EP2108451A1 - Dispositif d'exécution de réactions dans des échantillons - Google Patents

Dispositif d'exécution de réactions dans des échantillons Download PDF

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Publication number
EP2108451A1
EP2108451A1 EP08007209A EP08007209A EP2108451A1 EP 2108451 A1 EP2108451 A1 EP 2108451A1 EP 08007209 A EP08007209 A EP 08007209A EP 08007209 A EP08007209 A EP 08007209A EP 2108451 A1 EP2108451 A1 EP 2108451A1
Authority
EP
European Patent Office
Prior art keywords
unit
reaction
sample
reaction vessel
exchangeable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08007209A
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German (de)
English (en)
Inventor
Lutz Timmann
Mathias Baumgartner
Vinh Duong
Andreas Schirr
Stefan Roth
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Eppendorf SE
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Eppendorf SE
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Filing date
Publication date
Application filed by Eppendorf SE filed Critical Eppendorf SE
Priority to EP08007209A priority Critical patent/EP2108451A1/fr
Publication of EP2108451A1 publication Critical patent/EP2108451A1/fr
Withdrawn legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/028—Modular arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/04—Exchange or ejection of cartridges, containers or reservoirs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/141—Preventing contamination, tampering
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/02—Identification, exchange or storage of information
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/02—Identification, exchange or storage of information
    • B01L2300/021—Identification, e.g. bar codes
    • B01L2300/022—Transponder chips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1822—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using Peltier elements

Definitions

  • 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.
  • a thermal cycler for example, temperature cycles can be run, which are required for carrying out a polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • 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 ,
  • 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.
  • 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 ).
  • the base body is configured as a metal block containing bores as a receiving area into which the reaction vessels are then inserted.
  • the entire metal block 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.
  • Miniaturized thermal cyclers are known from the prior art, which seek to circumvent some of these disadvantages of conventional devices.
  • 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.
  • 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;
  • the integration of a temperature sensor and an optical detection system in the chip is possible.
  • 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.
  • a device is to be created that allows a more accurate, energy-efficient and better controlled performance of the reactions in the respective samples.
  • 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.
  • 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.
  • 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.
  • the interaction unit (s) in the exchangeable reaction unit 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.
  • samples can be stored or stored in the exchangeable reaction units.
  • 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.
  • reactions in the samples encompasses all possible influencing of the sample volumes in the reaction vessels.
  • these reactions include tempering (increasing, decreasing or maintaining the temperature) as well as various chemical, biological and physical reactions.
  • 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.
  • 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.
  • 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.
  • the term “unit for interaction” includes elements such as tempering devices, detection devices, radiation devices, sensors and any combination of these elements.
  • 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.
  • sample also includes reference material and controls.
  • 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.
  • reaction unit describes the combination of reaction vessel (with or without lid) and unit of interaction.
  • the interaction unit that can interact with the sample in the reaction vessel.
  • 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.).
  • the at least one exchangeable reaction unit is designed as a consumable article.
  • 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.
  • 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 ⁇ l.
  • other types of tempering devices may be used, such as electrical or inductive heating systems.
  • 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.
  • 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.
  • 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.
  • 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.
  • the at least one interaction unit is integrated into a control loop of the device.
  • the temperature control of the samples in the exchangeable reaction unit can be regulated very precisely by means of the integrated temperature sensor.
  • 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.
  • the exchangeable reaction unit has a plurality of reaction vessels and each of the plurality of reaction vessels is assigned its own interaction unit.
  • the exchangeable reaction unit has a plurality of reaction vessels and all reaction vessels are assigned a common interaction unit.
  • 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.
  • 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.
  • 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.
  • 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.
  • the exchangeable reaction unit is provided with an additional heating device for condensate avoidance in the at least one reaction vessel.
  • 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.
  • 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.
  • the base unit can also have a plurality of receiving areas for at least one exchangeable reaction unit.
  • the base unit is provided with a receiving area for a plurality of exchangeable reaction units.
  • the base unit has at least one further unit for interacting with the sample in the at least one reaction vessel.
  • 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.
  • the device preferably has a guide device.
  • 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.
  • 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.
  • 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.
  • 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.
  • a tempering device with a Peltier element based on silicon at the same time allows such an identification by integrating the identification function into the semiconductor element.
  • 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.
  • 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.
  • external devices control devices, screens, printers, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • first guide element 24 for example in the form of a recess
  • 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.
  • 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.
  • 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.
  • the device according to the invention may have a plurality, preferably at least two, first and second guide elements 24, 26.
  • this guiding or positioning device 24, 26 is also provided in all exemplary embodiments described below.
  • the invention is not limited only to the guide elements 24, 26 described and illustrated here.
  • 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.
  • 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.
  • 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.
  • 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 ,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the tempering body 30 serves as a heat sink or heating element for controlling the temperature of the rear side of the Peltier element.
  • the temperature control body 30 is a heat sink
  • the temperature control unit 40 Change in the sample temperature caused.
  • 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.
  • the exchangeable reaction unit 22 is preferably pressed against this tempering block 30.
  • 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.
  • 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.
  • 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.
  • 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.
  • a screw with an internal spring pin can be used, which comes to form an electrical contact to a male part to the plant.
  • 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 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.
  • 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.
  • the exchangeable reaction unit may also be joined by laser welding technology or the like.
  • the present invention is not limited to the manufacturing techniques mentioned here for the exchangeable reaction units 22.
  • the apply here mentioned manufacturing method of course, in an analogous manner for the embodiments discussed below.
  • 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
  • the interchangeable reaction unit 22 of this embodiment 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.
  • 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.
  • the tempering device 40 contains at least one Peltier element based on silicon, in which the identification function is also integrated.
  • RFID systems or barcodes can also be used as 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.
  • a simpler and better data analysis can be achieved.
  • 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.
  • FIG. 4 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.
  • a temperature sensor 54 is provided as an interaction unit in the removable reaction unit 22.
  • 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.
  • 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.
  • the present invention is not limited to any specific embodiments.
  • FIG. 5 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.
  • a radiation source 60 is provided as an interaction unit in the exchangeable reaction unit 22.
  • 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 structure and arrangement of these couplings 62 - 64 basically correspond again to those possibilities for the tempering device 40.
  • 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.
  • 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.
  • the detection device is not located on the base unit itself, but is located outside of another device.
  • the base unit of commercially available detection devices, such as fluorometer, photometer u. connect other laboratory equipment.
  • the radiation source 60 includes one or more light emitting diodes for fluorescence excitation of the sample 38 in the reaction vessel 32
  • the detection device 66 has corresponding photosensitive elements such as semiconductor detectors or photodiodes for receiving the fluorescence signals emitted by the sample 38.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • optical filters can also be integrated into the exchangeable reaction unit 22.
  • optical filters can also be integrated into the exchangeable reaction unit 22.
  • 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.
  • reaction vessels 32 can basically be selected arbitrarily.
  • reaction vessels will be used in typical array formats, i. for example 8, 12, 24, 96, 384, 1536, 6144 reaction vessels.
  • the interaction units of the exchangeable reaction unit can optionally also be integrated into the control loop of the device.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
EP08007209A 2008-04-11 2008-04-11 Dispositif d'exécution de réactions dans des échantillons Withdrawn EP2108451A1 (fr)

