radiation devices, sensors and any combination of these elements.

For the purposes of the present invention, the term "sample" encompasses all types of fluids, in particular liquids, solutions, suspensions, emulsions, reaction mixtures and the like, even in the frozen state, which, for example, are altered, measured, observed, stored and / or temporarily stored for specific purposes be and / or become. The term also includes reference material and controls.

The term "receiving area" describes a region of the base body into which the exchangeable reaction unit (s) can be placed. This area can be formed in one piece or even interrupted, so that there are several areas. In principle, the receiving area can be formed at any position on the base body of the base unit.

The term "reaction unit" describes the combination of reaction vessel (with or without lid) and unit of interaction. Thus, on, in, in, under the reaction vessel, including the lid, and / or integrated into a wall of the reaction vessel, including the top wall, is the interaction unit that can interact with the sample in the reaction vessel.

The term "interchangeable" in connection with the "reaction unit" means that it is not permanently connected to the base body, but is detachably inserted into the receiving area and can be replaced by the user.

The "at least one reaction vessel" in the exchangeable reaction unit basically comprises any number of reaction vessels. Typical numbers are in the range of 1 to about 10,000. Conventionally, numbers of reaction vessels corresponding to those typical array formats are used, such as 8, 12, 16, 24, 64, 96, 256, 384, 1024, 1536, 4096, 6144.

The coupling between the first and second coupling means and thus between the base unit and the interaction unit can be either contacting or non-contact (e.g., inductive, optical, infrared, etc.).

In one embodiment of the invention, the at least one exchangeable reaction unit is designed as a consumable article. In a consumable basically there is a lower risk of contamination and less cleaning. Since unused exchangeable reaction units with consequently unused interaction units are also available in this case, on the one hand very precise specifications can be given and on the other hand higher accuracies and safety in the functions of the respective interaction units can be achieved.

The at least one interaction unit may, for example, comprise at least one tempering device, which is arranged in direct or indirect thermal contact with, on, in, under and / or integrated in a wall of the at least one reaction vessel, around the sample in the at least one reaction vessel to temper, ie to increase, decrease or maintain the temperature of the sample. Due to the proximity of the tempering device to the reaction vessel, the thermal mass of the device and thus also the energy consumption of the device are significantly reduced while at the same time increasing the tempering speed and temperature control accuracy. If an indirect thermal contact is sought, the skilled person knows from the usual measures such as graphite foil, coatings, conductive pastes, etc. to select.

This tempering device preferably contains a Peltier element. The type and size of the Peltier element are adapted to the respective reaction vessels in the exchangeable reaction unit. At present, Peltier elements of very small dimensions are already available, which are suitable, for example, for tempering reaction vessels having a sample volume in the range from about 0.1 to 100 μl. Alternatively, other types of tempering devices may be used, such as electrical or inductive heating systems.

Alternatively or additionally, the at least one interaction unit may comprise at least one device for exciting or triggering a reaction of the sample in the at least one reaction vessel. This exciter includes, for example, a power supply device for supplying e.g. electromagnetic radiation, heat, etc. to the sample in the at least one reaction vessel, which in a specific embodiment may comprise a light source for fluorescence excitation of the sample.

Alternatively or additionally, the at least one interaction unit may further comprise at least one means for detecting a physical, chemical and / or biological property of the sample in the at least one reaction vessel. This detection device contains, for example, a temperature sensor for detecting a temperature of the at least one reaction vessel or the sample in the at least one reaction vessel and / or a device for detecting electromagnetic radiation emitted by the sample in the at least one reaction vessel or through the sample in FIG the at least one reaction vessel is allowed to pass through. In the case of the temperature sensor, this can either be in thermal contact with the at least one reaction vessel and / or with the sample in the at least one reaction vessel or be designed for contactless detection of the temperature of the at least one reaction vessel and / or the sample (38) in the at least one reaction vessel. Further detection devices contain, for example, sensors for detecting an electrical conductivity, a surface potential, a capacity and / or biosensors for detecting biological substances and / or properties of the samples. In particular, biosensors are conceivable that are based on the hybridization principle.

The integration of detection devices in the exchangeable reaction unit increases the accuracy of measurement, since the measurement of the measured values is very close to the sample and there is a defined geometric arrangement of the components involved with few interfaces.

In an advantageous embodiment of the invention, the at least one interaction unit is integrated into a control loop of the device. For example, the temperature control of the samples in the exchangeable reaction unit can be regulated very precisely by means of the integrated temperature sensor. As another example, a reaction in the samples upon termination of a desired chemical, biological, and / or physical property of the samples being monitored may be discontinued, interrupted, or varied.

