Classifications

• • 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
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00281—Individual reactor vessels
  • B01J2219/00283—Reactor vessels with top opening
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00308—Reactor vessels in a multiple arrangement interchangeably mounted in racks or blocks
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
  • B01J2219/00315—Microtiter plates
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00495—Means for heating or cooling the reaction vessels
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00585—Parallel processes
  • B01J2219/00587—High throughput processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00718—Type of compounds synthesised
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
  • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Definitions

• the subject of the present patent application is a device for the selective tempering of individual containers, in particular for use in molecular biology and in screening, especially in high-throughput screening (HTS).
• HTS high-throughput screening
• the containers in which the substances from the substance library are stored are generally composite containers, for example in the 96, 384 or 1 536 microtitration plate format.
• a composite container in 96-well microtitration plate format is described, for example, in US 4, 1 54.795.
• cluster racks which are composite devices for holding a large number of tubes.
• other formats are also conceivable, such as, for example, reaction vessels with a conical one Form as they are used for example for the amplification of nucleic acids.
• these containers are sealed by sealing.
• Recent developments here show possibilities to close such containers with individual lids.
• DE 44 1 2 286 describes machine-accessible lids that can also be used in the HTS environment.
• aughter plates are pipetted from a so-called “mother plate”. The “daughter plates” are then fed to the corresponding biological assay in the HTS.
• the older, but later published WO 99/1 6549 discloses a receiving plate for a group of 96 individual containers.
• Each of the individual receptacles of the receiving plate is equipped with its own heating device, which allows the individual container accommodated in this receptacle to be tempered, in particular thawed.
• the known temperature control device therefore has an extremely complex structure and is therefore correspondingly expensive to manufacture and sell. It is easy to see that the effort made here for 96 individual containers when using microtitration plates in the 384 or 1 536 format assumes economically unacceptable dimensions.
• DE 1 900 279 discloses a temperature control device with a plurality of temperature control elements which can be brought into heat exchange contact together with a corresponding plurality of containers of a group of containers.
• the temperature control elements can be displaced in the vertical direction, while the container assembly can be displaced relative to the temperature control elements in the horizontal plane. It is disadvantageous, however, that the heat emanating from the temperature-regulating elements can spread unhindered in the group of containers, and there is therefore the risk that, when a row of containers is selectively thawed, at least the immediately adjacent rows of containers are also undesirably thawed.
• this object is achieved by a device having the features of claim 1.
• the containers of the group of containers not to be tempered can be kept at a temperature by means of the receiving plate, which ensures that they remain frozen.
• the containers to be tempered by the heat exchange contact with the temperature control element are arranged in the area of an opening in the mounting plate and are therefore not cooled by the latter.
• the relative movements of the container assembly and temperature control element (s) can be brought about in a simple manner by a robot.
• Such robots are in any case present and fall in the form of pipetting or handling robots in modern systems, for example for carrying out molecular biological tests on samples accommodated in the containers of a group of containers therefore not important in determining the cost of the device according to the invention.
• a particular aspect of the present invention lies in the provision of at least one additional cooling zone which dissipates the heat given off by the temperature control element and not used for temperature control of the container.
• This additional cooling zone further increases the security against an undesired heat influence of containers of the group of containers that are not to be tempered. Independent protection is therefore also sought for this aspect.
• the hybridization of single-stranded nucleic acids may be mentioned as a further application of a device according to the invention for the selective tempering of individual containers of a group of containers.
• a device according to the invention for the selective tempering of individual containers of a group of containers.
• used a process that requires the temperature of the reaction vessel to a specific hybridization temperature - specific for each sequence. If several containers with different nucleic acid sequences are now to be hybridized in one work step, a device according to the invention is of considerable advantage, since several vessels can then be kept in parallel at different hybridization temperatures.
