EP0539369B1 - Platte mit einer mehrzahl von mulden zur aufnahme von chemischen und/oder biochemischen und/oder mikrobiologischen substanzen - Google Patents

Platte mit einer mehrzahl von mulden zur aufnahme von chemischen und/oder biochemischen und/oder mikrobiologischen substanzen Download PDF

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Publication number
EP0539369B1
EP0539369B1 EP91902508A EP91902508A EP0539369B1 EP 0539369 B1 EP0539369 B1 EP 0539369B1 EP 91902508 A EP91902508 A EP 91902508A EP 91902508 A EP91902508 A EP 91902508A EP 0539369 B1 EP0539369 B1 EP 0539369B1
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EP
European Patent Office
Prior art keywords
plate
wall
troughs
heat
thickness
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.)
Expired - Lifetime
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EP91902508A
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German (de)
English (en)
French (fr)
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EP0539369A1 (de
Inventor
Manfred Eigen
Wolfgang Simm
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Max Planck Gesellschaft zur Foerderung der Wissenschaften
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Max Planck Gesellschaft zur Foerderung der Wissenschaften
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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
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50853—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates with covers or lids
    • 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

Definitions

  • the invention relates to a plate made of plastic with a number of wells integrally formed with the plate for receiving chemical and / or biochemical and / or microbiological substances, the wells each having an inner space delimited by their inner surface and a wall, the inner surface of which remote outside comprises at least partially a heat exchange surface which can be brought into thermal contact with a temperature control substance.
  • Such plates are e.g. B. from US-A-3 356 462 or WO 90/05023 known. They are sold by several suppliers and are known as microtest plates or microtiter plates.
  • Some of the known plates have a rigid base which is surrounded on all sides by a raised edge. Troughs are arranged in the floor, which is over one millimeter thick, arranged in rows and columns. The bottom of the known plate is flat on its underside, which is remote from the depressions.
  • the known plates are offered with different trough volumes, which are usually between a few hundred microliters and a few milliliters.
  • the plates made of polystyrene or polyvinyl chloride are used to keep solutions at a constant temperature. This is done either for storage purposes or to run a reaction at a certain temperature. For this purpose, the plates are covered with the lid - after the solutions have been poured into the wells - and either placed in a refrigerator for storage or in an incubator, which is usually set to 37 ° C.
  • the known plates are not suitable for solutions whose reactions have to be controlled by frequent and rapid temperature changes, since cooling in a refrigerator or heating in an incubator takes far too long.
  • EP-A-0 318 255 examines the rapid temperature change of liquids.
  • the cuvette proposed for this purpose contains a closed chamber with a metal base, the cuvette having to meet certain geometrical and thermal conditions so that it can be filled due to the capillary action, it does not deform in the base area when heated, and the absorbed liquid is quickly re-heated can.
  • the bottom of the cuvette is made of aluminum, which is completely unsuitable for most enzymatic reactions because the aluminum ions interfere with the reactions taking place in the liquids.
  • the known plastic reaction vessels are usually several centimeters high and have an outer diameter in the range from 12 to 18 mm. With a large number of samples or solutions to be processed, the space requirement and the time required for handling the many reaction vessels are correspondingly large.
  • the substances accommodated in the known reaction vessels are re-heated by thermostating the reaction vessels on their outside. This happens e.g. by immersing the reaction vessels in water baths of different temperatures.
  • thermostatted metal blocks with bores for the reaction vessels which are then thermostated by contact with the bore walls. The heat transfer can be improved by filling the holes with water or oil.
  • the temperature of the samples is changed by placing the reaction vessels in other water baths or metal blocks that are set to the new desired temperature.
  • the temperature of the substances takes on the new value only slowly, since the plastic reaction vessels have a thick wall, through which only poor heat transport is possible.
  • the thickness of the wall is required for manufacturing reasons and because of the required mechanical strength of the reaction vessels to be handled individually. E.g. the reaction vessels are used in centrifuges that rotate at high speed. The mechanical loads that occur are one reason for the stable thick wall of the plastic reaction vessels.
  • microtiter plates with cup-shaped reaction vessels are known, which were designed as disposable items.
  • the reaction vessels have thin walls.
  • the design of these plates depended on certain mechanical and chemical properties, so that the troughs have widely varying wall thicknesses from 0.05 to 0.5 mm. The heat transfer behavior is not considered in this patent.
  • the invention is therefore based on the object of developing a plate of the type mentioned in such a way that the disadvantages mentioned above are avoided.
  • the troughs of the plate are closed by a lid
  • the plate is made of a thermally deformable plastic film with a thickness of less than 0.5 mm and a thermal conductivity greater than 0.1 watt / (K m) and the wall thickness of the trough is significantly less than the thickness of the plastic film, so that the troughs have a heat transmission value which is greater than 5 x 10 ⁇ 4 W / (K mm3) and for which the formulaic relationship applies, in which A is the size of the heat exchange surface, ⁇ the thermal conductivity of the material forming the wall, V the volume of the interior of the trough, x the wall thickness of the wall measured as the distance between the heat exchange surface and the inner surface, and W the heat transfer value.
