WO2002087760A1 - Procede et dispositif pour stocker et doser de petites quantites de liquide - Google Patents
Procede et dispositif pour stocker et doser de petites quantites de liquide Download PDFInfo
- Publication number
- WO2002087760A1 WO2002087760A1 PCT/CH2002/000218 CH0200218W WO02087760A1 WO 2002087760 A1 WO2002087760 A1 WO 2002087760A1 CH 0200218 W CH0200218 W CH 0200218W WO 02087760 A1 WO02087760 A1 WO 02087760A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- capillary
- dosieφlatten
- liquid
- plate
- plate stack
- Prior art date
Links
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
- B01L3/502—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
- B01L3/02—Burettes; Pipettes
- B01L3/0241—Drop counters; Drop formers
-
- 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
- B01L3/02—Burettes; Pipettes
- B01L3/0241—Drop counters; Drop formers
- B01L3/0244—Drop counters; Drop formers using pins
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/02—Adapting objects or devices to another
- B01L2200/025—Align devices or objects to ensure defined positions relative to each other
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0605—Metering of fluids
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0829—Multi-well plates; Microtitration plates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
-
- 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
Definitions
- the invention is in the field of chemical / biological analysis and relates to a method and an arrangement according to the preambles of the corresponding claims.
- the method and arrangement serve for the storage and metering of small amounts of liquid, in particular for the parallel metering of small amounts of different liquids, as is necessary, for example, for the provision of samples by taking dissolved substances from substance libraries.
- Substance libraries contain large numbers of different substances, for example chemical compounds produced by combinatorial chemistry.
- a specific, usually very small amount (aliquot) of each substance or of a selected number of substances is taken from a substance library of this type, in which the substances are usually stored in dissolved form, for specific, biological or pharmaceutical tests and subjected to the test ,
- the tests or at least the sample preparations necessary for the tests are carried out in parallel on the largest possible number of substances.
- the substances are placed in cavities of microtest plates and in these, for example, by adding reaction partners, by incubation and / or treated by separation and then subjected to physical measurements.
- the plates preferably have a standardized shape and have 96, 384 or 1536 cavities (according to standards of the Society for Biomolecular Screening, SBS).
- arrangements of instruments are usually used, which are matched to the test plates or to the grid of the cavity arrangement on the test plates and with which all cavities of a plate simultaneously or different groups of cavities or individual cavities in succession and treated after a corresponding shift of the instrument arrangement relative to the test plate.
- Pipette arrangements are also used to introduce dissolved substances from a substance library into cavities on test plates.
- the substance library it is necessary for the substance library to be at the test plates and the instrument arrangement has a coordinated format that the substance library thus consists, for example, of a plurality of so-called library plates, a substance, for example dissolved in dimethyl sulfoxide, being stored in each cavity of each library plate.
- Such libraries thus consist, for example, of test plates with 96 wells each, from which aliquots are taken using pipette arrangements with 96 pipettes and placed on test plates with 96 cavities (one test plate from a library plate), 384 cavities (one test plate from four library plates) or 1536 cavitates (a test plate consisting of 16 library plates) can be transferred, whereby the pipettes must be cleaned after each dosing step.
- the library plates are usually stored at low temperatures and / or in a protective gas atmosphere. To remove substances, the library plates are removed from the protective gas atmosphere and warmed up at least to such an extent that the substance solutions are liquid.
- the object of the invention is now to demonstrate a method and an arrangement for storing and dosing small amounts of liquid, the method and the arrangement being intended to make it possible to meter amounts of liquid down to 0.1 ⁇ l or even less precisely and without contact and to carry out large numbers of such doses in parallel.
- the loss of liquids and the mutual contamination of successively metered liquids should be significantly smaller than is the case when using the known pipette arrangements.
- the mutual pollution mentioned should become negligible.
- the method and arrangement according to the invention should make it possible to set up and use substance libraries, it being possible for relatively large amounts of substance to be stored in the substance libraries, so that a large number of samples can be prepared from each substance without this affecting the substances.
- the method and arrangement according to the invention should, however, not only be usable in connection with substance libraries and with the taking of sample quantities from substance libraries, but also for any application in which the smallest quantities of liquid are to be metered, in particular metered in parallel.
- Dosie ⁇ latten each with at least one capillary opening running through the Dosie ⁇ latte with a given volume, advantageously with a plurality of such capillary openings, are used.
- a plurality of such Dosie ⁇ latten is stacked such that the capillary openings of the individual plates are exactly aligned.
- the aligned capillary openings of such a plate stack are then filled with liquid, for example only the one outer opening of the capillary openings running through the plate stack on the stack surface being brought into contact with the liquid and the liquid by the capillary action, possibly supported by a pressure difference, is drawn into the opening and through the stack.