In a further embodiment of the invention, the exchangeable reaction unit has a plurality of reaction vessels and each of the plurality of reaction vessels is assigned its own interaction unit. Alternatively, the exchangeable reaction unit has a plurality of reaction vessels and all reaction vessels are assigned a common interaction unit. According to a further alternative, the exchangeable reaction unit has a plurality of groups of reaction vessels and each of the plurality of groups of reaction vessels is assigned its own interaction unit. Furthermore, it is possible to realize mixed forms of said alternatives. Thus, it is conceivable, for example, that all reaction vessels of a replaceable reaction unit are assigned a common tempering device, but each reaction vessel has its own radiation source and its own radiation detector.

In a further embodiment, the exchangeable reaction unit, including the reaction vessel, is designed to carry out a PCR and / or a real-time PCR. The person skilled in the field of laboratory equipment will readily be able to select suitable materials and dimensions of the reaction vessels for this purpose.

According to a further aspect of the invention, the at least one reaction vessel can be designed to accommodate a sample with a minimum gas volume, so that, for example, condensate avoidance is not required. For this purpose, the reaction vessel may for example have an overflow area or have a flexible boundary surface. This embodiment has the particular advantage that no additional heating lid for heating the reaction vessel or the sample from above is required.

In an alternative embodiment, the exchangeable reaction unit is provided with an additional heating device for condensate avoidance in the at least one reaction vessel. Alternatively, the base device has a lid, which rests on the exchangeable reaction units during operation of the device. To avoid condensation, this cover can be configured as a conventional heated lid.

In a preferred embodiment of the invention, the second coupling device of the base unit is provided in the region of the receiving area and has a spring-loaded contact. The first coupling device on the exchangeable reaction unit also preferably has a spring-loaded contact. By the spring-loaded contact (s), a reliable electrical contact between the first and the second coupling device can be ensured even with different geometric designs, for example due to manufacturing tolerances. Alternatively, it is also possible to provide the coupling devices at locations other than in the receiving area of the base unit. In addition, non-contact couplings are possible in addition to the contacting coupling mentioned here, which may be advantageous in particular for the transmission of control data and measurement data.

In a still further embodiment of the invention, the base unit can also have a plurality of receiving areas for at least one exchangeable reaction unit.

Alternatively, the base unit is provided with a receiving area for a plurality of exchangeable reaction units.

According to yet another aspect of the present invention, the base unit has at least one further unit for interacting with the sample in the at least one reaction vessel. For example, the tempering devices and the temperature sensors can be integrated into the exchangeable reaction unit, while the radiation source and the detector for fluorescence measurement are further provided on the base device.

For easier and more accurate positioning of the replaceable reaction unit in the receiving area of the base unit, the device preferably has a guide device. In this way, a secure coupling between the first and second coupling devices is ensured. For example, the interchangeable reaction unit may be provided with at least one first guide member and the base unit with at least one corresponding second guide member or the interchangeable reaction unit is itself formed with a guide surface which can be guided in a correspondingly shaped receiving area of the base unit.

Furthermore, the base unit can also have an operating device with operating elements and / or display elements and optionally an interface for connection or communication of the base device with one or more external devices.

In yet another embodiment of the invention, the at least one exchangeable reaction unit further comprises at least one identification device for uniquely identifying the at least one replaceable reaction unit and / or the at least one reaction vessel in the replaceable reaction unit. By such an identification device, which may be implemented, for example, in the form of a semiconductor element, for example a silicon chip, a barcode, an RFID system or the like, the exchangeable reaction units and their reaction vessels can be uniquely identified, resulting in better, safer and easier data evaluation to carry out the reactions in the samples. This measure is particularly advantageous if the exchangeable reaction units be used successively on multiple devices or devices. In a special embodiment, a tempering device with a Peltier element based on silicon (in general: with a semiconductor element) at the same time allows such an identification by integrating the identification function into the semiconductor element.