  • the object underlying the invention is completely achieved in this way. Because the heat transfer value of the new plate is greater than 5 x 10 ⁇ 4 W / (K mm3), rapid heat transport through the wall into and out of the trough is possible. Depending on the selected material of the plate and the required volume of the trough, the person skilled in the art can now choose the size of the heat exchange surface and the wall thickness of the trough in compliance with the relationship given above. A large number of wells are provided per plate, so that simple handling of, for example, reaction solutions to be processed is possible.
  • the lid which can be closed, protects the troughs from dirt and dust in a manner known per se after the substances have been filled in.
  • Plates of the type mentioned at the outset are also known from EP-A-0 408 285, which has not been previously published. These plates are made by thermal deformation from an approximately 0.6 mm thick polycarbonate film. However, the troughs are not closed by a lid.
  • the wall thickness is approximately the same at least over the entire heat exchange surface.
  • This measure has the advantage that the substances accommodated in the trough are heated or cooled uniformly from all sides, which prevents the formation of disturbing temperature gradients in the substances.
  • the heat transfer value is greater than 1 x 10 ⁇ 3 W / (K mm3).
  • the one-piece design of plate and troughs has the advantage that the new plate is easy to manufacture, since the troughs do not have to be attached to the plate.
  • Another advantage is achieved in this embodiment if the plastic is thermally deformable.
  • thermally deformable plastic film makes it possible to manufacture the plate with a low weight using a fast and inexpensive manufacturing process, for example a deep-drawing process.
  • the heat exchange surface is arranged on the plate below its underside.
  • This measure has the advantage that the heat exchange surface for the respective tempering material is easily accessible from below the plate.
  • the plate can be inserted from above into a water bath or into a metal block that has a counter surface for the heat exchange surface.
  • the trough is designed as a cup-like protuberance, the outside of which is at least in sections the heat exchange surface.
  • the cup-like protuberance has a hollow cylindrical upper section connected to the underside of the plate and a hemispherical hollow lower section connected in one piece to this.
  • the volume of the interior is less than 200 mm3 and is preferably between 10 and 100 mm3.
  • the plate according to the invention is particularly well suited for such tests by this measure.
  • the trays of the new plate are at least filled to the extent that the solutions can regulate the moisture content of the air volume above their liquid surface without any significant changes in volume.
  • the new plate is characterized in that the lower section has a radius between 2 and 6 mm and that the wall thickness of the trough is thinner than 0.2 mm.
  • This measure which is very easy to achieve in terms of production technology, also provides the heat transmission value according to the invention, which is greater than 5 ⁇ 10 x W / (K mm3), in the case of sheets of plastic films which have a rather poor thermal conductivity.
  • the wall thickness is less than 0.08 mm.
  • the plate is made of polycarbonate.
  • the troughs can be formed, for example, by a deep-drawing process which is advantageous in terms of production technology.
  • the wells made of polycarbonate are advantageous reaction vessels for most chemical and / or biochemical and / or microbiological reactions, since polycarbonate is inert in this regard.
  • This embodiment is further developed in an advantageous manner in that the plate is made of a polycarbonate film, the thickness of which is less than 0.5 mm.
  • the plate has a number of troughs which are identical to one another.
  • This measure known per se, has the advantage that a large number of reactions can be carried out in parallel in the same plate, provided that all samples have to be subjected to the same temperature profile.
  • the troughs are arranged in rows and columns which have the same spacing of approximately 10 mm from one another.
  • This measure has the advantage, which is also known per se, that the troughs can be filled and emptied with multiple pipettes, which greatly simplifies the work during test preparation.
  • each region of the cover covering the opening of a trough can be connected to the plate by means of a connecting seam going around the respective opening.
  • each trough is subsequently provided with its own cover, through which the trough is sealed gas-tight.
  • the evaporation problem occurring at high temperatures and the condensation problem occurring at low temperatures are thus completely eliminated.
  • the liquid volume enclosed in the troughs does not change even with extreme and frequent temperature changes between high and low values.
  • This embodiment is developed particularly advantageously in that the lid is also made of a plastic film, in particular of the same material as the plate.
  • the cover film can be bonded to the plate in the area of the connecting seam under pressure and / or heat.
  • This measure ensures that no evaporation and / or condensation problems occur even with small amounts of liquid taken up in the troughs, even if the troughs are frequently re-tempered between high and low temperatures, so that an overpressure is established inside the trough. because the solution taken up has been heated or heated to higher or higher temperatures.
  • a particularly advantageous method for producing the plate from plastic is that a thermally deformable plastic film with a thickness of less than 0.5 mm and a thermal conductivity greater than 0.1 W / (K m) with its underside first from the top of a mold block is placed, which comprises upwardly open cup-like depressions, the interior of which have volumes less than 200 mm3; that a hot gas stream is directed in succession in the region of each cup-like depression for a certain period of time from above the film placed on top of it; and that the hot gas stream has a predetermined temperature that is close to the melting temperature of the film.