- the Dosie ⁇ latten are stored as a stack, in which stacks the capillary openings of the individual Dosie ⁇ latten are aligned with each other and the capillary openings formed in this way, completely penetrating the stack, are filled with liquid.
- Each plate closes the capillary openings of the adjacent plates and it is only necessary to use, for example, a blank plate on the end faces of the plate stack to cover the capillary openings of the dosage plates which are extremely positioned in the stack.
- the dosing step is repeated with further individual dosing plates or a corresponding number of dosing plates is subjected to removal as a stack.
- the Dosie ⁇ latten are, for example, 0.5 to 2 mm thick, the capillary openings have, for example, a round cross section from 0.05 to 1mm. With a plate thickness of 1mm, capillary openings with a diameter of 0.36mm should be provided for liquid quantities of 0.1 ⁇ l.
- the height of the plate stack is limited by the capillary rise height, which in turn depends on the cross section of the capillary openings and on the ratio of the cohesion in the liquid surface and the adhesion between liquid and capillary wall, the capillary wall must be wettable by the liquid.
- the rise height is inversely proportional to the radius of the capillary opening. For the water / glass system, the proportionality factor is approximately 15.
- the Dosie ⁇ latten consist for example of a suitable plastic, glass, metal, ceramic or a semiconductor material.
- the capillary openings are, for example, drilled or etched with a laser (plasma etching or wet etching).
- the plates can also be produced, for example, in an injection molding process, for example from polypropylene, with the capillary openings. the. If necessary, the inner surfaces of the capillary openings must be treated for good wettability or coated with another material.
- Those surfaces of the Dosie ⁇ latten, with which they lie against each other in the plateau stacks, are to be designed in such a way that there is as little as possible a capillary action between plates placed on top of one another, through which substances positioned in adjacent capillary openings could come into contact with one another.
- capillary braking can be achieved, for example, in that the surfaces of the dosing plates mentioned have a very small surface roughness and are advantageously not wettable or very little wettable by the liquid to be dosed.
- the desired low wettability of these surfaces can also be achieved with a suitable surface treatment or coating.
- Mechanical capillary brakes in the form of, for example, sharp edges can also be provided around the mouths of the capillary openings.
- the arrangement of the capillary openings on the plates advantageously corresponds to the arrangement of cavities on test plates into which the liquids are to be dosed.
- the dosing plates therefore have a grid-like arrangement of 12x8, 24x16 or 48x32 capillary openings with grid dimensions of 9 mm, 4.5 mm or 2.25 mm.
- 1 shows the use of methods and apparatus according to the invention for storing substances in substance libraries and for dosing small amounts of the library substances in cavities of test plates;
- FIGS. 5 and 6 show exemplary arrangements for filling the aligned capillary openings of a plate stack
- Figures 7 to 10 exemplary arrangements for dispensing the liquid cans from capillary openings of Dosie ⁇ latten.
- FIG. 1 shows a partially sectioned, three-dimensional representation of a plate stack 1 of Dosie ⁇ latten 2, in which plate stack 1 the capillary openings 3 of the Dosie ⁇ latten 2 are aligned with one another and form capillary openings 3 'which penetrate the plate stack 1 and are filled with liquid. Furthermore, the figure shows a Dosie ⁇ latte 2 lifted from the plate stack 1, which is positioned for dispensing the amounts of liquid from its capillary openings 3 on a test plate 4 with cavities 5.
- the plate stack 1 is positioned, for example, on a correspondingly perforated base 10.
- alignment means for example, alignment bolts 11 are fastened on the base 10 and the dosage plates 2 have, in addition to the capillary openings 3, alignment bores 12 into which the alignment bolts 11 engage.
- the Dosie ⁇ latten 2 can easily be separated from the plate stack 1 (arrow S), they advantageously have separating means, for example, as shown in FIG. 1, beveled edge regions 13 which allow each plate to be gripped under with a suitable tool. Alternating edge patterns can also be provided as separating means.
- Figures 2 to 4 show on a larger scale than Figure 1 sections through Dosie ⁇ latten 2 with differently designed capillary openings 3rd
- Figure 2 shows a Dosie ⁇ latte 2, which consists of a base material 20 and which is coated on its surfaces as a capillary brake with a non or poorly wettable material 21, in the capillary openings 3 with a wettable material 22.
- a Dosie ⁇ latte 2 which consists of a base material 20 and which is coated on its surfaces as a capillary brake with a non or poorly wettable material 21, in the capillary openings 3 with a wettable material 22.