Figur 1

eine schematische Darstellung des Grundaufbaus einer Vorrichtung zum Durchführen von Reaktionen in Proben gemäß der vorliegenden Erfindung;

Figur 2

eine schematische Schnittdarstellung des wesentlichen Teils eines ersten Ausführungsbeispiels einer Vorrichtung zum Durchführen von Reaktionen in Proben;

Figuren 3A

und 3B jeweils eine vergrößerte Teilschnittansicht von zwei Varianten der Einzelheit X in Fig. 2;

Figur 4

eine schematische Schnittdarstellung des wesentlichen Teils eines zweiten Ausführungsbeispiels einer Vorrichtung zum Durchführen von Reaktionen in Proben;

Figur 5

eine schematische Schnittdarstellung des wesentlichen Teils eines dritten Ausführungsbeispiels einer Vorrichtung zum Durchführen von Reaktionen in Proben;

Figur 6

eine schematische Schnittdarstellung des wesentlichen Teils eines vierten Ausführungsbeispiels einer Vorrichtung zum Durchführen von Reaktionen in Proben; und

Figur 7

eine schematische Schnittdarstellung des wesentlichen Teils eines fünften Ausführungsbeispiels einer Vorrichtung zum Durchführen von Reaktionen in Proben.

The above and other features and advantages of the present invention will become more apparent from the following description of various preferred embodiments with reference to the accompanying drawings. Show:

FIG. 1

a schematic representation of the basic structure of an apparatus for performing reactions in samples according to the present invention;

FIG. 2

a schematic sectional view of the essential part of a first embodiment of an apparatus for performing reactions in samples;

FIGS. 3A

and FIG. 3B is an enlarged fragmentary sectional view of two variants of the detail X in FIG Fig. 2 ;

FIG. 4

a schematic sectional view of the essential part of a second embodiment of an apparatus for performing reactions in samples;

FIG. 5

a schematic sectional view of the essential part of a third embodiment of an apparatus for performing reactions in samples;

FIG. 6

a schematic sectional view of the essential part of a fourth embodiment of an apparatus for performing reactions in samples; and

FIG. 7

a schematic sectional view of the essential part of a fifth embodiment of an apparatus for performing reactions in samples.

Referring to Fig. 1 First, the basic structure of the device according to the invention for performing reactions in samples will be explained in more detail.

The device has a base unit 10 with a base body 11, which is preferably provided with an operating device 12 for the user, the operating device 12 having display elements 14 and operating elements 16 for controlling and monitoring the desired reactions in samples. The base unit 10 usually also includes a controller (not shown) to independently control and monitor the flow of the reactions, in particular to control and communicate with the later-discussed interaction units of the base 10 and interchangeable reactors 22.

Optionally, the base unit 10 may also have an interface 18 via which the base unit can be connected to external devices (control devices, screens, printers, etc.) if required.

The base unit 10 is further provided with at least one receiving area 20 for at least one exchangeable reaction unit 22. It is possible within the scope of the invention to provide exactly one receiving area for exactly one exchangeable reaction unit, to provide exactly one receiving area for a plurality of exchangeable reaction units, to provide a plurality of receiving areas for exactly one exchangeable reaction unit or to provide a plurality of receiving areas for a plurality of exchangeable reaction units. The at least one receiving area 20 is preferably provided on the upper side of the base unit 10, without being restricted to this position. In one embodiment, the receiving area is formed in or on the temperature control body of the base unit.

In addition, the exchangeable reaction units 22 can also be advantageously designed as consumables. This reduces the cleaning effort and allows a lower risk of contamination of the reaction vessels in the removable Reaction units. In the context of the present invention, however, the exchangeable reaction units can of course also be designed as reusable articles.

A first embodiment of such a device for carrying out chemical and / or biological and / or physical reactions in samples will now be described with reference to FIG Fig. 2 described in detail.

Fig. 2 shows the section of the receiving area 20 of the base unit 10 with an exchangeable reaction unit 22 placed thereon. Embodiments with a plurality of receiving areas 20 and / or a plurality of exchangeable reaction units 22 are, of course, of analog construction.

As in the detail of Fig. 3A 3B, the exchangeable reaction unit 22 is preferably provided with at least one first guide element 24, for example in the form of a recess, and in the receiving area 20 of the base unit 10 a second guide element 26 is formed, for example, in the form of a corresponding guide pin, which in FIG the first guide member 24 can be performed to place the removable reaction unit 22 exactly on the receiving area 20 of the base unit. Accurate placement of the replaceable response unit 22 is important to the operation of the device, particularly with regard to secure coupling between the coupling devices, which will be discussed later.

While the first guide member 24 is formed on the exchangeable reaction unit 22, for example, in / on a side wall of the reaction vessel 32 explained later, the second guide member 26 is provided in the temperature control body 30 in / on the accommodating portion 20 of the base 10, for example.

As in the variant of Fig. 3B illustrated, it is for ease of positioning advantageous to form the guide bush 24 at least partially conical in order to facilitate the centering of the two guide elements 24, 26 to each other. Although not shown separately, it is of course also possible to make the guide pin 26 of the base unit 10 at least partially conical.