  • the simple combination of the thermal conductivity of the film, the thickness of the film and the volume of the cup-like depressions ensures that the relationship given above for the heat transfer value is maintained due to the wall thickness of the troughs formed during deep-drawing.
  • This method is developed particularly advantageously in that the hot gas stream is emitted from an outlet opening, the diameter of which is approximately equal to the diameter of the cup-like depressions and the distance from the top of the film is smaller than this diameter.
  • the mold block can be temperature-controlled and has a temperature below the melting point temperature of the film, preferably approximately 100 ° C.
  • This measure has the effect that the wall thickness of the troughs formed is approximately the same in the area of the heat exchange surface.
  • the plastic film is a polycarbonate film.
  • reaction vessels made of polycarbonate such as the wells formed in the plate, are inert to the chemical and / or biochemical and / or microbiological reactions or substances under consideration.
  • a rectangular flexible plate 2 is shown with one of its longitudinal edges 3 and one of its side edges 4 in section.
  • the plate 2 made of a rigid plastic film has a flat top 5 and a bottom 6 parallel to it.
  • the thickness measured between the top 5 and the bottom 6 is indicated at 7. As can be seen in FIG. 1, the thickness 7 is small compared to the transverse dimensions of the plate 2.
  • Through holes 9 are provided in the plate 2 and troughs 11 which are open at the top are formed.
  • the troughs 11 are arranged in rows 12 and columns 13, the rows 12 running parallel to the longitudinal edge 3 and the columns 13 parallel to the side edge 4.
  • the rows 12 or columns 13 each have a row or column spacing indicated at 14 or 15.
  • the troughs 11 which are circular in cross section have an in 2 shows the inner diameter 16 which can be seen better.
  • the row spacings 14 and the column spacings 15 are of the same size, the inner diameter 16 of the troughs 11, of course, being smaller than the row spacing 14 and the column spacing 15.
  • the troughs 11 lie with their openings 18 surrounded by a rounded opening edge 17 in the plane of the top 5 of the plate 2. They have a wall 20 delimiting their interior 19, which is designed in the manner of a cup-like protuberance 21 and in each of them identical troughs 11 below the bottom 6 of the plate 2.
  • the protuberance 21 has a hollow cylindrical upper section 22 and a hemispherical lower section 23 which is integral therewith and whose curved bottom wall 24 closes off the trough 11 at the bottom.
  • the top 5 merges with the formation of the circumferential rounded edge 17 directly as the inner surface 25 into the interior 19 of the trough 11, the bottom 6 with the formation of a groove 27 encircling the protuberance 21 as the outside 28 of the protuberance 21 essentially parallel to the curved one Inner surface 25 extends.
  • Crosspieces 29, which separate the individual openings 18 from one another, run between the individual troughs 11.
  • the bottom wall 24 has a thickness, indicated at 31, which is measured between the inner surface 25 and the outer side 28.
  • a correspondingly measured thickness is indicated at 32, which approximately corresponds to the thickness 31.
  • the troughs 11 each have a volume 33, which is essentially determined by their depth indicated at 34 and the inner diameter 16.
  • the depth 34 is measured between the bottom wall 24 and an imaginary maximum fill level indicated at 35 by a dashed line.
  • the fill level 35 is approximately at the level at which the curved opening edge 17 merges into the vertical inner surface 25. Because of the surface tension and the associated pre-curvature, the filling volume of the substances to be absorbed will be smaller than the maximum volume 33, especially in the case of small volumes 33.
  • the wells 11 of the plate 2 described so far serve to hold chemical and / or biochemical and / or microbiological substances which are stored in the wells 11 or are subjected to a reaction.
  • the volume 33 and the number of wells 11 per plate 2 depend on the substances to be received by the wells 11.
  • the row spacing 14 and the column spacing 15 are largely defined via the volume 33.
  • the thickness 7 of the plate 2 in the region of the webs 29 is selected so that the plate 2 has sufficient strength despite the closely lying troughs 11 and does not buckle when the troughs 11 are filled.
  • the thicknesses 31 and 32 of the wall 20 of the troughs 11 are chosen from a mechanical point of view such that the filled ones Do not tear or even tear down troughs 11 under the weight of the substances ingested.
  • the material from which the plate 2 is made and the thicknesses 31 and 32 of the wall 20 are also selected from a physical point of view.
  • the thicknesses 31 and 32, which - as can be seen in FIG. 2 - are significantly lower than the thickness 7, enable good heat transport into the interior 19 of the troughs 11 and out of the interior 19. This makes it possible to cool or re-heat the substances in the troughs very quickly by bringing the entire outside 28 as a heat exchange surface 28 'into contact with a temperature control substance of the desired temperature.
  • the size of the heat exchange surface 28 'corresponds to the outside 28 and is: A 75 mm2. According to the formula These numerical values result in a heat transfer value of approx. 4.5 x 10 ⁇ 3 W / (K mm3).
  • the new plate 2 thus makes it possible, for example, to carry out a large number of reactions in separate wells 11 in a small space, the reactions being very thermally controllable through the wall 20 of the wells.
