WO2000020117A2 - Method of and apparatus for removing a substance from a container - Google Patents

Method of and apparatus for removing a substance from a container

Info

Publication number
WO2000020117A2
WO2000020117A2 PCT/GB1999/003278 GB9903278W WO0020117A2 WO 2000020117 A2 WO2000020117 A2 WO 2000020117A2 GB 9903278 W GB9903278 W GB 9903278W WO 0020117 A2 WO0020117 A2 WO 0020117A2
Authority
WO
WIPO (PCT)
Prior art keywords
container
substance
sheet
well
fluid
Prior art date
Application number
PCT/GB1999/003278
Other languages
French (fr)
Other versions
WO2000020117A3 (en
Inventor
Anthony Robert Corless
Original Assignee
Central Research Laboratories Limited
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 Central Research Laboratories Limited filed Critical Central Research Laboratories Limited
Priority to AU61114/99A priority Critical patent/AU6111499A/en
Publication of WO2000020117A2 publication Critical patent/WO2000020117A2/en
Publication of WO2000020117A3 publication Critical patent/WO2000020117A3/en

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
    • B01L3/508—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
    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • 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
    • B01L3/0289—Apparatus for withdrawing or distributing predetermined quantities of fluid
    • B01L3/0293—Apparatus for withdrawing or distributing predetermined quantities of fluid for liquids
    • 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
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • 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
    • 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
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00364—Pipettes
    • B01J2219/00367—Pipettes capillary
    • B01J2219/00369—Pipettes capillary in multiple or parallel arrangements
    • 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
    • B01J2219/00452—Means for the recovery of reactants or products
    • B01J2219/00454—Means for the recovery of reactants or products by chemical cleavage from the solid support
    • 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
    • B01J2219/00277—Apparatus
    • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00646—Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports
    • B01J2219/00648—Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports by the use of solid 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • 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
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • 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
    • 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
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • 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
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes

Definitions

  • the present invention relates to a method of and apparatus for removing a substance from a container. It relates particularly, but not exclusively, to removing a substance which has been formed via a combinatorial process.
  • Combinatorial chemistry is a technique whereby many different chemical compounds are synthesised by multiple chemical reactions.
  • a library of chemical compounds may be formed on solid phase supports.
  • the solid phase supports are commonly known as beads. Beads of the size approximately a tenth of a millimetre in diameter are typically used in such reactions.
  • Libraries of chemical compounds are usually formed on a large number of beads. It is desirable to label each chemical compound of libraries in order to identify the chemical compound of interest attached to the beads.
  • Such identifiers may be physical or chemical. Physical identifiers may be in the form of a bar code or similar optical code (which may be applied to the bead by means of a laser), or an RF device.
  • HTS high-throughput screening
  • a method of transferring a chemical compound from a bead for further screening is disclosed in International Patent Application No. WO-A1-9715394 (Smithkline Beecham).
  • the walls of wells formed in a micro-titre plate are coated with a binding surface on which compounds may be synthesised.
  • the wells are then used to dispense the compounds synthesised in the wells into a further vessel for screening.
  • the compounds are dispensed by applying pressure to the liquid in the wells causing it to jet out of the hole into the further vessel.
  • a disadvantage of this method is that due to the very small volumes of fluid transferred, fluid may evaporate and not be transferred to the receiving container.
  • An aim of the present invention is to simplify the transfer of chemical compounds formed via a combinatorial process from a container into a further container.
  • Another aim of the invention is to transfer simplify the transfer of chemical compounds formed via a combinatorial process from a container into a further container for high-throughput screening, while still allowing the synthesis route of a compound being screened to be determined.
  • a method of removing a substance from a container comprising the steps of: a) introducing a fluid, preferably a liquid, into the container so that at least a portion of the substance is taken up by the fluid, and b) removing the fluid and the substance from the container by placing a sheet of absorbent material in sufficiently close proximity to the container so that the fluid and the substance are absorbed by the sheet and substantially retained by the sheet.
  • the sheet and the container are separated one from another after an amount of fluid has been absorbed by the sheet.
  • the sheet containing the fluid and the substance (which may be a compound) may then be dried, so that the substance is retained on the sheet in a dry form.
  • the sheet may then be rehydrated at a later date.
  • the substance associated with the sheet may then be screened in order to identify substances of interest or activity.
  • the sheet may have hydrophobic portions defined on it, so that the fluid and the substance are guided to, or maintained within, predetermined locations on the sheet.
  • the sheet may then be affixed to the further container.
  • the further container preferably has an array of wells formed therein.
  • the base of a well is defined by the sheet.
  • the openings of the wells may be covered by the sheet. Fluid may be
  • a substantially hydrophobic sheet may be bonded to the absorbent sheet either before it is affixed to the further container, or after it has been attached. Fluid, preferably a liquid, may then be added to the wells of the further container via the openings of the wells. The hydrophobic sheet may thus prevent leakage of the fluid from the base of the well via the absorbent sheet.
  • the sheet whether it be mainly hydrophobic or porous, is affixed to a container by adhesive, curing, mechanical fixing, heating, ultrasonic welding, or a combination of these techniques.
  • the container and/or the further container is a specially adapted 96- or 384-well micro-titre plate.
  • the container preferably has the same dimensions as a standard laboratory micro-titre plate, each well of the plate having a small aperture in its base, or its base being defined by a fine mesh.
  • an apparatus for removing a substance from a container comprising: an absorbent sheet, the sheet having defined thereon a plurality of hydrophilic regions whose boundaries are defined by hydrophobic portions, the hydrophilic regions being dimensioned and arranged so that they are capable of receiving contents from a plurality of wells formed in the container.
  • the absorbent sheet is a capillary membrane. It may be, for example, a Pall Gelman PredatorTM membrane.
  • the volume of fluid removed from the container is determined by the capacity of the membrane, and the dimensions of the hydrophilic areas defined on the membrane.
  • hydrophobic areas may be defined by heating sealing, or by printing of a polymer.
  • the polymer may be wax, or a wax/polymer mixture.
  • the hydrophobic portions define an array of hydrophilic cells on the sheet, the hydrophilic cells being dimensioned and arranged so that they are congruous with an array of wells formed in a container.
  • a container comprising a plurality of wells, the base of a well having at least one aperture, the at least one aperture being dimensioned so as to retain liquid in the well by way of surface tension.
  • the container preferably has defined therein an array of wells.
  • the wells may be defined by tapered walls, a base, and have an opening to allow the introduction of a fluid or an article into a well.
  • the exterior surface of the base of the wells may be hydrophobic so as to guide the fluid to a desired location.
  • the wells may have at least one aperture defined in their bases.
  • the at least one aperture is dimensioned so that liquid may be retained in the well via surface tension.
  • the at least one aperture is less than 1 mm in diameter.
  • the at least one aperture is less than 0.1 mm in diameter.
  • the apertures may have a considerably smaller aperture than this, for example, 25 microns in diameter.