Furthermore, the concept of the two interlocking guide elements 24, 26 can of course be reversed. In other words, the first guide element 24 may also be formed on the replaceable reaction unit 22 in the form of a pin and the second guide element 26 on the base device 26 in the form of a recess or guide bushing.

Of course, the device according to the invention may have a plurality, preferably at least two, first and second guide elements 24, 26.

Of course, this guiding or positioning device 24, 26 is also provided in all exemplary embodiments described below.

Of course, the invention is not limited only to the guide elements 24, 26 described and illustrated here. Thus, the guide elements may alternatively also be provided on the side surfaces of the exchangeable reaction unit 22 or of the receiving region 20 of the base unit 10 and be designed, for example, as grooves and webs which can be guided into one another. As a further alternative, it is also conceivable to provide the body of the exchangeable reaction unit 22 with a (preferably conical) guide surface, which fits into a correspondingly formed surface of the receiving region 20.

The replaceable reaction unit 22 has in particular a reaction vessel 32 for receiving a sample 38, which is provided with a filler neck 34 and a ventilation stub 36. In a particularly advantageous embodiment, the reaction vessel 32 may further have an overflow area or be formed with a flexible boundary surface (eg film) to minimize the gas volume of the reaction vessel 32, so that a condensate avoidance is not required. In the case of providing an overflow region, for example, the reaction vessel 32 can be filled with a sample amount that exceeds the volume of the reaction vessel 32, so that the reaction vessel is completely filled without an additional gas volume in the upper region of the reaction vessel and the excess amount of sample can flow into the overflow region ,

In such an embodiment of the reaction vessel, for example, no additional heated lid is required to heat the reaction vessel or the sample for condensate avoidance from above, without the present invention being limited to this variant.

Although in Fig. 2 If only one reaction vessel 32 is illustrated, the exchangeable reaction unit 22 can optionally also have a plurality of such reaction vessels 32. This applies in the same way for all embodiments described below.

On the base unit 10 facing side of the reaction vessel 32, a temperature control device 40 is arranged with a Peltier element as the first embodiment of an interaction unit in the removable reaction unit 22. In order to ensure good thermal contact between this tempering device 40 and the sample 38 in the reaction vessel 32, at least the wall 42 of the reaction vessel 32 contacting the tempering device 40 is as thin as possible and made of a material with good thermal conductivity. Suitable materials for the reaction vessels 32 include, for example, polypropylene and LSR (Liquid Silicon Rubber), without the invention being restricted to the use of these materials. As is known, these materials are also suitable for the reaction vessel 32 if a PCR or real-time PCR is to be carried out in it.

The tempering device 40 is used for tempering the reaction vessel 32 or the sample 38 therein. In other words, by means of this tempering device 40, the temperature of the sample 38 can be increased, decreased or maintained according to the need and the embodiment of the tempering device.

Depending on the mode of operation of the tempering device 40, this generates excess heat or cold, which must be dissipated. While in the case of the aforementioned US 2006/0288708 A1 this waste heat or cold is discharged via a fluid channel integrated into the exchangeable reaction unit, such fluid channels and thus also the leakage problems associated with these are avoided in the case of the present invention. In the present exemplary embodiment, the base unit 10 contains a tempering block 30 (for cooling or heating the tempering device 40 in the exchangeable reaction unit 22) with a sufficiently large thermal mass. Depending on the current operating mode of the tempering device 40, the tempering body 30 serves as a heat sink or heating element for controlling the temperature of the rear side of the Peltier element. Since the excess heat or cold is dissipated into the base unit 10 with the aid of the tempering block 30, there is no danger for the user when handling the exchangeable reaction units 22. An embodiment in which the temperature control body 30 is a heat sink is preferred, and the temperature control unit 40 Change in the sample temperature caused. In a particularly preferred embodiment, the heat sink provides a temperature level that is as constant as possible, with the tempering device 40 continuing to cause the sample temperature to change.

In order to ensure a good thermal contact between the tempering device 40 of the exchangeable reaction unit 22 and the tempering block 30 in the base unit 10, the exchangeable reaction unit 22 is preferably pressed against this tempering block 30. For this purpose, the exchangeable reaction unit 22, for example, a body 44 which rests on the reaction vessel 32 and generates the necessary contact pressure solely by its weight. Alternatively or additionally, a suitable tensioning device (not shown) may also be provided which, for example, can also be brought into engagement with the base unit 10. Other ways of applying the necessary forces for good thermal contact between components 30 and 40 also include vacuum systems, magnetic devices, and the like.