  • the material of the plate 2 is selected so that optical analysis methods, such as e.g. Absorption measurements or fluorescence measurements are possible.
  • the material must be transparent in the light wavelength range of interest, i.e. it must not have any significant absorption or fluorescence emission in this wavelength range.
  • the starting material is a thin film 36, for example made of a polycarbonate, with a thickness of 7.
  • This film 36 is placed on a tempered mold block 37, in which blind holes 38 are provided, which like the troughs 11 are arranged in rows 12 and columns 13 are arranged.
  • the blind holes 38 have a wall surface 40 which surrounds their interior 39 and which is smooth and self-contained.
  • the dimensions of the blind holes 38 are selected so that they correspond to the outer dimensions of the protuberances 21 to be formed. In the selected example, the blind holes have a diameter of approximately 6 mm and a depth of approximately 4 mm.
  • a heater indicated schematically at 43, is provided, by means of which the mold block 37 is heated uniformly to 100 ° C.
  • an air nozzle 45 is arranged above the mold block 37 and can be moved in the direction of the arrow 46.
  • the direction 46 runs parallel to the columns 13 or the rows 12, so that the air nozzle 45 can be positioned centrally over each individual blind hole 38.
  • the direction 46 is also aligned parallel to the top 5 of the film 36 placed on the mold block 37, so that the distance between the air nozzle and the top 5 remains constant.
  • the air nozzle 45 emits a hot air jet 47 at approximately 280 ° C., which emerges from its outlet opening 48 at a speed of approximately 2-5 m / sec approximately perpendicularly to the mold block 37.
  • the outlet opening 48 has a diameter of approximately 5 mm and is located 4 mm above the upper side 5 of the film 36.
  • the air nozzle 45 is successively positioned centrally over the individual blind holes 38, where it remains for approximately 3 to 5 seconds.
  • the hot air jet 47 striking the upper side 5 heats the film 36 to such an extent that it is plastically deformable.
  • the hot air jet 47 then blows the area of the film 36 originally located above the blind hole 38 into the interior 39 of the respective blind hole, the latter gradually extending and the original thickness 7 of the film 36 gradually decreasing in this area until finally the wall 20 of the trough 11 formed has the strengths 31 and 32 indicated in FIG. 2.
  • the right trough 11/1 is already finished, and the air nozzle 45 is located above the blind hole 38/2, in which the trough 11/2 is being formed.
  • the bottom 24 of the trough 11/2 has already partially moved into the interior 39/2 of the blind hole 38/2 and will continue to lie across the entire inner surface of the smooth inner wall of the blind hole 38/2.
  • the web 29 remains in the original thickness 7 of the film 36 between the troughs 11/1 and 11/2.
  • the film 36 consists of a polycarbonate with a thickness of 0.27 mm. Before the troughs 11 are formed, the film 36 is milky. However, it has been shown that the film 36 becomes transparent at a temperature of the hot air jet 47 of 280 ° C. and at a temperature of the mold block 37 of 100 ° C. in the region of the wall 20 of the molded troughs 11, as is the case for the above-mentioned optical analysis methods is required. The temperature of the mold block 37 to 100 ° C. which is not required for the actual shaping of the troughs 11 furthermore causes the outside 28 of the trough 11 to fit snugly against the wall surface 40 of the respective blind hole 38.
  • each trough 11 is also a smooth and uniform surface has, which is of great advantage for the temperature control of substances accommodated in the troughs 11.
  • the protuberances 21 have in fact almost identical contours, so that their heat exchange surface 28 'can be brought into direct contact with counter-surfaces formed corresponding to the blind bores 38 without the air layers interfering with the thermal transition. This is described below with reference to FIG. 10.
  • a cover plate shown in FIG. 4 which consists of a thin cover film 49.
  • through holes 50 are provided, which are arranged in the same pitch as the through holes 9 in the plate 2.
  • the cover film 49 has a flat top 51 and a bottom 52 parallel to it, with which it covers the plate 2 whose top 5 comes to rest.
  • the cover film 49 has a thickness 53 measured between the top 51 and the bottom 52, which is small compared to the transverse dimensions of the cover film 49.
  • the cover film 49 is bespw. made of a 0.1 mm polycarbonate.
  • the cover film 49 When placed on the plate 2, the cover film 49 is aligned so that the through holes 50 are aligned with the through holes 9. In this way, the cover film 49 and the plate 2 can be simultaneously connected to one another in a manner to be described in more detail and fastened on a carrying device.
  • the material preferably used for the cover film 49 is a 0.1 mm thick polycarbonate.
  • This film is transparent in the wavelength range of interest for the optical analysis methods used and has only a low intrinsic fluorescence.
  • the optical analysis methods can thus also be applied from above through the cover film 49; in particular, it is possible to measure the optical density of the substances accommodated in the recesses 11 in the radiation method through the cover film 49 and the bottom wall 24 of the wells.