- a wettable material 22 Depending on the wetting properties of the base material 20 and depending on the application, one or the other of the coatings 21 or 22 or both coatings 21 and 22 may also be missing.
- a corresponding surface treatment can also take the place of a surface coating.
- the Dosie ⁇ latten 2 it is advantageous to design the Dosie ⁇ latten 2 such that they can be manufactured as cheaply as possible and can therefore be used as disposable items.
- Figure 3 shows a Dosie ⁇ latte with sharp edges 23 around the mouths of the capillary openings 3 on one side of the plate. These sharp edges 23 serve as a capillary brake.
- the Dosie ⁇ latten 2 are only in this case directly in the region of the mouths 25 of the capillary openings. Dosie ⁇ latten 2 lying on top of each other are separated by a distance 24 between the mouths, which distance is advantageously so large that it does not have any capillary action. generated.
- the formations required to form the sharp edges 23 on one side of the Dosie ⁇ latten advantageously correspond to corresponding recesses on the opposite side of the Dosie ⁇ latten, such that formations and recesses can take over the alignment function for aligning the capillary openings of the individual plates.
- Figure 4 shows on a single Dosie ⁇ latte 2 two ways of designing the capillary openings 3, such that in the frozen liquid columns at the transition from one plate to the next a narrowing serving as a predetermined breaking point.
- the capillary openings 3 shown on the left taper from one side of the dosage plate to the other, so that each capillary opening has two orifices 25 and 25 'of different sizes.
- the capillary openings shown on the right have narrowed orifices 25.
- FIG. 5 shows a simple arrangement for filling the capillary openings 3 'penetrating a plate stack 1. It is an arrangement of filling pipettes 30 which carry seals 31 at their open ends directed towards the plate stack 1 and which can be pressed against the plate stack 1 by means of a support plate 32, for example.
- the filling pipettes 30 are charged from their upper, likewise open ends with the corresponding liquids 33, which are then drawn into the filling pipettes with an overpressure (arrows 34) or passively through the capillary action of the capillary openings 3 '.
- the plate which comes into contact with the filling cylinders is advantageously not used for metering.
- FIG. 6 illustrates a further method for filling capillary openings 3 ′ which penetrate a stack of dose plates 1. This method consists in positioning a liquid drop 35 on each capillary opening 25 on the top of the stack, which liquid drop 35 is then drawn into the capillary opening by the capillary action.
- FIGS. 7 to 10 show in a very schematic manner exemplary, simple arrangements for ejecting amounts of liquid from capillary openings 3 of dosage plates 2.
- FIG. 7 shows a device for ejecting the quantities of liquid with the aid of a pressure difference between the two sides of the dosage plate 2, that is to say by slightly increasing the pressure on one side of the dosage plate or slightly reducing the pressure on the other side.
- a Dosie ⁇ latte 2 is positioned on a corresponding test plate 4 such that each capillary opening 3 of the metering plate 2 is aligned with a cavity 5 of the test plate 4.
- a pressure chamber 40 is positioned above the dosage plate 2, which can be connected to a pressure source (arrow 41), in such a way that a very slight excess pressure can be created in the pressure chamber, with the aid of which the amounts of liquid are expelled from the capillary openings 3 into the cavities 5.
- FIG. 8 shows a device for ejecting the quantities of liquid by means of a shock-like deceleration of the dosage plate 2.
- the dosage plate 2 is operatively connected to compression springs 42, the compression springs being kept in a compressed state by means of suitable locking means (not shown).
- the test plate 4 in the cavities 5 of which the amounts of liquid are to be transferred, is arranged on the side of the metering plate 2 opposite the compression springs 42.
- the locking means are then deactivated so that the dosage plate 2 is accelerated against the test plate 4. nigt and is braked by the test plate or by other suitable braking means, the amounts of liquid are thrown into the cavities 5. ,
- FIG. 9 shows a device for mechanically ejecting the quantities of liquid.
- an arrangement of needles 43 is provided, which are pushed into the capillary openings 3 (arrows 44).
- a hydraulic or pneumatic linear motor or a piezoelectric drive is suitable for driving the needle arrangement.
- Figure 10 shows an application of Dosie ⁇ latte 2 in a closed fluid system.