In addition, the positioning of the tempering device 40 is of course not on the embodiment of Fig. 2 limited. Of course, this tempering device 40 can of course also be arranged above the reaction vessel 32 or laterally thereto. In addition, a plurality of such tempering devices 40 can optionally also be arranged in the exchangeable reaction unit 22 around the reaction vessel 32, which enables a more homogeneous and faster temperature control of the sample 38 in the reaction vessel 32. Further, the tempering devices 40 are not limited to any specific embodiments and not limited to the use of Peltier elements. With suitable positioning of a heater 40, this can also be used to avoid condensate in the reaction vessel 32.

For operating the tempering device 40 integrated in the exchangeable reaction unit 22, the exchangeable reaction unit 22 furthermore has a first coupling device 46 with electrical contacts, which are brought into contact with a corresponding second coupling device 50 on the base device 10. The second coupling device 50 of the base unit 10 is preferably provided in the region of the receiving area 20 and has sprung contacts in order to ensure a secure coupling even with different geometric dimensions and positioning, for example due to manufacturing tolerances. For example, a screw with an internal spring pin can be used, which comes to form an electrical contact to a male part to the plant. In addition, the first coupling device can be sprung, for example in the form of spring strips executed. The second coupling device 50 is arranged, for example, in a recess 48 in the receiving region 20 and connected to a corresponding connection 52 in the base device 10 in order to supply energy to the tempering device 40 and optionally also to monitor its operating state.

The first and the second coupling means 46, 50 of this embodiment (and analogously also those of all embodiments described below) form as mentioned preferably a spring-loaded contact system, but alternatively is also a rigid plug-socket system or a connection system via cable and plug or flex foil and plugs conceivable. As a further alternative contactless coupling systems can be used.

The exchangeable reaction unit 22 with the reaction vessel (s) 32 can be produced, for example, by injection molding, with the interaction unit 40 and the first coupling device 46 being previously inserted ("insert" technique). The thin walls 42 can be produced for example by the injection molding of films. Alternatively, the exchangeable reaction unit may also be joined by laser welding technology or the like. Of course, the present invention is not limited to the manufacturing techniques mentioned here for the exchangeable reaction units 22. In addition, the apply here mentioned manufacturing method, of course, in an analogous manner for the embodiments discussed below.

In the reaction vessels 32 of the exchangeable reaction units 22 - with a corresponding embodiment of the same - different reactions in samples 38 can be carried out. As already mentioned, the device according to the invention can advantageously be used, for example, for a PCR or real-time PCR. Furthermore, in the device, the upstream or downstream steps such as purification or analysis can be performed. Further possible applications of the reaction system according to the invention can be mentioned, for example: growth of bacteria, cultivation of yeasts, bead technology (eg protein purification), immunoprecipitation, enzyme reactions, transformations, denaturation of DNA, RNA or proteins, isolation of DNA fragments, plasmid Purification, hybridization, gentle thawing, storage of enzymes, nucleic acids, etc. at defined temperature, in vitro - translations, ligations, cell lysis, and much more

Although not shown in the drawings, the interchangeable reaction unit 22 of this embodiment (as well as all other embodiments) may be provided with identification means for uniquely identifying the replaceable reaction unit 22 and / or its reaction vessels 32 and thus their samples 38. Optionally, the exchangeable reaction unit 22 may have such an identification device or all the reaction vessels 32 may be provided with their own identification device.

For the identification device, a silicon chip is preferably used in the device according to the invention, on which the corresponding identification information is stored, without the invention being restricted to this embodiment. In a special embodiment, the tempering device 40 contains at least one Peltier element based on silicon, in which the identification function is also integrated.

Alternatively, for example, RFID systems or barcodes can also be used as the identification device.

By means of the identification device, the reliability of the assignment of the data in carrying out the reactions in the samples is increased, since it can be ensured that the correct reactions are carried out for all samples. In addition, a simpler and better data analysis can be achieved. These advantages are even more evident when the replaceable reaction units 22 used are to be used on multiple base units 10, for example, to successively perform multiple reactions on the same samples, or if the samples are to be stored in the reaction units 22 for longer times.

The identification numbers can either be assigned by the manufacturer during the manufacture of the exchangeable reaction units or by the user on site.

The device described above is suitable both as a laboratory device, but can also be used as a portable device for field use.

A second embodiment of a device according to the invention will now be referred to Fig. 4 explained in the same components with the same reference numerals as in the above Fig. 2 Marked are.

In the Fig. 4 illustrated device differs from the first embodiment described above in that in addition to the tempering device 40, a temperature sensor 54 is provided as an interaction unit in the removable reaction unit 22. Incidentally, this second embodiment corresponds to the first embodiment of Fig. 2 and a repeated description of the same or corresponding components will be omitted.