  • the base of a well may be formed by a fine mesh.
  • the container may have the same dimensions as a standard laboratory micro-titre plate, each well of the micro-titre plate having a small aperture in its base, or its base being defined by a fine mesh.
  • a system for removing a substance from a container comprising: a) means for locating at least one article, the at least one article having the substance associated therewith; b) placing means for introducing the at least one article into at least one well defined in a first container, the well having at least one aperture; c) fluid introducing means for introducing fluid into the at least one well; d) chemistry releasing means for releasing at least a portion of the substance into the fluid; and e) means for bringing an absorbent sheet in sufficiently close proximity to the at least one well so that the fluid and the substance are drawn onto and subsequently retained by the absorbent sheet.
  • the system may also include separating means for substantially separating the absorbent sheet from the first container.
  • a drying means may also be provided for drying the absorbent sheet, thereby retaining at least a portion of the substance on the absorbent sheet.
  • the system includes an affixing means for affixing the absorbent sheet to a further container, the further container having a plurality of wells formed therein.
  • the substance is preferably supported by a solid-phase support such as a resin bead.
  • a resin bead The substance has preferably been formed by a combinatorial process.
  • the resin bead may have a tag attached to it identifying the synthesis steps that the bead has undergone. This tag may be a physical tag such as an alpha-numeric code, a bar code, or an RF tag.
  • Methods for releasing a chemical compound from a bead into a fluid are well known in the art. These methods may release all of the chemical compound from the bead, or only a portion of the compound may be released, the rest remaining bound to the bead.
  • a well-known method is the use of a linker (which links the compound to a bead) which is disrupted by shining UV light onto the bead.
  • Figure 1 shows an isometric view of a capillary membrane sheet
  • Figure 2 shows a cross-sectional view of a bead within a well
  • Figure 3 shows a cross-sectional view of a capillary membrane sheet being brought into contact with a well
  • Figure 4 shows a cross-sectional view of a liquid from a well being drawn into a capillary membrane sheet
  • Figure 5 shows a cross-sectional view of a capillary membrane sheet being separated from a well
  • Figure 6 shows a cross-sectional view of a capillary membrane sheet bonded to form the base of a well.
  • FIG. 2 of the drawing a sectional view of a bead 10 within a well 12 is shown.
  • the well 12 shown in Figure 2 is defined by tapered walls 16, a base 18 and an opening 20.
  • the exterior surface 15 of the base of a well may be hydrophobic.
  • An array 14 of such wells 12 may comprise a micro-titre plate which is specially adapted for use with the apparatus. That is, each well of the micro-titre plate has an aperture in its base, or its base may be defined by a fine mesh.
  • a chemical compound has been formed on the bead 10.
  • the compound may have been formed on the bead 10 during a combinatorial process.
  • Bead 10 may have attached thereto a physical tag to enable the synthesis steps of the chemical compound to be identified. If the physical tag is an optical code, the optical code may be read from the bead 10 while bead 10 is situated in well 12.
  • a liquid 22 is added to the well 12 via the opening 20, as shown in Figure 3.
  • the liquid 22 may be present in the well 12 when the bead 10 is added.
  • the chemical compound held by the bead 10 is released into the liquid 22.
  • the chemical compound may be released by agitating the array of wells 14, heating the liquid 22 in the well 12, or by shining UV light onto the bead 10.
  • Other methods for releasing chemical compounds synthesised on solid phase supports such as beads are well known in the art and may also be used.
  • a cover 34 may be bonded or attached to the array 14 to cover the opening 20 of well 12 to stop the bead 10 from escaping from the well.
  • the base of the well 12 is formed from a fine mesh 24, such that the liquid
  • a single aperture may be formed in the base 18 of the well 12. The diameter of the single aperture may be dimensioned such that liquid 22 is held in well 12 via surface tension.
  • Capillary membrane sheet 26 is then brought into contact with the base of the well 12, as shown in Figure 4.
  • An isometric view of capillary membrane sheet 10 is shown in Figure 1.
  • An array of porous cells 28 are defined on the sheet by hydrophobic areas 30.
  • the porous portions of the membrane typically have areas ranging from 50 ⁇ n 2 to 2 mm 2 .
  • the dimensions of these defined areas will obviously depend upon the size of the wells of the micro-titre plate.
  • Membrane 26 is typically approximately 50 to 200 ⁇ m thick, with an open pore volume of 80% to 90%. Hence one can consider removing volumes of liquid of the order of 100 picolitre to 720 nanolitre.
  • the 22 liquid containing the chemical compound flows from the well 12 into the porous areas 28 of capillary membrane sheet 26, according to the capacity of the porous areas 28.
  • flow of liquid 22 from the well ceases and the membrane 26 is separated from the well 12.
  • Figure 5 An amount of the liquid is retained within the membrane 26.
  • a further membrane, and even subsequent membranes may be brought into contact with the well 12 in order to remove all of the liquid, and hence all of the chemical compound from the well.
  • membrane 26 may be dried and rehydrated at a later date in order to screen the compounds for activity.
  • Figure 6 indicates the membrane 26 (bearing the chemical compound) bonded to form the base of a well 38 in a further multi-well plate 36. Liquid may then be added to well 38 via the opening of the well, or through the membrane 26 itself, carrying the chemical compound and the liquid into the well where the compound may be screened for activity.
  • Membrane 26 is shown having a hydrophobic membrane 32 bonded to its underside. This ensures that leakage of the fluid from the well via membrane 26 is prevented.