• Figure 1 is a rough schematic perspective view of a temperature control device according to the invention.
• FIG. 2 shows a top view of the device according to FIG. 1;
• FIG. 3 shows a detailed view of a tempering mandrel
• 4 shows a roughly schematic side view of the temperature control device according to FIGS. 1 and 2;
• FIG. 5a 5b representations of a composite plate of a plurality of individual containers
• FIG. 5b shows a dimensioned side sectional view
• Fig. 6-8 roughly schematic representations of further embodiments of temperature control devices according to the invention.
• the arrangement according to the invention is based on two elements, namely on the one hand the special containers for storing and possibly treating the substances in the substance library and on the other hand the device for selective tempering.
• the composite container 30 comprises a plate 11, on the underside of which a plurality of individual containers 3 are molded, for example by injection molding. It is characteristic that the individual reaction containers 3 are arranged freely below the composite plate 11 and without connecting webs. At the top of the composite panel 1 1, the openings 1 3 of the containers 3 are provided (see Fig. 5b). These can be closed with individual lids, such as those e.g. are known from DE 44 1 2 286. However, other closure options are known to the person skilled in the art.
• the individual containers 3 do not necessarily have to be combined to form a permanent network 30.
• the distance A between the individual reaction containers 3 can be between approximately 1 mm and approximately 10 mm, preferably between approximately 2 mm and approximately 5 mm. 5b, the distance A has a value of 3.25 mm.
• the distance B from the edge of the openings 13 to the bottom of the container 3 can be between approximately 1 mm and approximately 100 mm, preferably between approximately 5 mm and approximately 35 mm. 5b, the distance B has a value of 22.6 mm.
• the length of the zone 14 freely hanging underneath the plate 11 (see FIG. 1) in the exemplary embodiment according to FIG. 5 is 1 8 mm.
• the shape of the containers 3 tapers at least over part of the distance from the opening 13 to the floor, preferably conically, so that there is sufficient space for the positioning of a tempering or Thawing mandrel 2 (see for example Fig. 2) is available.
• a tempering or Thawing mandrel 2 see for example Fig. 2
• the thickness of the composite panel 11 should therefore be between approximately 0.5 mm and approximately 5 mm, preferably between approximately 2 mm and approximately 4 mm. 5b, the plate 11 has a thickness of approximately 4 mm.
• the composite containers 3 can, for example, be made of thermally deformable plastic, such as polyethylene, polypropylene, polystyrene, polycarbonate, polyurethane or the like. They can be manufactured simply and inexpensively using injection molding processes.
• the tempering device 40 shown in more detail in FIGS. 1 to 4 is used according to the invention.
• the device 40 comprises a mounting plate 1, which is preferably made of a heat-conducting material, for example metal, preferably aluminum, brass or copper.
• the plate 1 can be cooled with the aid of cooling devices familiar to those skilled in the art, for example Peltier elements, compressor cooling units in conjunction with suitable heat transfer elements or the like. The purpose of this cooling is to keep the substances accommodated in the composite container 30 frozen after removal from the freezer.
• each longitudinal groove is provided with at least one opening 5.
• a temperature control element for example designed as a temperature control or thawing mandrel 2, can be inserted into each of the openings 5. The task of this tempering or thawing mandrel 2 is to temper or thaw the container 3 arranged in the area of the respective opening 5.
• the temperature control element 2 can be brought into physical heat exchange contact with the surface of the respective container 3 by a vertical movement in the direction of the arrow z, ie in the Z direction.
• several temperature control elements 2 are inserted into several openings 5.
• the openings 5 are surrounded by cooling zones 1 6, of which only one is shown in FIG. 2.
• These cooling zones serve to dissipate the heat emitted by the tempering or thawing mandrel 2, which is not used for tempering or thawing the container 3, as effectively as possible, so as to be able to prevent an undesirable influence of this heat on neighboring containers 3.
• the cooling zones 16 can, for example, comprise ring elements made of a thermally highly conductive material, which are thermally coupled to an external cooling device.
• the ring elements can, for example, be full rings made of copper or the like, or else ring tubes through which a cooling fluid flows. If several such additional cooling zones are provided, at least some of these cooling zones can be thermally coupled to a common cooling device.
• the temperature difference between the cooling zones 16 and the coolable receptacle 1 is advantageously between approximately 5 ° C. and approximately 50 ° C., preferably between approximately 20 ° C. and approximately 30 ° C.
• each of the longitudinal grooves 4 has a single opening 5.
• a linear movement unit 7 is provided with a movable rake 6, by means of which the composite container 30 accommodated in the plate 1 can be moved in the Y direction .