The temperature sensor 54 is disposed on a wall of the reaction vessel 32 and thus in direct thermal contact therewith to detect the temperature of the reaction vessel 32 and the sample 38 in the reaction vessel 32, respectively. The measurement data of the temperature sensor 54 are transmitted via a first (contacting or contactless) coupling device 56 of the exchangeable reaction unit 22 to a second coupling device 57 and corresponding further connections 58 of the base device 10. Structure and arrangement of these coupling devices and Connections 56-58 correspond to the embodiment variants described above for the tempering device 40.

The temperature sensor 54 allows direct monitoring of the temperature of the sample 38, so that a much more accurate temperature detection and thus also temperature of the sample 38 is made possible in comparison to conventional systems in which only the temperature of the provided in the base unit 10 tempering. If the exchangeable reaction unit 22 contains a plurality of reaction vessels 32, preferably each reaction vessel 32 is assigned its own temperature sensor 54, so that an individual temperature monitoring of several samples 38 in different reaction vessels is possible.

Instead of the contacting temperature detection by the temperature sensor 54, as in Fig. 4 As an alternative, the temperature sensor can also be designed for a non-contact measurement of the temperature of the reaction vessel 32 or the sample 38 in the reaction vessel 32. With respect to the temperature detection technology, the present invention is not limited to any specific embodiments.

A third embodiment of a device according to the invention will now be referred to Fig. 5 explained in the same components with the same reference numerals as in the above Fig. 2 Marked are.

In the Fig. 5 The apparatus shown differs from the first exemplary embodiment described above in that, in addition to the tempering device 40, a radiation source 60 is provided as an interaction unit in the exchangeable reaction unit 22. Incidentally, this third embodiment corresponds to the first embodiment of Fig. 2 and a repeated description of the same or corresponding components will be omitted.

The radiation source 60 is arranged next to the reaction vessel 32 in order to direct a corresponding radiation onto the sample 38 in the reaction vessel 32. The control of the radiation source 60 via a first coupling device 62 of the removable reaction unit 22, which via a second coupling device 63 with a corresponding terminal 64 of the base unit 10 is connected. The structure and arrangement of these couplings 62 - 64 basically correspond again to those possibilities for the tempering device 40.

If the sample 38 in the reaction vessel 32 is not only to be irradiated, but also a reaction of the sample 38 caused by this irradiation or a property of the sample 38 in connection with the respective radiation (eg, absorptivity, transmittance) are detected, the apparatus further includes This detection device 66 is arranged on the base device 10 or a cover of the base device 10 and serves for detecting electromagnetic radiation emitted by the sample 38 in the reaction vessel 32 itself (eg due to excitation of the sample 38 by the irradiation with the radiation source 60) or through the sample 38. In principle, a combination of the device according to the invention with an external detection device is also possible. In this embodiment, the detection device is not located on the base unit itself, but is located outside of another device. For example, it is possible the base unit of commercially available detection devices, such as fluorometer, photometer u. connect other laboratory equipment.

For example, in one embodiment, the radiation source 60 includes one or more light emitting diodes for fluorescence excitation of the sample 38 in the reaction vessel 32, and the detection device 66 has corresponding photosensitive elements such as semiconductor detectors or photodiodes for receiving the fluorescence signals emitted by the sample 38. In this case, the device of the invention is advantageously suitable for performing a real-time PCR.

The reaction vessel 32 is of course made in this third embodiment of a material which is at least partially permeable to the respective radiation of the radiation source 60 and the sample 38; This is true at least for the wall regions of the reaction vessel 32 facing the radiation source 60 and the radiation detector 66. It may also be advantageous to use the upper and the lateral walls of the reaction vessel 32, which none of the interaction units 40, 60 and 68, to provide reflective properties.

If the exchangeable reaction unit 22 contains a plurality of reaction vessels 32, either a separate radiation source 60 and a separate detector 66 can be assigned to each reaction vessel 32, or all the reaction vessels 32 are assigned a common radiation source 60 and a common detector 66. As a further embodiment, a common radiation source 60 can be assigned to all reaction vessels 32, but a separate detector 66 can be assigned to each reaction vessel 32.

Furthermore, this third embodiment, of course, with the in Fig. 4 illustrated embodiment are combined. That is, the exchangeable reaction unit 22 can contain both temperature sensors 54 and radiation sources 60 as an interaction unit. If the sample also emits radiation without external irradiation by the radiation source 60 (eg solely by thermal action), in this case only the detection device 66 on the base device 10 is sufficient and the radiation source 60 in the exchangeable reaction unit 22 can be dispensed with.