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

Abstract

A bead (10) holding a chemical compound is situated in a well (12) of a micro-titre plate (14). A liquid (22) is introduced into well (12) and the chemical compound is released into the liquid. The liquid (22) and the chemical compound may be removed from the well (12) by bringing a capillary membrane (26) into contact with the well (12). Liquid (22) is drawn into the capillary membrane (26) via capillary action. Membrane (26) has areas of hydrophobicity (30) defined thereon so that the liquid (22) and the compound are drawn into predefined areas of the membrane (26). The membrane (26) can be dried and rehydrated at a later date in order to screen the compounds for activity, or it may form the base of an array of wells of a further micro-titre plate. Screening for compounds of interest may then take place either on the sheet, or with the sheet forming the base of the further micro-titre plate.

Description

METHOD OF AND APPARATUS FOR REMOVING A SUBSTANCE FROM A CONTAINER
Technical Field
The present invention relates to a method of and apparatus for removing a substance from a container. It relates particularly, but not exclusively, to removing a substance which has been formed via a combinatorial process.
Background Art
Combinatorial chemistry is a technique whereby many different chemical compounds are synthesised by multiple chemical reactions. A library of chemical compounds may be formed on solid phase supports. The solid phase supports are commonly known as beads. Beads of the size approximately a tenth of a millimetre in diameter are typically used in such reactions. Libraries of chemical compounds are usually formed on a large number of beads. It is desirable to label each chemical compound of libraries in order to identify the chemical compound of interest attached to the beads. Such identifiers may be physical or chemical. Physical identifiers may be in the form of a bar code or similar optical code (which may be applied to the bead by means of a laser), or an RF device.
Following synthesis of the library of chemical compounds, the next stage is screening the compounds. This may be achieved by a method known as high-throughput screening (HTS). In HTS, the library (or a subset of the library) is reacted with a target compound in order to determine which compounds of the library show activity. Such reactions are usually performed with the chemical compounds being in an aqueous solution, rather than bound to a bead. As a result, the synthesis route of the chemical compounds may not be easily identified.
A method of transferring a chemical compound from a bead for further screening is disclosed in International Patent Application No. WO-A1-9715394 (Smithkline Beecham). In this method, the walls of wells formed in a micro-titre plate are coated with a binding surface on which compounds may be synthesised. The wells are then used to dispense the compounds synthesised in the wells into a further vessel for screening. The compounds are dispensed by applying pressure to the liquid in the wells causing it to jet out of the hole into the further vessel. A disadvantage of this method is that due to the very small volumes of fluid transferred, fluid may evaporate and not be transferred to the receiving container.
An aim of the present invention is to simplify the transfer of chemical compounds formed via a combinatorial process from a container into a further container. Another aim of the invention is to transfer simplify the transfer of chemical compounds formed via a combinatorial process from a container into a further container for high-throughput screening, while still allowing the synthesis route of a compound being screened to be determined.
Disclosure of Invention
According to a first aspect of the invention there is provided a method of removing a substance from a container, the method comprising the steps of: a) introducing a fluid, preferably a liquid, into the container so that at least a portion of the substance is taken up by the fluid, and b) removing the fluid and the substance from the container by placing a sheet of absorbent material in sufficiently close proximity to the container so that the fluid and the substance are absorbed by the sheet and substantially retained by the sheet.
Preferably the sheet and the container are separated one from another after an amount of fluid has been absorbed by the sheet. The sheet containing the fluid and the substance (which may be a compound) may then be dried, so that the substance is retained on the sheet in a dry form. The sheet may then be rehydrated at a later date. The substance associated with the sheet may then be screened in order to identify substances of interest or activity.
The sheet may have hydrophobic portions defined on it, so that the fluid and the substance are guided to, or maintained within, predetermined locations on the sheet.
The sheet may then be affixed to the further container. The further container preferably has an array of wells formed therein. Preferably the base of a well is defined by the sheet. Alternatively, the openings of the wells may be covered by the sheet. Fluid may be