• This ensures that each Container 3 of the composite container 30 can be pushed over a tempering or thawing position 5.
• the tempering or thawing mandrel 2 is designed to be displaceable in the X direction.
• the receiving plate 1 it is also possible for the receiving plate 1 to have a number of receptacles corresponding to the number of containers 3 of the container assembly 30, each of which is provided with an opening 5, and for the temperature control or thawing element 2 to be movable in all three spatial directions is, ie both in the X, Y and Z directions.
• the interior of the temperature control or thawing mandrel 2 is preferably made of ceramic material 8 with an electrically heatable coil 9.
• microwave or infrared heaters could also be used.
• heating coils embedded in a suitable material, such as ceramic have the advantage that their use, particularly in reaction mixtures with biologically active substances, does not damage these substances by radiation effects or the like.
• FIG. 4 shows another inventive detail in a special embodiment: If the tempering or thawing mandrel 2 moves upwards, it must be against the one to be thawed in order to achieve good heat transfer Container are pressed. However, there is a risk that the container assembly 30 will thereby be lifted out of the coolable receptacle 1. To prevent this, when the temperature control element 2 is raised, a counter-holding device, for example a counter-holding plate 15, is automatically shut down, which presses the container assembly 30 into the receiving grooves 4 of the coolable plate 1. When using a device for automatically removing or fitting a lid assigned to the individual container to be tempered, the counter-holding device can also be formed by a gripper arm of this lid handling device. This further simplifies the construction of the device according to the invention, since no separate counter-holding device needs to be provided.
• a counter-holding device for example a counter-holding plate 15
• the counter-holding device can also be formed by a gripper arm of this lid handling device. This further simplifies the construction
• this assembly 30 and a tempering element 2 had to be positioned in a plurality of linear relative movements relative to one another in order to temper individual containers 3 of a group of containers 30, there are also differently designed devices for selectively tempering individual containers 3.
• three such devices are shown roughly schematically by way of example only. The basic principle of these devices corresponds to the temperature control device known from the older, but later published WO 99/1 6549, can according to the invention however, all be equipped with additional cooling zones 1 6, as explained above.
• Peltier elements 18 are attached to each receptacle in such a way that a good thermal contact surface is created in the receptacle 4. It is known to the person skilled in the art that Peltier elements consist of a cooling side 19 and a heating side 20 and these can be exchanged accordingly by electrical polarity reversal.
• a temperature-adjustable plate 17 as in FIG. 6 (here, for example, on the floor) can be advantageous.
• the plate 1 7 should be cooled to dissipate the heat of heating.
• FIG. 7 Another embodiment according to the invention is shown in FIG. 7.
• individual receptacles 1 with depressions 4 for receiving containers 3 on the bottom are coupled to a Peltier element 1 8.
• the individual recordings are separated from one another by a heat insulation layer 28.
• a corresponding air duct 21 is attached to the floor for dissipating the heat and ensures the cooling of the Peltier elements 1 8 by means of a fan 1 2.
• the polarity reversal of the Peltier elements 18 can be used to achieve a selective temperature control or heating.
• cooling or heating liquid is supplied to the surroundings of the receptacles 4 for the containers 3.
• the corresponding coolable Receptacles 1 are individually separated from one another by an insulating layer 28 and each have bores 22 which can be charged with cooling or heating liquid.
• These can be corresponding cooling coils or, if the coolable receiving plate is made of metallic materials, corresponding bores with connections.
• the individual connections can all be controlled with a corresponding valve system so that individual receptacles can be selectively cooled or heated.
• FIGS. 6 to 8 are particularly suitable for nucleic acid hybridization in several containers with different sequences and thus hybridization temperatures. It should once again be expressly emphasized that these three embodiments are possibilities for an inventive implementation.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biochemistry (AREA)
• 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)
• Devices That Are Associated With Refrigeration Equipment (AREA)
• Devices For Use In Laboratory Experiments (AREA)

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Cited By (8)

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Citations (4)

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• 1999
  • 1999-02-05 DE DE1999104716 patent/DE19904716A1/de not_active Withdrawn
• 2000
  • 2000-02-04 WO PCT/EP2000/000899 patent/WO2000045953A1/de not_active Application Discontinuation
  • 2000-02-04 JP JP2000597062A patent/JP2002536155A/ja active Pending
  • 2000-02-04 EP EP00909146A patent/EP1148948A1/de not_active Withdrawn

Patent Citations (4)

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