  • the volume of solutions accommodated in the troughs 11 can change due to condensation and / or evaporation effects. This applies in particular if the solutions have to be re-tempered frequently between high and low temperatures, as occurs in the polymerase chain reaction (PCR), a frequently used method for the high amplification of individual nucleic acid strands.
  • PCR polymerase chain reaction
  • each connecting seam 55 a delimited circular area 57 of the cover film 49, each covering the opening 18 of an associated trough 11.
  • each trough 11 is covered, so to speak, with its own cover in the form of the circular region 57, which is connected by the connecting seam 55 to the webs 29 surrounding the trough 11 in such a way that each trough 11 is gas-tight with respect to the atmosphere and the other troughs 11 is completed.
  • the welding stamp 59 has a fully cylindrical base body 60 which carries at its upper end 61 an annular projection 62 which is integral with the base body 60.
  • the annular extension 62 delimits a circular recess 63, which is concentric with the base body 60 and thus with its longitudinal axis 64, and carries the annular end face 58 pointing away from the base body 60.
  • a profiling in the form of pyramids 65 arranged in rows is provided on the end face 58 surrounding the recess 63 in the form of a ring, which are formed in one piece with the annular extension 62 on their square base 66.
  • the tips 67 of the pyramids 65 point away from the base body 60 in a direction parallel to the longitudinal axis 64 of the welding stamp 59.
  • FIG. 7 shows a top view of the end face 58 in the direction of arrow VII from FIG. 6 in a detail.
  • the pyramids 65 are arranged in rows 68 and 69, which are offset from one another by half the width of the pyramid base 66.
  • the arrangement is such that between two rows 68/1 and 68/2, which are parallel to each other run and are not offset from one another, a row 69/1 runs, which is accordingly offset from rows 68/1 and 68/2 by half the width of the pyramid base 66.
  • the 68/2 series is immediately adjacent to the 69/1 series, followed by a 69/2 series, which runs parallel to the 69/1 series and is laterally aligned with it.
  • the welding stamp 59 is provided with a heater, indicated schematically at 71, by means of which the welding stamp 59, which is preferably made of V2A steel, is heated to approximately 280.degree.
  • the heated welding stamp 59 is placed from above onto the top 51 of the cover film 49 placed on the plate 2 in such a way that with its profiled, ring-shaped end face 58 it centrally centers the opening edge 17 of the trough lying under the cover film 49 and to be welded 11 surrounds.
  • the circular recess 63 has a diameter which is so large that the pyramid tips 67 come to lie outside the opening edge 17 on portions of the cover film 49 located above the webs 29.
  • the square base 66 of the pyramids 65 measures 0.5 ⁇ 0.5 mm and the tip 67 of the four-sided pyramid 65 lies 0.25 mm perpendicularly above the pyramid base 66, ie two pyramid sides lying opposite one another enclose an apex angle of 90 °.
  • up to three pyramids 65 are arranged one behind the other on the annular end face 58, so that the welding punch 59 has an overall outer diameter which is at least 6 base lengths of a pyramid 65 larger than the diameter of the recess 63.
  • the following method has proven itself for welding a cover film 49, the thickness 53 of which corresponds to approximately 0.1 mm, to a plate 2, the thickness 7 of which corresponds to approximately 0.27 mm.
  • the cover film 49 is placed on the plate 2 from above so that it covers the troughs 11 and that the through holes 50 are aligned with the through holes 9.
  • the welding stamp 59 heated to 280 ° C., is placed with its end face 58 at the top from above onto the upper side 51 of the cover film 49 in such a way that it is located centrally over a trough 11 which is located under the cover film 49 and is to be welded.
  • the pyramids 65 on the end face 58 now lie on the top 51 with their tips 67, which may penetrate somewhat into the material of the cover film 49, and heat them. In this way, the cover film 49 is preheated for about 13 seconds by the honeycomb-like profile of the end face 58.
  • each pyramid 67 penetrates into the covering film 49 and this in turn penetrates into the webs 29 of the plate 2.
  • the welding stamp 59 remains in this position for two seconds, then it is completely lifted off the cover film 49.
  • connection seam 55 which is a type of weld seam, is shown in FIG. 8 in a cross section along the line VIII-VIII from FIG. 5.
  • the cooled connecting seam 55 has a corresponding profile as the welding stamp 59.
  • the pyramids 65 have pressed into the preheated top 51 of the cover sheet 49 upside-down pyramid-like depressions 73, which correspond in shape to the pyramids 65.
  • the cover film 49 is also in the area of Indentations 73 penetrated with their underside 52 into the upper side 5 of the webs 29, which was indirectly preheated through the cover film 49, and there formed indentations 74 which correspond to the indentations 73.
  • a contact surface 75 has formed between the underside 52 of the cover film 49 and the top 5 of the plate 2, which has a zigzag cross-section.
  • the contact surface 75 is larger than the contact surface which existed before the welding between the underside 52 of the cover film 49 and the top 5 of the plate 2 in the area provided for the connecting seam 55.