"washed" through the absorbent sheet so that the substance attached to the sheet and the wash fluid are introduced into the wells of the further container. Screening for substances of activity or interest may then take place.
A substantially hydrophobic sheet may be bonded to the absorbent sheet either before it is affixed to the further container, or after it has been attached. Fluid, preferably a liquid, may then be added to the wells of the further container via the openings of the wells. The hydrophobic sheet may thus prevent leakage of the fluid from the base of the well via the absorbent sheet.
Preferably the sheet, whether it be mainly hydrophobic or porous, is affixed to a container by adhesive, curing, mechanical fixing, heating, ultrasonic welding, or a combination of these techniques.
Preferably the container and/or the further container is a specially adapted 96- or 384-well micro-titre plate. The container preferably has the same dimensions as a standard laboratory micro-titre plate, each well of the plate having a small aperture in its base, or its base being defined by a fine mesh.
According to a second aspect of the invention there is provided an apparatus for removing a substance from a container, the apparatus comprising: an absorbent sheet, the sheet having defined thereon a plurality of hydrophilic regions whose boundaries are defined by hydrophobic portions, the hydrophilic regions being dimensioned and arranged so that they are capable of receiving contents from a plurality of wells formed in the container.
Preferably the absorbent sheet is a capillary membrane. It may be, for example, a Pall Gelman Predator™ membrane. The volume of fluid removed from the container is determined by the capacity of the membrane, and the dimensions of the hydrophilic areas defined on the membrane.
These hydrophobic areas may be defined by heating sealing, or by printing of a polymer. The polymer may be wax, or a wax/polymer mixture. Preferably the hydrophobic portions define an array of hydrophilic cells on the sheet, the hydrophilic cells being dimensioned and arranged so that they are congruous with an array of wells formed in a container.
According to a third aspect of the invention there is provided a container comprising a plurality of wells, the base of a well having at least one aperture, the at least one aperture being dimensioned so as to retain liquid in the well by way of surface tension.
The container preferably has defined therein an array of wells. The wells may be defined by tapered walls, a base, and have an opening to allow the introduction of a fluid or an article into a well. The exterior surface of the base of the wells may be hydrophobic so as to guide the fluid to a desired location.
The wells may have at least one aperture defined in their bases. The at least one aperture is dimensioned so that liquid may be retained in the well via surface tension. Preferably the at least one aperture is less than 1 mm in diameter. Most preferably the at least one aperture is less than 0.1 mm in diameter. However, the apertures may have a considerably smaller aperture than this, for example, 25 microns in diameter. Alternatively, the base of a well may be formed by a fine mesh.
The container may have the same dimensions as a standard laboratory micro-titre plate, each well of the micro-titre plate having a small aperture in its base, or its base being defined by a fine mesh.
According to a further aspect of the invention there is provided a system for removing a substance from a container, the system comprising: a) means for locating at least one article, the at least one article having the substance associated therewith; b) placing means for introducing the at least one article into at least one well defined in a first container, the well having at least one aperture; c) fluid introducing means for introducing fluid into the at least one well; d) chemistry releasing means for releasing at least a portion of the substance into the fluid; and e) means for bringing an absorbent sheet in sufficiently close proximity to the at least one well so that the fluid and the substance are drawn onto and subsequently retained by the absorbent sheet. The system may also include separating means for substantially separating the absorbent sheet from the first container. A drying means may also be provided for drying the absorbent sheet, thereby retaining at least a portion of the substance on the absorbent sheet.
Preferably the system includes an affixing means for affixing the absorbent sheet to a further container, the further container having a plurality of wells formed therein.
The substance is preferably supported by a solid-phase support such as a resin bead. The substance has preferably been formed by a combinatorial process. The resin bead may have a tag attached to it identifying the synthesis steps that the bead has undergone. This tag may be a physical tag such as an alpha-numeric code, a bar code, or an RF tag.
Methods for releasing a chemical compound from a bead into a fluid are well known in the art. These methods may release all of the chemical compound from the bead, or only a portion of the compound may be released, the rest remaining bound to the bead. For example, a well-known method is the use of a linker (which links the compound to a bead) which is disrupted by shining UV light onto the bead.