With reference to Fig. 6 Now, a fourth embodiment of a device according to the invention will be described in more detail, wherein like components with the same reference numerals as in the above described Fig. 2 Marked are.

The embodiment of Fig. 6 differs from the above third embodiment in that the detection device is not provided on the base unit 10, but is also integrated as an interaction device 68 in the removable reaction unit 22. The measuring signals and the control signal of this detection device 68 are communicated with the base unit 10 via a first coupling device 70 of the exchangeable reaction unit 22, a second coupling device 71 in the receiving area 20 of the base unit 10 and the connections 72 in the base unit 10. The structure and arrangement of the coupling devices 62 to 64 basically correspond to those for the tempering device 40, wherein for detection devices especially the non-contact coupling systems can be used in an advantageous manner.

Incidentally, this fourth embodiment corresponds to the third embodiment of Fig. 5 although all the modifications and variants mentioned there can likewise be used here.

Fig. 7 shows as a fifth embodiment a modification of the above fourth embodiment of Fig. 6 , wherein the same or corresponding components with the same reference numerals as in Fig. 6 Marked are.

This embodiment differs from that in FIG Fig. 6 shown device in that the tempering device 40 is not integrated in the removable reaction unit 22, but that the tempering is provided as a further interaction unit 74 in the receiving area 20 of the base unit 10. In this case, the tempering device 74 is of course controlled directly via the terminals 52 in the base unit 10 and the first and the second coupling device 46, 50 can be omitted.

For the tempering device 74, the same statements apply analogously, as above in connection with the first embodiment of Fig. 2 are indicated.

This variant, in which the tempering device 74 is provided on the base unit 10, can of course also in the above-described embodiments of 4 and 5 be implemented.

Furthermore, in the context of the present invention, of course, all embodiments shown here can be combined with one another in any desired manner. To achieve the advantages of the present invention, only at least one of the interaction units 40, 54, 60, 68 need be integrated into the replaceable reaction unit 22.

Moreover, numerous other modifications and variations are possible within the scope of the present invention, which is defined by the appended claims.

For example, in combination with the radiation source 60 or the detection device 68, optical filters can also be integrated into the exchangeable reaction unit 22. Furthermore, in the replaceable reaction unit 22 and in its reaction vessel 32, it is also possible to use optically transparent or impermeable materials in a targeted manner in order to influence the radiation paths in a targeted manner and to avoid background, stray light and the like.

Further, in the above embodiments, the temperature sensor 54 is disposed respectively in the exchangeable reaction unit 22 outside of the reaction vessel 32 and on its outer wall, respectively. It is also conceivable that the temperature sensor for direct detection of the temperature of the sample 38 in the reaction vessel 32 projects into the reaction vessel.

Furthermore, the numbers of exchangeable reaction units 22 and the reaction vessels 32 can basically be selected arbitrarily. Usually, reaction vessels will be used in typical array formats, i. for example 8, 12, 24, 96, 384, 1536, 6144 reaction vessels.

Although not explicitly shown in the above embodiments, the interaction units of the exchangeable reaction unit can optionally also be integrated into the control loop of the device. For example, the tempering device can be regulated by means of the temperature sensor, or reactions in the samples can be interrupted or interrupted by means of other detection devices or the measures triggering these reactions (for example energy supply) can be terminated.

• Realisierung von hohen Temperiergeschwindigkeiten (Temperaturwechsel, Temperierraten)
• sehr genaue Messung der Probentemperatur (durch Messung dicht an der Probe
• genaue Regelung auf eine gewünschte Probentemperatur
• sehr gute Homogenität der Temperatur in der Probe
• individuelle Einstellung der Probenvolumina
• Möglichkeit der Verwendung unterschiedlicher Formate (Probenvolumen, Probenzahl, Form, Größe, etc.) der wechselbaren Reaktionseinheit auf einem Basisgerät
• Realisierung von Reaktionen in sehr kleinen Probenvolumina
• sehr geringer Energieverbrauch (durch geringe thermische Masse)
• höhere Messempfindlichkeiten bei der Detektion wie Fluoreszenzmessungen (durch kurze Lichtwege, weniger Übergänge, definierte geometrische Anordnung der Komponenten, kurze Toleranzketten)
• Möglichkeit von Realtime-Messungen (auch bei kleinsten Probenvolumina)
• Durchführung einer PCR mit erhöhter Spezifität, d.h. wenigen Nebenprodukten
• zeitgleiche Messung mehrerer Proben in verschiedenen Reaktionsgefäßen (z.B. mit unterschiedlichen Wellenlängen oder Temperaturen)
• einfaches und robustes System ohne bewegliche Teile
• Wegfall zusätzlicher Maßnahmen (z.B. Heizdeckel) zur Kondensatvermeidung

