WO2003055589A2 - Plaque de microtitration pour l'execution en parallele de plusieurs microsyntheses, en particulier a temperatures elevees - Google Patents

Plaque de microtitration pour l'execution en parallele de plusieurs microsyntheses, en particulier a temperatures elevees Download PDF

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Publication number
WO2003055589A2
WO2003055589A2 PCT/EP2002/014763 EP0214763W WO03055589A2 WO 2003055589 A2 WO2003055589 A2 WO 2003055589A2 EP 0214763 W EP0214763 W EP 0214763W WO 03055589 A2 WO03055589 A2 WO 03055589A2
Authority
WO
WIPO (PCT)
Prior art keywords
mikrotiteφlatte
film
chamber
chambers
plate
Prior art date
Application number
PCT/EP2002/014763
Other languages
German (de)
English (en)
Other versions
WO2003055589A3 (fr
Inventor
Jens Albert
Günter Mayer
Andreas Schober
Alexander Gross
Original Assignee
Institut für Physikalische Hochtechnologie e.V.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Institut für Physikalische Hochtechnologie e.V. filed Critical Institut für Physikalische Hochtechnologie e.V.
Publication of WO2003055589A2 publication Critical patent/WO2003055589A2/fr
Publication of WO2003055589A3 publication Critical patent/WO2003055589A3/fr

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Classifications

    • 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
    • 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
    • B01L3/50857—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 using arrays or bundles of open capillaries for holding 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
    • B01J2219/00286—Reactor vessels with top and bottom openings
    • 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
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00331—Details of the reactor vessels
    • B01J2219/00333—Closures attached to the reactor 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
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00423—Means for dispensing and evacuation of reagents using filtration, e.g. through porous frits
    • 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
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/005—Beads
    • 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
    • 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
    • B01J2219/00596—Solid-phase processes
    • 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
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • 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
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple 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
    • B01L3/50851—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
    • 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