According to a further aspect of the invention there is provided a substance removed from a container using the method and/or apparatus previously described.
According to another aspect of the invention there is provided a substance removed from a container by way of the system previously described.
Brief Description of Drawings
A number of embodiments of the invention will now be described, by way of example only, with reference to the accompanying Figures, in which:-
Figure 1 shows an isometric view of a capillary membrane sheet;
Figure 2 shows a cross-sectional view of a bead within a well;
Figure 3 shows a cross-sectional view of a capillary membrane sheet being brought into contact with a well; Figure 4 shows a cross-sectional view of a liquid from a well being drawn into a capillary membrane sheet;
Figure 5 shows a cross-sectional view of a capillary membrane sheet being separated from a well; and
Figure 6 shows a cross-sectional view of a capillary membrane sheet bonded to form the base of a well.
Best Modes for Carrying Out the Invention
A number of embodiments of the invention will now be described with reference to Figures 1 to 6. Referring to Figure 2 of the drawing, a sectional view of a bead 10 within a well 12 is shown. The well 12 shown in Figure 2 is defined by tapered walls 16, a base 18 and an opening 20. The exterior surface 15 of the base of a well may be hydrophobic. An array 14 of such wells 12 may comprise a micro-titre plate which is specially adapted for use with the apparatus. That is, each well of the micro-titre plate has an aperture in its base, or its base may be defined by a fine mesh.
A chemical compound has been formed on the bead 10. The compound may have been formed on the bead 10 during a combinatorial process. Bead 10 may have attached thereto a physical tag to enable the synthesis steps of the chemical compound to be identified. If the physical tag is an optical code, the optical code may be read from the bead 10 while bead 10 is situated in well 12.
A liquid 22 is added to the well 12 via the opening 20, as shown in Figure 3. Alternatively, the liquid 22 may be present in the well 12 when the bead 10 is added. The chemical compound held by the bead 10 is released into the liquid 22. The chemical compound may be released by agitating the array of wells 14, heating the liquid 22 in the well 12, or by shining UV light onto the bead 10. Other methods for releasing chemical compounds synthesised on solid phase supports such as beads are well known in the art and may also be used. A cover 34 may be bonded or attached to the array 14 to cover the opening 20 of well 12 to stop the bead 10 from escaping from the well. In this example, the base of the well 12 is formed from a fine mesh 24, such that the liquid
22 remains in the well 12 by the liquid's surface tension. Alternatively, a single aperture may be formed in the base 18 of the well 12. The diameter of the single aperture may be dimensioned such that liquid 22 is held in well 12 via surface tension.
Capillary membrane sheet 26 is then brought into contact with the base of the well 12, as shown in Figure 4. An isometric view of capillary membrane sheet 10 is shown in Figure 1. An array of porous cells 28 are defined on the sheet by hydrophobic areas 30. The porous portions of the membrane typically have areas ranging from 50 μn2 to 2 mm2. The dimensions of these defined areas will obviously depend upon the size of the wells of the micro-titre plate. Membrane 26 is typically approximately 50 to 200μm thick, with an open pore volume of 80% to 90%. Hence one can consider removing volumes of liquid of the order of 100 picolitre to 720 nanolitre.
The 22 liquid containing the chemical compound flows from the well 12 into the porous areas 28 of capillary membrane sheet 26, according to the capacity of the porous areas 28. When the fluid holding capacity of the membrane 26 has been exceeded, flow of liquid 22 from the well ceases and the membrane 26 is separated from the well 12. This is shown in Figure 5. An amount of the liquid is retained within the membrane 26. In the case of only part of the liquid being absorbed by the membrane 26, a further membrane, and even subsequent membranes, may be brought into contact with the well 12 in order to remove all of the liquid, and hence all of the chemical compound from the well. At this stage, membrane 26 may be dried and rehydrated at a later date in order to screen the compounds for activity.
Figure 6 indicates the membrane 26 (bearing the chemical compound) bonded to form the base of a well 38 in a further multi-well plate 36. Liquid may then be added to well 38 via the opening of the well, or through the membrane 26 itself, carrying the chemical compound and the liquid into the well where the compound may be screened for activity. Membrane 26 is shown having a hydrophobic membrane 32 bonded to its underside. This ensures that leakage of the fluid from the well via membrane 26 is prevented. The invention has been described by way of a number of embodiments and it will be appreciated that variation may be made to the aforementioned embodiments without departing from the scope of the invention.