  • the circular section 57 of the cover film 49 covering the opening 18 bulges up like a dome, so that a closed and welded plate 2 as described above has a lenticular curvature 76 of the cover film 49 above each trough 11.
  • the curvature 76 is only formed in the case of troughs 11 welded in a gastight manner, it is at the same time a visual indication that the formed connecting seam 55 has ensured a gas-tight closure of the trough 11 in question, which also withstands excess pressure inside the trough. If the cover film 49 does not have any bulges 76 after the welding, the welding process, for example, was faulty with regard to the dwell times, the temperature of the welding stamp 59 or the depth of penetration of the pyramids 65 into the upper side 51.
  • the temperature of the welding stamp 59, the dimensions of the pyramids 65 and the depth of penetration of the pyramids 65 into the upper side 51 of the cover film 49 are only examples of a cover film made of polycarbonate 0.1 mm thick and a plate 2 made of polycarbonate thick 0.27 mm specified. In the case of thicker polycarbonate films, the depth of penetration of the pyramids, which roughly corresponds to the thickness of the cover film, must be adapted to the new thicknesses.
  • the depth by which the pyramids 65 penetrate into the material of the cover film 59 is essential for the success of the welding process.
  • the welding process described above can be carried out by hand, the yield of correctly placed connecting seams 55 is significantly increased by using a welding device 78 shown in FIG. 9.
  • the welding device 78 has a flat, rectangular base plate 79 and a flat top plate 80 arranged above the base plate 79, which shows approximately the same transverse dimensions as the base plate 79.
  • the top plate 80 is fastened to the base plate 79 with the aid of four guide rods 81.
  • the front right guide rod 81/4 in FIG. 9 has been broken out for reasons of a clear representation.
  • a height-adjustable support plate 82 is provided, in the outer corners of which ball bushings 83 are embedded, through which the guide rods 81 pass.
  • an electrically operated drive motor 84 is fastened away from the support plate 82 with its flange 85 from above on the head plate 80.
  • Motor 84 has a motor shaft indicated at 86, which is connected to a ball screw drive indicated at 87.
  • the ball screw drive 87 is connected to the support plate 82 and serves to convert the rotary movement of the motor shaft 86 into the adjustment movement of the support plate 82 along the guide rods 81.
  • a heating block 89 Remote from the ball screw drive 87, a heating block 89 is provided in the center below the carrier plate 82 and is fastened to the carrier plate 82 from below by means of four spacer bolts 90.
  • the heating block 89 made of copper fulfills the function of the heating for the welding punches 59 indicated at 71 in FIG. 6, three of which are indicated in FIG. 9 are.
  • the welding punches 59/1, 59/2 and 59/3 are remote from the spacer bolts 90 in the heating block 89 from below and point with their end faces 58 pointing downward from the heating block 89.
  • the heating block 89 there is a blind hole 91 which penetrates it almost completely from right to left in FIG. 9 and into which an electrically heatable heating cartridge is inserted, which is not shown for reasons of clarity.
  • the temperature of the heating block 89 is measured in a suitable manner by a temperature sensor, not shown further, and is passed to a control circuit, also not shown, which in turn controls the heating cartridge.
  • a closed control loop is thus formed, by means of which the temperature of the heating block 89 is kept at a constant value, for example 280 ° C.
  • the heating block 89 heats the carrier plate 82 via the spacer bolts 90, which can lead to the ball bushings 83 jamming on the guide rods 81.
  • coolant bores 92 are provided in the carrier plate 82, via which the carrier plate 82 is connected to a thermostatic cooling circuit.
  • the temperature of the support plate 82 can be regulated independently of the temperature of the heating block 89 via an external thermostat, so that an easy adjustment of the support plate 82 along the guide rods 81 is ensured.
  • a receiving block 93 pointing upward is provided on the base plate 79 approximately in the middle under the heating block 89, which is height-adjustable via the support plate 82.
  • the receiving block 93 has a coolant bore 94 passing through it, which in the same way as the coolant bore 92 of the carrier plate 82 is connected to an external thermostat circuit which keeps the receiving block 93 at a constant and adjustable temperature.
  • the receiving block 93 has upwardly open cups 95 which are designed to receive the protrusions 21 projecting downward beyond the plate 2.
  • the cups 95 therefore have the same dimensions as the blind holes 38 shown in FIG. 3 in the mold block 37 and are arranged in rows 12 and columns 13 like the troughs 11.
  • a plate 2 is placed on the receiving block 93, which in turn is covered by a cover film 49.
  • a perforated mask 96 which overlaps the receiving block 93 from all sides from above, is placed over the covering film 49, which presses the covering film 49 onto the plate 2 and this in turn, with its troughs 11, into the receiving block 93.
  • Through holes 97 aligned with the welding punches 59 are provided in the shadow mask 96 and are also arranged in rows 12 and columns 13 in such a way that a hole 97 is aligned centrally over each recess 11.
  • the shadow mask 96, the cover film 49 and the plate 2 are shown broken off offset with respect to the receiving block 93.
  • a hole 97 and a welding stamp 59 are provided for each trough 11 of the plate 2.