  • Microtiter plate for parallel microsynthesis especially at elevated temperatures
  • the invention relates to a microtiter plate for parallel microsynthesis, especially at elevated temperatures, according to the preamble of the claims.
  • This microtiter plate can be used down to the nano range.
  • reaction containers in the simplest case designed as test tubes, have a typical capacity in the range from milliliters to in rare cases a few microliters. This Mii-iat urization not only allows an increasing parallelization of individual process steps, it also reduces running costs for the procurement or disposal of the chemical substances, biological materials and solvents used.
  • a growing sample throughput requires an increasing automation of as many process steps as possible. Constantly recurring steps, such as filling or emptying individual reaction vessels, are usually already carried out automatically. If many individual reaction containers are combined to form a reaction unit, not only must easy access to each individual reaction container be ensured, but also the shape of the entire reaction unit must enable automated handling during the synthesis. The lower the amount of chemical substances and solvents used, the more disruptive is the influence of evaporation effects that may occur. It is therefore imperative that the individual reaction containers are sealed tightly during a reaction, on the one hand in order to minimize evaporation effects and on the other hand to prevent the uncontrolled escape of reaction solutions during a reaction. As the reaction volume of an individual reaction container decreases, the design effort required for a tight seal increases.
  • micro or nano-matrix matrix can be produced from a silicon wafer, for example, by controlled etching processes.
  • the capacity of the individual cavities called microchambers can be significantly less than one microliter.
  • a tight closing of the microchambers is not possible with known methods. Due to the small dimensions of the individual Mil ⁇ Ohuntn extremely high capillary forces occur. The evaporation, the uncontrolled leakage or the crosstalk of the smallest amounts of reaction solutions during a reaction, especially at elevated temperatures, inevitably leads to incorrect results of a quantitative evaluation of the reaction carried out later.
  • the known locking mechanisms are not sufficient for a -VI-ü tohunt matrix with such small dimensions.
  • the invention is therefore based on the object of designing a microtite latte which can be used in the nanotiter range for parallel, simultaneous performance of many microsyntheses in such a way that the individual microchambers of the micro- or Nanoka ⁇ -mei matrix can be sealed tightly.
  • the closing before or the opening of the microchambers after a reaction should be able to be automated in order to allow an economical and efficient D ⁇ -rc --- j-üh - of the entire process.
  • the present invention describes a specially designed microtiter plate made from m-crosedictured chips or wafers in a sandwich process (bonding, gluing), designed as a nanotiter plate or as a chip or wafer format, with a specially designed chamber stitches, on the one hand by a geometrically designed, excellent edge limits the possible wetting, on the other hand significantly reduces evaporation and thus enables use under extreme conditions in a specially designed compact unit for microsynthesis in an automatic cover machine.
  • the MJ rohunt array according to the invention is constructed in several layers, preferably three layers.
  • the partitions are thinner than in the layers in between.
  • the partition walls can be delimited by parallel surfaces or inclined surfaces.
  • the uppermost layer has an overhang to the chambers towards the uppermost layer, the chamber walls of the layer underneath tapering, and the top and bottom layers are also tapered towards a film cover.
  • special foils are particularly suitable for sealing.
  • the use of structured Si chips as reaction chambers for parallel solid-phase chemistry at higher temperatures requires a structure that ensures a high degree of tightness. About transportation phenomena and to avoid cross-contamination, each chamber should be closed individually. This is achieved by pressing on a suitable film combination.
  • FIG. 1 shows a first embodiment according to the invention with non-parallel wall surfaces in part and in a longitudinal section
  • FIG. 2 shows a dimension for the first embodiment
  • FIG. 3 shows a second embodiment according to the invention with trapezoidal shape Wall cross-sections in extracts and in a longitudinal section
  • FIG. 4 shows a third exemplary embodiment according to the invention with parallel wall surfaces in part and in a longitudinal section; and FIG. 5 shows a part of a microplate or nanotiter plate according to the invention provided with covers in a longitudinal section.
  • each partition 10, 11, 12 consists of an upper smaller trapezoidal part 101, 111, 121, a middle larger trapezoidal part 102, 112, 122 and a lower trapezoidal part 103, 113, 123, which essentially corresponds to the corresponding upper part matches, but vice versa, with its longer parallel side attached to the base of the middle part.
  • chambers 17 are formed between the partition walls 10, 11, 12, the middle parts of which between the larger trapezoidal wall parts 102, 112 and 112, 122 are intended to hold the synthesis liquids and the upper and lower parts 171 and 172 between the trapezoidal wall parts 101 and 111 as well as 111 and 121 or 103 and 113 as well as 113 and 123 are in common and are identical to each other.
  • the intermediate walls 10, 11, 12 have contact surfaces 104, 114, 124 directed at right above at right angles to the plane of the drawing and contact surfaces 105, 115, 125 likewise directed at the bottom for not covers shown.
  • FIG. 2 shows the dimensions of the partition walls using the example of 10 and 11 in the three layers 14, 15, 16 and the chambers 17 with their partial chambers 171 and 172. It is clear from this that the contact areas 114 and 115 (as well as the contact areas not shown) are small (50 ⁇ m) in relation to the openings (1075 ⁇ m) of the partial chambers 171, 172 to the outside. Under the other conditions of the embodiment, the height of the chamber part 17 (490 ⁇ m) is almost as large as the height of the mutually identical chamber parts 171 and 172 taken together (500 ⁇ m).
  • the dimensions given in FIG. 2 also apply analogously to the following exemplary embodiments.
  • intermediate walls 10, 11, 12 are again shown, which belong to three layers 14, 15, 16 joined together and in layers 14 and 16 an upper one and have a lower smaller trapezoidal cross section 101, 111, 121 and 103, 113, 123 with corresponding contact surfaces 104, 114, 124 and 105, 115, 125.
  • the cross section of the intermediate wall has the shape of a double trapezoid 107, 117, 127, the trapezoids being connected to one unit with their shorter parallel sides.
  • the microtiter plate 13 shown in FIG. 3 From four layers, the double trapezoids 107, 117, 127 being broken down into single trapezoids, each of which then belongs to one layer. This does not change the chamber size and its filling.
  • the double trapezoids 107, 117, 127 can also consist of single trapezoids joined together with their larger parallel sides.
  • microplates or nanotiter plates 13 shown in FIGS. 1, 2 and 3 can be produced, for example, with the aid of etching technology, the use of which automatically results in trapezoidal angles.
  • the parallel-walled partition walls 22, 23, 24 each have protruding edges 223, 233, 243 on both sides, which prevent a liquid 31 from flowing up.
  • a firmly inserted sieve plate 32 divides an actual chamber 33 into a larger upper part 331, which contains the synthesis liquid 31 and synthesis beads 34, and a smaller lower part 332.
  • the parts 25, 26, 27 and 28, 29, 30, respectively, have openings 333 or 334 to the chambers 33 and, because of their parallel surface, prevent the pressed-on covers, not shown, from reaching behind the associated contact surfaces 251, 261, 271 or 281, 291, 301.
  • the statements relating to the previous figures also apply to FIG. 4, at least analogously , 5, a micro- and nano-structured titer plate 35 (chip size 16 * 16 mm) is provided with covers 38 which have been pressed firmly against the contact surfaces 351 and 352 of the titer plate 35 and any transition of a substance 36 from a chamber 37 into the prevent neighboring ones.
  • the covers 38 are of identical design and consist of the titer plate 35 from an approximately 0.5 mm thick sealing film 39 (55-72 sh hardness) made of chemically inert material (Teflon, Viton, etc.), which is on the side of the titer plate 35 is provided with an adhesive, preferably with a self-adhesive layer. This is followed by an approximately 0.1 mm thick vapor barrier 40 made of aluminum or another suitable metal which is glued into the covers 38 on both sides.
  • the outer layer 41 is an approximately 1 mm thick elastic film which is self-adhesive on one side and, for example. made of polyurethane or silicone (hardness approx. 90 sh).
  • the elastic layer has a pressure-equalizing effect; the covers 38 protrude convexly into the opening areas 371, 372 between the contact surfaces 351, 352.
  • the invention ensures optimal tightness and practically no weight loss.
  • the proposed microtiter plate is preferably suitable for use in combinatorial chemistry, biotechnology and screening.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