- Fluid connections 45 are tightly connected to the mouths of the capillary openings 3 on both sides of the dosing plate 2. By moving the fluid through the capillary openings 3 of the dosage plate 2, the amounts of liquid positioned in the capillary openings 3 are expelled or flushed out.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Clinical Laboratory Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Sampling And Sample Adjustment (AREA)
- Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH7912001 | 2001-04-30 | ||
CH791/01 | 2001-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002087760A1 true WO2002087760A1 (fr) | 2002-11-07 |
Family
ID=4537000
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CH2002/000218 WO2002087760A1 (fr) | 2001-04-30 | 2002-04-19 | Procede et dispositif pour stocker et doser de petites quantites de liquide |
Country Status (1)
Country | Link |
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WO (1) | WO2002087760A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003055589A2 (fr) * | 2001-12-31 | 2003-07-10 | Institut für Physikalische Hochtechnologie e.V. | Plaque de microtitration pour l'execution en parallele de plusieurs microsyntheses, en particulier a temperatures elevees |
DE10332296B3 (de) * | 2003-07-16 | 2005-04-28 | Fraunhofer Ges Forschung | Substratstapel, insbesondere für die Kryokonservierung biologischer Proben |
WO2005094995A1 (fr) * | 2004-03-31 | 2005-10-13 | Epr Labautomation Ag | Procede et dispositif de stockage et de distribution de petites quantites de liquides |
WO2006024392A2 (fr) * | 2004-08-30 | 2006-03-09 | P.A.L.M. Microlaser Technologies Ag | Unite de logement pour objets biologiques et procede et dispositif pour traiter les objets biologiques loges dans ladite unite |
DE102006059543B4 (de) * | 2006-12-16 | 2015-02-05 | Institut für Luft- und Kältetechnik gGmbH | Vorrichtung zur Aufnahme und Fixierung von Gewebezüchtungs-Konstrukten |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4111754A (en) * | 1976-11-29 | 1978-09-05 | Hydow Park | Immunological testing devices and methods |
EP0776700A1 (fr) * | 1995-12-08 | 1997-06-04 | The Institute of Physical and Chemical Research ( RIKEN) | Méthode de purification et de transfert d'échantillons de DNA séquencés vers des systèmes de séparation/détection et plaques à cet usage |
WO1999034920A1 (fr) * | 1998-01-12 | 1999-07-15 | Massachusetts Institute Of Technology | Procede pour effectuer des dosages microscopiques |
WO2000056456A1 (fr) * | 1999-03-19 | 2000-09-28 | Genencor International, Inc. | Plaque d'essais a trous traversants multiples pour criblage a haut debit |
-
2002
- 2002-04-19 WO PCT/CH2002/000218 patent/WO2002087760A1/fr not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4111754A (en) * | 1976-11-29 | 1978-09-05 | Hydow Park | Immunological testing devices and methods |
EP0776700A1 (fr) * | 1995-12-08 | 1997-06-04 | The Institute of Physical and Chemical Research ( RIKEN) | Méthode de purification et de transfert d'échantillons de DNA séquencés vers des systèmes de séparation/détection et plaques à cet usage |
WO1999034920A1 (fr) * | 1998-01-12 | 1999-07-15 | Massachusetts Institute Of Technology | Procede pour effectuer des dosages microscopiques |
WO2000056456A1 (fr) * | 1999-03-19 | 2000-09-28 | Genencor International, Inc. | Plaque d'essais a trous traversants multiples pour criblage a haut debit |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003055589A2 (fr) * | 2001-12-31 | 2003-07-10 | Institut für Physikalische Hochtechnologie e.V. | Plaque de microtitration pour l'execution en parallele de plusieurs microsyntheses, en particulier a temperatures elevees |
WO2003055589A3 (fr) * | 2001-12-31 | 2003-11-06 | Inst Physikalische Hochtech Ev | Plaque de microtitration pour l'execution en parallele de plusieurs microsyntheses, en particulier a temperatures elevees |
DE10332296B3 (de) * | 2003-07-16 | 2005-04-28 | Fraunhofer Ges Forschung | Substratstapel, insbesondere für die Kryokonservierung biologischer Proben |
WO2005094995A1 (fr) * | 2004-03-31 | 2005-10-13 | Epr Labautomation Ag | Procede et dispositif de stockage et de distribution de petites quantites de liquides |
WO2006024392A2 (fr) * | 2004-08-30 | 2006-03-09 | P.A.L.M. Microlaser Technologies Ag | Unite de logement pour objets biologiques et procede et dispositif pour traiter les objets biologiques loges dans ladite unite |
WO2006024392A3 (fr) * | 2004-08-30 | 2006-06-01 | Palm Microlaser Tech Gmbh | Unite de logement pour objets biologiques et procede et dispositif pour traiter les objets biologiques loges dans ladite unite |
DE102006059543B4 (de) * | 2006-12-16 | 2015-02-05 | Institut für Luft- und Kältetechnik gGmbH | Vorrichtung zur Aufnahme und Fixierung von Gewebezüchtungs-Konstrukten |
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