Claims

Claims
1. A method of removing a substance from a container, the method comprising the steps of: a) introducing a fluid, preferably a liquid, into the container so that at least a portion of the substance is taken up by the fluid, and b) removing the fluid and the substance from the container by placing a sheet of absorbent material in sufficiently close proximity to the container so that the fluid and the substance are absorbed by the sheet and substantially retained by the sheet.
2. A method according to claim 1 including the step of drying the sheet, retaining the fluid, so that the substance is retained thereon.
3. A method according to claim 1 or 2 wherein the substance is guided to, or held within, predetermined locations on the sheet.
4. A method according to claim 3 wherein the substance is guided to, or held within, predetermined locations on the sheet by way of hydrophobic portions defined on the sheet.
5. A method according to claim 1 or 2 including the step of affixing the sheet to a further container, the further container having an array of wells formed therein whereby the base of a well is substantially defined by a hydrophilic portion of the sheet, so that the substance may be transferred from the sheet to the further container.
6. A method according to claim 5 wherein the absorbent sheet is affixed to the further container by any one of the following methods taken from a) gluing, b) curing, c) mechanical fixing, d) heating, and e) ultrasonic welding.
7. A method according to any preceding claim which is used to screen a chemical compound from a member of a library of chemical compounds formed via a combinatorial process.
8. Apparatus for removing a substance from a container, the apparatus comprising: an absorbent sheet, the absorbent sheet having defined thereon a plurality of hydrophilic regions whose boundaries are defined by hydrophobic portions, the hydrophilic regions being dimensioned and arranged so that they are capable of receiving contents from a plurality of wells formed in the container.
9. Apparatus according to claim 8 wherein the absorbent sheet is a capillary membrane.
10. Apparatus according to claim 8 or 9 wherein the hydrophobic portions of the absorbent sheet are formed by heat sealing.
11. Apparatus according to claim 8 or 9 wherein the hydrophobic portions of the absorbent sheet are formed by printing of a polymer.
12. Apparatus according to claim 11 wherein the polymer is wax, or a wax/polymer mixture.
13. A container comprising a plurality of wells, the base of a well having at least one aperture, the at least one aperture being dimensioned so as to retain liquid in the well by way of surface tension.
14. A container according to claim 13 wherein the diameter of the aperture is less than 0J x 10"3m.
15. A container according to claim 14 wherein the diameter of the aperture is less than 25 x 10~6m.
16. A system for removing a substance from a container, the system comprising: a) means for locating at least one article, the at least one article having the substance associated therewith; b) placing means for introducing the at least one article into at least one well defined in a first container, the well having at least one aperture; c) fluid introducing means for introducing fluid into the well; d) chemistry releasing means for releasing at least a portion of the substance into the fluid; and e) means for bringing an absorbent sheet in sufficiently close proximity to the well so that the fluid and the substance are drawn onto and subsequently retained by the absorbent sheet.
17. System according to claim 16 including means for substantially separating the absorbent sheet and the first container one from another.
18. System according to claim 16 or 17 including means for drying the absorbent sheet thereby retaining at least a portion of the substance on the absorbent sheet.
19. System according to any of claims 16 to 18 including means for affixing the absorbent sheet to a further container, the further container having a plurality of wells formed therein.
20. A substance removed from a container using the method claimed in any of 1 claims to 7.
21. A substance removed from a container using the apparatus claimed in any of claims 8 to 12.
22. A substance removed from a container using the system claimed in any of claims 16 to 19.
23. Method substantially as described herein with reference to Figures 2 to 6 of the accompanying drawing.
24. Apparatus substantially as described herein with reference to Figures 1 to 6 of the accompanying drawing.
PCT/GB1999/003278 1998-10-02 1999-10-04 Method of and apparatus for removing a substance from a container WO2000020117A2 (en)

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GB2417913A (en) * 2004-09-08 2006-03-15 Schlumberger Holdings Microfluidic separator
GB2417913B (en) * 2004-09-08 2009-04-08 Schlumberger Holdings Microfluidic separator
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US9999217B2 (en) 2010-07-26 2018-06-19 Biomatrica, Inc. Compositions for stabilizing DNA, RNA, and proteins in blood and other biological samples during shipping and storage at ambient temperatures
US9725703B2 (en) 2012-12-20 2017-08-08 Biomatrica, Inc. Formulations and methods for stabilizing PCR reagents
US10064404B2 (en) 2014-06-10 2018-09-04 Biomatrica, Inc. Stabilization of thrombocytes at ambient temperatures
US10772319B2 (en) 2014-06-10 2020-09-15 Biomatrica, Inc. Stabilization of thrombocytes at ambient temperatures
US11672247B2 (en) 2014-06-10 2023-06-13 Biomatrica, Inc. Stabilization of thrombocytes at ambient temperatures
US10568317B2 (en) 2015-12-08 2020-02-25 Biomatrica, Inc. Reduction of erythrocyte sedimentation rate
US11116205B2 (en) 2015-12-08 2021-09-14 Biomatrica, Inc. Reduction of erythrocyte sedimentation rate

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