L'invention concerne une plaque de microtitration permettant l'exécution simultanée de plusieurs microsynthèses à des températures élevées, cette plaque pouvant être utilisée à l'échelle nanométrique. Ladite plaque doit être conçue de telle sorte que les différentes microchambres de la matrice à microchambres ou nanochambres puissent être hermétiquement fermées et que la fermeture et l'ouverture de ces microchambres, respectivement avant et après une réaction, puissent être automatisées. Selon l'invention, les substances de remplissage se trouvent dans des chambres ouvertes sur le dessus et le dessous, ces chambres étant séparées les unes des autres par des cloisons et pouvant être fermées par des couvercles. La plaque présente, au moins dans la zone des chambres, une structure multicouche étanche et l'épaisseur des cloisons au niveau des ouvertures des chambres est réduite par rapport à leur épaisseur à l'intérieur de celles-ci. Entre les zones de cloison d'épaisseur différente sont formées des arêtes saillantes.
PCT/EP2002/014763 2001-12-31 2002-12-27 Plaque de microtitration pour l'execution en parallele de plusieurs microsyntheses, en particulier a temperatures elevees WO2003055589A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10164575.9 2001-12-31
DE10164575 2001-12-31

Publications (2)

Publication Number Publication Date
WO2003055589A2 true WO2003055589A2 (fr) 2003-07-10
WO2003055589A3 WO2003055589A3 (fr) 2003-11-06

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001559A2 (fr) * 1993-07-02 1995-01-12 Evotec Biosystems Gmbh Porte-echantillons et son utilisation
WO1999034920A1 (fr) * 1998-01-12 1999-07-15 Massachusetts Institute Of Technology Procede pour effectuer des dosages microscopiques
US6044981A (en) * 1994-03-07 2000-04-04 The Regents Of The University Of California Microfabricated filter with specially constructed channel walls, and containment well and capsule constructed with such filters
US6157456A (en) * 1997-03-11 2000-12-05 Hvass; Per Cuvette for spectrophotometrical analysis
WO2001014063A1 (fr) * 1999-08-25 2001-03-01 Alphahelix Ab Dispositif et procede permettant de manipuler et de traiter des echantillons et/ou des melanges reactionnels de petit volume
WO2001061054A2 (fr) * 2000-02-18 2001-08-23 Board Of Trustees Of The Leland Stanford Junior University Appareils et procedes de conduite en parallele de reactions sur des microvolumes
US20010036674A1 (en) * 2000-02-23 2001-11-01 Indermuhle Pierre F. Chips having elevated sample surfaces
DE10025698A1 (de) * 2000-05-23 2001-11-29 Merck Patent Gmbh Vorrichtung für die parallele Mikrosynthese
WO2002049763A2 (fr) * 2000-12-18 2002-06-27 Institut für Physikalische Hochtechnologie e.V. Dispositif d'extraction et d'emission de substances liquides
WO2002087760A1 (fr) * 2001-04-30 2002-11-07 Epr Labautomation Ag Procede et dispositif pour stocker et doser de petites quantites de liquide

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001559A2 (fr) * 1993-07-02 1995-01-12 Evotec Biosystems Gmbh Porte-echantillons et son utilisation
US6044981A (en) * 1994-03-07 2000-04-04 The Regents Of The University Of California Microfabricated filter with specially constructed channel walls, and containment well and capsule constructed with such filters
US6157456A (en) * 1997-03-11 2000-12-05 Hvass; Per Cuvette for spectrophotometrical analysis
WO1999034920A1 (fr) * 1998-01-12 1999-07-15 Massachusetts Institute Of Technology Procede pour effectuer des dosages microscopiques
WO2001014063A1 (fr) * 1999-08-25 2001-03-01 Alphahelix Ab Dispositif et procede permettant de manipuler et de traiter des echantillons et/ou des melanges reactionnels de petit volume
WO2001061054A2 (fr) * 2000-02-18 2001-08-23 Board Of Trustees Of The Leland Stanford Junior University Appareils et procedes de conduite en parallele de reactions sur des microvolumes
US20010036674A1 (en) * 2000-02-23 2001-11-01 Indermuhle Pierre F. Chips having elevated sample surfaces
DE10025698A1 (de) * 2000-05-23 2001-11-29 Merck Patent Gmbh Vorrichtung für die parallele Mikrosynthese
WO2002049763A2 (fr) * 2000-12-18 2002-06-27 Institut für Physikalische Hochtechnologie e.V. Dispositif d'extraction et d'emission de substances liquides
WO2002087760A1 (fr) * 2001-04-30 2002-11-07 Epr Labautomation Ag Procede et dispositif pour stocker et doser de petites quantites de liquide

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Publication number Publication date
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