With the device according to the invention for carrying out reactions in samples, depending on the specific embodiment, the advantages listed below can be achieved individually or in different combinations, in particular:

• Realization of high tempering rates (temperature change, tempering rates)
• very accurate measurement of the sample temperature (by measuring close to the sample
• accurate control to a desired sample temperature
• very good homogeneity of the temperature in the sample
• individual adjustment of the sample volumes
• Possibility of using different formats (sample volume, number of samples, shape, size, etc.) of the exchangeable reaction unit on a base unit
• Realization of reactions in very small sample volumes
• very low energy consumption (due to low thermal mass)
• higher detection sensitivities such as fluorescence measurements (due to short light paths, fewer transitions, defined geometrical arrangement of the components, short tolerance chains)
• Possibility of real-time measurements (even for the smallest sample volumes)
• Performing a PCR with increased specificity, ie few by-products
• Simultaneous measurement of several samples in different reaction vessels (eg with different wavelengths or temperatures)
• simple and robust system without moving parts
• Elimination of additional measures (eg heated lid) for condensate avoidance

Claims (15)

Apparatus for performing reactions in samples, comprising a base unit (10) having at least one receiving area (20) for at least one replaceable reaction unit (22); and at least one exchangeable reaction unit (22) having at least one reaction vessel (32) for a sample (38) and designed to be placed in the receiving area (20) of the base unit (10),
characterized,
in that the exchangeable reaction unit (22) comprises at least one unit (40; 54; 60; 68) for interacting with the sample (38) in the at least one reaction vessel (32) and a first coupling device (46; 56; 62; 70) connected to the interaction unit comprises; and
in that the base unit (10) has a second coupling device (50; 57; 63; 71) for coupling to the first coupling device (46; 56; 62; 70) of the exchangeable reaction unit (22) for coupling to the interaction unit (40; 54; 60 68). Device according to claim 1,
characterized,
the at least one changeable reaction unit (22) is designed as a consumable item. Apparatus according to claim 1 or 2,
characterized,
in that the at least one interaction unit (40; 54; 60; 68) comprises at least one tempering device (40) which is in thermal contact with the at least one reaction vessel (32) is arranged to temper the sample (38) in the at least one reaction vessel (32). Device according to claim 3,
characterized,
in that the at least one tempering device (40) contains a Peltier element. Device according to one of claims 1 to 4,
characterized,
in that the at least one interaction unit (40; 54; 60; 68) comprises at least one means (60) for exciting a reaction of the sample (38) in the at least one reaction vessel (32). Device according to one of claims 1 to 5,
characterized,
in that the at least one interaction unit (40; 54; 60; 68) comprises at least one means (54; 68) for detecting a physical, chemical and / or biological property of the sample (38) in the at least one reaction vessel (32). Device according to one of claims 1 to 6,
characterized,
in that the at least one interaction unit (40; 54; 60; 68) of the exchangeable reaction unit (22) is integrated into a control circuit of the apparatus. Device according to one of claims 1 to 7,
characterized,
in that the replaceable reaction unit (22) or the reaction vessel (32) is designed to carry out a PCR and / or a real-time PCR. Device according to one of claims 1 to 8,
characterized,
in that the at least one reaction vessel (32) is designed to receive a sample (38) with a minimum gas volume. Device according to one of claims 1 to 8,
characterized,
that the device comprises a further heating device to avoid condensation in the at least one reaction vessel (32) at least. Device according to one of claims 1 to 10,
characterized,
in that the base unit (10) has at least one further unit (66; 74) for interaction with the sample (38) in the at least one reaction vessel (32). Device according to one of claims 1 to 11,
characterized,
in that the device furthermore has a guide device (24, 26) for positioning the exchangeable reaction unit (22) in the receiving region (20) of the base device (10). Device according to one of claims 1 to 12,
characterized,
in that the at least one exchangeable reaction unit (22) furthermore has at least one identification device for uniquely identifying the at least one exchangeable reaction unit (22) and / or the at least one reaction vessel (32) in the exchangeable reaction unit. Device according to claim 13,
characterized,
that the identification device is part of the interaction unit. Device according to claim 14,
characterized,
in that the interaction unit (40) is a tempering device with a silicon-based Peltier element into which an identification function is integrated.

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