  • the base 98/1 has one mounting hole 99 pointing upwards, to which a mounting clip, which can be designed, for example, as a spring clip or a latch, is attached in order to press the shadow mask 96 down onto the receiving block 93.
  • the welding device 78 described so far operates as follows:
  • the carrier plate 82 is in the raised starting position shown in FIG. 9.
  • a plate 2 to be welded is placed on the receiving block 93 from above in such a way that the troughs 11 with their protuberances 21 come to rest in the cups 95.
  • the troughs 11, which point upwards with their opening 18, are already filled with the desired substances and covered by a cover film 49, or are now filled accordingly and then covered with a cover film 49, which is oriented such that their through holes 50 are aligned with the through holes 9 align in plate 2.
  • the shadow mask 96 is put over the plate 2 covered in this way, its through holes 97 coming to lie centrally over the troughs 11. With the aid of the fastening clips provided on the bases 98, the shadow mask 96 is pressed firmly down onto the receiving block 93.
  • the heating block 89 is heated to 280 ° C. via the heating cartridge inserted in the blind hole 91. This temperature also has that which is thermally conductively connected to the heating block 89 Welding stamp 59 on. Via the ball screw drive 87, the rotational movement of the motor shaft 86 of the drive motor 84 is converted into a downward movement of the carrier plate 82 which is guided via the ball bushings 83 and the guide rods 81. When the carrier plate 82 and thus the heating block 89 go down, the welding punches 59/1 and 59/2 slide from above into the associated holes 97/1 and 97/2 of the shadow mask 96.
  • the translation of the ball screw drive 87 and the number of revolutions the motor shaft 86 are dimensioned such that at the end of the downward movement of the carrier plate 82 the welding punches 59 with their end face 58 or the tips 67 of the pyramids 65 come to lie precisely on the upper side 51 of the cover film 49, as has already been described above.
  • the welding device 78 In this position, in which the welding punches 59 preheat the cover film 49 and the plate 2 in the region of the connecting seams 55 to be applied, the welding device 78 remains for approximately 13 seconds. After this preheating time, the carrier plate 82 is gradually moved downward by 0.1 mm further from the motor 84 via the ball screw drive 87 to the receiving block 93, so that the pyramids 65 on the end face 58 of the welding stamp 59 into the cover film 49 and this into the Penetrate webs 29 of the carrier plate 2.
  • the motor 84 is actuated so that its motor shaft 86 rotates in the opposite direction to the previous direction of rotation and thus via the ball screw drive 87 the carrier plate 82 and thus the heating block 89 and the welding stamp 59 again in the starting position shown in FIG. 9 starts up.
  • the shadow mask 96 can be removed and the welded plate 2 as shown in FIG. 5 is removed from the receiving block 93.
  • the receiving block 93 and thus its cups 95 are thermostated via the coolant bore 94 to a temperature as required by the respective substances, for example to 10 ° C.
  • the troughs 11 lie with their heat exchange surface 28 'closely against the inner wall of the respective cup 95, so that because of the low thickness 31 of the wall 20 of the troughs 11, the substances in the troughs 11 are kept at the same temperature as the receiving block 93 itself.
  • the heat possibly supplied to the substances during welding is immediately dissipated through the wall 20 into the receiving block 93 due to the good heat transfer.
  • the substances can, for example, be prepared reaction solutions for biochemical and / or microbiological test methods, which are supplied to the user in portioned and welded form in the new plates 2.
  • the substances to be examined by the user can, for example, be contained in the troughs 11 Test solutions are introduced by piercing the arches 76 covering the openings 18 of the troughs 11 from above with a thin cannula. The substances to be examined are then injected into the test solutions located in the wells 11.
  • a capillary-like channel remains in the arch 76. No moisture exchange with the surrounding atmosphere is possible via this channel, so that the volume of the substances or solutions contained in the gas-tight welded troughs 11 does not change due to condensation or evaporation effects.
  • the troughs 11 of the new plate 2 are filled on site, for example in the chemical laboratory, and sealed gas-tight with a cover film 49 using the new welding device.
  • the fixed grid dimension of the columns 13 and rows 12 makes it possible to fill several troughs 11 simultaneously with a known multiple pipette.
  • FIG. 10 shows a plate 2 with gas-tightly closed troughs 11, in which there are, for example, solutions whose course of the reaction can be influenced via their temperature.
  • the solutions have either been filled into the wells 11 on site or were already in the welded plate 2 and were subsequently inoculated by the user with the substances to be examined - for example DNA molecules to be examined.
  • the plate 2 prepared in this way is inserted from above into a thermoblock 101 which has blind holes 102 which are open at the top, which serve to receive the cup-like protuberances 21.
  • the blind holes 102 have the same shape as the blind holes 38 in the mold block 37 used for producing the plate 2.
  • their inner wall 103 lies directly against the heat transfer surface 28 ′ of the protuberances 21. There are therefore no air layers interfering with the heat transfer between the thermoblock 101 and the interior 19 of the troughs 11 between the outside 28 and the inner wall 103 acting as counter surface 103 '.