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Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
EP0258017A2 (fr) 1986-08-22 1988-03-02 F. Hoffmann-La Roche Ag Enzyme thermostable purifiée et procédé d'amplification, de détection et/ou de clonage de séquences d'acide nucléique à l'aide de cette enzyme
US4889818A (en) 1986-08-22 1989-12-26 Cetus Corporation Purified thermostable enzyme
WO1993022053A1 (fr) * 1992-05-01 1993-11-11 Trustees Of The University Of Pennsylvania Structures de detection micro-usinees
US5475610A (en) 1990-11-29 1995-12-12 The Perkin-Elmer Corporation Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control
WO1998009728A1 (fr) * 1996-09-06 1998-03-12 Central Research Laboratories Limited Appareil et procede de cyclage thermique d'un echantillon
WO1998050147A1 (fr) 1997-05-09 1998-11-12 The Regents Of The University Of California Chambres de reaction microfabriquees a effet peltier pour cyclage thermique
US5928907A (en) 1994-04-29 1999-07-27 The Perkin-Elmer Corporation., Applied Biosystems Division System for real time detection of nucleic acid amplification products
WO1999048608A2 (fr) * 1998-03-23 1999-09-30 Cepheid Systeme de reacteur multi-site a commande dynamique independante de sites de reaction individuels
WO2003019158A2 (fr) * 2001-08-21 2003-03-06 Bestmann, Lukas Systeme d'analyse thermo-optique pour reactions biochimiques
US6602473B1 (en) * 1995-06-20 2003-08-05 The Regents Of The University Of California Temperature control apparatus
US6703236B2 (en) 1990-11-29 2004-03-09 Applera Corporation Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control
US20060288708A1 (en) 2004-12-08 2006-12-28 George Maltezos Thermal management techniques, apparatus and methods for use in microfluidic devices

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4683202B1 (fr) 1985-03-28 1990-11-27 Cetus Corp
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
US4683195B1 (fr) 1986-01-30 1990-11-27 Cetus Corp
EP0258017A2 (fr) 1986-08-22 1988-03-02 F. Hoffmann-La Roche Ag Enzyme thermostable purifiée et procédé d'amplification, de détection et/ou de clonage de séquences d'acide nucléique à l'aide de cette enzyme
US4889818A (en) 1986-08-22 1989-12-26 Cetus Corporation Purified thermostable enzyme
US5475610A (en) 1990-11-29 1995-12-12 The Perkin-Elmer Corporation Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control
US6703236B2 (en) 1990-11-29 2004-03-09 Applera Corporation Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control
WO1993022053A1 (fr) * 1992-05-01 1993-11-11 Trustees Of The University Of Pennsylvania Structures de detection micro-usinees
US5928907A (en) 1994-04-29 1999-07-27 The Perkin-Elmer Corporation., Applied Biosystems Division System for real time detection of nucleic acid amplification products
US6602473B1 (en) * 1995-06-20 2003-08-05 The Regents Of The University Of California Temperature control apparatus
WO1998009728A1 (fr) * 1996-09-06 1998-03-12 Central Research Laboratories Limited Appareil et procede de cyclage thermique d'un echantillon
WO1998050147A1 (fr) 1997-05-09 1998-11-12 The Regents Of The University Of California Chambres de reaction microfabriquees a effet peltier pour cyclage thermique
WO1999048608A2 (fr) * 1998-03-23 1999-09-30 Cepheid Systeme de reacteur multi-site a commande dynamique independante de sites de reaction individuels
WO2003019158A2 (fr) * 2001-08-21 2003-03-06 Bestmann, Lukas Systeme d'analyse thermo-optique pour reactions biochimiques
US20060288708A1 (en) 2004-12-08 2006-12-28 George Maltezos Thermal management techniques, apparatus and methods for use in microfluidic devices

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