  • thermoblock 101 In the thermoblock, upwardly open threaded bores 104 are also provided, which are aligned with the through holes 50 and 9 in the cover film 49 and in the plate 2 when the plate 2 is inserted in the thermoblock 101. Screws 105 are screwed into the threaded bores 104 from above through the through holes 50 and 9, and thus the plate 2 closed with the cover film 49 is firmly connected to the thermoblock 101.
  • the upper side of the thermoblock 101 comes to lie close to the underside 6 of the plate 2, and the protuberances 21 are pressed firmly against the inner wall 103 of the blind holes 102 with their heat exchange surface 28 '.
  • the solutions in the troughs 11 take on the temperature of the thermoblock 101 within a few seconds. If, for example, the solutions are to be stored for a long time at a low temperature, the thermoblock 101, which is made of a good heat-conducting metal, is tempered, for example, to + 4 ° C. by means of a thermostat connected to it.
  • thermoblock 101 When the reaction in the solutions is to be started, the thermoblock 101 is suitably heated to the reaction temperature of the solutions which, due to the good heat transfer, follow the temperature change of the thermoblock 101 almost immediately.
  • the temperature change of the thermoblock 101 itself can be effected in a manner known per se by immersing the thermoblock 101 in water baths of different temperatures, bringing it into heat-conducting contact with preheated further metal blocks or moving it along a metal rail on which a temperature gradient is established.
  • the metal rail with the temperature gradient enables the temperature of the thermoblock 101 and thus the temperature of the solutions in the wells 11 to be changed cyclically.
  • the thermoblock 101 is, for example, first at 37 ° C. for 60 seconds , then held at 72 ° C for 120 seconds, then at 94 ° C for 60 seconds and then again at 37 ° C for 60 seconds etc. Because of the gas-tight closure of the individual troughs even at excess pressure, none then saturated with water vapor escapes even at high temperatures Air from inside the troughs. The vapor content of the air volume above the absorbed liquid changes, but since no air or steam can escape from the well, the initially set total concentrations in the wells do not change in the course of the many temperature cycles. This ensures a good yield in the experiments.
  • the solutions are at least partially reused, for example to analyze them using a separating gel.
  • the curvature 76 is pierced with the syringe indicated at 107 in FIG. 10 and part of the solution is removed.
  • the solution remaining in the trough 11 can be stored, for example, in the manner described above.
  • the hole formed during the removal from the curvature 76 does not result in any significant moisture exchange, it can be described. close it again with an adhesive film.
  • the transverse dimensions of the new plate 2 and the row and column spacings 14 and 15 essentially depend on the filling volume 33 of the troughs 11 desired in each case.
  • the thermoblocks 101, receptacle blocks 93 and mold blocks 37 used in each case are adapted to these distances.
  • the thickness 7 of the film 36 is chosen so that the troughs 11 in the finished plate 2 have a bottom wall 24, the thickness 31 of which is in the range of 0.04 mm, so that the heat transmission value has the required high value.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Hematology (AREA)
  • Analytical Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Devices For Use In Laboratory Experiments (AREA)
  • Vaporization, Distillation, Condensation, Sublimation, And Cold Traps (AREA)
  • Blow-Moulding Or Thermoforming Of Plastics Or The Like (AREA)
EP91902508A 1990-07-18 1991-01-29 Platte mit einer mehrzahl von mulden zur aufnahme von chemischen und/oder biochemischen und/oder mikrobiologischen substanzen Expired - Lifetime EP0539369B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4022792A DE4022792A1 (de) 1990-07-18 1990-07-18 Platte mit zumindest einer mulde zur aufnahme von chemischen und/oder biochemischen und/oder mikrobiologischen substanzen und verfahren zur herstellung der platte
DE4022792 1990-07-18
PCT/DE1991/000082 WO1992001513A1 (de) 1990-07-18 1991-01-29 Platte mit zumindest einer mulde zur aufnahme von chemischen und/oder biochemischen und/oder mikrobiologischen substanzen und verfahren zur herstellung der platte

Publications (2)

Publication Number Publication Date
EP0539369A1 EP0539369A1 (de) 1993-05-05
EP0539369B1 true EP0539369B1 (de) 1995-08-02

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Country Status (5)

Country Link
EP (1) EP0539369B1 (enrdf_load_stackoverflow)
JP (1) JPH06500727A (enrdf_load_stackoverflow)
AT (1) ATE125732T1 (enrdf_load_stackoverflow)
DE (2) DE4022792A1 (enrdf_load_stackoverflow)
WO (1) WO1992001513A1 (enrdf_load_stackoverflow)

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Also Published As

Publication number Publication date
WO1992001513A1 (de) 1992-02-06
JPH06500727A (ja) 1994-01-27
DE59106171D1 (de) 1995-09-07
DE4022792A1 (de) 1992-02-06
EP0539369A1 (de) 1993-05-05
DE4022792C2 (enrdf_load_stackoverflow) 1993-08-05
ATE125732T1 (de) 1995-08-15

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